mercaptopurine and Colitis

The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear.. To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models.. Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale.. There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.

Topics: Adult; Colitis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphoma; Male; Mercaptopurine; Middle Aged; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

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

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

Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD.. IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL].. Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients.. Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Topics: Azathioprine; Colitis; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Prospective Studies; Quality of Life; Thioguanine

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.

Topics: Animals; Azathioprine; Bacteria; Biological Availability; Colitis; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Mice

Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.. Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7. Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.

Topics: Administration, Rectal; Animals; Autophagy; Autophagy-Related Protein 7; Azoxymethane; beta Catenin; Caco-2 Cells; Colitis; Colitis-Associated Neoplasms; Colon; Dextran Sulfate; Gene Knockdown Techniques; HCT116 Cells; Humans; Intestinal Mucosa; Mercaptopurine; Mice; Mice, Transgenic; Neuropeptides; rac1 GTP-Binding Protein; Thioguanine; Wnt Signaling Pathway

Infective issues about anti-tumor necrosis factor (TNF)-α agents in inflammatory bowel disease (IBD) remain controversial, especially when compared with nonbiological treatments. This study aimed to evaluate the incidence and prevalence of several infections in anti-TNF-α-exposed patients compared with nonbiological treatments.. All naïve IBD subjects treated with anti-TNF-α and matched nonbiologic-exposed patients were included.. Among 3453 patients in the database, 288 anti-TNF-α-exposed subjects and 288 nonbiologic-exposed IBD controls met inclusion criteria. Fifty-eight infections (20.1%) occurred during anti-TNF-α treatment versus 23 (8%) in the matched group (odds ratio [OR] 2.9, P < 0.001) (incidence 5.72 vs 0.96/100 patient-years, incidence ratio [IR] 6, P < 0.001). IR was higher for anti-TNF-α versus mesalamine/sulfasalazine (IR 40.8, P < 0.001), similar to azathioprine/6-mercaptopurine/methotrexate (IR 0.78, P = 0.32) and lower than corticosteroids (IR 0.05, P < 0.001). The incidence rate of serious infections was 1.3 in the anti-TNF-α-exposed versus 0.38/100 patient-years in nonexposed subjects (IR 3.44, P = 0.002), without significant difference between anti-TNF-α and azathioprine/6-mercaptopurine/methotrexate (1.3 vs 3.03/100 patient-years, IR 0.43, P = 0.1). Predictors of infections in anti-TNF-α-exposed patients were concomitant use of systemic steroids (OR 1.9, P = 0.02) or azathioprine (OR 2.6, P = 0.01) and a body mass index < 18.5 at time of infection (OR 2.2, P = 0.01).. The risk of developing infections during anti-TNF-α therapy remains high, although not dissimilar to that found for other immunosuppressants, while concomitant immunosuppression and malnutrition appear the most important causes of infection.

Topics: Azathioprine; Colitis; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate; Risk Assessment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG).. C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed.. Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt. Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.

Topics: Administration, Oral; Administration, Rectal; Animals; Autophagy; Bacteroides thetaiotaomicron; Cells, Cultured; Colitis; Colon; Cytokines; Dextran Sulfate; Enterococcus faecalis; Epithelial Cells; Escherichia coli; Female; Fibroblasts; Gastrointestinal Microbiome; Host-Pathogen Interactions; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Intestinal Mucosa; Macrophages; Male; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucin-2; RNA, Messenger; T-Lymphocytes; Thioguanine

Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease.. 5-ASA was encapsulated in standard phospholipid liposomes while 6-MP required encapsulation in nonphospholipid liposomes to obtain equivalent drug loading. Encapsulation efficiency was measured by size-exclusion chromatography/high-performance liquid chromatogtaphy (HPLC). Liposomal formulations or solution of the drugs were injected into unligated jejunum to compare pharmacokinetics and into ligated loops of rat ileum and colon to evaluate local delivery. Dextran sulfate and acetic acid induced colitis were used as models of lower intestinal inflammation. Plasma, tissue and luminal drug and metabolite levels were measured by liquid scintillation counting or HPLC.. Encapsulation efficiency of 6-MP was dependent on lipid content and composition. While liposomal encapsulation significantly reduced systemic absorption of 5-ASA this was not the case for 6-MP. Liposomal adherence to intestinal tissue resulted in increased tissue levels for 5-ASA; however, 6-MP local tissue levels were not improved compared to solution drug.. Nonphospholipid liposomes optimize encapsulation of 6-MP. While liposomal formulations show potential for local drug delivery to diseased bowel, drug physicochemical properties, absorption, and metabolic profiles dictate tissue-targeting potential. Liposomes reduce systemic availability from paracellular absorption of hydrophilic 5-ASA, but fail to improve local tissue delivery of 6-MP, a molecule absorbed by passive membrane permeation that undergoes extensive first- pass metabolism.

Topics: Algorithms; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Transport, Active; Caco-2 Cells; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Colitis; Drug Carriers; Drug Compounding; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Absorption; Liposomes; Male; Mercaptopurine; Mesalamine; Rats; Rats, Sprague-Dawley

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

Many patients with microscopic colitis will respond to antidiarrheal medications or to anti-inflammatory therapy with 5-aminosalicylates, although a few require corticosteroids. Some patients do not tolerate corticosteroid side effects, and a small subset are dependent on or refractory to corticosteroids. We report our experience with azathioprine and 6-mercaptopurine in patients with microscopic colitis.

Topics: Adult; Aged; Aged, 80 and over; Azathioprine; Colitis; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Azathioprine; Colitis; Collagen; Female; Humans; Immunosuppressive Agents; Lymphocytes; Male; Mercaptopurine; Middle Aged; Steroids

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

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

This study was undertaken to determine if asymptomatic children and adolescents with inflammatory bowel disease and moderate to severe anorectosigmoid inflammation might remain symptom-free for at least 12 months without specific intrarectal therapy. We prospectively studied 13 asymptomatic patients 6-21 years of age (four with Crohn's disease and nine with nonspecific colitis) with previously documented anorectosigmoid inflammation. Of these 13, four had moderate to severe anorectosigmoid inflammation both endoscopically and histologically. These four patients (two with Crohn's disease and two with nonspecific colitis) were entered into the second phase of the study. Three were receiving sulfasalazine, and one received methylprednisolone, 4 mg/day, and 6-mercaptopurine, 50 mg/day. None received intrarectal therapy. Clinical evaluation revealed that all four remained asymptomatic for 12 months despite the continued presence of moderate to severe anorectosigmoid inflammation. These results indicate that in children and adolescents with inflammatory bowel disease, the presence of inflammation of the anorectosigmoid does not necessarily correlate with or presage the onset of symptoms of proctosigmoiditis. Therefore, active inflammation of the anorectosigmoid is not the sole prerequisite for intrarectal therapy. The clinician should be guided by the symptoms of the patient, not by the presence or absence of active anorectosigmoid inflammation.

Topics: Adolescent; Child; Child, Preschool; Colitis; Crohn Disease; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methylprednisolone; Proctocolitis; Prospective Studies; Sulfasalazine

Topics: Azathioprine; Colitis; Female; Humans; Lymphoma, Non-Hodgkin; Mercaptopurine; Middle Aged

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