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Optimizing the Use of Thiopurines in Inflammatory Bowel Disease

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Optimizing the Use of Thiopurines in Inflammatory Bowel Disease TAJ0010.1177/2040622315579063Therapeutic Advances in Chronic DiseaseRM Goel, P Blaker 579063research-article2015 Therapeutic Advances in Chronic Disease Review Ther Adv Chronic Dis Optimizing the use of thiopurines in 2015, Vol. 6(3) 138 –146 DOI: 10.1177/ inflammatory bowel disease 2040622315579063 © The Author(s), 2015. Reprints and permissions: Rishi M. Goel, Paul Blaker, Alex Mentzer, Steven C.M. Fong, Anthony M. Marinaki and http://www.sagepub.co.uk/ Jeremy D. Sanderson journalsPermissions.nav Abstract: Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed. Keywords: gastroenterology, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, drugs, thiopurines, azathioprine Introduction UC and CD. Thiopurine therapy is usually intro- Correspondence to: Rishi M. Goel, MBBS BSc Inflammatory bowel disease (IBD) comprises duced as steroid-sparing therapy in UC when a MRCP ulcerative colitis (UC) and Crohn’s disease (CD). patient’s condition fails to respond to two courses Guy’s & St Thomas’ Hospitals – The disease courses are characterized by periods of steroid therapy. In addition, certain clinical sce- Gastroenterology, of relapse and remission. Both IBDs are clinically narios such as presentations of acute severe colitis Westminster Bridge Road, London SE1 7EH, UK and histologically distinct but also share many treated with rescue therapy may require early thio- [email protected] common genetic and clinical factors. purine therapy to maintain remission. Thiopurines Paul Blaker, MBBS MRCP are generally used earlier in CD as they provide PhD Alex Mentzer, MBBS UC was first described in 1859 by Samuel Wilks. long-term disease course modification which ster- Steven C.M. Fong, MBBS Features of UC are confluent mural inflammation oid therapy does not provide. A recent prospective Jeremy D. Sanderson, MBBS MD which begins in the rectum and extends proxi- study concluded that early azathioprine (AZA) Guy’s & St Thomas’ mally with sparing of the terminal ileum and therapy (within 8 weeks of diagnosis) provided no Hospitals – Gastroenterology, London, small bowel. Sulfasalazine was the first drug benefit in sustaining steroid-free remission com- UK introduced to treat the disease in the 1940s, fol- pared with placebo [Panés et al. 2013]. It did, how- Anthony M. Marinaki, PhD Guy’s & St Thomas’ lowed by steroid treatment in the 1950s. ever, show that AZA was more effective in Hospitals - Clinical preventing moderate–severe relapses. The main Chemistry, London, UK Patients with terminal ileitis were first reported in limitation of this study was the use of steroid-free the early 1900s. Burrill Bernard Crohn described remission as an endpoint. There is a wealth of evi- a series of cases in 1932 and subsequently this dence including a Cochrane Library analysis form of IBD became known as CD. Its hallmark reporting the effectiveness of thiopurines in main- is discontinuous chronic granulomatous inflam- tenance of remission in CD [Prefontaine et al. mation, which commonly involves the terminal 2010]. This suggests that thiopurines provide long- ileum but can affect any part of the gastrointesti- term disease modification which steroids do not; nal tract. In contrast with UC, CD may feature however, steroid therapy has a role in early disease transmural inflammation which can result in pen- treatment as a bridge to maintenance thiopurine etrating or structuring disease. therapy. Surgery is usually indicated for patients in whom medical therapy has failed or is refractory. The treatment for both diseases involves immuno- suppressant medication. Mesalazine preparations AZA was first synthesized in 1957 by George are used as first-line treatment for UC, with corti- Herbert Hitchings and Gertrude Elion. They costeroid therapy used in the early treatment of hypothesized that the growth of rapidly dividing 138 http://taj.sagepub.com RM Goel, P Blaker et al. Figure 1. A simplified schematic of the thiopurine metabolic pathway. AO, aldehyde oxidase; AZA, azathioprine; MeMP, methylmercaptopurine; MP, mercaptopurine; TGMP, thioguanine monophosphate; TGN, thioguanine nucleotide; TIMP, thioinosine monophosphate; TPMT, thiopurine-S-methyltransferase; TUA, thiouric acid; XDH, xanthine dehydrogenase. cells could be arrested with antimetabolites of Figure 1 shows a simplified version of the path- nucleic acid bases [Elion, 