mercaptopurine and Crohn-Disease

Conventional medications for Crohn's disease (CD) include anti-inflammatory drugs, immunosuppressants and corticosteroids. If an individual does not respond, or loses response to first-line treatments, then biologic therapies such as tumour necrosis factor-alpha (TNF-α) antagonists such as adalimumab are considered for treating CD. Maintenance of remission of CD is a clinically important goal, as disease relapse can negatively affect quality of life.. To assess the efficacy and safety of adalimumab for maintenance of remission in people with quiescent CD.. We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and clinicaltrials.gov from inception to April 2019.. We considered for inclusion randomized controlled trials (RCTs) comparing adalimumab to placebo or to an active comparator.. We analyzed data on an intention-to-treat basis. We calculated risk ratios (RRs) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The primary outcome was failure to maintain clinical remission. We define clinical remission as a Crohn's Disease Activity Index (CDAI) score of < 150. Secondary outcomes were failure to maintain clinical response, endoscopic remission, endoscopic response, histological remission and adverse events (AEs). We assessed biases using the Cochrane 'Risk of bias' tool. We used GRADE to assess the overall certainty of evidence supporting the primary outcome.. We included six RCTs (1158 participants). We rated four trials at low risk of bias and two trials at unclear risk of bias. All participants had moderate-to-severe CD that was in clinical remission. Four studies were placebo-controlled (1012 participants). Two studies (70 participants) compared adalimumab to active medication (azathioprine, mesalamine or 6-mercaptopurine) in participants who had an ileocolic resection prior to study enrolment. Adalimumab versus placebo Fifty-nine per cent (252/430) of participants treated with adalimumab failed to maintain clinical remission at 52 to 56 weeks, compared with 86% (217/253) of participants receiving placebo (RR 0.70, 95% CI 0.64 to 0.77; 3 studies, 683 participants; high-certainty evidence). Among those who received prior TNF-α antagonist therapy, 69% (129/186) of adalimumab participants failed to maintain clinical or endoscopic response at 52 to 56 weeks, compared with 93% (108/116) of participants who received placebo (RR 0.76, 95% CI 0.68 to 0.85; 2 studies, 302 participants; moderate-certainty evidence). Fifty-one per cent (192/374) of participants who received adalimumab failed to maintain clinical remission at 24 to 26 weeks, compared with 79% (149/188) of those who received placebo (RR 0.66, 95% CI 0.52 to 0.83; 2 studies, 554 participants; moderate-certainty evidence). Eighty-seven per cent (561/643) of participants who received adalimumab reported an AE compared with 85% (315/369) of participants who received placebo (RR 1.01, 95% CI 0.94 to 1.09; 4 studies, 1012 participants; high-certainty evidence). Serious adverse events were seen in 8% (52/643) of participants who received adalimumab and 14% (53/369) of participants who received placebo (RR 0.56, 95% CI 0.39 to 0.80; 4 studies, 1012 participants; moderate-certainty evidence) and withdrawal due to AEs was reported in 7% (45/643) of adalimumab participants compared to 13% (48/369) of placebo participants (RR 0.59, 95% CI 0.38 to 0.91; 4 studies, 1012 participants; moderate-certainty evidence). Commonly-reported AEs included CD aggravation, arthralgia, nasopharyngitis, urinary tract infections, headache, nausea, fatigue and abdominal pain. Adalimumab versus active comparators No studies reported failure to maintain clinical remission. One study reported on failure to maintain clinical response and endoscopic remission at 104 weeks in ileocolic resection participants who received either adalimumab, azathioprine or mesalamine as post-surgical mainten. Adalimumab is an effective therapy for maintenance of clinical remission in people with quiescent CD. Adalimumab is also effective in those who have previously been treated with TNF-α antagonists. The effect of adalimumab in the post-surgical setting is uncertain. More research is needed in people with recent bowel surgery for CD to better determine treatment plans following surgery. Future research should continue to explore factors that influence initial and subsequent biologic selection for people with moderate-to-severe CD. Studies comparing adalimumab to other active medications are needed, to help determine the optimal maintenance therapy for CD.

Topics: Adalimumab; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Crohn Disease; Drug Administration Schedule; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Middle Aged; Patient Dropouts; Placebos; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial.. To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD.. We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers.. Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion.. Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life.. Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of an. Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction; Secondary Prevention

Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety.

Topics: Anti-Inflammatory Agents; Azathioprine; Biological Products; Clinical Decision-Making; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Mercaptopurine; Methotrexate; Purines; Risk Factors; Thioguanine; Treatment Outcome

The need for immune suppressive strategies in the control of chronic inflammatory bowel diseases originated in the 1960s following the perception of a relative inefficacy of salazopyrin and its derivatives. In some 50 years upon an anecdotal claim, the indication for thiopurines in the management of inflammatory bowel diseases has come of age.. The aim of this minireview is to give an overview, after the historical premises, of the current use of thiopurines in the context of inflammatory bowel diseases.. Through MEDLINE searches, we reviewed the literature of the last two decades.. For Crohn's disease, the 1980 trial of 6-mercaptopurine for steroid sparing and fistula closure proved pivotal. The analysis of withdrawal experiments and of numerous open trials has established the efficacy of thiopurines for ulcerative colitis. In this indication, cutting-edge data are now showing that because targeting dysplasia, thiopurines can induce mucosal/histological healing, thus abolishing or delaying the need for pre-emptive (tumor prophylactic) colectomy.. In UC thiopurines may be recognized to effect a treat-to-target strategy, joining the modern algorithms of rheumatologic disorders.

Topics: Adrenal Cortex Hormones; Biological Products; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Prognosis; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug-Related Side Effects and Adverse Reactions; Humans; Mercaptopurine; Metabolic Networks and Pathways; Methyltransferases; Pharmacogenomic Testing; Pyrophosphatases; Thioguanine

The main role of therapy in Crohn's disease (CD) is to achieve long-term clinical remission, and to allow for normal growth and development of children. The immunomodulatory drugs used for the maintenance of remission in CD include thiopurines (azathioprine and 6-mercaptopurine) and methotrexate (MTX). Development of hepatosplenic T-cell lymphoma in some patients with inflammatory bowel disease, treated with thiopurines only or in combination with anti-tumor necrosis factor agents, resulted in a growing interest in the therapeutic application of MTX in children suffering from CD. This review summarizes the literature on the therapeutic role of MTX in children with CD. MTX is often administered as a second-line immunomodulator, and 1-year clinical remission was reported in 25-69% of children with CD after excluding for the use of thiopurines. Initial data on MTX effectiveness in mucosal healing, and as a first-line immunomodulator in pediatric patients with CD, are promising. A definite conclusion, however, may only be made on the basis of additional research with a larger number of subjects.

Topics: Adolescent; Azathioprine; Child; Crohn Disease; Drug Administration Schedule; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Patient Safety; Remission Induction; Treatment Outcome; Tumor Necrosis Factor-alpha

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5mg/kg/day for azathioprine and 1.5mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Mercaptopurine

Prevention of relapse is a major issue in the management of quiescent Crohn's disease (CD). Current therapies (e.g. methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant adverse events. Interventions that are effective and safe for maintenance of remission in CD are desirable.. The primary objectives were to evaluate the efficacy and safety of enteral nutrition for the maintenance of remission in CD and to assess the impact of formula composition on effectiveness.. We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to 27 July 2018. We also searched references of retrieved studies and reviews.. Randomised controlled trials (RCTs) including participants of any age with quiescent CD were considered for inclusion. Studies that compared enteral nutrition with no intervention, placebo or any other intervention were selected for review.. Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included anthropometric measures (i.e. height and weight), quality of life (QoL), adverse events, serious adverse events and withdrawal due to adverse events. We calculated the risk ratio and 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference and 95% CI. A random-effects model was used for the statistical analysis. We used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes.. Four RCTs (262 adult participants) met the inclusion criteria. One study (N = 33) compared an elemental diet to a non-elemental (polymeric) diet. One study (N = 51) compared a half elemental diet to a regular free diet. Another study (N = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group. One study (N= 83) compared a polymeric diet to mesalamine. Two studies were rated as high risk of bias due to lack of blinding or incomplete outcome data. The other two studies were judged to have an unclear risk of bias. The studies were not pooled due to differences in control interventions and the way outcomes were assessed.The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to adverse events is uncertain. Fifty-eight per cent (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57% (8/14) of participants in the polymeric diet group (RR 1.01, 95% CI 0.56 to 1.84; very low certainty evidence). Thirty-two per cent (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95% CI 0.59 to 159.93; low certainty evidence). Anthropometric measures, QoL, adverse events and serious adverse events were not reported as outcomes.The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates is uncertain. Thirty-five per cent (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64% (16/25) of participants in the free diet group (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). No adverse events were reported. This study reported no differences in weight change between the two diet groups. Height and QoL were not reported as outcomes.The effect of an elemental diet compared to 6-MP on relapse rates or adverse events is uncertain. Thirty-eight per cent (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23% (7/30) of participants in the 6-MP group (RR 1.61; 95% CI 0.73 to 3.53; very low certainty evidence). Three per cent (1/32) of participants in the elemental diet group had an adverse event compared to 13% (4/30) of participants in the 6-MP group (RR 0.23, 95% CI 0.03 to 1.98; low certainty evidence). Adverse events in the elemental d. The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Crohn Disease; Diet; Enteral Nutrition; Food, Formulated; Humans; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Randomized Controlled Trials as Topic; Secondary Prevention

Crohn's disease (CD) is a chronic inflammatory disease that confers a higher risk of cancer than in the general population. New, large, population-based studies in the past decade show that patients with CD are at higher risk of colorectal, small bowel, melanoma, and cervical cancer. Patients who use thiopurines are at additional risk of development of lymphoma and nonmelanoma skin cancer. Preventive surveillance for cancers of the colorectum, skin, and uterine cervix is advised.

Topics: Colorectal Neoplasms; Crohn Disease; Early Detection of Cancer; Female; Humans; Immunosuppressive Agents; Intestinal Neoplasms; Intestine, Small; Lymphoma; Male; Melanoma; Mercaptopurine; Risk Factors; Skin Neoplasms; Uterine Cervical Neoplasms

Crohn's disease (CD) is a chronic, progressive, and disabling inflammatory bowel disease (IBD) with an uncertain etiopathogenesis. CD can involve any site of the gastrointestinal tract from the mouth to the anus, and is associated with serious complications, such as bowel strictures, perforations, and fistula formation. The incidence and prevalence rates of CD in Korea are still lower compared with those in Western countries, but they have been rapidly increasing during the recent decades. Although there are no definitive curative modalities for CD, various medical and surgical therapies have been applied for the treatment of this disease. Concerning CD management, there have been substantial discrepancies among clinicians according to their personal experience and preference. To suggest recommendable approaches to the diverse problems of CD and to minimize the variations in treatment among physicians, guidelines for the management of CD were first published in 2012 by the IBD Study Group of the Korean Association for the Study of the Intestinal Diseases. These are the revised guidelines based on updated evidence, accumulated since 2012. These guidelines were developed by using mainly adaptation methods, and encompass induction and maintenance treatment of CD, treatment based on disease location, treatment of CD complications, including stricture and fistula, surgical treatment, and prevention of postoperative recurrence. These are the second Korean guidelines for the management of CD and will be continuously revised as new evidence is collected.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Crohn Disease; Humans; Infliximab; Mercaptopurine; Mesalamine; Methotrexate; Prednisolone; Severity of Illness Index; Tumor Necrosis Factor-alpha

Preoperative immunosuppressive use among patients with Crohn's disease or ulcerative colitis may lead to an increased risk of postoperative complications. There is limited information on the preoperative safety profile of methotrexate (MTX) in inflammatory bowel disease (IBD).. A retrospective study of patients who underwent abdominal surgery for IBD between 1993 and 2012 was performed and records abstracted, including preoperative use of MTX, azathioprine/6-mercaptopurine, antitumor necrosis factor, and corticosteroids. Early postoperative complications, including death, septic, and nonseptic complications were identified. A meta-analysis was also performed on the use of preoperative MTX in patients with IBD or rheumatoid arthritis.. A total of 180 patients with IBD underwent abdominal surgery. A total of 15 patients received MTX either monotherapy or in combination therapy. Total early postoperative complications were identified in 71 (39%) patients, specifically 5 patients on oral MTX. A total of 51 cases (28%) of septic complications and 20 (11%) nonseptic. No significant association between the use of MTX and early postoperative complications was found. The odds ratio (OR) of complications versus no complications associated with MTX was 0.75 (95% CI, 0.25-2.29) and with azathioprine/6-mercaptopurine, OR 1.48 (95% CI, 0.77-2.84). The odds of a septic complication associated with MTX were 0.58 (95% CI, 0.09-3.73), and higher in azathioprine/6-mercaptopurine, OR 3.97 (95% CI, 1.03-15.3). Our meta-analysis also did not reveal an increased risk of postoperative complications in IBD or rheumatoid arthritis on preoperative MTX (OR 0.62, 95% CI, 0.34-1.15).. Preoperative MTX use does not seem to be associated with early postoperative complications in IBD.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Middle Aged; Odds Ratio; Postoperative Complications; Preoperative Period; Retrospective Studies; Sepsis; Tumor Necrosis Factor-alpha; Young Adult

The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.. The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease.. We searched MEDLINE, EMBASE and the Cochrane Library from inception to 30 October 2015. Review articles and conference proceedings were also searched to identify additional studies.. Randomized controlled trials (RCTs) of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion.. Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.. Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remis. Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission.

Topics: Adult; Antimetabolites; Azathioprine; Crohn Disease; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Mercaptopurine; Mesalamine; Prednisone; Randomized Controlled Trials as Topic; Sulfasalazine; Withholding Treatment

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; History, 20th Century; History, 21st Century; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha

The magnitude of the efficacy of anti-tumour necrosis factor (TNF) therapy in preventing and treating postoperative Crohn's disease recurrence has yet to be determined.. We searched MEDLINE, the Cochrane Library, and EMBASE. The primary endpoints, and clinical and endoscopic recurrence, were analysed using the Mantel-Haenszel and DerSimonian and Laird methods.. Nine controlled trials (n=362) that evaluated the efficacy of anti-TNF therapy in preventing (n=7) or treating (n=2) postoperative recurrence were included. Anti-TNF therapy was more effective at preventing (n=6) endoscopic recurrence than the control arms (odds ratio 0.05; 95% confidence interval 0.02-0.13, P<0.0001; NNT=1.9). Anti-TNF therapy was more effective at preventing (n=5) clinical recurrence than the control arms (odds ratio 0.10; 95% confidence interval 0.05-0.21, P<0.0001; NNT=2.4). Anti-TNF therapy was more effective than control arms at treating endoscopic postoperative recurrence (n=2; odds ratio 16.64; 95% confidence interval 2.51-110.27, P<0.004; NNT=2.3). Neither heterogeneity nor publication bias was observed.. Anti-TNF agents may be more effective in preventing clinical and endoscopic postoperative Crohn's disease recurrence than control treatment (thiopurines or mesalamine). Efficacy in treating postoperative Crohn's disease recurrence will require further investigation. Large randomised controlled trials are awaited.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Observational Studies as Topic; Odds Ratio; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Secondary Prevention; Treatment Outcome; Tumor Necrosis Factor-alpha

Crohn's disease and ulcerative colitis are chronic inflammatory conditions affecting the gut and can present at any age with increased numbers of diagnoses seen in many countries in recent years. The thiopurine drugs, azathioprine and 6-mercaptopurine, are commonly used to maintain remission in Crohn's disease and ulcerative colitis; however, the use of these drugs may be limited by the development of pancreatitis in some individuals. Recent data indicate a genetic risk factor and provides a potential immune-mediated mechanism for thiopurine-induced pancreatitis. Management of thiopurine-induced pancreatitis requires exclusion of the triggering drug, which leads to prompt resolution of symptoms. This thiopurine side-effect may limit therapeutic options for future management of patients.

Topics: Animals; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Genetic Predisposition to Disease; Humans; Mercaptopurine; Pancreatitis; Risk Factors

The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Topics: Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Nausea; Neoplasms; Neutropenia; Opportunistic Infections; Pancreatitis

Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genotype; Histocompatibility Antigens Class II; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pharmacogenetics; Polymorphism, Single Nucleotide; Purine-Pyrimidine Metabolism, Inborn Errors; Pyrophosphatases

The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease.. To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease.. We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015.. Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded.. At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria.. Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20. Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Prodrugs; Randomized Controlled Trials as Topic

Thiopurines have been shown to effectively maintain remission of both Crohn's disease (CD) and ulcerative colitis (UC), and to behave as disease modifiers if used for >12 months in UC. Gastric intolerance manifesting as nausea constitutes a demanding drawback of thiopurines, at times forcing treatment discontinuance. A few studies have now indicated that some patients might tolerate mercaptopurine (6-MP) for azathioprine. In this paper, we review the literature, and reappraise our own data against the published figures. The data which form the basis for this study span over all visit reports that were released between January 2008 and December 2011 in a primary care Hospital, in Turin, Italy. For the aim of this study we searched our own database and the MedLine using the key-words "azathioprine", "mercaptopurine", "thiopurine", "inflammatory bowel disease", "Crohn's disease", "ulcerative colitis". We retrieved 85 azathioprine prescriptions for 42 UC, 37 CD, and 6 miscellaneous patients. There were 10 episodes of gastric intolerance to azathioprine, which were switched to 6-MP: 6 out of 10 (60%) responded and tolerated the switch drug in a median follow-up of 66 months. Female gender prevailed (p=0.038) in the azathioprine intolerant subset. A trial with 6-MP is worth being offered to azathioprine intolerant inflammatory bowel disease subjects at any center matching the standard figures of specific performance.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Substitution; Female; Gastrointestinal Agents; Humans; Italy; Male; Mercaptopurine; Middle Aged; Nausea; Remission Induction; Sex Factors; Time Factors; Treatment Outcome; Young Adult

The thiopurine (TP) analogs azathioprine and mercaptopurine have proven efficacy in inducing and maintaining clinical remission in Crohn's disease (CD). Their impact on the long-term need for surgery is uncertain since studies have reported conflicting results. The aim of this systematic review was to summarize and evaluate evidence of the published literature regarding those studies assessing the impact of TPs on the risk of first surgical resection in CD.. We searched Medline, EMBASE, CINAHL, and hand searched reference lists of identified articles, without language restrictions in August 2013.. Seventeen retrospective observational studies (eight population based, three multicenter, and six referral center) representing 21,632 participants met our inclusion criteria. Of these 10 studies involving 12,586 participants provided data on the hazard ratio (HR) and 95% confidence intervals (CIs) evaluating use of TPs and surgical risk. The combined pooled HR of first intestinal resection with TP use was 0.59 (95% CI 0.48-0.73).. TP use is associated with a 40% lowered risk of surgical resection in patients with CD. Despite significant reductions in rates of surgical resection in patients with CD over the last 5 decades and increasing use of TPs, a large proportion of patients with CD still require resectional surgery.

Topics: Azathioprine; Confidence Intervals; Crohn Disease; Digestive System Surgical Procedures; Disease Management; Humans; Immunosuppressive Agents; Mercaptopurine; Observational Studies as Topic; Organ Sparing Treatments; Outcome Assessment, Health Care; Proportional Hazards Models; Remission Induction; Retrospective Studies; Risk Assessment

The incidence and prevalence of Crohn's disease are increasing, particularly in the Western world and Asia. Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease. The use of corticosteroids, despite their efficacy, may be associated with several drawbacks. This review article provides a comprehensive account of the role of corticosteroids in inducing remission in adult patients with Crohn's disease, including aspects such as approaches to corticosteroid sparing and to minimize the risk of corticosteroid dependency, as well as the role of newer corticosteroids such as budesonide in reducing systemic adverse effects.

Topics: Adrenal Cortex Hormones; Azathioprine; Budesonide; Clinical Trials as Topic; Crohn Disease; Humans; Mercaptopurine; Mesalamine; Tumor Necrosis Factor-alpha

The therapy of Crohn's disease is constantly evolving. It is widely recognized that clinical assessment does not stage disease activity accurately and that endoscopic healing is associated with improved long-term outcomes. Disease management is therefore transitioning to a new paradigm that includes direct assessment of disease severity (endoscopically in most patients), followed by assessment of mucosal healing. New approaches have helped optimize the use of the thiopurines, methotrexate and anti-TNF agents. Novel agents with different mechanisms of action are expanding our therapeutic armamentarium. The major challenge of the future will be to identify patient subgroups best suited to particular therapeutic approaches. In the meantime, studies of comparative effectiveness will be crucial in positioning therapies relative to each other.

Topics: Azathioprine; Crohn Disease; Drug Monitoring; Gastrointestinal Agents; Humans; Mercaptopurine; Methotrexate; Tumor Necrosis Factor-alpha

Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year.. To provide a review of the evidence for thiopurine or anti-TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease.. A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti-TNF', 'Crohn's disease', 'post-operative' and 'recurrence'.. Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti-TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse.. At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti-TNF use is limited though promising, with its routine use guided by early assessment of relapse.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Crohn Disease; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Randomized Controlled Trials as Topic; Secondary Prevention; Smoking; Tumor Necrosis Factor-alpha

Crohn's disease is a chronic incurable condition that normally requires lifelong treatment. Whilst the anti-TNF agents have revolutionised the management of Crohn's disease over the last fifteen years, they are not a panacea. In particular, in part due to their immunogenic nature, loss of response limits their long term effectiveness in many patients. The only other long term disease-modifying options are the immunomodulators, methotrexate, azathioprine and mercaptopurine. Therefore, given the limited number of drugs available to treat Crohn's disease, it is important that efforts are made to ensure that drugs are used in the best way possible as once a drug is deemed ineffective, it is rarely used again. For the growing number of patients who have active disease despite having been exposed to all standard therapies, failure to optimise drug therapy may lead to missed opportunities in the management of their disease. In this review, optimisation of drugs commonly used in the management of Crohn's disease will be discussed.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate

Crohn's disease is a chronic, progressive and disabling condition. New therapeutic goals have emerged in Crohn's disease such as the need to look beyond symptoms by achieving mucosal healing that is known to be associated with better outcomes. Anti-TNF (Tumour Necrosis Factor) therapy is the most potent drug class to induce and maintain mucosal healing in Crohn's disease. Recent evidence indicates that the efficacy profile of thiopurines has been overestimated while the increased risk of malignancies (lymphoma, non-melanoma skin cancers, myeloid disorders) has been underestimated. Methotrexate is well-tolerated, but its potential for disease modification is unknown. Achieving mucosal healing in patients with early Crohn's disease might be the best way to change disease course and patients' life. In 2014, anti-TNF treatment should be the first-line therapy in patients with Crohn's disease who suffer from severe and/or complicated disease and in those with poor prognostic factors. In the remaining patients, a rapid step-up approach based on a tight monitoring is recommended.

Topics: Adalimumab; Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Certolizumab Pegol; Crohn Disease; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Polyethylene Glycols; Practice Guidelines as Topic; Tumor Necrosis Factor-alpha

Crohn's disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear.. The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD.. We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register). We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language.. Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery.. Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi(2) and I(2) statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria.. Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA). One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty-eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I(2) = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated th. Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted.

Topics: Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Randomized Controlled Trials as Topic; Remission Induction; Secondary Prevention

Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of previously published Cochrane reviews.. The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy.. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 9, 2014 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies.. Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion.. The primary outcome was failure to enter remission and withdraw from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome.. Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that meta-analysis was considered to be inappropriate. GRADE analyses indicated that the quality of evidence was very low to low for most outcomes due to sparse data and inadequate blinding. Three small studies which employed low dose oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients. There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infliximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Topics: Antibodies, Monoclonal; Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Mercaptopurine; Methotrexate; Prednisone; Randomized Controlled Trials as Topic; Steroids

Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate

Inflammatory bowel diseases are chronic conditions that frequently affect patients during their childbearing years. Considering the characteristics of disease and the medications used to treat it, several issues arise in the care of these patients when they attempt or achieve conception. We review the most current evidence concerning fertility and pregnancy outcomes in patients with inflammatory bowel diseases. With the exception of those women who undergo pelvic surgery, patients with inflammatory bowel diseases have no decreased fertility. Sulfasalazine decreases fertility in men. When looking at obstetrical outcomes, active disease at conception is associated with an increased risk of preterm delivery and low birth weight. While most medications used to treat inflammatory bowel diseases are low risk, some precautions need to be taken and the risk-to-benefit ratio needs to be considered on an individualized basis. In general, aminosalicylates and thiopurines should be continued, but methotrexate is contraindicated. Anti-tumour necrosis factor agents are considered safe to continue but full monoclonal antibodies do cross the placenta. As a general rule, the it is important to counsel women that conception is optimal when disease is in remission, as adverse obstetrical outcomes are directly associated with disease activity. Clinicians need to educate patients before, during and after conception, emphasizing treatment compliance.

Topics: Adalimumab; Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Breast Feeding; Certolizumab Pegol; Colitis, Ulcerative; Contraindications; Crohn Disease; Cyclosporine; Female; Fertility; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Natalizumab; Polyethylene Glycols; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far, a definite cure of the disease is still out of scope. An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy. Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine, are widely used in the therapy of chronic active inflammatory bowel disease (IBD). Their steroid sparing potential and efficacy in remission maintenance are out of doubt. Unfortunately, untoward adverse events are frequently observed and may preclude further administration or be life threatening. This review will focus on new aspects of thiopurine therapy in IBD, its efficacy and safety.

Topics: Animals; Anti-Infective Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Mercaptopurine; Patient Selection; Purines; Remission Induction; Risk Factors; Thioguanine; Treatment Outcome; Wound Healing

The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.. The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease.. A literature search for relevant studies (inception to June 13, 2012) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.. Randomized controlled trials (RCTs) of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion.. Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.. Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remis. Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Induction Chemotherapy; Mercaptopurine; Randomized Controlled Trials as Topic

To review the optimal strategy to prevent recurrence of Crohn's disease (CD) after surgery, with particular emphasis on the risk factors that predict postoperative recurrence, methods of monitoring for recurrence and medications used to prevent postoperative recurrence.. MEDLINE and the Cochrane Library were searched for clinical trials and meta-analyses that studied postoperative recurrence and prophylactic medications in CD.. The most significant factor that predicted postoperative recurrence was patient smoking status. Smokers had an increased risk of recurrence (odds ratio = 2.15; 95% confidence interval (CI) = 1.42-3.27). Similarly, perforating CD appeared to be associated with a higher recurrence rate compared with nonperforating CD (hazard ratio = 1.50; 95% CI = 1.16-1.93). The optimal monitoring strategy for postoperative recurrence has yet to be established. Nonetheless, ileocolonoscopy is considered to be the gold standard. Noninvasive imaging techniques including contrast ultrasonography and capsule endoscopy appear to be useful for postoperative monitoring. A number of meta-analyses found that mesalazine, nitroimidazole antibiotics and purine analogues (azathioprine/6-mercaptopurine) significantly reduced the risk of postoperative recurrence when compared with placebo. Additionally, recent randomized controlled trials have suggested that an early intervention with infliximab is likely to prevent recurrence after ileocolonic resection. Likewise, in prospective studies, biological therapy (infliximab/adalimumab) reduced clinical and endoscopic CD activity in patients with early endoscopic recurrence after surgery.. Although additional evidence is necessary, endoscopic monitoring and treatment step-up should be used to prevent postoperative recurrence of CD.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Colectomy; Colon; Colonoscopy; Crohn Disease; Humans; Ileum; Immunosuppressive Agents; Infliximab; Intestinal Perforation; Mercaptopurine; Mesalamine; Nitroimidazoles; Odds Ratio; Proportional Hazards Models; Risk Factors; Secondary Prevention; Smoking; Treatment Outcome

Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear.. To summarise the data on the association between NRH and thiopurine therapy in patients with IBD.. A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included.. Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naïve IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH.. The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Focal Nodular Hyperplasia; Humans; Immunosuppressive Agents; Incidence; Male; Mercaptopurine; Risk Factors; Thioguanine; Time Factors

Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals.. To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets.. A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies).. Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine.. This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies

Topics: Azathioprine; Crohn Disease; Gastroenterology; Humans; Mercaptopurine; Methotrexate; Remission Induction; Societies, Medical; Tumor Necrosis Factor-alpha; United States

Up to 75% of patients with Crohn's disease (CD) will have intestinal resection during their life. Most patients will, however, develop postoperative recurrence (endoscopic, clinical or surgical). Several medical and surgical strategies have been attempted to prevent postoperative recurrence. This review evaluates the efficacy of different drug regimens and surgical techniques in the prevention of clinical, endoscopic and surgical postoperative recurrence of CD.. A literature search for randomized controlled trials on medical or surgical interventions was performed. The endpoints for efficacy were clinical, endoscopic and surgical recurrence. Meta-analyses were performed in case two or more RCTs evaluated the same drug or surgical technique.. Mesalamine is more effective in preventing clinical recurrence than placebo (P=0,012), as well as nitroimidazolic antibiotics at one year follow-up (P<0.001) and thiopurines (P=0.018). Nitroimidazolic antibiotics are also more effective than placebo in preventing endoscopic recurrence (P=0.037), as well as thiopurines (P=0.015) and infliximab (P=0.006). Budenoside, probiotics, Interleukin-10 nor any of the different surgical procedures showed any significant difference compared to placebo in postoperative recurrence rates of CD.. Among the different drug regimens and surgical techniques, only thiopurines and nitroimidazolic antibiotics are able to reduce postoperative clinical as well as endoscopic recurrence of CD. Mesalamine and infliximab also seem to be superior to placebo in preventing clinical recurrence and endoscopic recurrence, respectively. There is a paucity of trials evaluating long-term follow-up and prevention of surgical recurrence of CD.

Topics: Anastomosis, Surgical; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Interleukin-10; Intestine, Small; Laparoscopy; Mercaptopurine; Mesalamine; Nitroimidazoles; Probiotics; Secondary Prevention; Treatment Outcome

Randomized trials support the use of the thiopurines and anti-TNF monoclonal antibodies in treating Crohn disease. New therapeutic approaches and laboratory assays have helped optimize the use of these agents. Thiopurine methyltransferase activity should always be determined to avoid thiopurines in individuals with absent enzyme activity. The role of metabolite-adjusted dosing when initiating thiopurines is not settled. Measuring metabolites helps guide management in patients failing therapy. Loss of response to anti-TNF therapy is mitigated by maintenance therapy and concomitant immunomodulators. When loss of response to infliximab occurs, management is guided by the serum concentrations of infliximab and antibodies to infliximab.

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Tumor Necrosis Factor-alpha

No drug therapy is completely risk free, and the costs associated with non-response and adverse effects can exceed the cost of the therapy. The ultimate goal of pharmacogenetic research is to find robust genetic predictors of drug response that enable the development of prospective genetic tests to reliably identify patients at risk of non-response or of developing an adverse effect prior to the drug being prescribed. Currently, thiopurine S-methyltransferase (TPMT) deficiency is the only pharmacogenetic factor that is prospectively assessed before azathioprine or 6-mercaptopurine immunomodulation is commenced in patients with Crohn's disease (CD). As yet no other inherited determinant of drug response has made the transition from bench to bedside for the management of this disease. In this review we summarize what is known about TPMT deficiency and explore whether there is evidence to support a role of other genetic polymorphisms in predicting the response of CD patients to thiopurine drugs, methotrexate, and anti-tumor necrosis factor α (TNFα) therapy.

Topics: Antibodies, Monoclonal; Azathioprine; Biotransformation; Crohn Disease; Drug Hypersensitivity; Drug Interactions; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Humans; Immunologic Factors; Infliximab; Mercaptopurine; Methotrexate; Patient Selection; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Precision Medicine; Purine-Pyrimidine Metabolism, Inborn Errors; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of a previously published Cochrane review.. The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy.. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 27, 2012 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies.. Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion.. The primary outcome was failure to failure to enter remission and withdrawal from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention to treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome.. Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to pool the data for meta-analysis. Three small studies which employed low doses of oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69) The other study assessing combination therapy utilized subcutaneous methotrex. There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infiximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Topics: Antibodies, Monoclonal; Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Mercaptopurine; Methotrexate; Prednisone; Randomized Controlled Trials as Topic; Steroids

Thiopurine agents have been shown to be effective in maintaining remission in patients with Crohn's disease. There is less evidence for the efficacy of these treatments in ulcerative colitis. Consequently, the effect of thiopurines in the latter disease continues to be the subject of debate and controversy remains on whether these drugs are equally effective in both diseases. The present article aims to review, from a practical point of view, the evidence of the efficacy of thiopurines in ulcerative colitis, current indications for this treatment, safety in patients with inflammatory bowel disease and the treatment optimization strategies proposed.

Topics: Azathioprine; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Disease Susceptibility; Dose-Response Relationship, Drug; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Mercaptopurine; Meta-Analysis as Topic; Neoplasms; Prodrugs; Remission Induction; Treatment Outcome

Poorly controlled Crohn's disease (CD) often requires surgery for such complications as strictures, fistulas, and abscesses. The goal of postoperative treatment is to suppress or prevent inflammation and maintain mucosal healing. Probiotics, antibiotics, 5-aminosalicylates, immunomodulators, and antibodies to tumor necrosis factor are all used to prevent postoperative recurrence. In this article, recent studies are reviewed. Azathioprine/6-mercaptopurine are moderately effective at preventing and treating postoperative CD, whereas infliximab/adalimumab are highly effective and probiotics and 5-aminosalicylates minimally effective. We base the choice of postoperative medical therapy on the patient's risk profile for postoperative recurrence. Whatever postoperative therapy is used, the mucosa should be assessed within 12 months to determine if the approach is effective. If active inflammation is found, then treatment should be intensified. By treating CD aggressively after a first surgery, future surgeries can be delayed or averted.

Topics: Adalimumab; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colonoscopy; Crohn Disease; Humans; Immunosuppressive Agents; Infliximab; Intestinal Mucosa; Mercaptopurine; Mesalamine; Postoperative Care; Probiotics; Risk Factors; Secondary Prevention; Tumor Necrosis Factor-alpha

Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno-occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6-mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease.

Topics: Azathioprine; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Liver; Male; Mercaptopurine; Middle Aged

There remains controversy regarding the efficacy of thiopurine analogs (azathioprine (AZA) and 6-mercaptopurine (6-MP)), methotrexate (MTX), and cyclosporine for the treatment of inflammatory bowel disease (IBD). We performed an updated systematic review of the literature to clarify the efficacy of immunosuppressive therapy at inducing remission and preventing relapse in ulcerative colitis (UC) and Crohn's disease (CD).. Only parallel group randomized controlled trials (RCTs) were considered eligible. Studies with adult IBD patients receiving immunosuppressive therapy compared with placebo for at least 14 days and up to 17 weeks for active disease, or at least 6 months in quiescent disease were analyzed. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat analysis. The data were summarized using relative risk (RR) and pooled using a random effects model.. Data on MTX and cyclosporine in IBD were limited although there were some data to support the use of intramuscular MTX in CD but not UC. There were five trials of AZA/6-MP in 380 active CD patients and there was no significant effect of therapy inducing remission (RR=0.87; 95% confidence interval (CI)=0.71-1.06). In quiescent CD, there were two trials involving 198 patients with no significant benefit of active therapy preventing relapse compared with placebo (RR=0.64; 95% CI=0.34-1.23). There were, however, three additional AZA withdrawal trials in 163 patients that indicated continuing medication did prevent relapse (RR=0.39; 95% CI=0.21-0.74). There were two AZA RCTs in 130 active UC patients that suggested a trend for benefit of therapy, but this did not reach statistical significance (RR=0.85; 95% CI=0.71-1.01). In quiescent UC, there were three trials involving 127 patients and there was a statistically significant benefit of AZA preventing relapse (RR=0.60; 95% CI=0.37-0.95).. Most evidence relates to AZA/6-MP where there is no statistically significant benefit at inducing remission in active CD and UC. Thiopurine analogs may prevent relapse in quiescent UC and CD. However, there is a paucity of data for immunosuppressive therapy in IBD and more research is needed.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Injections, Intramuscular; Mercaptopurine; Methotrexate; Remission Induction; Secondary Prevention; Treatment Failure

Crohn's disease and ulcerative colitis, together popularly known as inflammatory bowel disease (IBD), are characterized by a number of extraintestinal manifestations. Although infrequent, acute pancreatitis, and less often chronic pancreatitis, may occur as a result of the disease itself or secondary to the medications used in the treatment. The increased incidence of acute pancreatitis in Crohn's disease can be explained based on the high predisposition to cholesterol as well as pigment stones as a result of ileal disease, anatomic abnormalities of the duodenum, immunologic disturbances associated with IBD, and, above all, to the side effects of many medications used in the treatment. Sulfasalazine, 5-aminosalicylic acid, azathioprine, and 6-mercaptopurine are well known to cause acute pancreatitis as a result of a possible idiosyncratic mechanism. Crohn's disease and ulcerative colitis share many clinical manifestations and treatment modalities. Nonspecific elevations of serum pancreatic enzymes in IBD make it difficult to avoid over diagnosis of acute pancreatitis, particularly in patients with Crohn's disease who suffer from abdominal pain often. The IBD-pancreas association is further reflected in many reports of exocrine as well as endocrine pancreatic insufficiency.

Topics: Acute Disease; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Pancreatitis; Sulfasalazine

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.

Topics: Adalimumab; Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azathioprine; Crohn Disease; Fatal Outcome; Humans; Infliximab; Leukemia-Lymphoma, Adult T-Cell; Liver Neoplasms; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Male; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.. To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.. Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.. Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.. Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.. Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment of > 17 weeks resulted in an OR of 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.. Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. Adverse events were more common among patients on active therapy.

Topics: Adult; Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction

The immunomodulators (6-mercaptopurine, azathioprine and methotrexate) and biologics (infliximab, adalimumab, certolizumab and natalizumab) are medications essential in the management of pediatric inflammatory bowel disease. If properly utilized, these medications can control active disease, reduce corticosteroid exposure, induce remission, and promote normal growth and development. However, these medications also have significant toxicity and increase the risk of infections and lymphoma. This article provides information about the safety and efficacy of these medications in the treatment of children with Crohn's disease and ulcerative colitis.

Topics: Antibodies, Monoclonal; Child; Colitis, Ulcerative; Crohn Disease; Humans; Immunologic Factors; Infections; Lymphoma; Mercaptopurine; Treatment Outcome

The decision to start immunosuppressive therapy comes with benefits and risks. Patient selection is as important as medication selection, because some patients are not appropriate for certain therapies. The decision is based on many factors, including diagnosis, level of disease activity, comorbidities, and sometimes socioeconomic status. Frank discussion about side effects, possible adverse events (different from side effects), and monitoring protocols needs to occur after the clinician has decided on a therapy. Some therapies require additional screening prior to initiation (eg, tuberculosis testing before initiating biologics). Steroids are aggressive treatment, but need to have an end point. Thiopurines need to be monitored routinely with blood tests, and are associated with short-term side effects that can lead to discontinuation in about 20% of patients. Methotrexate is perhaps underused by community practitioners despite an adequate evidence base for its use for active inflammatory disease. Methotrexate may also be helpful in patients with arthralgias, but must be monitored. Biologics now target two molecules (tumor necrosis factor [TNF]-α and TNF-α4 integrins). However, because anti-adhesion molecule therapy is associated with a lethal central nervous system infection estimated to occur in 1 of 1,000 patients, this approach tends to be used as a third- or fourth-line therapy. Anti-TNFs are used for Crohn's disease and ulcerative colitis with good results; however, immune reactions, infections, and neoplasms have resulted from their use.

Topics: Algorithms; Colitis, Ulcerative; Counseling; Crohn Disease; Glucocorticoids; Humans; Immunization Schedule; Immunosuppressive Agents; Medical History Taking; Mercaptopurine; Methotrexate; Methyltransferases; Patient Selection; Tumor Necrosis Factor-alpha

traditional immunosuppressants, including azathioprine, remain the mainstay of therapy in steroid dependent/refractory patients with inflammatory bowel diseases (IBD). The main limitations of its use are its side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity. Major complications occur in patients with low thiopurine-S-methyltransferase (TPMT) enzyme activity; however, the clinical relevance of these tests remains conflictive.. in this review, the authors aim to summarize the new data regarding the relationship between the pharmacology of thiopurines and pathogenesis of adverse events.. readers will gain an understanding of the metabolism of thiopurines, side effect profile, pharmacological background of side effects, importance of metabolite monitoring, clinical relevance of inherited differences in drug metabolism and other conditions (e.g., concomitant use of allopurinol) which can modify enzyme activity. By gaining an understanding of the pharmacology and metabolism of thiopurines, clinicians will be able to optimize thiopurine therapy in IBD.. TPMT testing and metabolite monitoring are still not considered the standard of care, and clinicians will continue to choose the approach that best suits their clinical practice and patient needs. Regardless of what strategy is chosen, patients need to be carefully monitored and well informed about the potential risks.

Topics: Azathioprine; Crohn Disease; Drug Monitoring; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases

The therapy of Crohn's disease depends on its disease activity. For those different disease activities (such as flare, chronic active disease, remission) varying treatment concepts are followed. This overview presents important concepts in the treatment of Crohn's disease.

Topics: Adrenal Cortex Hormones; Azathioprine; Biological Products; Colectomy; Combined Modality Therapy; Crohn Disease; Humans; Mercaptopurine; Mesalamine; Methotrexate

The therapeutic role of 6-mercaptopurine and azathioprine remains controversial due to their perceived relatively slow-acting effect and adverse effects. A meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission of quiescent Crohn's disease.. To assess the efficacy of azathioprine and 6-mercaptopurine for maintenance of remission in quiescent Crohn's disease.. Pertinent studies were selected using the MEDLINE data base (1966-May 1998), the Cochrane Controlled Trials Register, the Inflammatory Bowel Disease register, as well as abstracts from major gastrointestinal research meetings and references from published articles and review. This search strategy was updated (1998-May 2008) using the MEDLINE, EMBASE and International Pharmaceutical Abstracts databases, the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.. Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with quiescent Crohn's disease.. Data were extracted by three independent observers (EP, MC, LRS) based on the intention to treat principle. Peto odds ratios and 95% confidence intervals for maintenance of remission, steroid sparing, and withdrawals due to adverse effects were calculated. Numbers needed to treat or harm (NNT, NNH respectively) for the maintenance of remission, steroid sparing, and withdrawals due to adverse effects were also determined.. Seven trials of azathioprine therapy and one of 6-mercaptopurine were included in the review. Azathioprine and 6-mercaptopurine had a positive effect on maintaining remission. The Peto odds ratio (OR) for maintenance of remission with azathioprine was 2.32 (95% CI 1.55 to 3.49) with a NNT of 6. The Peto OR for maintenance of remission with 6-mercaptopurine was 3.32 (95% CI 1.40 to 7.87) with a of 4. Higher doses of azathioprine improved response. A steroid sparing effect with azathioprine was noted, with a Peto OR of 5.22 (95% CI 1.06 to 25.68) and NNT of 3 for quiescent disease. Withdrawals due to adverse events were more common in patients treated with azathioprine (Peto OR 3.74; 95% CI 1.48 to 9.45, NNH = 20) than with placebo.. Azathioprine and 6-mercaptopurine are more effective than placebo for maintenance of remission in Crohn's disease. Higher response rates were obtained with azathioprine than 6-mercaptopurine. However, the one study evaluating 6-mercaptopurine used a relatively low dose of the drug. Future studies should look at the effect of higher doses of 6-mercaptopurine. There is weak evidence for a steroid sparing effect with azathioprine treatment.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Prodrugs; Randomized Controlled Trials as Topic; Remission Induction

To evaluate the efficacy and safety of purine analogs (azathioprine, 6-mercaptopurine (6-MP)) in the prevention of postoperative recurrence in Crohn's disease (CD).. We searched MEDLINE, the Cochrane Library, and EMBASE. The primary end points, clinical and endoscopic recurrence at 1 and 2 years, and safety were analyzed by the methods of Peto and Der Simonian and Laird.. Four controlled trials enrolled 433 patients and compared azathioprine (n=3) or (6-MP) (n=1) with control arms (placebo with or without antibiotic induction therapy or mesalamine). In the overall analysis, purine analogs were more effective than control arms in preventing clinical recurrence at 1 year (mean difference, 95% confidence interval (CI): 8, 1-15%, P=0.021, number needed to treat (NNT)=13) and 2 years (mean difference, 95% CI: 13%, 2-24%, P=0.018, NNT=8). In sensitivity analyses, the efficacy of purine analogs was superior to that of placebo for the prevention of clinical and endoscopic recurrence at 1 year (mean differences, 95% CI: 13, 1.8-25%, P=0.025, NNT=7, and 23%, 9-37%, P=0.0016, NNT=4, respectively). At 1 year, in the overall analysis, purine analogs were more effective than control arms were in preventing severe (i2-4) endoscopic recurrence (mean difference, CI 95%: 15, 1.8-29%, P=0.026, NNT=7), but they were not effective in the prevention of very severe (i3-4) recurrence. The rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in control arms (17.2 vs. 9.8%, respectively, P=0.021).. Purine analogs are more effective than placebo in preventing both clinical and endoscopic postoperative recurrence in CD, but they are associated with a higher rate of adverse events leading to drug withdrawal.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Recurrence

Complex perianal fistulas have a negative impact on the quality of life of sufferers and should be treated. Correct diagnosis, characterization and classification of the fistulas are essential to optimize treatment. Nevertheless, in the case of patients whose fistulas are associated with Crohn's disease, complete closure is particularly difficult to achieve. Systemic medical treatments (antibiotics, thiopurines and other immunomodulatory agents, and, more recently, anti-tumor necrosis factor-alpha agents such as infliximab) have been tried with varying degrees of success. Combined medical (including infliximab) and less aggressive surgical therapy (drainage and seton placement) offer the best outcomes in complex Crohn's fistulas while more aggressive surgical procedures such as fistulotomy or fistulectomy may increase the risk of incontinence. This review will focus on emerging novel treatments for perianal disease in Crohn's patients. These include locally applied infliximab or tacrolimus, fistula plugs, instillation of fibrin glue and the use of adult expanded adipose-derived stem cell injection. More well-designed controlled studies are required to confirm the effectiveness of these emerging treatments.

Topics: Anti-Bacterial Agents; Azathioprine; Crohn Disease; Humans; Immunologic Factors; Mercaptopurine; Rectal Fistula; Tumor Necrosis Factor-alpha

The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.. To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.. Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.. Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.. Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.. Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment > 17 weeks increased the OR to 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.. Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The OR of response increases after > 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on active therapy.

Topics: Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction

Recognizing inflammatory bowel disease (IBD) is straightforward when alarm symptoms are present, such as bloody diarrhea and weight loss. When the presentation is subtle or atypical, physicians must determine which patients warrant evaluation for IBD. Appropriate use of noninvasive tests can help identify which patients should undergo further investigation.. Currently IBD serologies lack high enough sensitivity and specificity to make them useful as a screening test for distinguishing IBD from other disorders, but they may have a role in classifying subtypes of IBD. Fecal markers seem promising for helping to differentiate IBD from irritable bowl syndrome and for monitoring disease activity. Pharmacogenetically guided dosing is recommended for safe use of thiopurines but ongoing routine laboratory monitoring remains important. Thiopurine metabolite measurement can be useful but may not be needed in all cases.. Primary care physicians should continue to rely on routine laboratory tests and clinical suspicion to decide which patients with abdominal pain to refer to a gastroenterologist. Serology panels are not useful for IBD screening as the results may lead to unnecessary procedures. Although fecal markers do show promise as a screening test for IBD, patient resistance to providing stool samples may limit its usefulness in disease monitoring. Thiopurine metabolite levels are best used in conjunction with clinical status and routine laboratory tests to monitor clinical response and adverse events.

Topics: Adolescent; Azathioprine; Biomarkers; Child; Child, Preschool; Clinical Laboratory Techniques; Colitis, Ulcerative; Crohn Disease; Diagnosis, Differential; Feces; Female; Humans; Incidence; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pediatrics; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index

Topics: Azathioprine; Clinical Trials as Topic; Crohn Disease; Drug Administration Schedule; Evidence-Based Medicine; Humans; Immunologic Factors; Leukocyte Count; Mercaptopurine; Methyltransferases; Monitoring, Physiologic; Pharmacogenetics; Polymorphism, Genetic; Pyrophosphatases; Remission Induction

Azathioprine and 6-mercaptopurine (6-MP) are effective in inflammatory bowel disease (IBD). However, between 10% and 29% of patients treated with these drugs are forced to stop therapy due to side effects. Pulmonary toxicity due to azathioprine/6-MP has been reported infrequently. We describe 3 patients who developed severe, noninfectious pulmonary toxicity within 1 month after the initiation of azathioprine or 6-MP for the treatment of IBD colitis (2 Crohn's disease and 1 ulcerative colitis). All patients presented with dyspnea, cough, and fever after initiation of azathioprine/6-MP. Evaluation for infectious etiologies, including bronchoscopy (3/3 patients) and open-lung biopsy (2/3 patients) was negative. Histopathologic examination of the lung biopsies revealed bronchiolitis obliterans organizing pneumonia in one, and usual interstitial pneumonitis in another patient. Cessation of purine analog therapy resulted in clinical improvement in all 3 cases. Azathioprine/6-MP-related pulmonary toxicity is a rare but serious side effect, and it is important for clinicians to have a high index of suspicion for this adverse reaction which occurs within 1 month after initiation of treatment for IBD.

Topics: Adult; Aged; Azathioprine; Crohn Disease; Female; Humans; Immunosuppressive Agents; Lung Diseases; Male; Mercaptopurine; Severity of Illness Index

Inflammatory bowel disease encompasses a group of diseases with poorly defined etiology that affect the digestive tract. These diseases are characterized by their chronic course and by periods of disease activity, of variable severity, that alternate with periods of clinical remission. In the last few years, inflammatory bowel disease has been the object of intense research, which has increased knowledge of the physiopathogenic mechanisms involved. This has enabled the development of a new generation of biotechnological drugs effective in patients previously considered to be refractory to medical treatment and has allowed the accumulated corticosteroid dose to be reduced and the indications for surgery and hospital admissions to be decreased, thus improving quality of life. In addition, some classical drugs have been demonstrated to be effective in recurrence prevention after surgery for Crohn's disease and in the prevention of dysplasia and colorectal cancer in inflammatory bowel disease.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Certolizumab Pegol; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colectomy; Colitis, Ulcerative; Colorectal Neoplasms; Controlled Clinical Trials as Topic; Crohn Disease; Cyclosporine; Gastrointestinal Agents; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Infusions, Intravenous; Mercaptopurine; Meta-Analysis as Topic; Polyethylene Glycols; Quality of Life; Rectal Fistula; Recurrence; Time Factors

This article reviews current data to optimize the use of both older and newer drugs in inflammatory bowel disease. For patients with severe ulcerative colitis (UC), steroid dosing has been clarified, and a mega-analysis of steroid outcomes and toxicities has been reported. In regard to mesalamine, recent information has suggested benefit of a higher dose of pH-dependent release mesalamine for patients with moderate UC. Also, a once-daily formulation with Multi-Matrix System (MMX) technology (Shire Pharmaceuticals, Wayne, PA), has been approved. In regard to cyclosporine, two centers have reported an increased rate of colectomy over a long-duration follow-up of a cyclosporin A course given for UC. Additional information regarding thiopurines has been published, including the use of metabolite testing and duration of therapy for these drugs. Lastly, additional information regarding the optimal method for using anti-tumor necrosis factor therapy continues to accumulate.

Topics: Absorptiometry, Photon; Adalimumab; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Colectomy; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Cyclosporine; Humans; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Mesalamine; Patient Compliance; Prednisone; Treatment Failure

Topics: Antibodies, Monoclonal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Remission Induction

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MTX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Mesalamine; Methotrexate; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Sulfasalazine; Treatment Outcome

Genetic research in inflammatory bowel disease, especially in Crohn's disease, has made significant progress during recent years. There have been > 10 total genome scans that have been performed, and susceptibility loci on several chromosomes have been identified. Together with candidate gene studies, these scans have led to the identification of several susceptibility genes, with CARD15 being the most important. These genetic data have already provided important insights into the pathophysiology of inflammatory bowel disease and are stimulating future research. On the other hand, genotype-phenotype associations have illustrated the heterogenic nature of the disease. Although the clinical application of this knowledge is so far limited, there is significant optimism that an individual management of patients based on genetic data will be possible in the near future.

