Classic Drugs in the Time of New Drugs

Real-world, Long-term Outcomes of Thiopurine Monotherapy in 1016 Patients With Inflammatory Bowel Disease

Ashkan Rezazadeh Ardabili; Steven Jeuring; Zlatan Mujagic; Liekele Oostenbrug; Mariëlle Romberg-Camps; Daisy Jonkers; Adriaan van Bodegraven; Marieke Pierik

Disclosures

Aliment Pharmacol Ther. 2022;56(6):1030-1043. 

In This Article

Abstract and Introduction

Abstract

Background: Thiopurines remain recommended as maintenance therapy in patients with inflammatory bowel disease (IBD). Despite their widespread use, long-term effectiveness data are sparse and safety is an increasingly debated topic which thwarts proper delineation in the current IBD treatment algorithm.

Aims: To document effectiveness and safety of thiopurine monotherapy in patients with IBD, using the population-based IBD South-Limburg (IBDSL) cohort

Methods: All patients starting thiopurine monotherapy as maintenance between 1991 and 2014 were included. Therapy was defined as effective if there was no escalation to biologicals, no course of corticosteroids, no surgery and no hospitalisation for active disease during treatment. Long-term effectiveness was assessed by adjusting for differences in follow-up using Kaplan–Meier analyses. Mid- to long-term safety regarding cancer incidence and clinically relevant liver disease was documented.

Results: In total, 1016 patients (643 Crohn's disease [CD]; 373 ulcerative colitis [UC]) received thiopurine monotherapy at a median of 15.2 (Q1-Q3 4.2–48.5) months after diagnosis. During follow-up, effectiveness rates at 1, 5 and 10 years were 64%, 45%, 32%, respectively, in CD and and 66%, 41%, 36%, respectively in UC. No statistically significant differences in effectiveness were observed after stratification for era of initiation (pre-biological vs biological, CD: p = 0.56; UC: p = 0.43). Sixteen non-melanoma skin cancers (incidence rate [IR] 3.33/1000 PY), five lymphomas (IR 1.04/1000 PY) and one urinary tract cancer (IR 0.21/1000 PY) were recorded. Two cases of portal hypertension were identified.

Conclusion: In real-world practice, thiopurine monotherapy remains effective, safe and durable for patients with CD or UC, including in the era of biologics.

Introduction

Thiopurines have held a place in the treatment of Crohn's disease (CD) as well as ulcerative colitis (UC) patients for over 40 years. Thiopurines have proven to be valuable in maintaining (medically induced) remission, corticosteroid-sparing regimens, reducing post-operative recurrence, delaying disease progression, and, in combination with anti-TNF, in preventing anti-drug antibody formation with or without increasing through levels.[1–7] Aside from their effectiveness, thiopurines are an attractive treatment option due to their widespread availability, oral administration route, well-outlined knowledge of potential adverse events, lack of immunogenicity and accessibility due to lower costs compared to biologicals or biosimilars.

Despite the growing armamentarium of biologicals, thiopurines are still recommended as monotherapy in first or second-line maintenance treatment in patients with moderate-to-severe CD and steroid-dependent UC in current and recent international Inflammatory bowel disease (IBD) treatment guidelines.[8–11] Although extensively and widely used, effectiveness is an increasingly debated topic, particularly since the introduction of biologicals and the overall quality of evidence for their efficacy remains low. In trials with strongly-selected CD patients, such as in the RAPID and AZTEC trials, no statistical difference in efficacy was observed when comparing early use of azathioprine to either placebo or conventional thiopurine use respectively. In two older randomised trials conducted in UC patients, no benefit for thiopurines was found.[12–15] In addition, in the early years of infliximab therapy, combination therapy resulted in higher rates of clinical and endoscopic remission in comparison to monotherapy of thiopurines or infliximab.[5,6] In observational studies in real-world settings it has been suggested that thiopurine monotherapy benefits IBD patients. However, these studies were limited by relatively small numbers or short follow-up of patients.[16–23] Furthermore, in a recent large observational study from the UK, a lower, overall effectiveness rate of thiopurine monotherapy in CD patients as compared to UC patients was reported and the authors suggested a potential re-evaluation of thiopurine use in CD.[24]

Another frequently debated concern over thiopurines is its safety profile, including an increased risk of (viral) infections (e.g. Epstein–Barr virus [EBV]; human papillomavirus [HPV]), potential liver manifestations (e.g. hepatotoxicity and nodular regenerative hyperplasia [NRH]) as well as the long-term risk of non-melanoma skin cancers (NMSC), lymphomas, urinary tract cancer and cervical cancer.[25–28] These safety issues, in combination with the sparsity of long-term data on thiopurine effectiveness, opened discussions on the benefit–risk balance of thiopurines in comparison to biologicals. However, biologicals and small molecules have also been associated with an increased risk of opportunistic and serious infections, as well as certain cancers, and long-term population data on safety are still limited.[29,30]

The aforementioned observations concerning the benefit–risk balance have also fuelled questioning on the position of thiopurines in the IBD treatment algorithm.[26,31] Interestingly, particularly in the perspective of consensus guidelines, such as the ECCO's, a recent international survey among more than 400 IBD physicians revealed that the majority of physicians still resort to thiopurines in a substantial proportion of patients and believe that thiopurines will still be an important part of the IBD treatment in the future. Moreover, 70% of respondents (strongly) agreed that thiopurines are effective as monotherapy in both CD and UC.[32]

In consideration of the ongoing discussion and limited real-world long-term evidence, this study aimed to assess the long-term effectiveness and safety of thiopurine monotherapy in both CD and UC patients in a population-based study.

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