mercaptopurine and Colitis--Ulcerative

This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American guidelines, azathioprine, mercaptopurine, and methotrexate monotherapy are not recommended for induction therapy. Thiopurines are recommended in combination with infliximab. Tofacitinib has been shown to be an effective induction agent. Cyclosporine or tacrolimus are calcineurin inhibitors that can be used as induction therapy. Thiopurine monotherapy is suggested or recommended as maintenance therapy for patients who have achieved steroid-induced remission. Methotrexate monotherapy is not recommended. Tofacitinib has been shown to be an effective maintenance agent in moderate to severe disease.

Topics: Azathioprine; Colitis, Ulcerative; Contraindications, Drug; Glucocorticoids; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Meta-Analysis as Topic; Methotrexate; Piperidines; Pyrimidines; Remission Induction

Topics: Aged; Colitis, Ulcerative; Endoscopy; Epstein-Barr Virus Infections; Humans; Magnetic Resonance Imaging; Male; Mercaptopurine; Rectum; Time Factors

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

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

Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC.. Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE.. Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo.. All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC.

Topics: Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Practice Guidelines as Topic

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by a relapsing and remitting course. The direct and indirect costs of the treatment of UC are high, and the quality of life of patients is reduced, especially during exacerbation of the disease. The incidence and prevalence of UC in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Various medical and surgical therapies, including biologics, are currently used for the management of UC. However, many challenging issues exist, which sometimes lead to differences in practice between clinicians. Therefore, the Inflammatory Bowel Disease Study Group of the Korean Association for the Study of Intestinal Diseases established the first Korean guideline for the management of UC in 2012. This is an update of the first guideline. It was generally made by the adaptation of several foreign guidelines as was the first edition, and encompasses treatment of active colitis, maintenance of remission, and indication of surgery for UC. The specific recommendations are presented with the quality of evidence and classification of recommendations.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; C-Reactive Protein; Colitis, Ulcerative; Cyclosporine; Humans; Mercaptopurine; Mesalamine; Parenteral Nutrition; Prednisolone; Severity of Illness Index; Steroids; 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

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.. To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.. The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included.. Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included.. Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.. Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, op. Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Randomized Controlled Trials as Topic; Secondary Prevention; Sulfasalazine

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

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

Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis.. The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis.. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only.. Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion.. Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.. Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia. The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

Topics: Administration, Oral; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Methotrexate; Sulfasalazine

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

TNF-α has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-α therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with con- ventional therapy.. The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC.. Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR =1.82; 95% CI 1.24 to 2.67) and clinical response (RR =1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy.. Our meta-analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy.

Topics: Adalimumab; Aminosalicylic Acids; Azathioprine; Colectomy; Colitis, Ulcerative; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha

Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80-90% of patients. The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient. The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor (TNF) agents.. Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis. In a recent study, infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis.. Anti-TNF therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate-to-severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates, corticosteroids and immune modulators. Alternatives to infliximab are ADA and golimumab. Future research is needed to further assess the long-term efficacy and safety of ADA and golimumab in ulcerative colitis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Cyclosporine; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Corticosteroids and 5-aminosalicylates are the most commonly used therapies. However, many patients require immunosuppressive therapy for steroid-refractory and steroid-dependent disease. Methotrexate is a medication that is effective for treating a variety of inflammatory diseases, including Crohn's disease. This review was performed to determine the effectiveness of methotrexate treatment in UC patients. This review is an update of a previously published Cochrane review.. To assess the efficacy and safety of methotrexate for induction of remission in patients with UC.. MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register were searched from from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only.. Randomized controlled trials comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion.. Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria.. Two studies (n = 101 patients) were included in the review. One study (n = 67) compared oral methotrexate 12.5 mg/week) to placebo. The other study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). The placebo-controlled study was judged to be at low risk of bias. The other study was judged to be at high risk of bias due to an open-label design. There was no statistically significant difference in clinical remission rates between methotrexate and placebo patients. Forty-seven per cent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). There were no statistically significant differences in the proportion of patients who achieved clinical remission and withdrawal from steroids in the study comparing oral methotrexate to 6-mercaptopurine and 5-aminosalicylic acid. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data (18 and 9 events respectively) and and high risk of bias. In the placebo-controlled trial two patients (7%) were withdrawn from the methotrexate group due to adverse events (leucopenia, migraine) compared to one patient (3%) who had a rash in the placebo group (RR 2.47, 95% CI 0.23 to 25.91). Adverse events experienced by methotrexate patients in the active comparator study included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia.. Although methotrexate was well-tolerated, the studies showed no benefit for methotrexate over placebo or active comparators. The results for efficacy outcomes between methotrexate and placebo, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration would be effective for induction therapy is unknown. At present there is no evidence supporting the use of methotrexate for induction of remission in active ulcerative colitis. A trial in which larger numbers of patients receive a higher dose of oral methotrexate should be considered. Currently there are two large ongoing placebo-controlled trials (METEOR and MERIT-UC) assessing the efficacy and safety of intramuscular or subcutaneous methotrexate in patients with active UC which may help resolve the evidence supporting the use of methotrexate as therapy for active of ulcerative colitis.

Topics: Administration, Oral; Anti-Inflammatory Agents; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Induction Chemotherapy; Mercaptopurine; Mesalamine; Methotrexate; Randomized Controlled Trials as Topic

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

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; Colitis, Ulcerative; Drug Resistance; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine

Topics: Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Substance Withdrawal Syndrome; Time Factors

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.. To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.. The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to June 2012. A manual search was also performed using references from these articles as well as review articles, and proceedings from major gastrointestinal meetings. Authors of maintenance trials were asked about unpublished studies.. Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included.. Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.. Six studies including 286 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalamine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). All of the studies which used active comparators were open label. When placebo and active comparator studies were pooled to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.. Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (Issue 1, 2007).

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Randomized Controlled Trials as Topic; Secondary Prevention; Sulfasalazine

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

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

The goals of treatment for ulcerative colitis (UC) are to induce and maintain corticosteroid-free remission, thereby reducing hospitalizations and surgeries and preventing longer-term disease complications including colorectal cancer. Despite an incomplete evidence base, thiopurine immunomodulators remain a principle therapeutic option for patients failing aminosalicylate monotherapy and requiring multiple courses of corticosteroids. In this review, we outline the current evidence supporting the role of thiopurines in achieving these treatment goals in UC, including discussions of the important safety issues regarding their use. We also explore some of the recent evidence emerging in regards to the risks of lymphoproliferative disease, dosage optimization strategies and the role of thiopurines in achieving mucosal healing in UC and ultimately changing natural history outcomes for our patients.

Topics: Animals; Clinical Trials as Topic; Colitis, Ulcerative; Humans; Immunologic Factors; Immunosuppressive Agents; Mercaptopurine

Ulcerative colitis (UC) is a chronic disease featuring recurrent inflammation of the colonic mucosa. The goal of medical treatment is to rapidly induce a steroid-free remission while at the same time preventing complications of the disease itself and its treatment. The choice of treatment depends on severity, localization and the course of the disease. For proctitis, topical therapy with 5-aminosalicylic acid (5-ASA) compounds is used. More extensive or severe disease should be treated with oral and local 5-ASA compounds and corticosteroids to induce remission. Patients who do not respond to this treatment require hospitalization. Intravenous steroids or, when refractory, calcineurin inhibitors (cyclosporine, tacrolimus), tumor necrosis factor-α antibodies (infliximab) or immunomodulators (azathioprine, 6-mercaptopurine) are then called for. Indications for emergency surgery include refractory toxic megacolon, perforation, and continuous severe colorectal bleeding. Close collaboration between gastroenterologist and surgeon is mandatory in order not to delay surgical therapy when needed. This article is intended to give a general, practice-orientated overview of the key issues in ulcerative colitis treatment. Recommendations are based on published consensus guidelines derived from national and international guidelines on the treatment of ulcerative colitis.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Cyclosporine; Endoscopy; Gastroenterology; Humans; Infliximab; Mercaptopurine; Mesalamine; Remission Induction; Steroids; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

Debate exists regarding to whether thiopurine therapy is as effective in ulcerative colitis (UC) as it is in Crohn's disease.. To review systematically the efficacy of azathioprine (AZA) and mercaptopurine (MP) in UC, and to conduct a meta-analysis of randomized clinical trials evaluating the efficacy of AZA/MP for the induction or maintenance of UC clinical remission.. Evaluating AZA/MP for induction and/or maintenance of clinical remission of UC. Randomized-controlled-trials comparing AZA/MP with placebo/5-aminosalicylates were included in the meta-analysis.. Electronic and manual. Study quality: Independently assessed by two reviewers.. By 'intention-to-treat'.. Thirty noncontrolled studies (1632 patients) were included in the systematic review. Mean efficacy of AZA/MP was 65% for induction and 76% for maintenance of the remission. Seven controlled studies were included in the meta-analysis. (i) Induction of remission: four studies (89 AZA/MP-treated patients) showed mean efficacy of 73% vs. 64% in controls (OR = 1.59; 95% CI = 0.59-4.29). (ii) Maintenance of remission: six studies (124 AZA/MP-treated patients) showed mean efficacy of 60% vs. 37% in controls (OR = 2.56; 95% CI = 1.51-4.34). When only studies comparing AZA/MP vs. placebo were considered, OR was 2.59 (95% CI = 1.26-5.3), absolute risk reduction was 23% and number-needed-to-treat (NNT) to prevent one recurrence was 5.. Thiopurine drugs (AZA/MP) are more effective than placebo for the prevention of relapse in UC, with an NNT of 5 and an absolute risk reduction of 23%.

Topics: Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction; Secondary Prevention; Treatment Outcome

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

Published trials evaluating the efficacy of 6-thioguanine anti-metabolites in the treatment of ulcerative colitis (UC) have yielded conflicting results. We performed a systematic review and meta-analysis to evaluate the clinical efficacy of 6-thioguanine anti-metabolites for the maintenance of clinical remission after standard induction with corticosteroids.. A comprehensive search of online databases was conducted. Only randomized controlled trials with 6-thioguanine antimetabolites within a minimum duration of follow-up of 6 months were selected.. Five trials were included in the meta-analysis. The pooled relative risk estimate for "success of treatment" with azathioprine (AZA) compared to 5-aminosalicylic acid or placebo was 1.42 [95% confidence interval (CI): 0.93-2.17, p = 0.109]; when only trials of a higher quality were used, a pooled relative risk estimate of 2.05 (95% CI: 1.30-3.23, p = 0.002) was obtained.. Pooled results demonstrated a modest efficacy of AZA for the treatment of ulcerative colitis. However, the use of AZA for the management of UC is not based on high-quality evidence.

Topics: Antimetabolites; Azathioprine; Colitis, Ulcerative; Evidence-Based Medicine; Humans; Mercaptopurine; Randomized Controlled Trials as Topic

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.. To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.. The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies.. Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.. Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown.. Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases).. Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.

Topics: Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction; Secondary Prevention

Ulcerative colitis is a chronic disease with recurrent symptoms and significant morbidity. The precise etiology is still unknown. As many as 25 percent of patients with ulcerative colitis have extraintestinal manifestations. The diagnosis is made endoscopically. Tests such as perinuclear antineutrophilic cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies are promising, but not yet recommended for routine use. Treatment is based on the extent and severity of the disease. Rectal therapy with 5-aminosalicylic acid compounds is used for proctitis. More extensive disease requires treatment with oral 5-aminosalicylic acid compounds and oral corticosteroids. The side effects of steroids limit their usefulness for chronic therapy. Patients who do not respond to treatment with oral corticosteroids require hospitalization and intravenous steroids. Refractory symptoms may be treated with azathioprine or infliximab. Surgical treatment of ulcerative colitis is reserved for patients who fail medical therapy or who develop severe hemorrhage, perforation, or cancer. Longstanding ulcerative colitis is associated with an increased risk of colon cancer. Patients should receive an initial screening colonoscopy eight years after the onset of pancolitis and 12 to 15 years after the onset of left-sided disease; follow-up colonoscopy should be repeated every two to three years.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Antibodies, Monoclonal; Azathioprine; Colectomy; Colitis, Ulcerative; Colonoscopy; Diagnosis, Differential; Gastrointestinal Agents; Humans; Infliximab; 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

Topics: Anti-Allergic Agents; Anti-Inflammatory Agents; Colitis, Ulcerative; Drugs, Chinese Herbal; Humans; Immunosuppressive Agents; Mercaptopurine; Prednisolone; Sulfasalazine; Tacrolimus; Time Factors

Topics: Antimetabolites; Azathioprine; Colitis, Ulcerative; Evidence-Based Medicine; Humans; Mercaptopurine; Remission Induction; Treatment Outcome

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

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

Crohn's disease (CD) and ulcerative colitis (UC) are common and heterogeneous chronic inflammatory bowel disorders of childhood that account for up to 25% of all patients with inflammatory bowel disease (IBD). In CD, the familial pattern of disease concordance would suggest that genetics contribute to disease etiology. Children are more likely to have proximal small bowel disease complicated by stricture formation, fistulization and the need for surgical intervention. The predisposition for small bowel disease has been associated with mutations of the nucleotide oligomerization domain 2 (NOD2)/Caspase activation and recruitment domain 15 (CARD15) gene on chromosome 16 in 1/3 of patients with CD. Homozygous patients also show an early age at disease onset and a relatively high relative risk for isolated stricturing distal ileal disease. The potential clinical role for NOD2 testing in either the diagnosis or the therapeutic management of patients with CD has yet to be determined. The precise age of onset of CD and UC can be difficult in children. Subclinical phases of disease can be identified through a decrease in weight and height velocity, and a delay in pubertal development. However, a confident distinction between CD and UC also remains a taxonomic dilemma in 25% of pediatric patients with IBD, despite recent technological advances in diagnostic techniques, including gadolinium enhanced magnetic resonance imaging (MRI) and capsule endoscopy, and serological testing. The early introduction of immunomodulators, including azathioprine and 6-mercaptopurine have proven efficacy in maintaining long-term remission without concurrent corticosteroids. The pharmacogenomic of 6-MP metabolism has been shown to be useful in predicting susceptibility to antimetabolite induced toxicity, and possibly allowing physician's to individualize drug therapy to improve clinical response. Novel treatment strategies, including infliximab are being developed in Pediatrics with the aim at improving overall treatment efficacy and potentially avoid surgery.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Child; Colitis, Ulcerative; Environment; Genetic Predisposition to Disease; Humans; Ileus; Immunoglobulin A; Immunoglobulin G; Inflammatory Bowel Diseases; Intracellular Signaling Peptides and Proteins; Mass Screening; Mercaptopurine; Mesalamine; Nod2 Signaling Adaptor Protein; Risk Factors

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

Ulcerative colitis (UC) has been known as inflammatory bowel disease. Progress in UC management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. We here review about immunosuppressants in management of UC; Cyclosporine A (CsA) has been used for the induction therapy in steroid resistant refractory UC. Although it has been reported that CsA has high response rate in severe UC, long-term efficacy (maintenance of remission) has not been proven. To improve maintenance therapy, immunosuppressant has been re-considered in management of UC. In recent years, it has been reported that efficacy of 6-mercaptopurine/azathioprine in maintenance of remission of UC is superior to 5-aminosalicylate (5-ASA). Pharmacological studies have indicated thiopurine methyltransferase (TPMT) activity is essential for maintenance of blood concentration of 6-thioguanine nucleotide (6-TG).