Topics: Adaptor Proteins, Signal Transducing; Animals; Clinical Trials as Topic; Crohn Disease; Genetic Predisposition to Disease; Glucocorticoids; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Mercaptopurine; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Personal Health Services; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide

Postoperative recurrences art frequent in Crohn's disease. Early recurrent lesions in the neoterminal ileum after ileocoIonic anastomosis is the most important risk factor for symptomatic recurrence of Crohn's disease after curative surgical resection. Others risk factors are ileocolonic anastomosis, perforating indication of surgery and smoking status. Many drugs have been evaluated for the prevention of clinical postoperative recurrence: Antibiotics, particularly metronidazole ornidazole, and a little benefice of mesalamine. Azathioprine and 6 mercaptopurine have been recently evaluated; with a not clear clinical effect for prevention of clinical recurrence after resection in Crohn's disease. Several authors have proposed an empiric strategy for the prevention of recurrence after curative resection, based essentially on existence and severity of early endoscopic recurrence.

Topics: Algorithms; Anastomosis, Surgical; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colon; Crohn Disease; Endoscopy; Female; Humans; Ileum; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Metronidazole; Odds Ratio; Randomized Controlled Trials as Topic; Risk; Risk Factors; Secondary Prevention; Smoking; Time Factors

The natural history of Crohn disease is characterized by recurrent bouts of active disease, the consequences of which can severely impair sufferers' physical and social functioning. Not only does the illness cause day-to-day morbidity for children but the consequence of the chronic inflammatory process also commonly results in the need for major intestinal surgery. The present challenge facing physicians treating children with Crohn disease is to alleviate symptoms and prolong periods of remission via the use of specifically targeted therapies while minimizing toxicity and promoting normal growth and development. Although systemic corticosteroids are effective in inducing clinical remission, they are of little or no benefit in maintaining remission and can contribute to linear growth retardation. Immunomodulating drugs such as azathioprine, 6-mercaptopurine and methotrexate have proved effective for inducing and maintaining remission of active Crohn disease. These agents are now commonly prescribed in children at diagnosis, after a severe attack or after surgery or in those who become corticosteroid-dependent or corticosteroid-resistant. Their use is not without potential adverse effects and not all patients respond well to these agents. With the introduction of biologic agents, notably the tumor necrosis factor-alpha monoclonal antibody infliximab, progress has been made in targeting specific pathogenetic mechanisms of Crohn disease and potentially altering the underlying disease process. Published experience in children is currently limited, but infliximab has been shown to improve symptoms and achieve corticosteroid independence in this age group. Unresolved issues with infliximab and other emerging biologic agents, including long-term safety, necessitate a degree of caution in selecting appropriate patients for treatment and with careful monitoring of their effects. The collection of contemporary natural history data is crucial to facilitate the better integration of current and emerging therapies in an attempt to alter the natural history of Crohn disease in children.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Child; Crohn Disease; Disease-Free Survival; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate

The first intention in the management of patients with inflammatory bowel disease (IBD) is the improvement of quality of life. It is important to avoid unnecessary investigations and to protect the patients from therapeutic approaches, which efficacy is not proven. The following remarks are based on the guidelines of The German Society of Gastroenterology for diagnosis and therapy of ulcerative colitis and Crohn's disease, which include an accurate diagnosis, the treatment of the acute phase, the maintaining of remission and the management of complications. The therapy depends on the severity of the acute phase and on the localisation of the disease. Immunosuppressive therapy with azathioprine or mercaptopurine is indicated in patients with steroid-dependent or steroid-resistant disease.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Azathioprine; Colitis, Ulcerative; Controlled Clinical Trials as Topic; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Placebos; Practice Guidelines as Topic; Quality of Life; Remission Induction; Time Factors

Topics: Apoptosis; Azathioprine; CD28 Antigens; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Meta-Analysis as Topic; Nucleic Acids; Prodrugs; Randomized Controlled Trials as Topic; T-Lymphocytes

Crohn's disease in childhood is a chronic relapsing condition. Fifteen to forty per cent of children with Crohn's disease have growth retardation (Griffiths 1993a). Some treatment modalities including corticosteroids have been implicated in growth failure but it is thought mainly to be secondary to uncontrolled disease activity (Motil 1993; Markowitz 1993). Growth is fundamental to the practice of pediatrics, so by taking growth as the primary outcome measure we address issues important to both patients, their families and pediatricians.. To evaluate the effectiveness of the different modalities available for the treatment of childhood Crohn's disease with regard to the reversal of growth failure and the promotion of normal growth.. Searches were made of the following databases using the Collaborative Review Group Search Strategy: EMBASE (1984-2004), MEDLINE (1966-2004), The Cochrane Central Register of Controlled Trials, The Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register and the Science Citation Index. Abstracts from the major gastrointestinal research meetings and references from published articles were also reviewed.. Randomized controlled trials pertaining to children less than 18 years of age with Crohn's disease were selected. Those with growth as an outcome measure were included in the review.. Data extraction and assessment of the methodological quality of each trial was independently reviewed by two reviewers. Only one good quality randomized controlled trial was included in the review and therefore no statistical analysis was possible.. Three randomized controlled trials were identified. One was of good methodological quality (Markowitz 2000). This study looked at the use of 6-mercaptopurine (6-MP) as a steroid sparing agent. No difference in linear growth was observed between the intervention and placebo groups, although the total steroid dose received over the 18 month follow up period was reduced in the group receiving 6-MP. The two remaining randomized controlled trials (Sanderson 1987; Thomas 1993a) consider the use of enteral feeding versus corticosteroids for induction of remission, with height velocity standard deviation score at 6 months as an outcome measure. Although of less rigorous methodological quality, the results of these studies are discussed in detail in the review. In both studies height velocity standard deviation scores were significantly increased in the enteral feeding group compared with the corticosteroid group.. In addition to these randomized controlled trials, a body of lower quality evidence does exist relevant to two other important interventions; the use of supplemental enteral nutrition (Morin 1980; Belli 1988; Israel 1995) and the judicious use of surgical interventions in pre-pubertal children with refractory disease (Alperstein 1985; Lipson 1990; McLain 1990). Newer treatments, such as infliximab, are now becoming more widely used and may offer advantages in promoting growth. These effects are as yet unstudied. This review highlights the need for large, multi centre studies of the different treatment options in paediatric Crohn's disease and the importance of standardised measurements of growth, such as height velocity standard deviation scores and height standard deviation scores as outcome measures.

Topics: Adrenal Cortex Hormones; Antimetabolites; Child; Crohn Disease; Enteral Nutrition; Growth Disorders; Humans; Mercaptopurine; Prednisolone; Randomized Controlled Trials as Topic

In Crohn's disease therapeutic concepts are according to distinct conditions. Course of the disease, the individual disease pattern and the aim of treatment are of particular significance. Care of patients with Crohn's disease requires interdisciplinary cooperation between gastroenterologists and surgeons. Primary therapy in mild to moderate disease comprises aminosalicylates and budesonide. Treatment of refractory or severe cases are corticosteroids. Immunosuppressive therapy is indicated in all kinds of complicated disease. First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications. Maintenance of remission should not be done on a regular basis but rather regarding the individual patients' situation. Risks have to be carefully balanced with possible benefits. The most important aim of treatment is quality of life.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Algorithms; Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Child; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Mycophenolic Acid; Practice Guidelines as Topic; Prognosis; Remission Induction; Risk Factors; Time Factors

Crohn's disease (CD) is a granulomatous systemic disorder of unknown etiology. Obvious pulmonary involvement is exceptional in patients with CD. We report a case of a 38-year-old man who suffered from CD for more than 14 years and was treated with oral steroids for more than 10 years. Surgical excision of parts of the ileum was performed for life-threatening ileal bleeding caused by CD. After acute tapering of oral steroids, pulmonary symptoms and radiologic abnormalities were noted. Lung biopsy through thoracoscopy was performed and revealed signs of chronic inflammation with multiple subepithelial noncaseating and epithelioid granulomas on pathologic examination. Intravenous steroids were required in the initial management of life-threatening pulmonary dysfunction after diagnostic thoracoscopy and led to marked improvement. Tuberculocidal therapy was performed until all microbiological cultures were negative. Oral steroid dosage had slowly been tapered over 1 month. He was discharged with clinical and radiologic improvements. After 36 months, the patient's condition is stable on continued treatment with prednisolone and mesalazine.

Topics: Adult; Angiography; Biopsy, Needle; Combined Modality Therapy; Crohn Disease; Drug Therapy, Combination; Follow-Up Studies; Granuloma; Humans; Ileum; Immunohistochemistry; Laparotomy; Lung Diseases; Male; Mercaptopurine; Prednisolone; Risk Assessment; Severity of Illness Index; Tomography, X-Ray Computed

More than half of Crohn's disease patients require surgery during the course of their disease. Although endoscopic recurrence does not necessarily imply that patients have symptom recurrence, the high need for repeated surgery indicates that lesions gradually developing after surgical remission lead to fibrostenosis or other complications. Despite multiple clinical trials a clear medical strategy to prevent disease recurrence has not been identified. Future well designed collaborative trials with specified end points are needed to optimize clinical practice in the prevention of postoperative Crohn's disease recurrence.

Topics: Aminosalicylic Acids; Anti-Bacterial Agents; Budesonide; Crohn Disease; Decision Trees; Humans; Mercaptopurine; Postoperative Period; Recurrence

Details of the efficacy of the various drugs used in Crohn's disease are not readily available.. We have reviewed all placebo controlled trials of the commonly used drugs in Crohn's disease for both the induction and maintenance of remission to determine the efficacy and to calculate the numbers needed to treat (NNTs) to achieve a specified benefit for each drug.. Both the drug response rates and the NNTs (with 95% confidence intervals) are tabulated for each drug.. Prednisolone/prednisone is the most effective drug to achieve remission with a remission rate of 60% and an NNT for remission of 3 (95% confidence interval: 2-6). Aminosalicylates are only moderately effective in achieving remission with an overall NNT of 10 (95% confidence interval: 6-75), but more effective in high-dose (e.g. NNT for Pentasa 4 g daily = 4; 95% confidence interval: 2.6-9), and less effective in maintaining remission with an NNT of 14 (95% confidence interval: 9-29). Both azathioprine and infliximab are associated with remission induction and maintenance rates of 40-66% and NNTs of 3-5. Methotrexate intramuscularly has a remission induction rate of 39% and an NNT of 5 (95% confidence interval: 3-25).

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Humans; Infliximab; Mercaptopurine; Methotrexate; Randomized Controlled Trials as Topic

The clinical management of Crohn's disease can be considered in relation to the treatment of acute disease and the maintenance of remission. The medication used to achieve these two goals may or may not be the same. Some patients with mildly active disease may respond to high-dose (4 g/day) mesalazine (mesalamine), and 5-aminosalicylic acid may also be helpful in weaning a patient off steroids after treatment for a flare-up. However, the value of 5-aminosalicylic acid in maintaining remission in Crohn's disease remains controversial. Subgroups of patients may be helped: for example, patients with Crohn's disease who have experienced a relapse within the last 2 years may benefit. Steroids form the first-line therapy for acute episodes of inflammation but do not maintain remission. Azathioprine and mercaptopurine are the first-line drugs for the maintenance of remission in moderate to severe Crohn's disease, and by titrating the dose up from 2 mg/kg daily, some previously resistant patients will be brought into remission. One-half of patients who do not tolerate azathioprine will tolerate mercaptopurine. Methotrexate is effective in inducing and maintaining remission, and is useful for patients who fail azathioprine treatment. Thalidomide is not proven in controlled studies, but two open studies have demonstrated its efficacy. The optimal dose, however, remains to be defined. Purified liquid diets with food exclusion can induce remission in patients with active disease, but food exclusion is difficult to maintain long term. Infliximab can induce and maintain remission in patients resistant to other therapies, with two-thirds of patients initially responding to treatment. One-third go into remission and, of those who respond to a single treatment, approximately one-half maintain remission when treated regularly for a year. Infliximab is, however, associated with an increased risk of infection, and its effect on cancer incidence is uncertain. The development of antibodies against the drug is associated with a loss of effect and allergic infusion reactions. In summary, simple proven therapies should be used first, because of their safety and benefit in some patients. However, aggressive therapy should be used when needed.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Chronic Disease; Crohn Disease; Humans; Infliximab; Mercaptopurine; Mesalamine; Methotrexate; Prognosis; Steroids; Thalidomide

6-Mercaptopurine and its prodrug azathioprine remain the mainstay of immunomodulator therapy for the maintenance of a steroid-free remission in patients with IBD. Recent evidence suggests that the cytotoxic and immunosuppressive effects of azathioprine might be mediated via the induction of lymphocyte apoptosis by its active metabolites, 6-thioguanine nucleotides. The therapeutic benefits of thiopurines have been shown to correlate with the concentration of 6-thioguanine nucleotides. Inherited differences in drug metabolism and disposition can significantly impact the safety and efficacy of these drugs. The thiopurine methyltransferase enzyme plays an important role in the metabolism of 6-mercaptopurine and azathioprine and in the determination of thiopurine cytotoxicity. By gaining an understanding of the pharmacology and metabolism of thiopurine therapy and putting it into the clinical context, clinicians will be able to optimize thiopurine therapy in IBD.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Pregnancy

Topics: Antimetabolites; Azathioprine; Crohn Disease; Hematologic Tests; Humans; Leukocyte Count; Mercaptopurine

Therapeutic research in Crohn's disease has been intensified in recent years. This has led to many novel approaches and insights into the mechanism of action of "classic" drugs. Antibiotics remain valuable but do not offer benefit when used in addition to corticosteroids. Immunomodulators remain the cornerstone for maintenance therapy, although certain corticosteroid-dependent patients can be switched to maintenance therapy with topical steroids. Azathioprine and 6-mercaptopurine remain efficient beyond 4 years in patients with relapses and elevated C-reactive protein in spite of this therapy. Infliximab has shown efficiency in maintenance of active and fistulizing Crohn's disease. In addition, "automatic reinfusion" was found to be superior to "on-demand" treatment. Infusion reactions and loss of response, most often caused by antibodies against infliximab, can be prevented with immunomodulators and corticosteroid infusions before dosing. Such alternative anti-tumor necrosis factor agents as adalimumab or CDP-870 may be less immunogenic. Other biologic agents, such as the anti-integrin monoclonal antibody natalizumab, were shown to be effective in maintaining remission and somewhat less so in induction of remission. Finally, much attention is being paid to alteration of the luminal flora with probiotics and helminth ova. Extracorporeal apheresis and even stem cell transplantation were found to be effective in isolated patients, but these therapies warrant further prospective and controlled investigation.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Natalizumab; Remission Induction; Tumor Necrosis Factor-alpha

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Azathioprine; Budesonide; Colitis, Ulcerative; Colonoscopy; Controlled Clinical Trials as Topic; Crohn Disease; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Metronidazole; Pouchitis; Remission Induction; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Ultrasonography

Crohn's disease (CD), a chronic relapsing inflammatory condition of the intestines, is a common cause of gastrointestinal morbidity in young people. Although the aetiology of CD is unknown, host, genetic and environmental influences are clearly important. Glucocorticoids remain the mainstay of treatment for active CD, however only two-third of patients will respond and side effects are considerable. Surgery is often undesirable or impracticable and therefore alternative medical strategies have been sought. In recent years, there has been much interest in two areas of IBD therapy-the use of established immunomodulators, and the development of novel biological therapies. In this review, we have selected two areas of particular controversy-the use of purine analogues (azathioprine (AZA) and 6-mercaptopurine (6-MP)) and the introduction of anti-tumour necrosis factor alpha (TNFalpha) therapy and have examined the data for efficacy, safety and tolerability of these medications.

Topics: Animals; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Humans; Infliximab; Mercaptopurine; Tumor Necrosis Factor-alpha

Management of Crohn's disease has changed considerably in recent years. The discovery of tumor necrosis factor (TNF) as a pivotal cytokine in the inflammatory cascade has led to the development of several neutralizing antibodies, soluble receptors, and small molecules, interfering with TNF gene transcription and expression. Infliximab is the only monoclonal antibody that is commercially available. This potent molecule is effective for both active and fistulizing disease in the acute and maintenance phases of treatment. In addition to anti-TNF agents, weekly methotrexate injection and the classic "antimetabolites" azathioprine and 6-mercaptopurine remain highly valuable as maintenance drugs. "Tailored" antimetabolite therapy has now become possible with metabolite measurements and determination of the TPMT gene. The active metabolite thioguanine itself could be a promising alternative in patients who are intolerant of 6-mercaptopurine. In fistulizing disease, infliximab is becoming the treatment of choice, although fistula tracks do not disappear permanently and many patients still need surgical intervention.

Topics: Antibodies, Monoclonal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Treatment Outcome

The evolving medical armamentarium holds promise for more precise and effective therapies for IBD. The experience with anti-TNF therapy, particularly infliximab, illustrates the potential efficacy of therapies targeted at specific mediators or pathways involved in the pathogenesis. Advances in molecular technology have enabled the development of novel and potentially effective targeted therapies. Equally important is the increasing scientific understanding of the pathogenesis of IBD, which will likely improve the ability to stratify disease and to select therapies based on genotypic, immunologic, and phenotypic profiles in the future.

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Gastrointestinal Agents; Glucocorticoids; Humans; Infliximab; Mercaptopurine; Sulfasalazine; Tumor Necrosis Factor-alpha

In the past years there have been many exciting developments in IBD management. New therapies and concepts of remission induction and of maintenance have been developed. This paper is intending to bring together the basic topics in patient-management in the various medical fields that represent the most accepted ways of therapies. The introduction deals with the most common aspects of Crohn's disease and that of the ulcerative colitis. It describes the treatment of ulcerative colitis according to the different groups of patients and the degree of activity. First it analyses the possible ways leading to the remission, then the prevention of relapse, lastly the other therapeutic options which have not been given any evidence of so far. The main standards of Crohn's disease therapy are presented on the bases of the small bowel Crohn's disease. After discussing the essential principles in treating the complications it carries on the treating of the large bowel Crohn's disease and then it is completed with the consideration of prevention of the relapse and the supportive therapeutic possibilities.

Topics: Acute Disease; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine; Prednisolone; Recurrence; Risk Factors; Severity of Illness Index; Sulfasalazine

Linear growth retardation is a major complication of Crohn's disease that occurs in children. It is related both to undernutrition and to direct effects of the inflammatory process on the growth axis. Enteral nutrition (elemental, semi-elemental or polymeric diet) employed as the sole source of nutrition remains a mainstay of treatment of active Crohn's disease because it corrects nutritional deficits, has anti-inflammatory effects, heals mucosal inflammation and stimulates growth. Conventional corticosteroids have adverse effects on growth and preliminary data suggest that an ileal-release preparation of budesonide may also suppress linear growth. 6-Mercaptopurine (6-MP) and its prodrug azathioprine maintain remission in children with Crohn's disease. These treatments thus have the potential to improve growth velocity and final adult height.

Topics: Adrenal Cortex Hormones; Budesonide; Child; Child Nutritional Physiological Phenomena; Crohn Disease; Diet; Growth Disorders; Humans; Mercaptopurine

Despite conventional medical and/or surgical intervention, endoscopic and symptomatic relapse is common among individuals with Crohn's disease (CD). Treatment goals have therefore been refocused to include achieving control of active disease and maintaining remission with agents associated with a minimum of toxic adverse effects. Conventional treatment regimens have been used with varying success in regard to these therapeutic goals. Traditionally, aminosalicylates have been considered effective in inducing a response in some patients with mild-to-moderate CD but have demonstrated little or no long-term benefit in controlled clinical trials. Glucocorticosteroid therapy is associated with higher rates of response in patients with active CD; however, clinical benefits are frequently offset by the common occurrence of corticosteroid-related toxicity. Oral controlled-release budesonide has demonstrated comparable efficacy to prednisolone with less risk for adverse effects, although many questions remain regarding the long-term use of this agent. Response to standard immunosuppressive agents such as azathioprine and 6-mercaptopurine in patients with active disease may require 3 to 6 months from initiation of treatment. These agents are therefore considered most valuable as maintenance therapy, providing consistent long-term benefit in patients with chronic refractory or corticosteroid-dependent disease. Although the incidence of allergic adverse effects is relatively low with azathioprine/6-mercaptopurine, more serious adverse effects, including bone marrow suppression, hepatotoxicity, pancreatitis, and infectious complications, can occur. Limited success in the treatment of perianal disease has been achieved with antibiotics such as metronidazole and the immunosuppressives cyclosporine and azathioprine/6-mercaptopurine. Although broader use of immunosuppressive agents has allowed improvement in the maintenance of remission in patients with CD, long-term safety data with these agents are lacking, concerns about toxicity and the potential risk for neoplasia remain, and attenuation of response with chronic immunosuppressive use can occur. Therefore, innovative therapeutic approaches are needed to meet key treatment goals often not addressed by conventional therapies.

Topics: Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Budesonide; Clinical Trials as Topic; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Methotrexate; Prednisone; Quality of Life; Recurrence; Sulfasalazine; Treatment Outcome

Corticosteroids are considered a drug of choice for the treatment of patients with moderately to severely active Crohn's disease (CD), an inflammatory bowel disease characterized by chronic recurrent flares of disease activity. However, among patients receiving corticosteroid therapy for induction of remission, 20% have corticosteroid-refractory disease and 36% of those with an initial response develop corticosteroid dependency within 1 year. Chronic corticosteroid exposure in patients who are corticosteroid dependent increases the risk for serious drug-related adverse effects. Withdrawal or reduction of corticosteroid therapy without exacerbation of symptoms is therefore recognized as an important goal of treatment. Therapies that have been shown to facilitate "steroid sparing' include the immunomodulators azathioprine/6-mercaptopurine and methotrexate and the antitumor necrosis factor-alpha monoclonal antibody infliximab. In corticosteroid-dependent patients, budesonide may be substituted for conventional corticosteroid therapy without loss of response and with less risk for toxicity, but its long-term efficacy requires further evaluation. A preliminary controlled study suggests that the investigational anti-TNF monoclonal antibody CDP-571 may also be clinically beneficial as a corticosteroid-sparing agent. This review summarizes the clinical evidence that supports consideration of these agents as alternatives in patients with CD who are dependent on, refractory to, or intolerant of conventional corticosteroid therapy.

Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Clinical Trials as Topic; Crohn Disease; Cyclosporine; Etanercept; Female; Gastrointestinal Agents; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Methotrexate; Receptors, Tumor Necrosis Factor; Thalidomide; Treatment Outcome

Fistulas are common in patients with Crohn's disease and, when associated with inflammatory disease and established for several weeks, tend to be chronic. Perianal fistulas are the most frequent complication of, and are most often associated with, colonic disease. Perianal fistulas commonly require surgical resection and permanent ileostomy. Antibiotics, cyclosporine, methotrexate and thalidomide have been used in uncontrolled trials; only azathioprine, 6-mercaptopurine and infliximab have been assessed in double-blind, placebo controlled studies. Relapse of the fistula occurs with all drugs, unless treatment is continued long term. Each drug differs in its onset of action and long term tolerability. An approach to fistulizing disease in Crohn's disease is suggested.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Azathioprine; Colonic Diseases; Crohn Disease; Cyclosporine; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Intestinal Fistula; Mercaptopurine; Methotrexate; Rectal Fistula; Thalidomide

To assess the effectiveness of azathioprine in maintaining remission of quiescent Crohn's disease.. Pertinent studies were selected using the MEDLINE data base (1966 - May 1998), the Cochrane Controlled Trials Register, the Inflammatory Bowel Disease Trials Register, as well as abstracts from major gastrointestinal research meetings and references from published articles and reviews.. Five randomized, double-blind, placebo-controlled trials of azathioprine therapy were identified. Two of these trials consisted solely of patients with quiescent Crohn's disease. Three trials had multiple therapeutic arms for both induction of remission and maintenance of remission.. Data were extracted by three independent observers (GRM, GF, LRS) based on the intention to treat principle. Peto odds ratios for the overall maintenance of remission, steroid sparing, and withdrawals due to adverse effects were calculated, and from these, 95% confidence intervals were derived. Numbers needed to treat or harm (NNT, NNH respectively) for the maintenance of remission, steroid sparing, and withdrawals due to adverse effects were also determined.. Azathioprine had a positive effect on maintaining remission. The Peto odds ratio for maintenance of remission was 2.16 (CI 1.35 - 3.47) with an NNT of 7. A higher dose improved response. A steroid sparing effect was noted, with a Peto odds ratio of 5.22 (CI 1.06 - 25.68) and NNT of 3 for quiescent disease. The Peto odds ratio for withdrawals due to adverse events was 4.36 (CI 1.63 - 11.67), the NNH (Number Needed to Harm) was 19.. Azathioprine is effective in maintaining remission. There is evidence for a steroid sparing effect.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Prodrugs

To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.. Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched.. Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms.. Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView).. The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.. Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.

Topics: Antimetabolites; Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Mercaptopurine; Remission Induction

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Remission Induction

The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.

Topics: Base Sequence; Colitis, Ulcerative; Crohn Disease; Cytokines; Gene Expression Profiling; Genetic Linkage; HLA Antigens; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Polymorphism, Genetic; Receptors, Cytokine

This review focuses on data reported in the last year on medical treatment of Crohn's disease and ulcerative colitis. In Crohn's disease, a broad range of cytokine-based therapies are currently being tested. Although all are very exciting, the anti-tumor-necrosis-factor (TNF) approach remains the most effective, with infliximab (a chimeric monoclonal antibody directed against TNF) being the most active agent. With repeated infusions every 8 weeks, remission is induced and can be maintained even in refractory patients with no major apparent side effects. Thalidomide, an oral agent with anti-TNF effects, shows promise in non-controlled experience. Important new data on azathioprine/6-mercaptopurine (6-MP) and its metabolites are also helpful. Methotrexate can induce remissions in 6-MP-allergic or refractory Crohn's patients and has now shown efficacy as a maintenance agent. Beneficial effects are also reported for a variety of new agents: mycophenolate mofetil, tacrolimus (FK506), growth hormone, and granulocyte colony-stimulating factor (G-CSF). Important observations in ulcerative colitis (UC) over the past year include evidence of a protective effect of 5-aminosalicylic acid (5-ASA) with respect to colorectal cancer, negative results from a study for heparin monotherapy, and results from a comparison of mycophenolate mofetil versus azathioprine as maintenance therapy. Epidemiologically, the negative association between appendectomy and UC was corroborated in a meta-analysis, suggesting an immunologic role for this organ. Finally, in chronic pouchitis, probiotic therapy was found to maintain remissions very significantly.

Topics: Adjuvants, Immunologic; Aminosalicylic Acids; Antimetabolites; Appendectomy; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Mycophenolic Acid; Remission Induction

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Digestive System Surgical Procedures; Humans; Interleukin-10; Mercaptopurine; Mesalamine; Prognosis; Randomized Controlled Trials as Topic; Secondary Prevention

Different hematologic abnormalities are often encountered in patients with inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs. Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. We present two cases with combination of these entities along with a literature review and treatment options. Immune thrombocytopenic purpura in these patients presented as an extraintestinal manifestation of inflammatory bowel disease mediated by a disturbance of the immune system.

Topics: Adolescent; Adult; Anemia; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocytosis; Leukopenia; Male; Mercaptopurine; Prednisone; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Thrombocytosis

Despite intense investigative efforts, the causes of ulcerative colitis and Crohn's disease remain elusive. The mainstay of medical therapy focuses on inhibition of the effects of the inflammatory mediators operant in inflammatory bowel disease because the causes of these two chronic disorders are unknown. During recent years, the physician's armamentarium for medical treatment of inflammatory bowel disease has increased substantially. In this article, the current standard medical therapies available for treatment of patients with inflammatory bowel disease are reviewed along with their efficacy; the side effects and status of other investigative drugs also are reviewed.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Nutritional Physiological Phenomena

A 39-yr-old white male with a prolonged history of Crohn's disease presented with worsening diarrhea associated with an increasingly painful rash of both lower extremities as well as left ankle swelling. A skin biopsy revealed an acute leukocytoclastic vasculitis. Intravenous hydrocortisone followed by oral prednisone achieved a rapid remission of the both cutaneous and gastrointestinal manifestations. Long-term remission has been maintained with 6-mercaptopurine and mesalamine. The rare association between cutaneous vasculitis and Crohn's disease is discussed and earlier reported cases reviewed.

Topics: Adult; Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Vessels; Crohn Disease; Humans; Hydrocortisone; Male; Mercaptopurine; Mesalamine; Prednisone; Vasculitis, Leukocytoclastic, Cutaneous

I present the progressive development of treatment with immunosuppressive drugs for Crohn's disease and ulcerative colitis, starting with rationale, failure of corticosteroids for maintenance, early observations, controlled trials, collaborations, toxicity (including fear of neoplasms), and considerations in pregnancy. Emphasis is on 6-mercaptopurine and azathioprine. Observations on methotrexate and cyclosporine are included, as well as advice on when to initiate immunosuppressive therapy, what is occurring currently, and what is expected to occur in the near future.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; History, 20th Century; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications

To assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn disease and the effectiveness of azathioprine in maintaining remission of quiescent disease.. Pertinent studies were selected from the MEDLINE database (1966 to May 1994), abstracts from major gastrointestinal meetings, and references from published articles and reviews.. Nine randomized, placebo-controlled trials of azathioprine or 6-mercaptopurine therapy were identified: Four addressed active disease, two addressed quiescent disease, and three had multiple therapeutic arms.. Data were extracted by three independent observers on the basis of the intention-to-treat principle and were analyzed with logistic regression. Each study was given a quality score on the basis of predetermined criteria.. Compared with placebo, azathioprine or 6-mercaptopurine therapy had an odds ratio of response of 3.09 (95% CI, 2.45 to 3.91) in patients with active Crohn disease. When the single trial that used 6-mercaptopurine in active disease was excluded from the analysis, the odds ratio of response was 1.45 (CI, 1.12 to 1.87). No trials of quiescent disease used 6-mercaptopurine; the odds ratio of response in these trials of quiescent disease was 2.27 (CI, 1.76 to 2.93). For active disease, continuation of therapy for at least 17 weeks improved response (P = 0.03). For quiescent disease, a higher dose improved response (P = 0.008). Increased cumulative dose improved response in both groups (P < 0.001 for active disease and P = 0.01 for quiescent disease). A steroid-sparing effect was seen in active disease (odds ratio, 3.69 (CI, 2.12 to 6.42) and in quiescent disease (odds ratio, 4.64 [CI, 1.00 to 21.54]). Fistulae improved with therapy (odds ratio, 4.44 [CI, 1.50 to 13.20]). Adverse events requiring withdrawal from a trial, primarily allergy, leukopenia, pancreatitis, and nausea, were increased with therapy (odds ratio, 5.26 [CI, 2.20 to 12.60]).. Azathioprine and 6-mercaptopurine are effective in treating active Crohn disease and in maintaining remission. Cumulative dose was an important factor in predicting response. Adverse effects were more common among patients receiving therapy.

Topics: Azathioprine; Crohn Disease; Drug Administration Schedule; Humans; Intestinal Fistula; Mercaptopurine; Odds Ratio; Randomized Controlled Trials as Topic; Remission Induction

Initial standard medical treatment for inflammatory bowel disease (IBD) includes a 5-aminosalicylic acid (5-ASA) compound (oral, local or combined) and corticosteroids (oral, local or combined). In both ulcerative colitis and Crohn's disease 5-ASA has proved effective in the acute phase of the disease. As maintenance treatment, it is effective in ulcerative colitis and in some instances also in Crohn's disease. Steroids can be used in active IBD, but their effectiveness as maintenance treatment has never been proven, although in practice low-dose steroids are used for chronic treatment. When the above-mentioned preparations are unsuccessful, other medications could be tried. Flagyl could be used when the colon is involved in Crohn's disease or when anal fistulation develops, but it often fails to maintain its effect after only a few weeks. For refractory IBD more potent immunomodulators are needed. 6-Mercaptopurine and azathioprine have been shown to be effective in ulcerative colitis and Crohn's disease with a response rate between 60 and 70%. Their optimal effect is only reached after 3-4 months. These drugs are therefore not of value for treatment in the acute phase of the disease. 6-Mercaptopurine or azathioprine can be used best in combination with steroids in situations where dose reduction of the latter drug repeatedly leads to relapse. They have therefore a steroid-sparing effect and initiate cessation of the long-term severe side-effects of steroids. Another possibility is the use of methotrexate in patients with refractory ulcerative colitis or Crohn's disease.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Mercaptopurine; Mesalamine; Methotrexate; Metronidazole

We review clinical experience with the immunosuppressive drugs 6-mercaptopurine (6-MP) and azathioprine, cyclosporine, and methotrexate in the management of patients with Crohn's disease. 6-MP and azathioprine are closely related structurally. Their exact mechanism of action is unknown, but both cause immunosuppression by interfering with nucleic acid metabolism in the immunological sequence that follows antigenic stimulation. 6-MP and azathioprine have proved most useful for two indications: reducing steroid requirements and healing fistulas. Among patients who are dependent on steroids for control of active inflammatory Crohn's disease, approximately 50% can be completely weaned from prednisone, and an additional 25% can tolerate a substantial dose reduction when treated with 6-MP or azathioprine. Likewise, 6-MP is effective in closing fistulas in approximately one third of patients and in reducing fistula drainage in an additional one third. However, the onset of action is slow and the results may be dose dependent. Cyclosporine, a selective immunosuppressant drug, inhibits T lymphocytes by inhibiting expression of interleukin-2 and its receptors. Its principal usefulness may be in patients with disabling fistulas or active steroid-refractory colitis who cannot tolerate the several months required for a remission induced by 6-MP or azathioprine. Methotrexate, a dihydrofolate reductase inhibitor, has antimetabolite and antiinflammatory properties. Methotrexate is only slightly, if at all, faster acting than 6-MP or azathioprine. Its principal usefulness may therefore be in cases when these other drugs have not been tolerated or are ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Azathioprine; Crohn Disease; Cyclosporins; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Remission Induction

Perianal complications of Crohn's disease are fairly common in the adult and pediatric populations. Transrectal ultrasonography is effective for the diagnosis and follow-up of patients with anorectal abscesses and fistulas in Crohn's disease. Metronidazole and 6-mercaptopurine therapy have been used effectively to treat perianal complications of Crohn's disease in the pediatric population. Asymptomatic perianal fistulas in a patient with Crohn's disease do not require treatment. If a fistula is symptomatic and involves only a small portion of the sphincter mechanism, conventional fistulotomy may be performed with good results. Complex fistulas that involve larger areas of the sphincter are best treated by optimizing medical management and seton placement. The management of rectovaginal fistulas in the presence of Crohn's disease is controversial. Conventional fistulotomy and transvaginal mucosal advancement flap with diverting ileostomy have been advocated as primary treatment modalities. Rectovaginal fistulas secondary to ulcerative colitis may be treated by ileoanal pouch anastomosis and primary repair.

Topics: Abscess; Adult; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Female; Humans; Male; Mercaptopurine; Metronidazole; Proctitis; Rectal Fistula; Rectovaginal Fistula

Crohn's disease is a chronic inflammatory intestinal disorder characterized in most patients by repeated episodes of diminished and exacerbated symptoms. Recent controlled trials demonstrated that oral preparations of 5-aminosalicylic acid decrease recurrence rates by approximately 40% when administered long-term to patients with quiescent Crohn's disease. Orally administered corticosteroids, sulfasalazine, metronidazole, azathioprine, and cyclosporine have not proved of benefit in the prevention of recurrences of Crohn's disease. Nonetheless, corticosteroids, metronidazole, and azathioprine can control chronically active disease. Methotrexate may have some benefit in the treatment of active Crohn's disease, but its role in maintenance of remission has not been investigated. Elimination diets seem to prolong periods of symptomatic remission. Further studies are needed to define subgroups of patients who are most likely to benefit from preventive therapy.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Azathioprine; Clinical Trials as Topic; Crohn Disease; Cyclosporine; Humans; Mercaptopurine; Mesalamine; Methotrexate; Recurrence; Remission Induction; Sulfasalazine

The standard therapy of ulcerative colitis and Crohn's disease is based on the treatment with corticosteroids, sulfasalazine and 5-aminosalicylic acid (mesalazine). Depending on the localization and the extent of bowel inflammation these drugs are given topically (proctosigmoiditis, left-side colitis) or systemically (total and subtotal colitis). Azathioprin and metronidazole are considered to be reserve drugs (the latter one having proven to be effective only in Crohn's disease). During the last years, the efficacy of several new agents has been investigated. At present, their routine administration cannot be advised. The clinical usefulness of new topical corticosteroids showing both high antiinflammatory effect and no or at least minor systemic side effects is promising.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Mesalamine; Sulfasalazine

Topics: Aminosalicylic Acids; Azathioprine; Crohn Disease; Drug Administration Schedule; Drug Therapy, Combination; Humans; Mercaptopurine; Mesalamine; Prednisone; Randomized Controlled Trials as Topic; Recurrence; Sulfasalazine

Topics: Antineoplastic Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Mercaptopurine; Methotrexate

Topics: Adrenal Cortex Hormones; Azathioprine; Crohn Disease; Cyclosporins; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Multicenter Studies as Topic; Opportunistic Infections

Topics: Azathioprine; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Risk Factors

The role of immunosuppressives in the treatment of Crohn's disease and ulcerative colitis will be reviewed. This will include a comprehensive presentation of the uncontrolled and controlled studies in both diseases. The author's personal experiences with more than 400 patients will be summarized, including efficacy and short- and long-term toxicity. A review of the literature regarding the risk of superinfections and neoplasia will be presented. Finally, specific indications for the use of 6-MP/azathioprine will be listed.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine

The history of immunosuppressant drug use, both azathioprine (Aza) and 6-mercaptopurine (6-MP), in inflammatory bowel disease (IBD) over the past 20 years is briefly reviewed. The two drugs appear identical in their pharmacologic and biologic effects. Azathioprine is converted to 6-MP while in the body. Conflicting reports on the effectiveness of Aza have been published. The major National Cooperative Crohn's Disease Study (NCCDS) has found no advantage in Aza over placebo. In contrast, 6-MP was found to be effective in a large randomized trial. The shortcomings of the NCCDS reports are discussed with possible explanations for their negative findings. Our own studies, dating from 1968, are reviewed with 38 patients having been treated for up to 18 years, always in combination with small doses of steroids. Our results with Aza are similar to those of Present and Korelitz with 6-MP; about 70% of previously intractable patients improved substantially. Both Aza and 6-MP bring about healing and closure of most fistulas. Side effects can be serious but are usually manageable and, to some extent, preventable by appropriate dosage schedules. Since Aza has been approved for another benign, presumably autoimmune disease--rheumatoid arthritis--and because of its extensive use in other autoimmune diseases, we prefer to use Aza in selected patients with Crohn's disease who have failed to respond to more conventional modes of therapy. The use of immunosuppressants in ulcerative colitis is less clearly indicated.

Topics: Adolescent; Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; Mercaptopurine; Middle Aged

Topics: Adolescent; Adult; Azathioprine; Crohn Disease; Diagnosis, Differential; Humans; Intestinal Absorption; Male; Mercaptopurine; Metronidazole; Parenteral Nutrition, Total; Prednisone; Sulfasalazine; Water-Electrolyte Balance

Topics: Adrenal Cortex Hormones; Azathioprine; Colitis, Ulcerative; Crohn Disease; Delivery, Obstetric; Female; Fertility; Humans; Mercaptopurine; Pregnancy; Pregnancy Complications; Radiography; Sulfasalazine

Both topical steroids and sulfasalazine are useful for patients with ulcerative proctitis and distal colitis. For patients with more extensive ulcerative colitis with moderate symptoms, prednisone and/or sulfasalazine will result in improvement in about 80% of patients. Parenteral corticosteroids or ACTH should be used in the setting of severe colitis and antibiotics added if the patient appears toxic. Sulfasalazine is of proven efficacy as maintenance therapy in ulcerative colitis. Prednisone and sulfasalazine are useful in Crohn's disease, although the latter is of limited use in patients with ileitis alone. Immunosuppressive agents such as azathioprine and 6-mercaptopurine may be especially helpful in Crohn's patients refractory to other drugs or dependent on high doses of steroids. Azathioprine is of proven usefulness as maintenance treatment of Crohn's disease. Metronidazole is as effective as sulfasalazine in Crohn's disease involving the colon and has an important role in severe perineal disease. New forms of steroid enemas and topical and oral forms of 5-aminosalicylate based on sulfasalazine should be available soon for patients with both ulcerative colitis and Crohn's disease.

Topics: Adrenal Cortex Hormones; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Drug Therapy, Combination; Humans; Mercaptopurine; Sulfasalazine

Topics: Adolescent; Adult; Crohn Disease; Fistula; Gastric Fistula; Humans; Intestinal Fistula; Mercaptopurine; Middle Aged; Parenteral Nutrition; Skin Diseases

Topics: Adult; Alkylating Agents; Antimetabolites; Azathioprine; Child; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Cromolyn Sodium; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Metronidazole

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Chlorambucil; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Granulomatosis with Polyangiitis; Hepatitis; Humans; Immune Complex Diseases; Immunosuppressive Agents; Infections; Liver Cirrhosis, Biliary; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Nephrotic Syndrome; Ophthalmia, Sympathetic; Psoriasis; Thioguanine; Uveitis

Topics: Alkylating Agents; Anemia, Hemolytic, Autoimmune; Antibodies; Antimetabolites; Arthritis, Rheumatoid; Azathioprine; Blood Coagulation Disorders; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Dermatomyositis; Factor VIII; Hepatitis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Prednisolone; Purpura, Thrombocytopenic; Scleroderma, Systemic

Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia.. To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease.. The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up.. Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.

Topics: Anemia; Azathioprine; Crohn Disease; Genotype; Humans; Leukopenia; Mercaptopurine; Pyrophosphatases

The impact of severity and location of Crohn's disease (CD) endoscopic ulcers on endoscopic remission in patients treated with antitumor necrosis factor is poorly known. We aimed to describe the endoscopic evolution of CD lesions in a prospective cohort of patients treated with infliximab (IFX) in combo therapy.. We conducted a post hoc analysis of the TAILORIX randomized controlled trial, which studied biologic-naïve patients with active CD and endoscopic ulcers receiving IFX combo therapy. Ileocolonoscopies were performed at week 0, 12, and 54. Endoscopic healing was defined as the absence of ulcers and complete endoscopic remission as CD Endoscopic Index of Severity (CDEIS) <3. Ileocolonic segments were scored separately for remission by blinded readers.. A total of 122 (median disease duration: 7 months) patients were included, corresponding with 379 diseased segments. The median (IQR) CDEIS scores at week 0, 12, and 54 were 9.9 (6.1-14.4), 2.4 (0.2-4.6), and 0.2 (0.0-3.7), respectively. At weeks 12 and 54, the rates of endoscopic healing and complete endoscopic remission were 41% and 61% and 61% and 73%, respectively. Median CDEIS scores were similar among patients with deep ulcers at baseline and those with only superficial ulcers at week 12 and 54. Segmental remission rates were lower both at week 12 and 54 in the ileum compared with colonic segments (P < 0.01 all comparisons) and in the rectum (P = 0.02 and P = 0.03).. In biologic-naive patients with CD treated with IFX combo therapy, the severity of endoscopic lesions at the baseline did not influence healing rates. Endoscopic remission occurs less frequently in the ileum compared with the colon.

Topics: Adult; Azathioprine; Colon; Colonoscopy; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Ileum; Immunosuppressive Agents; Infliximab; Intestinal Mucosa; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Middle Aged; Rectum; Remission Induction; Severity of Illness Index; Treatment Outcome; Young Adult

Long-term outcomes of early combined immunosuppression [top-down] compared to conventional management [step-up] in recently diagnosed Crohn's disease [CD] are unknown. We aimed to investigate long-term outcomes of participants of the Step-up/Top-down-trial.. Trial participants' medical records were reviewed retrospectively. For 16 semesters following the 2-year trial, we recorded: clinical activity, medication use, flares, hospitalization, surgery and fistulas. Colonoscopy reports were scored as: endoscopic remission, aphthous/small ulcers or large ulcers. The primary endpoint was the proportion of semesters in remission.. Data were available from 119/133 patients [step-up n = 60]. During a median follow-up of 8 years, clinical remission rates were similar (70% vs 73% [p = 0.85] in step-up and top-down patients, respectively). A shorter time to flare was observed in step-up patients [median five vs nine semesters, p = 0.01]. Cumulatively, 62% of step-up patients used corticosteroids compared to 41% of top-down patients [p = 0.02]. Anti-tumour necrosis factor [anti-TNF] use was higher in the step-up group [73% vs 54%, p = 0.04]. No differences were found in to time to CD hospitalization [respectively 13 vs 14 semesters, p = 0.30], new fistula [14 vs 15 semesters, p = 0.20] or CD surgery [14 vs 15 semesters, p = 0.25]. Mucosal healing 2 years after treatment was associated with a reduced anti-TNF use, but not with differences in other long-term outcomes. Endoscopic remission occurred at similar rates between groups.. Top-down treatment did not result in increased clinical remission during long-term follow-up, compared to step-up treatment. However, lower relapse rates and a reduced use of anti-TNF agents and corticosteroids were observed. No difference was found in rates of endoscopic remission, hospitalization, surgery or new fistulas.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Biological Products; Colonoscopy; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Infliximab; Intestinal Fistula; Intestinal Mucosa; Male; Mercaptopurine; Methotrexate; Retrospective Studies; Symptom Flare Up; Time Factors; Tumor Necrosis Factor-alpha; Wound Healing; Young Adult

Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear.. To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial.. We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity.. There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/mL vs 5.4 ± 4.3 μg/mL: P <.001). Adalimumab trough level of 5.0 μg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×10. Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).

Topics: Adalimumab; Anti-Inflammatory Agents; Antibodies; Crohn Disease; Drug Therapy, Combination; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Sensitivity and Specificity; Thionucleotides; Treatment Outcome

Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.. We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).. Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; p. Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.. Medical Research Council.

Topics: Administration, Oral; Adolescent; Adult; Aged; Crohn Disease; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Recurrence; Secondary Prevention; Smoking; Treatment Outcome; Young Adult

Exclusive Enteral Nutrition (EEN) induction in children with luminal Crohn's disease (CD) gives early mucosal healing (MH), but the long-term benefits of EEN-induced MH are just emerging.. We prospectively followed an Australian cohort of newly diagnosed children with predominantly luminal CD who completed at least six weeks EEN and with paired clinical Pediatric Crohn's Disease Activity Index (PCDAI), biochemical (C-reactive protein; CRP) and endoscopic assessment at diagnosis and post EEN. All commenced immunomodulators (IMs) early (<3 months from diagnosis) and had a minimum of 1 year follow-up. Complete MH was a simple endoscopic score for Crohn's disease (SES-CD) of 0, and SES-CD≥1 was ascribed to active endoscopic disease (aED) and further divided into near complete MH (SES 1-3), mild active disease (SES-CD 4-10) and moderate to severe disease (SES-CD>10). The primary outcome was long-term supervised sustained remission (SR) on IMs alone without need for corticosteroids, infliximab (IFX) or surgery.. A total of 54 eligible children (33 males) completing EEN induction were analysed. The median duration between pre and post EEN assessments was 60.5 days [interquartile range (IQR), 56-69.5]. Post EEN: clinical remission (PCDAI < 10) was observed in 45/54 (83%), and biochemical remission (PCDAI < 10 and CRP < 5 mg/dl) was observed in 39/54 (72%). Complete MH was observed in 18/54 (33%), near complete in 10/54(19%). SR was superior in those with complete MH vs. aED; 13/18, (72%) vs. 10/36 (28%), p = 0.003 at 1 year, 8/16, (50%) vs. 3/24, (8%), p = 0.008 at 2 years and (8/16, (50%) vs. 1/19, (6%), p = 0.005) at 3 years. Near-complete MH did not lead to superior SR.. Only complete MH post EEN induction predicts more favourable SR for up to 3 years.

Topics: Azathioprine; Child; Combined Modality Therapy; Crohn Disease; Enteral Nutrition; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kaplan-Meier Estimate; Male; Mercaptopurine; Proportional Hazards Models; Prospective Studies; Remission Induction; Severity of Illness Index; Treatment Outcome; Wound Healing

The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test). Nine patients out of 100 (Crohn's disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p = 0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Exome; Female; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; Mercaptopurine; Methyltransferases; Mutation; Sulfurtransferases

Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence.. In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560.. Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively.. Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring.. AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Topics: Adalimumab; Adult; Antibodies, Monoclonal, Humanized; Azathioprine; Colonoscopy; Crohn Disease; Female; Humans; Male; Mercaptopurine; Metronidazole; Middle Aged; Recurrence; Treatment Outcome

Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimetabolites; Biological Availability; Cell Adhesion; Crohn Disease; Delayed-Action Preparations; Double-Blind Method; E-Selectin; Female; Gastrointestinal Agents; Gastrointestinal Tract; Humans; Intestinal Absorption; Male; Mercaptopurine; Middle Aged; Surveys and Questionnaires; T-Lymphocytes; Treatment Outcome

More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD.. In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]).. Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85).. Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Dosage Calculations; Female; Gastrointestinal Agents; Genetic Testing; Genetic Variation; Heterozygote; Homozygote; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Netherlands; Pharmacogenetics; Phenotype; Predictive Value of Tests; Prospective Studies; Risk Factors; Thrombocytopenia; Treatment Outcome; Young Adult

Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs.. This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs.. The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters.. Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Topics: Anti-Inflammatory Agents; Combined Modality Therapy; Cost-Benefit Analysis; Crohn Disease; Digestive System Surgical Procedures; Drainage; Drug Therapy, Combination; Europe; Gastrointestinal Agents; Health Care Costs; Humans; Magnetic Resonance Imaging; Mercaptopurine; Quality of Life; Rectal Fistula; Surveys and Questionnaires; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Crohn's disease recurs in the majority of patients after intestinal resection.. To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence.. As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.. A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).. In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Topics: Adalimumab; Adult; Aged; Azathioprine; Colonoscopy; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Metronidazole; Middle Aged; Postoperative Period; Recurrence; Risk Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease.. In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809.. This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events.. Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality.. AbbVie Pharmaceuticals.

Topics: Adalimumab; Adult; Antimetabolites; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Infliximab; Male; Mercaptopurine; Methotrexate; Treatment Outcome; Tumor Necrosis Factor-alpha

Adalimumab has been shown to be effective and well tolerated in patients with Crohn's disease. This analysis reports the results of a cohort of Japanese patients with moderate to severe Crohn's disease who were evaluated for up to 3years to assess the long-term use of adalimumab.. The study consisted of a double-blind part and an open-label part. Patients were included either in the 52-week double-blind, placebo-controlled part of the study followed by a 96-week open-label extension or in the open-label part from the beginning or in the event of a flare. Patients were treated with adalimumab and evaluated for up to 148weeks as 3 data cohorts: the all-adalimumab cohort (patients receiving ≥1 injection of adalimumab), the 148-week follow-up subcohort (patients who completed 148weeks of follow-up after the first adalimumab dose), and the dose-escalation subcohort (patients receiving adalimumab doses that increased to 80mg every other week).. In the all-adalimumab cohort (n=79), clinical remission rates were approximately 30% after 36weeks of exposure to adalimumab and for the remainder of the study (35%, 33%, and 28% for weeks 48, 108, and 144, respectively). An improvement in quality of life was also maintained over the same period. In the dose-escalation subcohort (n=40), the clinical remission rate was 75% (6/8) 48weeks after dose escalation. Adalimumab was tolerated, and no deaths were reported.. Adalimumab is effective for maintaining long-term clinical remission in Japanese patients with moderate to severe Crohn's disease (NCT00445432).

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Azathioprine; Crohn Disease; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Japan; Maintenance Chemotherapy; Male; Mercaptopurine; Middle Aged; Quality of Life; Remission Induction; Severity of Illness Index; Time Factors; Young Adult

Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients.. Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months.. The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 × 10(8) red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 × 10(8) RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively.. Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.

