Multicenter Study Tracks Ofatumumab Effectiveness and Infection Risks in Multiple Sclerosis

A multicenter retrospective study conducted across four tertiary multiple sclerosis referral centers in Italy has demonstrated that the subcutaneous anti-CD20 monoclonal antibody ofatumumab substantially curtails clinical relapses and focal inflammatory lesions in adults with relapsing multiple sclerosis, whether patients initiate the drug as a first-line therapy or switch from prior treatments. Evaluating 424 adult patients monitored for a mean duration of 1.32 years, the investigation identified a 94.5 percent overall reduction in annualized relapse rates alongside widespread suppression of active magnetic resonance imaging activity. While clinical and radiological effectiveness remained remarkably consistent between treatment-naïve individuals and those previously managed with moderate- or high-efficacy therapies, the analysis uncovered a distinct safety divergence regarding infectious complications. Specifically, individuals transitioning to ofatumumab from high-efficacy therapies faced a significantly higher incidence of infections compared to treatment-naïve individuals and those switching from moderate-efficacy regimens, highlighting the critical role of cumulative immunological history in routine clinical management.

Multiple sclerosis represents a chronic, immune-mediated disorder of the central nervous system characterized by multifocal inflammatory demyelination, axonal injury, and widespread neurodegeneration that causes long-term neurological disability in young adults. Neuropathological studies have established that disease progression involves acute inflammatory lesions, slowly expanding demyelinating plaques, compartmentalized meningeal inflammation, and sustained microglial activation. Over the past decade, immunological research has confirmed that B cells play a central pathogenic role beyond their conventional function as precursors to antibody-producing cells. Circulating B cells operate as potent antigen-presenting cells and prolific sources of pro-inflammatory cytokines that trigger aberrant T-cell activation and facilitate infiltration into central nervous system tissue. Clonal relationships identified among B-cell populations isolated from peripheral blood, cerebrospinal fluid, and neural parenchyma demonstrate an active recirculating axis that perpetuates smoldering inflammation, providing a firm biological rationale for the selective deployment of monoclonal antibodies targeting CD20-expressing B cells.

Formulated for subcutaneous self-administration, ofatumumab is a fully human anti-CD20 monoclonal antibody engineered to achieve rapid and sustained depletion of peripheral B cells while maintaining stable pharmacokinetic and pharmacodynamic profiles. In the pivotal randomized ASCLEPIOS clinical trials, ofatumumab demonstrated superiority over the oral disease-modifying therapy teriflunomide across clinical relapse endpoints and magnetic resonance imaging parameters, while the long-term ALITHIOS extension study confirmed durable efficacy alongside a stable safety record with monthly dosing. However, clinical trial cohorts remain restricted by rigorous eligibility criteria that exclude patients with extended disease durations, comorbidities, or diverse sequences of prior therapies. In routine clinical practice, evaluating how previous treatment exposure shapes the effectiveness and safety of ofatumumab represents an essential therapeutic objective. Transitions between disease-modifying therapy classes carry potential risks of altered therapeutic responsiveness, rebound inflammatory activity, or elevated infectious complications, yet published real-world evidence examining ofatumumab has previously been limited to single-center cohorts or small multicenter datasets.

To address this knowledge gap under routine healthcare conditions, researchers evaluated medical records across four tertiary Italian referral centers in Bari, Genoa, Turin, and Cagliari. Reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines and approved by local ethics committees, the retrospective study implemented standardized extraction procedures that verified data completeness and consistency across all sites. The cohort enrolled adults aged 18 years or older diagnosed with relapsing multiple sclerosis under the 2017 McDonald criteria who initiated ofatumumab between March 2022 and March 2025 and completed at least one clinical or radiological follow-up assessment. Patients were stratified into three distinct clinical groups: treatment-naïve individuals starting ofatumumab as their initial therapy, patients switching from moderate-efficacy therapies including interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, and azathioprine, and patients switching from high-efficacy therapies including natalizumab, ocrelizumab, sphingosine-1-phosphate receptor modulators, cladribine, and alemtuzumab.

Among the 424 patients analyzed over a mean follow-up of 1.32 years, mean age at ofatumumab initiation was 39.1 years, and 215 individuals, representing 50.7 percent, were female. Patients had a mean disease duration of 10.3 years, an average latency from diagnosis to ofatumumab initiation of 7.6 years, and a baseline median Expanded Disability Status Scale score of 2.5 with an interquartile range of 1.5 to 3.5. Treatment-naïve individuals accounted for 23.8 percent of the cohort, while 76.2 percent were switchers, including 113 moderate-efficacy switchers and 210 high-efficacy switchers. Patients experienced an average of 2.19 prior relapses, with an annualized rate of 0.51 in the preceding year. Pre-treatment neuroimaging identified gadolinium-enhancing T1 lesions in 24.1 percent of patients and new or enlarging T2 lesions in 52.6 percent. Baseline inflammatory lesions appeared more often in naïve patients than switchers: enhancing lesions in 49.5 percent versus 17.3 percent, and T2 lesions in 62.4 percent versus 49.4 percent.

Therapeutic evaluation revealed that ofatumumab induced a marked, statistically significant reduction in relapse activity across the multicenter cohort. Negative binomial regression modeling adjusted for patient age, sex, baseline disability score, and preceding relapse history demonstrated that the adjusted annualized relapse rate fell from 0.486 before treatment to 0.027 during ofatumumab administration, representing a 94.5 percent relative reduction with a p-value below 0.001. This pronounced therapeutic effect proved consistent across all treatment sequences when examined individually. Among treatment-naïve patients, the adjusted annualized relapse rate dropped from 0.792 prior to therapy down to 0.032 while receiving ofatumumab. Patients switching from moderate-efficacy therapies experienced a parallel decline from 0.529 to 0.025, and individuals transitioning from high-efficacy therapies exhibited a reduction from 0.346 to 0.022. Statistical comparisons of rate ratios confirmed that the relative magnitude of relapse suppression did not differ significantly between treatment-naïve individuals and either switcher group, indicating uniform clinical flare suppression regardless of prior drug exposure.

