Divergent Immunological and Neurotrophic Responses to CD20 Depletion in Relapsing and Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with distinct subtypes, relapsing MS (RMS) and primary progressive MS (PPMS), which differ in clinical course and underlying immunopathology. Cytokines are pleiotropic mediators of inflammatory and regenerative processes and are considered important contributors to the pathophysiology of MS. Ocrelizumab, a CD20-targeting monoclonal antibody, is approved for the treatment of patients with RMS and PPMS, yet its effects on circulating cytokines and neurotrophic factors remain incompletely understood.

In this prospective observational study, 84 patients with MS (57 RMS, 27 PPMS) were analyzed regarding demographic data, disease activity and serum cytokine profiles before and 6 months after the start of ocrelizumab therapy.

Baseline analyses revealed distinct cytokine signatures between patients with RMS and PPMS, with higher levels of several proinflammatory cytokines and chemokines in patients with RMS. Following ocrelizumab treatment, divergent cytokine profiles between patients with RMS and PPMS were partially attenuated, with significant modulation of Th1-associated chemokines and an increase in brain-derived neurotrophic factor (BDNF) observed in patients with RMS. In contrast, cytokine signatures in patients with PPMS remained largely unaffected by ocrelizumab treatment. Patients with RMS with disease activity during the first 6 months of ocrelizumab treatment showed a significant increase in different chemokines compared to baseline compared with patients without disease activity or those with PPMS.

Our findings support divergent immunological mechanisms in RMS and PPMS, with a stronger cytokine-driven pathology and more pronounced immunomodulatory effects of ocrelizumab on the cytokine profile in patients with RMS.