Topics: Adolescent; Adult; Allopurinol; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Medication Adherence; Mercaptopurine; Middle Aged; Treatment Outcome; Young Adult

6-Mercaptopurine is often used as maintenance therapy in patients with Crohn's disease. However, toxicities like myelosuppression limit its clinical benefit.. To evaluate the efficacy of elemental diet versus 6-mercaptopurine as maintenance therapy in Crohn's disease.. Ninety-five eligible patients with Crohn's disease activity index ≤150 were randomly assigned to: 6-mercaptopurine (0.5-1.5mg/kg/day, n=30); Elental as an elemental diet (≥900 kcal/day, n=32); none (control, n=33). In the three groups, patients were and remained on 5-aminosalicylic acid (2250-3000 mg/day). Patients were observed for 2 years and the rate of relapse (Crohn's disease activity index ≥200) was monitored.. At 24 months, the fractions of patients who had maintained remission were 60%, 46.9% and 27.2% for 6-mercaptopurine, Elental and the control groups, respectively. Log-rank test showed better efficacy for 6-mercaptopurine (P=0.0041) and Elental (P=0.0348) versus control. No significant difference was found between 6-mercaptopurine and Elental. Further, in the 6-mercaptopurine group, 2 patients experienced liver injury and one developed alopecia.. This 24 months comparison study showed that Elental as maintenance therapy in Crohn's disease patients was as effective as 6-mercaptopurine. Elental should be useful for long-term maintenance therapy in Crohn's disease. This is the first comparison study evaluating nutritional therapy versus 6-mercaptopurine.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Food, Formulated; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Longitudinal Studies; Maintenance Chemotherapy; Male; Mercaptopurine; Mesalamine; Recurrence; Young Adult

Adverse events (AE) leading to discontinuation or dose-reduction of thiopurine therapy (TP) occur in 9-28% of patients with inflammatory bowel disease. 6-Thioguanine (6-TG) has been proposed as an alternative treatment in patients intolerant for azathioprine (AZA), but some concerns have been raised about drug safety.. We evaluated in a prospective manner the tolerance and efficacy of 6-TG in 23 Crohn's disease (CD) patients (13 men, median age 41 (19-65) years) with prior intolerance (n=18) or resistance (n=5) to AZA and/or 6-mercaptopurine (6-MP). In addition, eight patients had tried mycophenolate mofetil. Seventeen patients (74%) had undergone intestinal resection, often several times.. Patients were treated with a median daily dose of 40 mg 6-TG (range 20-60) for 259 (15-2272) days. Seven of 13 patients (54%) with active disease went into remission after 8 (4-26) weeks. Sixteen patients (70%) experienced AE that lead to discontinuation (n=10) after 85 (15-451) days or dose reduction (n=6) after 78 (10-853) days. Ten of 18 patients (56%) with prior TP-intolerance discontinued 6-TG treatment due to AE compared to none of five patients with TP-resistance (p=0.046). Of 13 patients that tolerated 6-TG, eight discontinued the drug due to therapeutic failure (n=5) or safety concerns (n=3). Eight patients (35%) continued treatment beyond 12 months. There was no significant difference in maximum thioguanine nucleotide levels between patients with AE leading to discontinuation/dose reduction and patients without AE, 652 (99-2488) vs. 551 (392-1574) pmol/8 x 10(8) RBC; p=0.80.. In this cohort of CD patients with severe disease failing traditional thiopurine treatment, a small fraction (22%) had long-term benefit of 6-TG-treatment. 6-TG therapy seems to offer a limited therapeutic gain for patients intolerant to both AZA and 6-MP and other treatment options should be considered.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Azathioprine; Crohn Disease; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prospective Studies; Remission Induction; Severity of Illness Index; Sweden; Thioguanine; Young Adult

There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients.. Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography.. The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations.. The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.

Topics: Administration, Oral; Azathioprine; Biomarkers, Pharmacological; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Erythrocyte Count; Humans; Immunosuppressive Agents; Japan; Leukocyte Count; Mercaptopurine; Methyltransferases; Mutation; Odds Ratio; Remission Induction; Thioguanine; Treatment Outcome

The benefit to risk ratio of concomitant immunosuppressives with scheduled infliximab (IFX) maintenance therapy for Crohn's disease is an issue of debate. We aimed to study the influence of immunosuppressives discontinuation in patients in remission with combination therapy in an open-label, randomized, controlled trial.. Patients with controlled disease > or = 6 months after the start of IFX (5 mg/kg intravenously) combined with immunosuppressives were randomized to continue (Con) or to interrupt (Dis) immunosuppressives, while all patients received scheduled IFX maintenance therapy for 104 weeks. Primary end point was the proportion of patients who required a decrease in IFX dosing interval or stopped IFX therapy. Secondary end points included IFX trough levels, safety, and mucosal healing.. A similar proportion (24/40, 60% Con) and (22/40, 55% Dis) of patients needed a change in IFX dosing interval or stopped IFX therapy (11/40 Con, 9/40 Dis). C-reactive protein (CRP) was higher and IFX trough levels were lower in the Dis group (Dis: CRP, 2.8 mg/L; interquartile range [IQR], 1.0-8.0; Con: CRP, 1.6 mg/L; IQR, 1.0-5.6, P < .005; trough IFX: Dis: 1.65 microg/mL; IQR, 0.54-3.68; Con: 2.87 microg/mL; IQR, 1.35-4.72, P < .0001). Low IFX trough levels correlated with increased CRP and clinical score. Mucosal ulcers were absent at week 104 in 64% (Con) and 61% (Dis) of evaluated patients with ongoing response to IFX.. Continuation of immunosuppressives beyond 6 months offers no clear benefit over scheduled IFX monotherapy but is associated with higher median IFX trough and decreased CRP levels. The impact of these observations on long-term outcomes needs to be explored further.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Belgium; C-Reactive Protein; Crohn Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; France; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Intestinal Mucosa; Male; Mercaptopurine; Methotrexate; Middle Aged; Prospective Studies; Treatment Outcome

Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Crohn Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Female; Gene Frequency; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Phenotype; Postoperative Period; Prospective Studies; Thioguanine; Thionucleotides; Time Factors

A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA.. After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).. After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity.. Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Crohn Disease; Dose-Response Relationship, Drug; Erythrocyte Indices; Female; Genotype; Guanine Nucleotides; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Remission Induction; Thionucleotides; Thrombocytopenia

No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn's disease. The aim of the current trial was to compare 6-mercaptopurine (6-MP) and mesalamine with placebo for the prevention of clinical, endoscopic, and radiographic recurrence of Crohn's disease after resection and ileocolic anastomosis.. Five centers randomized 131 patients to receive 6-MP (50 mg), mesalamine (3 g), or placebo daily in a double-blind, double-dummy trial. Patients had clinical assessments at 7 weeks and then every 3 months; colonoscopy at 6, 12, and 24 months; and small bowel series at 12 and 24 months. End points were clinical, endoscopic, and radiographic recurrence rates at 24 months.. Clinical recurrence rates (intent to treat) by life-table analysis at 24 months were 50% (95% confidence interval [CI], 34%-68%), 58% (95% CI, 41%-75%), and 77% (95% CI, 61%-91%) in patients receiving 6-MP, mesalamine, and placebo, respectively. Endoscopic recurrence rates were 43% (95% CI, 28%-63%), 63% (95% CI, 47%-79%), and 64% (95% CI, 46%-81%), and radiographic recurrence rates were 33% (95% CI, 19%-54%), 46% (95% CI, 29%-66%), and 49% (95% CI, 30%-72%), respectively. 6-MP was more effective than placebo ( P < 0.05) at preventing clinical and endoscopic recurrence over 2 years. Patient withdrawals resulted in 69% of the study population evaluable for the clinical recurrence end point.. 6-MP, 50 mg daily, was more effective than placebo at preventing postoperative recurrence of Crohn's disease and should be considered as a maintenance therapy after ileocolic resection.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Digestive System Surgical Procedures; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Postoperative Period; Remission Induction; Secondary Prevention; Survival Analysis; Treatment Outcome

A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy.. Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities.. Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity.. 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Topics: Adult; Antimetabolites; Azathioprine; Child; Crohn Disease; Drug Resistance; Female; Humans; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Pilot Projects; Thioguanine; Treatment Outcome

Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD). We report the results of a prospective, placebo-controlled, multicenter trial evaluating the combination of 6-MP and prednisone as therapy for children with newly diagnosed moderate-to-severe CD.. Fifty-five children (age, 13+/-2 years) were randomized to treatment with 6-MP (1.5 mg x kg(-1) x day(-1)) or placebo within 8 weeks of initial diagnosis. Both groups also received prednisone (40 mg/day). Prednisone dosage adjustments were based on a defined schedule determined by the change in a subject's disease activity score, and steroid administration was discontinued as remission was achieved. Study treatment with 6-MP or placebo continued for 18 months.. Groups were comparable for age, sex, and site and activity of disease. In the 6-MP group, the duration of steroid use was shorter (P<0.001) and the cumulative steroid dose lower at 6, 12, and 18 months (P<0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P = 0.007). Growth was comparable in both groups. No clinically significant adverse events occurred, although mild leukopenia and increases in aminotransferase activity were noted in the 6-MP group.. Addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. 6-MP should be part of the initial treatment regimen for children with newly diagnosed moderate-to-severe CD.

Topics: Adolescent; Child; Crohn Disease; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; Glucocorticoids; Growth; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prednisone; Prospective Studies

To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis.. Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted.. Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy.. Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus

Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.31 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mg/kg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.

Topics: Administration, Oral; Adolescent; Adult; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Rectal Fistula; Recurrence; Tacrolimus; Treatment Outcome

To determine outcome following treatment of refractory Crohn's disease with intravenous (i.v.) cyclosporine (CYA).. The medical records of 18 patients with refractory Crohn's disease treated with i.v. CYA were reviewed. Nine patients had refractory inflammatory Crohn's disease and nine patients had complex fistulizing Crohn's disease. All patients were initially treated with i.v. CYA (4 mg/kg/day). Patients who responded were converted to standard oral CYA. Patient outcomes were classified as complete response, partial response, or nonresponse.. Four of nine patients with severe inflammatory Crohn's disease and seven of nine patients with fistulizing Crohn's disease had a partial response to i.v. CYA. Four of four responding patients in the inflammatory group and four of six responding patients in the fistulizing group (plus one initial nonresponder) maintained or improved their response during oral CYA therapy. After discontinuing oral CYA, all four patients in the inflammatory group and five of seven patients in the fistulizing group relapsed despite 1-17 wk of concomitant treatment with azathioprine or 6-mercaptopurine (AZA/6MP). Two patients who received overlapping CYA and AZA/6MP for 17 and 23 wk maintained long-term responses. CYA toxicity was minimal: reversible nephrotoxicity (n = 2), headache (n = 2), oral candidiasis (n = 1), paresthesia (n = 2).. I.v. CYA appears to benefit both refractory inflammatory and fistulizing Crohn's disease. Most patients who respond to i.v. CYA will maintain their response during oral CYA therapy. However, the majority of these patients relapse when oral CYA is discontinued, probably because of inadequate duration of overlap with the slow acting maintenance drugs, AZA/6MP.

Topics: Administration, Oral; Adolescent; Adult; Azathioprine; Crohn Disease; Cyclosporine; Drug Therapy, Combination; Female; Fistula; Humans; Immunosuppressive Agents; Injections, Intravenous; Male; Mercaptopurine; Middle Aged; Treatment Outcome

The objective of this study was to describe the clinical outcome of children with Crohn's disease treated with subcutaneous methotrexate.. Fourteen patients (10 boys) with extensive Crohn's disease diagnosed at a mean age of 10.6 +/- 3.6 years had previously received various medical therapies for 4.3 +/- 4.0 years. Because of the severity of their disease, 6-mercaptopurine had been introduced but discontinued because of the patients' failure to respond (n = 11) or the development of pancreatitis (n = 3). Subsequently, low-dose, weekly, subcutaneous methotrexate was initiated. Pediatric Crohn's Disease Activity Index scores and prednisone requirement were followed as outcome measures.. Overall, 9 (64%) of the 14 patients showed improvement, including 6 (55%) of 11 patients who had previously received an adequate trial of 6-mercaptopurine and all three patients who were intolerant of 6-mercaptopurine. Improvement in clinical and laboratory measures occurred by 4 weeks and were similar whether (n = 8) or not (n = 6) the dose of corticosteroids was increased before the start of subcutaneous methotrexate. Three patients were tapered from their initial methotrexate dose after the minimization of corticosteroids and remain well. One patient receiving daily corticosteroids died suddenly after acute onset of illness. Among patients responding, methotrexate was discontinued because of side effects (n = 2) or electively (n = 2). Of the latter two patients, one has resumed methotrexate after disease relapse, whereas the other patient has had a sustained remission.. Low-dose, weekly, subcutaneous methotrexate can induce remission in some pediatric patients with Crohn's disease who fail to adequately respond to other immunomodulator medications.

Topics: Adolescent; Child; Child, Preschool; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Male; Mercaptopurine; Methotrexate; Prospective Studies; Recurrence; Remission Induction; Risk Factors; Treatment Outcome

At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD).. To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD.. Patients with active CD, who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied.. Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinically indicated.. Eighty-four patients were included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26 patients). The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups. The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar. However, when each patient was evaluated as his or her own control, the reduction in steroid dose, the general well being, and the reduction in abdominal pain were significantly better in the methotrexate treated patients.. Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD.

Topics: Abdominal Pain; Administration, Oral; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Chronic Disease; Crohn Disease; Double-Blind Method; Evaluation Studies as Topic; Female; Follow-Up Studies; Health Status; Humans; Immunosuppressive Agents; Israel; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Placebos; Recurrence; Remission Induction; Treatment Outcome

This prospective, open trial of treatment was conducted to determine whether cyclosporine A (CSA) is effective in inducing remission in children with severe, active Crohn's colitis refractory to other medical treatment and if remission may be maintained by 6-mercaptopurine (6-MP) and 5-aminosalicylic acid (5-ASA) after discontinuing CSA.. Ten children (five males, five females), ages 1.2-16 yr (mean 11), all had failed to respond to 4 wk of treatment with i.v. methylprednisolone and total parenteral nutrition/elemental diet; three were already receiving 6-mercaptopurine. CSA was initially given as a twice daily i.v. dosage and was switched to oral CSA when a clinical response was observed. At the same time, corticosteroids were switched to the oral route and tapered over the next 3 months. Patients were grouped by treatment outcome. "Responders" were those who achieved remission with i.v. CSA therapy, "relapsers" were those who achieved remission with i.v. CSA but relapsed later, and nonresponders had not achieved remission after 4 wk of i.v. CSA. Responders were given 6-MP with intent to discontinue CSA after 6 months and maintain remission by 6-MP and 5-ASA.. There were seven responders to CSA. For all patients, the Pediatric Crohn's Disease Activity Index (PCDAI) (score range 0-100) had a mean value of 55 (range 40-65) just before treatment; PCDAI improved to a mean of 19 (range 5-42.5) after 2 wk of CSA therapy. Four of the seven responders discontinued CSA after 6 months and remain well on 6-MP and 5ASA alone for 22, 13, 8, and 3 months. One patient had massive GI bleeding (from active Crohn's colitis), which stopped within 48 h of CSA treatment. There were three relapsers (at 2-6 months of CSA), and three were nonresponders. Three patients who were already receiving 6-MP before CSA therapy either did not respond to CSA or relapsed while receiving it. The six nonresponders and relapsers required surgical resection. Transient side effects included hypertension responding to nifedipine in one child and hirsutism and tremors in another.. We conclude that CSA offers a good remission rate for children with severe Crohn's colitis failing other medical treatment, although relapse was common especially if the child was already on 6-MP. In addition, CSA may offer "temporizing" therapy in severe, active Crohn's colitis; this may allow surgery to be performed electively, with time for psychosocial and nutritional preparation before surgery.

Topics: Adolescent; Child; Child, Preschool; Colitis; Combined Modality Therapy; Crohn Disease; Cyclosporine; Female; Gastrointestinal Agents; Humans; Infant; Male; Mercaptopurine; Prospective Studies; Recurrence; Remission Induction; Time Factors

The aim of this study was to assess whether in steroid-resistant patients with pediatric inflammatory bowel disease (IBD) a combination of cyclosporine and azathioprine (or 6-mercaptopurine) could induce remission and subsequently permit maintenance on azathioprine/6-mercaptopurine as the sole immunosuppressive agent. Two boys and six girls (six with ulcerative colitis and two with Crohn's disease; ages 3-17 years) received 100-200 micrograms/kg/day cyclosporine intravenously and then 4-10 mg/kg/day orally. Doses were adjusted to achieve trough serum cyclosporine levels of 100-200 mu/L (Abbott's TDX assay). Seven of the eight patients received azathioprine/6-mercaptopurine, and all were given a 5-aminosalicylate preparation and corticosteroids. The latter drugs were continued and then tapered off as clinical status allowed. Cyclosporine was continued for 3-10 months in those who responded. In seven of eight patients, there was a rapid clinical response; one patient showed a transient response, but recurrent bleeding led to total colectomy 9 days after starting cyclosporine. Of the seven responders, three were able to discontinue prednisone and cyclosporine and are doing well on azathioprine at long-term follow-up (2-5 years). One who did not receive azathioprine/6-mercaptopurine maintained remission for 2 years after cyclosporine was stopped, one experienced a disease flare-up 5 months after start of cyclosporine treatment and required colectomy, one who did not tolerate 6-mercaptopurine had a flare-up during cyclosporine tapering and underwent surgery at 6 months, and one started to flare up with cyclosporine tapering at 6 months and was scheduled for surgery. No significant complications of treatment were observed. Seven patients had an initial response and four of them have so far not required surgery. These preliminary findings suggest that azathioprine/6-mercaptopurine can be used safely to maintain cyclosporine-induced remission in children with IBD.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Remission Induction; Treatment Outcome

6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood.. To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment.. Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months.. Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography.. Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 6-TG (p < 0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p < 0.005), but did not correlate with erythrocyte 6-MP metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels.. These results suggest that high performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.

Topics: Adolescent; Adult; Child; Chromatography, High Pressure Liquid; Crohn Disease; Erythrocytes; Humans; Immunosuppressive Agents; Mercaptopurine; Patient Compliance; Thioguanine; Treatment Outcome

To assess the efficacy of 6-mercaptopurine in I.B.D. treatment.. 21 patients with chronic active disease (8 patients with ulcerative colitis and 13 with Crohn's disease) and mean follow-up 5 years for both diseases (range ulcerative colitis 1-11 and Crohn's disease 1-14 years, respectively). The indications of inmunosuppressor treatment were: corticosteroid dependence (3 ulcerative colitis; 6 Crohn's disease), refractory disease (5 ulcerative colitis; 4 Crohn's disease), fistulae (5 Crohn's disease) and perianal disease (4 Crohn's disease). All patients received a mean dose of 30 mg/day of prednisone. Complete, partial and clinical remission, of failure of treatment are defined.. The mean dose of 6-mercaptopurine was 90 mg/day with a response mean time of 3.4 months and 12 months of duration (range 1-36). Complete or partial clinical remission was achieved in 77.7% of all the patients (steroid dependent 88.8%, refractory disease 77.7%, fistulae 40%, perianal disease 100% of all the patients (steroid dependent 88.8%, refractory disease 77.7%, fistulae 40%, perianal disease 100%), in 87% of ulcerative colitis patients (steroid dependent 100%, refractory 80%) and in 61.5% of Crohn's disease patients (steroid dependent 83.7%, refractory disease 75%). Secondary effects were observed in two patients.. Our results suggest that 6-mercaptopurine is an effective and safe drug in the treatment of patients with ulcerative colitis and Crohn's disease in corticosteroid dependent, refractory and perianal disease, its efficacy being less in fistulae.

Topics: Adrenal Cortex Hormones; Adult; Aged; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged

Topics: Azathioprine; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Risk Factors

Topics: Adolescent; Adult; Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Metronidazole

We studied the clinical effects of long-term immunosuppressive treatment in 42 patients with severe Crohn's disease and extensive colonic involvement. Mean observation period before and after start of therapy exceeded 5 years. All but one of the patients receiving azathioprine or 6-mercaptopurine improved, and 11 of 42 attained complete remission during therapy. Cyclophosphamide was substituted for azathioprine with inferior results in four patients with pancreatitis soon after initiation of azathioprine therapy. The frequency of both local and systemic complications decreased significantly during the period of therapy. Prednisolone could be withdrawn in 25 patients and reduced to less than 7.5 mg every other day in the others. The average remission period after withdrawal of all drugs in 10 patients was 40 months. The results were superior to those in a surgical series with comparable observation time drawn from the same background population. Aside from pancreatitis in four patients, no serious side effects were seen. Fertility was unaffected. The data demonstrate the feasibility of long-term azathioprine (6-mercaptopurine) treatment in extensive Crohn's disease.

Topics: Adolescent; Adult; Azathioprine; Clinical Trials as Topic; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prednisolone; Quality of Life; Time Factors

Topics: Azathioprine; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Humans; Mercaptopurine

Topics: Adjuvants, Pharmaceutic; Azathioprine; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Humans; Mercaptopurine

To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data showed that improvement occurred in 26 of 39 courses of 6-MP (67%) as compared with three of 39 courses of placebo (8%) (P less than 0.001). Non-crossover data likewise confirmed the superiority of 6-MP. The drug was more effective than placebo in closing fistulas (31 vs 6%) and in permitting discontinuation or reduction of steroid dosage (75 vs. 36%) (P less than 0.001). The onset of response to 6-MP was often delayed, with 32% of patients taking longer than three months to respond, and 19% taking longer than four months. Adverse side effects to 6-MP occurred in 10% of patients and were uniformly reversible. We conclude that 6-MP is an effective and useful agent in the management of Crohn's disease.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Fistula; Follow-Up Studies; Humans; Male; Mercaptopurine; Middle Aged; Placebos; Random Allocation; Research Design; Sulfasalazine; Time Factors

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Drug Therapy, Combination; Humans; Mercaptopurine; Pancreatitis; Placebos; Prednisone; Random Allocation; Remission, Spontaneous; Sulfasalazine; Time Factors

Topics: Adult; Alkylating Agents; Antimetabolites; Azathioprine; Child; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Cromolyn Sodium; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Metronidazole

Topics: Alkylating Agents; Anemia, Hemolytic, Autoimmune; Antibodies; Antimetabolites; Arthritis, Rheumatoid; Azathioprine; Blood Coagulation Disorders; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Dermatomyositis; Factor VIII; Hepatitis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Prednisolone; Purpura, Thrombocytopenic; Scleroderma, Systemic

A 36-year-old woman presented to the emergency department with a 1-day history of purulent perianal and vulvar discharge. She had a 25-year history of Crohn's disease (CD), and 13 years prior had received a total colectomy with end ileostomy. She had vulvar biopsies 5 years prior to presentation, demonstrating noncaseating granulomas consistent with metastatic Crohn's disease (MCD). Throughout the course of her disease, she had a failed treatment with adalimumab, certolizumab, methotrexate, and 6-mercaptopurine. She had received a radical vulvectomy 1 year prior to presenting to control recurrent vulvar abscesses and MCD while receiving monthly subcutaneous infliximab 10 mg/kg body weight. Dermatology was consulted at presentation, and the physical examination revealed tender, linear ulcerations with a granulated appearance and depigmentation on the natal cleft and vulva (Figures 1 and 2). Computerized tomography (CT) scan of the abdomen and pelvis indicated thickening of soft tissue without evidence of abscesses, fluid collection, or fistulae. Given the distribution and morphology of lesions with a history of biopsy-proven MCD, the patient was diagnosed with a flare of MCD.

Topics: Abscess; Adult; Crohn Disease; Female; Humans; Infliximab; Mercaptopurine; Methotrexate; Neoplasms; Recurrence

The temporal trends in medical treatment and long-term outcomes of patients with Crohn's disease (CD) have not been well elucidated in China over the past 2 decades. Accordingly, we aimed to evaluate the treatment paradigm and long-term clinical course of Chinese patients with CD in a hospital-based cohort.. All adult patients newly diagnosed with CD (n = 1338) between 1999 and 2019 in the Sir Run Run Shaw Hospital were included in this cohort. Medication utilization, disease outcomes, and risk factors were investigated.. Overall, 48.7%, 35.6%, 67.8%, and 61.6% of patients used 5-aminosalicylates (5-ASA), corticosteroids, thiopurines, and infliximab (IFX), respectively. The cumulative risk of 5-ASA and corticosteroid initiation decreased during follow-up, whereas that of IFX initiation increased. Throughout a median follow-up duration of 26.4 (interquartile range, 12.0-49.2) months, a total of 486 and 300 patients underwent hospitalization and surgery, respectively. Of the 1097 patients with B1/B2 disease behavior at diagnosis, 10.3% experienced phenotype progression. The hospitalization rate decreased after 2015; however, surgery and phenotype progression rates did not significantly change. A Cox regression analysis indicated that IFX use since diagnosis was a contributing factor for lower rates of hospitalization and phenotype progression, whereas thiopurine use was associated with a lower surgery rate.. Infliximab use was observed to increase as 5-ASA and corticosteroid use decreased. Additionally, hospitalization rates decreased following temporal changes in IFX management, yet the surgery and phenotype progression rates remained the same.

Topics: Cohort Studies; Crohn Disease; Gastrointestinal Agents; Hospitals; Humans; Immunologic Factors; Infliximab; Mercaptopurine; Prognosis; Retrospective Studies; Treatment Outcome

Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn's disease (CD). Reported effectiveness and tolerability rates have been variable across studies. There are only sparse data in Asian population regarding the long-term efficacy and safety of thiopurines.. Records of 5351 patients followed up at inflammatory bowel disease (IBD) clinic, All India Institute of Medical Sciences, New Delhi from 2004 to 2020 were evaluated retrospectively. Safety was evaluated in terms of long-term adverse events and development of malignancy.. Of 5351 patients with IBD, 1093 who received thiopurine for > 3 months (UC = 788 [proctitis-1.9%, left-sided colitis-44.9%, & pancolitis-53.1%] & CD = 305 [inflammatory-42.6%, stricturing-46.9%, & fistulizing-10.5%]) were included (60.8%-male patients). Follow up and treatment duration on thiopurine were 7 (4-12) years and 39.4 ± 40.3 months, respectively, with 254 (23.2%) patients receiving thiopurines for more than 5 and 68 (6.2%) receiving for more than 10 years. Three hundred and fifty-nine (UC: 249 [31.6%]; CD: 110 [36.1%]; P = 0.1) patients developed adverse events; commonest was myelosuppression (23.4%) followed by gastrointestinal intolerance (3%), flu-like illness (1.7%), and arthralgia/myalgia (1.4%). Myelosuppression was the commonest cause of thiopurine withdrawal. No patient (including 254 patients on thiopurine for ≥ 5 years) developed lymphoma or non-melanoma skin cancer. The cumulative probability of staying free from adverse events in overall IBD cohort at 1, 2, and 5 years was 78.6%, 71.9%, and 68.4%, respectively, and this was comparable between UC and CD (P = 0.09).. Long-term follow up of patients with IBD from northern India on thiopurine monotherapy demonstrated minimal risk of development of lymphoma as well as non-melanoma skin cancer.

Topics: Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Humans; India; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Retrospective Studies; Risk Factors; Skin Neoplasms

In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity.. We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival.. We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient.. Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase.. Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

Topics: Adolescent; Antimetabolites; Azathioprine; Biomarkers, Pharmacological; Child; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Female; Guanine Nucleotides; Humans; Male; Mercaptopurine; Netherlands; Retrospective Studies; Thionucleotides; Withholding Treatment

In Crohn's disease, combination therapy with anti-tumor necrosis factor (anti-TNF) agents and azathioprine/mercaptopurine has been shown to be superior to monotherapy with one of these treatments alone.

Topics: Azathioprine; Crohn Disease; Gastroenterologists; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Tumor Necrosis Factor Inhibitors

Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD.. To determine the durable clinical remission rate in adults with Crohn's disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years.. We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey-Bradshaw Index (HBI) < 5 points for CD and partial Mayo Score (pMS) < 2 points in UC). The primary endpoint was sustained clinical remission on thiopurines during a 5-year follow-up. This included patients who had not relapsed or discontinued the drug due to side effects. The secondary endpoint was clinical relapse over the follow-up period, which was defined as HBI > 5 in CD and pMS > 2 in UC.. There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug.. This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Agents; Humans; Male; Mercaptopurine; Middle Aged; Quebec; Recurrence; Remission Induction; Retrospective Studies; Time Factors; Treatment Outcome

Combining therapy with a thiopurine is favored when commencing infliximab in Crohn's disease; however, the optimal 6-thioguanine nucleotide (TGN) level and how long to continue thiopurines after induction are uncertain. We aimed to compare outcomes after induction and during maintenance in combination therapy versus infliximab monotherapy in Crohn's and to examine whether TGN levels were associated with outcomes.. Crohn's patients induced with infliximab with or without concomitant thiopurines were retrospectively identified. Response to induction and clinical outcomes in subsequent 6-month maintenance semesters were analyzed. A TGN level ≥235 pmol/8 × 10. In 89 patients, response to induction was higher in combination therapy than monotherapy (74 vs 47%, P = 0.04). This benefit was only seen in patients with a therapeutic TGN (odds ratio 3.72, confidence interval 1.07-13.0, P = 0.04). Combination therapy during induction yielded a three times longer time to subsequent need for treatment escalation or treatment failure compared with monotherapy (29 vs 9 months, P = 0.01), with both therapeutic and subtherapeutic TGNs independent predictors on multivariate analysis. Among 370 semesters, there was no difference in outcomes between combination therapy and monotherapy (P = 0.42), nor when combination semesters were stratified by therapeutic versus subtherapeutic TGN (P = 0.56). In semester 1 only, a significantly higher remission rate was observed with therapeutic compared with subtherapeutic TGN (76% vs 33%, P = 0.02).. Combination therapy dosed with an optimized thiopurine was superior to infliximab monotherapy for induction of response, durability of response, and clinical outcomes in the first 6 months following induction. Thereafter, combination therapy yielded no clinical advantage, supporting consideration of thiopurine withdrawal on a case-by-case basis.

Topics: Azathioprine; Biomarkers; Crohn Disease; Drug Therapy, Combination; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Male; Mercaptopurine; Remission Induction; Retrospective Studies; Thionucleotides; Treatment Outcome

Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX.. This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups.. One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001).. Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD.

Topics: Adult; Antimetabolites; Azathioprine; Biological Products; Crohn Disease; Drug Monitoring; Drug Synergism; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infliximab; Japan; Male; Mercaptopurine; Retrospective Studies; Risk Assessment; Treatment Outcome

In paediatric patients with Crohn's disease, the role of combination therapy, infliximab plus immunomodulators [thiopurine or methotrexate], is debated and data are sparse. We examined whether infliximab plus immunomodulators, compared to infliximab therapy alone, reduces the risk of treatment failure measured by intestinal surgery or switching type of anti-tumour necrosis factor [TNF] α agent within 24 months.. Using Danish registries, we identified patients with Crohn's disease, aged ≤ 20 years at the time of the first infliximab treatment, and retrieved data on their co-medications. We used Cox regression models to examine surgery or switching type of anti-TNFα agent from January 1, 2003 to December 31, 2015.. We included 581 patients. The 2-year cumulative percentage of surgery was 8.5% among patients receiving combination therapy and 14.5% in those receiving infliximab alone. The adjusted 2-year hazard ratio [HR] of surgeries was 0.53 (95% confidence interval [CI] 0.32-0.88) in patients receiving combination therapy, compared to patients receiving infliximab alone. When examining a switch of anti-TNFα we included 536 patients. Within 2 years, 18.3% experienced a switch among patients receiving combination therapy and 24.8% in patients treated with infliximab alone, corresponding to an adjusted HR of 0.66 [95% CI 0.45-0.97] in patients receiving combination therapy.. The HR of intestinal surgeries and the risk of a switch to another anti-TNFα was reduced in paediatric and adolescent patients receiving combination therapy, compared to patients receiving only infliximab. These results suggest a benefit for infliximab therapy combined with immunomodulators, but these need to be confirmed in data with additional clinical information.

Topics: Adalimumab; Adolescent; Azathioprine; Child; Crohn Disease; Denmark; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunologic Factors; Infliximab; Male; Mercaptopurine; Methotrexate; Treatment Failure; Tumor Necrosis Factor-alpha; Young Adult

Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn's disease (CD), including their impact on need for surgery.. Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines.. Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015).. Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Agents; Humans; Male; Mercaptopurine; Outcome Assessment, Health Care; Retrospective Studies; United Kingdom

Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child.. Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest.. Among 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51).. Biologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Biological Products; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Intestinal Mucosa; Mercaptopurine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Prospective Studies; United States

Topics: Azathioprine; Crohn Disease; Humans; Mercaptopurine

The additional value of azathioprine concomitant treatment on infliximab pharmacokinetics in children is not well described yet.. In the present study, we aimed to describe the relationship between thiopurine metabolite levels, infliximab trough levels, anti-IFX antibody formation, and clinical and laboratory markers of disease activity in pediatric patients with Crohn's disease, and to assess non-adherence.. Data were collected prospectively during repeated visits from pediatric patients followed for Crohn's disease in two Czech pediatric inflammatory bowel disease centers between January 2016 and June 2017. Thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine) were measured by high-performance liquid chromatography. Infliximab trough levels and anti-IFX antibody serum levels were measured routinely by ELISA. The risk of loss of response to infliximab therapy was also assessed.. A significant association between infliximab serum levels and 6-thioguanine erythrocyte levels was observed when tested as categorical variables (63 patients, 321 observations). To predict infliximab levels > 5 µg/mL, we propose a 6-thioguanine cutoff of 278 pmol/8 × 10. Thiopurine metabolite monitoring in pediatric patients with Crohn's disease is useful when optimizing combination therapy. Pediatric patients with undetectable 6-thioguanine levels are more likely to lose response to infliximab therapy. When targeting optimal infliximab levels, the 6-thioguanine cutoff levels in children appear to be higher than in adults.

Topics: Adolescent; Azathioprine; Biomarkers; Child; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunologic Factors; Infliximab; Longitudinal Studies; Male; Mercaptopurine; Prospective Studies

Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression, and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, and thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations.. We performed fluorescence-activated cell sorting or CyTOF analysis on blood from 728 Crohn's disease, 464 ulcerative colitis, and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use.. We observed few immune cell types commonly affected in IBD (lowered natural killer cells, B cells, and CD45RA. We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs.

Topics: Adult; B-Lymphocytes; Case-Control Studies; Cohort Studies; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Female; Humans; Immune System; Immunophenotyping; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Severity of Illness Index; Surveys and Questionnaires; T-Lymphocytes; Tumor Necrosis Factor-alpha

A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was successfully treating her Crohn's disease. We measured MP and its metabolites in plasma and breast milk and found after 4 hours of intake of MP, no MP or its metabolites in breast milk. We concluded that 4 hours after intake of MP, no exposure of the suckling infant to MP and its metabolites was found while being breastfed.

Topics: Adult; Breast Feeding; Crohn Disease; Female; Humans; Infant; Lactation; Mercaptopurine; Milk, Human; Pregnancy

Thiopurines are drugs widely used in patients for the maintenance of remission in inflammatory bowel disease. The optimal plasma levels are known, but there is controversy about whether the need for other drugs is reduced or is cost-effective. The aim of this study is to describe the use of the optimised treatment with thiopurines in paediatric patients with inflammatory bowel disease followed up in this Unit since the introduction of determining the drug levels.. A descriptive retrospective study was conducted in which the plasma values of 6-thioguanine (6-TGN), 6-methyl-mercapto-purine (6-MMP), and their ratios were analysed using liquid chromatography. Other variables were collected, such as clinical status, analytical and demographic variables of patients with inflammatory bowel disease followed up in this Unit.. A total of 72 patients were included, and 149 determinations of metabolites were performed. The 6-TGN levels were found to below the therapeutic range in 61.5% of patients (in 7 cases due to lack of adherence to therapy), and 6-MMP was in the toxicity range in 7.4%. After the determination of 77 specimens, some action was taken, such as modifying the dose, change of formula, or withdrawing the drug. Only 9 patients were scaled to a biological drug (13.4% of the total on single therapy). No association was found between the activity of the disease and the thiopurine levels.. In our experience, the monitoring of thiopurine levels helped to modify the drug dose that the patient received, adjusting their therapeutic levels, and potentially avoiding the addition of new drugs.

Topics: Adolescent; Child; Child, Preschool; Chromatography, Liquid; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

Patients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn's disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan.. Patients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population.. A total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1).. There is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients.

Topics: Adalimumab; Adult; Aged; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Databases, Factual; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Incidence; Infliximab; Japan; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Risk Factors; Skin Neoplasms; Tumor Necrosis Factor-alpha

Thiopurine and allopurinol in combination are associated with clinical remission in inflammatory bowel diseases but their influence on subsequent outcomes is unclear. We compared outcomes during exposure to both thiopurines and allopurinol versus thiopurines alone.. We established a nationwide cohort of patients with inflammatory bowel diseases exposed to thiopurines ± allopurinol during 1999-2014, using registry data. Patients were followed until hospitalization, surgery, anti-TNFα, or death (as a primary composite outcome). We used Poisson regression analyses to calculate incidence rate ratios overall and stratified by calendar period (assuming the combined exposure was unintended before 2009).. A total of 10,367 patients with inflammatory bowel diseases (Crohn's disease,. Our nationwide inflammatory bowel disease cohort study shows that concomitant thiopurine-allopurinol is as safe to use as thiopurines alone, with a tendency towards a positive effect on clinical outcomes in recent calendar periods when combined use was intended.

Topics: Adult; Allopurinol; Azathioprine; Colitis, Ulcerative; Crohn Disease; Denmark; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Remission Induction; Severity of Illness Index; Signal Transduction; Thioguanine; Treatment Outcome

Topics: Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Treatment Outcome; Vulva; Young Adult

Thiopurines, alone or in combination with other agents, have a pivotal role in the treatment of specific gastrointestinal and hepatological disorders. In inflammatory bowel disease and autoimmune hepatitis thiopurines have proven their value as steroid sparing agents for the maintenance of remission and may be considered for preventing postoperative Crohn disease recurrence where there is moderate risk of this occurring. Their use with infliximab therapy reduces antibody formation and increases biologic drug levels. The routine clinical use of thiopurines has, however, been questioned due to a number of potential adverse effects. The aim of this article is to provide information regarding the use, and in particular, safety of these agents in clinical practice in the light of such potentially severe, albeit rare, effects.

Topics: Azathioprine; Child; Crohn Disease; Gastrointestinal Agents; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Recurrence

Patients with Crohn's disease experiencing endoscopic postoperative recurrence (POR) may benefit from antitumor necrosis factor (TNF) agents but scarce data on this are available. Our aim was to assess the efficacy of anti-TNF in improving mucosal lesions in patients with endoscopic POR.. Multicenter, retrospective, study of patients with Crohn's disease who underwent therapy with anti-TNF agents for endoscopic POR (Rutgeerts score > i1). Treatment outcomes were assessed by the findings in the last ileocolonoscopy performed after anti-TNF therapy was initiated. Endoscopic improvement and remission were defined as any reduction in the baseline Rutgeerts score and by a Rutgeerts score < i2, respectively.. A total of 179 patients were included, 83 were treated with infliximab and 96 with adalimumab. Median time on anti-TNF therapy at the last endoscopic assessment was 31 months (interquartile range, 13-54). Endoscopic improvement was observed in 61%, including 42% who achieved endoscopic remission. Concomitant use of thiopurines and treatment with infliximab were associated with endoscopic improvement (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.04-4.46; P = 0.03, and OR 2.34, 95% CI 1.18-4.62; P < 0.01, respectively) and endoscopic remission (OR 3.16, 95% CI 1.65-6.05; P < 0.01, and OR 2.01, 95% CI 1.05-3.88; P = 0.04, respectively) in the multivariable logistic regression analysis. These results were confirmed in a propensity-matched score analysis.. In patients with endoscopic POR, anti-TNF agents improve mucosal lesions in almost two-thirds of the patients. In this setting, concomitant use of thiopurines and use of infliximab seem to be more effective in improving mucosal lesions.

Topics: Adalimumab; Adolescent; Adult; Anti-Inflammatory Agents; Colonoscopy; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Intestinal Mucosa; Male; Mercaptopurine; Propensity Score; Recurrence; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

The prevalence of Crohn disease (CD) is increasing in Asia, but data from Southeast Asian population are scarce.The databases of 2 university-based national tertiary referral centers located in Bangkok, Thailand, were retrospectively reviewed for adult patients diagnosed with CD during January 2000 to December 2017. Disease characteristics, diagnosis, treatment, and outcomes were described and compared between the 2000 to 2009 cohort (cohort A) and the 2010 to 2017 cohort (cohort B).One hundred eighty-two patients (mean age: 46.4 years, 50% male) with 993 patient-years of follow-up were included. Thirteen percent had a history of intestinal resection, but were not diagnosed until disease recurrence. Another 6% were diagnosed at the time of first surgery. There was no improvement in diagnostic proficiency between cohorts. Mesalamine, corticosteroids, thiopurines, and biologics were prescribed in 75.8%, 81.3%, 84.6%, and 13.7% of patients, respectively (P > .05 between cohorts). Notably, thiopurines were started earlier in cohort B. Median time to the start of thiopurines was 6.2 and 1.65 months in cohort A and B, respectively (P < .01). However, the cumulative 5-year rates of disease behavior progression (P = .43), hospitalization (P = .14), and bowel surgery (P = .29) were not significantly different between cohorts. Subgroup analysis including only patients who required thiopurines showed the early use of thiopurines to be associated with lower risk of intestinal surgery after diagnosis (hazard ratio: 0.30, 95% confidence interval: 0.11-0.85).Early disease recognition and early introduction of immunomodulators may prevent long-term complications and reduce unnecessary surgery in CD.

Topics: Adult; Crohn Disease; Digestive System Surgical Procedures; Female; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Thailand

Thiopurines, commonly used to treat inflammatory bowel disease, cause lymphopenia and red blood cell macrocytosis, requiring therapeutic monitoring. Mean corpuscular volume/white blood cell (MCV/WBC) ratio has been proposed as a surrogate for therapeutic monitoring. Our aim was to investigate MCV/WBC ratio for assessing clinical response to thiopurines among pediatric patients with inflammatory bowel disease.. We performed a retrospective cross-sectional study at a tertiary care center using laboratory results and standardized physician global assessments (PGA) among pediatric patients taking thiopurines. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin, and 6-thioguanine nucleotides were assessed when available. The primary outcome was association between MCV/WBC ratio and clinical remission assessed by ESR, CRP, calprotectin, or PGA. We also used a composite outcome requiring all available data to be normal. Analyses were limited to 1 occurrence per patient, >60 days after starting thiopurine, and comparators were required to be within 14 days of one another.. A total of 471 patients met inclusion criteria. MCV/WBC ratio poorly predicted quiescent disease as defined by PGA (area under receiver operating characteristic curve [AuROC] 0.55, 95% confidence interval [CI] 0.43-0.66). MCV/WBC ratio better predicted quiescent disease defined as normal CRP (AuROC 0.64, 95% CI 0.58-0.70) or normal ESR (AuROC 0.59, 95% CI 0.52-0.66). When the composite outcome measure was used, MCV/WBC ratio had an AuROC of 0.65 (95% CI 0.59-0.70), indicating it is reasonably accurate in discriminating between clinical remission and active disease.. MCV/WBC ratio is a noninferior, easy, and low-cost alternative to thiopurine metabolite monitoring.

Topics: Adolescent; Area Under Curve; Azathioprine; C-Reactive Protein; Child; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Erythrocyte Indices; Feces; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Leukocyte Count; Leukocyte L1 Antigen Complex; Male; Mercaptopurine; Predictive Value of Tests; Retrospective Studies; ROC Curve; Severity of Illness Index; Thionucleotides; Young Adult

Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.. The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure.. We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004).. Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes.. Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion.

Topics: Adalimumab; Adult; Age Factors; Antibodies; Azathioprine; Cohort Studies; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Factors; Serum Albumin; Smoking; Treatment Failure; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Young Adult

Off-label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off-label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before.. To assess the proportion and characteristics of off-label prescribing for IBD in tertiary care centres in the Netherlands.. A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off-label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni- and multivariable analyses were used to identify patient-specific characteristics predictive of increased off-label use.. For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off-label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off-label drugs. Commonly prescribed off-label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non-thiopurine/methotrexate off-label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off-label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off-label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001).. About one-fifth of prescriptions for IBD were off-label and one-third of IBD patients, especially ulcerative colitis patients, were exposed to off-label drugs.

Topics: Adolescent; Adult; Allopurinol; Beclomethasone; Colitis, Ulcerative; Crohn Disease; Databases, Factual; Female; Humans; Male; Mercaptopurine; Methotrexate; Netherlands; Off-Label Use; Thioguanine; Young Adult

A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration.. We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation.. The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months.. NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Erythrocyte Indices; Female; Gastrointestinal Agents; Genetic Predisposition to Disease; Heterozygote; Humans; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Middle Aged; Mutation, Missense; Pyrophosphatases; Retrospective Studies; Risk Factors; Time Factors; Tokyo; Treatment Outcome; Young Adult

The aim of this study was to assess whether sustained 6-thioguaninenucleotide (6-TGN) levels were associated with improved long-term outcomes in patients with inflammatory bowel diseases (IBD).. Cross-sectional data have shown that thiopurine metabolites are correlated with clinical efficacy in patient receiving thiopurines for IBD but the role for serial measurements through treatment course is unclear.. We conducted a retrospective cohort study including patients with IBD on thiopurine monotherapy and had serial 6-TGN levels measured. Predictive variables included demographics, disease phenotype, 6-TGN levels (nadir, median, and peak levels). The primary outcome was the development of a disease relapse. The secondary outcome was the need for IBD surgery.. Two hundred eighteen 6-TGN samples from 87 patients were analyzed. Nadir and median 6-TGN levels were significantly higher in patients who did not relapse [185 and 233 pmol per 8×10 red blood cells (RBCs)] as compared with levels in patients who did relapse (150 and 167 pmol per 8×10 RBCs, P=0.025) but there was no significant difference in peak 6-TGN level. When adjusted for confounding factors, a nadir 6-TGN level ≥161 and a median 6-TGN level ≥264 were associated with a significant decrease in the rate of disease exacerbation (hazard ratio: 0.5; 95% confidence interval, 0.26-0.87; P=0.016 and hazard ratio: 0.4; 95% confidence interval, 0.2-0.82; P=0.14).. Serial thiopurine metabolite level assessments and dose adjustment aiming to maintain higher 6-TGN levels may be helpful to improve long-term outcomes in patients with IBD.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Biomarkers; Colitis, Ulcerative; Crohn Disease; Digestive System Surgical Procedures; Drug Monitoring; Female; Gastrointestinal Agents; Guanine Nucleotides; Humans; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Predictive Value of Tests; Recurrence; Remission Induction; Retrospective Studies; Thionucleotides; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR.. This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors.. A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001).. Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

Topics: Adolescent; Adult; Aged; Azathioprine; Cohort Studies; Colectomy; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestine, Small; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Observational Studies as Topic; Recurrence; Retrospective Studies; Risk Factors; Secondary Prevention; Young Adult

Topics: Acute Disease; Adult; Azathioprine; Budesonide; Crohn Disease; Drug Substitution; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Sialadenitis; Submandibular Gland; Ultrasonography

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine

The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of. Ninety-six Japanese patients with IBD were enrolled. Genotyping for the. Genetic variants of exon 1 and exon 3 of. Mutations in exon 1 of

Topics: Adolescent; Adult; Aged; Asian People; Child; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Erythrocyte Indices; Exons; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Immunosuppressive Agents; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methyltransferases; Middle Aged; Nudix Hydrolases; Polymorphism, Single Nucleotide; Prednisolone; Pyrophosphatases; Retrospective Studies; Risk Factors; Young Adult

Two meta-analyses have found that the risk of relapse in Crohn's disease (CD) was ~40 and 50% 1 and 2 years, respectively, after withdrawal of anti-tumour necrosis factor-α (anti-TNFα). The aim of this study was to evaluate relapse rates in CD when thiopurine therapy was optimized before anti-TNFα withdrawal.. An observational study was conducted including patients with CD in remission with optimized thiopurine therapy before anti-TNFα withdrawal. We defined optimized thiopurine therapy as 6-thioguanine levels of at least 150 nmol/mmol haemoglobin (∼300 pmol×10 red blood cells) and clinical/biochemical remission as Harvey-Bradshaw Index of 5 or less and faecal calprotectin of 200 µg/g or less.. We included 33 patients (median age: 31 years, 55% males, and median disease duration: 7 years) followed for a median of 36 months. A total of three (9%) patients relapsed during the first year and six patients (in total 27%) relapsed after 2 years. After 2 years, none of the additional patients relapsed. The disease duration and duration of anti-TNFα treatment and faecal calprotectin levels before inclusion did not predict relapse. Calprotectin levels of at least 180 after 1 year predicted relapse at year 2.. This study found that 73% of patients with CD maintained remission (>2 years) when thiopurine therapy was optimized before withdrawal of anti-TNFα. Additional prospective evidence is needed to confirm the findings.

Topics: Adalimumab; Adult; Crohn Disease; Feces; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Leukocyte L1 Antigen Complex; Male; Mercaptopurine; Recurrence; Thioguanine; Tumor Necrosis Factor-alpha; Withholding Treatment; Young Adult

Topics: Adult; Allopurinol; Crohn Disease; Drug Therapy, Combination; Enzyme Inhibitors; Focal Nodular Hyperplasia; Humans; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine

Topics: Adult; Biomarkers; C-Reactive Protein; Clinical Competence; Crohn Disease; Fatal Outcome; Humans; Immunosuppressive Agents; Interdisciplinary Communication; Male; Medical Errors; Medication Errors; Mercaptopurine; Methyltransferases; Nurse's Role; Nurses; Patient Care Team; Personnel Management

Topics: Adult; Antibodies, Monoclonal, Humanized; Crohn Disease; Digestive System Surgical Procedures; Female; Glucocorticoids; Humans; Infusions, Intravenous; Jejunum; Male; Mercaptopurine; Pancreatitis; Recurrence; Risk Assessment; Young Adult

Crohn's disease (CD) frequently manifests in the second and third decades of life. Malnutrition and corticosteroid therapy may affect bone mineralization and delay bone growth. Our aim was to study bone mineral density and factors associated low bone mineral density (BMD) in pediatric CD.. A cross-sectional observational study in children with CD (aged 5 to <18 years) was done. Demographic and treatment details were noted. Vitamin D levels <20 ng/mL were considered as deficiency. Bone mineral density was evaluated with dual-energy X-ray absorptiometry (DEXA) scan and Z score of <-2 SD was considered as low BMD. Data was analyzed descriptively.. In 30 cases with CD enrolled over 1 year, mean age of the patients was 13.8±3.0 years. Age of onset and diagnosis was 11.4±3.2 years and 13.4±2.8 years, respectively. 73.3% were in the underweight category. All cases received azathioprine whereas 86.7% were receiving corticosteroids. Vitamin D deficiency was seen in 86.7% cases. A low BMD was evident in 70% children. Overall, low BMI (p=0.005) and vitamin D deficiency (p=0.005) were associated with low BMD. However, no association between severity grade of vitamin D deficiency and low BMD was found. Treatment with corticosteroid was associated with low BMD in 76.9% cases (p=0.069).. Low BMD was frequent in children with CD and was associated with low BMI and vitamin D deficiency.

Topics: Absorptiometry, Photon; Adolescent; Body Mass Index; Bone Density; Child; Child, Preschool; Crohn Disease; Cross-Sectional Studies; Female; Glucocorticoids; Humans; India; Male; Mercaptopurine; Vitamin D Deficiency

The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohn's disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs).. Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 10 red blood cell therapeutic).. At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41-13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01-1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87-7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08-0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure.. Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.