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Drug Therapy, Combination; Guanine Nucleotides; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Mycophenolic Acid; Tacrolimus; Thionucleotides

Guidelines for treatment of ulcerative colitis in children have been created by the working group of the Japanese Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Japanese Society for Pediatric Inflammatory Bowel Disease. The ideas of these guidelines, with regard to the fundamental differences in medical treatment between children and adults, included (1) for children, intensive medical treatment including appropriate systemic management is important during the acute phase of illness. (2) Treatment with steroids, which can cause growth disturbances, should not be continued for long period of time. (3) Pulsed steroid therapy, selective removal of blood cells, and intravenous infusion of cyclosporin are included in the therapeutic option for severe and fluminant cases.

Topics: Azathioprine; Child; Colitis, Ulcerative; Contraindications; Cyclosporins; Growth Disorders; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Practice Guidelines as Topic; Prednisolone; Pulse Therapy, Drug; Quality of Life

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

Ulcerative colitis is characterized by chronic inflammation of the colon. Typical symptoms are diarrhoea, rectal bleeding, abdominal pain and fever. The aetiology of the disease is unclear. The inflammation can be localized in the rectum or can extend to the left side or the whole colon. Treatment for induction and remission maintenance depends on the severity and extension of mucosal inflammation. Topical 5-aminosalicylates have been shown in studies to be the treatment of choice in mild to moderate ulcerative colitis. Oral 5-aminosalicylates can be used in distal, mild and moderate ulcerative colitis and for remission maintenance. For patients with a more extended or severe inflammation, oral or i.v. corticosteroids should be used. Patients with severe and/or chronic disease require immunosuppressive therapy with azathioprine or 6-mercaptopurine. For patients with severe, chronic, refractory disease, cyclosporine i.v. can be used. If no response to treatment is seen, proctocolectomy should be considered. Biological agents such as beta-Interferon seem to be effective in mild to moderately ulcerative colitis, but further studies have to be performed.

Topics: Administration, Oral; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Colectomy; Colitis, Ulcerative; Cyclosporins; Double-Blind Method; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Interferon-beta; Mercaptopurine; Mesalamine; Pilot Projects; Placebos; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Time Factors; Treatment Outcome

The medical management of patients with severe ulcerative colitis requires initial stabilization, careful and repeated evaluations to exclude confounding or coexisting diagnoses, and timely delivery of appropriate medications. Medical therapies for these patients are potent but may be toxic, and administration must be done by experienced medical professionals, with adequate access to appropriate laboratory, radiographic, endoscopic, and surgical facilities. Patients who fail to respond to high-dose intravenous corticosteroids in a timely basis should be evaluated for cyclosporin therapy, or proceed to surgery. The promise of newer, investigational therapies to induce and maintain remission must be borne out by large controlled trials.

Topics: Adrenal Cortex Hormones; Azathioprine; Colitis, Ulcerative; Cyclosporine; Decision Trees; Drug Administration Schedule; Humans; Immunosuppressive Agents; Mercaptopurine; Severity of Illness Index

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole. Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn's ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfa-free 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds, systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.) are potent and fast-acting drugs for treating UC, Crohn's ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC. Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP, methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Medicine, Chinese Traditional; Mercaptopurine

To clarify the effectiveness and safety of azathioprine (AZA) and 6-mercaptopurine (6MP) in the induction and maintenance of remission in ulcerative colitis (UC) by using a systematic review of published studies. Studies were searched for from within the 1966 to March 2003 MEDLINE database, Cochrane Library 2003 issue 1, and the 1981 to March 2003 Japana Centra Revuo Medicina database. References from published studies and reviews were also obtained. Randomized, placebo-controlled trials of oral AZA or 6MP therapy in adult patients with active or quiescent UC were included. Ratios for the induction and maintenance of remission, the steroid-sparing effect, and the incidence of adverse drug reactions (ADRs) were compared and evaluated between the two study arms and expressed by the odds ratio (OR) specific for the individual studies and the meta-analytic summary for the OR. We could find no randomized controlled trial for 6MP therapy. However, four clinical trials for AZA therapy were included in this meta-analysis. For the induction of remission, the pooled OR of the response to AZA therapy compared with placebo in active UC was 1.45 (95% Confidence Interval (CI): 0.68 to 3.08). For the maintenance of remission, the pooled OR for AZA therapy was 2.26 (95% CI: 1.27 to 4.01). The number needed to treat (NNT) to prevent one recurrence was 6 patients. The pooled OR for AZA therapy's ADRs compared with placebo was 2.11 (95% CI: 0.92 to 4.84). From the viewpoint of effectiveness and safety, this meta-analysis suggests that AZA might be useful in the maintenance of remission in UC patients.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Confidence Intervals; Humans; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction

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

Ulcerative colitis (UC) is an idiopathic inflammatory condition of the large intestine. Recent advances in our understanding of the pathogenesis of UC have led to the development of novel treatments for this often debilitating condition. Aside from aminosalicylates and corticosteroids, drugs that have been used for decades in the treatment of UC, biologic agents, in addition to medications targeting specific effector mechanisms involved in the inflammatory cascade, have been used in patients with UC with varying degrees of success. Clinicians have never had as many therapeutic options for UC as they do today. Herein we review the variety of treatment options, both standard and investigational, that are available for patients with UC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Butyrates; Colitis, Ulcerative; Cyclosporine; Epidermal Growth Factor; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Interferons; Mercaptopurine; Plasmapheresis; Probiotics; Remission Induction; Thiazoles

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

Ulcerative colitis is a chronic inflammatory bowel disease. The disease is diagnosed on the basis of clinical parameters and endoscopic-histologic evaluation. 5-aminosalicylic acid (5-ASA, mesalamine) represents the first-line treatment of choice. For patients with distal and left-sided disease the use of rectal preparations is effective. Most patients respond to 5-ASA suppositories or to topic steroids such as budesonide suppositories or hydrocortisone foam. For patients with extended disease, oral medications are mandatory. In case of low- to moderate-grade inflammation, 5-ASA preparations should be implemented. In the case of severe disease treatment with steroids is required. Following induction of remission, prophylactic treatment with 5-ASA (1.5 g/d) should be maintained. For patients with frequent or severe relapses, immunosuppressive therapy with azathioprine or 6-mercaptopurine is indicated. In case of a fulminant course of disease, treatment with intravenous cyclosporine is required in patients who have not responded to high-dose intravenous steroids. When all conservative treatment options fail, proctocolectomy with construction of an ileoanal pouch should be performed. New therapeutic strategies such as infliximab and interferons are being evaluated in clinical trials. The long-term complications of ulcerative colitis include steroid-induced osteoporosis and anemia and should be treated adequately. Finally, the risk for development of colorectal cancer increases steadily with disease duration and dysplasia should be screened for by endoscopic surveillance programs.

Topics: Administration, Oral; Adrenal Cortex Hormones; Aminosalicylic Acids; Anemia; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antiviral Agents; Azathioprine; Budesonide; Clinical Trials as Topic; Colectomy; Colitis, Ulcerative; Colonic Pouches; Colonoscopy; Colorectal Neoplasms; Cyclosporins; Gastrointestinal Agents; Humans; Hydrocortisone; Immunosuppressive Agents; Infliximab; Injections, Intravenous; Interferons; Mercaptopurine; Mesalamine; Osteoporosis; Placebos; Practice Guidelines as Topic; Recurrence; Remission Induction; Risk Factors; Suppositories; Time Factors

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Mercaptopurine; Proctocolectomy, Restorative

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

Distal ulcerative colitis may prove to be resistant to steroids and aminosalicylates, but total colectomy is more difficult to justify than in severe extensive colitis. Immunosuppression is of established benefit in generalized colitis, but there are no data available specific to distal disease.. To determine whether the protocol-driven use of immunosuppressants in resistant distal ulcerative colitis is of similar efficacy and safety to that in extensive disease.. Two hundred and twenty-eight patients with distal ulcerative colitis seen in a 5-year period were identified from a prospective database. Details of 52 who had received immunosuppression were analysed.. The 52 patients received 68 courses of therapy (53 azathioprine, five mercaptopurine, 10 ciclosporin). The thiopurines yielded clinically valuable responses in only 43% of courses, with failure of response in 16% and toxicity in 34%. Ciclosporin was helpful on only two of 10 occasions. Eight patients required total colectomy. Adverse events were typical of those normally associated with immunosuppressants, with potential risk to life in seven patients; treatment was discontinued because of toxicity on a total of 31% of occasions.. Immunosuppression appears to be of lower efficacy and higher toxicity in resistant distal colitis than when used in more extensive colitis.

Topics: Adult; Aged; Azathioprine; Colitis, Ulcerative; Cyclosporine; Databases, Factual; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Treatment Outcome

Seventy percent of patients with ulcerative colitis can expect to experience a relapse over a 12 month period. Sulfasalazine was the first drug demonstrated to reduce this relapse rate to 21 percent. Subsequent studies have demonstrated that 5-aminosalicylic acid (5-ASA) is the main active component, and preparations containing only 5-ASA have similar efficacy to sulfasalazine. 5-ASA is readily absorbed from the small intestine; to achieve high a colonic lumenal concentration therefore requires special release formulation. A variety of 5-ASA preparations is available, differing in their release mechanism, efficacy and side effect profile. Most patients can be maintained in remission using oral 5-ASA medication. For patients with distal or left sided disease the use of rectal 5-ASA is also of proven benefit in maintaining remission. Some patients with frequent or severe relapses require stronger immunosuppression, and in these patients azathioprine or 6-mercaptopurine (6-MP) are of proven benefit. Azathioprine is also invaluable for maintaining remission in patients who have been treated with cyclosporin for a fulminant acute episode of colitis. The exciting spectre of natural bacterial therapies (probiotics) deserves further exploration.

Topics: Administration, Oral; Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Remission Induction

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Child; Chronic Disease; Colectomy; Colitis, Ulcerative; Humans; Mercaptopurine; Steroids; Treatment Outcome

Ulcerative colitis distal to the splenic flexure includes disease confined to the rectum (proctitis), rectosigmoid (proctosigmoiditis or distal colitis), or extending to the descending colon or splenic flexure (left-sided colitis). These subtypes represent up to 60% to 80% of newly presenting cases of ulcerative colitis. Although these conditions are defined by the extent of colon that is affected, they also share the characteristic of being amenable to topical therapy. In general, the course of disease is milder and symptoms are less severe than in patients with more extensive colonic involvement. Nonetheless, symptoms may significantly impair patients' health-related quality of life. Treatment options include the oral and/or rectal 5-aminosalicylate (5-ASA) preparations. Rectal therapy delivering higher concentrations of active medication (5-ASA or glucocorticoids) directly to the inflamed mucosa while minimizing systemic absorption provides a highly effective and safe treatment. Oral glucocorticoids are indicated in patients who are resistant to or intolerant of 5-ASA therapy. Immunomodulators have an important role in individuals with glucocorticoid dependent or glucocorticoid refractory disease. This article reviews the clinical diagnosis and current medical management of ulcerative proctitis, proctosigmoiditis, and left-sided ulcerative colitis, including patients resistant to conventional medical therapy.

Topics: Administration, Oral; Administration, Rectal; Administration, Topical; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Prednisone; Proctocolitis; Sigmoidoscopy

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

5-aminosalicylic compounds and corticosteroids are standard drugs, which have been used for treatment of ulcerative colitis (UC). Although unusually we experience severe active UC, such as refractory cases to these drugs. Immunosuppressive agents are introduced and effective for these cases. In the treatment for UC, 6-mercaptopurine and azathioprine are effective, but it takes a few months until their optimum effect. So these drugs are not suitable for severe active UC which needs rapid treatment. On the other hand, newer immunosuppressive agents such as cyclosporin, tacrolimus have a rapid onset of action. These drugs are very effective, but have side effects. We will review immunosuppressive treatment strategy of UC.

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Cytokines; Depression, Chemical; Humans; Immunosuppressive Agents; Mercaptopurine; Tacrolimus

The management of patients with acute, severe ulcerative colitis requires careful in-hospital assessment of the patient and the coordinated treatment of a team of experienced gastroenterologists and surgeons. Complete understanding of the potential complications and their management, especially toxic megacolon, is essential. We review the current medical arsenal and advocate a standardized approach to management that includes continuous, high dose intravenous hydrocortisone, more aggressive use of topical steroids as well as feeding the patients and continuing (but not initiating) oral 5-aminosalicylic acid (5-ASA) agents. For those patients whose disease proves refractory to intravenous steroids, intravenous cyclosporin (with an acute response rate of 82%) is an essential component in the medical management of these patients. Antibiotics should be used only when specifically indicated. Total parenteral nutrition has not been shown to be helpful in the acute setting. Air contrast barium enema and colonoscopy have been used to predict response but may be dangerous diagnostic modalities in these acutely ill patients and are no better than good clinical judgement. We review and advocate long-term management of acute response using 6-mercaptopurine or azathioprine. The surgical experience and the postoperative complications of the ileal pouch anal anastomosis, which include acute pouchitis in 50-60%, chronic pouchitis in 5-10% and recent reports of dysplasia among patients with chronic pouchitis, must be considered before colectomy is advised. Over 80% of patients with acute severe colitis can be spared colectomy using our current arsenal of medical therapies.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Colectomy; Colitis, Ulcerative; Contraindications; Cyclosporine; Heparin; Humans; Immunosuppressive Agents; Megacolon, Toxic; Mercaptopurine; Prognosis; Treatment Outcome

Effective medical treatment of ulcerative colitis is available. However, 20-40% of patients remain refractory and become steroid dependent, or have chronic activity. Azathioprine and its metabolite 6-mercaptopurine have been found to be effective in this setting, although duration of treatment and doses are not entirely clear. Neither is widely used in Europe for this indication. Methotrexate has no definitive place in the treatment of refractory colitis. Intravenous cyclosporin A induces remission in a considerable number of patients; follow-up treatment is, however, not defined. This approach may be useful to allow elective surgery. A number of other treatments have been proposed including chloroquine, interferons and anti-cytokines. None of these can currently be recommended for clinical practice. Anti-inflammatory cytokines such as interleukin-10 may be good candidates.

