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Subrata Ghosh - One of the best experts on this subject based on the ideXlab platform.
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comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in crohn s disease a network meta analysis
Gastroenterology, 2015Co-Authors: Glen Hazlewood, Subrata Ghosh, Cynthia H Seow, Corey A. Siegel, Ali Rezaie, Meredith A Borman, Remo Panaccione, Ellen Kuenzig, George Tomlinson, Gil Y MelmedAbstract:Background & Aims There is controversy regarding the best treatment for patients with Crohn's disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohn's disease, based on direct and indirect evidence. Methods We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, Azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohn's disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI). Results Infliximab, the combination of infliximab and Azathioprine (infliximab + Azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti–tumor necrosis factor agents, infliximab + Azathioprine (OR, 3.1; 95% CrI, 1.4–7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0–4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + Azathioprine were superior to Azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6–5.1), infliximab (OR, 1.6; 95% CrI, 1.0–2.5), infliximab + Azathioprine (OR, 3.0; 95% CrI, 1.7–5.5) for maintenance of remission. Adalimumab and infliximab + Azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4–4.6) and infliximab + Azathioprine (OR, 2.6; 95% CrI, 1.3–6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2–4.6). Conclusions Based on a network meta-analysis, adalimumab and infliximab + Azathioprine are the most effective therapies for induction and maintenance of remission of Crohn's disease.
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combination therapy with infliximab and Azathioprine is superior to monotherapy with either agent in ulcerative colitis
Gastroenterology, 2014Co-Authors: Remo Panaccione, Subrata Ghosh, Stephen Middleton, Juan R Marquez, Boyd B Scott, Laurence Flint, Hubert Van Hoogstraten, Annie C Chen, Hanzhe Zheng, Silvio DaneseAbstract:Background & Aims The comparative efficacy and safety of infliximab and Azathioprine therapy alone or in combination for ulcerative colitis (UC) have not been evaluated previously. Methods This randomized, double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy, Azathioprine monotherapy, or the 2 drugs combined in tumor necrosis factor-α antagonist-naive adults with moderate to severe UC. Patients were assigned randomly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, and 14 plus daily oral placebo capsules; oral Azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule; or combination therapy with the 2 drugs. Corticosteroid-free clinical remission (primary end point, week 16) was evaluated at weeks 8 and 16. The study was terminated before the enrollment target was reached. Results A total of 239 patients were included in efficacy analyses. Baseline characteristics were similar between treatment groups. Corticosteroid-free remission at week 16 was achieved by 39.7% (31 of 78) of patients receiving infliximab/Azathioprine, compared with 22.1% (17 of 77) receiving infliximab alone ( P = .017) and 23.7% (18 of 76) receiving Azathioprine alone ( P = .032). Mucosal healing at week 16 occurred in 62.8% (49 of 78) of patients receiving infliximab/Azathioprine, compared with 54.6% (42 of 77) receiving infliximab ( P = .295) and 36.8% (28 of 76) receiving Azathioprine ( P = .001). Serious infections occurred in 2 patients (1 patient receiving infliximab, and 1 patient receiving Azathioprine). Conclusions Anti–tumor necrosis factor-α–naive patients with moderate to severe UC treated with infliximab plus Azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy. Combination therapy led to significantly better mucosal healing than Azathioprine monotherapy. ClinicalTrials.gov number, NCT00537316.
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relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low dose Azathioprine
Alimentary Pharmacology & Therapeutics, 2002Co-Authors: Simon Campbell, Kathleen Kingstone, Subrata GhoshAbstract:Background: It is well-recognized that patients with low thiopurine methyltransferase activity are more susceptible to the development of bone marrow suppression side-effects. Aim: To study the impact of thiopurine methyltransferase activity on the clinical course of inflammatory bowel disease patients treated with low-dose Azathioprine (< 2 mg/kg). Methods: We measured the thiopurine methyltransferase activity of blood samples from 113 inflammatory bowel disease patients who were taking azathiopurine, had discontinued Azathioprine because of side-effects, or had never taken Azathioprine. The thiopurine methyltransferase activity was compared with that of 17 healthy controls. Relapse rates and time to first relapse were compared in inflammatory bowel disease patients and stratified according to their thiopurine methyltransferase activity. Results: Patients who became neutropenic had a significantly lower mean thiopurine methyltransferase activity than that of patients who developed other side-effects (analysis of variance, P 20 nmol/mL red blood cells/h. There was a significantly lower number of relapses in inflammatory bowel disease patients with lower thiopurine methyltransferase levels (P < 0.05). Conclusions: The mean thiopurine methyltransferase activity was significantly lower in patients on a low dose of Azathioprine in remission compared with those who relapsed. The thiopurine methyltransferase activity was significantly lower in patients who discontinued Azathioprine due to neutropenia than in those who discontinued due to other side-effects.