Topics: Adalimumab; Adolescent; Adult; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome; Young Adult

Most Crohn's disease (CD) patients develop endoscopic recurrence within one year of intestinal resection. The best treatment method to prevent post-operative CD recurrence remains uncertain.. A total of 155 CD patients from 2 referral centres, who were undergoing intestinal resection with ileo-colonic anastomosis (January 2004-January 2015), were included. All subjects received preventive therapy with tumour necrosis factor antagonists (anti-TNFs), thiopurinesor mesalazine. The primary outcome was the rate of endoscopic recurrence (Rutgeerts score ≥i2) in the 3 treatment groups.. Patients treated with anti-TNFs were at significantly lower risk of endoscopic recurrence during the follow-up than those receiving thiopurines or mesalazine (incidence rates of 2.2, 3.0 and 4.8 per 100 person-months, respectively, log-rank, p = 0.011). The median time to recurrence was significantly longer in patients treated with anti-TNFs than in those who received thiopurines or mesalazine (37.0, 13.7, and 16.8 months, respectively, log-rank, p = 0.011). Anti-TNFs were more effective than mesalazine (univariable analysis, hazard ratio [HR] 0.45, 95% CI 0.26-0.77, p = 0.004; multivariable analysis, HR 0.45, 95% CI 0.26-0.77, p = 0.004), and non-significantly superior over thiopurines.. Anti-TNF therapy was the most effective strategy for the prevention of endoscopic CD recurrence.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colectomy; Colonoscopy; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Postoperative Period; Proportional Hazards Models; Recurrence; Retrospective Studies; Secondary Prevention; Treatment Outcome; Tumor Necrosis Factor-alpha

Postoperative recurrence of Crohn's disease is common. This study sought to assess whether the postoperative management should be based on biological therapy alone or combined with thiopurines and whether the therapy should be started immediately after surgery or guided by either endoscopic or clinical recurrence.. A Markov model was developed to estimate expected health outcomes in quality-adjusted life years (QALYs) and costs in Canadian dollars (CAD$) accrued by hypothetical patients with high recurrence risk after ileocolic resection. Eight strategies of postoperative management were evaluated. A lifetime time horizon, an annual discount rate of 5%, a societal perspective, and a cost-effectiveness threshold of 50,000 CAD$/QALY were assumed. Deterministic and probabilistic sensitivity analyses were conducted. The model was validated against randomized trials and historical cohorts.. Three strategies dominated the others: endoscopy-guided full step-up therapy (14.80 QALYs, CAD$ 462,180), thiopurines immediately post-surgery plus endoscopy-guided biological step-up therapy (14.89 QALYs, CAD$ 464,099) and combination therapy immediately post-surgery (14.94 QALYs, CAD$ 483,685). The second strategy was the most cost-effective, assuming a cost-effectiveness threshold of 50,000 CAD$/QALY. Probabilistic sensitivity analysis showed that the second strategy has the highest probability of being the optimal alternative in all comparisons at cost-effectiveness thresholds from 30,000 to 100,000 CAD$/QALY. The strategies guided only by clinical recurrence and those using biologics alone were dominated.. According to this decision analysis, thiopurines immediately after surgery and addition of biologics guided by endoscopic recurrence is the optimal strategy of postoperative management in patients with Crohn's disease with high risk of recurrence (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B654).

Topics: Adult; Biological Therapy; Canada; Cost-Benefit Analysis; Crohn Disease; Decision Support Techniques; Endoscopy; Female; Humans; Male; Markov Chains; Mercaptopurine; Postoperative Period; Quality-Adjusted Life Years; Recurrence; Thioguanine

Topics: Antibodies, Monoclonal; Azathioprine; Biosimilar Pharmaceuticals; Crohn Disease; Gastrointestinal Agents; Humans; Infliximab; Mercaptopurine; Treatment Outcome

Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of antidrug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown.. This was a retrospective observational multicenter study of patients with Crohn's disease (CD) treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de novo combination, or IFX monotherapy. The primary endpoint was risk of ADA appearance.. Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1-year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared with past thiopurine failures (16.1%) (log rank P = .54). ADA was found in 46.6% of the monotherapy group and was significantly different compared with past thiopurine responders (P = .007) and past thiopurine failures (P = .007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group (hazard ratio, 0.47 [95% CI, 0.22-1.00] and 0.32 [95% CI, 0.11-0.93], respectively).. Thiopurines-IFX cotherapy in patients with Crohn's disease is associated with reduced ADA formation compared with IFX monotherapy. This is probably regardless of initial thiopurine therapeutic effect.

Topics: Adolescent; Adult; Antibody Formation; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunologic Factors; Infliximab; Male; Mercaptopurine; Retrospective Studies; Treatment Outcome; Young Adult

Thiopurines are commonly used drugs in the therapy of Crohn's disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn's disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn's disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn's disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment.

Topics: Alleles; Animals; Autophagy; Autophagy-Related Proteins; Cell Membrane Structures; Cell Movement; Cells, Cultured; Colitis, Ulcerative; Crohn Disease; Cytoskeleton; Dendritic Cells; Female; Genetic Predisposition to Disease; Humans; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Knockout; Polymorphism, Genetic; rac1 GTP-Binding Protein; Risk; RNA, Small Interfering

Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited.. To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease.. Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease.. One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046).. In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.

Topics: Adult; Aged; Azathioprine; Cohort Studies; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Treatment Failure

Anti-adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking.. To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients.. The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as 'sero-reversal', elevation of drug levels and regained clinical response were the sought outcomes.. Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics.. In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies.

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunologic Factors; Male; Mercaptopurine; Methotrexate; Treatment Outcome; Young Adult

Medical treatment options and strategies for Crohn's disease (CD) have changed over the past decades. To assess its impact, we studied the evolution of the long-term disease outcome in the Dutch Inflammatory Bowel Disease South Limburg (IBDSL) cohort.. In total, 1,162 CD patients were included. Three eras were distinguished: 1991-1998 (n=316), 1999-2005 (n=387), and 2006-2011 (n=459), and patients were followed until 2014. Medication exposure and the rates of hospitalization, surgery, and phenotype progression were estimated using Kaplan-Meier survival analyses and compared between eras by multivariable Cox regression models. Second, propensity score matching was used to assess the relation between medication use and the long-term outcome.. Over time, the immunomodulator exposure rate increased from 30.6% in the era 1991-1998 to 70.8% in the era 2006-2011 at 5 years. Similar, biological exposure increased from 3.1% (era 1991-1998) to 41.2% (era 2006-2011). In parallel, the hospitalization rate attenuated from 65.9% to 44.2% and the surgery rate from 42.9% to 17.4% at 5 years, respectively (both P<0.01). Progression to a complicated phenotype has not changed over time (21.2% in the era 1991-1998 vs. 21.3% in the era 2006-2011, P=0.93). Immunomodulator users had a similar risk of hospitalization, surgery, or phenotype progression as propensity score-matched nonusers (P>0.05 for all analyses). Similar results were found for biological users (P>0.05 for all analyses).. Between 1991 and 2014, the hospitalization and surgery rates decreased, whereas progression to complicated disease is still common in CD. These improvements were not significantly related to the use of immunomodulators and biologicals.

Topics: Adalimumab; Adult; Antirheumatic Agents; Azathioprine; Biological Products; Crohn Disease; Digestive System Surgical Procedures; Female; Glucocorticoids; Hospitalization; Humans; Immunologic Factors; Infliximab; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Middle Aged; Multivariate Analysis; Netherlands; Prednisone; Propensity Score; Proportional Hazards Models; Severity of Illness Index; Young Adult

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.

Topics: Adult; Apoptosis; Caspase 3; Caspase 9; Crohn Disease; Humans; Immunosuppressive Agents; Killer Cells, Natural; Mercaptopurine; Middle Aged; rac1 GTP-Binding Protein; Young Adult

The ENCORE registry aimed at comparing the long-term safety of Crohn's disease [CD] treatment with infliximab [Remicade®] and with conventional therapies in real-world clinical practice.. The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories.. Patients who received infliximab [N = 1541], conventional therapies [N = 1121], or switched to infliximab [N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure-adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]).. Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade®] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azathioprine; Crohn Disease; Demyelinating Diseases; Drug Substitution; Drug Therapy, Combination; Female; Gastrointestinal Agents; Hematologic Diseases; Humans; Immunosuppressive Agents; Infections; Infliximab; Infusions, Intravenous; Lymphoproliferative Disorders; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Mortality; Narcotics; Prednisone; Prospective Studies; Registries; Risk Factors; Sulfasalazine; Time Factors; Young Adult

This study assessed the efficacy and safety of methotrexate (MTX) compared with thiopurines (TPs) for refractory Crohn's disease.. Fifty-one consecutive patients who were refractory or intolerant to TPs and steroid-dependent were retrospectively analyzed. MTX (20 mg/wk, subcutaneous) was adopted for inducing and maintaining clinical remission (CR). Fifty-seven patients who were naive to immunosuppressant and prescribed azathioprine (2 mg·kg·d) or mercaptopurine (1 mg·kg·d) were simultaneously recruited.. By week 16, the CR rate was 68.6% and 78.9% in the MTX and TPs groups, respectively (P = 0.222). Patients with disease duration ≤3 years were more likely to achieve CR with MTX (odds ratio = 7.667, P = 0.019). By week 64, the CR rate of patients achieved remission at week 16 was 45.7% and 44.4% in the MTX and TPs groups, respectively (P = 0.910). Normalization of high-sensitivity C-reactive protein level (relative risk = 11.221, P = 0.003) and platelet count (relative risk = 9.672, P = 0.004) at week 16 predicted the efficacy of maintaining remission with MTX. Among patients with remission at week 16, the mucosal healing rates at week 36 were 47.4% with MTX and 47.1% with TPs (P ≈ 1.000). Fifteen (29.4%) patients on MTX and 25 (43.9%) on TPs experienced adverse events (P = 0.121).. MTX is effective in inducing and maintaining CR and achieving mucosal healing in patients with refractory Crohn's disease, and its efficacy is comparable to that of TPs for naive patients. The side effects of MTX were mild and tolerable.

Topics: Adult; Azathioprine; Crohn Disease; Drug Resistance; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Male; Mercaptopurine; Methotrexate; Quality of Life; Research Design; Retrospective Studies; Treatment Outcome; Young Adult

Evidence that thiopurines impact on the risk of surgery in elderly onset inflammatory bowel disease (EO-IBD) is lacking. We aimed to compare the rates of surgery in EO-IBD (>60 years at diagnosis) with adult-onset IBD (18-59 yrs), and examine the impact of thiopurines on surgical risk in EO-IBD.. Using a U.K. database between 1990 and 2010, we compared rates of surgery between adult-onset IBD and EO-IBD using survival analysis. Ulcerative colitis (UC) and Crohn's disease (CD) were analyzed separately. Cox proportional hazard modeling was used to determine the adjusted relative risk of surgery. We further assessed the impact of duration of thiopurine treatment on risk of surgery.. We identified 2758 of 9515 patients with UC and 1349 of 6490 patients with CD, with EO-IBD. Cumulative 1, 5, and 10 years risk of colectomy was similar in EO-UC (2.2, 4.5, and 5.8%, respectively) and AO-UC (2.2, 5.0, and 7.3%, respectively; P = 0.15). Cumulative 1, 5, and 10 years risk of first intestinal surgery was lower in EO-CD (9.5, 14.6, and 17.9%, respectively) than AO-CD (12.2, 19.0, and 24.4%, respectively; P < 0.001). Early steroid use, steroid dependency, and thiopurine use was associated with higher risk of colectomy in EO-UC. Among EO-UC receiving thiopurines for >12 months, there was a 70% reduction in risk of colectomy (hazard ratio. 0.30; 95% confidence interval, 0.15-0.58). Thiopurines were not associated with a reduced risk of surgery in EO-CD.. Risk of colectomy in EO-UC does not differ from AO-UC, but the risk of surgery in EO-CD is significantly lower than in AO-CD. Sustained thiopurine use of 12 months or more duration in EO-UC reduces the risk colectomy, but does not impact on the risk of surgery in EO-CD. These findings are important given the greater risk of thiopurine-associated lymphoma in the elderly.

Topics: Adolescent; Adult; Age Factors; Aged; Azathioprine; Cohort Studies; Colectomy; Colitis, Ulcerative; Crohn Disease; Databases, Factual; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Risk Factors; Survival Analysis; United Kingdom; Young Adult

We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication.

Topics: Adalimumab; Anti-Inflammatory Agents; Crohn Disease; Epstein-Barr Virus Infections; Humans; Immunologic Factors; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Rituximab; Young Adult

The present study evaluated the clinical characteristics of Korean patients with Crohn's disease (CD) according to their age at diagnosis in a nationwide multicenter cohort study.. A total of 1224 patients diagnosed with CD between 1982 and 2008 in 32 hospitals were included, and age at diagnosis was categorized as ≤ 16 (G1), 17-40 (G2), 41-59 (G3) and ≥ 60 (G4) years old. The baseline characteristics, medication, and intestinal resection were compared according to the age at diagnosis.. The number of patients in each age group was 155 (G1; 12.7%), 919 (G2; 75.1%), 120 (G3; 9.8%), and 30 (G4; 2.5%). The frequencies of ileocolonic disease in the late adult onset and elderly onset groups were lower than those in the other groups (P < 0.001). The cumulative probabilities of thiopurine and anti-tumor necrosis factor use in late adult onset and elderly onset groups were significantly reduced compared with those of the other groups (P < 0.01). However, the risk of the first intestinal resection was not different among the age groups. The ileal location (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.11-2.27), complicated behavior (HR: 3.35; 95% CI: 2.63-4.27), and early thiopurine use (HR: 0.27; 95% CI: 0.17-0.43) were associated with the first intestinal resection, whereas the age at diagnosis was not a risk factor.. Elderly onset CD may be related to favorable outcomes in Korea. Thus, the heterogeneity of this disease should be considered when developing a tailored strategy for the treatment of CD.

Topics: Adalimumab; Adolescent; Adult; Age of Onset; Azathioprine; Cohort Studies; Crohn Disease; Digestive System Surgical Procedures; Female; Follow-Up Studies; Humans; Infliximab; Intestines; Male; Mercaptopurine; Middle Aged; Multicenter Studies as Topic; Prognosis; Republic of Korea; Time Factors; Young Adult

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Postoperative Period; Smokers

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child; Crohn Disease; Drug Administration Schedule; Drug Monitoring; Drug Resistance, Multiple; Gastrointestinal Agents; Growth Disorders; Humans; Immunosuppressive Agents; Induction Chemotherapy; Injections, Subcutaneous; Maintenance Chemotherapy; Male; Mercaptopurine; Remission Induction; Ustekinumab

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with t

Topics: Adult; Alopecia; Anti-Inflammatory Agents; Asian People; Azathioprine; Chi-Square Distribution; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Japan; Kaplan-Meier Estimate; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Pyrophosphatases; Risk Factors; Severity of Illness Index; Treatment Outcome; Young Adult

The intracellular N-terminal domain of the nucleoside and drug transporter human concentrative nucleoside transporter (hCNT)3 was used as bait in a glutathione S-transferase pull-down approach, to identify hCNT3 protein partners, using human colon homogenates as a prey source. Galectin (Gal)-4 was identified as a potential hCNT3 partner in the colon. The biochemical validation of the Gal-4-hCNT3 interaction was verified by targeted pull-down assays and coimmunoprecipitation experiments in HT-29 cells, which endogenously express hCNT3 and Gal-4. Furthermore, Gal-4 was shown to colocalize with hCNT3 in HT-29 cells. The biologic significance of this interaction was obtained from experiments in which Gal-4 was knocked down, showing that this protein is a regulator of hCNT3 trafficking and retention at the cell membrane, reducing its plasma membrane location by 70%. Conversely, the addition of Gal-4 increased hCNT3 location at the plasma membrane by 77%, thereby demonstrating that this lectin modulates hCNT3 function in colonic cells. The integrity of this partnership may be clinically relevant, because hCNT3 may be responsible for the translocation of thiopurines, such as 6-mercaptopurine, a front-line treatment in inflammatory bowel disease. The expression of Gal-4 and hCNT3 proteins is not impaired in inflamed colon from patients with Crohn's disease, thereby anticipating the integrity of this system for drug targeting.

Topics: Colon; Crohn Disease; Galectin 4; Gene Expression Regulation; Gene Knockdown Techniques; HT29 Cells; Humans; Membrane Transport Proteins; Mercaptopurine; Protein Transport; RNA Interference

Early stages of Crohn's disease [CD] are predominantly inflammatory and early treatment could be useful to change the natural history of CD. We aimed to evaluate the impact of early treatment in our cohort of CD patients.. We retrospectively reviewed clinical records of all CD patients at our centre who have received immunomodulators. Time from diagnosis to first CD-related major abdominal surgery or end of follow-up was considered. Dates of diagnosis, of starting immunomodulators (thiopurines / anti-tumour necrosis factor [TNF]), and of the first CD-related surgery when appropriate were collected.. Of 422 patients who received thiopurines, 189 operated patients started thiopurines after a median of 117 months (interquartile range [IQR] 44-196) since diagnosis; non-operated patients, after a median of 30 months [IQR 6-128], p < 0,005. Odds ratio [OR] for surgery was 1.006 (95% confidence interval [CI]1.004-1008) for each month of delay in starting thiopurines. Among 272 patients who received anti-TNFs, 137 operated patients started anti-TNFs after a median of 166 months [IQR 90-233] since diagnosis; non-operated patients after a median of 59 months [IQR 14-162]; p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting anti-TNFs. Among 467 patients who received thiopurines and/or anti-TNF, 210 operated patients started any immunomodulator after a median of 120 months [IQR 48-197] since diagnosis and non-operated patients after a median of 30 months [IQR 6-126], p < 0,005. OR for surgery was 1.008 [95% CI 1.005-1.010] for each month of delay in starting immunomodulators.. In our experience, time between diagnosis and thiopurine or anti-TNF initiation was associated with the risk of major abdominal surgery in Crohn's disease.

Topics: Adult; Analysis of Variance; Azathioprine; Cohort Studies; Colectomy; Crohn Disease; Databases, Factual; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Laparotomy; Logistic Models; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Retrospective Studies; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

The aims of this study were to evaluate the frequency of entero-urinary fistulas in a cohort of Crohn's disease (CD) patients and to analyse the outcomes of medical and surgical therapy.. This multicentre retrospective study included all CD patients with entero-urinary fistulas diagnosed by the presence of clinical symptoms and confirmed at surgery or by radiological or endoscopic techniques. We evaluated outcomes of medical and surgical therapy. We defined remission as absence of clinical symptoms with a radiological confirmation of fistula closure. Cox regression analysis was performed to evaluate factors predictive of achieving remission without need for surgery.. Of 6081 CD patients screened, 97 had entero-urinary fistulas (frequency 1.6%). Seventy-five percent of fistulas occurred in men. After a median follow-up of 91 months, 96% of patients were in sustained remission. Thirty-three patients (35%) received anti-tumour necrosis factor (TNF) therapy. Of these, 45% achieved sustained remission (median follow-up 35 months) without needing surgery. More than 80% of patients required surgery, which induced remission (median follow-up 101 months) in 99% of them. Only the use of anti-TNF agents was associated with an increased rate of remission without need for surgery (hazard ratio 0.23, 95% confidence interval 0.12-0.44; p < 0.001).. In this large cohort of CD patients, the frequency of entero-urinary fistulas was lower than previously described. More than 80% of patients required surgery, and in all but one of them surgery induced sustained remission. In a selected subgroup of patients, anti-TNF may induce long-term fistula remission and radiographic closure, making it possible to avoid surgery.

Topics: Adalimumab; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Case-Control Studies; Combined Modality Therapy; Crohn Disease; Female; Follow-Up Studies; Humans; Infliximab; Intestinal Fistula; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Remission Induction; Retrospective Studies; Treatment Outcome; Ureteral Diseases; Urinary Bladder Diseases; Urinary Fistula; Young Adult

The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene-gene interaction in a Crohn's disease (CD) population.. A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center. The association between four XDH variants (p.Gly172Arg, p.Asn1109Thr, p.Arg149Cys, and p.Thr910Lys) and thiopurine-induced leukopenia was analyzed in cases with early leukopenia (n = 66), late leukopenia (n = 264), and in controls without leukopenia (n = 632). Three non-synonymous SNPs, which we previously reported association with thiopurine-induced leukopenia, NUDT15 (p.Arg139Cys), SUCLA2 (p.Ser199Thr), and TPMT *3C were selected for epistasis analysis with the XDH variants.. There was no significant association for two variants of XDH and thiopurine-induced leukopenia. In the epistasis analysis, only XDH (p.Asn1109Thr) * SUCLA2 (p.Ser199Thr) showed a statistically significant association with early leukopenia [odds ratio (OR) = 0.16; p = 0.03]. After genotype stratification, a positive association on the background of SUCLA2 wild-type (199Ser) between the XDH (p.Asn1109Thr) and early leukopenia (OR = 4.39; p = 0.01) was detected.. Genes associated with thiopurine-induced leukopenia can act in a complex interactive manner. Further studies are warranted to explore the mechanisms underlying the effects of the combination of XDH (p.Asn1109Thr) and SUCLA2 (199Ser) on thiopurine-induced leukopenia.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Child; Crohn Disease; Epistasis, Genetic; Female; Follow-Up Studies; Genetic Markers; Genotype; Humans; Immunosuppressive Agents; Leukopenia; Logistic Models; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Republic of Korea; Succinate-CoA Ligases; Treatment Outcome; Xanthine Dehydrogenase; Young Adult

Long-term treatment with thiopurines is associated with a decreased risk of Crohn's disease (CD) flare but an increased risk of various cancers depending on gender, age, and presence of extensive colitis. We evaluated risks and benefits of withdrawing thiopurines in patients with CD in prolonged remission.. We developed a Markov model assessing risks and benefits of withdrawing thiopurines compared to continuing thiopurines in a lifetime horizon. The model was stratified by age (35 and 65 years old at thiopurine withdrawal), gender and presence of extensive colitis. Parameter estimates were taken from French cohorts and hospital databases, cancer and death national registries and published literature. Life expectancy, rates of relapse, serious adverse events, and causes-of-death were evaluated.. In patients without extensive colitis, continuing thiopurines increased life expectancy up to 0.03 years for 35 year-old men and women but decreased life expectancy down to 0.07 years for 65 year-old men and women. Withdrawal strategy became the preferred strategy at 40.6 years for men, and 45.7 years for women without extensive colitis. In patients with extensive colitis, continuation strategy was the preferred strategy regardless of age. Risk-benefit analysis was not modified by duration of CD activity.. Factors determining life expectancy associated with withdrawal or continuation of thiopurines in patients with CD and in sustained clinical remission vary substantially according to gender, age and presence of extensive colitis. Individual decisions to continue or withdraw thiopurines in patients with CD in sustained remission should take into account these parameters.

Topics: Adult; Aged; Azathioprine; Crohn Disease; Female; France; Humans; Immunosuppressive Agents; Life Expectancy; Male; Mercaptopurine; Middle Aged; Withholding Treatment

Previous data on inflammatory bowel disease (IBD) relapse during pregnancy mainly originate from retrospective studies. The aim of this study was therefore (i) to evaluate the effect of active disease at conception and IBD disease type on disease relapse during pregnancy and (ii) to study the effects of disease relapse during pregnancy on birth outcomes in a prospective cohort with adequate representation of current treatments.. From 2008 to 2014, IBD women were recruited from an ongoing prospective clinical cohort. All patients with confirmed IBD diagnosis with a pregnancy wish or pregnancy were prospectively followed-up until pregnancy and delivery. Disease relapse was measured at each visit. Birth outcomes were recorded from the obstetrician.. A total of 298 pregnancies were observed in 229 IBD patients (157 Crohn's disease (CD), 66 ulcerative colitis (UC), and 6 IBD unclassified), resulting in 226 live births. Active disease at conception was strongly associated with disease relapse during pregnancy (aOR=7.66, 95% confidence interval (CI): 3.77-15.54). UC patients experienced relapse during pregnancy more often than CD patients, independent of maternal age, smoking, periconceptional disease activity, previous IBD surgery, and the use of immunosuppressives or anti-tumor necrosis factor (TNF) (aOR=3.71, 95% CI:1.86-7.40). Disease relapse was not associated with adverse birth outcomes such as spontaneous abortion, low-birth weight, or preterm birth.. This study confirms that active disease around conception increases the risk of disease relapse during pregnancy. In addition, UC patients relapse more often during pregnancy than CD patients. Birth outcomes were excellent, reflecting the stringent follow-up and treatment of this group of patients.

Topics: Abortion, Spontaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Low Birth Weight; Infant, Newborn; Inflammatory Bowel Diseases; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Prospective Studies; Recurrence; Tumor Necrosis Factor-alpha

Background and Aims. Thiopurines are used in the treatment of Crohn's disease (CD) and thiopurine S-methyltransferase (TPMT) activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT. Methods. This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb) who were followed for 1 year. Patients started at full dose of azathioprine (2-2.5 mg/kg) or 6-mercaptopurine (1-1.5 mg/kg) were compared to patients started at low dose. Harvey-Bradshaw index, treatment failure, and drug-related adverse events were recorded. Results. Our study included 134 patients. Both groups had similar incidences of drug-related adverse events and discontinuation of therapy due to side effects. Fifty-six percent of all adverse events occurred within 31 days and 92% occurred within 3 months of therapy. Clinical response favored the full-dose group at 6 months (69% versus 27%, p = 0.0542). Conclusions. Our study indicates that it is safe to start patients on full-dose thiopurine when they have a normal TPMT given its very similar toxicity profile to patients started on low dose. This may also positively impact efficacy.

Topics: Adult; Azathioprine; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Middle Aged; Retrospective Studies; Young Adult

The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Practice Guidelines as Topic; Pregnancy

Clinical efficacy and risk of complications are associated with intracellular levels of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurines (6-MMP) in patients with Crohn's disease. Therapeutic monitoring of thiopurine metabolites is not widely available. Surrogate markers such as hematologic indices (MCV, leukopenia) have been proposed.. To evaluate accuracy of hematologic indices for prediction of therapeutic levels of thiopurine metabolites.. A retrospective cross-sectional study. We included patients treated with thiopurines for IBD between February 2008 and November 2013. Hematologic indices were correlated with thiopurine metabolites and compared to pre-treatment levels.. A total of 168 patients with 608 measurements were included. Macrocytosis was observed in 4.5 % of the patients. On multivariate analysis, macrocytosis was associated with 6-TGN levels >235 pmol/8 × 10(8) erythrocytes and 6-mmp levels >5,700 pmol/8 × 10(8) erythrocytes. Therapeutic 6-TGN levels were associated with MCV, ΔMCV, macrocytosis and lymphocyte count. Sensitivity and Spearman's r correlation for prediction of therapeutic metabolite levels were poor for all hematologic indices.. Although macrocytosis and an elevated MCV are associated with therapeutic 6-TGN levels, the correlation is weak. None of the evaluated hematologic indices is a reliable surrogate marker for thiopurine metabolite levels.

Topics: Anti-Inflammatory Agents; Azathioprine; Biomarkers; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Drug Monitoring; Erythrocyte Indices; Female; Guanine Nucleotides; Hematologic Tests; Hemoglobins; Humans; Lymphocyte Count; Male; Mercaptopurine; Platelet Count; Predictive Value of Tests; Retrospective Studies; Thionucleotides; Treatment Outcome

The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD.. We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/μL) and nonleukopenic (n = 76, WBC count ≥ 4,000/μL) patients.. The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan-Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively).. Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet's disease.

Topics: Adolescent; Adult; Aged; Azathioprine; Behcet Syndrome; Colitis, Ulcerative; Comorbidity; Crohn Disease; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukopenia; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Prognosis; Remission Induction; Retrospective Studies; Young Adult

The ideal manner of thiopurine use in inflammatory bowel disease has not been defined. We aimed at investigating the attitudes of Italian gastroenterologists on thiopurine use.. A web-based survey was performed among 295 gastroenterologists.. Overall, 70 surveys were completed. At baseline, thiopurine methyltransferase genotype and phenotype were not assessed by 87.1% and 97.1% of respondents, respectively. At treatment onset, 17.1% adopted full weight-calculated dose while 80.0% preferred escalating the dose. During treatment, 87.1% and 64.3% reduced the dose for myelo- and liver toxicity, respectively; 48.6% for increased pancreatic enzymes, 17.1% for fever, and 5.7% for arthralgia. A systematic shift from one thiopurine to the other was reported by 4.3% of respondents in case of failure, and by 5.7% for adverse effects. Forty-four gastroenterologists (62.9%) stopped thiopurine treatment after 5-7 years.. Several discrepancies regarding the use of thiopurines in clinical practice were found, deviating from available guidelines. A more standardised attitude is needed in clinical practice.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastroenterology; Guideline Adherence; Humans; Immunosuppressive Agents; Italy; Mercaptopurine; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'

Topics: Azathioprine; Behcet Syndrome; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; Mercaptopurine

To establish the risk factors for initial surgery in patients with Crohn's disease (CD) in Central China.. The subjects of this study were patients with CD treated at Zhongnan Hospital of Wuhan University, an IBD center in Wuhan City, Central China, between January, 1992 and June, 2012. We conducted uni- and multivariate analyses of the risk factors for initial surgery for CD in these patients.. A total of 197 patients with CD were included in this study. The cumulative incidence of initial surgery was 21.8, 28.9, and 32.5%, at 1, 5, and 10 years, respectively, after the onset of symptoms. Analysis using multivariate Cox models showed that the relative risk for initial surgery was lower in patients who were younger than 16 years at diagnosis (HR = 0.57, 95% CI 0.34-0.96, P = 0.034). The risk increased in patients with stricturing (HR = 4.75, 95% CI 2.48-9.11), those with CD showing penetrating behavior at diagnosis (HR = 5.14, 95% CI 2.54-10.39), and those with a history of appendectomy (HR = 1.87, 95% CI 1.03-3.40). Azathioprine (AZA) treatment appeared to decrease the risk for initial surgery in patients with non-penetrating and non-stricturing CD (HR = 0.14, 95% CI 0.13-3.10).. Age at diagnosis, disease behavior, and a history of appendectomy appeared to have an impact on the risk for initial surgery. AZA treatment might be helpful for decreasing the risk of needing initial surgery for patients in whom stricturing or fistulizing disease has not yet developed.

Topics: Adolescent; Adult; Age Factors; Aged; Analysis of Variance; Appendectomy; Child; China; Crohn Disease; Digestive System Surgical Procedures; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Middle Aged; Risk Factors; Young Adult

The impact of thiopurine (TP) use on perianal surgery is uncertain. Our aim was to determine trends in perianal surgery and the impact of timing and duration of TPs on the risk of first perianal surgery.. We identified a population-based cohort of incident cases of Crohn's disease between 1995 and 2009. We used Kaplan-Meier analysis to determine trends in TP usage and first perianal surgery by era of diagnosis: era 1 (1995-2002) and era 2 (2003-2009). We quantified the impact of duration and timing of TPs on the risk of perianal surgery using a Cox regression model.. We identified a cohort of 5235 incident cases of Crohn's disease. The 5-year cumulative probability of first perianal surgery decreased from 2.7% to 1.7% between era 1 and era 2, respectively (P = 0.03). TP use for greater than 18 months was associated with a 40% risk reduction for first perianal surgery (hazard ratio: 0.60, 95% confidence interval: 0.39-0.95) and 49% if TPs were used for 2 years or more (hazard ratio: 0.51, 95% confidence interval: 0.32-0.99). There was no demonstrable additional benefit from early TP use within the first year after diagnosis (hazard ratio: 0.85, 95% confidence interval: 0.52-1.40, P = 0.53).. Over the past 15 years, TP use has increased by 50%, whereas perianal surgery rates have decreased by 37% among UK population with Crohn's disease. Sustained use for 18 months was associated with a reduced risk of perianal surgery by almost a half in the first 5 years after diagnosis.

Topics: Adolescent; Adult; Anus Diseases; Azathioprine; Crohn Disease; Digestive System Surgical Procedures; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Male; Mercaptopurine; Middle Aged; Perineum; Prospective Studies; Risk Assessment; Time Factors; Treatment Outcome; United Kingdom; Young Adult

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; Mercaptopurine

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-α blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-α blocker naïve and 160 TNF-α blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-α blocker users, and 0.45 for TNF-α-blocker-naïve patients. The adjusted risk ratio of TB in IBD patients receiving TNF-α blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-α blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-α blockers. Treatment with TNF-α blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-α blocker therapy.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Infliximab; Latent Tuberculosis; Male; Mercaptopurine; Mycobacterium tuberculosis; Republic of Korea; Retrospective Studies; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples and application of genome-wide association studies.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Comparative Genomic Hybridization; Crohn Disease; DNA Copy Number Variations; Drug Resistance; Exome; Female; Genome-Wide Association Study; Hepatitis, Autoimmune; High-Throughput Nucleotide Sequencing; Humans; Male; Mercaptopurine; Metabolic Networks and Pathways; Methyltransferases; Middle Aged; Mutation

Anti-tumor necrosis factor (anti-TNF) agents are widely used to treat patients with moderate-to-severe inflammatory bowel disease (IBD). We aimed to identify the risk factors for adverse skin lesions in patients with IBD receiving anti-TNF agents and assess the effect of concomitant use of azathioprine/6-mercaptopurine (AZA/6 MP).. A total of 500 patients (404 with Crohn's disease, 96 with ulcerative colitis) who received anti-TNF agents between June 2002 and July 2013 were identified and retrospectively investigated. We compared 47 patients with IBD with skin lesions with 443 patients with IBD without skin lesions to identify risk factors by univariate and multivariate analysis. The Kaplan-Meier method was used to estimate the cumulative incidence of adverse skin lesions in relation to the concomitant use of AZA/6 MP.. Eczematiform eruptions (n = 18, 38%) were the most common skin lesion type, followed by psoriasiform lesions (n = 13, 28%). A response to topical steroids was seen in 70% (33/47) of patients with skin lesions, and anti-TNF agents had to be discontinued in 9% (4/47). Concomitant use of AZA/6 MP decreased the risk of skin lesions in univariate (hazard ratio, 0.452; 95% CI, 0.251-0.814; P = 0.008) and multivariate (hazard ratio, 0.437; 95% CI, 0.242-0.790; P = 0.006) analysis. In addition, the cumulative incidence of adverse skin lesions was lower in patients on concomitant maintenance with AZA/6 MP (P = 0.009) than in those on anti-TNF monotherapy.. Concomitant use of AZA/6 MP may decrease the occurrence of adverse skin lesions in patients receiving anti-TNF therapy.

Topics: Adolescent; Adult; Aged; Azathioprine; Body Mass Index; Colitis, Ulcerative; Crohn Disease; Drug Eruptions; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Psoriasis; Retrospective Studies; Risk Factors; Smoking; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha; Young Adult

To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate (5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase (NAT) 1 and 2.. Concentrations of thioguanine nucleotides (TGN) and methymercaptopurine nucleotides (MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients (3 females and 9 males, median age 16 years) with inflammatory bowel disease (6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines (7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase (ITPA) and thiopurine methyl transferase (TPMT) genes was performed using PCR assays.. Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 10(8) erythrocytes (range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations (absolute mean reduction 109 pmol/8 × 10(8) erythrocytes) was observed (median 221 pmol/8 × 10(8) erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration (P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study.. NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.

Topics: Adolescent; Anti-Inflammatory Agents; Arylamine N-Acetyltransferase; Azathioprine; Biotransformation; Child; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Genotype; Humans; Isoenzymes; Male; Mercaptopurine; Mesalamine; Pharmacogenetics; Phenotype; Pilot Projects; Polymorphism, Genetic; Retrospective Studies; Time Factors; Treatment Outcome

The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy.. Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy.. Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01).. This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.

Topics: Adolescent; Adult; Aged; Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Factors; Thioinosine; Thionucleotides; Treatment Failure; Young Adult

Thiopurines are effective for maintenance of remission in inflammatory bowel disease (IBD) in only about half of patients. Predictors of response may assist in selecting the most appropriate patients for thiopurine therapy. Thiopurines inhibit Rac1, a GTPase that exerts an antiapoptotic effect on T-lymphocytes. A genetic association was recently demonstrated between a Rac1 single nucleotide polymorphism (SNP) and poorer response to thiopurines in adult patients with Crohn disease. We aimed to determine whether Rac1 SNPs are associated with response to thiopurines in children with IBD.. Children with IBD treated with thiopurines were prospectively followed for 1 year and were genotyped for 3 Rac1 SNPs previously found to be relevant to IBD: rs10951982, rs4720672, and rs34932801. The rate of sustained steroid-free remission (SSFR) without treatment escalation by 12 months was compared between wild types (WTs) and heterozygotes.. A total of 59 patients were studied (63% boys, 80% having Crohn disease, mean age 13 ± 4.1). Nineteen of the 41 WT (46%) and 9 of the 15 (60%) heterozygotes for rs10951982 were in SSFR (P = 0.55). Similarly, 21 of the 45 (47%) WT and 8 of the 12 (67%) heterozygotes for rs4720672 were in remission (P = 0.33). Finally, 21 of the 45 (47%) WT and 3 of the 5 (60%) heterozygotes for rs34932801 were in remission (P = 0.66). All of the 3 comparisons remained nonsignificant in a sensitivity analysis of only the patients with Crohn disease.. We did not find an association between 3 Rac1 SNPs and thiopurine effectiveness by 12 months in a prospective study of children with IBD. Other predictors of response should be sought to optimize patient selection for thiopurine therapy.

Topics: Adolescent; Azathioprine; Child; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Enzyme Inhibitors; Female; Genetic Association Studies; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Israel; Longitudinal Studies; Male; Mercaptopurine; Polymorphism, Single Nucleotide; rac1 GTP-Binding Protein; Remission Induction

In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown.. The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities.. Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31).. This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.

Topics: Adolescent; Adult; Age Factors; Aged; Alanine Transaminase; Aspartate Aminotransferases; Azathioprine; Body Mass Index; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Fatty Liver; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Middle Aged; Retrospective Studies; Risk Factors; Sex Factors; Ultrasonography; Young Adult

Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients.. We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases.. Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohn's Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms.. Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.

Topics: Adolescent; Azathioprine; Child; Crohn Disease; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Pancreatitis

Optimal levels of the thiopurine metabolite, 6-thioguanine nucleotides [6-TGN] correlate with remission of inflammatory bowel disease [IBD]. Apart from variations in the thiopurine methyl transferase [TPMT] gene, little is known about other predictors of 6-TGN levels. Obesity adversely affects response to infliximab and adalimumab and clinical course in IBD, but little is known about the interaction of thiopurines and obesity. We investigated the relationship between body mass index [BMI] and 6-TGN levels and sought to examine other predictors of 6-TGN levels.. This retrospective cohort study included patients with concurrent measurements of 6-TGN and BMI. The association between 6-TGN and clinical variables including BMI was estimated using a multivariable linear regression model.. Of 132 observations, 77 [58%] had Crohn's disease and 55 [42%] ulcerative colitis. BMI, smoking, and TPMT levels were associated with 6-TGN levels in multivariable analysis. Every 5kg/m(2) increase in BMI was associated with an 8% decrease in 6-TGN (0.92; 95% confidence interval [CI] 0.87-0.98; p = 0.009). Smokers had higher 6-TGN levels in comparison with non-/ex-smokers [1.43; 95% CI 1.02-2.02; p = 0.041]. Patients with intermediate TPMT had higher 6-TGN compared to those with normal levels [2.13; 95% CI 1.62-2.80; p < 0.001]. Obese patients were more likely to have sub-therapeutic 6-TGN levels and a higher methyl mercaptopurine nucleotide [MMPN/TGN] ratio despite a similar dose of thiopurines.. Active smoking and intermediate TPMT values were associated with higher 6-TGN levels but increasing BMI resulted in lower 6-TGN and higher MMPN levels. This may explain the worse outcome that has been reported previously in obese IBD subjects.

Topics: Adult; Azathioprine; Biomarkers; Body Mass Index; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Linear Models; Male; Mercaptopurine; Middle Aged; Obesity; Retrospective Studies; Smoking; Thionucleotides; Treatment Outcome

To determine the incidence and predictors of thiopurine-related adverse events.. Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid (5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios (OR) with 95% CI. Effect modification by age and sex were explored.. Our cohort had a median follow-up duration of 5.8 years [interquartile range (IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions (7.1%), acute pancreatitis (6.2%), gastrointestinal intolerance (5.4%), leucopenia (3.7%), hepatotoxicity (3.4%), infection (1.1%) and other reasons (4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40 (39.4%, P = 0.007). A sex-by-age interaction (P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event (age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males (age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables (disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation.. Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.

Topics: Adolescent; Adult; Age Factors; Alberta; Anti-Inflammatory Agents; Azathioprine; Crohn Disease; Female; Gastrointestinal Agents; Humans; Logistic Models; Male; Mercaptopurine; Multivariate Analysis; Odds Ratio; Registries; Retrospective Studies; Risk Factors; Sex Factors; Time Factors; Treatment Outcome; Young Adult

Thiopurines are effective drugs in treating ulcerative colitis (UC) and Crohn's disease (CD) even if studies that specifically investigate these drugs' profile of efficacy in UC compared with CD are scarce. Our aim was to compare the profile of efficacy of thiopurines in patients with UC and CD.. We perfomed a longitudinal observational study evaluating steroid-free clinical remission (CR) and mucosal healing (MH) in all patients with UC and CD who would complete 2 years of maintenance treatment with thiopurines. In patients with UC, CR and MH were assessed before starting treatment and 2 years later using the Mayo score (CR = Mayo score <2; MH = Mayo subscore ≤1). In patients with CD, CR and MH were assessed at the same time points using the Crohn's disease activity index (CR = Crohn's disease activity index < 150) and the Simplified Endoscopic Score for Crohn's Disease (MH = Simplified Endoscopic Score for Crohn's Disease < 2). The efficacy of thiopurines was assessed through intention-to-treat and per-protocol analyses.. The study included 205 steroid-dependent patients (104 UC; 101 CD), 140 of whom (70 UC; 70 CD) completed the 2-year observation period. Steroid-free CR was recorded in 43 patients with UC and 37 with CD (intention-to-treat: 41% versus 36%; P = 0.6; per-protocol: 61% versus 53%; P = 0.4); MH was obtained in 38 patients with UC and 17 with CD (intention-to-treat: 36% versus 16%; P < 0.01; odds ratio, 2.9; per-protocol: 54% versus 25%; P < 0.01; odds ratio, 3.7).. Thiopurines are effective in maintaining steroid-free CR in both UC and CD although they show a better profile of efficacy in terms of MH in cases of UC.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Colitis, Ulcerative; Crohn Disease; Endoscopy; Female; Humans; Intestinal Mucosa; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Prospective Studies; Remission Induction; Young Adult

The impact of thiopurines (TP) on the long-term outcome of early Crohn disease (CD) is still controversial. The present study designed as a comparison of conventional step-care to alternative treatment paradigms for disease progression.This longitudinal cohort study examined the established CD patients from a university-based inflammatory bowel disease referral center. Outcomes of mucosal healing (MH), CD-related surgery or hospitalization, and clinical remission were compared based on timing of initiation of TP therapy. The cumulative incidence of events was estimated by Kaplan-Meier method.One-hundred ninety patients with early CD were included. After a median follow-up of 57 months (interquartile range, 31.3-76.2), 29 patients undergone abdominal surgeries, 48 patients hospitalized, and 68 patients experienced clinical flares. A higher cumulative proportion of patients in the top-down (TD) group achieving MH than both the accelerated step-up (AC) group and conventional management (CM) group at month 36 (78.8% vs 39.9% and 42.2%, respectively; P = 0.001). There was a trend, albeit not significant, for an increased proportion of patients free of CD-related intestinal surgery in the TD group at month 60 (P = 0.16). However, among secondary outcomes, an early TP-based AC or TD strategy was not associated with improvement in clinical remission rates compared with a CM strategy at month 60 (P = 0.79). No significant difference was observed between early TP and CM for rates of MH, CD-related intestinal surgery or hospitalization, and clinical remission.Both AC and CM strategy were minimally effective for disease modification. TD strategy has the potential of achieving higher rates MH. Our results support the TD strategy in patients with early CD at risk for a disabling course.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Azathioprine; Crohn Disease; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Tertiary Care Centers; Treatment Outcome; Young Adult

Topics: Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Gastrointestinal Agents; Genetic Variation; Humans; Leukopenia; Male; Mercaptopurine; Methyltransferases; Thrombocytopenia

Thiopurines have been associated with both clinical improvement and mucosal healing in treating Crohn disease (CD). Unfortunately, the high rate of adverse events (AEs) leading to drug withdrawal represents a major limitation in the use of these drugs.To evaluate the safety of thiopurines in patients with CD. To identify predictive factors associated with the development of thiopurine-induced AEs and withdrawal.This longitudinal cohort study examined patients from a university-based IBD referral center. Time-to-event analysis was performed with the Kaplan-Meier curve. Cox regression analysis was performed to identify potential predictive factors of AEs.Two hundred sixty-seven CD patients on thiopurines were included. A total of 143 AEs occurred at a median of 7.4 months (interquartile range, 3.7-15.3 months) after starting treatment. The cumulative incidence of AEs was 26%, with an annual risk of 4.3% per patient-year of treatment. The most frequent was leucopenia (41/267, 15.36%), followed by infections (29/267, 10.86%). Independent factors predictive of leucopenia were lower baseline hemoglobin (hazard ratio (HR), 0.34; 95% confidence interval (CI) 0.18-0.67) and the concomitant use of 5-aminosalicylic acid (HR, 3.05; 95% CI 1.44-8.76). Of the 28.44% (76/267) CD patients discontinued therapy, 14.61% due to AEs. A lower body mass index, the presence of extraintestinal manifestation, and the incidence of leucopenia independently predicted thiopurine withdrawal. In total, 37.5% of these patients restarted thiopurines and 52.3% of them had AEs again.About a quarter of patients on thiopurine therapy had AEs during follow-up and 1 of 7 patients had to discontinue thiopurines due to AEs.

Topics: Adult; Azathioprine; Body Mass Index; China; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Mercaptopurine; Prospective Studies; Regression Analysis; Retrospective Studies; Socioeconomic Factors

There is conflicting evidence on the effects of thiopurines (azathioprine or mercaptopurine) and anti-tumor necrosis factor (TNF) therapies on rates of surgery among patients with Crohn's disease (CD). We aimed to identify factors that identify patients who are unlikely to respond to medical therapy and will therefore require surgery.. We performed a retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry to identify 425 patients diagnosed with CD who received a prescription of a thiopurine and/or an anti-TNF agent from a referral center, from July 1, 1975, through September 13, 2012. We collected data on CD-related abdominal surgery after therapy and disease features when therapy was instituted. Cox proportional regression models were used to associate disease features with outcomes after adjusting for potential confounders. Risk estimates were presented as hazard rate ratios (HRRs) with 95% confidence intervals (CIs).. Among patients given thiopurines, stricturing disease (adjusted HR, 4.63; 95% CI, 2.00-10.71), ileal location (adjusted HR, 6.20; 95% CI, 1.64-23.42), and ileocolonic location (adjusted HR, 3.71; 95% CI, 1.08-12.74) at the time of prescription were associated significantly with the need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with patients prescribed only a thiopurine (adjusted HR, 0.41; 95% CI, 0.22-0.75). Among patients given anti-TNF agents, stricturing (adjusted HR, 6.17; 95% CI, 2.81-13.54) and penetrating disease (adjusted HR, 3.39; 95% CI, 1.45-7.92) at the time of prescription were associated significantly with surgery. Older age at diagnosis (17-40 y) reduced the risk for abdominal surgery (adjusted HR, 0.41; 95% CI, 0.21-0.80) compared with a younger age group (≤16 y). Surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines (adjusted HR, 0.33; 95% CI, 0.13-0.68) or anti-TNF agents (adjusted HR, 0.49; 95% CI, 0.25-0.96). Terminal ileal disease location was not associated with a stricturing phenotype.. Based on a retrospective database analysis, patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages; delayed treatment increases rates of treatment failure.

Topics: Adalimumab; Adolescent; Adult; Alberta; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Crohn Disease; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Factors; Treatment Failure; Young Adult

Appropriate influenza vaccination is important for patients with inflammatory bowel disease under immunosuppressive therapy. The purpose of this study was to evaluate the influence of immunosuppressive therapy on the immune response to the trivalent influenza vaccine in adult patients with inflammatory bowel disease.. In this cohort study, 91 participants received a single dose of influenza vaccine for the 2010/2011 season. Serum samples were collected at 3 different times (pre-vaccination, 3 weeks post-vaccination, and after flu season) to measure hemagglutination inhibition antibody titers. Immune responses were compared based on immunosuppressive therapy.. Among the 88 subjects who completed the study, the influenza vaccine induced a more than 4-fold increase in the mean antibody level for all flu strains. The overall seroprotection proportion (post-vaccination titer ≥ 1:40) was 81% for H1N1, 61% for H3N2, and 86% for B. Treatment with an immunomodulator reduced the immune response to the H1N1 strain (OR=0.20, p=0.01), and treatment with infliximab reduced the immune response to the other strains (H3N2 strain: OR=0.37, p=0.02; B strain: OR=0.18, p=0.03). Combination therapy with azathioprine/6-mercaptopurine and infliximab significantly inhibited the immune response to H1N1 (OR=0.056, p=0.02).. Infliximab and/or immunomodulators inhibit immune responses to some strains of trivalent influenza vaccination in adults with inflammatory bowel disease. For optimization of the trivalent influenza vaccination for patients with adult inflammatory bowel disease treated with immunosuppressive agents, establishing an effective vaccination method is crucial.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Viral; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunity, Active; Immunosuppressive Agents; Infliximab; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza Vaccines; Male; Mercaptopurine; Methotrexate; Middle Aged; Prospective Studies; Tacrolimus

Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients.. We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate.. Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group.. In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.

Topics: Adalimumab; Adolescent; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Child; Child Development; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Male; Matched-Pair Analysis; Mercaptopurine; Methotrexate; Propensity Score; Prospective Studies; Severity of Illness Index; Treatment Outcome

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Topics: Aged, 80 and over; Antibodies, Monoclonal; Crohn Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Nocardia Infections; Opportunistic Infections; Pneumonia, Bacterial

There is a new debate on the role of thiopurines in Crohn's disease. This viewpoint discusses the current evidence and balances thiopurines against other treatment options in the therapeutic algorithm of Crohn's disease.

