Ofatumumab in multiple sclerosis: 2-year immune profiling and clinical correlates

Antonio Esposito, Luca Corsaro, Ilaria Delle Cave, Fabiana Capasso, Giuseppe Corsini, Giuseppina Matrone, Vincenza Cerbone, Maria Petracca, Antonio Carotenuto, Roberta Lanzillo, Giulia Scalia, Giuseppe Castaldo, Vincenzo Brescia Morra, Marcello Moccia

Journal of Neurology 2026 September 8

INTRODUCTION: Anti-CD20 monoclonal antibodies, such as ofatumumab, have significantly improved the management of multiple sclerosis (MS). Still, their long-term immunological effects, particularly on non-B-cell populations, remain poorly explored. We characterized longitudinal changes in circulating lymphocyte subsets and explored their clinical correlates in people with MS treated with ofatumumab.

METHODS: We conducted an observational cohort study including adults with MS who initiated ofatumumab and had paired baseline and on‑treatment assessments after at least 2 years (n=34). Immunophenotyping quantified total lymphocytes and subsets (CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD20+, CD56+, CD27+, CD27+CD3+, CD27+CD19+, CD3+CD20 +). Longitudinal change was modeled with linear mixed‑effects regression (fixed effects: age, sex, follow‑up duration, comorbidities, BMI, previous DMT; random intercept for subject). Annualized percentage change of each laboratory measure was related to relapses, MRI activity, EDSS progression, NEDA‑3, and EDSS improvement using multivariable logistic regression with the same covariates.

RESULTS: Over approximately 2 years of treatment, we observed increased total lymphocytes (Coeff 251.47; 95% CI 29.29-473.64; p=0.027), CD3+ (368.79; 183.66-553.91; p<0.01), CD3+CD4+ (239.82; 107.32-372.33; p<0.01), CD3+CD8+ (132.36; 52.92-211.80; p<0.01), CD27+ (275.37; 124.11-426.63; p<0.01), and CD27+CD3+ lymphocytes (451.99; 300.40-603.58; p<0.01), and decreased CD19+ (- 181.55; -234.40 to -128.70; p<0.01), CD20+ (- 181.55; -234.40 to -128.70; p<0.01), and CD27+CD19+ lymphocytes (- 1.82; -2.74 to -0.91; p<0.01). No significant associations emerged between changes of lymphocytes and relapses, MRI activity, EDSS progression, NEDA‑3, or EDSS improvement.

CONCLUSION: In this exploratory, descriptive, real-world cohort, ofatumumab was associated with sustained B-cell depletion (CD19+/CD20 +) and parallel increases in broad T-cell compartments. No associations with clinical or MRI outcomes were detected; these negative findings should be interpreted cautiously within the hypothesis-generating design, given the small sample size and low frequency of disease-activity events.

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