Immunomodulation with AZA/6‐MP/MTX: Current Use in IBD

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are potent immunomodulators that have been used in the management of IBD for more than 30 years. Methotrexate (MTX) is less widely used, partly based on custom but also because of concerns regarding toxicity. This brief review will highlight some of the key issues arising from the numerous studies published since 2000, most involving adult patients. AZA/6-MP are now much more widely used than in the past. Markowitz et al (2001) surveyed the membership of NASPGHAN and compared the results with those of an identical survey in 1990. Significantly more now used these agents for Crohn's disease (CD) in children with growth failure, perianal and non-perianal fistulas, and for post-operative prophylaxis. Early use (following diagnosis) has probably increased – partly due to the publication of a frequently cited pediatric randomised controlled trial (RCT) (Markowitz et al 2000) showing that this practice reduced relapse frequency. This was hardly surprising given the known effects of AZA in adults, but of course that trial did not address the complex risk / benefit issues for routine use. Does immunomodulator therapy alter the natural history of IBD? In a recent retrospective study of 2573 adults with CD seen over 25 years during which AZA and MTX usage increased progressively (initially unused and in the final phase used in 56%) the risk of resection, strictures and penetrating disease was unaltered.(1) Can the use of these agents reduce the risk of osteoporosis? Osteoporosis is a special concern in young people given that bone demineralisation early in life increases the risk of osteoporosis in later years. In a DXA scan study of adults with CD and UC, remission for >3 years and AZA usage were associated with significantly increased bone mineral density. (2) In my Department we undertook a retrospective cohort study to explore the possibility that patient characteristics (clinical, laboratory, radiological and endoscopic findings) at the time of first presentation with IBD might identify those who would subsequently receive AZA. The most significant finding was that those requiring IV corticosteroids at presentation usually ran a difficult course afterwards requiring AZA treatment. This supports the view that such patients should be considered for AZA therapy from the outset. No other patient characteristic usefully predicted the need for AZA. In an important 30 year retrospective review the efficacy of AZA in 622 recipients among 2205 IBD patients was examined (3). This study provides information that could not easily be obtained from prospective studies. The RCT evidence in support of immunomodulator therapy is stronger for CD than UC. Here, however, AZA was even more likely to achieve remission in UC than in CD. Given the concerns about toxicity with AZA/6-MP there is a long-standing question regarding optimal treatment duration. This study provides compelling evidence that the effectiveness of AZA does not wane over time, and when discontinued relapse rates at 1, 3 and 5 yr were increased. Importantly, the risk of relapse was no less in those who had taken AZA for longer periods. Consistent with this study, two recent randomised placebo controlled withdrawal studies have shown that discontinuation after 2 and 3.5 years of treatment respectively was associated with an increased risk of relapse. It appears that the traditional practice of withdrawing treatment after a few years may not be well founded. Given their proven efficacy AZA/6-MP might be used in all patients as maintenance therapy were it not for the risk of side-effects. Most published series suggest that some form of adverse effect occurs in 10-15% of patients. These drugs are subject complex metabolism, and thiopurine methyltransferase (TPMT) is a key enzyme. Enzyme activity in Caucasian populations has a tri-modal distribution, being high (89%), intermediate (11%), or low (0.3%). Those with low levels have high levels of 6-thioguanine nucleotides (6-TGN). 6-TGN levels are important, being associated with both immunosuppression and myelosuppression. Measurement of TPMT activity (phenotype) or genotyping may identify those at high risk of myelosuppression with standard doses of AZA/6-MP. However, there is much debate about the merits of measuring TPMT. This is one of the first examples of pharmacogenetic research potentially assisting clinical practice. Unfortunately, myelosuppression may occur even in those with normal enzyme activity, and so blood count monitoring is still necessary. Some therefore argue that TPMT measurement it not justified. A recent economic cost analysis supported its routine measurement, but as so often the generalisability of the study's findings may be argued. There are other potentially important reports in relation to TPMT. It is inhibited in vitro by aminosalicylates, raising concerns about co-treatment with such agents. Low TPMT activity might have a potential for causing long-term toxicity. Children with acute lymphoblastic leukaemia may be at increased risk of later developing secondary treatment-related malignancy (acute myelogenous leukaemia) if they have a low TPMT level and have received thiopurines. Of course they have additional risk factors, being treated with various other anti-neoplastic drugs, and these concerns may not be relevant to IBD patients. There are several contradictory studies (underpowered) examining the correlation between RBC 6-TGN levels and induction of remission. A recent meta-analysis has now reported that higher levels are indeed associated with remission (4). The authors suggest that 6-TGN level measurement might be useful in specific circumstances - identifying those who unlikely to responder (6-TGN level greater than the effective threshold), those who are non-compliant (very low 6-TGN levels). There has been discussion for many years about the possibility that AZA/6-MP might be associated with an increased risk of lymphoma, as is reported in transplant patients. A recent meta-analysis of cohort studies suggested that there was a four-fold increased incidence of lymphoma in patients with IBD patients treated with a thiopurine (5). There was considerable heterogeneity between the studies which included patients from specialist centres. Large population based studies have failed to identify this association. The increased risk could be due to treatment or disease severity, association not necessarily indicating causation. Generally it is agreed that the risk must be small and that the risk / benefit ratio firmly supports the use of these drugs in IBD. Although there is convincing RCT evidence that MTX is effective in CD it is much less widely used than the thiopurines. A recent survey of Canadian gastroenterologists indicated that 33% never used it, and 61% considered it a second-line therapy. Of the paediatric gastroenterologists surveyed, 17.6% never used it. This reluctance is perhaps related to perhaps unjustified concerns about potential side effects. A recent Cochrane review (CD003459) concluded that MTX (25 mg/wk, IM) is an effective treatment in adults with chronically active steroid resistant CD. In those who respond MTX also appears effective in maintaining remission. However, unlike rheumatoid arthritis in which low dose oral MTX has a central role in disease management, there is a lack of evidence for this strategy in IBD. Two studies compared MTX with AZA and 6-MP and found no difference, but they lacked statistical power. MTX metabolism is complex, and a subject of pharmacogenetic research. A recent study examined the frequency of various potentially relevant polymorphisms in patients with IBD. An association was reported between a mutation in the methylenetetrahydrofolate reductase enzyme gene and the risk of side effects (6).

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