Topics: Azathioprine; Clinical Trials as Topic; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Remission Induction

To date, no large-scale studies have evaluated the prognosis of Crohn's disease (CD) over a period of 3 decades in non-Caucasian populations. The aims of this study were to update the current information on the long-term prognosis of CD using a large series of patients and to evaluate changes in treatment paradigms over time and their impact on the prognosis of CD in Korea.. We retrospectively analyzed 2043 Korean patients with CD who visited the Asan Medical Center. The study subjects were divided into 3 groups according to the year of diagnosis (cohort 1: 1981-2000, cohort 2: 2001-2005, and cohort 3: 2006-2012).. Azathioprine/6-mercaptopurine and anti-tumor necrosis factor agents have been used increasingly more frequently and earlier over the past 30 years, with a 5-year cumulative probability of prescription of 28.9% and 1.4%, respectively, in cohort 1 and 88.1% and 23.7%, respectively, in cohort 3 (P < 0.001). A total of 726 patients (35.5%) underwent intestinal resection, with a cumulative probability of intestinal resection 10, 20, and 30 years after diagnosis of 43.5%, 70.0%, and 76.1%, respectively. The cumulative probability of surgery was significantly lower in cohort 3 than in cohort 1 (P = 0.012). Early use of azathioprine/6-mercaptopurine was significantly associated with delayed need for intestinal resection by multivariate Cox analysis (hazard ratio: 0.63, 95% confidence interval: 0.46-0.85).. Korean patients with CD may have a similar clinical course to Westerners, as indicated by the intestinal resection rate. The surgery rate has decreased over time, and early use of azathioprine/6-mercaptopurine was related to its decrease.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Crohn Disease; Female; Follow-Up Studies; Hospitals; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prognosis; Republic of Korea; Retrospective Studies; Time Factors; Young Adult

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Two large studies concluded that AZA started early after diagnosis of Crohn's disease have no late maintenance value. This is contrary to previous studies on 6MP for Crohn's disease and could lead to negating the value of two of the few drugs that have been proven successful. We here outline the many reasons why 6MP remains a valuable drug in the treatment of Crohn's disease.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Treatment Outcome

The efficacy of thiopurines (TPs) in altering the risk of surgery in Crohn's disease (CD) remains controversial. We evaluated the impact of TP therapy, optimal timing, and duration of TP therapy on first intestinal resection rates using a population-based cohort.. We constructed a population-based cohort of incident cases of CD between 1989 and 2005. We used the Kaplan-Meier analysis to calculate time trends in TP use and first intestinal resection in three groups defined by time period of diagnosis: 1989-1993, 1994-1999, and 2000-2005 groups A, B, and C, respectively. We quantified impact of duration and timing of TP treatment on likelihood of surgery using Cox regression and propensity score matching.. We identified 5,640 eligible patients with CD. The 5-year cumulative probability of TP use increased from 12, 18, to 25% ( P<0.0001) while probability of first intestinal resection decreased from 15, 12 to 9% (P<0.001) in groups A, B, and C, respectively. Patients treated with at least 6 months of TP therapy had a 44% reduction in the risk of surgery (hazards ratio (HR): 0.56; 95% confidence interval (CI): 0.37-0.85) and those receiving at least 12 months of TP therapy had a 69% reduction in the risk of surgery (HR: 0.31; 95% CI: 0.22-0.44). Early treatment (<12 months from diagnosis) vs. late treatment with TP showed no additional benefit in reducing risk of surgery (HR: 0.41; 95% CI: 0.27-0.61 vs. 0.21; 95% CI: 0.13-0.34).. Over the past 20 years, TP use has doubled, whereas intestinal surgery has fallen by one-third among the UK population of Crohn's patients. Prolonged exposure is associated with a reduced likelihood of surgery whereby more than 12 months TP therapy reduces the risk of first intestinal surgery two-fold; however, early initiation of TP treatment offered no apparent additional benefit.

Topics: Adult; Azathioprine; Crohn Disease; Digestive System Surgical Procedures; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Propensity Score; Prospective Studies; Risk Assessment; Time Factors; Treatment Outcome; United Kingdom

Topics: Child; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine

Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up.. Fecal samples from 10 Crohn's disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing.. After quality control, 6,194-11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025). Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001) and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01).. Shifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course.

Topics: Adult; Aged; Antimetabolites; Colitis, Ulcerative; Crohn Disease; Disease Progression; Feces; Female; Genetic Variation; Humans; Immunologic Factors; Intestines; Male; Mercaptopurine; Microbiota; Middle Aged; Prospective Studies; Recurrence; Remission Induction; RNA, Ribosomal, 16S; Tumor Necrosis Factor-alpha

The natural course of Crohn's disease (CD), with continuing relapses and remissions, leads to irreversible intestinal damage. Early adoption of immunomodulator therapy has been proposed in order to address this; however, it is still uncertain whether early immunomodulator therapy could affect the natural course of the disease in real practice. We evaluated the efficacy of such therapy on the prognosis of newly diagnosed patients with CD.. This retrospective study included 168 patients who were newly diagnosed with CD and who started treatment at Severance Hospital, Seoul, Korea between January 2006 and March 2013. The short- and long-term outcomes were compared between patients treated with early immunomodulator therapy and those treated with conventional therapy.. A Kaplan-Meier analysis identified that administration of immunomodulators within 6 months after diagnosis of CD was superior to conventional therapy in terms of clinical remission and corticosteroid-free remission rates (P=0.043 and P=0.035). However, P=0.827). Patients with a baseline elevated CRP level were more likely to relapse (P<0.005). Drug-related adverse events were more frequent in the early immunomodulator therapy group than in the conventional therapy group P=0.029).. Early immunomodulator therapy was more effective than conventional therapy in inducing remission, but not in preventing relapse. Baseline high CRP level was a significant indicator of relapse.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; C-Reactive Protein; Cohort Studies; Crohn Disease; Early Medical Intervention; Female; Humans; Immunologic Factors; Immunosuppressive Agents; Kaplan-Meier Estimate; Logistic Models; Male; Mercaptopurine; Remission Induction; Retrospective Studies; Treatment Outcome; Young Adult

Infliximab withdrawal in patients with Crohn's disease on concomitant antimetabolite therapy is considered to be superior if obtained after a maintenance therapy period compared to induction alone.. We retrospectively analyzed the outcome of Crohn's disease patients treated with infliximab and an antimetabolite after infliximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy. The time to relapse was analyzed using univariate and multivariate analyses. The model was adjusted according to the period of infliximab withdrawal.. A total of 92 patients were included, 54 in the induction alone group. The patient characteristics were identical in the two groups except for the period of infliximab withdrawal. After a median follow-up period of 47.1 (interquartile range=4.4-110.2) months, 66 patients (72%) experienced a relapse. After a year-adjustment, no significant difference was observed between the two groups. Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking, previous antimetabolite failure, and perianal disease. After relapse, 53 patients (80%) were retreated with infliximab. After infliximab retreatment, clinical remission was observed in 47 patients (89%) at weeks 8-10.. In Crohn's disease patients, the probability of relapse on antimetabolite therapy after infliximab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antimetabolites; Azathioprine; Crohn Disease; Female; Follow-Up Studies; Humans; Infliximab; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Recurrence; Remission Induction; Retreatment; Retrospective Studies; Risk Factors; Treatment Failure; Withholding Treatment; Young Adult

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Topics: Adalimumab; Adolescent; Adrenal Cortex Hormones; Algorithms; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Child; Crohn Disease; Enteral Nutrition; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Remission Induction; Thalidomide; Tumor Necrosis Factor-alpha

Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD.. The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices.. The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919  pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001).. We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Crohn Disease; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Odds Ratio; Thionucleotides; Treatment Failure

Earlier introduction of immunomodulators (IM) thiopurine or methotrexate is advocated to improve Crohn's disease (CD) outcomes, but whether abdominal surgery can be prevented remains controversial.. A specialist-referred cohort of CD was recruited from 1970 to 2009. Early IM use was defined as commencement of azathioprine or methotrexate within 3 years of CD diagnosis and adherence of at least 6 months. Propensity score matching was conducted to correct for confounders influencing early IM introduction. Outcomes of interest were rates of initial and recurrent major abdominal surgery for CD and their predictive factors.. A total of 1035 consecutive patients with CD (13,061 patient-years) were recruited. The risk of first and recurrent major abdominal surgery at 1, 5, and 10 years were 17.5%, 28.4%, and 39.5% and 5.9%, 19.0%, and 33.3%, respectively. Early IM use increased over time from 1.3% to 55.3% (P < 0.0001) and was a significant independent predictor of lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35-0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25-0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16-0.56). Using propensity score matching, early IM significantly reduced surgical rates (HR, 0.54; 95% CI, 0.37-0.79). Number needed to treat to prevent a surgical event at 5 years from diagnosis and after initial surgery was 6.99 (95% CI, 5.34-11.95) and 8.59 (95% CI, 6.26-23.93), respectively.. Early IM use with thiopurines or methotrexate was significantly associated with the reduced need for abdominal and perianal surgery in CD.

Topics: Abdomen; Adolescent; Adult; Aged; Aged, 80 and over; Anal Canal; Azathioprine; Child; Child, Preschool; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Middle Aged; Prognosis; Retrospective Studies; Secondary Prevention; Young Adult

To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.. The multi-center Pediatric Inflammatory Bowel Disease Network (PIBDNet) cohort study prospectively collected data on thiopurine naïve patients initiating mercaptopurine (6MP) or azathioprine. Patients with a diagnosis of Crohn's disease (CD) were included in our study upon entering remission as determined by physician global assessment (PGA) within 365 d of initiation of thiopurines. The primary outcome of the study was maintenance of steroid-free remission (SFR) at each follow up visit. Patients were considered treatment failures if there had been a change in PGA from remission to mild, moderate or severe disease; disease relapse between visits; need for rescue therapy (biologic therapy, methotrexate, steroids); thiopurine discontinuation, hospitalization or surgical intervention. A secondary outcome defined treatment failure as a change from remission to moderate or severe (not mild) in addition to the previously defined criteria.. Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Forty-five of 65 (69%) of included patients achieved remission within 180 d of thiopurine initiation. For the primary outcome, 47% and 23% of patients remained in SFR at 6 and 12 mo. The mean thiopurine dose at initiation for the 65 included patients was 0.89 ± 0.31 mg/kg per day. Metabolite levels were obtained in 48% (31/65) of the included patients with a mean 6TG level of 258 pmole/8 × 10(8) RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo.. Thiopurines were less effective in maintaining remission for pediatric CD in this "real world" cohort than has been previously described. Variation in thiopurine dosing and metabolite measurement was found among practitioners.

Topics: Adolescent; Age Factors; Anti-Inflammatory Agents; Azathioprine; Child; Crohn Disease; Drug Monitoring; Female; Gastrointestinal Agents; Humans; Male; Mercaptopurine; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Registries; Remission Induction; Severity of Illness Index; Steroids; Time Factors; Treatment Outcome; United States

Topics: Azathioprine; Crohn Disease; Digestive System Surgical Procedures; Humans; Mercaptopurine

Topics: Azathioprine; Crohn Disease; Digestive System Surgical Procedures; Humans; Mercaptopurine

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors.. To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse.. This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively.. 237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4-8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035). Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007).. Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.

Topics: Adult; Azathioprine; C-Reactive Protein; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Recurrence; Retrospective Studies; Risk Factors

Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells.

Topics: Adult; Antigens, CD; Azathioprine; Cells, Cultured; Chemokines; Crohn Disease; Female; Gene Expression Profiling; Genome-Wide Association Study; Humans; Interferons; Killer Cells, Natural; Lipopolysaccharides; Male; Mercaptopurine; Ribosomes; Signal Transduction; Toll-Like Receptor 4; Transcription Factors; Transcriptome; Up-Regulation

Topics: Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate

Topics: Adalimumab; Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Middle Aged; Purpura; Tumor Necrosis Factor-alpha; Vasculitis, Leukocytoclastic, Cutaneous

Anti-tumor necrosis factor (TNF) antibodies are effective in maintaining remission in Crohn's disease. However, a significant proportion of patients lose response to these agents with time. This study aimed to determine whether the introduction of a thiopurine in patients who have lost response to anti-TNF monotherapy results in regained response.. Five patients (four males; aged 22-38 years) with active Crohn's disease, who had an initial response to anti-TNF therapy but had lost response, were commenced on azathioprine or mercaptopurine at standard doses while continuing anti-TNF therapy. All had previously failed thiopurine therapy prior to starting anti-TNF treatment.. All patients experienced improved clinical symptoms within 2-6 months, with benefit sustained over a mean follow-up of 19 months. Two patients with an elevated C-reactive protein at the time of thiopurine addition demonstrated a fall in C-reactive protein. Colonoscopy before and after thiopurine addition in four patients showed improvement in all, with mucosal healing achieved in two. No adverse effects of treatment were noted.. Addition of a thiopurine in patients who have lost response to anti-TNF monotherapy is an effective strategy to recapture response even if the patient has previously failed thiopurine therapy. Thiopurines may reduce immunogenicity or act synergistically with anti-TNF therapy.

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Crohn Disease; Drug Substitution; Drug Synergism; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Treatment Failure; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Topics: Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate

Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines.. A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated.. The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003).. Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.

Topics: Adolescent; Adult; Azathioprine; Biomarkers, Tumor; Child; Child, Preschool; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Prospective Studies; Retrospective Studies; Young Adult

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immunosuppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corticosteroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn's disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-aminosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in patients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless clinicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utilizing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?

Topics: Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Mercaptopurine; Recurrence; Remission Induction; Serologic Tests; Time Factors; Treatment Outcome

Thiopurine use in inflammatory bowel disease (IBD) is well established for maintenance of disease remission. Approximately 3% of patients with IBD develop thiopurine-induced pancreatitis (TIP) as an idiosyncratic reaction. Patients diagnosed as having TIP are largely considered not to be candidates for future use of this drug. We hypothesize that previous TIP is not an absolute contraindication to retrialing a different thiopurine.. This case series is a retrospective chart review of those patients with IBD in whom thiopurines were successfully reintroduced following suspected TIP. The patients were all cared for in 2 Australasian pediatric IBD services. Four cases are presented of TIP appropriately related temporally to azathioprine commencement, with no other apparent cause of pancreatitis identified. All of these patients were trialled on 6-mercaptopurine according to clinical need and this was well tolerated in all cases.. This report is the largest case series to date focusing on the reintroduction of a thiopurine following suspected thiopurine induced pancreatitis. All of the patients had a typical presentation of TIP. This case series should call into question the assumption that suspected TIP is an absolute contraindication for the future use of this class of drug. Cautious reintroduction of a thiopurine, in a controlled setting, should be considered in certain circumstances. The clinical relevance of this option is most marked in patients with complicated disease requiring long-term immunosuppression, in whom other therapies are poorly tolerated or contraindicated.

Topics: Adolescent; Azathioprine; Child; Child, Preschool; Contraindications; Crohn Disease; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Medical Records; Mercaptopurine; Pancreatitis; Retrospective Studies; Secondary Prevention

Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.. A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed.. Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE.. Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.

Topics: Adolescent; Adult; Age Factors; Chemical and Drug Induced Liver Injury; Cohort Studies; Crohn Disease; Female; Genotype; Glutathione Transferase; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Multivariate Analysis; Pancreatitis; Polymorphism, Genetic; Retrospective Studies; Risk Factors; Severity of Illness Index; Smoking; Young Adult

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Controlled Clinical Trials as Topic; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine

Combination therapy of thiopurines and anti-tumor necrosis factor alpha (TNF-α) antibodies is the most effective medical treatment of Crohn's disease (CD). Data on thiopurines and anti-TNF-α antibodies in preventing surgical recurrence (need for re-resection) of CD are scarce. Therefore, we analyzed which factors were involved in surgical recurrence of CD in a large cohort of patients with CD operated in a regional and a university hospital.. This is a retrospective cohort study of 567 patients who underwent surgery for CD. Clinical data and risk factors for surgical recurrence were analyzed, focusing on medical therapy and hospital type.. Overall, 237 (41.8%) patients developed a surgical recurrence, after a median of 70 (2-482) months. Before surgical recurrence, 235 patients (41.4%) and 116 patients (20.5%) used thiopurines and anti-TNF-α antibodies, respectively. Multivariate analysis identified 3 independent risk factors associated with surgical recurrence of CD. A higher risk was seen in patients with colonic disease compared with patients with ileal disease (hazard ratio, 1.56; 95% confidence interval, 1.10-2.21; P = 0.012) and in patients using multiple types of medication (hazard ratio, 1.38; 95% confidence interval, 1.25-1.54; P < 0.001). However, a lower risk was seen in patients using thiopurines (hazard ratio, 0.51; 95% confidence interval, 0.34-0.77; P = 0.001).. Thiopurines are effective in preventing surgical recurrence of CD. The role of anti-TNF-α antibodies seems promising as well. Combination therapy of thiopurines and anti-TNF-α antibodies for prevention of surgical recurrence of CD should be studied in a randomized trial.

Topics: Academic Medical Centers; Adolescent; Adult; Antibodies, Monoclonal; Azathioprine; Combined Modality Therapy; Crohn Disease; Cross-Sectional Studies; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Postoperative Complications; Prognosis; Retrospective Studies; Secondary Prevention; Survival Rate; Tumor Necrosis Factor-alpha; Young Adult

Topics: Azathioprine; Crohn Disease; Gastroenterology; Humans; Mercaptopurine; Methotrexate; Remission Induction; Societies, Medical; Tumor Necrosis Factor-alpha; United States

In increasingly aging populations, awareness of outcomes of older patients treated with biologics is becoming more important. However, few studies to date have investigated the safety and durability of anti-tumor necrosis factor (TNF) therapy in this subgroup.. This was a retrospective single-center study with cases comprising all IBD patients who began anti-TNF treatment at age >60 years. Cases of Crohn's disease (CD) and ulcerative colitis (UC) were identified from medical record review. Our controls consisted of patients younger than age 60 years on anti-TNF treatment and patients >60 years on treatment with immunomodulators. Kaplan-Meier survival estimates were used to calculate the probability of remaining on anti-TNF therapy.. We identified a total of 54 IBD patients who initiated anti-TNF therapy over the age of 60 years (mean 73, range 61-97 years). Among these, a total of 38 patients (70%) discontinued anti-TNF therapy after a mean of 24.1 months. At 12 months after initiation, 75% of patients older than age 60 years were still on anti-TNF agents compared to 93% among younger users and 82% among older AZA users (P < 0.05). Compared to older AZA users, older anti-TNF users remained more likely to require early therapy cessation (hazard ratio 2.21, 95% confidence interval 1.29-3.78).. The IBD population older than age 60 at the time of initiation of anti-TNF therapy is at higher risk for discontinuation of therapy. They may also be particularly vulnerable to infectious complications requiring hospitalization, suggesting the need for careful monitoring during therapy.

Topics: Adalimumab; Adult; Age Factors; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Certolizumab Pegol; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Infliximab; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Polyethylene Glycols; Proportional Hazards Models; Retrospective Studies; Treatment Failure; Withholding Treatment

Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.

Topics: Ascites; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Intestinal Obstruction; Liver Function Tests; Male; Mercaptopurine; Portal System; Sclerosis; Young Adult

Topics: Crohn Disease; Food, Formulated; Humans; Immunosuppressive Agents; Male; Mercaptopurine

The guideline offers best practice advice on the care of adults, children and young people with Crohn's disease.. To provide clinically effective and cost-effective evidence-based recommendations to guide clinical practice in a clinical guideline commissioned by the National Institute for Health and Clinical Excellence (NICE).. A systematic review of the evidence including critical appraisal, meta-analysis and cost-effectiveness modelling.. Thirty-one evidence-based recommendations covering induction and maintenance therapy are available. Five key priorities for implementation are identified together with nine future research recommendations. Three guideline versions are available: short (containing just the recommendations), full (containing the full evidence base) and an Understanding NICE guidance for patients and carers. Algorithms have been produced together with a NICE pathway and implementation tools.. These are the first evidence-based clinical and cost-effectiveness guidelines for Crohn's disease in the United Kingdom.

Topics: Adolescent; Adult; Azathioprine; Child; Cost-Benefit Analysis; Crohn Disease; Disease Management; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Pregnancy; State Medicine; United Kingdom; Young Adult

Topics: Aged; Allopurinol; Azathioprine; Biotransformation; Bone Marrow Diseases; Crohn Disease; Drug Interactions; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Xanthine Oxidase

Methotrexate is an immunosuppressant that is used to treat patients with Crohn's disease (CD). However, there are few data on the long-term effects of methotrexate maintenance therapy for these patients. We assessed the sustained clinical benefits and tolerability of methotrexate monotherapy after thiopurine therapy in patients with CD.. We analyzed data from 3 hospitals on 174 consecutive patients with CD (age, 35 ± 12 y) who received methotrexate monotherapy after thiopurine therapy (23% also did not respond to anti-tumor necrosis factor therapy) from 2000 to 2010. We assessed patient characteristics and the tolerability and sustained clinical benefits of the treatment. Sustained clinical benefit was defined as ongoing use of methotrexate or intentional discontinuation of successful therapy before the end-of-study point.. The number of patients with sustained clinical benefits from methotrexate monotherapy were 98 (86%), 50 (63%), 27 (47%), and 3 (20%), at 6, 12, 24, and 60 months, respectively. Forty-five patients (26%) discontinued methotrexate because of intolerance, particularly within 6 months after therapy began. Adverse responses generally were mild; only 1 patient required admission to the hospital for infection with cytomegalovirus, and no drug-related deaths were reported. Intolerance of the preceding thiopurine therapy was associated with adverse events during methotrexate therapy.. In a large cohort study of patients who received methotrexate monotherapy after thiopurine therapy for CD, 47% continued to receive the therapy or intentionally discontinued successful therapy within 2 years, and 20% did so within 5 years. Long-term use of methotrexate was well tolerated and relatively safe.

Topics: Adolescent; Adult; Crohn Disease; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Retrospective Studies; Treatment Outcome; Young Adult

To assess the levels of red blood cell thiopurine methyltransferase (TPMT) in subjects with inflammatory bowel disease (IBD) and to determine how these levels impacted thiopurine dosing and leukopenia over the first six months of therapy.. A retrospective chart review was performed on all adult IBD patients (n=423, 88.2% Caucasian) who had TPMT levels measured by 11 participating gastroenterologists in Manitoba between 2008 and 2010. In addition to descriptive data, white blood cell count, dose and reason for discontinuation were analyzed for the first six months of therapy. Patients receiving ≥2.0 mg/kg of azathioprine (AZA) or ≥1.0 mg/kg of 6-mercapatopurine were considered to be 'substantially' dosed.. Of the 423 patients, 8.3% had intermediate levels and 93.4% had normal levels of TPMT. Only one subject had a low level. A total of 216 patients had sufficient data to be included for full analysis. Patients with intermediate TPMT levels were generally started at lower doses of thiopurine than patients with normal TPMT levels (mean [± SD] 1.0±0.6 mg/kg versus 1.8±0.5 mg/kg). Of the subjects with normal TPMT levels, only 37.8% were dosed with ≥2.0 mg/kg of AZA. Each month, approximately 5% of subjects were leukopenic. These subjects received a mean overall AZA dose of 1.9±0.3 mg/kg and had a mean white blood cell count of 3.8±0.4×10(9)/L.. Normal TPMT levels did not prevent the development of leukopenia, although life-threatening leukopenia was rare. Physicians are not using TPMT levels to substantially dose thiopurines at the outset, which may limit the speed at which adequate doses are reached to facilitate remission.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Manitoba; Mercaptopurine; Methyltransferases; Middle Aged; Retrospective Studies; Young Adult

Crohn's disease is rare in South African black people and primary sclerosing cholangitis (PSC) is also rare in black patients with IBD, from South Africa. The presence of HLA-B27 is generally associated with seronegative spondylo-arthropathies and correlates with the occurrence of ankylosing spondylitis, recurrent mouth ulcers and uveitis, in patients with IBD. We describe two women with the combination of Crohn's disease, PSC and HLA-B27 from our cohort of the last 5 years of three black patients with Crohn's disease. Crohn's disease, PSC and HLA-B27 respectively, occur rarely in black South Africans and their concurrent presence in two black women suggests a pathogenetic link of HLA-B27 between Crohn's disease and PSC in this population. Female gender might be an additional determinant in this setting.

Topics: Adult; Alkaline Phosphatase; Azathioprine; Back Pain; Black People; Cholagogues and Choleretics; Cholangiopancreatography, Magnetic Resonance; Cholangitis, Sclerosing; Colonoscopy; Crohn Disease; Diarrhea; Female; gamma-Glutamyltransferase; Genetic Predisposition to Disease; HLA-B27 Antigen; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate; Severity of Illness Index; South Africa; Treatment Outcome; Ursodeoxycholic Acid

A number of treatments have been shown to reduce the risk of postoperative recurrence of Crohn's disease (CD). The optimal strategy is unknown. The aim was to evaluate the comparative cost-effectiveness of postoperative strategies to prevent clinical recurrence of CD.. Three prophylactic strategies were compared to "no prophylaxis"; mesalamine, azathioprine (AZA) / 6-mercaptopurine (6-MP), and infliximab. The probability of clinical recurrence, endoscopic recurrence, and therapy discontinuation due to adverse drug reactions (ADRs) were extracted from randomized controlled trials (RCTs). Quality-of-life scores and treatment costs were derived from published data. The primary model evaluated quality-adjusted life years (QALYs) and cost-effectiveness at 1 year after surgery. Sensitivity analysis assessed the impact of a range of recurrence rates on cost-effectiveness. An exploratory analysis evaluated cost-effectiveness outcomes 5 years after surgery.. A strategy of "no prophylaxis" was the least expensive one at 1 and 5 years after surgery. Compared to this approach, AZA/6-MP had the most favorable incremental cost-effectiveness ratio (ICER) ($299,188/QALY gained), and yielded the highest net health benefits of the medication strategies at 1 year. Sensitivity analysis determined that the ICER of AZA/6-MP was preferable to mesalamine up to a recurrence rate of 52%, but mesalamine dominated at higher rates. In the 5-year exploratory analysis, mesalamine had the most favorable ICER over 5 years ($244,177/QALY gained).. Compared to no prophylactic treatment, AZA/6-MP has the most favorable ICER in the prevention of clinical recurrence of postoperative CD up to 1 year. At 5 years, mesalamine had the most favorable ICER in this model.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Cost-Benefit Analysis; Crohn Disease; Decision Trees; Health Care Costs; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Mesalamine; Monte Carlo Method; Postoperative Period; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Secondary Prevention

Little is known about the factors that predict clinical relapse in Crohn's disease patients receiving thiopurine therapy to maintain remission. The objective of this study was, therefore, to investigate these factors.. A total of 82 Crohn's disease patients who received their first course of azathioprine or 6-mercaptopurine treatment at Severance Hospital between June 1996 and July 2007 were recruited to the study. During the follow-up period (25.5 ± 16.6 months) 19 patients (23.2%) discontinued the medication because of significant adverse effects. Forty-five patients who continued to receive thiopurines to maintain medically or surgically induced remission were enrolled in the study. After adjusting the maintenance dose, patients in remission were followed at 2-3 month intervals. Relapse was defined as a Crohn's disease activity index ≥ 150.. The male-to-female ratio was 1.5:1 and the mean age was 26.3 ± 7.1 years. Cumulative relapse was 18.0% after one year and 49.2% after three years. According to multivariate Cox regression analysis, younger age (<30 years) at thiopurine therapy and increased C-reactive protein level (≥ 0.5 mg/dL) at remission were independent predictors of relapse (hazard ratio 19.751, 95%-confidence interval (CI) 1.996-195.402, P = 0.011 and hazard ratio 9.001, 95% CI 1.583-51.181, P = 0.013, respectively).. Younger age (<30 years) and increased C-reactive protein level at remission were independent predictors of relapse in Crohn's disease patients receiving thiopurines to maintain remission. These high-risk groups warrant closer observation and possibly early introduction of biological agents.

Topics: Adult; Age Factors; Azathioprine; Biomarkers; C-Reactive Protein; Crohn Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Predictive Value of Tests; Prognosis; Recurrence; Regression Analysis; Republic of Korea; Retrospective Studies; Treatment Outcome

Inflammatory bowel disease (IBD), common in Melbourne, was rare but is now increasing in incidence in Hong Kong (HK). To investigate whether these are the same diseases in the West and East, potential causes of changing incidence, and to plan resource needs, an appreciation of clinical characteristics in contrasting populations is essential.. Disease characteristics were collected from prospectively populated IBD databases in two specialist centers in Melbourne, Australia and HK.. Of 795 patients (Crohn's disease [CD] : ulcerative colitis [UC] Melbourne 272:159 and HK 161:203), the age of diagnosis was higher, there were proportionally more male patients with CD but no UC sex difference, fewer patients were current or ex-smokers (CD 8% vs 50%; UC 17% vs 35%) and a family history of IBD was less common (2% vs 11%; P < 0.001) in HK compared to Melbourne. Stricturing and perianal CD were more common in HK (12% vs 6%; P < 0.001; and 29% vs 16%; P = 0.001, respectively). In HK for UC, more patients had extensive disease at diagnosis (42% vs 22%) but colectomy was less common (7% vs 20%; P < 0.001). In Melbourne there was greater steroid use at diagnosis and patients were more likely to receive an immunomodulator or anti-tumor necrosis factor agent.. IBD in HK was diagnosed at an older age, and had more complicated disease behavior than in Melbourne. Medical therapy, however, was less intense in HK. These differences may relate to real differences in disease or delayed diagnosis due to late presentation and less disease recognition in HK.

Topics: Adolescent; Adult; Age Factors; Anal Canal; Analysis of Variance; Chi-Square Distribution; Colectomy; Colitis, Ulcerative; Constriction, Pathologic; Crohn Disease; Cyclosporine; Female; Hong Kong; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Multivariate Analysis; Proportional Hazards Models; Sex Factors; Smoking; Steroids; Tumor Necrosis Factor Inhibitors; Victoria; Young Adult

We hypothesised that nonadherence to thiopurines is more common in adolescents than in adults with inflammatory bowel disease.. We sought factors associated with thiopurine nonadherence defined by thiopurine metabolite levels.. Multivariate logistic regression confirmed that adolescents (odds ratio [OR] 4.6 [95% confidence interval [CI] 1.9-11.5]; P < 0.01) compared with adults, patients with Crohn disease (OR 3.3 [CI 1.1-10.5] P = 0.04) compared with ulcerative colitis, and patients living in more socially deprived areas (OR 1.03 [CI 1.0-1.1] P = 0.02) were more likely to be nonadherent to thiopurines.. Adolescents are more frequently nonadherent than adults: prospective studies are required to determine the reasons for nonadherence in adolescents.

Topics: Adolescent; Colitis, Ulcerative; Confidence Intervals; Crohn Disease; Female; Hospitalization; Humans; Logistic Models; Male; Medication Adherence; Mercaptopurine; Multivariate Analysis; Odds Ratio; Prospective Studies; Treatment Outcome; Young Adult

The prodrugs azathioprine and 6-mercaptopurine, which are well-established anticancer and immunosuppressive agents, are extensively metabolized by activating and inactivating enzymes. Whereas the 6-thioguanine nucleotides (TGN) are currently being considered as major active metabolites, methylthioinosine nucleotides seem to contribute to the cytotoxic effect as well. Thiopurine-related adverse drug reactions and thiopurine failure are frequent. Thus, therapeutic monitoring of TGN and methylthioinosine derivatives has been suggested to improve thiopurine therapy, however with limited success. To elucidate systematically underlying molecular mechanisms as potential explanation for interindividual variability of thiopurine response, we developed a novel highly specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of eleven mono-, di-, and triphosphates of thioguanosine, methylthioinosine, methylthioguanosine, and thioinosine. Using stable isotope-labeled analogues as internal standards obtained by chemical synthesis, an intra- and interassay variability below 8% and an accuracy of 92% to 107% were achieved in spiked quality control samples with known standards. All eleven metabolites could be determined in red blood cells from patients with inflammatory bowel diseases and long-term azathioprine therapy. Thus, our novel method opens a new avenue for the understanding of the thiopurine metabolism by quantitation of all important thiopurine nucleotide metabolites in one run.

Topics: Azathioprine; Chromatography, High Pressure Liquid; Crohn Disease; Erythrocytes; Guanine Nucleotides; Humans; Immunosuppressive Agents; Isotope Labeling; Mercaptopurine; Methylthioinosine; Tandem Mass Spectrometry; Thionucleotides

Anti-tumor necrosis factor (TNF) therapy heals many Crohn's disease (CD) anal fistulas clinically but the rate, extent, and durability of deep tissue healing and factors influencing long-term outcome are unknown.. Consecutive patients with CD-related perianal (anal, rectovaginal, anolabial) fistulas treated with infliximab or adalimumab were monitored prospectively both clinically and radiologically using magnetic resonance imaging (MRI).. Forty-one consecutive patients with CD-related perianal fistulas were treated with infliximab (n = 32) or adalimumab (n = 9; following infliximab failure) in combination with a thiopurine (unless intolerant). Fifty-eight percent of all patients, comprising 66% and 43% of infliximab and adalimumab-treated patients, respectively, demonstrated remission or response at 3 years. Thirty-three percent of infliximab treated patients maintained clinical remission at 3 years. Radiological healing lagged behind clinical remission by a median of 12 months. The likelihood of clinical remission at any time was five times greater in patients who had early clinical response within 6 weeks than those without. A higher number of fistula tracts was associated with reduced clinical remission. All patients who achieved radiological healing maintained healing on infliximab treatment, while only 43% maintained healing after cessation of anti-TNF therapy.. Combination anti-TNF and thiopurine therapy provides sustained benefit in patients with perianal CD fistula. Early clinical response is associated with subsequent clinical remission. Radiological healing is slower than clinical healing. Radiologically healed fistula tracts maintain healing on infliximab but can recur after cessation of therapy.

Topics: Adalimumab; Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Crohn Disease; Drug Combinations; Female; Follow-Up Studies; Gastrointestinal Agents; Humans; Infliximab; Magnetic Resonance Imaging; Male; Mercaptopurine; Middle Aged; Perineum; Prognosis; Prospective Studies; Rectal Fistula; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

Medical therapy for Crohn's disease (CD) has changed significantly over the past 20 years with increasing use of immunosuppressives. In contrast, surgery rates are still high and there is little evidence that disease outcomes for CD have changed over the past decades. The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population-based Veszprem province database.. Data of 506 incident CD patients were analyzed (age at diagnosis: 31.5 years, s.d. 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups by the year of diagnosis (cohort A: 1977-1989, cohort B: 1990-1998 and cohort C: 1999-2008).. Overall, azathioprine (AZA), systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1- and 5-year probability of AZA use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In a multivariate Cox-regression analysis, decade of diagnosis (P < 0.001, hazard ratio (HR)(cohorts B-C): 2.88-6.53), age at onset (P = 0.008, HR: 1.76), disease behavior at diagnosis (P < 0.001, HR(complicated): 1.76-2.07), and need for systemic steroids (P < 0.001, HR: 2.71) were significantly associated with the time to initiation of AZA therapy. Early AZA use was significantly associated with the time to intestinal surgery in CD patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28-0.65) and after matching on propensity scores for AZA use (HR: 0.42, 95% CI: 0.26-0.67).. This population-based inception cohort has shown that the recent reduction in surgical rates was independently associated with increased and earlier AZA use.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Chi-Square Distribution; Cohort Studies; Crohn Disease; Female; Gastrointestinal Agents; Humans; Hungary; Immunosuppressive Agents; Incidence; Infliximab; Logistic Models; Male; Mercaptopurine; Mesalamine; Methotrexate; Phenotype; Proportional Hazards Models; Retrospective Studies; Steroids; Sulfasalazine; Surveys and Questionnaires

6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective for induction and maintenance therapy of Crohn's disease (CD) and ulcerative colitis (UC). There is an increased risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with 6-MP/AZA. Little, however, is known about the prognosis of IBD patients treated with 6-MP/AZA who develop lymphoma.. We conducted a retrospective review of 8780 records from three tertiary IBD centers and the records of 600 lymphoma patients from an academic Hematology and Oncology Center. The primary endpoint variable was survival of IBD patients with a lymphoma diagnosis treated or not treated with 6-MP/AZA. A secondary endpoint was the relative survival rate (by gender, race, and ethnicity) extrapolated from the Surveillance Epidemiology and End Results (SEER) database, computed for each subject.. Fourteen IBD patients were diagnosed with lymphoma. Twelve had CD and two had UC. Seven patients had treatment with 6-MP/AZA and seven had not. Two patients who received 6-MP/AZA died (both 1 year after diagnosis) and two patients who had not received 6-MP/AZA died (one after 2 years, another 3 years after diagnosis), all from lymphoma. Survival at last follow-up was similar to expected survival based on extrapolated SEER data for both 6-MP/AZA treated and untreated patients.. We found no differences of survival with lymphoma between IBD patients and expected survival for the general population. Also, the prognosis for those IBD patients treated with 6-MP/AZA was not worse than lymphoma patients not treated with 6-MP/AZA. Statistical analysis, however, was limited by the small sample size and heterogeneity of the patients studied.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Lymphoma; Male; Mercaptopurine; Middle Aged; Prognosis; Retrospective Studies; Survival Rate; Tertiary Care Centers; Young Adult

It remains to be shown whether inflammatory bowel disease (IBD) is associated with an increased risk of primary intestinal lymphoproliferative disorders (PILD). We assessed this risk in the CESAME French nationwide prospective observational cohort.. In all, 680 gastroenterologists enrolled 19,486 patients with IBD (Crohn's disease in 60.3%) from May 2004 to June 2005. Follow-up ended on 31 December 2007. Available biopsy samples and surgical specimens from patients with PILD (n = 14) were centralized for review. The reference incidence of PILD in the general population was obtained from the Côte d'Or registry and was used as a comparator to assess the standardized incidence ratio (SIR). The influence of thiopurine exposure was explored in a nested case-control study.. In the CESAME population the crude incidence of PILD was 0.12/1000 patient-years, with a corresponding SIR of 17.51 (95% confidence interval [CI], 6.43-38.11; P < 0.0001). The risk was highest in patients exposed to thiopurines (SIR 49.52, 95% CI 13.49-126.8; P < 0.0001), while it did not reach statistical significance in patients naïve to thiopurines (SIR 4.83, 95% CI, 0.12-26.91; P = 0.37). The odds ratio associated with ongoing thiopurine exposure (vs. naïve) was 2.97 (95% CI, 0.30-infinity; P = 0.38). All 14 cases of PILD were non-Hodgkin's B-cell LD, 78.6% occurred in males, 85.7% arose in IBD lesions, and 45.5% were Epstein-Barr virus-positive. Eleven cases occurred in patients with Crohn's disease. Mean (SD) age at PILD diagnosis was 55.1 (5.6) years and the median time since IBD onset was 8.0 years (interquartile range, 3.0-15.8).. Patients with IBD have an increased risk of developing PILD.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Case-Control Studies; Child; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Incidence; Lymphoproliferative Disorders; Male; Mercaptopurine; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort.. Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought.. 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting.. This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Middle Aged; Purine Nucleotides; Retrospective Studies; Statistics, Nonparametric; Thioguanine; Treatment Outcome; Young Adult

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) with uncertain etiopathogenesis. CD can involve any site of gastrointestinal tract from the mouth to anus and is associated with serious complications such as bowel strictures, perforations, and fistula formation. The incidence and prevalence rates of CD in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Although there are no definitive curative modalities for CD, various medical and surgical therapies are currently applied for diverse clinical situations of CD. However, a lot of decisions on the management of CD are made depending on the personal experiences and choices of physicians. To suggest preferable approaches to diverse problems of CD and to minimize the variations according to physicians, guidelines for the management of CD are needed. Therefore, IBD Study Group of the Korean Association for the Study of the Intestinal Diseases has set out to develop the guidelines for the management of CD in Korea. These guidelines were developed using the adaptation methods and encompass the treatment of inflammatory disease, stricturing disease, and penetrating disease. The guidelines also cover the indication of surgery, prevention of recurrence after surgery, and CD in pregnancy and lactation. These are the first Korean guidelines for the management of CD and the update with further scientific data and evidences is needed.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Budesonide; Crohn Disease; Databases, Factual; Female; Fistula; Humans; Infliximab; Intestinal Perforation; Male; Mercaptopurine; Mesalamine; Methotrexate; Prednisolone; Pregnancy; Recurrence; Risk Factors; Severity of Illness Index; Sulfasalazine

Appropriate treatment of perianal fistulas in Crohn's disease (CD) involves accurate anatomic evaluation. EUS is an accepted imaging method for this purpose. The aim of the current study was to evaluate the clinical and endosonographic characteristics of perianal fistula in CD and to assess its impact on therapy.. All CD patients referred to the Sheba medical center from June 2004 to August 2008 for EUS examination of perianal fistulas were included. Perianal fistulas were diagnosed based on a clinical examination revealing at least one perianal cutaneous orifice. Demographic, clinical and therapeutic data was obtained. EUS was performed using an ultrasound scanner producing a 360° cross sectional image of the anal sphincters.. Fifty six patients were included in the study. Four patients were excluded from the final analysis: 3 because no fistula could be detected by EUS, and one due to inability to tolerate the examination. The mean CD duration was 10±9.16 years (range 1-37). Mean perianal disease duration was 5.3±6.5 (range 1-29) years. 27 patients had perianal involvement at presentation. Among the fistulas diagnosed, 13 were simple (25%) and 39 were (75%) complex. No correlation was found between CD duration or location, patients' age and gender or fistula location with fistula type or complexity. EUS results influenced patient management in 86% of the patients.. CD-associated perianal fistulas are mainly complex. EUS is a well tolerated and informative imaging modality, with significant impact on treatment.

Topics: Abscess; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Infective Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Anus Diseases; Azathioprine; Ciprofloxacin; Crohn Disease; Cutaneous Fistula; Endosonography; Female; Humans; Immunosuppressive Agents; Incidental Findings; Infliximab; Male; Mercaptopurine; Mesalamine; Metronidazole; Middle Aged; Rectal Fistula; Retrospective Studies; Tumor Necrosis Factor-alpha; Young Adult

A 21-year-old Caucasian man with a diagnosis of Crohn's disease (CD) at the age of 14 was admitted to our hospital due to CD flare-up while under scheduled adalimumab (ADA) maintenance therapy. His symptoms remained virtually unchanged following high dose corticosteroid therapy. Seven days later, combination therapy with ADA plus intensive granulocyte/monocyte adsorptive apheresis (GMA) was initiated, which induced clinical remission. Therefore, combination therapy with ADA plus intensive GMA appears to be an effective therapeutic option for patients with severe CD while under scheduled ADA maintenance therapy.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Colonoscopy; Combined Modality Therapy; Crohn Disease; Granulocytes; Humans; Immunosuppressive Agents; Leukapheresis; Leukocyte Reduction Procedures; Male; Mercaptopurine; Mesalamine; Metronidazole; Monocytes; Parenteral Nutrition, Total; Prednisolone; Remission Induction; Young Adult

Medical therapy for Crohn's disease has changed significantly over the past 20 years with the increasing use of immunosuppressants. In contrast, surgery rates are still high and evidence about the the changes in the outcome of Crohn's disease over the past decades is scarce.. The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population-based Veszprém county database.. Data of 506 Crohn's disease patients were analyzed (age at diagnosis: 31.5 years, SD: 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups based on the year of diagnosis (cohort A: 1977-1989, cohort B: 1990-1998 and cohort C: 1999-2008).. Overall azathioprine, systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1 and 5-year probabilities of azathioprine use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In multivariate analysis, decade of diagnosis (P<0.001), age at onset (P = 0.008), disease behavior at diagnosis (P<0.001), and need for systemic steroids (P<0.001) were significantly associated with the time to initiation of azathioprine therapy. Early azathioprine use was significantly associated with the time to intestinal surgery in Crohn's disease patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28-0.65) and after matching on propensity scores for azathioprine use (HR: 0.42,95% CI:0.26-0.67).. This population-based inception cohort showed that reduction in surgical rates was independently associated with increased and earlier azathioprine use.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Cohort Studies; Colectomy; Crohn Disease; Digestive System Surgical Procedures; Female; Humans; Hungary; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Time Factors; Treatment Failure

Acute severe lower gastrointestinal bleeding in Crohn's disease is uncommon, but is a diagnostic and therapeutic challenge. We aimed to identify risk factors for acute lower gastrointestinal bleeding in patients with Crohn's disease and assess the cumulative probability of rebleeding in relation to therapeutic modality.. We retrospectively reviewed the medical records of 70 Crohn's patients (4.0%) with acute severe lower gastrointestinal bleeding and compared these with matched 140 Crohn's patients without bleeding.. The cumulative probability of bleeding after diagnosis of Crohn's disease was 1.7%, 3.6%, 6.5%, and 10.3% after 1, 5, 10, and 20 years respectively. At presentation, the median haemoglobin concentration was 8.4g/dL (range, 4.7-11.6g/dL). Use of azathioprine/6-mercaptopurine decreased the risk of lower gastrointestinal bleeding (OR: 0.525, 95% CI: 0.304-0.906, p=0.021). Bleeding recurred in 29 patients (41.4%) after a median time of 3.2 months (range, 15 days-94.7 months). One out of eleven patients treated with infliximab rebled. The cumulative probability of rebleeding tended to be lower in patients treated with infliximab than in those receiving other treatments (p=0.076).. Azathioprine/6-mercaptopurine may reduce the risk of acute severe lower gastrointestinal bleeding. The rebleeding is common, but infliximab may decrease rebleeding.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Asian People; Azathioprine; Blood Transfusion; Case-Control Studies; Colonic Diseases; Crohn Disease; Embolization, Therapeutic; Female; Gastrointestinal Hemorrhage; Hemoglobins; Hemostasis, Endoscopic; Humans; Ileal Diseases; Immunosuppressive Agents; Infliximab; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Recurrence; Republic of Korea; Retrospective Studies; Risk Factors; Young Adult

Crohn's disease is a chronic inflammatory bowel disease that can involve the whole gastrointestinal tract. The orofacial manifestation of Crohn's disease, which is rare, can develop irrespective of intestinal involvement. These orofacial lesions are often misdiagnosed as simple oral ulcers. Corticosteroids are the mainstay of therapy for orofacial Crohn's disease. However, infliximab, the chimeric monoclonal antibody to tumor necrosis factor-a, is now considered as a primary treatment because of the disease's relatively high rate of steroid resistance. We present a case of deep oral ulcer and periorbital swelling in a 65-year-old woman. She was diagnosed with intestinal Crohn's disease 7 years ago, which was in remission after treatment with an immunosuppressive agent (azathioprine). The patient was given the diagnosed with orofacial Crohn's disease and successfully treated with infliximab.

Topics: Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; Crohn Disease; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Oral Ulcer

To examine sex differences in medical therapy and clinical outcomes in pediatric patients with inflammatory bowel disease (IBD).. We performed a cross-sectional analysis of children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Network collected between May 2007 and May 2010. Clinical remission, disease severity, body mass index (BMI) z scores, normal height velocity, and medication use were analyzed by sex and age.. One thousand four hundred nine patients were included (993 had CD and 416 had UC). No significant sex differences were found in disease severity, BMI, height velocity, or use of medications. Further analysis of combination therapy with infliximab + 6-mercaptopurine/azathioprine and infliximab + methotrexate also did not reveal any differences. No sex differences were found after mediation use was stratified by age (those younger than 13 years and those 13 years old or older).. In this sample of CD and UC pediatric patients, no significant sex differences were found in disease severity, BMI, height velocity, or medication use. Our data do not support the use of sex as a major factor in patient risk stratification for children with IBD. In addition, despite concerns for sex-specific complications of some medications, our analysis did not suggest any sex differences in medication use.

Topics: Adolescent; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Body Height; Body Mass Index; Child; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Female; Growth; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Methotrexate; Severity of Illness Index; Sex Factors; Treatment Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Fatal Outcome; Humans; Immunosuppressive Agents; Infliximab; Lymphoma, T-Cell; Male; Mercaptopurine; Middle Aged

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mercaptopurine; Neoplasms

Topics: Azathioprine; Colorectal Neoplasms; Crohn Disease; Folic Acid; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Mesalamine

Immunosuppressant medications for Inflammatory Bowel Disease can help with both symptoms and disease progression. However, like immunosuppressants used in transplant patients, they are now suspect of contributing to nonmelenoma skin cancer (NMSC). Presented is a case of a 57-year-old Jewish man with Crohn's Disease who was diagnosed with a total of 84 NMSCs. We hope to elucidate the risk of immunosuppressants, particularly the thiopurines, on the development of NMSC.

Topics: Adenocarcinoma; Crohn Disease; Fatal Outcome; Hawaii; Humans; Immunosuppressive Agents; Intestinal Neoplasms; Male; Mercaptopurine; Middle Aged; Skin Neoplasms; Sunlight

Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.

Topics: Adult; Chemical and Drug Induced Liver Injury; Crohn Disease; Disease Progression; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine; Thrombocytopenia

Thiopurine drugs, azathioprine (Imuran) and 6-mercaptopurine (6-MP), are immunomodulators that have been shown to be effective at inducing and maintaining remission in inflammatory bowel disease. Although usually well-tolerated, the occurrence of side effects, typically myelotoxicity and hepatotoxicity, is a major drawback. The side effects can be classified as dose-dependent and independent. Both cholestatic hepatitis and endothelial injury, leading to vascular congestion and nodular regenerative hyperplasia, have been described during therapy with thiopurines, which can end up with portal hypertension. These injuries are potentially mediated by different metabolites. In this article we present a case of hyperammonaemic encephalopathy during therapy with 6-MP, possibly the first recorded in the literature, which probably resulted from the combination of thiopurine-induced liver injury with portal hypertension and the presence of spontaneous portosystemic venous shunts.

Topics: Aged; Chemical and Drug Induced Liver Injury; Crohn Disease; Hepatic Encephalopathy; Humans; Hyperammonemia; Hypertension, Portal; Immunosuppressive Agents; Male; Mercaptopurine; Portal Vein

Circulating concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methyl mercaptopurine (6-MMP) are associated with thiopurine efficacy and may predict toxicity. This study aimed to examine retrospectively the utility of measuring metabolite concentrations in patients with inflammatory bowel disease (IBD) who had continuing symptoms despite stable thiopurine treatment.. Concentrations of 6-TGN and 6-MMP were measured in lysates of washed red cells by high-performance liquid chromatography in peripheral blood drawn from 63 symptomatic patients with IBD (63% men, mean age 37, range 14-74 years, 67% Crohn's disease, 33% ulcerative colitis) treated with azathioprine or 6-mercaptopurine. Short-term clinical outcomes were examined.. 6-TGN concentrations weakly correlated with the thiopurine dose (r = 0.28, P = 0.08). On weight-based criteria, 50% of patients were underdosed. However, metabolite patterns suggested 7 (11%) patients were noncompliant, 18 (29%) were being underdosed, 33 (52%) were refractory to treatment with either appropriate (41%) or elevated (11%) metabolite concentrations, and 6 (10%) had a raised 6-MMP:6-TGN ratio consistent with aberrant thiopurine metabolism. The clinical outcome improved in 40 of 46 (87%) of patients in whom the course of action taken was as recommended by a metabolite-directed algorithm, while 3 of 17 patients (18%) improved where discordant actions were taken (P = 0.0001; Fisher's exact test). Fifteen patients (24%) avoided inappropriate escalation of therapy.. Dose-optimization or toxicity-avoidance strategies frequently result from metabolite testing in patients with inadequate efficacy from thiopurines, with evidence of better outcomes. Thiopurine metabolite testing is a potentially powerful tool for optimizing thiopurine usage in IBD.

Topics: Adolescent; Adult; Aged; Azathioprine; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Treatment Failure; Young Adult

The aim of this study was to analyse postoperative infection in patients undergoing surgery for Crohn's disease (CD) according to the use of preoperative immunosuppressants, including infliximab.. With IRB approval, the records of all patients with CD who underwent abdominal surgery between 2001 and 2008 were reviewed for comorbidity, preoperative medication, type of surgery, stoma construction and postoperative complications. Patients were divided into three categories according to the preoperative medication within 90 days of surgery as follows: infliximab (IFX), other drugs including steroids and/or immunosuppressive agents (OD) and no drugs (ND).. Two hundred and twenty-five patients were identified. Preoperative comorbidity, surgical indication and type of surgery were not significantly different among the three groups. Ileocolic resection was the most common procedure [50.8%, IFX group; 61.2%, OD group; 41.3%, ND group (P = 0.09)]. Other procedures included total colectomy (16%), protectomy (15%) and others (18%). Laparoscopic surgery was performed in 47.7%, 45.9% and 29.3% of patients in the IFX, OD and ND groups, respectively (P = 0.04). There were no differences in postoperative rates of infection [pneumonia (P = 0.14), wound infection (P = 0.35), abscess (P = 0.34) or anastomotic leakage (P = 0.44)]. Reoperation was needed in 3.0%, 8.2% and 2.6% of patients in the IFX, OD and ND groups, respectively. Multiple logistic regression found no relationship between infliximab use and infection.. There was no difference in the rate of postoperative complications among the groups of patients undergoing surgery for CD pretreated with IFX or other immunosuppressive drugs.

