A Concise History of Thiopurines for Inflammatory Bowel Disease: From Anecdotal Reporting to Treat-to-Target Algorithms

Author(s): Giovanni Clemente Actis*, Rinaldo Pellicano, Davide Giuseppe Ribaldone.

Journal Name: Reviews on Recent Clinical Trials

Volume 14 , Issue 1 , 2019

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Graphical Abstract:


Abstract:

Background: 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.

Objective: 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.

Method: Through MEDLINE searches, we reviewed the literature of the last two decades.

Results: 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.

Conclusion: In UC thiopurines may be recognized to effect a treat-to-target strategy, joining the modern algorithms of rheumatologic disorders.

Keywords: Azathioprine, crohn's disease, inflammatory bowel disease, mercaptopurine, thiopurines, treat-to-target, ulcerative colitis.

[1]
Aller MA, Arias N, Fuentes-Julian S, et al. Coupling inflammation with evo-devo. Med Hypotheses 2012; 78: 721-31.
[2]
Malekzadeh MM, Vahedi H, Gohari K, et al. Emerging epidemic of inflammatory bowel disease in a middle income country: A nation-wide study from Iran. Arch Iran Med 2016; 19: 2-15.
[3]
Holleran G, Lopetuso LR, Ianiro G, et al. Gut microbiota and inflammatory bowel disease: So far so gut! Minerva Gastroenterol Dietol 2017; 63: 373-84.
[4]
Watkinson G. Sulphasalazine: A review of 40 years’ experience. Drugs 1986; 32: 1-11.
[5]
Li W, Zhang ZM, Jiang XL. Once daily vs multiple daily mesalamine therapy for mild-to-moderate ulcerative colitis: A meta-analysis. Colorectal Dis 2016; 18: 214-23.
[6]
Kornbluth A, Sachar DB. Practice Parameters committee of the American college of gastroenterology. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, practice parameters committee. Am J Gastroenterol 2004; 99: 1371-85.
[7]
Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database Syst Rev 2016; 7: CD008870.
[8]
Margetts PJ, Churchill DN, Alexopoulou I. Interstitial nephritis in patients with IBD treated with mesalamine. J Clin Gastroenterol 2001; 32: 176-8.
[9]
Biasi F, Leonarduzzi G, Oteiza PI, Poli G. IBD: Mechanisms, redox considerations, and therapeutic targets. Antioxid Redox Signal 2013; 19: 1711-47.
[10]
Michielan A, D’Inca’ R. Intestinal permeability in IBD: Pathogenesis, clinical evaluation, and therapy of leaky gut. Mediators Inflamm 2015; 2015: 628157.
[11]
Mitsuyama K, Matsumoto S, Masuda J, et al. Therapeutic strategies for targeting the IL-6/STAT-3 cytokine signaling pathway in IBD. Anticancer Res 2007; 27: 3749-56.
[12]
Schmetterer KG, Pickl WF. The IL-10/STAT-3 axis: Contributions to immune tolerance by thymus and peripherally-derived regulatory T-cells. Eur J Immunol 2017; 47: 1256-65.
[13]
Actis GC, Pellicano R. The pathologic galaxy modulating the genotype and phenotype of inflammatory bowel diseases: Comorbidity, contiguity, and genetic and epigenetic factors. Minerva Med 2016; 107: 401-12.
[14]
Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 2005; 102: 18129-34.
[15]
Mosca S, Bottino V, Camera A. Acute self-limited colitis complicating diagnostic colonoscopy. Am J Gastroenterol 2001; 96: 1669-70.
[16]
Holtmann MH, Galle PR. Current concepts of pathophysiological understanding and natural course of ulcerative colitis. Langenbecks Arch Surg 2004; 389: 341-9.
[17]
Hendriksen C, Kreiner S, Binder V. Long-term prognosis in ulcerative colitis – based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26: 158-63.
[18]
Gomollón F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s Disease 2016: Part 1: Diagnosis and medical management. J Crohn’s Colitis 2017; 11: 3-25.
[19]
Preiss JC, Zeitz M. Use of methotrexate in patients with IBD. Clin Exp Rheumatol 2010; 28: S151-5.
[20]
Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s Disease. N Engl J Med 1995; 332: 292-7.
[21]
Van Dieren J, Kuipers E, Samsom J, Nieuwenhuis EE, van der Woude CJ. Revisiting the immune modulators tacrolimus, methotrexate, and mycophenolate mofetil: Their mechanisms of action and role in the treatment of IBD. Inflamm Bowel Dis 2006; 12: 311-27.
[22]
Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate use in the treatment of IBD. Am J Gastroenterol 2000; 95: 3150-60.
[23]
Nobel Foundation. Autobiography of Gertrude B Elion, the Nobel Prize in Physiology or Medicine, 1988. Oncologist 2006; 11: 966-8.
[24]
Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64: 753-67.
[25]
Bean RH. The treatment of chronic ulcerative colitis with 6-mercaptopurine. Med J Aust 1962; 49: 592-3.
[26]
Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305: 20-2.
[27]
Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-MP. A long-term, randomized, double-blind study. N Engl J Med 1980; 302: 981-7.
[28]
Axelrad JE, Roy A, Lawlor G, Korelitz B, Lichtiger S. Thiopurines in IBD: Current evidence and historical perspectives. World J Gastroenterol 2016; 22: 10103-17.
[29]
Gargallo CJ, Lué A, Gomollón F. Biosimilars in inflammatory bowel disease. Minerva Med 2017; 108: 239-54.
[30]
Mahadevan U. Medical treatment of ulcerative colitis. Clin Colon Rectal Surg 2004; 17: 7-19.