Standardized magnetic resonance imaging based on MAGNIMS recommendations documented profound suppression of radiological disease activity following ofatumumab initiation. Across the total cohort, patients presenting gadolinium-enhancing T1 lesions plummeted from 24.1 percent at baseline to 2.1 percent on therapy, representing an absolute decline of 21.9 percentage points and a relative reduction of 91.2 percent. Enhancing lesions fell from 49.5 percent to 2.0 percent in naïve patients, and from 23.9 to 1.8 percent and 11.9 to 2.4 percent in moderate- and high-efficacy switchers, respectively. Concurrently, the proportion of individuals displaying new or enlarging T2 lesions decreased from 52.6 percent to 12.7 percent, yielding an absolute reduction of 39.9 percentage points and a relative decline of 75.8 percent. Subgroup evaluations confirmed robust T2 reductions across all categories, decreasing from 62.4 percent to 16.8 percent in treatment-naïve patients, from 76.1 percent to 12.4 percent in moderate-efficacy switchers, and from 35.2 percent to 11.0 percent in high-efficacy switchers.

Analysis of longitudinal disability trajectories and composite disease control parameters further substantiated clinical stability under ofatumumab. Over a 24-month observation period, the Kaplan-Meier estimate for confirmed disability worsening sustained for at least six months was 13.2 percent based on nineteen events across the cohort. Progression rates reached 10.7 percent in treatment-naïve individuals, 13.8 percent in moderate-efficacy switchers, and 5.7 percent in high-efficacy switchers, with adjusted hazard ratios showing no significant differences between groups. Confirmed disability improvement sustained for six months occurred in 9.5 percent of the cohort, documented in 9.1 percent of naïve patients, 2.9 percent of moderate-efficacy switchers, and 6.3 percent of high-efficacy switchers. Furthermore, among 237 participants with complete twelve-month follow-up data and corresponding neuroimaging scans, 79.3 percent achieved composite no evidence of disease activity status, or NEDA-3. Achievement rates remained uniform across groups at 76.8 percent in naïve patients, 81.5 percent in moderate-efficacy switchers, and 79.3 percent in high-efficacy switchers.

Regarding tolerability and retention, ofatumumab exhibited a favorable safety profile consistent with clinical trial observations. Overall, 17.8 percent of participants experienced at least one adverse event during the study period, with mild injection-related reactions constituting the most common complication, reported in 12.5 percent of patients without significant variance across treatment subgroups. Neoplasms occurred in three individuals, representing 0.7 percent of the cohort, comprising one colonic adenoma and two intraductal papillary mucinous neoplasms. Treatment discontinuation occurred in 19 patients, or 4.5 percent of the cohort, distributed among two treatment-naïve patients and seventeen switchers without statistically significant differences between subsets. Seven discontinuations were prompted by pregnancy planning or confirmed conception; in all instances, ofatumumab administration was temporarily halted upon pregnancy recognition. Six pregnancies progressed to full-term deliveries resulting in healthy neonates devoid of congenital malformations or obstetric complications, while one pregnancy remained uneventfully ongoing at data extraction, and therapy was subsequently resumed postpartum without adverse safety signals.

In contrast to uniform efficacy outcomes, infectious complications revealed a statistically significant divergence between patient groups. Overall, 5.4 percent of patients developed at least one infection during follow-up, predominantly manifesting as uncomplicated urinary tract infections without hospitalizations. However, infection rates varied starkly by prior therapy: 0.9 percent in treatment-naïve individuals, 1.7 percent in moderate-efficacy switchers, and 9.5 percent in high-efficacy switchers. Multivariable logistic regression identified prior high-efficacy therapy exposure as the sole independent predictor of infection risk. The adjusted odds of infection were significantly lower in naïve patients (odds ratio 0.10) and moderate-efficacy switchers (odds ratio 0.18) compared to high-efficacy switchers. Authors attributed this heightened susceptibility to the cumulative immunomodulatory burden from earlier agents rather than a direct ofatumumab toxicity. Acknowledged study limitations include the retrospective multicenter design, potential referral center selection bias, an average follow-up of 1.32 years, decentralized magnetic resonance imaging readings, and the absence of serial post-baseline immunoglobulin and lymphocyte monitoring.

Subject of Research: Real-world effectiveness and safety of ofatumumab in relapsing multiple sclerosis

Article Title: Real-World Effectiveness and Safety of Ofatumumab in Relapsing Multiple Sclerosis: Comparison of Treatment-Naïve Patients and Switchers in a Multicenter Cohort

Article References: Mangialardi, V., Macchitella, G., Vitobello, R., Teofilo, A., Cavalli, N., Lapucci, C., Vercellino, M., Idini, E., Frau, J., Iaffaldano, P., Cavalla, P., Inglese, M. M., Cocco, E., & Paolicelli, D. (2026). Real-World Effectiveness and Safety of Ofatumumab in Relapsing Multiple Sclerosis: Comparison of Treatment-Naïve Patients and Switchers in a Multicenter Cohort. Drugs – Real World Outcomes, 13(2), 279-287. https://doi.org/10.1007/s40801-026-00558-6

Image Credits: AI Generated

DOI: 10.1007/s40801-026-00558-6

Keywords: multiple sclerosis, ofatumumab, disease-modifying therapies, relapsing multiple sclerosis, B-cell depletion, real-world evidence, neuroimmunology, treatment sequencing, Real-World, Effectiveness, Safety, Relapsing