Topics: Adolescent; Adult; Aged; Anastomotic Leak; Antibodies, Monoclonal; Azathioprine; Colectomy; Crohn Disease; Drug Therapy, Combination; Female; Humans; Ileum; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Middle Aged; Pneumonia; Prednisone; Rectum; Retrospective Studies; Surgical Wound Infection; Young Adult

Ileal pouch-anal anastomosis continues to be confounded by Crohn's disease-like complications after surgery. Such patients experience significant morbidity and often require either pouch excision or diversion. This study evaluated the effectiveness in our hands of infliximab and/or azathioprine/6-mercaptopurine in treating this patient population.. We conducted a retrospective chart review of all patients who underwent IPAA who experienced Crohn's disease-like complications (pouch fistulas, stricturing small-bowel disease, or pouchitis unresponsive to antibiotics) after ileostomy closure. Patients were segregated according to treatment (azathioprine/6-mercaptopurine only, infliximab only, or both azathioprine/6-mercaptopurine and infliximab) and evaluated for clinical response defined by significant symptomatic improvement and avoidance of stoma.. Of 382 IPAAs, 32 (8.4%) patients developed Crohn's disease-like complications a mean of 17 months after stoma closure. Of these, 22 were treated with azathioprine/6-mercaptopurine and/or infliximab with one lost to follow-up. Overall mean follow-up was 97 ± 11.8 months. Failure rate (requiring stomas) was highest in the fistula group treated with infliximab and azathioprine/6-mercaptopurine (6/13, 46%). Patients with stricturing disease (6) or severe pouchitis (2) were all effectively treated with azathioprine/6-mercaptopurine (5/6) or infliximab (1 patient allergic to azathioprine/6-mercaptopurine) and none of these patients required stomas. In the group not receiving stomas, bowel frequency improved from 8.3 ± 1 to 5.7 ± 0.5 per day (P < .05).. Fistulizing disease after IPAA has the highest failure/stoma rate (46%) despite treatment with infliximab and/or azathioprine/6-mercaptopurine. IPAA patients with stricturing disease and/or antibiotic resistant pouchitis were successfully treated without stomas and all had resolution of symptoms, which suggests that fistulous disease after IPAA should be treated with infliximab, but stricturing disease and antibiotic resistant pouchitis may be effectively treated with azathioprine/6-mercaptopurine only. Such a protocol will potentially minimize the risks associated with infliximab in this difficult group of patients.

Topics: Adult; Anastomosis, Surgical; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Colonic Pouches; Crohn Disease; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Postoperative Complications; Proctocolectomy, Restorative; Retrospective Studies; Treatment Outcome

Topics: Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Female; Hand; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Nevus, Pigmented; Skin Neoplasms; Young Adult

Crohn's disease (CD) patients may be at increased risk for the development of Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), either through exposure to immunosuppressive medications or due to their underlying chronic inflammatory illness. There are limited data regarding the natural history of CD following treatment of lymphoma. We present a series of CD patients who were treated for lymphoma and describe the natural history of their CD following lymphoma treatment.. Retrospective case series from three academic referral centers was used. All CD patients with a history of lymphoma were identified. Demographic data, CD medication exposure, and surgical procedures before and after lymphoma treatment were recorded.. Nine CD patients with a history of lymphoma were identified. Eight individuals received chemotherapy, while one patient was observed without treatment. Eight patients remained free of lymphoma for a mean of 72.8 months (range 1-276 months). The ninth patient had recurrence of his HL 3 years after lymphoma diagnosis. Following lymphoma treatment, two patients had quiescent CD with no specific therapy. Three patients demonstrated significant clinical relapse of their CD and a fourth patient developed CD after treatment of her lymphoma, which ultimately required long-term immunomodulator therapy with 6-mercaptopurine or methotrexate in the first three patients, and azathioprine in the fourth. Four patients required CD surgery after lymphoma treatment.. We report on the clinical course of CD in patients who develop lymphoma. Significant clinical relapse of CD following successful medical treatment of lymphoma occurred frequently in patients with a history of this neoplasm.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Crohn Disease; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Lymphoma; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis often associated with inflammatory bowel disease (IBD). The literature has suggested that PG-IBD is usually associated with ulcerative colitis.. We reviewed the PG-IBD cases at the Mater Health Services' Adult Hospital in Brisbane between 1998 and 2009 through assessment of a comprehensive web database of IBD patients and verification of chart information of PG-IBD cases.. PG-IBD at Mater was associated with clinically mild colonic IBD, with erythema nodosum, and with female sex. All PG-IBD responded eventually to increased immunomodulatory therapy.. We discuss why PG-IBD is associated with clinically mild colonic IBD be it ulcerative colitis, Crohn's or indeterminate colitis.

Topics: Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporins; Female; Humans; Hydrocortisone; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Pyoderma Gangrenosum; Sex Factors; Wounds and Injuries

The introduction of immunosuppressants and biologic agents has led to active debate and research about optimal therapeutic strategies considering risk factors and predictors of clinical outcome in inflammatory bowel disease (IBD). Data about gender-specific treatment differences and risk factors is lacking for IBD. The aim of the present study was to evaluate gender-related differences in the treatment of a distinct IBD patient population treated in the Rhein-Main region, Germany.. Data about past medical history, disease status and medical treatment of 986 outpatients treated in ten gastroenterological practices and three hospitals were collected from November 1st 2005-July 31st 2007 and analyzed with regard to gender-related differences in therapy and disease management.. With the exception of an extended disease duration in women, no significant gender-related differences in demographic and clinical characteristics were observed. Men showed a significantly higher remission rate than women (p=0.025), while women received significantly less immunosuppressive medication compared to men (p=0.011). In addition, treatment with immunosuppressants was not different in women with child-bearing potential compared to menopausal women.. Our investigation demonstrates for the first time gender-specific differences in the therapeutic management in a large cohort of IBD patients.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Cyclosporine; Female; Germany; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Practice Patterns, Physicians'; Prospective Studies; Remission Induction; Severity of Illness Index; Sex Factors; Tacrolimus

Topics: Acyclovir; Antiviral Agents; Crohn Disease; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunosuppressive Agents; Male; Meningitis, Viral; Mercaptopurine; Middle Aged; Polyradiculopathy

To assess the incidence of hemophagocytic lymphohistiocytosis (HLH) in a well-defined population of children with inflammatory bowel disease (IBD) and evaluate the common clinical and laboratory characteristics of individuals with IBD who developed HLH.. We conducted a retrospective study of all children who developed HLH over an 8-year period. The incidence of HLH in patients with IBD was calculated using US census data and a statewide project examining the epidemiology of pediatric IBD.. Among children in Wisconsin, 20 cases of HLH occurred during the study period; 5 cases occurred in children with IBD. Common characteristics include: Crohn's disease (CD), thiopurine administration, fever lasting more than 5 days, lymphadenopathy, splenomegaly, anemia, lymphopenia, and elevated serum triglycerides and ferritin. Of the patients, 4 had primary Epstein-Barr virus infections. The incidence of HLH among all children in Wisconsin was 1.5 per 100 000 per year. The risk was more than 100-fold greater for children with CD (P < .00001).. Pediatric patients with CD are at increased risk for developing HLH; primary Epstein-Barr virus infection and thiopurine administration may be risk factors.

Topics: Adolescent; Anemia; Azathioprine; Crohn Disease; Epstein-Barr Virus Infections; Ferritins; Fever; Humans; Immunosuppressive Agents; Incidence; Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic; Lymphopenia; Mercaptopurine; Retrospective Studies; Splenomegaly; Triglycerides; Wisconsin

The aim was to investigate the impact of systemic steroid treatment (SST) and immunomodulators (IM) on disease course in children with inflammatory bowel disease (IBD).. All IBD patients in eastern Denmark <15 years of age diagnosed in the period 1998-2006 starting their first SST within 2 years of diagnosis were included.. In all, 205 IBD patients were included (105 Crohn's disease [CD], 100 ulcerative colitis [UC]). Eighty-seven CD (83%) and 77 (77%) UC patients started SST. In CD, 55 (63%), 25 (29%), and 7 (8%) had a complete response (CR), partial response (PR), or no response (NR), respectively, 30 days after initiation of SST. Fifty (58%) had a prolonged response (PRO) and 32 (37%) were steroid-dependent (SD). In UC, 49 (64%), 22 (28%), and 6 (8%) had CR, PR, and NR, respectively, and 38 (49%) and 38 (49%) were PRO and SD. The cumulative risk of surgery 1 year after starting SST was 11.5% and 7.8% for CD and UC patients, respectively. After a median follow-up period of 5.1 years, no difference in the risk of surgery or periods of activity and remission was found between PRO and SD in CD or UC. IM use was associated with a milder disease course in UC patients.. No difference in surgery rates or disease course was found between SD and PRO. Surgery rates were lower than rates from studies predating the era of IM, indicating a putative effect of IM on disease course.

Topics: Adolescent; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Denmark; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Mesalamine; Remission Induction; Time Factors; Treatment Outcome

Topics: Azathioprine; Colonic Diseases; Crohn Disease; Gastrointestinal Agents; Hemangioendothelioma; Hemangioma; Humans; Ileal Diseases; Immunocompromised Host; Immunologic Factors; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Splenic Neoplasms; Tumor Necrosis Factor-alpha

The clinical epidemiological studies included in this thesis fall into three parts. The first part includes studies on birth outcome in women with ulcerative colitis. The second part includes pharmacoepidemiological studies on birth outcome after anti-inflammatory drug therapy in pregnancy, including patients with ulcerative colitis and Crohn's disease. The third part (and the latest publications) includes birth outcome in women with Crohn's disease; and the methods of cohort establishment in these studies are developed and improved due to the knowledge gathered from conducting the earlier studies. The birth outcomes in women with ulcerative colitis are examined in a nationwide, Danish, cohort of women based on data from the Danish National Hospital Discharge Registry and the Danish Medical Birth Registry, and within a Hungarian case-control data set. Our data suggest: 1) Significantly increased risk of preterm birth when women give birth 0-6 months after establishment of the diagnosis. It is considered whether the increased risk may be influenced by disease activity around the time of establishing the diagnosis. 2) No increased risk of giving birth to children with low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). 3) Significantly increased risk of some selected congenital abnormalities (limb deficiencies, obstructive urinary and multiple congenital abnormalities). No other studies have examined the risk of selected congenital abnormalities in children born by women with ulcerative colitis. The pharmacoepidemiological studies on birth outcomes after use of anti-inflammatory drug therapy in pregnancy, including women with ulcerative colitis and Crohn's disease, are based on data from the Hungarian case-control data set, a countywide Danish prescription Database, the Danish National Hospital Discharge Registry, the Danish Medical Birth Registry, and review of selected medical records. After exposure to sulfasalazine during pregnancy our data suggest. No significantly increased overall relative risk of congenital abnormalities and no significantly increased risks of selected congenital abnormalities. After exposure to 5-aminosalicylic acid during pregnancy our data suggest. No significantly increased relative risk of low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). A significantly increased relative risk of preterm birth and stillbirth in ulcerative

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acid; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Confidence Intervals; Crohn Disease; Denmark; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Odds Ratio; Perinatal Care; Pharmacoepidemiology; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Registries; Sulfasalazine; Surveys and Questionnaires; Young Adult

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Colonoscopy; Crohn Disease; Diagnosis, Differential; General Practice; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Mesalamine; Prognosis

Topics: Adolescent; Alopecia; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow; Crohn Disease; Drug Hypersensitivity; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Methyltransferases; Pancytopenia; Phenotype; Purine-Pyrimidine Metabolism, Inborn Errors

The long-term benefits of combining scheduled infliximab with concomitant immunomodulators [azathioprine or 6-mercaptopurine (6-MP)] in patients with Crohn's disease are unclear. Historical cohort followed for 5 years after initiation of infliximab for active Crohn's disease. Data were available on 123 patients who received scheduled maintenance infliximab infusions, for up to 5 years after initiation of infliximab. Clinical remission rates in the entire cohort were 73% (82/113) at 1 year, 65% (65/100) at 2 years, and 58% (21/36) at 5 years. Remission rates with maintenance infliximab were significantly improved in those receiving concomitant immunomodulators at 1 year (86% versus 68%, P = 0.03), but not at 2 years (80% versus 72%, P = 0.4). In a multivariate logistic regression model, concomitant immunomodulator use was not associated with a significantly improved odds ratio of remission in patients on maintenance infliximab [odds ratio (OR) 1.1, 95% confidence intervals (CI) 0.9-1.2, P = 0.9]. The risk of surgery was significantly reduced in those receiving immunomodulators at the commencement of maintenance infliximab (OR 0.3, 95% CI 0.1-0.7, P = 0.01), but not in patients who continued maintenance concomitant therapy (OR 0.4, 95% CI 0.1-1.5, P = 0.1). The combination of maintenance infliximab and an immunomodulator produced modest improvements in outcomes beyond maintenance infliximab alone in this cohort.

Topics: Adult; Antibodies, Monoclonal; Azathioprine; Chi-Square Distribution; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunologic Factors; Infliximab; Infusions, Intravenous; Logistic Models; Male; Mercaptopurine; Middle Aged; Regression Analysis; Remission Induction; Statistics, Nonparametric; Treatment Outcome

Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab.. A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy.. CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy.. Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Topics: Adolescent; Adult; Age Factors; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Chi-Square Distribution; Crohn Disease; Female; Gastrointestinal Agents; Genetic Predisposition to Disease; Humans; Infliximab; Israel; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Mutation; Nod2 Signaling Adaptor Protein; Phenotype; Retrospective Studies; Steroids; Treatment Outcome; Young Adult

Azathioprine (AZA) liver toxicity arises in approximately 3% of inflammatory bowel disease patients and may result in treatment discontinuation.. To describe the tolerance to mercaptopurine (MP) in patients with previous AZA-related liver injury.. Retrospective description of 31 patients (14 Crohn's, 17 ulcerative colitis), in which AZA therapy was interrupted because of liver injury, with MP started as alternative therapy.. Mean AZA dose was 2.2 +/- 0.4 mg x kg/day. Median (interquartile range) of AZA exposure when liver injury was detected was 2 months (1-5.2). The type of AZA-related injury was cytolitic in 32%, cholestatic in 39% and mixed in 29%. After a median of 2.5 months (0.7-5.2), the therapy was switched to MP at a mean dose of 1.3 +/- 0.2 mg x kg/day. Median of follow-up of MP therapy was 32 months (8-54). In 87.1% of patients (95%CI: 70-96%), MP was tolerated without further liver injury; of these, 77.4% tolerated full MP doses and 9.7% tolerated lower doses. In a further cohort of 12.9% of patients, (95%CI: 3-29%), liver injury reappeared (two cholestasis, two mixed), 1-3 months after the onset of MP exposure.. The administration of MP is a good alternative in patients with AZA-related liver injury, before thiopurines are definitely discarded.

Topics: Adolescent; Adult; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Smoking and a lack of immunosuppressive (IS) therapy are considered risk factors for intestinal surgery in Crohn's disease (CD). Good evidence for the latter is lacking. The objective of this study was to evaluate the impact of thiopurine treatment on surgical recurrence in patients after first intestinal resection for CD and its possible interaction with smoking.. Data on 326 patients after first intestinal resection were retrieved retrospectively, and subjects were grouped according to their postoperative exposure to thiopurines. Treatment with either azathioprine (AZA) or 6-mercaptopurine (6-MP) was recorded on 161 patients (49%). Smoking status was assessed by directly contacting the patients.. Surgical recurrence occurred in 151/326 (46.3%) patients after a median time of 71 (range 3-265) months. Cox regression revealed a significant reduction of re-operation rate in patients treated with AZA/6-MP for > or = 36 months as compared with patients treated for 3-35 months, for less than 3 months, and to those without postoperative treatment with AZA/6-MP (P=0.004). Cox regression analysis revealed treatment with thiopurines for > or = 36 months (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.23-0.76, P=0.004) and smoking (HR 1.6; 95% CI 1.14-2.4, P=0.008) as independent predictors for surgical recurrence. Furthermore, longer duration of disease tended to be protective (HR 0.99; 95% CI 0.99-1.0, P=0.067).. Long-term maintenance treatment with AZA/6-MP reduces the risk of surgical recurrence in patients with CD. We also identified smoking as a risk factor for surgical recurrence.

Topics: Adolescent; Adult; Age Distribution; Azathioprine; Cohort Studies; Colectomy; Crohn Disease; Female; Follow-Up Studies; Humans; Incidence; Male; Mercaptopurine; Postoperative Care; Probability; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution; Smoking; Statistics, Nonparametric; Time Factors; Treatment Outcome; Young Adult

Clinically diagnosed metastasis to the thyroid gland is exceptionally rare and may present diagnostic issues on fine needle aspiration. The most common primary sites of metastases to the thyroid are cancers of the lung, breast, skin (especially melanoma), colon, and kidney. Herein, we report a case of metastatic Merkel cell carcinoma to the thyroid presenting as a 2.1-cm solid nodule in a 50-year-old male with a previous history of Merkel cell carcinoma of the upper extremity. The aspirates were moderately to highly cellular featuring small to intermediate sized cells with scant to no cytoplasm, round-to-oval nuclei with finely dispersed chromatin, and predominantly arranged as scattered single cells. There was focal nuclear molding, numerous mitoses, and karyorrhectic nuclei. The differential diagnosis centered on the "small round blue cell" tumor group such as medullary thyroid carcinoma and non-Hodgkin lymphoma. However, in light of our patient's previous history, the FNA findings were most consistent with a metastasis of Merkel cell carcinoma. In patients with a known history of a primary neoplasm, the differential diagnosis of a thyroid nodule should always include potential metastasis.

Topics: Biopsy, Fine-Needle; Carcinoma, Merkel Cell; Carcinoma, Small Cell; Crohn Disease; Diagnosis, Differential; Fibrosis; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Skin Neoplasms; Thyroid Neoplasms

Topics: Antimetabolites, Antineoplastic; Crohn Disease; Female; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Middle Aged; Treatment Outcome

Topics: Adult; Amyloidosis; Crohn Disease; Edema; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Nephrotic Syndrome; Prednisolone; Serum Amyloid A Protein

Several reports suggest an increased rate of adverse reactions to azathioprine in patients with Crohn's disease.. To compare the incidence of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease (IBD) with that in patients with vasculitis.. This retrospective analysis was performed using data collected in three databases by two university hospitals (241 patients with IBD and 108 patients with vasculitis) and one general district hospital (72 patients with IBD).. The cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease equalled that of ulcerative colitis (UC) (2.6% vs. 3.7%) and this did not differ from vasculitis patients (2.6% vs.1.9%). In addition, the cumulative incidence of thiopurine-induced acute pancreatitis in UC patients was not different from that in vasculitis patients. In the IBD group, 100% of thiopurine-induced acute pancreatitis patients were women, whereas in the vasculitis group the two observed thiopurine-induced acute pancreatitis cases (n = 2 of 2) concerned were men (P = 0.012).. In this study, the alleged higher cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease compared with vasculitis or UC patients was not confirmed. Female gender appears to be a risk factor for developing thiopurine-induced acute pancreatitis in IBD patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimetabolites; Azathioprine; Crohn Disease; Female; Humans; Male; Mercaptopurine; Middle Aged; Pancreatitis; Retrospective Studies; Statistics as Topic; Young Adult

Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients.. Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses.. Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 10⁹/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03–10.57, P = 0.036).. These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Colitis, Ulcerative; Crohn Disease; Exons; Female; Humans; Immunosuppressive Agents; Japan; Male; Mercaptopurine; Middle Aged; Multidrug Resistance-Associated Proteins; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Budesonide; Chromosomes, Human, Pair 7; Combined Modality Therapy; Crohn Disease; Cytarabine; Drug Therapy, Combination; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunosuppressive Agents; Leukemia, Monocytic, Acute; Male; Mercaptopurine; Mesalamine; Methyltransferases; Monosomy; Myelodysplastic Syndromes; Prednisone; Young Adult

Topics: Antibodies, Monoclonal; Combined Modality Therapy; Crohn Disease; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Postoperative Care; Secondary Prevention; Treatment Outcome

Topics: Adolescent; Anti-Inflammatory Agents; Antibodies, Monoclonal; Anus Diseases; Colostomy; Combined Modality Therapy; Crohn Disease; Female; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine

Benefits of immunosuppressive therapy in Crohn's disease have been demonstrated in controlled trials; however, it is unclear whether these drugs alter the longer-term natural history of this condition.. To assess changes in disease outcomes in a population-based cohort of patients diagnosed in Cardiff from 1986 to 2003. Case notes from Crohn's disease incidence studies in Cardiff were reviewed retrospectively for disease characteristics and follow-up information on drug therapy, and the need for surgery for Crohn's disease. The study population was divided into three groups by year of diagnosis (Group A=1986-1991, Group B=1992-1997 and Group C=1998-2003).. 341 patients were included. Kaplan-Meier (KM) analysis showed increasing use of immunosuppressants over time. At 5 years after diagnosis this was 11% in Group A, 28% in Group B, and 45% in Group C (p=0.001) and the median time to start of thiopurines was 77, 21 and 11 months in Group A, B and C respectively. There was a significant reduction in long-term steroid use at 5 years post diagnosis: 45 (44%), 31 (31%) and 24 (19%) patients in Group A, B and C respectively (p=0.001). KM analysis showed a significant reduction in the cumulative probability of intestinal surgery: At 5 years this was 59% (Group A), 37% (Group B) and 25% (Group C) (p=0.001). In a multivariate Cox analysis, year of diagnosis, disease location, oral corticosteroids within 3 months of diagnosis and early thiopurine use (within the first year of diagnosis) were all independent factors affecting likelihood of intestinal surgery.. This population-based cohort shows marked changes in rates of surgery, and the reduction is independently associated with year of diagnosis, and associated temporally with increased and earlier thiopurine use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Child; Child, Preschool; Crohn Disease; Digestive System Surgical Procedures; Drug Administration Schedule; Epidemiologic Methods; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Neoplasms; Wales; Young Adult

Thiopurines are a common, effective means of maintaining remission in pediatric Crohn disease (CD). Methotrexate (MTX) may be considered for those intolerant of or unresponsive to thiopurines. The purpose of this study was to examine the effectiveness of MTX as maintenance therapy in patients previously treated with thiopurines.. All of the patients at Nationwide Children's Hospital from 1998 to 2007 with an International Classification of Diseases code indicative of CD were identified. Patients with a diagnosis of CD, a history of prior thiopurine use, no current infliximab therapy, and at least 6 months of follow-up after MTX initiation were included. The primary outcome was defined as steroid-/infliximab-free remission determined by the physician global assessment at 6 and 12 months. Secondary outcomes included subsequent treatment with infliximab and/or corticosteroids, rate of discontinuation of MTX, and adverse events (AEs).. Twenty-seven patients (17 boys, 63%) with a mean age at diagnosis of 12.3 ± 0.7 years and mean disease duration of 1.49 ± 0.3 years were identified. Indications for MTX included nonresponse to thiopurines, AE, and poor adherence to thiopurines. At 6 and 12 months, 13 of 27 patients (48.1%) and 9 of 27 patients (33.3%), respectively, were in steroid-/infliximab-free remission. A total of 10 patients (37.0%) required infliximab therapy during the 12-month period and 5 patients discontinued MTX. Nausea was the most commonly reported AE. Transient transaminase elevation occurred in 4 patients and transient leukopenia in 2 patients.. MTX can be effective as maintenance therapy for patients with pediatric CD previously intolerant of or unresponsive to thiopurines; however, greater than one third of this cohort required escalation to antitumor necrosis factor therapy within 12 months following MTX initiation. MTX was well tolerated.

Topics: Antibodies, Monoclonal; Child; Crohn Disease; Drug Tolerance; Female; Humans; Infliximab; Leukopenia; Male; Mercaptopurine; Methotrexate; Methyltransferases; Nausea; Outcome Assessment, Health Care; Patient Compliance; Remission Induction; Retrospective Studies; Transaminases

6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported.. This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated.. Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 10(8) red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P < 0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed.. The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported.

Topics: Adolescent; Azathioprine; Biomarkers, Pharmacological; Child; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Female; Follow-Up Studies; Guanine Nucleotides; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Japan; Male; Mercaptopurine; Remission Induction; Retrospective Studies; Thionucleotides; Treatment Outcome

Allopurinol has been presented as a safe and effective adjunct to thiopurine therapy in inflammatory bowel disease (IBD). We aimed to determine the rate of infectious complications and clinical successes with a combination of thiopurine/allopurinol in IBD, and to identify which variables predict 6-thioguanine, 6-methylmercaptopurine, and white blood cell levels. Additionally we aimed to identify which variables predict complications.. A retrospective database search identified patients with inflammatory bowel disease on both thiopurines and allopurinol. Regression modeling was used to identify which variables predicted metabolite levels, white blood cell levels, and complications.. Twenty-seven subjects were found, with 20 treated intentionally and 7 inadvertently after a concurrent gout diagnosis. Thirteen of 20 patients had a major clinical improvement and 7 of 16 stopped steroids. Five infectious complications occurred. These included 2 cases of shingles, and one each of PCP, EBV, and viral meningitis. Significant predictors of metabolite levels included the dose of thiopurine and allopurinol, age, and BMI. Low white blood cell count levels were associated with increased doses, high BMI, and older age. Despite having only 5 events, there was a difference in absolute lymphocyte count between patients with and without infection (median 200 per mm³ vs 850 per mm³ respectively, p=0.0503).. Adjunctive allopurinol therapy in shunting patients produced major clinical improvement in 48% of patients. However, a surprising number of opportunistic infections have occurred. Low absolute lymphocyte count may be a previously unrecognized indicator of risk of opportunistic infections.

Topics: Adult; Allopurinol; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Opportunistic Infections; Retrospective Studies; Young Adult

Adalimumab is a fully-humanized anti-TNF a antibody that has showed its efficacy in Crohn's disease (CD) adult patients. Its less immunogenic composition seems to be an advantage compared to previous anti-TNF α, mainly infliximab. Good response to adalimumab has been reported in patients naïve to infliximab, in those in whom infliximab has shown no efficacy and in those intolerant or who have lost previous response to it. Adalimumab has shown also its efficacy as a second-line anti-TNF α in small series of paediatric CD but data regarding its use in children naïve to infliximab are scarce.. To report our experience with adalimumab as first line anti-TNF α treatment in paediatric CD.. Four CD paediatric patients (2 boys) previously naïve to infliximab have received adalimumab. Mean age at diagnosis: 13 years, 4 months. Adalimumab was initiated in our patients soon after diagnosis (mean time from diagnosis: 8.5 months, range: 1 month 15 days-14 months) at decreasing loading doses (160 mg and 80 mg two weeks after) and then 40 mg subsequently every two weeks.. The four patients entered in remission after the first dose of adalimumab (mean previous PCDAI: 35, mean PCDAI after first dose: 3.6). No adverse effects were registered. Azathioprine was stopped after 4 months of combination therapy, without loss of efficacy or adverse reactions attributable to immunogenicity. All the 4 patients have remained in remission on adalimumab monotherapy for a mean follow-up of 17 months (range 9-20 months).. Adalimumab has shown its efficacy in our paediatric CD patients naïve to other anti-TNF α drugs. Early introduction of anti-TNF α antibodies in these patients could help to a better control of the disease. Its less immunogenicity and the possibility of a home-based administration are advantages when compared to other parenteral anti-TNF treatments. Change to monotherapy after prior successful combination therapy with azathioprine and adalimumab is a safe strategy that can help to minimize possible risks of intensive immunomodulation.

Topics: Adalimumab; Adolescent; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Crohn Disease; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Crohn Disease; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Treatment Outcome

Topics: Antibodies, Monoclonal; Crohn Disease; Exanthema; Female; Gastrointestinal Agents; Humans; Infliximab; Mercaptopurine; Methotrexate; Middle Aged; Peripheral Nervous System Diseases; Steroids; Treatment Outcome; Tumor Necrosis Factor-alpha

The main cause of azathioprine (AZA)/6-mercaptopurine (6MP)-induced adverse reactions is a reduction in the activities of the metabolizing enzymes thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA). Adverse reactions develop at a high frequency in Japanese patients at half the dose required for European and American patients; however, the association with TPMT and ITPA gene polymorphisms in Japanese has not been fully investigated.. Gene mutations of TPMT and ITPA, the major AZA/6-MP -metabolizing enzymes, were investigated retrospectively in 16 Japanese patients with inflammatory bowel disease (IBD) in whom AZA/6MP treatment induced adverse reactions.. The TPMT gene was found to have a wild-type sequence in all patients, but in the ITPA gene a mutation, 94C>A, was detected at a rate of 50% (8/16), with 83.3% (5/6) occurring in patients with acute bone marrow suppression and 75% (3/4) in those with agranulocytosis. The 94C>A allele frequency was 10 of 32 (0.313; 95% CI, 0.180-0.486). Adverse reactions developed earlier in patients with the 94C>A mutation. However, in half the patients, no gene polymorphism was noted.. It is suggested that the ITPA gene mutation is closely related to the adverse reactions of AZA/6-MP in Japanese patients, and screening for the mutant allele is useful for predicting the most serious adverse reactions, agranulocytosis and acute bone marrow suppression.

Topics: Adolescent; Adult; Aged; Asian People; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inosine Triphosphatase; Japan; Male; Mercaptopurine; Methyltransferases; Middle Aged; Mutation; Polymorphism, Genetic; Pyrophosphatases; Retrospective Studies; Young Adult

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Crohn Disease; Female; Humans; Immunocompromised Host; Infliximab; Lymphoma, T-Cell; Male; Mercaptopurine; Young Adult

Immunomodulatory drugs play a major role in maintaining remission and steroid sparing in children with Crohn disease. Although thiopurine agents are commonly used, unresponsiveness or intolerance to these drugs is common. The efficacy of methotrexate in maintenance of remission has been shown in adult Crohn disease; however, pediatric data are limited. Our goal was to evaluate the efficacy and safety of methotrexate in induction and maintenance of clinical remission in children with active Crohn disease who failed thiopurine treatment.. In a retrospective multicenter study, efficacy of methotrexate in inducing and maintaining remission or response was assessed by Harvey-Bradshaw activity index, paediatric Crohn disease activity index and steroid use, in 25 children with Crohn disease, refractory or intolerant to thiopurine analogues.. Crohn disease was diagnosed at a mean age of 11.1 +/- 3.1 years and methotrexate was initiated at age 14.5 +/- 3.1 years. The median methotrexate dose was 12.5 mg/m2. Remission was achieved in 16 patients (64%), and response in 6 patients (24%). Out of 18 patients treated for longer than 6 months, 83% were in remission or response after 12 months of treatment. The mean duration of remission and response was 10.8 +/- 8.8 months. Steroid withdrawal was possible in 12/16 patients (75%) receiving steroids at methotrexate introduction. Adverse effects were observed in 6 patients (24%) including nausea and vomiting in 3, elevation of liver enzymes in 2 and pancreatitis in 1 patient.. Methotrexate is beneficial in maintaining remission and steroid-sparing treatment in children with Crohn disease following failure of thiopurine therapy.

Topics: Administration, Oral; Adolescent; Azathioprine; Child; Crohn Disease; Drug Resistance; Drug Tolerance; Female; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Male; Mercaptopurine; Methotrexate; Remission Induction; Retrospective Studies; Steroids

A 15-year-old, woman, Crohn's disease patient, who carried the TPMT *3C heterozygous mutant, complained of alopecia 3 days after starting 6-mercaptopurine (6-MP) and then developed severe myelosuppression 6 weeks after starting 6-MP. The alopecia involved scalp hair only (body hair preserved) and was dominant in the temporal region. Following these side effects, transient remission of Crohn's disease occurred. Myelosuppression due to 6-MP is a rare but life-threatening side effect that is difficult to predict despite continuous monitoring of complete blood cell counts. In the present case, 6-MP-induced alopecia preceded myelosuppression and progressed rapidly as the myelosuppression worsened.

Topics: Adolescent; Alopecia; Bone Marrow; Crohn Disease; Female; Humans; Mercaptopurine

Topics: Adult; Allopurinol; Azathioprine; Clostridioides difficile; Colitis, Ulcerative; Crohn Disease; Drug Interactions; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Female; Gout; Gout Suppressants; Histoplasmosis; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Psoas Abscess; Tumor Necrosis Factor-alpha

Topics: Anemia, Sickle Cell; Antibodies, Monoclonal; Antiviral Agents; Child; Crohn Disease; Cytomegalovirus; Cytomegalovirus Infections; Fatal Outcome; Ganciclovir; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine

We sought to determine whether treatment with steroids, immunosuppressives (ISs), and anti-tumor necrosis factor (TNF) agents is associated with an increased risk of adverse events in patients with Crohn's disease (CD).. This study analyzed claims from patients with CD and controls without CD from the United States with private insurance (2002-2005). Patients were classified by treatment with steroids, ISs, anti-TNF agents, combinations of two or three, and none of these medications. Follow-up adverse events in patients with CD and controls were compared across different treatment categories and are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Within the CD patients, a subset analysis examined the relationship between therapies and outcomes.. A total of 22,310 patients with CD (8,581 longitudinal cohort cases) and 111,550 controls were identified. Compared with the controls, CD patients had higher rate ratios for all pre-specified events. Within the CD patient population subgroup, monotherapy with steroids, ISs, or anti-TNF agents was associated with an increased risk of tuberculosis (TB) (HR 2.7; 95% CI, 1.0-7.3), candidiasis (HR 2.7; 95% CI, 1.8-4.0), herpes zoster (HR 1.7; 95% CI, 1.0-2.7), sepsis (HR 1.3; 95% CI, 1.1-1.5), demyelinating conditions (HR 3.2; 95% CI, 1.5-6.9), and cervical dysplasia (HR 1.5; 95% CI, 1.2-2.0) as compared with patients not receiving these medications. The use of two or three of these medications further increased these risks: TB (HR 7.4; 95% CI, 2.1-26.3), candidiasis (HR 3.8; 95% CI, 2.0-7.6), herpes zoster (HR 3.7; 95% CI, 1.8-7.5), sepsis (HR 1.6; 95% CI, 1.2-2.1), and cervical dysplasia (HR 1.8; 95% CI, 1.1-3.0).. Treatment with steroids, ISs, or anti-TNF agents singly and in combination in patients with CD is associated with increased risks of infection, demyelinating disorders, and cervical dysplasia.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Budesonide; Case-Control Studies; Comorbidity; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Middle Aged; Outcome Assessment, Health Care; Prednisone; Prevalence; Proportional Hazards Models; Steroids; United States

There is currently no standard of care for the management of postoperative Crohn's disease (CD), partly because data from definitive trials are lacking. Despite the absence of such data, many experts advocate the selective use of azathioprine (AZA) or 6-mercaptopurine (6MP) in the prevention of postoperative recurrence in patients with risk factors for recurrence. In the current issue of The American Journal of Gastroenterology, Peyrin-Biroulet and colleagues quantified the efficacy of AZA/6MP in this setting by performing a meta-analysis of AZA/6MP trials. The implications of this work, both for the current management of postoperative Crohn's and the future design of clinical trials that are definitive in this group of patients, are discussed.

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Recurrence

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor beta CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention.

Topics: Adult; Azathioprine; Carcinogens; Cell Proliferation; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Lymphocyte Activation; Male; Mercaptopurine; Mutagenicity Tests; Mutagens; Mutation; Regression Analysis; T-Lymphocytes

Orbital myositis is an extremely rare extra-intestinal manifestation of Crohn's disease. Herein we describe a patient with self-limiting episodes of episcleritis and uveitis prior to the diagnosis of Crohn's disease, and subsequent development of recurrent orbital myositis with radiological features mimicking thyroid eye disease.

Topics: Adult; Crohn Disease; Diagnosis, Differential; Female; Glucocorticoids; Graves Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Mercaptopurine; Methylprednisolone; Oculomotor Muscles; Orbital Myositis; Recurrence; Scleritis; Tomography, X-Ray Computed; Uveitis, Anterior

The pivotal role of optimizing pharmacotherapy is generally accepted in somatic rehabilitation of various specialities like cardiopulmonary rehabilitation. No data exist as to whether significant modifications of pharmacotherapy occur during gastroenterological rehabilitation of Crohn's Disease (CD) patients.. A single centre chart review was performed including patients with International Classification of Disease Codes for CD (ICD K50). The Harvey-Bradshaw activity index (HBI) and CD medications were protocolled at the beginning and end of in-patient rehabilitation.. 337 of 355 patients with ICD K50 fulfilled the predefined diagnostic criteria of mild to moderate CD (250 female, 87 male, average age of 40 (95% confidenceinterval, 29-51)). Disease activity decreased from 4.9 to 3.7 by 1.2 (0.75-1.37) Units during 23 (20-35) days. On admission, 120 (36%) patients received one and 158 (47%) received two to five CD drugs. CD drug prescriptions changed in 162 (48%) patients. Overall, 116 (34%) patients received systemic steroids which were stopped in 14 patients (p<0.05). In the remaining 102 patients the cortisol equivalence doses decreased from 77 to 56 mg by 21 (14-28) mg. The number of patients on azathioprine (AZT) increased from 98 to 108 (p<0.05). The average AZT dose increased from 1.81 to 1.99 mg/kg in 97 rehabilitants continuously treated.. Our results describe an association between rehabilitation and significant changes of CD-specific pharmacotherapy in line with current treatment guidelines. This supports the concept that future studies on effects of gastroenterological rehabilitation should control for changes in pharmacotherapy.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Biological Products; Combined Modality Therapy; Crohn Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Germany; Guideline Adherence; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Middle Aged

The in vitro susceptibility of human- and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP, even at high concentrations (> or =64.0 microg/ml). Among rapidly growing mycobacteria, Mycobacterium phlei was susceptible to 6-MP and AZA whereas Mycobacterium smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-aminosalycilic acid [mesalamine]) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin, used as control drugs, were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6-MP and ciprofloxacin resulted in significantly higher CFU than use of ciprofloxacin alone. These data may partially explain the paradoxical response of Crohn's disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs, i.e., they do not worsen with anti-inflammatory treatment as would be expected with a microbiological etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn's disease: AZA drugs may confound interpretation of data on therapeutic responses for both antibiotic-treated and control groups.

Topics: Animals; Azathioprine; Bacteriological Techniques; Cattle; Cattle Diseases; Colony Count, Microbial; Crohn Disease; Culture Media; Humans; Immunosuppressive Agents; Mercaptopurine; Microbial Sensitivity Tests; Mycobacterium avium subsp. paratuberculosis; Paratuberculosis; Reagent Kits, Diagnostic

Thiopurines are a mainstay of immunomodulator therapy in inflammatory bowel disease (IBD). Despite their efficacy, some patients may have a poor response due to inability to achieve adequate levels of the active metabolite, 6-thioguanine (6-TGN). Others experience hepatotoxicity, which correlates with excessive 6-methylmercaptopurine (6-MMP) levels. Two adult studies have demonstrated successful manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor, to achieve more optimal thiopurine levels. The aim was to retrospectively characterize the utility of allopurinol to optimize thiopurine metabolite levels in pediatric IBD patients.. Thirteen patients received allopurinol daily (100 mg in patients >or=30 kg and 50 mg <30 kg), and their thiopurine dose was simultaneously reduced to 25%-50% of the previous maintenance dose. Metabolite levels and other screening labs were checked 2-4 weeks later.. The mean azathioprine dose was decreased from 148.1 to 59.6 mg daily (60% of the mean original dose). The mean 6-TGN level increased from 173 to 303 pmol/8 x 10(8) red blood cell count (RBC) (P = 0.03), and the mean 6-MMP level decreased from 7888 to 2315 pmol/8 x 10(8) RBC (P < 0.001). Elevated transaminase levels improved or resolved in all patients. Two patients experienced reversible neutropenia. At the conclusion of the study 9 patients (69%) remained on combination therapy with a mean duration of follow-up of 162.8 +/- 119.2 days.. Combination therapy successfully shunted thiopurine metabolites to a more favorable pattern. Reversible neutropenia was the most common side effect (2 patients). Long-term prospective studies are needed in this patient population.

Topics: Adolescent; Allopurinol; Antimetabolites; Child; Child, Preschool; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Prognosis; Remission Induction; Retrospective Studies; Treatment Outcome

The thiopurines, azathioprine (AZA) and mercaptopurine are extensively used in Crohn's discase (CD). Thiopurine bioactivation can be diverted by either thiopurine methyltransferase (TPMT), or by xanthine oxidase/dehydrogenase (XOD) which forms 6-thiouric acid (6TU).. To investigate whether chronic inflammation could influence small intestinal XOD activity using urinary excretion of 6TU as a surrogate marker of XOD activity.. 6-Thiouric acid excretion was compared between 32 CD patients and nine dermatology patients (control group), on AZA. Six CD patients were interesting: five with low TPMT activity (one deficient, four intermediate), and one receiving AZA/allopurinol co-therapy.. There was no statistical difference in 6TU excretion between the CD and control group. CD location, severity or surgery did not affect excretion. The TPMT-deficient patient excreted 89% of daily AZA dose as 6TU, but excretion by TPMT carriers was essentially normal. Concurrent 5-aminosalicylic acid therapy increased 6TU excretion significantly (median 32.9%), consistent with inhibiting TPMT. 6TU was undetectable in the patient on AZA/allopurinol co-therapy.. The results refuted our hypothesis, but fitted a model where most of an oral thiopurine dose effectively escapes first-pass metabolism by gut XOD, but is heavily catabolized by TPMT. Bioavailability of thiopurines may be competitively inhibited by dietary purines.

Topics: Adult; Biological Availability; Case-Control Studies; Crohn Disease; Female; Humans; Immunosuppressive Agents; Intestine, Small; Mercaptopurine; Methyltransferases; Uric Acid; Xanthine Oxidase

To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease.. Twenty nine previously confirmed Crohn's disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment.. In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses.. About one-third of the previously AZA-intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Steroids

Topics: Acrodermatitis; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Crohn Disease; Drug Eruptions; Drug Interactions; Drug Therapy, Combination; Female; Humans; Mercaptopurine; Mesalamine; Methyltransferases; Mucous Membrane; Paresthesia; Skin

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Infliximab; Mercaptopurine; Mesalamine; Methotrexate; Remission Induction; Treatment Outcome

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Remission Induction; Time Factors

Treatment disparities between African Americans (AA) and Caucasians exist in multiple diseases. There are limited studies in inflammatory bowel disease (IBD). Our objectives were to assess differences in IBD therapies between AA and Caucasians, controlling for disease severity.. We identified outpatients with ulcerative colitis (UC) or Crohn's disease (CD) evaluated at the University of Maryland and the Baltimore Veterans Affairs Medical Center from 1997-2005. We assessed medications used and the presence of covariates by race.. We identified 406 patients; 102 were AA (25%). AA were less likely to receive steroids (56% versus 68%; P = 0.02), mercaptopurine/azathioprine (6-MP/AZA) (28% versus 40%; P = 0.03), infliximab (IFX) (10% versus 20%; P = 0.03), or either 6-MP/AZA or IFX (28% versus 44%; P = 0.005). Age at diagnosis <40 (odds ratio [OR] 2.22, 95% confidence interval [CI] 1.06-4.54), steroid use (OR 4.75, 95% CI 1.93-11.7), and CD (OR 6.25, 95% CI 3.22-12.5) were positively associated with IFX use, while AA (OR 0.50, 95% CI 0.23-1.08) was negatively associated with IFX use. Age at diagnosis <40 (OR 1.84, 95% CI 1.12-3.23), steroid use (OR 10.2, 95% CI 5.37-19.2), and CD (OR 2.32, 95% CI 1.43-3.20) were positively associated with either 6-MP/AZA or IFX use, while AA (OR 0.57, 95% CI 0.32-1.01) was negatively associated with 6-MP/AZA or IFX use.. There were trends toward lower odds of treatment with IFX or either 6-MP/AZA or IFX in AA when compared with Caucasians. Further studies are needed to determine if these differences are due to less severe disease in AA patients or due to disparities in care.

Topics: Adult; Antibodies, Monoclonal; Azathioprine; Black or African American; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Maryland; Mercaptopurine; Middle Aged; Steroids; White People

Azathioprine intolerance is a common clinical problem, requiring drug withdrawal in up to 30% of patients. The successful use of mercaptopurine is described, but data to support this strategy are needed.. To assess the tolerability of mercaptopurine in inflammatory bowel disease patients previously intolerant of azathioprine, and identify predictive factors.. Sixty-one azathioprine-intolerant patients (31 males, median age at diagnosis 32 years, 31 with Crohn's disease, 30 with ulcerative colitis) who had been treated with mercaptopurine were identified. Intolerances included nausea and vomiting, flu-like illness, neutropenia, hepatotoxicity and pancreatitis.. Mercaptopurine was tolerated by 59% (36 of 61) of azathioprine-intolerant patients (median dose 1.0 mg/kg), 61% (17 of 28) in patients with azathioprine-related nausea and vomiting, 61% (11 of 18) with flu-like illness, 33% (three of nine) with hepatotoxicity, 100% (one of one) with neutropenia, 100% (three of three) with rash and 0% (zero of one) with pancreatitis. Mercaptopurine intolerance was frequently for a different adverse event. Those intolerant of mercaptopurine were younger (28.4 years vs. 37.0 years; P = 0.014) and more frequently female (14/30 vs. 2/29, P = 0.027). Mercaptopurine tolerability was not affected by diagnosis, location, behaviour, surgery, smoking, family history or extra-intestinal manifestations.. Mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients, and treatment should be considered, particularly if intolerance was due to nausea, vomiting, flu-like illness or rash.

Topics: Adult; Age Distribution; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Sex Distribution; Statistics, Nonparametric

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are accepted as effective therapy for Crohn's disease and ulcerative colitis. Although general guidelines have been suggested for weight-based dosing of thiopurines, no standard of care has been established. Clinical trials have demonstrated efficacy for weight-based dosing of AZA at 2.5 mg/kg/day and 6-MP at 1.5 mg/kg/day. Escalation of dosing is recommended within 2 weeks of initiating therapy. The aim was to determine the prescribing practices of community practice gastroenterologists with respect to 6-MP/AZA dosing.. Questionnaires were distributed via a mail database or during gastroenterology society meetings to gastroenterologists in NY, NJ, and CT. Questionnaires ascertained starting doses of AZA/6-MP, use of thiopurine methyltransferase (TPMT) enzyme testing, and strategy for dose optimization.. A total of 145 questionnaires were collected. Twenty-four percent of gastroenterologists escalated the dose within 2 weeks after initiating therapy. The majority used weight-based dosing as their target of therapy. Thirty-five percent reported measuring TPMT levels and 46% used metabolite monitoring.. Most gastroenterologists take longer than recommended to raise the dose of AZA/6-MP. Although the majority of gastroenterologists reported maximal dosages based on weight, there may be a delay in achieving this goal. Optimizing dosing of AZA/6-MP may improve efficacy and reduce the need to use additional therapy.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Data Collection; Gastroenterology; Humans; Immunosuppressive Agents; Mercaptopurine; Practice Guidelines as Topic

The immunomodulators (IMs) 6-mercaptopurine and azathioprine decrease corticosteroid dependence and maintain remission in Crohn's disease (CD). We describe IM use in newly diagnosed pediatric CD, comparing outcomes of "early" versus "late" initiation of therapy.. Data were obtained from pediatric CD patients enrolled in a prospective, multicenter observational study. Moderate/severe disease patients treated with IM were compared for outcomes of remission, corticosteroid use, infliximab therapy, hospitalizations, and CD-related surgery based on timing of initiation of IM therapy.. In all, 247 children met the criteria (60% male, mean age 11.9 years); 199 were treated with IM within 1 year of diagnosis; 150 between 0-3 months (early), 49 between 3-12 months (late). Both groups showed a decrease in corticosteroid use by 12 months, at which time proportionately fewer early group patients had received corticosteroids in the preceding quarter (22%) than late groups patients (41%)(P = 0.013). The number of hospitalizations per patient was also noted to be significantly lower in the early group over the 2-year follow-up (P = 0.03). No difference was noted in the rates of remission, infliximab use over time, or surgery.. 80% of children with newly diagnosed moderate to severe CD are treated with IM within 1 year. Early IM use is associated with reduced corticosteroid exposure and possibly fewer hospitalizations per patient.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Child; Crohn Disease; Female; Gastrointestinal Agents; Hospitalization; Humans; Immunologic Factors; Infliximab; Male; Mercaptopurine; Prospective Studies

To examine the relationship between medication adherence and quality of life (QOL) in adolescent patients with inflammatory bowel disease (IBD) utilizing a multimethod adherence assessment approach.. Medication adherence in 36 adolescents with IBD was assessed via interviews, pill counts, and biological assays. QOL was assessed via patient and parent report. Pediatric gastroenterologists provided disease severity assessments.. Hierarchical multiple regression analyses revealed that adherence contributed significant variance to patient-reported QOL but not parent-reported QOL. Nonadherence to 6-MP/azathioprine was related to poorer patient-reported physical health QOL. Greater self-reported 5-ASA adherence was related to poorer overall psychological health QOL, and particularly social functioning QOL.. Results provide preliminary support for the negative effects of 6-MP/azathioprine nonadherence on QOL and an inverse relationship between 5-ASA adherence and QOL in this population. Adherence burden in patients and the utility of multimethod adherence assessment in research are discussed.

Topics: Adolescent; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Depression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Guanine Nucleotides; Humans; Illness Behavior; Male; Medication Adherence; Mercaptopurine; Mesalamine; Quality of Life; Thionucleotides

Topics: Abnormalities, Drug-Induced; Crohn Disease; Female; Fetus; Humans; Immunosuppressive Agents; Mercaptopurine; Pregnancy; Pregnancy Complications

Topics: Adolescent; Biopsy; Child; Crohn Disease; Female; Humans; Male; Mercaptopurine; Nephritis, Interstitial; Prednisone; Remission Induction

In a 23-year-old female with colonic Crohn's disease 6-mercaptopurine 100 mg daily (1.7 mg/kg) was added to mesalamine and prednisolone therapy because of ongoing disease activity. One month later she had fever and a pancytopenia. 6-methylmercaptopurine ribonucleotides levels were extremely elevated (57,000 pmol/8x10(8) red blood cells) and 6-thioguanine nucleotides levels were subtherapeutically (126 pmol/8x10(8) red blood cells). Genotyping showed a wildtype thiopurine S-methyltransferase TPMT(H/H) (*1/*1) genotype and a wildtype inosine triphosphate pyrophosphatase gene. TPMT and inosine triphosphate pyrophosphatase activity were normal. The pancytopenia recovered spontaneously within a few weeks, parallel with decreasing 6-methylmercaptopurine ribonucleotides levels after interrupting 6-mercaptopurine treatment. Epstein-Barrvirus, Cytomegalovirus and Herpesvirus infections were excluded by serology. This is the first report of pancytopenia due to extremely high 6-methylmercaptopurine ribonucleotides levels. No relation was found with the genotype of TPMT and inosine triphosphate pyrophosphatase enzymes, which play key roles in the thiopurine metabolic pathway. Apparently, 6-methylmercaptopurine ribonucleotides metabolites can cause pancytopenia, as was already known for 6-thioguanine nucleotides.

Topics: Adult; Crohn Disease; Female; Humans; Mercaptopurine; Methyltransferases; Pancytopenia; Thioinosine; Thionucleotides

To assess the prevalence of adherence to prescribed medications in children with Crohn disease and to identify possible factors associated with nonadherence.. This was a cross-sectional study of 51 pediatric patients with Crohn disease who were prescribed maintenance therapy with a thiopurine immunomodulator (6-mercaptopurine or azathioprine) and/or mesalamine during a 180-day period. Medication adherence rates were calculated from a validated formula using pharmacy records, and nonadherence was defined as a refill rate of <80% of the prescribed medication. Seventy-five percent of patients were prescribed thiopurine immunomodulators and 86% were prescribed mesalamine.. The prevalence of nonadherence was 50% for the thiopurine immunomodulators and 66% for mesalamine. The mean number of emergency department visits for patients adherent to mesalamine was significantly greater than the nonadherent group (P < 0.0008). Having an emergency department visit increased the chances of a patient being adherent to mesalamine therapy by >9-fold (odds ratio, 9.6; 95% confidence interval, 1.87-52.17). The mean number of total health care visits was significantly greater for patients adherent to mesalamine (6.1 +/- 0.8) compared with those who were not adherent (3.0 +/- 0.4) (P < 0.001).. These findings suggest that nonadherence to thiopurine immunomodulator or mesalamine therapy in pediatric patients with Crohn disease is common. Having a health care visit was associated with being adherent.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Crohn Disease; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Prevalence; Treatment Refusal

Few studies have described patients with foregut dysmotility in inflammatory bowel disease. The aim of this case series was to evaluate clinical characteristics of 5 patients with inflammatory bowel disease and symptoms and signs of upper gut dysmotility.. We describe a series of four patients with Crohn's disease and one with indeterminate colitis who presented with severe symptoms and signs of gastroparesis. We reviewed medical records of all cases. Gastric emptying of a solid meal was assessed by scintigraphy. Small bowel enteroclysis, gastroduodenoscopy and colonoscopy with biopsies were performed to estimate the activity of the disease and to exclude organic obstruction. None of the patients had any signs of active inflammation or stricture. All of the patients had markedly delayed gastric emptying with a mean t 1/2 of 234 minutes (range 110-380 minutes; normal values 54-94 minutes).. Clinicians should consider impaired gastric emptying when evaluating patients with Crohn's disease and severe symptoms of upper gut dysmotility, which cannot be attributed to active inflammation or organic obstruction of the digestive tract. Symptoms in these patients are refractory to various therapeutic interventions including tube feeding and gastric surgery.