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Interleukin-10; Mercaptopurine; Methotrexate

Women with ulcerative colitis (UC) are usually young and thus likely to undergo pregnancy. They should be advised to conceive when the disease is quiescent. Steroids and salicylates may be used normally during pregnancy, possibly without exceeding a dose of 2g/day for mesalazine. Azathioprine can be maintained if its indication is clear cut. Cyclosporin seems to be without additional risk in the pregnant woman, its use being limited to acute steroid-refractory disease, as an alternative to surgery.

Topics: Adrenal Cortex Hormones; Antidiarrheals; Azathioprine; Breast Feeding; Colitis, Ulcerative; Cyclosporine; Female; Humans; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Sulfasalazine

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

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

Corticosteroids remain the primary therapeutic agent to induce remission in moderate to severe ulcerative colitis (UC) and Crohn's disease because of their rapidity of action in comparison to other agents. Mild UC and/or Crohn's disease of the colon and terminal small bowel may be treated with azulfidine first. However, if patients are intolerant of these medications, dipentum or asacol may be used. Occasionally, patients with Crohn's colitis but not UC may respond to metronidazole. Immunosuppressive agents such as 6-mercaptopurine are very useful for steroid-dependent inflammatory bowel disease, as a substitute for long-term corticosteroids. Cyclosporine, although it has been proposed as an alternative to other antimetabolite or immunosuppressive therapy, is of benefit in fewer than 25% of cases of UC or Crohn's disease. Rowasa enemas are useful for left-sided disease in UC or Crohn's disease of the colon; however, use in children may be difficult in view of psychosocial issues that must be considered.

Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Child; Child, Preschool; Clinical Trials as Topic; Colitis, Ulcerative; Combined Modality Therapy; Cyclosporine; Humans; Infant; Intestinal Mucosa; Mercaptopurine; Mesalamine; Sulfasalazine

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

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

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

Topics: Aminosalicylic Acids; Azathioprine; Colitis, Ulcerative; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Prognosis; Sulfasalazine

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: 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: 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

Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC.. In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis.. Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline.. Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

Topics: Colitis, Ulcerative; Humans; Mercaptopurine; Mesalamine; Prospective Studies; Remission Induction

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

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

Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment.. We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥ 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change.. In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess.. Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539.

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Male; Mercaptopurine; Methotrexate; Middle Aged; Quality of Life; Remission Induction; Treatment Outcome; Tumor Necrosis Factor-alpha

Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy.. We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54.. Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis.. Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631.

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Inflammatory Agents; Antibodies, Monoclonal; Colitis, Ulcerative; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Middle Aged; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor-alpha

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

The effect of granulocyte and monocyte adsorption apheresis (GMA) on prevention of relapse of ulcerative colitis (UC) is not clear. This was a pilot open-labeled, prospective, randomized, unblinded study to compare the tolerability and efficacy of intermittent GMA (once every 2 weeks) with mercaptopurine to maintain remission of UC. Twenty-one patients with UC, who had achieved remission by induction therapies were randomly assigned to receive either intermittent GMA (N = 10) or oral mercaptopurine (0.5 mg/kg per day; N = 11). The study period was 24 months. The rate of the patients maintaining remission and the incidences of adverse effects were compared between the two groups. At 24 months, seven of 10 patients (70.0%) on intermittent GMA and seven of 11 patients (63.6%, P = 1.00) on oral mercaptopurine were still in remission. Three patients relapsed in each group. One patient taking mercaptopurine, but none receiving intermittent GMA, dropped out because of adverse effects. Intermittent therapy with GMA was well tolerated and a substantial proportion of patients maintained remission. Intermittent GMA therapy in maintaining remission of UC merits further investigation.

Topics: Adolescent; Adult; Colitis, Ulcerative; Female; Granulocytes; Humans; Immunosuppressive Agents; Leukapheresis; Male; Mercaptopurine; Middle Aged; Monocytes; Pilot Projects; Prospective Studies; Recurrence; Statistics, Nonparametric; Survival Analysis; Treatment Outcome

Although the efficacy of tacrolimus for inducing remission of refractory ulcerative colitis (UC) is established, its efficacy for maintaining remission of UC has not been evaluated.. The aim of this study was to evaluate the efficacy of tacrolimus compared with thiopurines for maintaining remission in patients with refractory UC.. Twenty-four UC patients treated with tacrolimus and 34 treated with thiopurines to maintain remission were enrolled as the tacrolimus group and the thiopurine group, respectively. In the tacrolimus group, 82.8% of the patients were treated with tacrolimus for induction of the remission, whereas 70% of the patients in the thiopurine group were induced remission with either corticosteroid or cytapheresis. Proportions of patients who kept steroid-free remission between the tacrolimus and the thiopurine groups were compared. Maintenance of remission using tacrolimus or thiopurines was defined as no need for other therapies other than aminosalicylates without relapse for at least 3 months. Secondarily, to determine whether the response to thiopurines affects the long-term efficacy of tacrolimus maintenance therapy, the overall cumulative relapse-free survival based on the Kaplan-Meier method was estimated in thiopurine-naive or thiopurine-intolerant patients and thiopurine-refractory ones in the tacrolimus group.. Remission was successfully maintained in 17 patients (70.8%) of the tacrolimus group, and 28 patients (82.4%) of the thiopurine group. The overall cumulative relapse-free survival of thiopurine-naive or thiopurine-intolerant patients in the tacrolimus group was similar to that in the thiopurine group, and significantly higher than that of thiopurine-refractory patients in the tacrolimus group.. Maintenance therapy with tacrolimus for patients with UC could be considered an alternative to thiopurine therapy.

Topics: Adolescent; Adult; Aged; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Remission Induction; Secondary Prevention; Tacrolimus; Treatment Outcome; Young Adult

6-Mercaptopurine (6-MP) is an effective maintenance medication in patients with ulcerative colitis (UC), but toxic effects like myelosuppression limit its clinical benefit. In the blood, 6-thioguanine (6-TGN) is formed from 6-MP and mediates the therapeutic efficacy and most of the toxicities of 6-MP. The level of 6-TGN depends on the activity of thiopurine methyltransferase (TPMT), inherited as 1 of its 3 polymorphic forms with low, moderate, or normal/high activity. Accordingly, the 6-MP dose needs to be pharmacogenetically guided.. Patients with quiescent UC received 6-MP as maintenance therapy and 6-TGN was assayed as its concentrations in red blood cells (RBCs) done by high-performance liquid chromatography. In a preliminary investigation, 30 mg/day 6-MP (n = 50) was given orally over 12 weeks to determine the time course of blood 6-TGN level. Then 257 patients were given 6-MP at 15-80 mg/day in a stepwise manner based on RBC 6-TGN, white blood cell count, and body weight to monitor 6-MP efficacy and safety profiles.. At 30 mg/day 6-MP, RBC 6-TGN peaked over 4-8 weeks. In the main dosing study, the mean RBC 6-TGN level in patients who remained in remission during the 1-year observation time (n = 151) was 322.3 +/- 119.5 pmole/8 x 10(8) RBC versus 204.8 +/- 78.7 pmole/8 x 10(8) RBC in patients (n = 19) who relapsed (P < 0.001). Bone marrow suppression was seen almost exclusively at high 6-TGN concentration ranges. Further, a regression plot showed an inverse relationship between 6-TGN levels in RBC and TPMT enzyme activity.. By regularly measuring RBC 6-TGN in patients with quiescent UC receiving 6-MP as maintenance therapy, we could monitor bone marrow suppression as well as other toxic side effects. Potentially, this strategy should enable physicians to avoid thiopurine-related adverse effects and identify individuals who may benefit most from 6-MP maintenance therapy.

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Diseases; Colitis, Ulcerative; Drug Monitoring; Erythrocytes; Humans; Immunosuppressive Agents; Leukapheresis; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Prednisolone; Thioguanine; Treatment Outcome; Young Adult

In ulcerative colitis (UC) gut bacteria drive inflammation. Bacterial recognition and T-cell responses are shaped by intestinal dendritic cells (DCs); therapeutic effects of probiotic bacteria may relate to modulation of intestinal DC. The probiotic mixture, VSL#3, increases interleukin (IL)-10 and downregulates IL-12p40 production by DC in vitro. We evaluated in vivo effects of oral VSL#3 and steroids on colonic DC in patients with acute UC.. Rectal biopsies were obtained from patients with active UC before and after treatment with VSL#3, corticosteroids, or placebo, and from healthy controls. Myeloid colonic DC were studied from freshly isolated lamina propria cells using multicolor flow cytometry. Surface expression of activation markers, CD40, CD86, pattern recognition receptors, Toll-like receptor (TLR)-2 and TLR-4 were assessed. Changed function was measured from ongoing intracellular IL-10, IL-12p40, IL-6, and IL-13 production.. Acute UC colonic myeloid DC were producing more IL-10 and IL-12p40 than control DC (P = 0.01). In VSL#3-treated patients DC TLR-2 expression decreased (P < 0.05), IL-10 production increased and IL-12p40 production decreased (P < 0.005); 10/14 patients on VSL#3 showed a clinical response. Corticosteroids also resulted in increased IL-10 and reduced IL-12p40 production by DC. Conversely, in patients on placebo, TLR-2 expression and intensity of staining for IL-12p40 and IL-6 increased (all P < 0.05); 5/14 patients on placebo showed a clinical response (P = NS).. Despite small numbers of human colonic DC available, we showed that treatment of UC patients with probiotic VSL#3 and corticosteroids induced "favorable" intestinal DC function in vivo, increasing regulatory cytokines and lowering proinflammatory cytokines and TLR expression. These effects may contribute to therapeutic benefit.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; B7-2 Antigen; CD40 Antigens; Colitis, Ulcerative; Colon; Dendritic Cells; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-12 Subunit p40; Interleukin-13; Interleukin-6; Male; Mercaptopurine; Mesalamine; Middle Aged; Probiotics; Receptors, Pattern Recognition; 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

Topics: Adult; Aged; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Combined Modality Therapy; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Humans; Immunosuppressive Agents; Infliximab; Leukapheresis; Male; Mercaptopurine; Mesalamine; Middle Aged; Remission Induction; Treatment Failure; Treatment Outcome

6-thioguanine (6-TG) has emerged as a promising therapeutic alternative in patients with Crohn's disease intolerant or resistant to azathioprine (AZA) and/or 6-mercaptopurine (6-MP). The aim of the present study was to evaluate the safety and efficacy of 6-TG in patients with ulcerative colitis (UC) or indeterminate colitis (IC) intolerant or resistant to AZA/6-MP.. Twenty patients with an acute flare, steroid-dependent or steroid-refractory disease attending our outpatient department were included in the study. Measurement of 6-TG nucleotide levels was done to check compliance. Complete, partial and non-response were defined by means of the clinical activity index and the daily steroid demand. Secondary outcome parameters included changes in cumulative steroid doses, C-reactive protein (CRP) levels, and an endoscopic score.. Out of 20 patients 4 were excluded owing to noncompliance; 2/16 compliant patients (13%) had to be prematurely withdrawn because of adverse events, which ceased upon drug discontinuation. By per-protocol analysis, 5/14 patients (36%) were complete, 6/14 (43%) partial and 3/14 (21%) non-responders. In addition to the reduction of the cumulative steroid dose over 3 months, CRP decreased in the study population and the endoscopic score decreased in treatment responders.. Treatment with 6-TG was effective in patients with UC or IC previously intolerant or resistant to AZA/6-MP. Future work is needed to define a subpopulation of patients at low risk for its potential hepatotoxicity, which we assume will benefit from 6-TG.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Biomarkers; C-Reactive Protein; Colitis, Ulcerative; Dose-Response Relationship, Drug; Endoscopy, Gastrointestinal; Female; Genotype; Guanine Nucleotides; Humans; Male; Mercaptopurine; Methylthioinosine; Methyltransferases; Middle Aged; Orosomucoid; Patient Compliance; Prospective Studies; Quality of Life; Thioguanine; Thionucleotides; Treatment Outcome

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

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

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

Topics: Azathioprine; Clinical Trials as Topic; Colitis, Ulcerative; Cromolyn Sodium; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Mercaptopurine; Prednisone; Pregnancy; Pregnancy Complications; Recurrence; Research; Sulfasalazine

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

To evaluate responses to medical therapy in ulcerative colitis, rectal biopsies of patients with active untreated disease, individuals with positive and negative sigmoidoscopic findings treated with salicylazosulfapyridine, prednisone and 6-mercaptopurine, alone and in combinations and noncolitis controls were compared histologically. Predominant histological observations were analyzed statistically. There were fewer crypt abscesses but more mucosal edema after all forms of therapy. Quantitative histopathological analysis failed to demonstrate that the response to one drug was significantly different from another.

Topics: Biopsy; Clinical Trials as Topic; Colitis, Ulcerative; Drug Evaluation; Drug Therapy, Combination; Humans; Intestinal Mucosa; Mercaptopurine; Prednisone; Rectum; Remission, Spontaneous; Sigmoidoscopy; Sulfasalazine

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

Topics: Azathioprine; Colitis, Ulcerative; Humans; Immunologic Factors; Immunosuppressive Agents; Mercaptopurine

Though not exempt from adverse events, azathioprine (AZA) is an inexpensive and effective drug in the induction and maintenance treatment of patients with inflammatory bowel disease. We present the case of a 20-year-old female patient with left-side ulcerative colitis in whom AZA was started at a dose of 1.5 mg/kg/day due to dependence on corticoids (thiopurine methyltransferase activity: 14.9 U/mL). Two weeks after starting treatment she began to report excessive hair loss, resulting in an almost complete loss of scalp hair.

