Multiple Sclerosis Anti-CD20 Drug Linked to Bowel Disease Risk

The anti-CD20 agent rituximab was associated with a higher risk of inflammatory bowel disease (IBD) in people with relapsing-remitting multiple sclerosis (MS) compared with other disease-modifying treatments (DMTs), a population-based cohort study in Sweden showed.

The crude incidence rate of IBD was 110 per 100,000 person-years for rituximab, 13 for comparator DMTs, and 41 for the general population, reported Peter Alping, MD, PhD, of the Karolinska Institutet in Stockholm.

After adjusting for demographics and MS characteristics, the hazard ratio for comparator DMTs versus rituximab was 0.10 (95% CI 0.04-0.22), Alping said at MSToronto2026, the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). The findings were published simultaneously in JAMA Neurology.

The cumulative incidence of IBD was less than 2% at 10 years, even in the rituximab group, Alping stated.

“Anti-CD20 therapies have proven to be among the most effective at reducing acute inflammatory activity in MS, and the first anti-CD20 therapy investigated for MS, rituximab, was never taken to market but was followed by newer alternatives,” he said. “Despite this, rituximab has been increasingly used off-label to treat MS and is now the most commonly used MS therapy in Sweden.”

Recent reports, including cases in the FDA Adverse Event Reporting System, have raised concerns about increased IBD risk after treatment with rituximab or the anti-CD20 drugs ocrelizumab (Ocrevus) and ofatumumab (Kesimpta). The ocrelizumab label includes a warning for immune-mediated colitis.

“Most of the discourse around safety for anti-CD20 treatment has revolved around severe infections and reduced vaccination response,” Alping pointed out. “We looked into the risk of inflammatory bowel disease following anti-CD20 treatment in multiple sclerosis.”

The researchers used data from the Swedish MS register to study 9,251 MS patients who started treatment with rituximab or a comparator DMT — natalizumab (Tysabri), dimethyl fumarate (Tecfidera), or fingolimod (Gilenya) — from 2011 through 2023. These initiations were matched with general population comparator episodes from the Swedish population. Participants were ages 18 to 55 years with at least 10 years of lookback time (5 years for dispensed drugs) and no evidence of previous IBD.

The researchers defined new-onset IBD as two or more records on separate dates with ICD codes for Crohn’s disease, ulcerative colitis, or indeterminate colitis.

The analysis included 13,748 therapy episodes — 6,481 for rituximab, 2,976 for natalizumab, 2,767 for dimethyl fumarate, and 1,524 for fingolimod — and 61,065 matched general population episodes. The mean age of MS patients in the exposure groups ranged from 35 to 38 years.

A total of 164 IBD events occurred during follow-up: 40 with rituximab, four with comparator DMTs, and 120 in the general population. In the rituximab group, 62% of IBD events were classified as Crohn’s disease, compared with 29% in the general population.

In a fully adjusted model, the number needed to harm at 5 years was 131 (95% CI 93-228) for rituximab versus comparator DMTs, Alping reported. “The interpretation of this number is that if we were to treat 131 patients with rituximab instead of the comparator DMTs, we would have caused one case of IBD at 5 years according to the model,” he said.

In Sweden, “we don’t really use the other anti-CD20 antibodies too much,” Alping observed. “Given what we know about the biology of these drugs, it is likely, I would say, that this is a class effect, but more research is needed.”

The outcome definition was based on ICD codes, he acknowledged. “We didn’t have access to colonoscopy, for example, but when we used a stricter definition also based on ICD codes, it gave consistent results,” he said. There also were few IBD events among comparator DMTs.

“Our takeaway is that clinicians and persons with MS should probably be aware of the risk of IBD and remain vigilant for gastrointestinal symptoms during treatment with anti-CD20 therapy, and also be careful when initiating treatment with anti-CD20 therapy in persons with MS and a history of IBD,” Alping said.