Topics: Adrenal Cortex Hormones; Adult; Antimetabolites; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Gastroenterostomy; Gastroparesis; Humans; Mercaptopurine; Middle Aged; Thioguanine; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal; Crohn Disease; Diagnosis, Differential; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Follow-Up Studies; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Laparotomy; Male; Mercaptopurine; Mucormycosis; Rhizopus; Rupture, Spontaneous; Stomach Rupture; Tomography, X-Ray Computed

Crohn's disease (CD) is associated with increased risk of adverse birth outcomes. However, existing studies have not taken into account the impact of drug treatment. We examined the impact of drug treatment on birth outcomes--low birth weight (LBW), preterm birth, LBW at term, and congenital abnormalities (CAs)--among CD women.. A nationwide Danish cohort study of 900 children born to CD women between 1996 and 2004, based on the National Registry of Patients, the Birth Registry, and the nationwide prescription database. Pregnancies were classified according to receipt of prescriptions for CD medication: no drugs (reference group), 5-aminosalicylic acid (5-ASA)/sulfasalazine, steroids, and azathioprine (AZA)/6-mercaptopurine (6-MP). We used logistic regression analyses to estimate the relative risk of birth outcomes with 95% confidence intervals. We used a proxy measure for disease activity.. Preterm births were more prevalent among steroid- and AZA/6-MP-exposed women (12.3% and 25%, respectively) compared with the reference group (6.5%). CAs were more prevalent among AZA/6-MP-exposed compared with reference group (15.4%vs 5.7%). Among steroid exposed, the risk of preterm birth was 1.4 (95% CI 0.6-3.3). Among AZA/6-MP exposed, the risk of preterm birth and CAs was 4.2 (95% CI 1.4-12.5) and 2.9 (95% CI 0.9-8.9), respectively.. The relative risk of adverse birth outcomes among CD women varied by type of drugs prescribed during pregnancy. The risk of preterm birth and CAs was greater when AZA/6-MP was prescribed, even after adjusting for confounders. However, further information is needed to determine whether the associations are causal.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Confidence Intervals; Congenital Abnormalities; Crohn Disease; Denmark; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Mercaptopurine; Mesalamine; Population Surveillance; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Risk Factors; Sulfasalazine

High frequency of incomplete or non-response to azathioprine (AZA) and/or mercaptopurine (MP) limit their use in Crohn's disease (CD). Non-adherence is considered to be of relevance for ineffectiveness.. To assess adherence to thiopurines in CD out-patients treated in a single gastroenterology practice.. Patients were eligible for inclusion if they received AZA/MP for at least 3 months. After follow-up of 3 months, adherence to AZA/MP was assessed by quantitation of relevant thiopurine metabolite levels in red blood cells as well as by patients' self-report using standardized questionnaire.. Sixty-five patients were prospectively included. Six patients (9.2%) had metabolite profiles indicative of non-adherence. Self-assessed questionnaire revealed non-adherence in four of 56 patients (7.1%). Therapeutic drug monitoring (TDM) and self-assessment as two independent methods had a concordance rate of 75%. Metabolite levels and self-assessed adherence were not significantly different between patients in remission compared with those with active disease.. Out-patients with CD treated in a single gastroenterology practice had a satisfactory adherence (>90%) to thiopurine therapy. Different measures of adherence (TDM and self-report) applied to the same patient suggest comparable levels. TDM appears to be a reliable tool to assess adherence to thiopurines in clinical practice.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Middle Aged; Patient Compliance; Surveys and Questionnaires

To determine whether long-term low-dose prednisone (LTLDP) therapy has a decelerating effect on growth velocity and whether this therapy is effective in the maintenance of remission in the subgroup of pediatric patients with Crohn disease (CD) who had previously experienced flares on more than 1 occasion when prednisone was discontinued.. A retrospective chart review of patients was done. Our sample consisted of patients 6 to 17 years of age with CD who had received uninterrupted prednisone at an average daily dose of 0.1 to 0.4 mg x kg(-1) x day(-1) for at least 8 weeks. Their heights were plotted on sex-appropriate growth charts at 4 time points: 1 year before LTLDP, at therapy onset, at therapy discontinuation, and 1 year after therapy was discontinued. The height velocities (HVs) were compared with the normal HV established by Tanner. The disease activities of 2 groups were compared: LTLDP plus azathioprine/6-mercaptopurine (AZA/6-MP) and LTLDP alone.. One hundred two patients were included. The mean age of our sample was 13.7 +/- 2.7 years (standard deviation). The mean dose of prednisone dose was 0.18 +/- 0.07 mg x kg(-1) x day(-1)), for a mean duration of therapy of 14.4 +/- 7.2 months. Throughout the study, 78% of patients had normal HV. Growth deceleration was seen in 19% of patients with prior normal growth. Of this group, 31% had "catch-up" growth 1 year after prednisone was discontinued; the remaining 69% did not. Catch-up growth was more likely in patients who had reached the expected age peak HV, which is defined as 12.5 years for girls and 13.5 years for boys (P = 0.04). In addition, 6 patients reached the peak HV after LTLDP discontinuation; 13 did not. We found no difference in the maintenance of remission rate between the compared groups.. A minority of our study population had growth deceleration. Age was an important factor for subsequent catch-up growth. LTLDP efficacy to maintain remission was not different from that of LTLDP plus AZA/6-MP; differences in concomitant therapies (eg, antibiotics, infliximab) between the 2 groups were not statistically significant.

Topics: Adolescent; Age Factors; Anti-Inflammatory Agents; Azathioprine; Child; Crohn Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Growth; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prednisone; Remission Induction; Retrospective Studies; Time Factors; Treatment Outcome

There is limited information on the optimal use of thiopurinic immunomodulators in inflammatory bowel disease (IBD) and the dosage, efficacy and toxicity of these drugs has not been clearly established.. To evaluate clinical outcomes and the toxicity of thiopurinic immunomodulators in clinical practice (effectiveness), as well as possible associated variables.. Data were obtained from a database of patients with ulcerative colitis and Crohn's disease who started treatment with azathioprine or 6-mercaptopurine with an identical predetermined schedule and follow-up. Remission, relapse and toxicity were defined and analyzed and their relationship with clinical, biologic and demographic variables was evaluated with multivariate analysis.. We evaluated 150 courses of treatment in 126 patients. Treatment was given to induce clinical remission in 118 courses and 62% of the patients reached this outcome, which was maintained for a mean of 52 months. The only variable associated with poor response was perianal disease. Adverse events were detected in 34% of the courses and were the main cause of treatment withdrawal. Factors significantly associated with withdrawal due to adverse events were starting with full doses of thiopurinic drugs (OR, 4.26; 95% CI, 1.12-16.32) and cotreatment with infliximab (OR, 5.6; 95% CI, 1.17-27.1).. Some clinical variables such as disease phenotype, the use of full doses of thiopurinic drugs from the start of treatment, and co-treatments can have a notable influence on adverse effects and thus on the effectiveness of this therapy in IBD.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Combined Modality Therapy; Crohn Disease; Digestive System Diseases; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Middle Aged; Neutropenia; Patient Acceptance of Health Care; Remission Induction; Reoperation; Retrospective Studies

The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohn's disease, but the comparative efficacy and safety of methotrexate have seldom been examined. We report outcomes with methotrexate treatment in pediatric patients previously refractory to or intolerant of thiopurines.. In a four-center, retrospective cohort study, efficacy of methotrexate in maintaining remission was assessed by PCDAI measurements, steroid use, and height velocity. Patients served as their own historical controls. Multivariable analysis controlled for route of methotrexate administration, reason for thiopurine discontinuation, baseline disease activity, and disease duration.. Forty-two percent of 60 children treated with methotrexate were in clinical remission without steroids at both 6 and 12 months. A strong steroid sparing effect was observed compared with the year prior to methotrexate (P<0.001). Success rates were similar in previously thiopurine-intolerant and refractory patients. Height velocity increased from -1.9 SDS to -0.14 SDS (P=0.004) in the year following therapy. In a median 3-yr follow-up, a third of the patients did not require escalation of therapy; the others required step-up therapy with infliximab or surgery. Eight children (13%) stopped methotrexate due to adverse events, including, most commonly, elevated liver enzymes, and one serious episode of sepsis.. Methotrexate appears effective in maintaining remission in pediatric Crohn's disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.

Topics: Adolescent; Chi-Square Distribution; Child; Crohn Disease; Female; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Mercaptopurine; Methotrexate; Retrospective Studies; Statistics, Nonparametric; Treatment Failure; Treatment Outcome

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic

The goals of this study were to identify markers in a patient's presentation and disease progression that predict the need for the use of immunomodulators in a pediatric population.. Although immunomodulator safety and efficacy have been documented in Crohn's disease, models for predicting outcome and the need for immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) early in the disease course have not been investigated in children or adults.. Data on newly diagnosed Crohn's disease patients were prospectively collected within 3 weeks of diagnosis, 6 months after diagnosis, and 1 year after diagnosis. Information collected at each visit included medication use and disease activity assessment.. A total of 57 patients who were followed for > or = 6 months were evaluated. Overall, 34 of 57 (59.6%) were started on immunomodulators within 1 year of diagnosis. Mean serum albumin (3.35 g/dL vs. 3.7 g/dL, P = 0.013) and hematocrit (33.3% vs. 35.9%, P = 0.023) at diagnosis were lower, and erythrocyte sedimentation rate (32 vs. 12, P = 0.011) at diagnosis was higher in patients who required immunomodulators. The total Pediatric Crohn's Disease Activity Index score as well as the physical examination score and patient recall score within the PCDAI at diagnosis were not different among those who received immunomodulators and those that did not.. Immunomodulators are frequently used within 1 year of diagnosis in pediatric Crohn's disease. Lower serum albumin levels and hematocrit, and elevated erythrocyte sedimentation rate at diagnosis may predict the need for immunomodulators earlier in the disease course.

Topics: Adolescent; Azathioprine; Biomarkers; Chi-Square Distribution; Child; Child, Preschool; Crohn Disease; Disease Progression; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Predictive Value of Tests; Prospective Studies; Statistics, Nonparametric

Topics: Aged; Antibodies, Monoclonal; Brain; Brain Neoplasms; Crohn Disease; Diagnosis, Differential; Epstein-Barr Virus Infections; Fatal Outcome; Female; Groin; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infliximab; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Magnetic Resonance Imaging; Mercaptopurine; Tomography, X-Ray Computed; Unconsciousness

Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking.. To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD.. 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study.. Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored.. 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11,450 pmol/8 x 10(8) red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015).. After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

Topics: Adolescent; Adult; Aged; Antimetabolites; Azathioprine; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Female; Gene Expression; Genotype; Humans; Inosine Triphosphatase; Male; Mercaptopurine; Methyltransferases; Middle Aged; Phenotype; Polymorphism, Genetic; Prospective Studies; Pyrophosphatases; Treatment Outcome

Thiopurinic immunomodulators are effective for maintaining symptom remission in Crohn's disease. Little is known, however, about their effect on patients' quality of life or psychological well-being. The present study aimed to determine whether remission induced by thiopurinic immunomodulators returns levels of quality of life and psychological well-being to normal.. A case-control study was performed. Cases were 33 patients with Crohn's disease treated with azathioprine or 6-mercaptopurine and in stable remission for at least 6 months. Sixty-six healthy individuals matched 2:1 by age and sex and 14 patients with active Crohn's disease were included as control groups. Quality of life was evaluated with the Short Form (SF-36) questionnaire, and the respective Hamilton rating scales were used for anxiety and depression. ANOVA with Bonferroni's correction was used for multiple comparisons.. SF-36 global scores were 85 in the study group, 85 in healthy controls (P = 1), and 58.6 in patients with active disease (P < 0.001 for the comparison with the other 2 groups). The differences between values were 0 (95% CI -4-4), 26.4 (95% CI 20-32), and 26.4 (95% CI 19-33), respectively. The respective anxiety and depression scores were 6.5, 5.5, and 16.2 and 3.7, 3.3, and 10.9. No significant differences were observed in any of the SF-36 domains between case and control groups, whereas in patients with active disease, all domains were significantly worse.. Thiopurinic immunomodulator-induced remission restores normal levels of quality of life and psychological well-being in Crohn's disease patients.

Topics: Adult; Anxiety; Case-Control Studies; Crohn Disease; Depression; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Quality of Life; Remission Induction

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.

Topics: Abscess; Adult; Anus Diseases; Bone Marrow; Crohn Disease; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Ileitis; Immunosuppressive Agents; Leukocyte Count; Male; Mercaptopurine; Mesalamine; Neutropenia

Topics: Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Nucleotides; Remission Induction; Thioguanine

We evaluated how our use of thiopurines was altered by determination of thiopurine methyltransferase (TPMT) level and drug dose adjustment guided by a 6-mercaptopurine metabolite assay. We further examined whether these resulted in better selection of the drug dose, improved control of disease, and decreased corticosteroid use in pediatric inflammatory bowel disease (IBD).. This is a retrospective review of 101 pediatric patients with IBD receiving a stable dose of azathioprine (AZA) for 4 months or longer. The study group (n = 64) consisted of patients who received AZA and had metabolite levels measured. The comparison group (n = 37) consisted of patients who were receiving AZA before the availability of metabolite measurement. The TPMT level was measured in study group patients before starting AZA.. Patients with normal TPMT level received a higher starting dose of AZA than in patients who were heterozygous for TPMT deficiency (1.7 vs 0.9 mg/[kg x d], P < 0.0001). Study group patients received a higher starting dose (1.6 vs 1.2 mg/[kg x d], P = 0.001) and a higher final dose of AZA (2.4 vs 1.7 mg/[kg x d], P < 0.0001) compared with patients in the comparison group. These patients also had more dose adjustments (0.8 vs 0.4 mg/kg, P < 0.002). The number of disease exacerbations per patient per year was 55% less in the study group (95% CI, 17%-76%, P < 0.0001). The study group patients received less prednisone (P < 0.0001) and had lower disease activity scores (P < 0.05). There was no difference between groups in infliximab use or surgery rate.. Azathioprine dose adjustment using a 6-mercaptopurine metabolite assay was associated with use of higher doses, improved control of disease and decreased corticosteroid use in pediatric patients with IBD.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Guanine Nucleotides; Heterozygote; Humans; Infant; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Prednisone; Remission Induction; Retrospective Studies; Thionucleotides

Recurrence of Crohn's disease (CD) after surgery is common. Azathioprine/6-mercaptopurine (Aza/6-MP) is effective in controlling medically induced remission but, so far, has only been sparsely investigated after surgically induced remission. This study comprises a subset of CD patients considered to have an aggressive disease course and chosen for treatment with Aza postoperatively.. In 1989-2000, a total of 100 patients with CD were given Aza/6-MP as a postoperative prophylaxis. Fourteen Aza/6-MP-intolerant patients were compared with 28 Aza-tolerant patients, matched for gender, age, and duration of disease. Patients were prospectively registered for symptoms using a modified Crohn's disease activity index (CDAI) and perceived health was assessed on a visual analogue scale (VAS). The primary outcome variable was the modified CDAI postoperatively integrated over time; other variables were time to first relapse (modified CDAI >or= 150), time to first repeated surgery, number of courses of steroids, and repeated surgery per year of follow-up. Patients were followed for a median of 84.7 months (23.2-140).. The modified CDAI integrated over time was 93 for Aza-treated patients compared with 184 for controls (p=0.01) and time to first relapse was 53 and 24 months, respectively (p<0.05). Aza-treated patients needed fewer courses of corticosteroids (p=0.05) compared with controls. Perceived health did not differ between the groups, nor did need of repeated surgery. Time to first repeat operation was 53 and 37 months, respectively.. In CD patients considered to have an aggressive disease course, Aza reduced symptoms after surgery and prolonged the time to symptomatic relapse. The findings support a role for Aza as a postoperative maintenance treatment in CD.

Topics: Adolescent; Adult; Aged; Azathioprine; Crohn Disease; Female; Humans; Male; Mercaptopurine; Middle Aged; Postoperative Period; Recurrence; Reoperation

5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product.. To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third.. A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide.. The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects.. Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Cross Reactions; Drug Hypersensitivity; Exanthema; Herpes Simplex; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Phenylhydrazines; Prednisone

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Remission Induction

Topics: Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Secondary Prevention

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Child; Child Welfare; Clinical Trials as Topic; Crohn Disease; Decision Making; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Quality of Life; Severity of Illness Index

Topics: Azathioprine; Child; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Patient Care Planning; Phenotype; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Severity of Illness Index

Topics: Azathioprine; Child; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Patient Care Planning; Patient Selection; Phenotype; Practice Guidelines as Topic; Prognosis; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index

Topics: Adolescent; Antibodies, Monoclonal; Crohn Disease; Fatal Outcome; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Liver Neoplasms; Lymphoma, T-Cell; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Inosine Triphosphatase; Leukopenia; Mercaptopurine; Pyrophosphatases

6-Thioguanine (6-tioguanine) nucleotides are the active metabolites of azathioprine.. The aim of the study was to evaluate the rate of clinical remission without steroids in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine, the medium- and long-term efficacy and the predictive factors of clinical response when monitoring 6-tioguanine.. Steroid-dependent Crohn's disease and ulcerative colitis patients receiving either azathioprine or not (treated later with a daily dose of 2.5 mg/kg) were prospectively included. 6-tioguanine was monitored at 1 and 2 months and every 3 months thereafter for 1 year. The azathioprine dose was adapted to reach a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells. Thiopurine methyltransferase genotype/phenotype was evaluated in some patients.. A total of 106 patients were prospectively included (70 Crohn's disease, 36 ulcerative colitis). The clinical remission rate without steroids in patients receiving azathioprine, in intention-to-treat analysis, was 72% and 59% at 6 and 12 months, respectively. The remission rate was significantly higher in patients with 6-tioguanine >250 pmol/8 x 10(8) RBC (86% and 69% at 6 and 12 months, respectively; P < 0.01). No significant difference was observed between Crohn's disease and ulcerative colitis patients whether treated by azathioprine or not on inclusion. In the univariate analysis, the absence of Crohn's disease stenosis, a 6-tioguanine level >250 pmol/8 x 10(8) RBC, and an increase of erythrocyte mean corpuscular volume were the factors predictive of a favourable clinical response. In the multivariate analysis, only a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells was a predictive factor of favourable clinical remission.. Clinical remission without steroids is significantly more likely when monitoring 6-tioguanine so as to reach a level of >250 pmol/8 x 10(8) red blood cells in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine (86% and 69% at 6 and 12 months, respectively).

Topics: Adolescent; Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Phenotype; Prospective Studies; Treatment Outcome

The correlation between combined chemotherapy, including 6-mercaptopurine, and development of excessive number of melanocytic nevi in childhood has been previously reported and studied. As of yet, no such relation has been reported in adults. We recently observed a 27-year-old female patient who developed numerous benign melanocytic nevi during a 20-month period while taking 6-mercaptopurine for Crohn's disease. The appearance of many nevi was worrisome to the patient from a cosmetic and medical perspective (given the higher risk of melanoma associated with large numbers of nevi).

Topics: Adult; Crohn Disease; Drug Eruptions; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Nevus, Pigmented; Skin Neoplasms

Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable.. All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed.. Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects.. Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.

Topics: Adult; Azathioprine; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Retrospective Studies; Spain; Treatment Outcome

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Gene Frequency; Genetic Markers; Genotype; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Treatment Outcome

Topics: Adult; Azathioprine; Crohn Disease; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Pancreatitis

During treatment for inflammatory bowel disease (IBD) 2 men with ulcerative colitis, aged 52 and 38 years, and a 37-year-old man with Crohn's disease developed Epstein-Barr virus (EBV)-related non-Hodgkin's B-cell lymphoma. The first 2 patients underwent proctocolectomy and the use of immunosuppressive agents was discontinued, after which the lymphoma disappeared. The third patient had icterus, hepatosplenomegaly and pancytopenia; he died from multiple organ failure. Azathioprine and 6-mercaptopurine are first choice therapy in the treatment of steroid-refractory IBD. These immunomodulating agents are associated with the development of EBV-positive lymphomas in the setting of solid organ transplantation. This type of lymphoma is a rare complication in IBD, although the incidence in referral centres appears to be increasing. Since azathioprine is an important drug in IBD, there is a need for identification of IBD patients at risk of developing a lymphoma. EBV-DNA in plasma or in faeces may be a candidate tumour marker.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Epstein-Barr Virus Infections; Fatal Outcome; Humans; Immunosuppressive Agents; Incidence; Lymphoma, B-Cell; Male; Mercaptopurine; Middle Aged; Risk Factors

Azathioprine (AZA) is effective for the maintenance of a steroid free remission in Crohn's disease (CD). Thiopurine methyltransferase (TPMT) is important for the metabolism of AZA and influences the production of active AZA metabolites. AZA dose selection based on pharmacogenetic testing of TPMT and metabolite monitoring (MM) may offer a safety and efficacy advantage over traditional dosing strategies. We performed a decision analysis to estimate the potential costs and effectiveness of TPMT screening and MM as disease management strategies for CD.. Strategies applying TPMT and/or MM to influence treatment decisions were compared to community care (CC). The impact on toxicity minimization and improved time to initial and sustained response was evaluated. A 1-yr model was developed from the third-party payer perspective for mild to moderately chronically active, steroid-treated CD patients. Effectiveness and toxicity defined by time to response CD activity index (CDAI <150, +/- steroids) or time to sustained response (CDAI <150, off steroids x 8 wk) and reduction in leukopenic events, respectively. One- and two-way sensitivity analyses were conducted to determine the effect of varying individual estimates from those used in the base-case analysis.. MM, TPMT, and TPMT + MM strategies as compared to CC achieved an earlier time to initial response (18.66, 18.96, and 19.10 vs. 22.41 wk, respectively) and sustained response (39.83, 42.91, and 39.8 vs. 45.36 wk, respectively). The least costly strategy at 1 yr was TPMT ($3,861) and the most costly strategy was CC ($7,142). Each alternative strategy was shown to dominate CC (i.e., less costs and faster time to response or sustained response). The cost-effectiveness rankings were robust to sensitivity analyses on key variables.. The addition of alternative strategies to CC may improve AZA outcomes and reduce the total cost of care for steroid treated chronically active CD patients, with TPMT being more beneficial for initial response to treatment and MM being more beneficial for sustained response to treatment.

Topics: Azathioprine; Community Health Services; Cost-Benefit Analysis; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Genetic Testing; Health Care Costs; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Time Factors; Treatment Outcome

Topics: Adult; Crohn Disease; Female; Fever; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine; Remission Induction; Severity of Illness Index; Time Factors

Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD).. A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response.. The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (12 U/mL blood (P < 0.001). Patients with TPMT activity 12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%.. Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Logistic Models; Male; Mercaptopurine; Methyltransferases; Prospective Studies; Remission Induction; Thionucleotides; Treatment Outcome

6-Mercaptopurine (6-MP) has shown efficacy in the treatment of Crohn's disease when used in conjunction with corticosteroids. Sparse literature to date suggests that 6-MP is effective when used without steroids. We therefore studied the efficacy of 6-MP in corticosteroid-naive Crohn's patients.. We conducted a retrospective chart review of 24 patients who were treated with 6-MP but had never received any form of steroid treatment at any time. 6-MP efficacy was assessed with serial modified Harvey-Bradshaw scores. In addition to overall response, data were also analyzed according to the indication for treating with 6-MP (disease activity, fistulae, or both). The time to relapse and the treatments required were also analyzed.. Overall, remission or significant improvement was seen in 20 patients (83% of original group). Seven patients (29%) achieved complete remission; another 13 patients (54%) demonstrated significant clinical improvement. By indication, 89% of patients treated for activity, 50% of patients treated for activity and fistula, and 100% of patients treated for fistula alone showed response. Drug effect required a median of 5.7 months to occur (for all patients: range, 1.7-37.9 months). Thirteen of the twenty patients who improved or remitted on 6-MP eventually relapsed, usually due to stopping 6-MP, at a median of 13.8 months (range, 0.9-57.8). Relapse was less frequent if patients continued 6-MP. Treatment of relapses required only antibiotics, and/or restarting 6-MP (or increasing the dose) in most patients.. 6-MP is an effective medication for use in steroid-naive patients and is likely to be effective in patients who have received steroids in the past but are not currently receiving them. Relapses occur despite continued therapy, but are often easily treated, and do not require initiating steroids.

Topics: Adult; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Risk Assessment; Severity of Illness Index; Steroids; Treatment Outcome

There are conflicting reports on the role of azathioprine (AZA) thioguanine nucleotide (TGN) metabolites in optimising therapy for inflammatory bowel disease (IBD). The aim of this study was to investigate TGN intrapatient variation, and the relationship between TGN concentrations and disease activity in IBD patients taking long term constant dose AZA.. TGN and methylmercaptopurine nucleotide (MeMPN) concentrations were measured at intervals over a two year period. Disease activity was assessed at each clinic visit using the Crohn's disease activity index or Walmsley simple index for ulcerative colitis.. Serial TGNs were measured in 159 patients (3-14 TGN assays, median 6). Intrapatient variation in TGN concentrations was 1-5-fold (median 1.6); the incidence of non-compliance was 13%. At the end of two years, 131 patients were evaluable at TGN steady state. Of this group, patients who remained in remission had significantly higher mean TGN concentrations than those patients who developed active disease (median TGNs 236 v 175, respectively; median difference 44 pmol (95% confidence interval 1-92); p = 0.04). MeMPN concentrations were not related to AZA efficacy or toxicity.. This study has shown that lower TGN concentrations were linked to the development of active disease, and that TGNs may act as useful markers of compliance. However, it is clear that repeat TGN measurements are required for an unambiguous index of active metabolite exposure. In view of the high intrapatient variability in TGN production over time, TGN measurements may not be currently advocated for routine clinical use.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Patient Compliance; Thioguanine; Treatment Outcome

We aimed at determining the utility of measuring 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in inflammatory bowel disease (IBD) patients on azathioprine (AZA) or 6-mercaptopurine (6-MP), whether the described therapeutic range for 6-TG (235-400 pmol/8 x 10(8) red blood cells, RBC) correlated with clinical remission or leukopenia, and if 6-MMP level was a marker for hepatotoxicity (>5,700 pmol/8 x 10(8) RBC).. Study eligibility included an IBD diagnosis of >6 months and either active disease or disease remission of <6 months and the use of AZA/6-MP for >10 wk consecutively. Metabolite levels were evaluated against clinical status, CBC, and hepatic parameters.. Seventy-four of 166 AZA/6-MP users were eligible. 6-TG levels >235 pmol/8 x 10(8) RBC were found in 22/59 (38%) with active disease and in 7/15 with remission (47%, p= 0.16). There was a trend of higher 6-TG levels among those in remission versus those with active disease (mean 325 +/- 284 vs 223 +/- 159 pmol/8 x 10(8) RBC, p= 0.2). No hepatotoxicity was observed, although 12.2% had 6-MMP levels > 5,700 pmol/8 x 10(8) RBC. The correlation between 6-MP dose and 6-TG levels was weak (r = 0.22, p= 0.08). The 6-TG level did not correlate with WBC. There were five instances, each of markedly low levels of both 6-TG and 6-MMP, suggesting noncompliance and of marked 6-MMP levels versus 6-TG.. There was a poor correlation between 6-TG levels and remission. Nonetheless, the measurements of these levels are helpful when patients are on high doses but not achieving remission since noncompliance or metabolism favoring 6-MMP can be established.

Topics: Adult; Azathioprine; Biomarkers; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Inflammatory Bowel Diseases; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Thioguanine; Treatment Outcome

Topics: Azathioprine; Clinical Trials as Topic; Crohn Disease; Digestive System Surgical Procedures; Humans; Immunosuppressive Agents; Mercaptopurine; Postoperative Period; Secondary Prevention; Treatment Outcome

Azathioprine (AZA) or 6-mercaptopurine (6-MP) are the immunosuppressive drugs of choice in the treatment of inflammatory bowel disorders (IBD). Optimal dosage for AZA is around 2.5 mg/kg body weight and induction of remission by these drugs may take 6 - 7 months. Intramuscularly applied Methotrexate (MTX) is the second choice, while its efficacy starts earlier than that of AZA; studies assessing oral low-dose MTX treatment are lacking. Cyclosporin is the standard treatment in case of steroid-refractory severe ulcerative colitis. This drug may also be used in patients with severe extraintestinal manifestations of IBD. Regarding other immunosuppressive drugs such as mycophenolic acid or 6-thioguanine respective controlled clinical study data are not available. The risk of malignancy using immunosuppressive drugs such as AZA is low and furthermore, especially AZA and 6-MP can be used rather safely during pregnancy.

Topics: Administration, Oral; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Injections, Intramuscular; Male; Mercaptopurine; Methotrexate; Placebos; Pregnancy; Randomized Controlled Trials as Topic; Remission Induction; Retrospective Studies; Safety; Time Factors

The aim of this study was to assess the possible benefit of postoperative immunosuppressive drugs administration (ie, azathioprine, 6-mercaptopurine, or methotrexate) on long-term surgical recurrence rate after second anastomotic ileocolonic resection.. From 1984 to 2000, 26 patients with CD underwent second resection for ileocolonic anastomotic recurrence. There were 14 women and 12 men (mean age +/- SD: 34 +/- 9 years). Two groups of patients were compared according to the postoperative treatment: immunosuppressive (IS) drugs group was composed of 14 patients, and control group was composed of 12 patients receiving either salicylates (n = 5) or no treatment (n = 7).. Clinical recurrence rate at 3 years was significantly lower in the IS group than in the control group (3/12, 25% vs 6/10, 60%; P < 0.05). Although not significant, after a mean follow-up of 80 +/- 46 months (extr. 17-178 months) after the second resection, clinical recurrence rate at follow-up was also lower in IS group (6/14, 43%) than in control group (9/12, 75%). The mean delay of recurrence was similar in both groups (27 +/- 13 months vs 28 +/- 21; NS). A third intestinal resection was performed less frequently in the IS group than in control group (2/14, 17% vs 7/12, 58%; P < 0.02).. In patients treated with IS drugs, the rate of postoperative recurrence after second ileocolonic CD resection is lower than in untreated patients. Our results suggest that IS drugs should be evaluated prospectively for prevention of second postoperative CD recurrence.

Topics: Adult; Azathioprine; Colon; Crohn Disease; Female; Gastrointestinal Agents; Humans; Ileum; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Postoperative Care; Recurrence; Reoperation; Retrospective Studies; Treatment Outcome

Thiopurine drugs are commonly used immunosuppressants in the treatment of inflammatory bowel disease (IBD) as well as in autoimmune hepatitis (AIH), rheumatic diseases and in transplantation medicine. The relatively narrow therapeutic range requires useful therapy control. Therefore, the purpose of this study was to further investigate the rationale and usefulness of therapeutic drug monitoring in the surveillance of thiopurine drug therapy in Crohn's disease, ulcerative colitis and autoimmune hepatitis.. 6-Thioguanine nucleotide (TGN) and 6-methylmercaptopurine nucleotide (MMPN) levels were measured in 182 IBD patients and 18 AIH patients using HPLC-UV.. In our cohort of IBD patients, 18% had TGN levels < 235 pmol/8 x 10 red blood cells (RBC) (recommended range, 235-450 pmol/8 x 10 RBC), 41% of these patients were sent for drug failure. Twenty-four per cent of the IBD patients had TGN levels > 450 pmol/8 x 10 RBC, but only 27% of these experienced adverse effects. Fifty-nine per cent of the patients having drug failure had TGN levels in the recommended range and could therefore be classified as non-responders. In the AIH cohort 33% of the patients had TGN levels below the recommended range but showed clinical response to therapy. MMPN levels increased with the duration of treatment and could be useful for controlling compliance. There was 8.8% of IBD patients who were heterozygous for non-functional TPMT alleles.. TGN monitoring did not identify significant differences between patient groups but allowed the identification of non-responders from non-compliant patients and allowed the differentiation of mild side effects, such as malaise, from genuine toxicity caused by highly increased TGN levels.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Female; Guanine Nucleotides; Hepatitis, Autoimmune; Heterozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Purines; Thioguanine; Thionucleotides

Topics: Aged; Azathioprine; Carcinoma, Squamous Cell; Crohn Disease; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Neoplasm Invasiveness; Uterine Cervical Neoplasms

Topics: Acute Disease; Adult; Age Factors; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Budesonide; Child; Controlled Clinical Trials as Topic; Crohn Disease; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Meta-Analysis as Topic; Nutritional Physiological Phenomena; Prednisolone; Time Factors

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Child; Crohn Disease; Enzyme Inhibitors; Female; Folic Acid Antagonists; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Mesalamine; Meta-Analysis as Topic; Methotrexate; Placebos; Postoperative Care; Prednisolone; Pregnancy; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Risk Factors; Time Factors

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Child; Chronic Disease; Contraindications; Crohn Disease; Endoscopy; Enzyme Inhibitors; Female; Folic Acid Antagonists; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Methotrexate; Mycophenolic Acid; Nutritional Physiological Phenomena; Placebos; Prednisone; Pregnancy; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Retrospective Studies; Time Factors; Ultrasonography

6-Thioguanine (6-TG) is a thiopurine analogue that is closely related to 6-mercaptopurine (6-MP) and azathioprine (AZA). These agents have potent cytotoxic and immunomodulatory effects and are useful in the treatment of a variety of conditions, including inflammatory bowel disease. Both 6-MP and AZA are widely used and are known to cause hepatotoxicity in a proportion of patients. 6-Thioguanine is being increasingly used in the treatment of inflammatory bowel disease but has not been reported to cause liver injury in this context. We describe a case of significant elevation of serum transaminases in a patient treated with 6-TG for a flare of Crohn's disease. We believe the temporal association of the abnormal liver enzymes in this patient, in the absence of other offending agents, argues strongly in favor of 6-TG as a cause of liver enzyme abnormalities. This case highlights the need to monitor liver enzymes in patients treated with 6-TG and identifies the need for additional research focused on the mechanism of thiopurine-induced hepatic injury.

Topics: Adult; Alanine Transaminase; Antimetabolites, Antineoplastic; Aspartate Aminotransferases; Crohn Disease; Female; Humans; Liver; Liver Function Tests; Mercaptopurine; Thioguanine

: Azathioprine and mercaptopurine are commonly used in chronic active Crohn's disease. They share the disadvantage of a delayed onset of action and potentially serious side-effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease.. : Thirty-seven patients with chronic active Crohn's disease and a Crohn's disease activity index of > 150 were enrolled in this study. Inclusion criteria were steroid dependence (n = 19), steroid refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks; a dose escalation to 80 mg was allowed at week 12. Remission was defined as a Crohn's disease activity index of < 150 associated with a decrease of > 70 points; response was defined as a decrease of > 70 points in the Crohn's disease activity index.. : In the intention-to-treat analysis, 13 of 37 patients achieved remission (35%). Twelve of these 13 patients achieved remission after 4 weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6-Thioguanine was more effective in azathioprine-intolerant than in azathioprine-refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6-thioguanine. Adverse events included phototoxicity, pancreatitis, headache, nausea, alopecia, arthralgia, minor infections and reversible elevation of transaminases. Six patients required discontinuation of medication, two because of leucopenia.. : In this patient group with chronic active Crohn's disease, 6-thioguanine appeared to be effective with acceptable short-term toxicity, but long-term controlled trials are clearly needed to further define its role.

Topics: Adult; Chronic Disease; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prospective Studies; Treatment Outcome

To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercaptopurine (6-MP) chemotherapy.. The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed.. The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved.. This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.

Topics: Adult; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Oligospermia; Pregnancy; Pregnancy Outcome; Sperm Injections, Intracytoplasmic

Infliximab has been proven effective for treatment of active Crohn's and fistulizing Crohn's disease. We reviewed our experience with infliximab in patients with Crohn's disease to determine if its combination with immunomodulators leads to better response and longer periods of disease quiescence.. We performed a retrospective chart review of 122 patients with Crohn's disease who received infliximab infusions. Data were collected on patient demographics, clinical response to infliximab, fistula response, prednisone dose, infusion reactions/side effects, concomitant immunomodulator therapy, and time intervals between infliximab infusions.. Of 122 patients receiving infliximab infusions, 117 completed more than 2 wk of follow-up (400 infusions), and five patients had no follow-up. Co-therapies included azathioprine (AZA) in 47 (40.2%) patients, 6-mercaptopurine (6-MP) in 11 (9.4%), methotrexate (MTX) in 23 (19.7%), prednisone in 64 (54.7%), mesalamine in 51 (43.6%), and antibiotics in 16 (13.7%). Mean follow-up was 52 wk (14-864 days). Overall response rate to infliximab was similar between patients receiving immunomodulators (AZA/6-MP 87.9%, MTX 82.6%) and patients receiving infliximab alone (75%), although there was a trend toward higher response with AZA/6-MP (p = 0.10). More frequent drug reactions/side effects occurred in the infliximab alone group (22.2%) compared with patients receiving MTX (13.0%) and AZA/6-MP (13.8%), but this was not statistically significant. Prednisone dosage was reduced from a mean of 19.5 mg to 7.5 mg per day overall (p < 0.05). Fistula response and dosing intervals were not affected by concomitant immunosuppression.. Concomitant use of immunomodulators with infliximab in patients with Crohn's disease did not improve patient response to several parameters measured, including clinical response rate, dose reduction of prednisone, fistula response, and mean intervals between infliximab infusions.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Intestinal Fistula; Male; Medical Records; Mercaptopurine; Mesalamine; Middle Aged; Prednisone; Retrospective Studies; Treatment Outcome

The purine analogues 6-mercaptopurine (6-MP) and azathioprine have been found to be safe and efficacious in both inducing remission of Crohn's disease in adults and maintaining remission in adults and children. In addition, steroid-sparing effects are demonstrable in trials of both adults and children with Crohn's disease. Anecdotal reports of adults and very limited data from children also suggest that azathioprine and 6-MP might help prevent postoperative recurrence of Crohn's disease. Regarding safety, adults and children reported similar rates of adverse effects from the use of these agents: reported adverse effects in adults included significant infection (7.4%), pancreatitis (3.3%), neoplasm (3.1%), bone marrow suppression (2.0%), allergy (2.0%), and drug-induced hepatitis (0.3%). Most studies also suggest there is little, if any, probability that immunomodulatory therapy might increase the risk of malignancy in patients with Crohn's disease. Data are too limited to guide clinical decisions on how long immunomodulatory therapy should be continued, whether it is safe to take azathioprine and 6-MP during pregnancy, and whether men can take these agents at the time of conception. Although 6-MP and azathioprine have been used safely for over 30 years, the recent commercial availability of thiopurine methyltransferase (TPMT) genotype/phenotype testing and 6-MP metabolite testing offers the promise of limiting potential toxicity even more. As a result, these agents will continue to play a central therapeutic role for all clinicians caring for children or adults with Crohn's disease.

Topics: Adjuvants, Immunologic; Adult; Azathioprine; Child; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Rectal Fistula; Remission Induction; Treatment Outcome

6-mercaptopurine (6-MP) and azathioprine are important drugs for the treatment of inflammatory bowel disease (IBD) but their actions suppress host defense against infection. A challenging case of a 19-year-old female patient with quiescent Crohn's disease maintained with 6-MP presenting with dyspnea and a normal chest exam and x-ray is presented. She became ventilator-dependent and only after numerous investigations was diagnosed with cytomegalovirus (CMV) pneumonitis. A systematic literature review of CMV infections in IBD patients was performed. The present case is the first report of a patient with quiescent IBD maintained on 6-MP who developed CMV pneumonitis. Other reports have identified patients with active disease on multiple immunosuppressants who developed CMV pneumonitis and also highlight the risk of CMV colitis in refractory IBD. The authors review the approach to the diagnosis of CMV infections in IBD patients with atypical pneumonia and colitis and highlight the importance of considering CMV infection in these settings.

Topics: Adult; Crohn Disease; Cytomegalovirus; Cytomegalovirus Infections; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Pneumonia, Viral; Respiration, Artificial

There is a general lack of information on the care of inflammatory bowel disease (IBD) in a broad, geographically diverse, non-clinic population. The purposes of this study were (1) to compare a sample drawn from the membership of a national Crohn's and Colitis Foundation to published clinic-based and population-based IBD samples, (2) to describe current patterns of health care use, and (3) to determine if unexpected variations exist in how and by whom IBD is treated.. Mailed survey of 4453 members of the Crohn's and Colitis Foundation of Canada. The questionnaire, in members stated language of preference, included items on demographic and disease characteristics, general health behaviors and current and past IBD treatment. Each member received an initial and one reminder mailing.. Questionnaires were returned by 1787, 913, and 128 people with Crohn's disease, ulcerative colitis and indeterminate colitis, respectively. At least one operation had been performed on 1159 Crohn's disease patients, with risk increasing with duration of disease. Regional variation in surgical rates in ulcerative colitis patients was identified. 6-mercaptopurine/azathioprine was used by 24% of patients with Crohn's disease and 12% of patients with ulcerative colitis (95% CI for the difference: 8.9%-15%). In patients with Crohn's disease, use was not associated with gender, income or region of residence but was associated with age and markers of disease activity. Infliximab was used by 112 respondents (4%), the majority of whom had Crohn's disease. Variations in infliximab use based on region of residence and income were not seen. Sixty-eight percent of respondents indicated that they depended most on a gastroenterologist for their IBD care. There was significant regional variation in this. However, satisfaction with primary physician did not depend on physician type (for example, gastroenterologist versus general practitioner).. This study achieved the goal of obtaining a large, geographically diverse sample that is more representative of the general IBD population than a clinic sample would have been. We could find no evidence of significant regional variation in medical treatments due to gender, region of residence or income level. Differences were noted between different age groups, which deserves further attention.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Azathioprine; Canada; Colitis; Colitis, Ulcerative; Crohn Disease; Digestive System Surgical Procedures; Female; Gastroenterology; Health Services; Humans; Incidence; Inflammatory Bowel Diseases; Infliximab; Male; Mercaptopurine; Middle Aged; Patient Satisfaction; Population Surveillance

Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases.. : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP.. An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy.. Forty-nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13-21 days after TG was started. No haematological side-effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG.. TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

Topics: Adult; Antimetabolites; Azathioprine; Crohn Disease; Drug Resistance; Female; Humans; Male; Mercaptopurine; Middle Aged; Prospective Studies; Recurrence; Remission Induction; Thioguanine; Treatment Outcome

The efficacy of 6-mercaptopurine (6-MP) in the treatment and long-term maintenance of remission of inflammatory bowel disease and prevention of recurrence after resection in Crohn's disease have been established. Concern about 6-MP toxicity remains, especially the development of neoplasm. The aim of this study is to determine the incidence of all short- and long-term toxicity by follow-up of all patients with inflammatory bowel disease treated with 6-MP over a 20-year period.. We reviewed the office and hospital records and also determined the recent status of 410 patients with inflammatory bowel disease treated with 6-MP from 1980 to 1999. All toxicity was recorded.. There was a low incidence of early drug-related allergic reactions (3.9%) and pancreatitis (1.2%). Desensitization to either 6-MP or azathioprine is often successful with the same or the other drug. Significant leukopenia (

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Time Factors

This study was designed to evaluate the predictive factors of response of perianal Crohn's disease to azathioprine or 6-mercaptopurine.. Ninety-four patients (65 females; mean age, 31 years) with active perianal Crohn's disease were treated with azathioprine or 6-mercaptopurine for more than 6 (median, 27) months (median azathioprine dose, 2 mg/kg/day). The evolution of perianal lesions during azathioprine or 6-mercaptopurine therapy was analyzed retrospectively. Patients who had a clear anatomic improvement (fistula closure, fissure healing, stricture dilatation) and who did not develop any perianal complications requiring an antibiotic course or surgical intervention were considered responders regarding their perianal disease.. Three years after inclusion, the cumulative probabilities of remaining free of perianal complication and achieving a clear anatomic improvement were 0.47 (95 percent confidence interval, 0.36-0.58) and 0.4 (95 percent confidence interval, 0.29-0.53), respectively. On the whole, 27 patients (29 percent) were responders to azathioprine or 6-mercaptopurine therapy. The absence of fistula, duration of perianal disease shorter than 22 months, and aged 40 years or older at inclusion were three independent factors associated with response to azathioprine or 6-mercaptopurine therapy. There was no correlation between the response of perianal lesions and the achievement of intestinal remission with azathioprine or 6-mercaptopurine.. One-third of patients with perianal lesions of Crohn's disease demonstrated a clear improvement during azathioprine or 6-mercaptopurine therapy. Patients aged 40 years or older with a recent perianal disease and without fistula were the best responders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anus Diseases; Azathioprine; Confidence Intervals; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prognosis; Proportional Hazards Models; Rectal Fistula; Risk Factors; Secondary Prevention; Treatment Outcome

Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown.. To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease.. A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure.. Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event.. In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Topics: Abdominal Wall; Administration, Oral; Adolescent; Adult; Aged; Crohn Disease; Cutaneous Fistula; Cyclosporine; Female; Gastrointestinal Agents; Humans; Injections, Intramuscular; Intestinal Fistula; Male; Mercaptopurine; Middle Aged; Rectal Diseases; Retrospective Studies; Treatment Outcome; Urinary Bladder Diseases; Urinary Fistula; Vaginal Fistula

Azathioprine induced profound myelosuppression linked to TPMT deficiency has now been documented in many patient groups, including those with Crohn's disease. At the start of azathioprine or mercaptopurine therapy, measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression when treated with standard thiopurine dosages. During the initial months of azathioprine therapy a knowledge of TPMT status warns of early bone marrow toxicity. In patients established on azathioprine these is no clear evidence to suggest that TPMT is predictive of clinical response or drug toxicity, indicating a role for TPMT in the prediction of early events rather than long term control. In patients with Crohn's disease on long term azathioprine therapy, it is clear that myelosuppression, particularly leucopenia, is caused by other factors in addition to variable TPMT activity and therefore monitoring of blood cell counts throughout treatment is essential.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Biomarkers; Crohn Disease; Drug Interactions; Humans; Immunosuppressive Agents; Leukopenia; Mercaptopurine; Methyltransferases; Risk Factors; Sulfasalazine; Time Factors

Topics: Anti-Bacterial Agents; Azathioprine; Colon; Crohn Disease; Humans; Ileum; Immunosuppressive Agents; Mercaptopurine; Nitroimidazoles; Reoperation; Secondary Prevention

Fistulas occur in about one third of patients with Crohn's disease and rarely heal spontaneously. Conventional medical and surgical therapy often fails. The anti-TNF-alpha antibody infliximab offers a novel therapeutic option. By this approach, closure of fistulas was reported in 45% of cases. However, after discontinuation of therapy, most fistulas recurred. Azathioprine and 6-mercaptopurine (6-MP) are effective drugs in Crohn's disease and lead to closure of fistulas in 30-40% of cases. Thus, the aim of this study was to evaluate the combination of infliximab with 6-mercaptopurine/azathioprine as therapy for fistulas in patients with Crohn's disease.. A total of 16 patients (mean age 37 yr) with Crohn's fistulas resistant to conventional measures were treated with a combination of three or four infusions of infliximab and long term 6-MP/azathioprine. In all, 13 patients had perianal fistulas, two had abdominal fistulas, and one patient had both perianal and recto-vaginal fistulas. Therapy success was defined as complete closure of fistulas for a minimum observation period of 6 months after fistula closure.. In 12 (75%) of the 16 patients, we observed complete closure of the fistulas that persisted for >6 months (median follow-up 10 months, range 6-11 months). The median time to complete closure of fistulas was 14 days (range 2-36 days). In four patients, therapy success was not achieved.. Our pilot study reveals that concomitant and long term 6-MP/azathioprine therapy could prolong the effect of an initial infliximab therapy on fistula closure in patients with Crohn's disease. These data prompt larger controlled trials.

Topics: Adult; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Intestinal Fistula; Magnetic Resonance Imaging; Male; Mercaptopurine; Treatment Outcome

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Crohn Disease; Female; Humans; Infant, Newborn; Male; Mercaptopurine; Pregnancy; Pregnancy Complications; Teratogens

Topics: Adolescent; Azathioprine; Child, Preschool; Crohn Disease; Female; Genotype; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Pancytopenia

Topics: Anti-Inflammatory Agents; Azathioprine; Crohn Disease; Dose-Response Relationship, Drug; Genotype; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Steroids; Treatment Outcome

Topics: Adult; Crohn Disease; Fathers; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Mercaptopurine; Paternal Exposure; Risk Assessment; WAGR Syndrome

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters.. Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups 1 and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n = 9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood.. The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed.. There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely.

Topics: Adult; Azathioprine; Case-Control Studies; Crohn Disease; Drug Monitoring; Drug Therapy, Combination; Erythrocytes; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prospective Studies; Thioguanine; Time Factors

Azathioprine and its active metabolite 6-mercaptopurine are of increasing importance in the treatment of chronic inflammatory bowel disease. Most of the toxicity and the side effects of the medications are well known. However, it is relatively unknown that azathioprine toxicity itself can produce devastating diarrhea in patients with inflammatory bowel disease. This leads to great difficulties in differential diagnosis. We describe 2 patients with severe intestinal toxicity. This was life-threatening in 1 patient after reintroducing the drug. We therefore believe that any rechallenge with azathioprine should be only undertaken in a controlled hospital environment when a reaction to azathioprine is suspected. In addition, we found that this devastating intestinal toxicity did not reoccur after rechallenge with its active metabolite 6-mercaptopurine. Azathioprine and 6-mercaptopurine therefore cannot be used interchangeably.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Diarrhea; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged

Topics: Adolescent; Antimetabolites; Child; Child, Preschool; Crohn Disease; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Infant; Male; Mercaptopurine; Multicenter Studies as Topic; Prednisone; Randomized Controlled Trials as Topic; Treatment Outcome

The cost-utility of infliximab is unknown. The aim of this study was to determine the incremental cost-utility (CU(inc)) of medical therapy for Crohn's disease (CD) perianal fistula.. A Markov model was used to simulate a 1-year treatment period with the following: 6-mercaptopurine and metronidazole [6MP/met] (comparator), 3 infliximab infusions + 6MP/met as second-line therapy (intervention I), infliximab with episodic reinfusion (intervention II), and 6MP/met + infliximab as second-line therapy (intervention III). Utilities were elicited from patients with CD and healthy individuals by standard gamble, and costs were obtained from hospital billing data. Uncertainty was assessed by sensitivity analysis.. All strategies had similar effectiveness. Interventions I, II, and III were slightly more effective, but also more costly than 6MP/met (Intervention I: CU(inc) = $355,450/quality-adjusted life-years [QALY]; Intervention II: CU(inc) = $360,900/QALY; Intervention III: CU(inc) = $377,000/QALY). If the cost of infliximab were reduced to $304 per infusion, the CU(inc) for intervention II would be $54,050/QALY.. Based on available data, all strategies had similar effectiveness in our model, but infliximab was much more expensive than 6MP/met. The incremental benefit of infliximab for treating CD perianal fistulae over a 1-year period may not justify the higher cost. Prospective studies directly comparing 6MP/met and infliximab are warranted.