Topics: Adult; Alopecia; Azathioprine; Biomarkers; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Young Adult

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

thiopurines are used as maintenance therapy in patients with ulcerative colitis (UC). There are contradictory results regarding the relationship between adherence to treatment and risk of relapse.. to quantify and evaluate the trends in thiopurine prescription rates, and to determine the impact and risk factors of non-adherence.. analytical, observational, retrospective study of UC patients taking thiopurines included in the ENEIDA single-center registry from October 2017 to October 2019. Adult patients in clinical remission at the beginning of the study on thiopurines maintenance treatment for at least 6 months before recruitment were included. Adherence was evaluated with an electronic pharmaceutical prescription system. Adherence was considered when 80 % or more of the prescribed medication was dispensed at the pharmacy. Kaplan-Meier curves and a regression model were used to examine year-to-year treatment dispensation, and to identify factors associated with non-adherence.. a total of 41 patients were included, of whom 71 % were males with a mean age of 44 (14), and 26.8 % were concomitantly managed with biological therapy. Overall, 22 % were non-adherent to thiopurines. No predictive factors of non-adherence were identified. Adherence rate did not correlate with disease activity during two years of follow-up (OR 1.6; 95 % CI = 0.3-9.1). Left-sided colitis and concomitant biological treatment were related with disease relapse (p ≤ 0.01).. adherence to thiopurines in UC patients is high (78 %). Non-adherence is not related to clinical or pharmacological factors. Adherence rate was not associated with disease activity.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Female; Humans; Male; Mercaptopurine; Prevalence; Recurrence; Retrospective Studies

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

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

Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance.. Plasma concentrations of 5-ASA, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time-dependent or pH-dependent mesalazine or MMX) as monotherapy. Patients already on both time-dependent or pH-dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks.. Plasma 5-ASA and N-Ac-5-ASA levels were significantly higher in patients receiving time-dependent mesalazine (n = 12) compared with pH-dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time-dependent mesalazine to MMX decreased 6-TGN levels, increased those of 6-MMP, and increased 6-MMP/6-TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH-dependent mesalazine to MMX.. Time-dependent mesalazine has higher plasma 5-ASA and N-Ac-5-ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time-dependent mesalazine to MMX may lead to an increase of 6-MMP/6-TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Humans; Mercaptopurine; Mesalamine; Methyltransferases; 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

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

No population-based study has evaluated the natural course of UC over three decades in non-Caucasians. We aimed to assess the long-term natural course of Korean patients with UC in a population-based cohort.. This Korean population-based, Songpa-Kangdong IBD cohort included all patients (n=1013) newly diagnosed with UC during 1986-2015. Disease outcomes and their predictors were evaluated.. During the median follow-up of 105 months, the overall use of systemic corticosteroids, thiopurines and antitumour necrosis factor (anti-TNF) agents was 40.8%, 13.9% and 6.5%, respectively. Over time, the cumulative risk of commencing corticosteroids decreased, whereas that of commencing thiopurines and anti-TNF agents increased. During follow-up, 28.7% of 778 patients with proctitis or left-sided colitis at diagnosis experienced proximal disease extension. A total of 28 patients (2.8%) underwent colectomy, demonstrating cumulative risks of colectomy at 1, 5, 10, 20 and 30 years after diagnosis of 1.0%, 1.9%, 2.2%, 5.1% and 6.4%, respectively. Multivariate Cox regression analysis revealed that extensive colitis at diagnosis (HR 8.249, 95% CI 2.394 to 28.430), ever use of corticosteroids (HR 6.437, 95% CI 1.440 to 28.773) and diagnosis in the anti-TNF era (HR 0.224, 95% CI 0.057 to 0.886) were independent predictors of colectomy. The standardised mortality ratio in patients with UC was 0.725 (95% CI 0.508 to 1.004).. Korean patients with UC may have a better clinical course than Western patients, as indicated by a lower colectomy rate. The overall colectomy rate has continued to decrease over the past three decades.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Colectomy; Colitis, Ulcerative; Disease Progression; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prognosis; Republic of Korea; Risk Factors; Severity of Illness Index; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

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

Use of thiopurines for inflammatory bowel diseases (IBDs) is declining in some parts of the world. We aimed to explore outcomes of thiopurines and predictors of response in a real-world prospective cohort of children with dose optimization.. Children with IBD treated with thiopurines without biologics were enrolled. Dosing was guided by thiopurine S-methyltransferase-activity at baseline and by clinical response and toxicity at 4 months; 1 year into the study, therapeutic drug monitoring at 4 months was also considered in the decision making. The primary outcome was steroid-free remission without treatment escalation by 12 months (SFR), using the intention-to-treat approach.. A total of 129 children were included (74% Crohn disease [CD] and 26% ulcerative colitis [UC]). SFR was achieved in 37 (39%) CD and 13 (39%) UC patients, and SFR with normal erythrocyte sedimentation rate/C-reactive protein in 20 (21%) and 9 (27%), respectively. At 4 months, mean corpuscular volume/white blood cell ratio and Δ absolute neutrophil count weakly correlated with 6-thioguanine (r = 0.33, P = 0.02 and r = 0.32, P = 0.02, respectively). In CD, SFR was associated with 4-month median weighted Pediatric Crohn Disease Activity Index (2.5 [IQR 0-7.5] in responders vs 5 in nonresponders [0-12.5], P = 0.048) and Δabsolute neutrophil count (1.7 [IQR 0.7-4.1] vs 0.05 [-2.3-0.9]; P = 0.03). Mild drug-related adverse events were recorded in 30 children (22%), 3 required stopping the drug.. In this real-life prospective cohort using dose optimization, thiopurines were safe and effective in 21% of CD and 27% of UC patients, including normalization of C-reactive protein and erythrocyte sedimentation rate. Thiopurines remain a viable option in the treatment algorithm of mild-moderate pediatric IBD, especially in girls whose risk for lymphoma is lower.

Topics: Azathioprine; Child; Cohort Studies; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies

BACKGROUND Pancytopenia is a hematological condition which is characterized by decreases in all three cellular elements: RBC, WBC, and platelets. As a result, patients with pancytopenia are more prone to anemia, infections, and excessive bleeding. Pancytopenia can be caused by medications or drug interactions that suppress the bone marrow. This case report highlights a drug interaction between allopurinol and mercaptopurine which led to pancytopenia and septic infection, resulting in the patient's death. This could easily have been avoided if a clinical pharmacist had been consulted. CASE REPORT A 55-year-old female patient with a past medical history of gout, depression, back pain, and type 2 diabetes was recently diagnosed with ulcerative colitis and was discharged with a new prescription of mercaptopurine. After 2 months of concurrent use of allopurinol and mercaptopurine, she developed infected foot ulcers, which progressed rabidly to sepsis. At the time, her laboratory findings confirmed pancytopenia. Despite treatment, the patient died. CONCLUSIONS This case illustrates the importance of consulting a clinical pharmacist in order to avoid such medical error. The dose of mercaptopurine should be reduced to 25% of the recommended dose when it is given concurrently with allopurinol to reduce the risk of pancytopenia. Health care providers should think about the significant role of clinical pharmacy services. In our case, there were no clinical pharmacist involved in the care of this patient, and as a result of such negligence, the patient lost her life.

Topics: Allopurinol; Colitis, Ulcerative; Diabetic Foot; Drug Interactions; Fatal Outcome; Female; Gout; Gout Suppressants; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged; Pancytopenia; Pharmacists; Pharmacy Service, Hospital; Referral and Consultation; Sepsis

Thiopurines are used as maintenance therapy in ulcerative colitis (UC), but whether these drugs influence the natural history of the disease is unknown. We aimed to assess the effect of thiopurines in terms of colectomy, hospital admission, progression in disease extent and anti-tumour necrosis factor (TNF) therapy within 10 years from initiation.. Patients diagnosed with UC within the Örebro University Hospital catchment area, during 1963-2010, who initiated thiopurines (n=253) were included. To overcome the risk of confounding by indication, we compared patients who stopped treatment within 12 months because of an adverse reaction (n=76) with patients who continued therapy or discontinued due to other reasons (n=177) and assessed long-term outcomes using Cox regression with adjustment for potential confounding factors.. The cumulative probability of colectomy within 10 years was 19.5% in tolerant patients compared with 29.0% in intolerant (adjusted HR 0.49; 95% CI 0.21 to 0.73). The probability of hospital admission was 34.0% in tolerant versus 56.2% in intolerant patients (adjusted HR 0.36; 95% CI 0.23 to 0.56). The risk for progression in disease extent was 20.4% in tolerant patients compared with 48.8% in intolerant (adjusted HR 0.47; 95% CI 0.21 to 1.06). Within 10 years, 16.1% of tolerant and 27.5% of intolerant patients received anti-TNF therapy (adjusted HR 0.49; 95% CI 0.26 to 0.92).. Based on the novel approach of comparing patients tolerant and intolerant to thiopurines, we reveal that thiopurines have a profound beneficial impact of the natural history and long-term colectomy rates of UC.

Topics: Adult; Azathioprine; Colectomy; Colitis, Ulcerative; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Thioguanine; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Biopsy, Needle; Colitis, Ulcerative; Constriction, Pathologic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunohistochemistry; Infliximab; Male; Mercaptopurine; Middle Aged; Proctoscopy; Rare Diseases; Rectal Diseases; Risk Assessment; Severity of Illness Index; Sigmoidoscopy

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

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

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

Topics: Colitis, Ulcerative; Humans; Mercaptopurine; Mesalamine; Methotrexate; Remission Induction

Thiopurine drugs, such as thioguanine, mercaptopurine and azathioprine, are used for treating inflammatory bowel disease, such as ulcerative colitis. One must be aware of the serious side effects these drugs can have (e.g. bone marrow depression). A 56-year-old man with ulcerative colitis was treated with mercaptopurine. He developed leukopenia as a result. Thioguanine was started ten months later, resulting in life-threatening pancytopenia. Thiopurine methyltransferase (TPMT) genotyping proved that the patient was a poor metaboliser of thioguanine (TPMT3A*/3A*). Dose reduction is recommended for patients with reduced or absent TPMT activity. This life-threatening side effect could have been prevented by taking a number of relatively simple precautions.

Topics: Colitis, Ulcerative; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Pancytopenia; Thioguanine

Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC).. Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus.. Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush.. Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.

Topics: Adolescent; Child; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Male; Mercaptopurine; Recurrence; Retrospective Studies; Time; Treatment Outcome

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

Mucosal healing (MH) with thiopurines has been poorly investigated in ulcerative colitis (UC). We aimed to assess MH rate in UC patients treated with thiopurine monotherapy.. We retrospectively collected all UC patients treated with thiopurines more than 6 months who have undergone colonoscopy at baseline and after at least 6 months of treatment. Patients were recruited from January 2005 to May 2015 through a personal database and/or standardized hospital inpatient diagnostic dataset. Patients were excluded in case of any use of other immunomodulator or biological agent. MH was defined as a Mayo endoscopic subscore ≤1 and UCEIS ≤ 2. Histological healing (HH) was defined by the absence of epithelial polynuclear infiltrate, cryptic abscesses, or ulcerations.. In UC, thiopurine monotherapy is associated with MH in 43.7% and HH in 38%.

Topics: Adult; Azathioprine; Cohort Studies; Colitis, Ulcerative; Colonoscopy; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Odds Ratio; Retrospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome

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

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

Generalized essential telangiectasia (GET) is a notoriously difficult to treat disorder with no current satisfactory treatments. This case and discussion report the use of 6-mercaptopurine (6-MP) as a successful treatment for GET. Moreover, we show that GET may represent a state of increased angiogenesis, a paradigm shift from the current understanding that these telangiectasias represent dilatations of only pre-existing vessels. This new view of GET may drive others to look at novel agents for treatment.

J Drugs Dermatol. 2017;16(3):280-282.

Topics: Antigens, CD34; Antimetabolites, Antineoplastic; Biomarkers; Colitis, Ulcerative; Collagen Type IV; Endothelial Cells; Female; Fibrinogen; Humans; Lasers, Dye; Low-Level Light Therapy; Mercaptopurine; Metalloproteases; Middle Aged; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Telangiectasis

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

To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy.. Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis.. Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95% CI: 1.2-7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95% CI: 1.1-9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.9, and HR: 0.4, p = 0.006, 95% CI: 0.2-0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95% CI: 1.0-3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95% CI: 1.1-8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.8, and HR: 0.3, p = 0.011, 95% CI: 0.1-0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95% CI: 1.1-5.9).. Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Calcineurin Inhibitors; Colectomy; Colitis, Ulcerative; Disease Progression; Drug Resistance; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Leukapheresis; Maintenance Chemotherapy; Male; Mercaptopurine; Middle Aged; Prognosis; Protective Factors; Retrospective Studies; Risk Factors; Treatment Failure

Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment.. In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months.. We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died.. Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

Topics: Adult; Aged; Cohort Studies; Colectomy; Colitis, Ulcerative; Colonoscopy; Databases, Factual; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Steroids; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; Wound Healing; Young Adult

Thiopurines (azathioprine and 6-mercaptopurine) have been used in the management of UC patients for over three decades. Nearly half of patients with UC treated with thiopurines fail to achieve remission or lose remission during treatment. Factors associated with thiopurine failure are poorly understood. The primary aim of our study was to investigate patient-related factors which are associated with thiopurine failure.. TNF-alpha antagonist-naïve patients with histological diagnosis of UC, receiving thiopurine therapy, with follow-up data from 1 to 3 years were included in the study. Data regarding demographics, laboratory results, and disease characteristics were collected. The primary endpoint was failure of thiopurine therapy, defined as treatment with steroids, therapeutic escalation to TNF-alpha antagonist therapy, or need for surgery.. Of the 563 patients identified using ICD-9 codes, 78 TNF-alpha antagonist-naïve patients with a histological diagnosis of UC, receiving thiopurine treatment, were identified. Over the three-year follow-up period, 38 patients failed thiopurine treatment. On adjusted Cox regression, BMI < 25 kg/m(2) (HR 3, 95 % CI 1.55-5.83; p value = 0.001) was significantly associated with thiopurine failure. Furthermore, although not statistically significant, there was a strong trend toward thiopurine failure among patients with serum albumin level < 4 g/dL (HR 1.98, 95 % CI 0.97-4; p value = 0.06), non-smoking status (HR 2.2, 95 % CI 0.96-5.06; p value = 0.06), and higher degree of colon inflammation (HR 1.49, 95 % CI 0.96-2.32; p value = 0.08).. Our results show that low body mass index is associated with increased risk of failure of thiopurine treatment. Furthermore, there was a strong trend toward thiopurine failure among patients with low serum albumin level (<4gm/dL). These factors should be considered as markers of non-response to thiopurine monotherapy for patients with moderately severe ulcerative colitis.

