Thiopurines best practice.

Abstract

For over 30 years, the thiopurine immunomodulators, azathioprine (AZA), and 6-mercaptopurine (6MP) have been well established in inflammatory bowel disease treatment algorithms. Traditional use of thiopurines has focused on weight-based dosing, using 1 to 1.5 mg/kg for 6MP and 2 to 2.5 mg/kg for AZA.1 However, up to 60% of patients do not respond to a conventional dose and duration of thiopurine therapy, and up to 40% will experience some sort of adverse event leading to drug cessation.2 Combination therapy with a TNF antagonist and a thiopurine leads to the greatest proportion of patients with Crohn's disease or ulcerative colitis, achieving steroid free clinical remission and mucosal/endoscopic healing. Despite this, 45–60% of patients still fail to achieve these outcomes with standard weight-based dosing of thiopurines.3 Thiopurines are pro-drugs metabolized to produce the active metabolites 6-thioguanine nucleotides (6TGN) and 6-methylmercaptopurine (6MMP), but weight-based dosing of thiopurines does not correlate with 6TGN and 6MMP levels. 6TGN is the active metabolite responsible for therapeutic efficacy, and 6TGN levels above a threshold of 230–260 pmol/8 × 108 red blood cells improve remission rates (odds ratio of 3.15).4 For combination therapy with a TNF antagonist, optimizing thiopurine metabolites also improves remission rates.5 Mean corpuscular volume has also been shown to be a surrogate marker for 6TGN levels. So if a clinician is unable to measure 6TGN and 6MMP levels, a rise in mean corpuscular volume by at least 7 fL confers similar improvements in outcomes with combination therapy.6 Higher 6TGN levels also improve outcomes of TNF antagonist therapy by increasing TNF antagonist trough levels and decreasing the risk of anti-drug antibody formation.7 To achieve a therapeutic 6TGN level, when both 6TGN and 6MMP levels are low, the dose of thiopurine can be increased. Also, adding mesalazine can favorably affect thiopurine metabolites. For patients with high levels of 6MMP, low levels of 6TGN, adding 100 mg of allopurinol and reducing thiopurine dose by two-thirds, improves outcomes without any increased toxicity. Overcoming thiopurine-related adverse events to allow patients to remain on thiopurines is vital. Approximately 50% of patients who are intolerant to AZA will tolerate 6MP without recurrence of their adverse event.2 Furthermore, 75% to 80% of patients who are intolerant to conventional thiopurines can tolerate either allopurinol (with dose-reduced thiopurine) or 6-thioguanine (6TG).8 Combining these options can allow up to 85% of patients to remain on thiopurine therapy without complication. Clinicians also have concerns regarding risks associated with long-term use of combination therapy, and patients are usually interested in reducing their medication to the lowest levels possible. However, this has to be balanced against the risk of relapse and subsequent complications of uncontrolled inflammation. Data suggest that in patients who achieve clinical remission, de-escalating to monotherapy with either a thiopurine or a TNF antagonist leads to relapse rates of 20–50% after 1 year.9 However, the risk of relapse can be reduced to less than 10% if a number of key endpoints are achieved prior reducing therapy. From a disease activity perspective, these include normalization of the bowel at colonoscopy, normalization of C-reactive protein and hemoglobin levels and reduction in fecal calprotectin levels to less than 300 µg/g.9 It is feasible to continue with either agent as monotherapy; however, both drugs need to be maintained within their respective therapeutic ranges in order to prevent relapse. It has also been shown that length of time on therapy is important, as rates of relapse increase if a patient is on combination therapy for less than 2.5 years.10 For the newest available biologic agent vedolizumab, optimal treatment strategies are yet to be determined. In the landmark phase 3 studies, the combination of vedolizumab and a thiopurine led to higher vedolizumab trough levels and decreased anti-vedolizumab antibody formation; however, this did not translate to improved clinical outcomes. Studies are currently exploring these issues at the moment. In summary, in order for patients to have the best chance of both achieving and remaining in clinical and endoscopic remission, it is vital to optimize thiopurine metabolites and overcome any drug specific adverse event preventing a patient from tolerating a thiopurine. Similarly, when de-escalating therapy, it is important to ensure that drug levels remain within the therapeutic range and a patient is both in endoscopic and biochemical remission prior to drug cessation. This highlights that weight-based dosing of thiopurines is no longer standard of care and pro-active monitoring of both disease activity and drug levels are required to achieve these outcomes.