Matthias Schwab - One of the best experts on this subject based on the ideXlab platform.
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monitoring of thiopurine methyltransferase activity in postsurgical patients with crohn s disease during 1 year of treatment with Azathioprine or mesalazine
Therapeutic Drug Monitoring, 2007Co-Authors: Karin Dilger, Milan Lukas, Matthias Schwab, Elke Schaeffeler, Ulrike Strauch, Hans H Herfarth, Ralph MullerAbstract:Abstract Thiopurine methyltransferase (TPMT) activity determines biotransformation of Azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or Azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to Azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on Azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of Azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking Azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor Azathioprine significantly affected TPMT activity during a whole year of treatment.
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Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease impact of thiopurine s methyltransferase polymorphism
Pharmacogenetics, 2002Co-Authors: Matthias Schwab, Elke Schaffeler, Claudia Marx, Christine Fischer, Thomas Lang, Christoph Behrens, M Gregor, Michel Eichelbaum, Ulrich M Zanger, Bernd A KaskasAbstract:The efficacy of the immunosuppressants Azathioprine and 6-mercaptopurine has been well established in the therapy of inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious adverse drug reactions such as hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal disturbances. Whereas Azathioprine-related pancytopenia has been clearly linked to thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and Azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and Azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving Azathioprine therapy and had never experienced side effects. Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe Azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3; pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type. TPMT deficiency in one patient had led to pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that Azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT.
John T. Lear - One of the best experts on this subject based on the ideXlab platform.
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Azathioprine
BioDrugs, 1998Co-Authors: Alex Anstey, John T. LearAbstract:Azathioprine remains one of the most important and widely prescribed drugs for immunosuppression/immunomodulation in autoimmune disease over 30 years after its introduction. Extensive clinical experience with Azathioprine and steady progress in understanding its pharmacodynamic and pharmacokinetic characteristics provide a clear understanding of how this drug has gained importance in the treatment of autoimmune disease. This review highlights advances in the understanding of the metabolic fate of Azathioprine and relates these to the efficacy and toxicity profiles for the drug. Clinicians have been slow to appreciate advances in pharmacogenetics that relate to Azathioprine and how the common genetic polymorphism affecting the catabolic enzyme thiopurine methyltransferase may have profound effects on the toxicity and efficacy of the drug, as demonstrated by the lack of reference to this work in publications relating to Azathioprine. A current literature review has established that this information has, to a significant degree, now reached the medical disciplines that use Azathioprine, but there are still notable exceptions. The marked interpatient variability in Azathioprine metabolism is of particular significance in the context of clinical trials, which may reach doubtful or invalid conclusions by failing to consider this in trial protocols. Azathioprine is licensed for the treatment of only a limited range of autoimmune disorders, which is probably a reflection on the age of the drug. Widening the licence for a drug is both costly and time consuming, and it would make no commercial sense for manufacturers to do so, at this late stage of life, for Azathioprine. However, Azathioprine is now so well established as an immunomodulating drug in autoimmune disorders that it represents the gold standard by which other drugs are compared. A review of the literature shows that usage of Azathioprine goes considerably beyond the short list of licensed indications, and in many disciplines usage is continuing to increase as new immunotherapies are often too expensive or toxic to gain widespread acceptance. This review aims to provide an update on the clinical pharmacology of Azathioprine and relate this to the current indications for usage in the treatment of autoimmune disorders.
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Azathioprine in dermatology: a survey of current practice in the U.K.