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Biological Products; Biomarkers; Body Mass Index; Chi-Square Distribution; Colitis, Ulcerative; Digestive System Surgical Procedures; Drug Substitution; Female; Gastrointestinal Agents; Humans; Hypoalbuminemia; Male; Mercaptopurine; Middle Aged; Multivariate Analysis; Nutritional Status; Proportional Hazards Models; Retrospective Studies; Risk Factors; Serum Albumin; Serum Albumin, Human; Severity of Illness Index; Steroids; Time Factors; Treatment Failure; Tumor Necrosis Factor-alpha; Young Adult

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

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

Topics: Anti-Inflammatory Agents, Non-Steroidal; Atrial Fibrillation; Azathioprine; Cardiac Imaging Techniques; Colitis, Ulcerative; Fever; Heart Failure; Humans; Hypotension; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Mercaptopurine; Mesalamine; Middle Aged; Myocarditis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is chronically present in patients throughout their lives. Hence, the chronic nature of the disease invariably requires continuous medical treatment. Advances in medical therapy over the last decades and current developments offer increasing options and are closely associated with a better life quality in patients.. Recent developments in understanding the pathogenesis of UC are discussed. The current standard therapeutic regimens are outlined and recent developments and upcoming strategies introduced.. (1) Environmental factors that are yet to be defined contribute to the pathogenesis of UC. (2) An accelerated step-up therapy represents the current standard in UC. (3) Anti-integrins represent the most recently introduced pharmacological class in the therapy of UC. (4) Novel strategies including Janus kinase inhibitors are in the near future.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Biosimilar Pharmaceuticals; Colitis, Ulcerative; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Integrins; Janus Kinases; Mercaptopurine; Mesalamine; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Tumor Necrosis Factor-alpha

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

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

Topics: Antimetabolites; Colitis, Ulcerative; Female; Humans; Male; Melanoma; Mercaptopurine; Skin Neoplasms

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

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

The ideal length of treatment with thiopurines in patients with ulcerative colitis (UC) in sustained remission remains unknown. It is widely accepted that the drug withdrawal is associated with a worse outcome. The aim of this study was to analyze the outcome after this withdrawal and to identify predictors of relapse.. A multicenter and retrospective study was designed. A total of 102 patients with UC who discontinued thiopurines in a situation of sustained remission were included. All the patients were followed up until last revision or until relapse (understood as the occurrence of signs and symptoms of UC that required a rescue treatment).. After thiopurines withdrawal, overall relapse was recorded in 32.35% of the patients: 18.88% in the first year, 36.48% in the third, and 43.04% in the fifth year after withdrawal. On multivariate analysis, predictors of relapse were the time from diagnosis of UC until the starting of thiopurines (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02; P = 0.039), the number of relapses before the withdrawal (HR, 1.3; 95% CI, 1.01-1.66; P = 0.029), pancolitis (HR, 5.01; 95% CI, 1.95-26.43; P = 0.028), the duration of treatment with thiopurines (HR, 0.15; 95% CI, 0.03-0.66; P = 0.013) and the situation of biological remission at withdrawal (HR, 0.004; 95% CI, 0.0001-0.14; P = 0.002).. The withdrawal of thiopurines in patients with UC, although in sustained remission, is related to a high relapse rate. Clinical variables such as the extent of the disease, the duration of treatment or time from diagnosis to the start of thiopurines should be considered before stopping these drugs.

Topics: Adult; Aged; Azathioprine; Colitis, Ulcerative; Colonoscopy; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prognosis; Remission Induction; Retrospective Studies; Treatment Outcome; Withholding Treatment

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

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

Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), but recent studies suggest a lower risk than previously reported. The aim was to evaluate the incidence of dysplasia, CRC and related risk factors in UC patients from a Spanish nationwide database.. All UC patients were identified and retrospectively reviewed. Clinical-epidemiological data and the finding of dysplasia and/or CRC were collected.. A total of 831 UC patients were included. Twenty-six cases of CRC in 26 patients and 29 cases of high-grade dysplasia (HGD) in 24 patients were found, accounting for 55 diagnoses of advanced neoplasia (AN = CRC and/or HGD) in 45 patients (33% of them within the first 8 years after UC diagnosis). The cumulative risk of AN was 2, 5.3 and 14.7% at 10, 20 and 30 years, respectively. Concomitant primary sclerosing cholangitis (odds ratio [OR] 10.90; 95% confidence interval [CI] 3.75-31.76, p < 0.001), extensive UC (OR 2.10, 95% CI 1.01-4.38, p = 0.048), UC diagnosis at an older age (OR 2.23, 95% CI 1.03-4.83, p = 0.043) and appendectomy prior to UC diagnosis (OR 2.66, 95% CI 1.06-6.71, p = 0.038) were independent risk factors for AN. Use of thiopurines (OR 0.21, 95% CI 0.06-0.74, p = 0.015) and being in a surveillance colonoscopy programme (OR 0.33; 95% CI 0.16-0.67; p = 0.002) were independent protective factors for AN.. The risk of AN among UC patients is lower than previously reported but steadily increases from the time of UC diagnosis. The widespread use of thiopurines may have influenced this reduced incidence of UC-related neoplasias.

Topics: Adult; Aged; Aged, 80 and over; Colitis, Ulcerative; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Logistic Models; Male; Mercaptopurine; Middle Aged; Registries; Retrospective Studies; Risk Factors; Spain

The management of patients with ulcerative colitis who are dependent on corticosteroid for control of symptoms, or refractory to corticosteroids or standard immunosuppressive therapy, is challenging. The development of newer medical therapies has increased the options for managing patients in this situation, but access and funding remain limited. This guideline summarises the literature regarding this situation and provides guidance as to the management of refractory colitis in the New Zealand setting.

Topics: Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Appendectomy; Azathioprine; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Fecal Microbiota Transplantation; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Leukapheresis; Mercaptopurine; Mesalamine; Methotrexate; New Zealand; Pediatrics; Piperidines; Proctocolectomy, Restorative; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Recurrence; Severity of Illness Index; Tacrolimus; Tumor Necrosis Factor-alpha

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

An expert panel of the European Crohn's and Colitis Organisation (ECCO) and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) initiated a consensus process to produce the first pediatric specific ulcerative colitis (UC) guidelines based on a systematic literature review. Treatment strategies must reflect that pediatric-onset UC has a slightly different phenotype than adult-onset disease with more often extensive (pancolitis) and more aggressive disease course. Other pediatric-specific aspects include growth, puberty, bone density accrual and emotional development and body image acquisition. These differences and others influenced the development of pediatric treatment algorithms. It is recommended that virtually all children with UC must be treated with some maintenance therapy and 5-ASA requirement and dosing are often higher in children. A larger number of children are at risk for steroid-dependency, and this should not be tolerated; steroid sparing strategies with early use of immunosuppressors are recommended in high-risk patients. On the other hand, the safety profile of immunosuppressive therapy in children includes the rare forms of lymphomas and many future treatment years. Colectomy and pouch formation should be balanced in the treatment algorithms against the higher rate of future infertility in girls. The acute and on-going management of pediatric UC should be guided by evidence- and consensus-based balanced decisions, reflecting a vision of long-term treatment goals.

Topics: Adult; Age of Onset; Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Child; Colectomy; Colitis, Ulcerative; Drug Therapy, Combination; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Mesalamine; Practice Guidelines as Topic

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

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

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

Topics: Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Lymphoma; Male; Mercaptopurine

Topics: Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Lymphoma; Male; Mercaptopurine

Thiopurines are used as a maintenance therapy in patients with ulcerative colitis (UC). For some patients the metabolism of thiopurines is unfavorable, leading to increased adverse effects, including hepatotoxicity. There are many reports in the adult literature concerning the manipulation of thiopurine metabolism with allopurinol; however, there is only 1 publication in this respect for pediatric UC. We present 3 pediatric cases of UC wherein the combination of allopurinol and low-dose 6-mercaptopurine allowed for shunting of thiopurine metabolites to a more favorable pattern. This intervention supported clinical remission in all, including one case poorly responsive to infliximab.

Topics: Adolescent; Allopurinol; Antimetabolites; Child; Colitis, Ulcerative; Drug Therapy, Combination; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Thionucleotides

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

Little is known about the risk factors of colectomy in patients with ulcerative colitis (UC) under thiopurine treatment. The aim of the study was to determine the prevalence and the predictive risk factors of colectomy in an extensive cohort of patients with UC treated with thiopurines in Spain.. Among 5753 UC patients, we identified those diagnosed between 1980 and 2009 and treated with azathioprine or mercaptopurine (AZA/MP). We analyzed the age at diagnosis, familial history of IBD, extraintestinal manifestations (EIMs), disease extent, smoking status and treatment requirements (AZA/MP, cyclosporine (CsA) or anti-TNFα). Colectomies for dysplasia or cancer were excluded. Survival analysis and Cox proportional hazard regression were performed. Results were reported as hazard ratios (HR) with 95% CI.. Among the 1334 cases included, 119 patients (8.9%) required colectomy after a median time of 26 months (IQR 12-42) after AZA/MP initiation. Independent predictors of colectomy were: Extensive UC (HR 1.7, 95% CI: 1.1-2.6), EIMs (HR 1.5, 95% CI: 1.0-2.4), need for antiTNFα (HR 2.3, 95% CI: 1.5-3.4) and need for CsA (HR 2.4, 95% CI: 1.6-3.7). Patients requiring early introduction of AZA/MP had an increased risk of colectomy with a HR of 4.9 (95% CI: 3.2-7.8) when AZA/MP started in the first 33 months after UC diagnosis.. Nearly one-tenth of patients with UC under thiopurines require colectomy. Extensive UC, EIMs, need for CsA or anti-TNFα ever and an early need for AZA/MP treatment were associated with a higher risk of colectomy. These risk factors of colectomy could help to stratify risk in further controlled studies in UC.

Topics: Adult; Colectomy; Colitis, Ulcerative; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Mercaptopurine; Probability; Risk Factors; Severity of Illness Index; Spain; Tumor Necrosis Factor-alpha; Young Adult

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Cerebral Hemorrhage; Certolizumab Pegol; Colitis, Ulcerative; Diagnosis, Differential; Drug Therapy, Combination; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Intracranial Thrombosis; Magnetic Resonance Imaging; Male; Mercaptopurine; Middle Aged; Polyethylene Glycols; Prednisone; Tomography, X-Ray Computed

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Drug Interactions; Erythrocytes; Feces; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Leukocyte L1 Antigen Complex; Mercaptopurine; Mesalamine

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

There are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy.. Nationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001-2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case-control study was conducted to investigate the association between thiopurine use and MSC.. We included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6).. In this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.

Topics: Aged; Antimetabolites; Colitis, Ulcerative; Female; Humans; Incidence; Male; Melanoma; Melanoma, Cutaneous Malignant; Mercaptopurine; Middle Aged; Regression Analysis; Retrospective Studies; Risk; Skin Neoplasms; United States; Veterans

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

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

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

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Drug Resistance; Female; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Recurrence; Treatment Failure; Tumor Necrosis Factor-alpha; Young Adult

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

There is controversy over whether the treatment of patients with ulcerative colitis (UC) with thiopurines increases their risk of lymphoma. We evaluated the risk of lymphoma (ongoing, residual, and per year of therapy) among thiopurine-treated patients with UC.. We obtained nationwide data from the Veterans Affairs (VA) health care system from 2001 to 2011. We performed a retrospective cohort study, analyzing data on 36,891 patients from their date of diagnosis of UC in the VA health care system to a diagnosis of lymphoma or October 1, 2011 (subjects followed up for a median of 6.7 years). Thiopurine exposure was assessed using the VA pharmacy database. Patients who developed lymphoma were identified based on ICD-9 codes and confirmed by manual chart review.. In total, 4734 patients with UC (13%) were treated with thiopurines for a median of 1 year. Lymphoma developed in 119 patients who had not been treated with thiopurines, 18 who were treated with thiopurines, and 5 who had discontinued treatment with thiopurines. The incidence rates of lymphoma were 0.60 per 1000 person-years among patients who had not been treated with thiopurines, 2.31 among patients who were treated with thiopurines, and 0.28 among patients who had discontinued treatment with thiopurines. The incidence rates of lymphoma during the first year, second year, third year, fourth year, and >4 years of thiopurine therapy were 0.9, 1.6, 1.6, 5, and 8.9 per 1000 person-years, respectively. The age-, sex-, and race-adjusted hazard ratios of developing lymphoma were 4.2 (95% confidence interval, 2.5-6.8; P < .0001) while being treated with thiopurines and 0.5 (95% confidence interval, 0.2-1.3; P = .17) after discontinuing treatment with thiopurines compared with patients who had not been treated with thiopurines.. Based on a retrospective, nationwide cohort study, patients with UC have a 4-fold increase in risk of lymphoma while being treated with thiopurines compared with patients who have not been treated with thiopurines. The risk increases gradually for successive years of therapy. Discontinuing thiopurine therapy reduces the risk of lymphoma.