Topics: Adult; Antibodies, Monoclonal; Crohn Disease; Drug Costs; Drug Therapy, Combination; Female; Gastrointestinal Agents; Health Care Costs; Humans; Infliximab; Male; Mercaptopurine; Metronidazole; Middle Aged; Rectal Fistula

Crohn's disease of the esophagus is rare. We sought to determine the clinical features and outcome of patients with esophageal Crohn's disease seen at our institution.. Patients with esophageal Crohn's disease evaluated at Mayo Clinic Rochester between 1976 and 1998 were identified.. Twenty patients (0.2%) with esophageal involvement were identified. Median age at diagnosis was 31 years (range, 7-77 years). Eleven patients (55%) were female. Extraesophageal Crohn's disease preceded or was found at the same time as the diagnosis of esophageal Crohn's in all cases. Sixteen patients (80%) had symptoms referable to the esophagus. Endoscopic findings included ulcers in 17 (85%), erythema or erosions in 8 (40%), and strictures in 4 patients (20%). One patient had a fistula. The most common histological findings were active chronic inflammation (75%) and ulcer (30%). No granulomata were identified. Approximately one-half of our patients improved with first-line therapy. Eleven patients (55%) received immune modifier therapy. Six showed significant improvement on azathioprine, 6-mercaptopurine, or cyclosporine. Esophageal dilatation was required in six patients, and three patients required surgery.. Esophageal Crohn's disease may be underdiagnosed. Patients with Crohn's disease complaining of esophageal symptoms should undergo upper endoscopy with biopsies, and the diagnosis of esophageal Crohn's disease should be entertained if aphthous or deep ulcers or strictures are present. Immune modifier therapy should be considered for steroid-dependent and steroid-resistant cases.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Child; Child, Preschool; Crohn Disease; Data Interpretation, Statistical; Dilatation; Esophageal Diseases; Esophagoscopy; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Steroids

Topics: Antimetabolites; Crohn Disease; Humans; Mercaptopurine; Thioguanine

Topics: Adolescent; Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine

Mycophenolate mofetil (MMF) is a novel immunomodulator that may be effective in the treatment of chronic active and perianal Crohn's disease (CD). The aim of this study is to assess the efficacy of MMF in CD patients who failed or were intolerant of 6-mercaptopurine (6-MP) or azathioprine (AZA). Eleven CD patients were treated with MMF after a failed course of 6-MP/AZA, and their records reviewed retrospectively. Reasons for 6-MP/AZA intolerance or failure were recorded. Response to MMF was determined by calculation of the Harvey-Bradshaw index and ability to taper steroids. Adverse reactions to MMF were recorded. Eleven patients were identified who failed a previous trial of 6-MP/AZA and other immunomodulators and required immunomodulator therapy. Of 11 patients who started MMF, four had early adverse reactions within 8 weeks and stopped the medication. Of the remaining seven patients who took MMF for at least 8 weeks, one had a complete response, two had a partial response, and four had no response to the medication. In patients who failed 6-MP/AZA, MMF was of benefit in 3 of 11 patients with only one complete responder. This lower-than-expected response rate may indicate that patients who are resistant to 6-MP or AZA may also be resistant to MMF.

Topics: Adult; Azathioprine; Crohn Disease; Female; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Male; Mercaptopurine; Middle Aged; Mycophenolic Acid; Retrospective Studies; Treatment Failure

Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months. The patient's perianal disease was reviewed and evaluated for fistulas, drainage, induration, and tenderness. In addition, the patients were given a score using the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively scored upon initiation of treatment and after six months of therapy. Possible scores ranged from 0-20. Twenty patients met the study criteria. Five patients were considered treatment failures. One patient required a colostomy after 1.5 months of therapy, one developed pancreatitis, and three were noncompliant with therapy. Of the remaining 15 patients who were treated for > or =6 months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/- 1.72 after six months of therapy. The improvement was statistically significant (p < 0.001). AZA and 6-MP are effective treatments for healing significant perianal Crohn's disease in pediatrics.

Topics: Adolescent; Anus Diseases; Azathioprine; Chi-Square Distribution; Child; Child, Preschool; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Registries; Retrospective Studies; Treatment Outcome

Topics: Crohn Disease; Desensitization, Immunologic; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged

6-mercaptopurine (6-MP) and azathioprine (AZA) are used to treat inflammatory bowel disease (IBD). Side effects include infection, leukopenia, hepatitis, and pancreatitis. The level of thiopurine methyltransferase (TPMT), which metabolizes 6-MP to 6-methylmercaptopurine, may reflect the risk of side effects. We sought to evaluate the relationship between the side effects of these medications and the TPMT level of pediatric patients with IBD. The medical records of our patients who were diagnosed with IBD and who received 6-MP or AZA were reviewed for measured TPMT levels. All red blood cell (RBC) TPMT levels were determined at the Mayo Medical Laboratories, Rochester, MN. The occurrence of leukopenia, elevated aminotransferases, and pancreatitis was evaluated. Twenty-two patients, mean age 13.7 years, received 6-MP or AZA and had TPMT levels measured. The TPMT levels ranged 10.7-27.5 U/mL RBC with a mean of 17.2 +/- 3.2 U/mL RBC. Two children had levels below the accepted norm of 13.8 U/mL RBC. One of these patients (50%) developed both elevation of aminotransferases and leukopenia. Of all, 20 children had normal levels, 3 (15.0%) exhibited side effects: hepatitis (n = 2) and leukopenia (n = 1). We conclude that side effects of 6-MP or AZA occur despite normal TPMT levels.

Topics: Adolescent; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases

Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels.. To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels.. Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels.. Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.

Topics: Administration, Oral; Adult; Azathioprine; Biological Availability; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Therapeutic Equivalency; Treatment Outcome

Topics: Adolescent; Biopsy; Blood Vessels; Colon; Complement C3; Crohn Disease; Dapsone; Endoscopy, Gastrointestinal; Female; Humans; IgA Vasculitis; Immunoglobulin A; Immunoglobulin M; Mercaptopurine; Mesalamine; Prednisone; Skin; Vasculitis

Topics: Adrenal Cortex Hormones; Azathioprine; Crohn Disease; Digestive System Fistula; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Urinary Fistula; Wound Healing

Azathioprine is a useful therapy in patients with inflammatory bowel disease that is difficult to control. However, 10% of patients are unable to tolerate azathioprine, and the best form of treatment for this group of patients is unknown. The azathioprine metabolite 6-mercaptopurine may be a useful therapy for these patients.. To review our clinical experience of the use of the 6-mercaptopurine in inflammatory bowel disease patients who are intolerant of azathioprine.. All patients who were prescribed 6-mercaptopurine in a 2-year period were identified from pharmacy records. The case notes were reviewed and those who had previously been intolerant of azathioprine were included.. A total of 19 with either ulcerative colitis and Crohn's disease were included. The reasons for discontinuing azathioprine were side-effects (13 patients), failure of efficacy (four patients) and leucopenia (two patients). Eleven of the 19 patients (68%) tolerated 6-mercaptopurine, including seven out of 13 patients (54%) who discontinued azathioprine due to side-effects. The length of follow-up of patients on 6-mercaptopurine was between 126 and 780 days (median 390 days).. 6-mercaptopurine should be considered in patients with inflammatory bowel disease who require continuing immunosuppressive therapy, but are intolerant of azathioprine.

Topics: Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged

The aim of this study is to report on the first year experience with infliximab for Crohn's disease.. All Crohn's patients receiving infliximab at our institution in the first year of release were prospectively registered. Disease activity was scored at initial infusion, and at 1, 3, 7, and 12 wk. Results were tabulated separately for patients with luminal (L) or fistulous (F) Crohn's disease. Steroid withdrawal and adverse events were tabulated.. One hundred twenty-nine patients were treated (81 L, 48 F). Mean number of infusions/patient were 2.38 L, 3.23 F. Median time to response and remission was 8 and 9 days L; 9 and 10 days F, respectively. Initial infusion course response and remission rates at 3 wk were 65% and 31% L; 78% and 24% F, respectively. Rates were higher if concurrently treated with 6-mercaptopurine or azathioprine and improved with subsequent infusions. Relapse occurred in 78% at a mean 8.5 wk L and in 71% at a mean of 12.2 wk F. Steroid tapering was seen in >90%, with 54% completely off steroids after a second infusion. Infusion-related reactions were seen in up to 24% of patients. The incidence of side effects did not differ if on concurrent immunomodulatory therapy.. Clinical experience with infliximab closely parallels the results of the controlled clinical trials, and includes steroid-sparing effects.

Topics: Adult; Antibodies, Monoclonal; Azathioprine; Case-Control Studies; Crohn Disease; Female; Gastrointestinal Agents; Humans; Infliximab; Male; Mercaptopurine; Prednisone; Prospective Studies; Time Factors

The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohn's disease (CD).. We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy.. Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced > or = 50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk.. Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.

Topics: Adult; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Crohn Disease; Female; Gastrointestinal Agents; Humans; Infliximab; Male; Mercaptopurine; Prednisone; Severity of Illness Index; Time Factors

Our aim was to study the frequency, severity, and outcome of patients with Crohn's disease and ulcerative colitis treated with 6-mercaptopurine (6MP) who developed shingles during treatment, and to recommend management. While varicella can be severe in young people immunocompromised by steroids, the incidence of herpes zoster in older people with inflammatory bowel disease (IBD) and whether its severity is influenced by 6MP and azathioprine are unknown.. Data were collected from our IBD Center on 550 patients with IBD to identify those who developed shingles while on 6MP, its severity, the dose and duration of 6MP, and the management of the 6MP.. Twelve of 550 patients with IBD treated with 6MP developed shingles. In two with herpes zoster ophthalmicus the pain was prolonged, and one patient developed encephalitis which was brief and uncomplicated; in nine patients the course was benign. Acyclovir should be the treatment of choice even though it was available in only three cases.. Shingles occurs more often in IBD patients treated with 6MP than in those who are not, but the course is usually benign and there has been no mortality. The 6MP should be stopped temporarily until severity is established but if the underlying disease warrants further treatment the 6MP should be restarted.

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Child; Colitis, Ulcerative; Crohn Disease; Female; Herpes Zoster; Humans; Immunosuppressive Agents; Incidence; Male; Mercaptopurine; Risk Factors; Severity of Illness Index

Low bone mineral density (BMD) is a recognized complication of Crohn's disease (CD). The aim of this study was to identify the risk factors for low BMD in pediatric patients with CD.. One hundred nineteen subjects with CD ranging in age from 5 to 25 years were enrolled. BMD of the lumbar spine was measured by dual-energy x-ray absorptiometry. Growth parameters were assessed by examination. Disease-specific variables and use of selected medications were determined by chart review.. Powerful risk factors for low BMD z-score included hypoalbuminemia, exposure to nasogastric tube feeds, total parenteral nutrition, 6-mercaptopurine, and corticosteroids. Corticosteroid dosing at a level >7.5 mg/d, 5000 mg lifetime cumulative dose, or >12 months of lifetime exposure were significant risk factors for low BMD z-score. Weaker but significant associations with low BMD z-scores included measures of disease severity such as pediatric Crohn's disease activity index, hospital admissions, and length of hospital stay. Site and duration of disease were not predictive.. The presence of several clinically available factors was predictive of poor bone mineral status in this sample of subjects with CD. Hypoalbuminemia, corticosteroid exposure, nasogastric tube feeds, total parenteral nutrition, and 6-mercaptopurine were the most powerful risk factors for low bone mineral status.

Topics: Absorptiometry, Photon; Adolescent; Adrenal Cortex Hormones; Adult; Body Height; Body Weight; Bone Density; Child; Child, Preschool; Crohn Disease; Enteral Nutrition; Female; Humans; Lumbar Vertebrae; Male; Mercaptopurine; Multivariate Analysis; Parenteral Nutrition, Total; Risk Factors; Serum Albumin

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

6-Mercaptopurine (6MP) and azathioprine are immunomodulators used in the treatment of refractory Crohn's disease. Studies have confirmed their efficacy and value in maintenance of remission, but it is our purpose to determine how long 6MP/azathioprine should be continued once remission has been accomplished.. Careful follow-up was accomplished in patients with Crohn's disease seen at one medical center who were treated with 6MP for > or = 6 months, who achieved remission within 1 yr of initiation of therapy, and who were in prolonged clinical remission (> or = 6 months without steroids). The time-to-relapse was calculated in those who continued treatment, in those who stopped treatment for reasons other than a relapse, and in the whole sample, taking into account that they could be treated with the drug, or could not, as a function of time. The influence of concomitant variables on the time-to-relapse rate was evaluated.. A total of 120 patients met the inclusion criteria. The cumulative probabilities of relapse at 1, 2, 3, and 5 yr for those who continued to take 6MP and for those who stopped the therapy for reasons other than a relapse are as follows: Patients maintained on 6MP (n = 84): 1 yr, 29%; 2 yr, 45%; 3 yr, 55%; 5 yr, 61%. Patients who terminated 6MP (n = 36): 1 yr, 36%; 2 yr, 71%; 3 yr, 85%; 5 yr, 85%. Sex, distribution of disease, duration of disease, time to remission on 6MP, and concomitant 5-ASA use did not influence the relapse rates. Younger age was associated with a higher rate of relapse in patients who were maintained on 6MP. A higher daily dose of 6MP was associated with a higher relapse rate.. Discontinuation of 6MP, while Crohn's disease is in remission, leads to higher relapse rates and continuation of 6MP reduces the likelihood of relapse. Therefore, we favor the indefinite use of 6MP once remission has been achieved.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Confidence Intervals; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Probability; Proportional Hazards Models; Recurrence; Remission Induction; Sex Factors; Time Factors

Topics: Child; Crohn Disease; Humans; Mercaptopurine; Recurrence

Topics: Adult; Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Drug Interactions; Drug Therapy, Combination; Humans; Mercaptopurine; Pancreatitis

A 65-year-old man with Crohn's disease died of acute myeloblastic leukemia after treatment for 11.8 years with 6-mercaptopurine, 1.5 mg/kg/day (100 mg/day). On cytogenetic analysis, most of the malignant bone marrow cells had deletion of chromosome 7, the most frequently reported cytogenetic abnormality in chemotherapy-related acute leukemia. This finding, together with previous reports of acute leukemia and other malignancies following prolonged treatment with azathioprine or 6-mercaptopurine for nonmalignant conditions including inflammatory bowel disease, indicates that long-term use of these drugs for inflammatory bowel disease may increase the risk of malignancy. However, the magnitude of the risk is unknown.

Topics: Aged; Chromosome Deletion; Chromosomes, Human, Pair 7; Crohn Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Mercaptopurine

Our aim was to study the relationships between clinical efficacy of azathioprine, 6-mercaptopurine pharmacokinetics and changes in peripheral blood lymphocyte subpopulations induced by azathioprine treatment in Crohn's disease.. Twenty-three patients were prospectively followed up for 1 year. Peripheral blood counts, total lymphocytes, CD3+, CD4+, CD8+, CD25+, CD16+CD56+, CD57+ and CD19+ lymphocyte subpopulations were carried out, using flow cytometry, during azathioprine treatment. Pharmacokinetic studies were performed at day 8 and month 3 by measuring 6-mercaptopurine plasma concentration after an oral dose of azathioprine (2 mg/kg). Results were compared in responders (no activity and no steroids) and non-responders.. The decrease in peripheral blood leukocytes and neutrophils was significant after 1 month, reaching 49% and 48% of the pre-treatment values at 1 year; the one of lymphocytes was significant after 6 months and reached 41% at 1 year. Percentages of CD3+, CD4+, CD8+, CD57+, CD16+CD56+ and CD19+ lymphocytes remained unchanged whereas percentage of CD25+ lymphocytes increased from 10% to 28% (P < 0.01). There was a high inter and intraindividual variability of 6-mercaptopurine peak plasma concentration and area under the curve. No significant difference was found between responders (n = 14) and non responders (n = 7) for pharmacokinetic parameters and lymphocyte subpopulations; there was no correlation between lymphocyte subpopulation changes and 6-mercaptopurine pharmacokinetics.. Monitoring of 6-mercaptopurine plasma concentration and blood lymphocyte subpopulations is of little value in Crohn's disease patients treated with azathioprine.

Topics: Adult; Azathioprine; Crohn Disease; Female; Humans; Immunophenotyping; Immunosuppressive Agents; Kinetics; Lymphocyte Count; Lymphocyte Subsets; Male; Mercaptopurine; Middle Aged; Receptors, Interleukin-2

Topics: Crohn Disease; Data Interpretation, Statistical; Humans; Mercaptopurine

Topics: Azathioprine; Crohn Disease; Follow-Up Studies; Humans; Immunosuppressive Agents; Long-Term Care; Mercaptopurine; Recurrence; Retrospective Studies; Treatment Outcome

Recurrence of Crohn's disease after surgery is a common occurrence, pointing to the need for a strategy to prevent recurrent disease. We report the postoperative course of 10 patients who required intestinal resections for complications related to Crohn's disease.. All patients had a Pediatric Crohn's Disease Activity Index score of 10 or greater. Among these patients, 5 began treatment with 6-mercaptopurine in the perioperative period. All 10 had received various combinations of prednisone and salicylate compounds. Patients who were given 6-mercaptopurine did not discontinue the medication until 2 years after the surgery.. To date, none of the five patients who were placed on 6-mercaptopurine have had recurrence of their Crohn's disease (mean disease-free period 32.6 +/- 18.4 months). Among those five patients not receiving 6-mercaptopurine there have been three relapses (mean time to relapse 3.7 +/- 1.2 months). Log-rank sum analyses of Kaplan-Meier survival curves show benefit to patients receiving 6-mercaptopurine in preventing relapses after intestinal resection (p < 0.05).. Although the underlying pathophysiologic reasons leading to the high relapse rate after intestinal surgery in Crohn's disease are unknown, we conclude that treatment with 6-mercaptopurine in the perioperative period may be warranted to help prevent the recurrence of Crohn's disease after surgery.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Crohn Disease; Follow-Up Studies; Humans; Intestines; Mercaptopurine; Postoperative Period; Recurrence; Survival Analysis; Time Factors

Topics: Adult; Antimetabolites, Antineoplastic; Child; Crohn Disease; Humans; Mercaptopurine; Recurrence

Topics: Antimetabolites; Antimetabolites, Antineoplastic; Azathioprine; Chromatography, High Pressure Liquid; Crohn Disease; Humans; Mercaptopurine; Methylthioinosine; Thioguanine

Topics: Adolescent; Brain; Brain Abscess; Crohn Disease; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Mercaptopurine; Nocardia asteroides; Nocardia Infections; Prednisone; Radiography, Abdominal; Staphylococcus aureus; Tomography, X-Ray Computed

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Topics: Adolescent; Aminosalicylic Acids; Anti-Inflammatory Agents; Bone Marrow; Crohn Disease; Drug Interactions; Humans; Immunosuppressive Agents; Mercaptopurine; Prednisone

While 5-ASA and corticosteroids are still the mainstay of treatment, more potent immunosuppressive agents should be considered in refractory and steroid dependant patients not amenable to surgery. The activity and side effect profile of 6-MP/azathioprine, methotrexate and cyclosporine are now well established. Other agents such as mycophenolaat-mophetil, FK 506 and combination therapies may provide additional benefits in the future. Advances in the field of mucosal immunology have prompted interest in more specific immunologic approaches. Recombinant genetic engineering techniques enable us to test cytokines, anti cytokines, anti adhesion molecules etc. some of which with very promising clinical results. More data on long term safety and specific indications should be awaited before broader use of these agents can be advocated. An updated review is given from the current immunological based treatment modalities for both Crohn's disease and ulcerative colitis.

Topics: Antimetabolites, Antineoplastic; Azathioprine; Blood Component Removal; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Cytokines; Folic Acid Antagonists; Humans; Immunosuppressive Agents; Mercaptopurine; Methotrexate

Crohn's ulcerative gastrointestinal disease is presently managed through a variety of medical interventions, including-according to severity of illness-anti-inflammatory, immunosuppressive, and corticosteroid agents; and with remedial surgery to correct anatomical abnormalities caused by disease processes. The immunosuppressant azathioprine (or its metabolite, 6-mercaptopurine) is considered an efficient maintenance therapy for Crohn's, but there is always concern about bone-marrow suppression, liver damage, and other adverse effects. For how long persons with this disease should be given these drugs has not been determined.. Patients who were treated with azathioprine or 6-mercaptopurine for more than 6 months, and who were in prolonged clinical remission (> 6 months without steroids) were followed. The time-to-relapse was analysed in those on treatment, in those who stopped treatment for reasons other than a relapse, and in the whole sample, taking into account that they could be treated with the drugs or not, as a function of time. The influence of concomitant variables on time-to-relapse rate was examined using the Cox proportional hazard model.. In the 157 patients who continued to take the therapy, cumulative probabilities of relapse at 1 and 5 years were 11% and 32% respectively. Female gender, younger age, and a time for achieving remission more than 6 months were associated with a higher risk of relapse. In 42 patients who stopped therapy, probabilities of relapse at 1 and 5 years were 38% and 75%, respectively. Male gender, younger age and duration of remission less than 4 years were associated with a higher risk of relapse. After 4 years of remission on these drugs, the risk of relapse appeared to be similar, whether the therapy was maintained or stopped.. Taking into account the potential risks of long-term immunosuppressive therapy, the usefulness of maintaining azathioprine or 6-mercaptopurine in patients who have been in remission for more than 4 years is questionable.

Topics: Adolescent; Adult; Age Factors; Azathioprine; Crohn Disease; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Probability; Proportional Hazards Models; Recurrence; Remission Induction; Sex Factors; Time Factors; Treatment Outcome

Topics: Azathioprine; Crohn Disease; Humans; Mercaptopurine

Topics: Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

The effects of 6-mercaptopurine (6MP) in inflammatory bowel disease are believed to be primarily mediated by its metabolite 6-thioguanine (6TG). Our aim was to develop an assay for measuring leukocyte DNA 6TG levels in patients with Crohn's disease, and to correlate them with levels of 6TG in erythrocytes. Heparinized blood was obtained from 15 adolescent Crohn's disease patients receiving 6MP at an average dose of 1.3 mg.kg-1 day-1 (range 0.8-1.6 mg.kg-1 day-1) for a mean of 23.7 months (range 3-71 months). Leukocyte DNA and erythrocyte 6TG levels were measured by an HPLC assay. Leukocyte 6TG levels ranged from 100 to 2305 pmol/mg DNA, while erythrocyte 6TG levels ranged from 64 to 1038 pmol/8 x 10(8) red blood cells, demonstrating significant interpatient variability. Leukocyte DNA 6TG levels correlated directly with erythrocyte 6TG levels, as measured by the Spearman rank correlation coefficient (p < 0.05). The HPLC measurement of erythrocyte and leukocyte DNA 6TG levels can be useful clinically in monitoring compliance, as well as perhaps to tailor drug metabolite levels to achieve the desired clinical effect.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Crohn Disease; DNA; Erythrocytes; Female; Humans; Immunosuppressive Agents; Leukocytes; Linear Models; Male; Mercaptopurine; Patient Compliance; Thioguanine

Topics: Antimetabolites; Azathioprine; Crohn Disease; Humans; Mercaptopurine; Treatment Outcome

In patients with Crohn's disease arthritis of the large joints, osteomalacia, osteoporosis and aseptic bone necrosis as a consequence of malabsorption and glucocorticoid intake may occur. The case of a patient with long-standing Crohn's disease is presented who subsequently developed abacterial osteomyelitis of the jaw ("osteomyelitis sicca"). The symptoms of the osteomyelitis improved under immuno-suppressive therapy. Because the etiopathogenetic concepts for Crohn's disease and osteomyelitis sicca are similar, the latter could be a rare extraintestinal manifestation in Crohn's disease, not described previously.

Topics: Adult; Combined Modality Therapy; Crohn Disease; Debridement; Diagnostic Imaging; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Male; Mandibular Diseases; Mercaptopurine; Methylprednisolone; Osteomyelitis

Topics: Adolescent; Chickenpox; Crohn Disease; Fatal Outcome; Humans; Immunosuppression Therapy; Male; Mercaptopurine; Pneumonia, Viral; Prednisone; Respiratory Distress Syndrome; Risk Factors; Sulfasalazine

Topics: Azathioprine; Crohn Disease; Humans; Mercaptopurine; Methotrexate; Prednisone; Remission Induction

Low doses of 6-mercaptopurine (6MP) were used for the treatment of inflammatory bowel disease, and 20-30 mg/day was found to be effective for patients with ulcerative colitis who were corticosteroid-dependent or corticosteroid-resistant. Corticosteroid was tapered in 20 of 21 patients with ulcerative colitis. Of 15 patients who were refractory to conventional therapy, 11 responded to 6MP treatment. The same doses of 6MP were given to patients with Crohn's disease who were corticosteroid-dependent or who had associated fistula. Treatment with 6MP did not influence the changes in colonic or ileac lesions in Crohn's disease. However, the fistulas were closed or improved in 70% of 10 patients by 6MP treatment. The adverse effects of small doses of 6MP were minimal. These results confirm that immunosuppressive agents are effective for patients with inflammatory bowel disease. In a rat colitis model induced by immunization with trinitrobenzene (TNB), we used anti-CD4 monoclonal antibodies to prevent colonic inflammation; these antibodies were effective for this colitis model, suggesting that a novel therapy targeting CD4 intestinal lymphocytes may be feasible in the treatment of Crohn's disease.

Topics: Animals; Antibodies, Monoclonal; CD4 Antigens; Colitis; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Rats; Remission Induction; Trinitrobenzenesulfonic Acid

1) to determine the frequency of induced leukopenia in patients with refractory Crohn's disease treated with 6-Mercaptopurine (6-MP). 2) to determine the influence of 6-MP-induced leukopenia on achieving remission [including the three major specific goals of therapy: (a) elimination or reduction of steroids, (b) healing of abscesses and fistulas, and (c) elimination of recurrent intestinal obstruction] and the effect on the rate and percentage of improvement in the CCFA-IOIBD index of Crohn's disease activity after 3 months of 6-MP therapy. 3) to determine whether an improvement of leukopenia was accomplished by an increased risk of clinical bone marrow depression.. We reviewed the course of 98 consecutive patients with refractory Crohn's disease treated with 6-MP and compared the 51 who developed leukopenia and the 47 who did not, in regard to achievement of remission, length of time until remission, rate of recurrence, and time until recurrence.. 1) The mean time to remission was 8.8 wk for patients with leukopenia versus 14.3 wk for those without leukopenia. 2) A strong positive correlation exists between 6-MP induced leukopenia and the achievement and maintenance of remission in refractory Crohn's disease. This was evident in the analysis of response in specific goals and in the activity index. 3) There was no clinical evidence of bone marrow suppression in the 51 patients who developed 6-MP induced leukopenia.. 1) Increasing the dose of 6-MP in patients with refractory Crohn's disease who have not yet responded and who have not achieved leukopenia will very likely increase the efficacy of this drug. 2) Influenced by the results of this study, we have launched a double-blind prospective study to evaluate the relationship between the induction of leukopenia with 6-MP and the achievement of remission.

Topics: Adult; Crohn Disease; Dose-Response Relationship, Drug; Female; Humans; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Remission Induction; Time Factors

To assess whether children with inflammatory bowel disease (IBD) develop permanent impairment of linear growth, we analyzed records from 48 young adults who had IBD during childhood or early adolescence (Tanner I-III; 11.8 +/- 2.4 years old at diagnosis). All were fully grown (Tanner V; 21.1 +/- 3.0 years) at last examination. Adult heights were predicted from data obtained at or shortly after the diagnosis of IBD by three methods: height for age percentile, the Bailey-Pinneau (BP), and Roche-Wainer-Thissen (RWT) methods. Predicted adult heights were then compared with the actual ultimate height of each subject. Permanent growth failure occurred in 19-35% of subjects, depending upon the method used to assess growth. Overall, 31% (15 of 48) of the subjects had deficits of adult height identified by two or more methods, including 14 of 38 (37%) of those with Crohn's disease but only one of 10 with ulcerative colitis. Age at diagnosis of IBD, age at last examination, age at cessation of linear growth, and site of IBD did not differ between impaired and normal growth groups. Duration of corticosteroid use was longer (p < 0.05) in growth-impaired subjects. In addition, although 60% of all subjects had periods of poor growth that put them in height-for-age percentiles two or more major growth channels below previous percentiles, only 19% remained at these levels upon achieving their final adult heights. Permanent impairment of linear growth leading to clinically meaningful deficits of ultimate adult height is common in patients with IBD in childhood or early adolescence. New therapeutic approaches are needed to address this problem.

Topics: Adolescent; Adrenal Cortex Hormones; Anthropometry; Azathioprine; Body Height; Child; Colitis, Ulcerative; Crohn Disease; Enteral Nutrition; Female; Forecasting; Growth Disorders; Humans; Longitudinal Studies; Male; Mercaptopurine; Parenteral Nutrition; Retrospective Studies

We report our observations after 20 yr of clinical experience with 6-mercaptopurine (6-MP) in 148 patients with Crohn's disease who had not satisfactorily responded to steroids and other drugs. Specific therapeutic goals were established for each patient, and the NFIC (now CCFA)-IOIBD index of Crohn's disease activity was calculated pre- and post-therapy. Defined therapeutic goals were achieved in 68%. Major successes include 1) elimination of steroids (66% p < 0.001); 2) healing of internal fistulas and abscesses or improvement by elimination of discharge and tenderness (64% p < 0.05); and 3) healing or improvement by elimination of pain, tenderness and discharge of perirectal fistulas and abscesses (87%, p < 0.05). Other therapeutic goals which achieved 100% success were 1) healing or marked improvement of Crohn's disease of the stomach and duodenum; 2) permitting surgery to be performed electively after 6-MP allowed margins for surgical resection to be delineated. 6-MP was less effective in achieving the therapeutic goals of preventing recurrent small bowel obstruction (43%) and elimination of abdominal masses (55%). Seventy-eight percent of patients showed a reduction in the activity index with a mean of 43% (95% C.I. 36-51%). 6-MP was once again demonstrated to be effective in achieving major therapeutic goals in two of three patients with severe Crohn's disease. Accordingly, the need for surgical resection and subsequent extension of the disease is often postponed or eliminated.

Topics: Crohn Disease; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Recurrence; Severity of Illness Index; Time Factors

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Topics: Adolescent; Adult; Attitude of Health Personnel; Azathioprine; Child; Colitis; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Gastroenterology; Health Surveys; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Pediatrics; Remission Induction; Retrospective Studies; Societies, Medical; Surveys and Questionnaires

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Intestinal Neoplasms; Lymphoma; Mercaptopurine; Risk Factors

Topics: Adult; Chemical and Drug Induced Liver Injury; Crohn Disease; Humans; Inflammatory Bowel Diseases; Liver Function Tests; Male; Mercaptopurine

Topics: Adult; Azathioprine; Carcinoma; Colonic Neoplasms; Crohn Disease; Humans; Mercaptopurine

About 20% of patients with active Crohn's disease do not respond to acute-phase-therapy with glucocorticoids at an initial dose of 60 mg prednisolone-equivalent and stepwise dose reduction every week. In case of primary failure of this therapeutic scheme the dose of glucocorticoids has to be enhanced. If necessary a combination with total parenteral nutrition or tube feeding should be used. In case of early recurrence of inflammation during dose reduction or chronic steroid-dependent disease activity a combination of glucocorticoids with Azathioprine will be successful in about 75% of patients. In addition a combination of glucocorticoids with tube feeding (elemental or polymeric diet) will lead to remission of inflammatory activity in about 60 to 70% of these patients. In patients, who are still refractory to these therapeutic procedures, operation should be discussed.

Topics: Anti-Bacterial Agents; Azathioprine; Crohn Disease; Cyclosporins; Drug Resistance; Drug Therapy, Combination; Glucocorticoids; Humans; Mercaptopurine; Parenteral Nutrition

Topics: Azathioprine; Crohn Disease; Humans; Mercaptopurine

Nineteen patients (12 children and 7 adults) with severe Crohn's disease, all of whom were dependent on corticosteroids, were treated with 6-mercaptopurine. All patients received a daily dose of 6-mercaptopurine of 50 mg; in two pediatric patients with a poor response after 2 months, the dosage was increased to 75 mg/day. A complete or partial response to 6-mercaptopurine therapy was noted in 47% of patients, and therapy failed in 53%. The age of the patients, prior resection, or initial symptoms did not influence the response. The clinical response was better in male than in female patients and in patients with involvement of both the small intestine and the colon than in those with only enteritis. 6-Mercaptopurine is a possible alternative to long-term corticosteroid therapy or surgical treatment in selected patients with severe Crohn's disease.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Colonic Diseases; Crohn Disease; Female; Follow-Up Studies; Humans; Intestine, Small; Male; Mercaptopurine; Metronidazole; Middle Aged; Remission Induction; Retrospective Studies; Sulfasalazine; Time Factors

Topics: Adolescent; Crohn Disease; Humans; Mercaptopurine; Neoplasms

The efficacy and safety of therapy with azathioprine/6-mercaptopurine was studied in 78 patients with Crohn's disease. Mean duration of therapy was 1.6 years; 52 patients were treated greater than or equal to 6 months. All patients were also on other antiinflammatory medications. Evaluations included self-assessment and physician's assessment of well-being, functional capacity, general clinical response, clinical activities indices (National Foundation for Ileitis and Colitis/International Organization for the Study of Inflammatory Bowel Disease and Harvey-Bradshaw), and achievement of specific therapeutic goals. General clinical condition improved in 70% of the patients. Median response time was 3 months. The average Harvey-Bradshaw score decreased 37% with therapy, and a decrease of greater than or equal to 30% occurred in 66% of the subjects. An overall 72% achievement rate for specified therapeutic goals included controlling refractory disease, 73%; corticosteroid "sparing," 76%; and lessening fistulization, 63%. Nine patients got worse despite therapy. Adverse effects requiring discontinuation of therapy occurred in 10%, whereas dosages were briefly lowered for mild side effects in another 10%. This study demonstrates the effectiveness and safety of azathioprine/6-mercaptopurine in the majority of selected patients with chronic, unremitting, or steroid-requiring Crohn's disease.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Child, Preschool; Crohn Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Mercaptopurine; Middle Aged

Topics: Adolescent; Crohn Disease; Humans; Mercaptopurine

Although 6-mercaptopurine is often used to treat adolescents with intractable Crohn's disease, its long-term efficacy has not yet been studied in this population. This study shows data derived from 36 adolescents (mean age +/- SD, 16.5 +/- 3.3 years; 27 males, 9 females) treated at least 6 months with 6-mercaptopurine (1.5 mg.kg-1.day-1, maximum of 75 mg/day). Sites of Crohn's disease at the start of 6-mercaptopurine therapy included 17 ileocolic, 9 pancolic, 7 small bowel, and 3 partial colon. All had received corticosteroids, sulfasalazine, antibiotics, and nutritional support for 5.0 +/- 3.0 years before administering 6-mercaptopurine, but intractable symptoms persisted. Disease activity lessened during the first year of 6-mercaptopurine, reflected by a higher Lloyd-Still disease activity score (pre, 64 +/- 9 vs. 6-mercaptopurine, 72 +/- 11; P less than 0.0001). General activity, physical examination, nutrition, and laboratory subscores all improved (P less than 0.004). Lessened disease activity occurred despite concomitant decrease in duration of prednisone use (pre, 9.5 +/- 4.2 vs. 6-mercaptopurine, 6.6 +/- 4.9 months/year; P less than 0.001) and cumulative annual prednisone exposure (pre, 3672 +/- 2106 vs. 6-mercaptopurine, 1964 +/- 1460 mg; P less than 0.0007). The frequency of perianal fistulae and abscesses also decreased (P less than 0.01) during treatment. Annual rates of hospitalization decreased in 44% of subjects during 6-mercaptopurine treatment, while increasing in only 22%. Follow-up beyond 1 year of 6-mercaptopurine treatment showed continued remission in 23 of 30 subjects. No serious complications were seen. 6-mercaptopurine is an effective long-term therapy for adolescents with intractable Crohn's disease. While inducing remission, it also has a significant steroid-sparing effect which may be of particular benefit to this population.

Topics: Abscess; Adolescent; Adult; Anti-Bacterial Agents; Child; Crohn Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Prednisone; Rectal Diseases; Rectal Fistula; Sulfasalazine; Time Factors

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Radiography

Over the past 15 years (1974-1989), 126 patients with Crohn's disease received azathioprine (n = 123) or 6-mercaptopurine (n = 3). Seven patients were lost of follow-up during the first month and were not analyzed. Among the 119 patients analyzed (52 men, 67 women, mean age 31.6 years), the median duration of treatment was 9.1 months (range: 8 days to 15 years). Most of the 109 patients with active disease at the beginning of the immunosuppressive therapy were either steroid-dependent (n = 63) or steroid-resistant (n = 23); 19 had frequent relapses and/or extensive involvement of the gastrointestinal tract; 4 had severe perianal disease. Among these 109 patients, 25.4, 51, 60.4 and 64.4 percent were in clinical remission at 3, 6, 9 and 12 months (life-table analysis) respectively. There was no difference in outcome of patients with colonic, ileocolonic or small intestinal involvement. Steroid-resistant patients fared better than steroid-dependent patients (81 percent vs 59 percent of remission within the first year; p less than 0.001). In the 62 patients with quiescent disease treated with azathioprine or 6-mercaptopurine, previous remission had been achieved with immunosuppressive therapy in 52, 8 were treated after a bowel resection which was assumed to be curative; 2 had achieved remission after total parenteral nutrition. In these patients, the percentages of relapse were 15.3 at the end of the first year and 20.3 at the end of the second year. Among the 8 patients treated with azathioprine after bowel resection, only one relapse occurred 1.5 months after surgery. Nineteen percent of the patients had adverse reactions that required discontinuation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actuarial Analysis; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Crohn Disease; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Middle Aged; Recurrence; Remission Induction; Retrospective Studies

This study was undertaken to determine if asymptomatic children and adolescents with inflammatory bowel disease and moderate to severe anorectosigmoid inflammation might remain symptom-free for at least 12 months without specific intrarectal therapy. We prospectively studied 13 asymptomatic patients 6-21 years of age (four with Crohn's disease and nine with nonspecific colitis) with previously documented anorectosigmoid inflammation. Of these 13, four had moderate to severe anorectosigmoid inflammation both endoscopically and histologically. These four patients (two with Crohn's disease and two with nonspecific colitis) were entered into the second phase of the study. Three were receiving sulfasalazine, and one received methylprednisolone, 4 mg/day, and 6-mercaptopurine, 50 mg/day. None received intrarectal therapy. Clinical evaluation revealed that all four remained asymptomatic for 12 months despite the continued presence of moderate to severe anorectosigmoid inflammation. These results indicate that in children and adolescents with inflammatory bowel disease, the presence of inflammation of the anorectosigmoid does not necessarily correlate with or presage the onset of symptoms of proctosigmoiditis. Therefore, active inflammation of the anorectosigmoid is not the sole prerequisite for intrarectal therapy. The clinician should be guided by the symptoms of the patient, not by the presence or absence of active anorectosigmoid inflammation.

Topics: Adolescent; Child; Child, Preschool; Colitis; Crohn Disease; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methylprednisolone; Proctocolitis; Prospective Studies; Sulfasalazine

We reviewed the course of 500 patients with Crohn's disease to document the incidence, the nature, and the results of management of fistulas to the bladder. Seventeen patients (14 men and three women) had developed enterovesical fistulas: 16 had pneumaturia. The barium radiographs demonstrated the fistula in only 37%. All had received sulfasalazine, and most were treated with corticosteroids and antibiotics intermittently; two had successful control of their urinary symptoms on this regimen. Eight patients who received 6-mercaptopurine (6-MP) in addition tolerated the urinary fistula well, so that we encourage a trial of 6-MP for this complication of Crohn's disease. Six patients continue on medical therapy alone after a mean of 5.3 years. There were no instances of pyelonephritis during 60 patient years. Eleven patients eventually underwent bowel resection, but in only two was persistence of the enterovesical fistula the primary indication for elective surgery, and in both, it was the patient's choice. Visualization of the fistula on barium enema radiograph or presence of a connection between the sigmoid and the bladder were not associated with adverse outcome. An enterovesical fistula in Crohn's disease rarely leads to serious complications and can often be treated successfully with medical therapy alone: by itself, it need not serve as an indication for surgery.

Topics: Adult; Analgesics; Anti-Bacterial Agents; Crohn Disease; Female; Humans; Intestinal Fistula; Male; Mercaptopurine; Sulfasalazine; Urinary Bladder Fistula

Topics: Aminosalicylic Acids; Azathioprine; Colectomy; Crohn Disease; Diet; Glucocorticoids; Humans; Mercaptopurine; Metronidazole; Psychotherapy; Sulfasalazine

A patient with Crohn's disease developed acute pancreatitis 4 h after retaking one 50 mg dose of orally administered 6-mercaptopurine (6-MP). All seven previously reported patients who were rechallenged with 50 mg or more of 6-MP developed pancreatitis within 48 h. These findings suggest that 6-MP can produce pancreatitis due to an idiosyncratic immune-mediated response. Patients with this complication should not reuse 6-MP.

Topics: Adult; Crohn Disease; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Pancreatitis; Time Factors

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infections; Male; Mercaptopurine; Middle Aged; Neoplasms; Pancreatitis; Pregnancy; Time Factors

6-Mercaptopurine (6-MP) has an important role in the treatment of inflammatory bowel disease. Its most frequent short-term complication has proven to be pancreatitis, which we have now seen in 13 of 400 (3.25%) patients (12 Crohn's disease, 1 ulcerative colitis) and which we here describe. The timing of the pancreatitis was such that it could not be attributed to sulfasalazine, which was also being taken by 9 patients, or corticosteroids, which were being taken by 7 patients. The dosage of 6-MP ranged from 50 to 100 mg daily, and the pancreatitis, which was uncomplicated in all cases, occurred within 8-32 days with one exception (6.5 mo). Symptoms included epigastric pain, back pain, fever, and nausea. The serum amylase was elevated in 12 patients. The average elevation was 5.9 times normal. In all cases, the 6-MP was discontinued and symptoms and signs returned to normal over a period of 1-11 days. No other complications of 6-MP occurred; there was no leukopenia. Of 7 patients rechallenged with 6-MP, all developed recurrent pancreatitis, including 4 in less than 24 h. In 3 patients, desensitization attempted by a gradual increase in dose from 1/8 tablet (approximately 6 mg) daily also led to recurrence. The timing of the initial pancreatitis and the recurrence at rechallenge are best explained by an allergic reaction. 6-Mercaptopurine should not be reinstituted once it has caused pancreatitis.

Topics: Amylases; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Pancreatitis; Time Factors

Topics: Adult; Crohn Disease; Female; Humans; Leukopenia; Mercaptopurine; Xanthine Oxidase

Fistulae are distressing chronic complications of Crohn's disease which have served as one of the most common indications for surgical resection. While steroids and sulfasalazine have not been successful in closing fistulae, in a previous double-blind study 6-mercaptopurine (6-MP) was more effective than placebo in accomplishing this goal (31% vs 6%). Thirty-four patients with Crohn's disease fistulae were treated with 6-MP for a minimum period of 6 months. In 13 patients (39%) the fistulae closed completely, and in another 9 (26%) there was obvious improvement. All types of fistulae responded to 6-MP with the most impressive closures occurring in patients with fistulae of the abdominal wall and enteroenteric fistulae. The mean time to respond was 3.1 months, with 23% of patients taking longer than 4 months to show any response. Response was not related to other drugs (steroids, sulfasalazine) used in conjunction with the 6-MP. The site of intestinal involvement with Crohn's disease did not appear to play a significant role in the frequency or degree of response to 6-MP, but patients without prior resection and fistulae did better than those with fistulae occurring after surgery. The long-term response to fistulae was good if 6-MP was maintained, whereas exacerbation eventually followed discontinuation of 6-MP. 6-Mercaptopurine is an effective and useful drug in the treatment of fistulae, as it is in other manifestations of chronic unrelenting Crohn's disease.

Topics: Abdominal Muscles; Adolescent; Adult; Crohn Disease; Double-Blind Method; Female; Fistula; Humans; Intestinal Fistula; Male; Mercaptopurine; Middle Aged; Random Allocation; Rectal Fistula; Sulfasalazine; Vaginal Fistula

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Fetal Diseases; Humans; Infertility, Female; Infertility, Male; Male; Mercaptopurine; Metronidazole; Pregnancy; Pregnancy Complications; Risk; Sulfasalazine

Crohn's disease patients on long-term 6-mercaptopurine therapy (more than 4 months) were evaluated for activity of peripheral blood natural killer cells. Natural killer-cell cytolytic activity against K-562 tumor-cell targets was examined, as was natural killer-cell suppression of lymphoblastoid B-cell antibody production. In addition, these patients were studied for their ability to generate antitetanus-specific IgG-antibody-producing lymphoblastoid B cells following in vivo booster immunization. Crohn's disease patients on 6-mercaptopurine therapy had significant reductions in peripheral blood natural killer-cell activity against K-562 targets compared to normals, disease controls, and Crohn's disease patients not on 6-mercaptopurine. Natural killer-cell suppression of lymphoblastoid B-cell antibody production was likewise decreased in 6-mercaptopurine-treated patients compared to normal controls. In contrast, the in vivo generated lymphoblastoid B-cell antibody responses of Crohn's disease patients on 6-mercaptopurine therapy were not decreased compared to normal, while Crohn's disease patients not on 6-mercaptopurine therapy had significantly impaired IgG antitetanus antibody responses. These findings suggest that 6-mercaptopurine therapy in Crohn's disease affects several lymphoid subpopulations, resulting in a decreased natural killer-cell cytotoxic activity against K-562 target cells and a decreased natural killer-cell ability to suppress lymphoblastoid B-cell antibody production, as well as an improved humoral immune response following tetanus toxoid booster immunization.

Topics: Adult; Antibody Formation; B-Lymphocytes; Crohn Disease; Cytotoxicity, Immunologic; Enzyme-Linked Immunosorbent Assay; Female; Gastrointestinal Diseases; Humans; Killer Cells, Natural; Male; Mercaptopurine; Reference Values

Improvement in Crohn's disease after drug therapy was evaluated in 38 patients with evidence of rectal disease at sigmoidoscopy in whom the rectum later appeared normal. Rectal biopsies taken before and after therapy were examined histopathologically. Cell counts of the lamina propria connective tissue cells were used to evaluate mucosal changes. The drugs apparently responsible for conversion of the rectal mocosal appearance to normal were sulfasalazine, prednisone, and 6-mercaptopurine. There was complete healing histologically in 24 patients (63%). In the other 14, healing was incomplete as evidenced by microscopic chronic inflammation, microgranulomas, or occasional lymphangiectasia. There were both complete and incomplete responses to all three drugs, but the total numbers were too small to identify significant therapeutic differences. Cell counts confirmed the elimination of acute inflammation. Despite drug therapy, histological evidence of activity persisted in one-third of the patients in whom the appearance of the rectum became normal.

Topics: Biopsy; Cell Count; Crohn Disease; Drug Therapy, Combination; Evaluation Studies as Topic; Humans; Intestinal Mucosa; Mercaptopurine; Prednisone; Rectum; Sigmoidoscopy; Sulfasalazine

Two patients with inflammatory bowel disease who developed acute pancreatitis within 21 days of commencing treatment with 6-mercaptopurine are presented. Both were inadvertently reexposed to the drug and developed recurrent pancreatitis within 3 hr of a single dose.

Topics: Acute Disease; Adult; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Pancreatitis; Recurrence

Topics: Adrenal Cortex Hormones; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Metronidazole; Parenteral Nutrition, Total; Sulfasalazine

Topics: Acute Disease; Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Mercaptopurine; Methylprednisolone; Metronidazole; Parenteral Nutrition; Sulfasalazine

Topics: Animals; Antibody Formation; Autoimmune Diseases; Azathioprine; Crohn Disease; Dogs; Humans; Immunity, Cellular; Immunocompetence; Immunosuppressive Agents; Kidney Transplantation; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Prednisone; Rabbits

Topics: Azathioprine; Clinical Trials as Topic; Crohn Disease; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Humans; Mercaptopurine; Placebos; Prednisone; Random Allocation; Research Design; Sulfasalazine; United States

Topics: Crohn Disease; Humans; Mercaptopurine; Prednisone; Sulfasalazine

Topics: Adrenocorticotropic Hormone; Colitis, Ulcerative; Crohn Disease; Diet; Humans; Immunosuppressive Agents; Mercaptopurine; Parenteral Nutrition, Total; Sulfasalazine

Topics: Azathioprine; Crohn Disease; Humans; Mercaptopurine; Risk

Topics: Animals; Antineoplastic Agents; Crohn Disease; Female; Fertility; Fetus; Humans; Male; Mercaptopurine; Mice; Ovum; Pregnancy; Spermatozoa

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Azathioprine; Colectomy; Colitis, Ulcerative; Colon; Crohn Disease; Double-Blind Method; Follow-Up Studies; Humans; Ileostomy; Male; Mercaptopurine; Prednisone; Radiography; Recurrence; Sulfapyridine; Sulfasalazine

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Prednisolone; Remission, Spontaneous

Epithelial and connective-tissue cells were counted in rectal mucosal biopsies from 215 patients with ulcerative colitis, 98 patients with granulomatous colitis, and 50 controls. The results were analyzed statistically. Significantly decreased mucous goblet cells were found both in sigmoidoscopically abnormal ulcerative colitis and in granulomatous colitis, and they increased during the healing process. More pyknotic and karyorrhectic epithelial cells occurred in active ulcerative colitis than in granulomatous colitis. Inactive ulcerative colitis still manifested histologic evidence of acute and chronic inflammation, while sigmoidoscopically normal granulomatous colitis biopsies after previous gross rectal disease showed significantly increased macrophages in the lamina propria. Cell counts were valuable for differential diagnosis after the sigmoidoscopic appearance became normal. The acute inflammation of ulcerative colitis, as indicated by neutrophils, was decreased most notably following therapy with prednisone or 6-mercaptopurine. Chronic inflammation associated with fewer plasma cells was decreased after salicylazosulfapyridine as well as either of the other two drugs; macrophages, indicators of healing, increased most after 6-mercaptopurine combined with another anti-inflammatory agent.

Topics: Biopsy; Cell Count; Colitis, Ulcerative; Connective Tissue; Connective Tissue Cells; Crohn Disease; Diagnosis, Differential; Drug Therapy, Combination; Epithelial Cells; Epithelium; Humans; Intestinal Mucosa; Mercaptopurine; Prednisone; Rectum; Sigmoidoscopy; Sulfasalazine

Topics: Adrenocorticotropic Hormone; Atropine; Azathioprine; Colitis, Ulcerative; Crohn Disease; Diarrhea; Diet; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Nutrition Disorders; Pain; Prednisolone; Prednisone; Sulfasalazine

Topics: Anemia, Hemolytic, Autoimmune; Antigen-Antibody Reactions; Arthritis, Rheumatoid; Azathioprine; Crohn Disease; Cyclophosphamide; Female; Glomerulonephritis; Glucocorticoids; Hepatitis; Humans; Immunity; Immunity, Cellular; Immunosuppression Therapy; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Nephrotic Syndrome; Purpura, Thrombocytopenic

Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine

Topics: Adult; Autoimmune Diseases; Azathioprine; Colitis, Ulcerative; Crohn Disease; Evaluation Studies as Topic; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Colectomy; Crohn Disease; Female; Humans; Immunosuppressive Agents; Mercaptopurine

Topics: Adolescent; Arthritis, Juvenile; Cataract; Child; Child, Preschool; Chloroquine; Colitis, Ulcerative; Crohn Disease; Dermatomyositis; Female; Humans; Infant; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Nephrosis; Prednisolone; Purpura

Topics: Adult; Crohn Disease; Female; Gangrene; Humans; Intestinal Obstruction; Mercaptopurine; Prednisone; Pyoderma