[31]
Ben-Horin S, Goldstein I, Fudim E, et al. Early preservation of effector functions followed by eventual T-cell memory depletion: A model for the delayed onset of the effects of thiopurines. Gut 2009; 58: 396-403.
[32]
Cosnes J, Bourrier A, Lahare D, et al. Early administration of azathioprine vs conventional management of Crohn’s disease: A randomized controlled trial. Gastroenterology 2013; 145: 758-65.
[33]
Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s Disease. Gastroenterology 2013; 145: 766-74.
[34]
Marshall JK, Otley AR, Waqqas A, et al. Canadian Association of Gastroenterology position statement regarding the use of thiopurines for the treatment of IBD. Can J Gastroenterol Hepatol 2014; 28: 371-2.
[35]
Actis GC, Fadda M, Pellicano R, et al. The 17-yr single-center experience with the use of azathioprine to maintain remission in ulcerative colitis. Biomed Pharmacother 2009; 63: 362-5.
[36]
Cassinotti A, Actis GC, Duca P, et al. Maintenance treatment with azathioprine in ulcerative colitis: Outcome and predictive factors after drug withdrawal. Am J Gastroenterol 2009; 104: 2760-7.
[37]
Actis GC, Pellicano R, Rosina F. 6-MP for azathioprine intolerant IBD: Literature search and reappraisal of own data. Inflamm Allergy Drug Targets 2015; 14: 133-7.
[38]
Actis GC, Rosina F. Out-patient care for IBD at a primary referral hospital in Turin. Minerva Gastroenterol Dietol 2010; 56: 27-34.
[39]
Eriksson C, Rundquist S, Cao Y, Montgomery S, Halfvarson J. Impact of thiopurines on the natural history and outcome of ulcerative colitis: a cohort study. Gut 2018. Epub ahead of print [PMID: 29618498 DOI: 10.1136/gutjnl-2017-315521].
[40]
Margagnoni G, Fasci-Spurio F, Feigusch L, Koch M, Papi C, Aratari A. Long-term course of UC in the pre-biologic era. A retrospective study in a tertiary level Center. Minerva Gastroenterol Dietol 2014; 60: 275-83.
[41]
Saibeni S, Virgilio T, D’Incà R, et al. The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice. Dig Liver Dis 2008; 40: 814-20.
[42]
Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of IBD: A 30-yr experience. Gut 2002; 50: 485-9.
[43]
Bardhan KD, Simmonds N, Royston C, Dhar A, Edwards CM. Rotherham IBD Database Users Group. A UK IBD database: Making the effort worthwhile. J Crohn’s Colitis 2010; 4: 405-12.
[44]
Kirchgesner J, Lemaitre M, Rudnichi A, et al. Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: Analysis of the French administrative health databases 2009-2014. Aliment Pharmacol Ther 2017; 45: 37-49.
[45]
Allen PB, Olivera P, Emery P, et al. Review article: Moving towards common therapeutic goals in Crohn’s disease and rheumatoid arthritis. Aliment Pharmacol Ther 2017; 45: 1058-72.
[46]
Colombel JF, Rheinisch W, Mantzaris GJ, et al. Randomized clinical trial: Deep remission in biologic and immunomodulator naïve patients with Crohns disease - A SONIC post-hoc analysis. Aliment Pharmacol Ther 2015; 41: 734-46.
[47]
Prieux- Klotz C, Nahon S, Amiot A, et al. Rate and predictors of mucosal healing in UC treated with thiopurines: Results of a multicentric cohort study. Dig Dis Sci 2017; 62: 473-80.
[48]
Actis GC, Pellicano R, David E, Sapino A. Azathioprine, mucosal healing in UC, and the chemoprevention of colitic cancer: A clinical-practice-based forecast. Inflamm Allergy Drug Targets 2010; 9: 6-9.
[49]
Gong J, Zhu L, Guo Z, et al. Use of thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: A meta-analysis. PLoS One 2013; 8: e811487.
[50]
Eriksson C, Cao Y, Rundquist S, et al. Changes in medical management and colectomy rates; A population-based cohort study on the epidemiology and natural history of ulcerative colitis in Örebro, Sweden. Aliment Pharmacol Ther 2017; 46: 748-57.
[51]
Korelitz BI. Enduring value of thiopurines for inflammatory bowel disease therapy. Dig Dis Sci 2017; 62: 292-3.
[52]
Kansen HM, vanRheenen PF, Houwen RHJ, et al. Less anti-infliximab antibody formation in pediatric Crohn’s patients on concomitant immune modulators. J Pediatr Gastroenterol Nutr 2017; 65: 425-9.
[53]
Dart RJ, Irving PM. Optimizing use of thiopurines in inflammatory bowel disease. Expert Rev Clin Immunol 2017; 13: 877-88.
[54]
Kennedy NA, Kalla R, Warner B, et al. Thiopurine withdrawal during sustained clinical remission in IBD: relapse and recapture rates, with predictive factors in 237 patients. Aliment Pharmacol Ther 2014; 40: 1313-23.
[55]
Park MS, Kim DH, Kim DH, et al. Leukopenia predicts remission in patients with IBD and Behḉet on thiopurine maintenance. Dig Dis Sci 2015; 60: 195-204.
[56]
Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G, Hift R. Use of thiopurines in IBD is associated with an increased risk of non-melanoma skin cancer in an at-risk population: A cohort study. J Gastroenterol Hepatol 2012; 27: 385-9.
[57]
Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): A multicentre, randomised, controlled phase 3 trial. Lancet 2018; 390: 2779-89.


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VOLUME: 14
ISSUE: 1
Year: 2019
Page: [4 - 9]
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DOI: 10.2174/1574887113666180910120959
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