Topics: Adult; Aged; Antibodies, Monoclonal; Azathioprine; Cohort Studies; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Infliximab; Lymphoma; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Reproducibility of Results; Retrospective Studies; Risk Factors; United States; United States Department of Veterans Affairs

Topics: Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Infliximab; Lymphoma; Male; Mercaptopurine

Topics: Adult; Allopurinol; Colitis, Ulcerative; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Maternal-Fetal Exchange; Mercaptopurine; Pregnancy; Pregnancy Complications

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

Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP.. Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis.. Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI ≤ 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p = 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP.. Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Cytapheresis; Female; Follow-Up Studies; Humans; Immunologic Factors; Male; Mercaptopurine; Middle Aged; Patient Readmission; Prednisolone; Prognosis; Remission Induction; Severity of Illness Index; Time Factors; Young Adult

Topics: Adalimumab; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Middle Aged; Retrospective Studies; Steroids; Treatment Outcome

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

Health care planning demands a detailed knowledge of the course of chronic diseases in the Irish population. This study describes hospital admission rates, medication use and outcomes in a large cohort of patients with ulcerative colitis attending a tertiary referral centre in Ireland.. Four hundred and twenty-four patients who attended during the 18-year period from January 1991 to January 2009 were identified. Baseline demographics, hospital admission, medications required, extent of colitis and date of colectomy were recorded.. More than half (55.4%) of the patients were managed exclusively in an outpatient setting throughout diagnosis and follow-up. Systemic corticosteroids, thiopurines and infliximab were required by 70, 29.5 and 5% of the patients, respectively. Overall 5-year colectomy rate due to failure of medical therapy was 15.8%. Independent predictors of colectomy were hospital admission at first presentation (odds ratio 3.6, p < 0.0001) and pancolitis at diagnosis (odds ratio 2.3, p < 0.01).. The majority of patients with colitis have an uncomplicated disease course and do not require thiopurines, biologic agents or hospital admission. Principal management at a primary care level may be appropriate in many cases. Colectomy rates at a specialist centre in Ireland compare favourably with international figures.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antibodies, Monoclonal; Azathioprine; Child; Child, Preschool; Colectomy; Colitis, Ulcerative; Female; Hospitalization; Humans; Hydrocortisone; Immunosuppressive Agents; Infant; Infliximab; Ireland; Male; Mercaptopurine; Middle Aged; Prednisolone; Young Adult

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

The cumulative incidence of colectomy and the impact of 5-aminosalicylates (5-ASA), azathioprine, and antitumor necrosis factor (TNF) treatment on the long-term need for surgery are unknown in ulcerative colitis (UC) in the era of biologics.. This was an observational study of a referral center cohort. The cumulative incidence of UC-related colectomy was estimated using the Kaplan-Meier method. Independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. The electronic charts of 151 incident cases of UC from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010.. The median follow-up time per patient was 58 months. Twenty-one (14%) underwent surgery. The cumulative probabilities of colectomy were respectively 1.3% and 13.5% at 1 and 5 years from the time of diagnosis. The probability of receiving oral mesalamine at 5 years was 68.1%. The corresponding figures were 48.9% for azathioprine and 29.0% for infliximab. For corticosteroids, methotrexate, and cyclosporin these figures were 75%, 8.8%, and 11.5%, respectively. Using multivariate Cox proportional hazards regression analysis after propensity score adjustment, previous use of cyclosporin was the only independent predictor for colectomy (hazard ratio = 4.41; 95% confidence interval 1.75-1.13).. About one-tenth of patients still require colectomy for UC at 5 years in the era of biologics. Oral 5-ASA, azathioprine, and anti-TNF therapy are not associated with a reduced need for colectomy.

Topics: Adult; Colectomy; Colitis, Ulcerative; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Mesalamine; Prognosis; Prospective Studies; Referral and Consultation; Tumor Necrosis Factor-alpha; Young Adult

Thiopurine therapy effectively maintains remission in inflammatory bowel disease. However, many patients are unable to achieve optimum benefits from azathioprine or 6-mercaptopurine because of undesirable metabolism related to high thiopurine methyltransferase (TPMT) activity characterized by hepatic transaminitis secondary to increased 6-methylmercaptopurine (6-MMP) production and reduced levels of therapeutic 6-thioguanine nucleotide (6-TGN). Allopurinol can optimize this skewed metabolism. We discuss two brothers who were both diagnosed with ulcerative colitis (UC). Their disease remained active despite oral and topical mesalamines. Steroids followed by 6-mercaptopurine (MP) were unsuccessfully introduced for both patients and both were found to have high 6-MMP and low 6-TGN levels, despite normal TMPT enzyme activity, accompanied by transaminitis. Allopurinol was introduced in combination with MP dose reduction. For both brothers addition of allopurinol was associated with successful remission and optimized MP metabolites. These siblings with active UC illustrate that skewed thiopurine metabolism may occur despite normal TPMT enzyme activity and can lead to adverse events in the absence of disease control. We confirm previous data showing that addition of allopurinol can reverse this skewed metabolism, and reduce both hepatotoxicity and disease activity, but we now also introduce the concept of a family history of preferential MP metabolism as a clue to effective management for other family members.

Topics: Allopurinol; Antimetabolites; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guanine Nucleotides; Humans; Liver; Male; Mercaptopurine; Methyltransferases; Steroids; Thionucleotides; Treatment Outcome; 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

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

A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family-based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls.. In total, 89 patients with UC in remission, 35 first-degree relatives (UC-R), 24 nonrelated spouses (UC-NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar-drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment.. Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC-R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC-NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left-sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005).. An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined.

Topics: Adult; Azathioprine; Case-Control Studies; Colitis, Ulcerative; Colon; Female; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Intestinal Absorption; Intestine, Small; Male; Mercaptopurine; Permeability; Proctitis; Remission Induction; Risk Factors; Spouses; Sucrose; Tissue Distribution

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

Topics: Anecdotes as Topic; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colitis, Ulcerative; Diagnostic Errors; Disease Progression; Female; Gastrointestinal Hemorrhage; Hospitalization; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Patient Acceptance of Health Care; Recurrence; Shame; Students; Treatment Outcome; Young Adult

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

Colectomy rates for ulcerative colitis (UC) have been inconsistently reported. We assessed temporal trends of colectomy rates for UC, stratified by emergent vs. elective colectomy indication.. From 1997 to 2009, we identified adults hospitalized for a flare of UC. Medical charts were reviewed. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. Logistic regression analysis compared: (i) UC patients responding to medical management in hospital to those who underwent colectomy; (ii) UC patients who underwent an emergent vs. elective colectomy; and (iii) temporal trends of drug utilization.. From 1997 to 2009, colectomy rates significantly dropped for elective colectomies with an AAPC of -7.4% (95% confidence interval (CI): -10.8%, -3.9%). The rate of emergent colectomies remained stable with an AAPC of -1.4% (95% CI: -4.8%, 2.0%). Azathioprine/6-mercaptopurine prescriptions increased from 1997 to 2009 (odds ratio (OR)=1.15; 95% CI: 1.09-1.22) and infliximab use increased after 2005 (OR=1.68; 95% CI: 1.25-2.26). A 13% per year risk adjusted reduction in the odds of colectomy (OR=0.87; 95% CI: 0.83-0.92) was observed in UC patients responding to medical management compared with those who required colectomy. Emergent colectomy patients had a shorter duration of flare (<2 weeks vs. 2-8 weeks, OR=5.31; 95% CI: 1.58-17.81) and underwent colectomy early after diagnosis (<1 year vs. 1-3 years, OR=5.48; 95% CI: 2.18-13.79).. From 1997 to 2009, use of purine anti-metabolites increased and elective colectomy rates in UC patients decreased significantly. In contrast, emergent colectomy rates were stable, which may have been due to rapid progression of disease activity.

Topics: Adult; Aged; Alberta; Azathioprine; Colectomy; Colitis, Ulcerative; Drug Prescriptions; Elective Surgical Procedures; Emergency Treatment; Female; Humans; Immunosuppressive Agents; Linear Models; Logistic Models; Male; Medical Records; Mercaptopurine; Middle Aged; Odds Ratio; Retrospective Studies; Time Factors

Several drugs are currently available to maintain remission in patients who have responded after one or other type of induction therapy, depending on the initial severity of the outbreak. Salicylates are the drugs of choice to maintain remission after a mild-to-moderate outbreak controlled by salicylates or oral corticosteroids. To maintain remission after a severe outbreak or in patients with corticosteroid dependence or resistance, thiopurines are the drugs of choice. In patients who have failed to respond to thiopurines and in those with thiopurine intolerance, biological agents, mainly infliximab, can be used to maintain remission in patients after induction therapy with infliximab for a severe outbreak. However, these scenarios may not reflect reality of gastroenterologists' daily clinical practice. Treatment will therefore be based on the patient's individual characteristics (age, clinical course, previous treatment, adverse effects and personal preferences) as well as the physician's medical art.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Disease Management; Disease Progression; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Patient Preference; Practice Patterns, Physicians'; Salicylates; Tumor Necrosis Factor-alpha

Cyclosporine (CSA) is effective in the short-term for severe, steroid refractory ulcerative colitis; but its use has been limited by concerns about safety and colectomy-sparing rates. The aim of this study was to assess the long-term colectomy-sparing effects and safety of CSA in patients hospitalized for ulcerative colitis.. Review of the patients who underwent intravenous CSA for ulcerative colitis between 1989 and 2003.. A total of 71 patients with severe ulcerative colitis were treated with IV CSA. The median length of follow-up was 1.5 years (mean=3 y) (range 1 mo to 14 y) (IQR 0.6 to 4.6). Eighty-five percent (60/71) of patients responded to IV CSA and were discharged on oral CSA. Of these 60 patients, 26 were transitioned from CSA to 6MP. Of the 26 patients who were transitioned from CSA to 6MP, only 1 patient (4%) ultimately required colectomy; whereas colectomy was carried out in 76% (26/34) of the patients who were not transitioned from CSA to 6MP. Only concomitant 6MP therapy was associated with a reduced risk of colectomy (OR 0.01, 95% CI 0.001, 0.09, P<0.0001) on long-term follow-up in this group. Cumulative colectomy rates for the entire cohort were 39% (28/71) at 1 year, 42% (30/71) at 2 years, and 46% (33/71) at 5 years. Side effects were noted in two-thirds of the patients, the majority of which were mild.. CSA is an effective therapy for severe ulcerative colitis. Long-term efficacy is improved with transition to 6MP. Adverse events with CSA are frequent, but most are mild.

Topics: Adult; Colectomy; Colitis, Ulcerative; Cyclosporine; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Length of Stay; Male; Mercaptopurine; Middle Aged; Severity of Illness Index; Time Factors; Treatment Outcome

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

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

Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC.. Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy).. Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan-Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year.. Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Child; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Treatment Outcome

Topics: Acute Disease; Adolescent; Adult; Aged; Antibodies, Monoclonal; Colectomy; Colitis, Ulcerative; Cyclosporine; Drug Therapy, Combination; Female; Hospitalization; Humans; Immunosuppressive Agents; Infliximab; Length of Stay; Male; Mercaptopurine; Middle Aged; Salvage Therapy; Severity of Illness Index; Time Factors; 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

Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Middle Aged; Muscle Weakness

Topics: Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Tacrolimus

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

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

Mucosal healing (MH) has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Currently little is known about the efficacy of using thiopurine immunosuppressants in monotherapy to achieve and maintain long-term MH in UC. This study analyzes the efficacy and the clinical impact of MH in patients with UC responded to thiopurine immunosuppressants in the long term.. An open, observational, cohort study in 20 patients with UC had been in clinical remission in monotherapy with thiopurine immunosuppressants for at least 1 year. MH was assessed by endoscopy. The patients according to the Mayo Endoscopic Score (0 vs 1 and 2), were followed until the end of the study or patient relapse. (according to Truelove and Witts criteria).. Mean treatment time was 5.4 years. Twelve (60%) patients presented a Mayo Endoscopic Score of 0. A total of 18 patients were followed up for a median of 27.1 months. After endoscopy, 4 patients (22.2%) presented relapse, with a mean time of 27.5 months for a score ≥1 (95% CI; 18.2-36.8) versus 54.3 months for a score=0 (95% CI 47.2-61.3) (p=0.032).. This study shows the efficacy of thiopurine immunosuppressants in achieving mucosal healing in patients who respond to thiopurine immunosuppressants in the long term. We also observe the presence of endoscopy activity is not a rare event in this group of patients and is a predictor of early relapse.

Topics: Adolescent; Adult; Azathioprine; Cohort Studies; Colitis, Ulcerative; Colonoscopy; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Mercaptopurine; Middle Aged; Predictive Value of Tests; Treatment Outcome; Wound Healing; Young Adult

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

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

Topics: Acute Disease; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Prednisolone; Treatment Outcome

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

A case of hemophagocytic syndrome associated with ulcerative colitis is very rare. A 32-year-old man visited the hospital complaining of fever and severe abdominal pain for 7 days. He was diagnosed to have ulcerative colitis 2 years ago and had been treated with sulfasalazine. Three months ago, he had abdominal pain, weight loss, and hematochezia, so prednisolone and mercaptopurine were added to the treatment. On admission, the physical examination showed splenomegaly. Peripheral blood counts revealed pancytopenia, and bone marrow aspirate smears showed many histiocytes with active hemophagocytosis. There was no evidence of viral and bacterial infections and other neoplasms, which were commonly associated with hemophagocytic syndrome. He was successfully treated with high dose steroid. We report this case along with a review of the related literatures.

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow Cells; Colitis, Ulcerative; Colonoscopy; Dexamethasone; Humans; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Prednisolone; Sulfasalazine; Syndrome; Tomography, X-Ray Computed

The inverse correlation of appendectomy and ulcerative colitis is well known, but the effect of appendectomy on the clinical course of ulcerative colitis remains unclear. Although the majority of opinions were negative for the therapeutic advantage of appendectomy in patients with ulcerative colitis, advocates for positive effect of appendectomy have been proposed in a few case reports and a prospective study from Western countries. We herein report a case of ulcerative colitis who experienced clinical remission after appendectomy for acute appendicitis. The patient was 35 year old male and had been managed with immunosuppressant before appendectomy. The very acute change in clinical course and a long period of remission after appendectomy highly suggest the therapeutic effect of appendectomy for ulcerative colitis.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Appendectomy; Colitis, Ulcerative; Colonoscopy; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Tomography, X-Ray Computed; Treatment Outcome

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

A European consensus on the management of ulcerative colitis (UC) was recently published; however, there is no adequate evidence about adherence to such guidelines among gastroenterologists. This knowledge would allow the local evaluation of the situation and the adoption of actions to reduce the existent clinical variability.. A cross-sectional survey was conducted in Spain to assess the adherence to the European Crohn's and Colitis Organisation (ECCO) guidelines on mild to moderate UC. We surveyed 700 gastroenterologists, and finally a total of 530 gastroenterologists specialised in inflammatory bowel disease (GSIBDs) and general gastroenterologists (GGs), responded to the survey (76%).. Agreement with the guidelines was high; discrepancies included that only 25% of the GGs used the combination of oral and topical 5-aminosalycilic acid (5-ASA) for treating extensive UC vs 45% of the GISBDs. In addition, topical rectal steroids were considered as effective as topical mesalazine by 48% of the GGs vs 31% of the GSIBDs, indefinite treatment with 5-ASA was prescribed by only 26% of the GGs vs 41% of the GSIBDs, and the once daily dosing of 5-ASA was generally used by 46% of the GGs vs 51% of the GSIBDs.. The questionnaire showed a high degree of agreement between GGs and GSIBDs. Nevertheless, the GSIBD group showed closer agreement with the ECCO guidelines. Furthermore, some shortcomings were found in the GG group, in which increased maintenance treatment with 5-ASA, the use of a single daily dose of 5-ASA, and the use of combined oral and topical treatment for distal colitis should be advised.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Colitis, Ulcerative; Cross-Sectional Studies; Europe; Gastroenterology; Guideline Adherence; Humans; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Practice Guidelines as Topic; Practice Patterns, Physicians'; Spain; Surveys and Questionnaires

Azathioprine (AZA) and mercaptopurine (6-MP) are established as effective therapeutic drugs for the induction and maintenance of remission in patients with ulcerative colitis (UC). However, AZA is often intolerable due to adverse effects. Evidence regarding the approach of switching from AZA to 6-MP in patients of Asian ethnicity is lacking. We assessed the tolerability and usefulness of 6-MP in Japanese UC patients who had shown intolerance to AZA.. One-hundred and ten UC patients who had been treated with AZA and/or 6-MP from January 1985 to October 2008 were examined retrospectively.. Among 110 patients, 107 were treated first with AZA; only three were treated first with 6-MP. Thirty-five (33%) of the 107 patients were intolerant of AZA, with adverse effects including myelosuppression (8/35, 23%), hepatotoxicity (8/35, 23%), and abdominal symptoms (6/35, 17%). Among 35 AZA-intolerant patients, 23 were switched to 6-MP treatment. The cumulative probability of colectomy was significantly higher in patients not treated with 6-MP than in patients treated with 6-MP (log-rank test, P =0.0002). Among the 26 patients (23 AZA-intolerant and three AZA-untreated) treated with 6-MP, 22 (85%) could tolerate the therapy. Adverse effects due to 6-MP were abdominal symptoms (2/4), myelosuppression (1/4), and rash (1/4). The median initial dose of 6-MP was 20 mg/day, and the median final dose was 30 mg/day..  6-MP was tolerated in 83% of AZA-intolerant patients, and it was effective for maintenance therapy of UC patients. 6-MP treatment should be considered in AZA-intolerant patients.

