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• W2900687531 abstract "See “Evolving considerations for thiopurine therapy for inflammatory bowel diseases—a clinical practice update: commentary,” by Hanauer SB, Sandborn WJ, Lichtenstein GR, on page 36. See “Evolving considerations for thiopurine therapy for inflammatory bowel diseases—a clinical practice update: commentary,” by Hanauer SB, Sandborn WJ, Lichtenstein GR, on page 36. The number of drugs available for the treatment of inflammatory bowel disease (IBD) is ever growing, leading to more options and choices for the patient and treating physician. The upside of the new IBD drugs is clear; many patients benefit from these therapies, illustrated by the rapid onset of action in the case of anti-tumor necrosis factor (TNF) drugs or superior safety in the case of the newer anti-integrin antibodies. However, not so long ago, before the approval of infliximab as the first biologic for IBD in 1998, the arsenal of effective drugs was limited, comprising mainly corticosteroids, mesalazine, and thiopurines. More than 50 years of global experience with thiopurine therapy, even in the absence of active marketing authority, allowed estimates of its common and rare adverse effects.1Fraser A.G. Orchard T.R. Jewell D.P. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review.Gut. 2002; 50: 485-489Crossref PubMed Scopus (543) Google Scholar, 2Peyrin-Biroulet L. Khosrotehrani K. Carrat F. et al.Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.Gastroenterology. 2011; 141 (1621–1628 e1-5)Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar This is not yet the case for many of the more recently developed IBD drugs. Furthermore, these novel drugs come at an exceptionally high financial cost. Even in those fortunate countries that can afford biological therapies, their use has expanded to the point that the costs often dominate the drug budget for the country. In addition, the incidence of IBD is increasing in both Western countries and developing countries.3Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321 e2Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar For the majority of patients living in newly industrialized countries, both insured and uninsured, biological therapy is not funded. Thus, their cost effectiveness needs to be critically assessed in different settings, given 1 patient prescribed biologic monotherapy costs the same as many patients receiving thiopurine treatment (azathioprine 200 mg/p day costs between €180 and €280 per year in the Netherlands). Thiopurine therapy has proven its value in maintenance of remission, decreased need for surgery, lowered colorectal cancer risk, less phenotypic disease progression, and synergistic effects when used with infliximab therapy, including increased biologic drug levels and less antibody formation.4de Boer N.K.H. Peyrin-Biroulet L. Jharap B. et al.Thiopurines in inflammatory bowel disease: new findings and perspectives.J Crohns Colitis. 2018; 12: 610-620Crossref PubMed Scopus (50) Google Scholar Notwithstanding the extensive experience by many physicians, the clinical use of conventional immunosuppressive therapies has been questioned in recent years. The best practice is to use therapeutic drug monitoring not only with biologicals, but also with thiopurines to optimize treatment before stopping or switching to another class of drugs. In this issue of Gastroenterology, Hanauer et al5Hanauer S.B. Sandborn W.J. Lichtenstein G.R. Evolving considerations for thiopurine therapy for inflammatory bowel diseases—a clinical practice update: commentary.Gastroenterology. 2019; 156: 36-42Abstract Full Text Full Text PDF Scopus (29) Google Scholar share their expert opinion on the evolving use of thiopurines and methotrexate in daily practice. In their literature review, the importance of assessing the risks (infections and cancer risk) and benefits (maintenance of remission) of thiopurine therapy is highlighted. For proper (shared) decision making, the well-known toxicity profile of thiopurines should also be balanced against the profile of drugs that may follow where thiopurine therapy fails or is not considered. The most feared complication of thiopurine therapy is the development of a lymphoma. Several large studies have investigated the relationship of lymphoma and IBD therapies. The recent nationwide cohort study based on French National Health Insurance databases is illustrative.6Lemaitre M. Kirchgesner J. Rudnichi A. et al.Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease.JAMA. 2017; 318: 1679-1686Crossref PubMed Scopus (321) Google Scholar Including 189,289 patients, it was demonstrated that both thiopurine (adjusted hazard ratio of 2.6) and anti-TNF monotherapy (adjusted hazard ratio of 2.4) were associated with a similar small but statistically significant increased risk of lymphoma. Furthermore, combination therapy of thiopurine and anti-TNF was associated with a higher chance of developing a lymphoma (adjusted hazard ratio of 6.1). It is of clinical importance to emphasize that, despite the increased relative risks, the individual absolute risk remains low, especially in patients without additional risk factors such as a young age in male patients and negative Epstein-Barr virus serology.7Beaugerie L. Lymphoma: the bete noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease.Gastroenterology. 2013; 145: 927-930Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar In a second study, using the same design, the risk for serious and opportunistic infections during immunosuppressive treatment was assessed.8Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346 e10Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar Anti-TNF monotherapy was associated with increased risks of serious infections, mycobacterial infections, and fungal and bacterial infections, but with a decreased risk of opportunistic viral infection when compared with thiopurine monotherapy. Combination therapy was again associated with a greater risk of infectious complications. In general, the toxicity profiles when looking at serious complications seem not to differ greatly between thiopurine monotherapy and anti-TNF monotherapy. In patients with Crohn’s disease, and also patients with ulcerative colitis, infliximab is often combined with a thiopurine because this strategy leads to higher rates of corticosteroid-free clinical remission and mucosal healing.9Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2441) Google Scholar, 10Panaccione R. Ghosh S. Middleton S. et al.Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.Gastroenterology. 2014; 146: 392-400 e3Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar The toxicity and efficacy profile of any strategy should be weighed and openly discussed with the patient before initiation and balanced against the severity of the disease and desired treatment goals. Thiopurine therapy is often dropped from combination with a biologic after 6–12 months of remission in daily practice, but higher level evidence that withdrawing the thiopurine rather than the biologic in those patients with mild to moderate disease is limited.11Louis E. Mary J.Y. Vernier-Massouille G. et al.Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.Gastroenterology. 2012; 142 (quiz e31): 63-70 e5Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar The (ongoing) unravelling of the complexities of thiopurine or monoclonal antibody metabolism has paved the way for several clinical strategies to avoid or overcome adverse events, toxicity, or inefficacy, thereby creating possibilities to optimize and prolong safe therapies. However, there remains debate about how therapeutic drug monitoring should be used and improved, whether proactive or reactive, or to assess for pharmacokinetic versus pharmacodynamic failures. Future studies in search of practical and noninvasive predictors of response or toxicity may guide the development of more tailored strategies. In the case of thiopurines, anomalous genotypes of the thiopurine metabolizing enzymes thiopurine s-methyltransferase and NUDT15 have been associated with the development of leukopenia, and testing before the start of therapy is advocated and noted in international guidelines to avoid (early) myelotoxicity.12Coenen M.J. de Jong D.J. van Marrewijk C.J. et al.Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease.Gastroenterology. 2015; 149: 907-917 e7Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar In addition, a clinically relevant pharmacogenetic marker (HLA-DQA1–HLA-DRB1 variants) has been discovered for thiopurine induced pancreatitis.13Heap G.A. Weedon M.N. Bewshea C.M. et al.HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.Nat Genet. 2014; 46: 1131-1134Crossref PubMed Scopus (144) Google Scholar The specific mode of action of thiopurine therapy in IBD has been ascribed to the metabolite 6-thioguaninenucleotide (6-TGN) (more specifically 6-thioguanine triphosphate) that binds to the small GTPase Rac1, thereby inducing apoptosis of activated T lymphocytes.14Tiede I. Fritz G. Strand S. et al.CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.J Clin Invest. 