The British journal of dermatology, 1997Co-Authors: B. B. Tan, John T. Lear, David J. Gawkrodger, John S. C. EnglishAbstract:Azathioprine has an important role in treatment of many inflammatory dermatoses. In view of the current emphasis on evidence-based medicine, we performed a questionnaire-based survey to establish current practice in the use of Azathioprine by consultant dermatologists and associate specialists in the U.K. The response rate was 68%. In contrast with the manufacturer's recommendation, our data provide evidence that Azathioprine is useful in the treatment of a wide variety of dermatological diseases. However, there is still a need for controlled trials in some conditions. The most common conditions treated were pemphigoid, pemphigus and atopic eczema. In addition, we found that only 13% of dermatologists prescribe Azathioprine according to body weight. Most dermatologists felt that Azathioprine was well tolerated. No one tested for thiopurine methyltransferase (TPMT) activity, which is thought to be a predictor of severe myelosuppression. The combination of prescribing Azathioprine according to body weight and measuring TPMT activity would optimize efficacy and minimize potential severe myelotoxicity.
S. Lanzon-miller - One of the best experts on this subject based on the ideXlab platform.
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PWE-089 Outcomes of Patients with Crohn’S Disease: Azathioprine Tolerant and Azathioprine Intolerant
Gut, 2013Co-Authors: L.y. Lee, A. Gardezi, G. Macfaul, S. Lanzon-millerAbstract:Introduction Azathioprine is well established for the maintenance of remission in patients with Crohn’s disease and 87% patients on maintenance therapy are able to reduce steroid consumption. However, Azathioprine is less effective at treating disease recurrence and seven patients need to be treated to prevent one recurrence (1). Intolerance to Azathioprine occurs in almost a third of patients and it has been proposed that the intolerance to Azathioprine is a poor prognostic marker that may predispose patients to a more aggressive disease course. Methods A cross sectional study was performed using the Milton Keynes Hospital IBD database to compare outcomes of patients that were Azathioprine intolerant and those that were Azathioprine tolerant. A descriptive analysis of clinical features and outcomes of these two groups was performed. Results 141 patients were included for analysis of which 24.8% were intolerant to Azathioprine. The median age of Azathioprine intolerant patients was 47 and 31.4% were male. In the Azathioprine tolerant cohort, the median age was 36 and 41.5% were male. Azathioprine was not tolerated due to gastrointestinal side effects in 53.6%, neurological effects (depression/headaches/vertigo) in 17.9%, deranged LFTs in 17.9% and the arthralgia/neutropenia and cutaneous side effects making up the remaining cases. Conclusion Azathioprine is a drug that is not tolerated in nearly a quarter of Crohn’s disease patients and this effect demonstrated a sex bias towards females. Patients who were intolerant to Azathioprine were not more likely to undergo surgery or to have more strictures or fistulas. However, Azathioprine-intolerant patients were considerably more likely to have more active disease, to require monoclonal antibody therapy and steroids. Compared to patients who are able to use Azathioprine, for every 100 patients who are intolerant, 24 less will be in remission and 20 more will have moderate to severe disease. We conclude that patients with Azathioprine intolerance will have poorer symptom control, but does not predispose to a more aggressive disease course. Disclosure of Interest None Declared. Reference Pearson D, May G, Fick G, Sutherland L. Azathioprine for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews
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PWE-090 Outcomes of Patients with Ulcerative Colitis who are Azathioprine Tolerant and Azathioprine Intolerant
Gut, 2013Co-Authors: L.y. Lee, G. Macfaul, A Syed, S. Lanzon-millerAbstract:Introduction Azathioprine therapy is an immunosuppressive drug that is widely used in the management of ulcerative colitis. 