Topics: Adolescent; Adult; Aged; Azathioprine; Chi-Square Distribution; Colitis, Ulcerative; Drug Tolerance; Female; Humans; Immunosuppressive Agents; Japan; Male; Mercaptopurine; Middle Aged; Statistics, Nonparametric; Treatment Outcome

Topics: Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Influenza A virus; Influenza Vaccines; Influenza, Human; Mercaptopurine; Middle Aged; Vaccination

A total of 254 senior consultant gastroenterologists with valid e-mail addresses were identified from the membership list of the British Society of Gastroenterology (BSG) 2007.. They were sent by e-mail a questionnaire which dealt with aspects of clinical practice and addressed cancer prevention in ulcerative colitis (UC). Replies were received from 97 clinicians (38% response rate).. Ninety-one (94%) advised patients with established UC to take 5-aminosalicylate (5-ASA) compounds for life. Seventy-two of the 91 (79%) clinicians co-prescribed 5-ASA compounds with immune modulators for patients with UC. Only 3 clinicians advised patients to take folic acid as a daily supplement. A median of 20% (interquartile range 10%-50%) of their patients with UC were co-prescribed a 5-ASA compound and azathioprine or 6-mercaptopurine. Of these, a median of 3.5% (interquartile 1%-5%) developed neutropenia.. Future research needs to be directed at the long-term maintenance treatment and to address questions about which drugs should be used, in what combinations, and with what frequencies.

Topics: Adult; Colitis, Ulcerative; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Middle Aged; Practice Patterns, Physicians'; Treatment Outcome

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: 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

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

P-glycoprotein (P-gp), encoded by MDR-1, is a transmembrane efflux pump that has been involved in relevant clinical drug transport. It is expressed in lymphocytes, luminal epithelium of colon and other tissues with barrier function. MDR1 was proposed as a candidate gene for ulcerative colitis. The aim of the present work was to investigate the role of P-gp in therapeutic response of ulcerative colitis by studying its functionality in lymphocytes isolated from peripheral blood. Samples were taken from 27 patients with active colitis classified clinically in refractory (n = 16) and responders (n = 11) to treatment. Rhodamine 123 (a fluorescent P-glycoprotein substrate) efflux was studied by flow cytometry as absence and presence of an inhibitor (verapamil, 100 uM). Data were expressed evaluating the behaviour of two markers defined based on % of cells with maximum (M1)/minimum (M2) intracellular fluorescence, reflecting inactivity/activity of the pump. Results were compared with a group of healthy individuals (n = 68). Significant differences were observed in absence and presence of Verapamil inhibition, when comparing refractory vs. responders (p < 0.05) as well as refractory vs. healthy controls (p < 0.01). No differences were observed when comparing responders vs. controls (p > 0.05) (Kruskal-Wallis test and Dunn post-test). Rhodamine efflux assay was also performed in 12 patients who required therapeutic change; a significant diminish of rhodamine transport (p < 0.01) was observed without inhibitor when patients achieved clinical response. Finally, our results suggest a possible relevant role of P-gp in ulcerative colitis treatment response and a possible usefulness of P-gp functional assay in the early detection of individual therapeutic response.

Topics: Adult; Antibodies, Monoclonal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Case-Control Studies; Colitis, Ulcerative; Female; Flow Cytometry; Humans; Immunosuppressive Agents; Infliximab; Lymphocytes; Male; Mercaptopurine; Multidrug Resistance-Associated Proteins; Rhodamine 123; Verapamil

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

Some patients with ulcerative colitis (UC) require immunosuppressants as maintenance therapy.. To assess epidemiological, clinical and disease factors at diagnosis that predict immunosuppressant use in UC.. All UC patients diagnosed between 1992 and 2005 and currently managed in the inflammatory bowel disease (IBD) clinic were included. Forty-three patients who currently or previously received azathioprine (AZA) or mercaptopurine (MP) for UC were compared with 130 controls. Charts were reviewed and logistic regression analyses were applied to identify factors associated with AZA or MP use.. In univariate model, seven factors at diagnosis correlated with AZA use: male gender [odds ratio (OR) 2.2]; left-sided or extensive colitis or pancolitis (OR 8.7-14.1); systemic steroid use within the first 6 months of diagnosis (OR 5.1); more than 10 bowel movements daily (OR 6.4); persistent or mostly blood in stool (OR 2.8); endoscopic proven moderate to severe disease (OR 7.2-12.0) and requirement of hospitalization (OR 2.7) on diagnosis. In multivariate model, the first three factors were shown to be statistically significant.. Male gender, initial presentation with severe and extensive disease clinically and endoscopically, requirement of hospitalization on diagnosis or systemic steroids within 6 months of diagnosis are predictive factors for immunosuppressant use in UC.

Topics: Adult; Antimetabolites; Azathioprine; Case-Control Studies; Chronic Disease; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Predictive Value of Tests; Risk Assessment; Severity of Illness Index; Sex Factors; Treatment Outcome

Azathioprine (AZA) and 6-mercaptopurine (6-MP) have recently been used in Japanese pediatric patients with ulcerative colitis. The aims of this study were to evaluate both the therapeutic efficacy and safety of AZA/6-MP in this group of patients.. Fourteen members of the Japanese Society for Pediatric Inflammatory Bowel Disease reported 35 retrospective cases that received AZA/6-MP and were evaluated for adverse drug effects. In those who tolerated AZA/6-MP, disease activity and corticosteroid doses before and during the first 6 months of therapy were assessed.. AZA or 6-MP was safely used in 21 of 35 patients (60%) without adverse drug effects. The disease activity began to decrease from the first month of therapy and the maximum effect was achieved after 3 months. The mean daily prednisolone dose was decreased from 26.9 to 11.6 mg and dose reduction was achieved in 58% of patients after 6 months of therapy. Fourteen of the 35 patients (40%) experienced adverse drug effects, including leukopenia (n = 11), aplastic anemia (n = 1), pancreatitis (n = 1) and liver dysfunction (n = 1).. The majority of Japanese children with ulcerative colitis tolerated AZA/6-MP and experienced favorable effects. However, 40% experienced adverse drug effects, mainly myelosuppression.

Topics: Adolescent; Algorithms; Azathioprine; Child; Colitis, Ulcerative; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Japan; Leukopenia; Male; Mercaptopurine; Prednisolone; Retrospective Studies

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: 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

Human papilloma virus (HPV) has been found to be a precursor and risk factor for both cervical and anal dysplasia. Cervical dysplasia, which is the precursor to carcinoma, is associated with immunosuppression from a variety of causes; reports of anal dysplasia associated with immune suppression exist as well. A recent study published in abstract form only demonstrated that women with inflammatory bowel disease (IBD) had high rates of cervical dysplasia and that those on immune suppressants had even higher rates of dysplasia. We report a case of a 50-year-old woman with refractory ulcerative colitis chronically treated with 6-mercaptopurine that developed severe squamous dysplasia of the rectum. The dysplastic mucosa was found to be positive for p16 (associated with high-risk HPV) after immunostaining. A total colectomy was performed. This case highlights the importance of immune suppression in the development of dysplasia of the anus/cervix secondary to HPV infection.

Topics: Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged; Neoplasms, Squamous Cell; Papillomaviridae; Rectal Neoplasms

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

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

A 44-year-old women developed marked myopathy one year earlier, when she was treated with intravenous prednisolone for acute severe exacerbation of ulcerative colitis. When she was admitted to our hospital for another severe exacerbation, intravenous cyclosporine A was administered as monotherapy because she could not tolerate corticosteroid. The treatment was successful and she obtained complete remission. Cyclosporine A monotherapy is considered to be a valuable alternative to proctocolectomy for severe ulcerative colitis patients who cannot tolerate corticosteroid.

Topics: Adult; Colitis, Ulcerative; Cyclosporine; Female; Humans; Immunosuppressive Agents; Infusions, Intravenous; Mercaptopurine; Prednisolone; Treatment Outcome

The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA)/mercaptopurine (MP)-induced liver injury in a long-term follow-up study.. All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin were periodically monitored. "Abnormality-of-LTs" was defined as LTs between N (upper limit of the normal range) and 2 N, and "liver injury/hepatotoxicity" as LTs>2 N.. A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow-up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP-treated patients (690 patient-years follow-up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient-year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs>5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs.. In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine-induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only approximately 4% of the patients.

Topics: Adult; Algorithms; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Liver; Male; Mercaptopurine; Middle Aged; Time Factors

Topics: Adult; Algorithms; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Colonic Pouches; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Practice Guidelines as Topic; Proctocolectomy, Restorative; Tumor Necrosis Factor-alpha

To alert clinicians to a potential novel adverse drug effect of interferon beta 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferon beta 1a. Ulcerative colitis persisted despite discontinuation of interferon beta 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.

Topics: Adjuvants, Immunologic; Adult; Colitis, Ulcerative; Female; Glatiramer Acetate; Humans; Immunity, Innate; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Mercaptopurine; Multiple Sclerosis; Peptides; Prednisolone; Recurrence; Tacrolimus

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

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

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

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Infliximab; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Azathioprine; Colitis, Ulcerative; Colorectal Neoplasms; Humans; Mercaptopurine; Mesalamine

The risk of lymphoma in inflammatory bowel disease (IBD) has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. The link between immunosuppressive therapy and lymphoma risk is well established in patients with solid organ transplantations. In this population, it is postulated that lymphocytes infected with the Epstein-Barr virus (EBV) proliferate unchecked due to impaired cell-mediated immunity. A similar phenomenon may occur in IBD patients treated with multiple immunomodulators and biological agents. In this report, we describe a case of EBV-positive non-Hodgkin's lymphoma arising in the ileal pouch of a patient with ulcerative colitis. This patient was maintained on prednisone (>20 mg/day) for 8 months, cyclosporine for 7 months, and 6-mercaptopurine for nearly 2 years prior to a single infusion of infliximab (5 mg/kg). The cumulative effects of more than three agents, simultaneously and/or sequentially, may simulate posttransplantation immunosuppression and pose a significant threat of malignancy. Such patients may warrant more aggressive diagnostic surveillance and evaluation.

Topics: Adult; Anastomosis, Surgical; Antineoplastic Combined Chemotherapy Protocols; Colitis, Ulcerative; Colonic Pouches; Cyclosporine; Glucocorticoids; Humans; Ileum; Immunosuppressive Agents; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Mercaptopurine; Prednisone

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

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

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

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

In a 64-year-old man who had been treated with prednisolone (PSL) and 6-mercaptopurine (6MP) for a long period, for ulcerative colitis (UC), hepatocellular carcinoma (HCC) was detected incidentally. The UC was in remission with these medications. After he had been taking these medications for about 8 years, HCC was detected by computed tomography (CT), done for the evaluation of an other disease. Blood chemistry examination results were normal, except that the protein induced by vitamin K antagonist (PIVKA)-II level was 7940 AU/ml. We performed resection of liver segment V. With comparative genomic hybridization, chromosomal aberrations were recognized; these were gains of 1q, 3ptel-21, 8p12, and 22q11.23-22q13.1. Generally, HCC is associated with hepatitis virus infection in most cases, but in this patient, the HCC was not related to hepatitis C virus (HCV) or HBV. It is presumed that this case was related to the immunosuppressive therapy for UC and was associated with the gains of 1q, 3p, and 8p.

Topics: Carcinoma, Hepatocellular; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 8; Colitis, Ulcerative; Gene Amplification; Humans; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Karyotyping; Liver Neoplasms; Male; Mercaptopurine; Middle Aged; Nucleic Acid Hybridization; Tomography, X-Ray Computed

Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC.. Patients with UC who underwent a surveillance colonoscopy in 1996-1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC).. A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59-1.93) and 1.30 (95% confidence interval, .45-3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders.. In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC.

Topics: Adult; Azathioprine; Cell Transformation, Neoplastic; Colitis, Ulcerative; Colorectal Neoplasms; Disease Progression; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Proportional Hazards Models

Topics: Azathioprine; Chronic Disease; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Mercaptopurine; Patient Selection; Time Factors

6-mercaptopurine has proven to be effective in the treatment and maintenance of remission of ulcerative colitis (UC). The optimal duration of treatment with 6-MP is unknown. The intention of this study was to determine the best duration of treatment with 6-MP in terms of maintenance efficacy once remission has been achieved.. We reviewed the records from the inflammatory bowel disease (IBD) center at Lenox Hill Hospital and one large IBD practice in New York City of 334 patients treated with 6-MP for UC. These patients were followed from 4 months to 28.7 yr. Sixty-one patients were treated with 6-MP for at least 6 months and had at least a 3-month disease-free interval off steroids while on the medication. These patients were divided into two groups: Group 1 continued 6-MP and group 2 discontinued the drug at various times for reasons other than relapse. Time to relapse was calculated for both groups.. A Kaplan-Meier survival analysis was employed and differences between the two groups were analyzed using the log-rank test. The median time to relapse in group 2 was 24 wk and in group 1 was 58 wk (p < 0.05). There were no significant differences between the two groups in age, gender, extent of disease, use of concomitant 5-ASA products, dose of 6-MP during remission, duration of UC, and duration of treatment with 6-MP before remission was achieved.. Discontinuation of treatment with 6-MP while UC is in remission leads to a higher relapse rate than maintenance on 6-MP. Therefore, we favor the indefinite treatment with 6-MP in most patients.

