Real-world effectiveness and safety of ofatumumab in multiple sclerosis: a longitudinal study integrating clinical, cognitive, and MRI outcomes

Background: Despite the availability of several disease-modifying therapies for multiple sclerosis (MS) patients, the optimal strategy remains debated. High-efficacy therapies may better prevent subclinical disease activity and long-term disability; however, escalation remains frequent in real-world practice. Ofatumumab, an anti-CD20 monoclonal antibody, demonstrated robust efficacy and safety in clinical trials; however, real-world data are also essential.Objectives: To evaluate the effectiveness and safety of ofatumumab in relapsing MS (RMS), comparing outcomes between treatment-na & iuml;ve and previously treated patients, and identify predictors of suboptimal response.Design: Prospective longitudinal observational study of RMS patients followed at the Verona MS Center.Methods: Clinical assessments, annual 3.0T brain MRI, and comprehensive neuropsychological testing were performed throughout follow-up. Treatment effectiveness was evaluated using no evidence of disease activity (NEDA), progression independent of relapse activity (PIRA), and cognitive PIRA. Safety was assessed by recording adverse events and treatment discontinuations.Results: Eighty-nine RMS patients (68.5% female, mean age 38.0 +/- 10.4 years) were followed for a mean of 3 years. Overall, 91% achieved NEDA-3, with one relapse and one case of MRI activity. Seven patients (7.9%) developed PIRA, six of whom also fulfilled criteria for cognitive PIRA. Among 46 NEDA-3 patients who underwent longitudinal cognitive assessment, 37 (80.4%) did not exhibit cognitive worsening during follow-up and were classified as NEDA-4, indicating stability across clinical, radiological, and cognitive domains. In general, among patients with longitudinal cognitive data, 37 of 54 (68.5%) were NEDA-4. Na & iuml;ve and previously treated patients showed comparable outcomes. Patients who failed to maintain NEDA-3 were older and had higher baseline disability, whereas in multivariable analyses, baseline Expanded Disability Status Scale (EDSS) was the only factor independently associated with NEDA-3 loss. When cognitive outcomes were included, associations between baseline clinical variables and NEDA-4 loss were attenuated. Ofatumumab was well-tolerated, with mostly mild transient injection-related reactions and 2 (2.2%) treatment discontinuations due to adverse events.Conclusion: Ofatumumab provided sustained multidimensional disease control, high NEDA-4 rates, and excellent tolerability. Baseline EDSS was the primary predictor of suboptimal response, underscoring the importance of early intervention. These findings support early anti-CD20 therapy as an effective strategy to preserve neurological function and limit long-term progression.