2003; 111: 1133-1145Crossref PubMed Scopus (714) Google Scholar This apoptosis-inducing effect is the predominant mode of action when regular, relatively low, dosages are given for patients with IBD. The incorporation of 6-thioguanine nucleotides into DNA, leading to cytotoxicity, is mainly witnessed when thiopurines are administered in higher oncologic dosages.15Quemeneur L. Gerland L.M. Flacher M. et al.Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides.J Immunol. 2003; 170: 4986-4995Crossref PubMed Scopus (173) Google Scholar The adverse genotoxic effects of thiopurine therapy are largely caused by the latter pharmacodynamic effect. The 6-TGN levels are positively correlated with efficacy in patients with IBD,16Estevinho M.M. Afonso J. Rosa I. et al.A Systematic review and meta-analysis of 6-thioguanine nucleotide levels and clinical remission in inflammatory bowel disease.J Crohns Colitis. 2017; 11: 1381-1392Crossref PubMed Scopus (18) Google Scholar so in the case of inefficacy or loss of response an attempt should be made to increase the 6-TGN level. The dosage can be increased, or in case of a skewed metabolism (a preferential generation of methylated metabolites, measured as 6-methylmercaptopurine [6-MMP]) at the cost of 6-TGN) other drugs that beneficially influence metabolism can be coadministered, such as allopurinol. All allopurinol–thiopurine combination studies find similar pharmacokinetic effects, with associated improvement of efficacy and avoidance of adverse events.17Hoentjen F. Seinen M.L. Hanauer S.B. et al.Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease.Inflamm Bowel Dis. 2013; 19: 363-369Crossref PubMed Scopus (82) Google Scholar To avoid the formation of 6-MMP and associated toxicity, a third thiopurine, thioguanine, may be used.18Meijer B. Mulder C.J. Peters G.J. et al.Efficacy of thioguanine treatment in inflammatory bowel disease: a systematic review.World J Gastroenterol. 2016; 22: 9012-9021Crossref PubMed Scopus (42) Google Scholar, 19Pavlidis P. Ansari A. Duley J. et al.Splitting a therapeutic dose of thioguanine may avoid liver toxicity and be an efficacious treatment for severe inflammatory bowel disease: a 2-center observational cohort study.Inflamm Bowel Dis. 2014; 20: 2239-2246Crossref PubMed Scopus (27) Google Scholar The metabolism of this drug is less complex (Figure 1) and the pharmacologically active metabolites 6-TGN are generated in 1 enzymatic step. It has long been appreciated from the leukemia literature that thioguanine as well as azathioprine and mercaptopurine are associated with an increased risk of developing nodular regenerative hyperplasia and sinusoidal obstruction syndrome of the liver that may lead to noncirrhotic portal hypertension if drug exposure is continued. With careful studies using low-dose thioguanine, it has become apparent that this is most likely a dose-dependent phenomenon. Studies using a median dosage of 20 mg/d demonstrated no clear increased risk of nodular regenerative hyperplasia.20van Asseldonk D.P. Jharap B. Verheij J. et al.The prevalence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with thioguanine is not associated with clinically significant liver disease.Inflamm Bowel Dis. 2016; 22: 2112-2120Crossref PubMed Scopus (30) Google Scholar Currently thioguanine (20 or 10 mg/d) has been conditionally approved for the treatment of IBD in the Netherlands, where approximately 4000 patients with IBD are currently being treated.21Simsek M. Meijer B. van Bodegraven A.A. et al.Finding hidden treasures in old drugs: the challenges and importance of licensing generics.Drug Discov Today. 2017; 23: 17-21Crossref PubMed Scopus (41) Google Scholar Two registry studies are ongoing to evaluate the efficacy and toxicity before final evaluation. It is tempting to speculate that thioguanine may become the thiopurine of choice, and a head-to-head comparison study with azathioprine or mercaptopurine is awaited. Although thiopurines are considered antique by some, new insights and drug developments continue to evolve. It was demonstrated that low-dose azathioprine is effective in Asian populations, indicative of ethnic differences in thiopurine metabolism and pharmacodynamics.22Shi H.Y. Chan F.K. Leung W.K. et al.Low-dose azathioprine is effective in maintaining remission in steroid-dependent ulcerative colitis: results from a territory-wide Chinese population-based IBD registry.Therap Adv Gastroenterol. 2016; 9: 449-456Crossref PubMed Scopus (24) Google Scholar In 2017, it was observed in a colitis mouse model that thioguanine, but not mercaptopurine, is metabolized into 6-TGN by gut bacteria.23Oancea I. Movva R. Das I. et al.Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism.Gut. 2017; 66: 59-69Crossref PubMed Scopus (48) Google Scholar The local bacterial conversion after administration by enema correlated with a rapid decrease in intestinal inflammation and immune activation. This intriguing observation may lead to the development of new topical thioguanine formulations like suppositories or colon-release capsules.24Florin T.H.J. Wright J.D. Jambhrunkar S.D. et al.A well-tolerated and rapidly acting thiopurine for IBD?.Drug Discov Today. 2018 Sep 7; ([Epub ahead of print])Crossref PubMed Scopus (11) Google Scholar Based on the knowledge that thiopurines mainly exert their immunosuppressive potential by Rac1 blockade by 6-thioguanine triphosphate, attempts have been made to develop modified designer thiopurine analogues. In an experimental study using immune cells of patients with IBD, the compound B-0N induced an earlier and stronger T-cell apoptosis than mercaptopurine, but with less myelotoxicity and hepatotoxicity.25Atreya I. Diall A. Dvorsky R. et al.Designer Thiopurine-analogues for optimised Immunosuppression in inflammatory bowel diseases.J Crohns Colitis. 2016; 10: 1132-1143Crossref PubMed Google Scholar At a time of abundant new drug development and exponential growth in IBD drug costs, it is important to dispassionately reassess the place of new versus the established therapies, in a balanced way, so that responsible decisions are made for both patients and the healthcare budgets of countries globally. The thiopurines are not perfect regarding both efficacy and toxicity, but in recent years they may have been portrayed in a worse light than they deserved. No doubt, the thiopurines will be surpassed eventually by newer safe and economical (oral) therapies, but it is too early to discard these old friends. The Thiopurine Working Group is represented by (in alphabetic order): Vineet Ahuja, India Institute of Medical Sciences, Department of Gastroenterology and Human Nutritions, New Delhi, India; Sven Almer, Karolinska Institutet, Department of Medicine, Solna, Stockholm, Sweden (1) and Karolinska University Hospital, Department of Gastroenterology, Dermatology and Rheumatology, Stockholm, Sweden (2); Azhar Ansari, East Surrey Hospital, Department for Digestive Diseases, Surrey and Sussex Healthcare NHS Trust, Redhill, United Kingdom; Rupa Banerjee, Asian Institute of Gastroenterology, Department of Medical Gastroenterology, Hyderabad, India; Murray L. Barclay, Christchurch Hospital, Department of Gastroenterology, Christchurch, New Zealand; Jake Begun, Mater Hospital Brisbane, and Mater Research Institute, University of Queensland, Brisbane, Australia; Adriaan A. van Bodegraven, Zuyderland Medical Centre, Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Heerlen-Sittard-Geleen, The Netherlands (1) and Amsterdam UMC, Vrije Universiteit, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands (2); Jean-Frederic Colombel, Icahn School of Medicine at Mount Sinai, New York, New York; David P. Epstein, IBD Africa, Vincent Pallotti Hospital, Division of Medicine, Cape Town, South Africa; Timothy H.J. Florin, University of Queensland, Translational Research Institute, Mater Research, Queensland, Australia; Richard B. Gearry, Christchurch Hospital, University of Otago, Department of Medicine, Christchurch, New Zealand; Javier P. Gisbert, Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Rupert W. Leong, Concord Repatriation General Hospital, Gastroenterology and Liver Services, Concord NSW, Australia; Chris J.J. Mulder, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands; Markus F. Neurath, Universitätsklinikum Erlangen and University of Erlangen-Nürnberg, Department of Gastroenterology, Pneumology and Endocrinology, Erlangen, Germany; Graham L. Radford-Smith, Royal Brisbane and Women’s Hospital, QIMR Berghofer Medical Research Institute, and University of Queensland School of Medicine, Brisbane, Australia; Margien L. Seinen, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam, the Netherlands; Melek Simsek, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam, the Netherlands; and Miles P. Sparrow, The Alfred Hospital, Department of Gastroenterology, Melbourne, Australia. Evolving Considerations for Thiopurine Therapy for Inflammatory Bowel Diseases—A Clinical Practice Update: CommentaryGastroenterologyVol. 156Issue 1PreviewThiopurines (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. Full-Text PDF" @default.
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• W2900687531 title "Thiopurine Therapy in Inflammatory Bowel Diseases: Making New Friends Should Not Mean Losing Old Ones" @default.
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