Anti‐ CD20 Drugs and Natalizumab Confer Equal Protection Against Progression Independent of Relapse Activity ( PIRA ) in People With Multiple Sclerosis

ABSTRACT Background Highly effective (HE) disease‐modifying therapies (DMTs) reduce relapse‐associated worsening (RAW) and progression independent of relapse activity (PIRA). Natalizumab (NTZ) and anti‐CD20 agents show similar efficacy on relapse suppression, but long‐term comparative data on PIRA are limited. We aimed to compare PIRA accrual in relapsing–remitting MS (RRMS) patients treated with NTZ and anti‐CD20 drugs over a long follow‐up. Methods We included RRMS patients followed at our centre and recorded in the Italian MS and Related Disorders Register with at least 5 years of continuous treatment with NTZ or anti‐CD20 agents (Ocrelizumab, Rituximab, Ofatumumab), at least 3 Expanded Disability Status Scale (EDSS) assessments, and complete demographic and clinical data. Patients were matched for gender, age, EDSS, disease duration, MS phenotype at treatment initiation. Logistic regression and Cox proportional hazard models were applied. Results Of 267 eligible patients (178 NTZ, 89 anti‐CD20), optimal matching yielded 89 balanced pairs. A first PIRA event was observed in 27.0% of NTZ‐treated and 28.1% of anti‐CD20‐treated patients. The total number of PIRA events was comparable between NTZ‐treated and anti‐CD20‐treated patients (36 vs. 30; p = 0.451). Adjusted analyses revealed no significant differences in cumulative risk (RR: 1.48; 95% CI: 0.66–3.40; p = 0.333) or time to first PIRA event (HR: 1.51; 95% CI 0.83–2.77; p = 0.179). Conclusion In this real‐world cohort with long‐term follow‐up, NTZ and anti‐CD20 therapies showed no significant differences in PIRA accrual or time to first PIRA, suggesting comparable long‐term control of disability progression beyond relapse. Larger studies are warranted to confirm and refine these observations.