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

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.

To evaluate the effectiveness and safety of ofatumumab in relapsing MS (RMS), comparing outcomes between treatment-naïve and previously treated patients, and identify predictors of suboptimal response.

Prospective longitudinal observational study of RMS patients followed at the Verona MS Center.

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.

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. Naïve 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.

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.