1989]. Their work led to way illustrating the important enzymes and the discovery of thioguanine (TG, 2,6-diaminopu- metabolites [Blaker et al. 2012]. Initially, the rine) and mercaptopurine (MP). AZA, a derivative majority of absorbed AZA is metabolized to of MP, was subsequently produced to increase the MP; however, a small amount is metabolized to bioavailability of MP. Collectively, these drugs purine bases implicated with hypersensitivity belong to a group known as thiopurine analogues. reactions [McGovern et al. 2002]. MP is then metabolized via three different pathways. It may Despite being unlicensed for IBD, thiopurines are be oxidized by xanthine dehydrogenase and indicated in the treatment of both UC and CD, pri- aldehyde oxidase to form thiouric acid which marily as corticosteroid-sparing therapy and dis- undergoes urinary excretion [Remy, 1963]. ease-modifying drugs. For patients with UC taking Alternatively, MP can be methylated by thiopu- AZA, steroid-free, clinical and endoscopic remis- rine-S-methyltransferase (TPMT) to form meth- sion has been described in 53% of patients com- ylmercaptopurine (MeMP). MP can also be pared with 21% receiving mesalazine therapy metabolized by a group of enzymes known as the [Aridizzone et al. 2006]. In patients with CD, two purine salvage pathway to produce the pharma- Cochrane reviews have shown that AZA/MP is cologically active metabolites, TG monophos- more efficacious than placebo in inducing and phate, TG diphosphate and TG triphosphate. maintaining remission [Mowat et al. 2010]. More Collectively, these end metabolites are referred recently, a meta-analysis has shown that thiopurine to as TG nucleotides (TGNs). MeMP may also use is highly effective with an associated 40% reduc- be therapeutically efficacious, however it is tion of surgical resection in CD [Chatu et al. 2014]. widely accepted that TGNs are the primary mediators of therapeutic response. Biologic drugs are the latest addition to the thera- peutic armamentarium in managing IBD. Strong TGNs are incorporated into DNA, inhibiting its evidence advocating combination therapy in treat- synthesis and leading to DNA strand breakage thus ing moderate to severe CD comes from the hindering cell proliferation [Aarbakke et al. 1997]. SONIC trial, which found biologic with concomi- However, the main mechanism of immunomodula- tant thiopurine therapy more efficacious than tion is by inducing T-cell apoptosis by modulating either drug as monotherapy [Colombel et al. cell (Rac1) signalling [Tiede et al. 2003]. 2010]. This finding indicates yet another use for thiopurine drugs in the evolving treatment of IBD. Initiating and dosing thiopurine therapy There is much inter-individual variation in the Metabolism of thiopurines metabolism of thiopurines, both in their side AZA and MP are prodrugs that undergo extensive effects and efficacy. This is due to differences in metabolism via a complex enzymatic pathway. the amount of drug absorbed, idiosyncratic http://taj.sagepub.com 139 Therapeutic Advances in Chronic Disease 6(3) reactions, drug–drug reactions and polymorphic Monitoring thiopurine therapy variation in thiopurine enzyme metabolism. The When commencing thiopurine therapy, the full appropriate ideal dose for AZA is 2–2.5 mg/kg/ blood count (FBC) and liver function tests day and for MP is 0.75–1.5 mg/kg/day [Mowat (LFTs) should be monitored every 2 weeks for et al. 2010]. The dose of TG is not dependent on the first 2 months followed by every 3 months for the patient’s weight and is usually prescribed at a the duration of therapy. Pancreatitis and hepato- dose of 20 mg/day. toxicity are uncommon, however the purpose of blood monitoring is primarily to detect thiopu- The therapeutic onset after thiopurine initiation is rine-induced leucopenia during treatment with delayed as it takes between 12 and 17 weeks for approximately half of patients developing signs TGNs to be incorporated into DNA [Prefontaine within 2 months and nearly two-thirds within 4 et al. 2010]. This can have a great impact on clinical months of drug initiation [Colombel et al. 2000]. practice and acutely unwell patients often have to As a result, it is recommended that the FBC and be bridged to thiopurine therapy with intermediary LFTs be rechecked following any dose escalation. immunosuppressants such as corticosteroids. Patients developing flu-like illness, jaundice, abdominal pain and unexplained bleeding/bruis- MP is mainly metabolized by TPMT and has a ing should report these signs to their physician
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