Topics: Adult; Aged; Aged, 80 and over; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Recurrence; 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

The efficacy of azathioprine in the management of steroid-dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid-dependent and refractory patients.. To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid-dependent ulcerative colitis.. Survey of 34 patients with steroid-dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year.. Mean age was 39.1 +/- 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52-84%) and 72.7%, as per protocol (confidence interval 95%: 54-86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated.. Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid-dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prospective Studies; 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: Administration, Oral; Adult; Age Factors; Anti-Infective Agents; Azathioprine; Child; Chronic Disease; Ciprofloxacin; Colectomy; Colitis, Ulcerative; Controlled Clinical Trials as Topic; Diabetes Mellitus; Diagnosis, Differential; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Mercaptopurine; Methotrexate; Nutritional Physiological Phenomena; Pregnancy; Recurrence; Remission Induction; Risk Factors; Time Factors

Topics: Administration, Oral; Administration, Rectal; Aminosalicylic Acids; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Azathioprine; Colitis, Ulcerative; Colorectal Neoplasms; Controlled Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Meta-Analysis as Topic; Patient Selection; Placebos; Proctitis; Remission Induction; Suppositories; Time Factors

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

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: Azathioprine; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Infusions, Intravenous; Mercaptopurine; Randomized Controlled Trials as Topic; Treatment Outcome

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

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

Topics: Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Polymorphism, Single Nucleotide

To determine whether the use of azathioprine/6-mercaptopurine before colectomy is associated with an increased rate of postoperative complications.. All patients who underwent colectomy with ileal pouch-anal anastomosis for ulcerative colitis between 1997 and 1999 were identified. Medical records were abstracted for demographics, extent and duration of disease, dose and duration of corticosteroids and azathioprine/6-mercaptopurine, albumin, and Truelove/Witts score. Early (30-day) and late (6-month) complications were identified. Noncorticosteroid immunosuppressive use was coded as none, azathioprine/6-mercaptopurine within 1 week of surgery, or therapy with other immunosuppressive agents within 1 month of surgery. A logistic regression analysis assessed the association between these variables and complications.. Early complications occurred in 49 of 151 (32%) patients not treated with immunosuppressive agents, 12 of 46 (26%) azathioprine/6-mercaptopurine-treated patients, and 4 of 12 (33%) patients treated with other immunosuppressive agents (p = 0.71). Late complications occurred in 72 of 148 (49%), 20 of 46 (43%), and 8 of 12 (67%) patients in these same groups, respectively. Intravenous or oral steroids at doses of 40 mg/d or greater (p < 0.01) and severe or fulminant disease (p = 0.0094) were associated with greater early complication rates.. Early complications after restorative proctocolectomy for ulcerative colitis are associated with high dose steroids and severe disease but not use of azathioprine/6-mercaptopurine.

Topics: Adolescent; Adult; Aged; Anal Canal; Anastomosis, Surgical; Azathioprine; Child; Colitis, Ulcerative; Colonic Pouches; Female; Humans; Ileum; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Postoperative Complications; Preoperative Care; Proctocolectomy, Restorative; Retrospective Studies; Risk Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Secondary Prevention; Sulfasalazine

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

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 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

Topics: Child; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine

The effectiveness of 6-mercaptopurine combined with azathioprine in treating severe ulcerative colitis has been shown in several adult studies. Reported pediatric experiences are rare. The purpose of this study was to investigate the safety and the potential efficacy of 6-mercaptopurine and azathioprine in the treatment of active ulcerative colitis in a pediatric population.. The medical records of patients with active ulcerative colitis who were under observation at The Children's Hospital of Philadelphia and its satellite clinics from January 1984 through December 1997 were retrospectively reviewed. Patients were included who had received a diagnosis of ulcerative colitis, who met no criteria for Crohn's colitis, and who had received treatment with 6-mercaptopurine and azathioprine. They were then analyzed for the development of side effects, the indication to use 6-mercaptopurine and azathioprine, and the ability to discontinue corticosteroid use in those patients taking 5-acetylsalicylic acid products who were corticosteroid-dependent or whose disease was refractory to treatment. Excluded from the corticosteroid analyses were patients who underwent surgery for their disease and patients treated with 5-acetylsalicylic acid only. Statistical analysis was performed by the Kaplan-Meier survival curve and paired Student's t-test.. In a review of 200 medical records of patients with active ulcerative colitis, 20 patients met the criteria. The patients' average age at the initiation of treatment with 6-mercaptopurine and azathioprine was 13.8 years. Sixteen patients (80%) were corticosteroid dependent and 3 (15%) had ulcerative colitis refractory to corticosteroid treatment. One patient had severe colitis treated with 5-acetylsalicylic acid only. Discontinuation of corticosteroid was accomplished in 12 (75%) of 16 patients. The median time to discontinuation of corticosteroid after initiation of 6-mercaptopurine and azathioprine therapy was 8.4 months. Eight patients (67%), observed from 3 months to 65 months, have continued without corticosteroid therapy. Side effects included pancreatitis and shingles that resulted in discontinuation of 5-acetylsalicylic acid, leukopenia corrected by withholding 6-mercaptopurine, and self-resolved hepatitis.. The data support the safety of 6-mercaptopurine and azathioprine use in the treatment of pediatric patients with ulcerative colitis; side effects were minimal and reversible. Eighteen (90%) of 20 patients tolerated the therapy well. The results also show that 12 (75%) of 16 pediatric patients with ulcerative colitis will benefit from the use of 6-mercaptopurine and azathioprine after initial discontinuation of corticosteroid therapy. Although 6-mercaptopurine and azathioprine may not prevent further relapses, medical management of these flares may be less intense and may not require long-term corticosteroid use. Prospective clinical trials in pediatric patients are necessary to delineate further the role of 6-mercaptopurine and azathioprine in pediatric ulcerative colitis.

Topics: Adolescent; Azathioprine; Child; Colitis, Ulcerative; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Retrospective Studies; Treatment Outcome

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

Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago's 5-yr CSA experience in these patients.. All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university's IBD database, with additional information from patient charts and physician files.. A total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of "noncolectomy survival" of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery.. CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for "elective" colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

Topics: Adolescent; Adult; Aged; Azathioprine; Child; Colectomy; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Longitudinal Studies; Male; Mercaptopurine; Middle Aged; Retreatment; Steroids; Treatment Outcome

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

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

A 68-yr-old man with steroid refractory distal ulcerative colitis was treated with low-dose 6-mercaptopurine, and corticosteroids were successfully discontinued. He later presented with dyspnea and fever, was diagnosed with Pneumocystis carinii pneumonia by bronchoalveolar lavage, and died despite aggressive therapy. Serological tests for HIV were negative, and his white blood cell count was normal. This is the first report of P. carinii pneumonia complicating therapy of inflammatory bowel disease with 6-mercaptopurine. Although the mechanism is not entirely clear, 6-mercaptopurine appears to decrease cell-mediated immunity. Opportunistic infections such as P. carinii pneumonia should be added to the list of potential bronchopulmonary complications of antimetabolite immunosuppressive therapy of inflammatory bowel disease.

Topics: Aged; Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Betamethasone; Bronchoalveolar Lavage Fluid; Colitis, Ulcerative; Fatal Outcome; Glucocorticoids; HIV Seronegativity; Humans; Immunity, Cellular; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Opportunistic Infections; Pneumonia, Pneumocystis; Prednisolone; Sulfasalazine

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

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

Topics: Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Mercaptopurine; Mesalamine; Steroids; Time Factors

To determine the long term outcome of ulcerative colitis in patients treated with 6-MP.. The charts of 105 chronic refractory ulcerative colitis patients treated with 6-MP from 1973-1992 were reviewed. The focus was placed on clinical response, subsequent breakthrough while maintaining 6-MP, and relapse rates when 6-MP was discontinued.. Complete clinical remission was achieved in 68 patients (65%), partial remission was achieved in 25 patients (24%), and 12 patients (11%) failed to achieve remission. Of complete responders who continued 6-MP, 35% had a breakthrough, although complete remission was restored in 88% with the majority not requiring systemic steroids. Of complete responders who discontinued 6-MP, 87% subsequently relapsed. There were few major toxicities associated with 6-MP use.. 6-MP is a reasonably safe and effective treatment for refractory ulcerative colitis. Patients who discontinue 6-MP after successful treatment have high relapse rates, therefore, 6-MP must be maintained long term to sustain remission.

Topics: Adult; Aminosalicylic Acids; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Colitis, Ulcerative; Female; Humans; Life Tables; Male; Mercaptopurine; Mesalamine; Prednisone; Recurrence; Remission Induction; Time Factors; Treatment Outcome

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

After failure of medical therapy, children with refractory inflammatory bowel disease may require surgical intervention. In this article the authors describe one child in whom, after traditional therapies for refractory ulcerative colitis failed, full remission of the disease occurred after the addition of 6-mercaptopurine and cyclosporine A to her medical regimen. 6-Mercaptopurine has been used with increasing frequency in refractory inflammatory bowel disease; the use of cyclosporine A for this condition is still under investigation.

Topics: Child; Colitis, Ulcerative; Combined Modality Therapy; Cyclosporine; Drug Therapy, Combination; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methylprednisolone; Parenteral Nutrition, Total; Sulfasalazine

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 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

We report our observations over 18 years (1970-1988) on 81 compliant patients with resistant ulcerative colitis who received 91 courses of treatment with 6-mercaptopurine (6-MP) for at least 4 months. These represent 172 patient years of 6-MP therapy and 308 years of observation after initiating 6-MP. In all patients, treatment with sulfasalazine and steroids had failed; most (96%) were dependent on systemic steroids and still symptomatic. The mean treatment period with 6-MP was 1.8 yr. In 42 out of 87 courses (48%) of 6-MP steroids could be eliminated, and in another 11 (13%) could be significantly reduced, for a total response rate of 61%. When four patients not on steroids were included, the response rate was 63%. The steroids were discontinued after a mean treatment time of 10 wk, and the 42 patients remained steroid free for the remainder of 6-MP treatment. Follow-up data after discontinuing 6-MP in 29 patients from this group show the mean time to relapse was 21 months with a median time of 12.5 months. We conclude that 6-MP is effective in inducing remission, eliminating steroids, and maintaining remission in many patients with refractory ulcerative colitis. Patients should be made aware of this option before colectomy is recommended.

Topics: Adrenocorticotropic Hormone; Adult; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Male; Mercaptopurine; Prednisone; Recurrence; Remission Induction; Sulfasalazine; Time Factors

Topics: Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pregnancy; Pregnancy Complications; Radiography

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: 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

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: Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine

Topics: Adrenocorticotropic Hormone; Colitis, Ulcerative; Crohn Disease; Diet; Humans; Immunosuppressive Agents; Mercaptopurine; Parenteral Nutrition, Total; Sulfasalazine

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: Biopsy; Cell Count; Colitis, Ulcerative; Connective Tissue; Connective Tissue Cells; Drug Therapy, Combination; Epithelial Cells; Epithelium; Humans; Intestinal Mucosa; Mercaptopurine; Prednisone; Rectum; Sulfasalazine

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

The radiographic and endoscopic features of the colonic ulcers during the course of a case of systemic lupus erythematosus are illustrated. Barium enema revealed the "collar button" type of penetrating ulcers in the left half of the colon and endoscopy demonstrated multiple round- or oval-shaped discrete ulcers, so-called "punched-out" ulcers with pale mucosa. These findings are compared with those of the reported cases of systemic lupus erythematosus and ulcerative colitis. Steroid and 6-mercaptopurine therapy was effective in this case.

Topics: Adult; Colitis, Ulcerative; Colonic Diseases; Diagnosis, Differential; Endoscopy; Female; Humans; Lupus Erythematosus, Systemic; Mercaptopurine; Prednisolone; Radiography; Ulcer

Topics: Adrenocorticotropic Hormone; Atropine; Azathioprine; Colitis, Ulcerative; Crohn Disease; Diarrhea; Diet; Glucocorticoids; Humans; Immunosuppressive Agents; Mercaptopurine; Nutrition Disorders; Pain; Prednisolone; Prednisone; Sulfasalazine

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Child; Child, Preschool; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Leukopenia; Male; Mercaptopurine; Nausea; Prednisone; Radiography; Recurrence; Sulfasalazine; Time Factors; Vomiting

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Child; Child, Preschool; Colitis, Ulcerative; Female; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Nausea; Recurrence; Sigmoidoscopy; Sulfasalazine; Time Factors

Topics: Adult; Autoimmune Diseases; Azathioprine; Colitis, Ulcerative; Crohn Disease; Evaluation Studies as Topic; Humans; Immunosuppressive Agents; Male; Mercaptopurine

Topics: Autoimmune Diseases; Azathioprine; Child; Cholestasis; Colitis, Ulcerative; Humans; Mercaptopurine; Methylprednisolone; Psychophysiologic Disorders

Topics: Adolescent; Age Factors; Antigen-Antibody Reactions; Autoantibodies; Azathioprine; Child; Colitis, Ulcerative; Female; Germany, West; Humans; Male; Mercaptopurine; Radiography; Time Factors

Topics: Adolescent; Autoimmune Diseases; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Collagen Diseases; Cyclophosphamide; Humans; Mercaptopurine; Nephrotic Syndrome

Topics: Adolescent; Adult; Aged; Anemia, Hemolytic, Autoimmune; Autoimmune Diseases; Azathioprine; Colitis, Ulcerative; Female; Humans; Lectins; Leukemia; Male; Mercaptopurine; Middle Aged; Nephrotic Syndrome; Purpura, Thrombotic Thrombocytopenic

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; Colitis, Ulcerative; Female; Humans; Male; Mercaptopurine; Middle Aged

Topics: Antimetabolites; Azathioprine; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Mercaptopurine

Topics: Adolescent; Adult; Azathioprine; Body Temperature; Colitis, Ulcerative; Female; Humans; Male; Mercaptopurine; Middle Aged; Rectal Diseases

Topics: Allergy and Immunology; Animals, Laboratory; Antigen-Antibody Reactions; Antineoplastic Agents; Autoimmune Diseases; Azathioprine; Colitis; Colitis, Ulcerative; Fluorescent Antibody Technique; Immunosuppressive Agents; Intestines; Mechlorethamine; Mercaptopurine; Pharmacology; Research

Topics: Colitis; Colitis, Ulcerative; Humans; Mercaptopurine