Rituximab Linked to 10-fold Higher IBD Risk in MS

Treatment with the anti-CD20 medication rituximab was linked to a nearly 10-fold increased risk for inflammatory bowel disease (IBD) in patients with relapsing-remitting multiple sclerosis (MS).Results of a large Swedish registry-based study involving more than 9200 patients with relapsing-remitting MS (RRMS) showed that the association persisted even after adjustment for demographic and disease-related factors, although the absolute risk was low. Crohn’s disease accounted for most IBD cases in the rituximab group.Peter Alping, MD, PhD“Our results suggest rituximab increases the risk of developing IBD in persons with RRMS,” study investigator Peter Alping, MD, PhD, postdoctoral researcher at the Division of Clinical Epidemiology, Department of Medicine at Karolinska Institutet in Solna, Sweden, told Medscape Medical News. He added, “Although the cumulative incidence of IBD remained below 2% at 10 years after therapy start.”The study was presented on October 22 at the joint ACTRIMS-ECTRIMS meeting MSToronto2026 in Toronto, Ontario, Canada, and simultaneously published online in JAMA Neurology.Why Look at IBD Risk?Anti-CD20 therapies, which reduce B-cell activity, are effective treatments for MS. Although rituximab is not approved by the FDA for MS, it is widely used off-label in Sweden, where it is the most commonly prescribed MS therapy.However, case reports and pharmacovigilance analyses have raised concerns about new or worsening IBD during anti-CD20 treatment.Previous research has also linked MS and IBD, suggesting that having either condition is associated with an approximately 50% increased risk for the other. This makes it difficult to determine whether IBD developing during MS treatment is related to MS itself or the medication.Using Swedish national health registers, researchers compared new-onset IBD among patients with RRMS receiving rituximab, those receiving other commonly used disease-modifying therapies (DMTs), and those without MS.The analysis included 13,748 therapy episodes among 9251 patients with RRMS, including 6481 with rituximab, 2976 with natalizumab, 2767 with dimethyl fumarate, and 1524 with fingolimod initiated between January 2011 and December 2023 among patients (mean ages of exposure groups, 35-38 years) with no history of IBD and at least 10 years of prior medical records.The researchers grouped the three other DMTs into one comparison group. The general population comparison included 61,065 matched records from 40,925 individuals without MS.The primary outcome was a new IBD diagnosis, identified through at least two separate medical records documenting Crohn’s disease, ulcerative colitis, or indeterminate colitis.Patients were followed until an IBD diagnosis, treatment discontinuation, death, emigration, or the end of available data.The researchers also adjusted the analyses for demographic and MS-related factors, including disease duration, previous relapses, prior treatments, and disability.More IBD Cases With RituximabDuring follow-up, 164 individuals developed IBD, including 40 in the rituximab group, four in the other MS treatment group, and 120 in the general population.The incidence of new IBD cases per 100,000 person-years was 110.4 among patients receiving rituximab compared with 13.4 among those receiving other DMTs and 40.7 in the general population.After adjusting for differences in patient characteristics and MS disease history, patients receiving other DMTs were less likely to develop IBD than those receiving rituximab (hazard ratio, 0.10).The adjusted rate was 134.3 new IBD cases per 100,000 person-years with rituximab, compared with 10.8 in the comparator group.The researchers estimated that for every 131 MS patients treated with rituximab rather than another DMT for 5 years, one additional patient would develop IBD. The comparison included natalizumab, dimethyl fumarate, and fingolimod.Despite the higher risk with rituximab, fewer than 2% of patients in any treatment group developed IBD within 10 years of starting therapy.Balancing Benefit and RiskThe median time until an IBD diagnosis was 2.9 years among those receiving rituximab, 1.8 years among those receiving other DMTs, and 2.8 years in the general population.Crohn’s disease accounted for 62% of IBD cases in the rituximab group compared with 29% in the general population and 25% in the other DMT group. Ulcerative colitis accounted for 15% of cases in the rituximab group, while the remaining 22% were classified as unclassified IBD.The study had several limitations, including the small number of IBD cases among those receiving other MS therapies, potential residual confounding, reliance on diagnostic codes to classify IBD, and its focus on rituximab in a single country.Choosing rituximab requires weighing the potential risk of developing IBD against the risk for MS relapses with alternative treatments.“It is important for clinicians to take the increased IBD risk into account when discussing treatment options with their patients and staying vigilant for gastrointestinal symptoms during treatment,” Alping said.However, he emphasized that the potential risk must be weighed against the benefits of effective MS treatment.“Rituximab and other anti-CD20 therapies are also among the most effective treatments for the acute inflammatory component of MS,” Alping said, adding that clinicians must balance the risk for adverse effects against the risk of recurring relapses if another treatment is chosen.A Low, but Real RiskAaron Miller, MD, medical director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis in New York City, who was not involved in the study, said the findings are consistent with previous reports linking anti-CD20 therapies to gastrointestinal inflammation.“The risk of IBD with rituximab is clearly increased over both the population taking other MS disease-modifying drugs or the non-MS population,” Miller, who is also a professor of neurology at Icahn School of Medicine at Mount Sinai in New York City, told Medscape Medical News. However, he emphasized that the risk is very low, at approximately one case per 1000 patient-years.IBD is listed as a warning in the prescribing information for ocrelizumab, Miller noted, but not for ublituximab or ofatumumab. He also added that the mechanism to explain the occurrence of colitis is unclear.Overall, he does not expect the findings to change MS treatment decisions or clinical monitoring but emphasized the importance of educating patients about the “low, but real, risk of IBD with anti-CD20 agents.”Disclosure information for study authors is available in the original study publication. Miller reported having no relevant financial disclosures.