20% of patients with normal TPMT are not able to tolerate the drug and 30% do not respond [1]. For patients who are intolerant to Azathioprine, other medicines have been proposed and these include methotrexate, mercaptopurine and infliximab. Methods A cross sectional study was performed using the Milton Keynes Hospital IBD database to compare patients were Azathioprine intolerant and those that were Azathioprine tolerant. A descriptive analysis of clinical features and outcomes of these two groups was performed. Disease activity scores were based on the montreal classification ranging from S0 (clinical remission) to S3 (severe disease). Results 98 patients were recruited of which 32.7% were intolerant to Azathioprine. The median age of Azathioprine intolerant patients was 47.5 years and 30.3% were male. In the Azathioprine tolerant cohort, the median age was 46 years and 53.0% were male. Azathioprine was not tolerated due to deranged liver function tests in 43.3%, gastrointestinal symptoms of nausea/vomiting in 23.3%, cutaneous side effects in 10.0%, migraines in 6.7% and infections in 3.3%. Conclusion Azathioprine is a drug that is not tolerated in nearly a third of Ulcerative Colitis patients and this effect demonstrated a sex bias towards females. The most likely reason for Azathioprine intolerance was deranged liver function tests, however, intolerable gastrointestinal symptoms are noted. The intolerance of Azathioprine is not a prognostic marker that patients will be more likely to undergo colectomy or that their ulcerative colitis will become extensive. However, there is evidence that compared to Azathioprine tolerant patients, for every 100 who are intolerant, 8 less will be in remission and 6 will have more severe disease. Finally, we note that prolonged use of low-dose steroids in modern practise is utilised rarely and it is feasible that this trend may lead to increased symptoms at a population level. Disclosure of Interest None Declared. References M. Wahed, J. R. Louis-Auguste, L. M. Baxter, J. K. Limdi, S. A. Mccartney, J. O. Lindsay, and S. L. Bloom, “Efficacy of methotrexate in Crohn’s disease and ulcerative colitis patients unresponsive or intolerant to Azathioprine/mercaptopurine,” Alimentary Pharmacology & Therapeutic s, vol. 30, no. 6, pp. 614–620, 2009.
Jacques Cosnes - One of the best experts on this subject based on the ideXlab platform.
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Is There Still A Room For Azathioprine Monotherapy In Inflammatory Bowel Disease?
Current Drug Targets, 2013Co-Authors: Anne Bourrier, Philippe Seksik, Jacques CosnesAbstract:Azathioprine is an efficient maintenance treatment of IBD, able to maintain a complete clinical and anatomical remission in about one third of patients. However there are concerns regarding its long term tolerance, particularly myelosuppression and malignancy. Azathioprine is not required in about one third of Crohn's Disease patients and more than half of Ulcerative Colitis patients who will experience a mild disease course. In patients with more severe disease, although anti-TNF agents are more powerful and act more rapidly, there is a subset of patients with moderate-to-severe IBD without important anatomical damage who may achieve a prolonged steroid-free clinical and anatomical remission on Azathioprine monotherapy. It is thus advised to initiate Azathioprine monotherapy in these intermediate cases, and to continue Azathioprine if anatomical remission is achieved.
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Predictive factors of response of perianal Crohn's disease to Azathioprine or 6-mercaptopurine.
Diseases of The Colon & Rectum, 2003Co-Authors: Thierry Lecomte, J. F. Contou, Laurent Beaugerie, Franck Carbonnel, Stéphane Cattan, Jean-pierre Gendre, Jacques CosnesAbstract:PURPOSE: This study was designed to evaluate the predictive factors of response of perianal Crohn’s disease to Azathioprine or 6-mercaptopurine. METHODS: Ninety-four patients (65 females; mean age, 31 years) with active perianal Crohn’s disease were treated with Azathioprine or 6-mercaptopurine for more than 6 (median, 27) months (median Azathioprine dose, 2 mg/kg/day). The evolution of perianal lesions during Azathioprine or 6-mercaptopurine therapy was analyzed retrospectively. Patients who had a clear anatomic improvement (fistula closure, fissure healing, stricture dilatation) and who did not develop any perianal complications requiring an antibiotic course or surgical intervention were considered responders regarding their perianal disease. RESULTS: Three years after inclusion, the cumulative probabilities of remaining free of perianal complication and achieving a clear anatomic improvement were 0.47 (95 percent confidence interval, 0.36–0.58) and 0.4 (95 percent confidence interval, 0.29–0.53), respectively. On the whole, 27 patients (29 percent) were responders to Azathioprine or 6-mercaptopurine therapy. The absence of fistula, duration of perianal disease shorter than 22 months, and aged 40 years or older at inclusion were three independent factors associated with response to Azathioprine or 6-mercaptopurine therapy. There was no correlation between the response of perianal lesions and the achievement of intestinal remission with Azathioprine or 6-mercaptopurine. CONCLUSION: One-third of patients with perianal lesions of Crohn’s disease demonstrated a clear improvement during Azathioprine or 6-mercaptopurine therapy. Patients aged 40 years or older with a recent perianal disease and without fistula were the best responders.
