Comparative effectiveness of anti-CD20 therapies and S1P receptor modulators in late-onset multiple sclerosis: real-world evidence from the MSBase registry

Abstract

BACKGROUND: Late-onset multiple sclerosis (LOMS), defined by symptom onset after age 50, is increasingly recognised as a distinct clinical entity. Evidence comparing disease-modifying therapies (DMTs) in this subgroup remains limited. OBJECTIVES: To compare clinical outcomes of anti-CD20 monoclonal antibodies and sphingosine-1-phosphate receptor modulators (S1PRMs) in LOMS. DESIGN: Multicentre, observational cohort study based on real-world data from an international multiple sclerosis registry. METHODS: We analysed data from the MSBase registry, including relapsing-remitting LOMS patients treated with anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) or S1PRMs (fingolimod, ozanimod, siponimod, ponesimod) for ⩾6 months. Primary outcomes were annualised relapse rate (ARR), Expanded Disability Status Scale (EDSS) change, confirmed disability worsening (CDW), progression independent of relapse activity (PIRA), and PIRA without MRI activity (PIRMA). Analyses used inverse probability of treatment weighting (IPTW). Causal forest and best linear projector (BLP) models explored effect modification. RESULTS: After weighting, 347 patients (median age 53.7 years; 69 female; median follow-up 6.9 years) were included. No significant differences were found for ARR, EDSS change, CDW, PIRA, or PIRMA. Exploratory analyses suggested greater anti-CD20 benefit in patients with earlier onset (⩽55 years), shorter disease duration (⩽2 years from diagnosis), and lower disability (EDSS < 3). CONCLUSIONS: In this real-world LOMS cohort, no statistically significant differences were observed between anti-CD20 and S1PRM therapies. Exploratory analyses suggested anti-CD20 may be associated with better outcomes in selected subgroups; these findings are hypothesis-generating. TRIAL REGISTRATION: Not applicable. How two main treatments for late-onset multiple sclerosis compare in real life Multiple sclerosis (MS) is a disease where the immune system attacks the brain and spinal cord. When MS begins after the age of 50, it is called late-onset multiple sclerosis (LOMS). This form of MS can progress faster and respond differently to treatment compared to cases that start earlier in life. In this study, we compared two important groups of modern MS treatments: - Anti-CD20 therapies, which target specific immune cells, and - S1P receptor modulators, which prevent immune cells from reaching the brain. We analysed real-world data from an international MS registry called MSBase, including people with relapsing LOMS who had used one of these therapies for at least six months. We looked at how often relapses occurred, how disability changed over time, and whether disability increased independently of relapses. The results showed that, overall, both treatment types worked similarly in preventing relapses and disability worsening. However, in some patients-especially those younger than 55, with early disease and lower disability-anti-CD20 therapies appeared to have a small advantage. These findings suggest that both therapies are effective for most people with late-onset MS, but that starting anti-CD20 treatment early may be beneficial for selected patients. This information can help doctors personalise treatment plans for older adults living with MS.