Do Thiopurines Still Play a Role in Treating IBD?

The role of thiopurines in the treatment of inflammatory bowel disease (IBD) has evolved since their introduction in the late 1960s to that of a therapeutic agent most effective for maintaining remission of Crohn disease (CD) and ulcerative colitis (UC), according to Stephen B. Hanauer, MD, who spoke on the topic at the virtual Interdisciplinary Autoimmune Summit 2020 on July 12.

Dr Hanauer is a professor of medicine and gastroenterologist at Northwestern University in Chicago, Illinois.

Dr Hanauer reviewed several studies and reviews that found that thiopurines such as azathioprine are effective for treating CD and UC. A meta-analysis conducted in 1995 “demonstrated there was indeed an impact in both active Crohn treatment and maintenance of remission,” he explained. This led to more widespread use and acceptance of thiopurines for the treatment of CD.

“Adequately powered trials are still needed to determine the safety and efficacy of both azathioprine and 6-MP compared with other active maintenance therapies,” Dr Hanauer stated.

He explained, “We have two key opportunities to treat CD—early in the course of the disease or in the post-operative setting in which surgically induced remission has been achieved but there is a near-inevitable recurrence of CD if the patient remains untreated.” In fact, Dr Hanauer noted, one study showed that thiopurines showed better outcomes in maintaining remission than infliximab in post-operative treatment.

Recent Cochrane meta-analyses show that in patients with longstanding CD, thiopurines are not effective for inducing remission but are effective for maintaining remission, for steroid sparing, and for preventing post-operative recurrence of disease, Dr Hanauer stated.

Among the strongest—and relatively new—indications for thiopurines is in combination with biologics for CD and UC. In the SONIC trial, patients with moderately severe CD who were also biologic naïve and immunomodulator naïve were randomized prospectively to receive azathioprine monotherapy, infliximab monotherapy, or a combination of these agents. In the results, Dr Hanauer stated, “We see a clear 13-point increase in clinical remission without steroids at week 26,” with 57% of patients on combination therapy achieving remission, compared with 30% on azathioprine alone and 44% on infliximab alone.”  

In the SUCCESS study of patients with UC, the combination of infliximab and azathioprine demonstrated superior results to either therapy alone in both mucosal healing and steroid-free remission at week 16.

Dr Hanauer conceded that there are risks involved in the use of thiopurines, including heightened risk of lymphoma, nonmelanotic skin cancers, and myelodysplasia. He noted that the incidence of lymphoma in patients treated with thiopurines is 5 times the incidence in the general population.

“We must consider the absolute risk,” which is 0.26 in unexposed patients per 1000 patient-years; 0.54 in patients treated with thiopurines; 0.41 patients treated with anti-tumor necrosis factor inhibitors (TNFis; and 0.95 in patients who receive combination therapy.

Dr Hanauer reviewed the guidelines of gastrointestinal societies in the United States, Canada, and Europe, pointing out that they largely agree on key points regarding the use of thiopurines for the treatment of IBD—advising against using these agents as monotherapy to induce remission but recommending them in combination therapy with other agents, including anti-TNFis, to sustain remission of IBD.

“I do believe there is a future for thiopurines in IBD therapy but there is the need for further comparative effectiveness and safety studies,” he said.

—Rebecca Mashaw

Reference:

Hanauer, SB. The role for immunosuppressives in IBD in the biologic era. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 12, 2020.