Is intrathecal anti-CD20 an option to target compartmentalized CNS inflammation in progressive MS?

Is intrathecal anti-CD20 an option to target compartmentalized CNS inflammation in progressive MS? B cells have gained enormous attention in the treatment of multiple sclerosis (MS). While our earlier pathogenic understanding of its cause primarily focused on B cell–derived plasma cells producing self-reactive antibodies, more recent findings support the theory that B cells themselves substantially contribute to MS pathogenesis. This conceptual change was primarily triggered by the empirical observation that anti-CD20–mediated B-cell depletion is effective in the treatment of relapsing-remitting MS (RRMS). Clearly exceeding the initial expectations, IV rituximab led to a rapid and lasting halt in the formation of new CNS lesions in patients with RRMS. 1 Its further humanized successor ocrelizumab, 2 as well as the human anti-CD20 antibody ofatumumab, 3 confirmed these encouraging findings. The clinical efficacy of anti-CD20 provided greater appreciation of the fact that antigen-specific B cells are important antigen-presenting cells (APCs), 4,5 most likely due to their unique capability to directly bind larger conforma-tional antigens at very low concentrations via their B-cell receptor. Furthermore, B cells could be identified as a major source of proinflammatory cytokines, 6 activating other APCs and fostering development of encephalitogenic T cells, jointly consolidating the concept that in RRMS, B cells exert distinctive pathogenic properties that can be targeted by systemic anti-CD20 treatment. Emerging evidence suggests that throughout the chronic course of MS, pathogenic B-cell function gradually shifts from the periphery into the inflamed CNS. This notion is supported by the observation of B-cell follicle-like lymphatic tissue in the meninges of a proportion of patients with secondary progressive MS. 7 Development of such ectopic structures is generally believed to indicate reproduction and differentiation of pathogenic lymphocytes within the target organ itself; this may partially explain why in later stages of MS clinical progression decreasingly correlates with MRI-detectable CNS infiltration while his-topathology remains inflammatory. 8 In this setting of compartmentalized CNS inflammation, systemically applied MS agents, in particular molecularly large monoclonal antibodies, may lose their effectiveness. Supporting this notion, only 0.1% of systemically infused anti-CD20 can be found within the CSF, 9 raising the concern that parenchymal B cells as well as meningeal B cells and/or B-cell follicles cannot be reached and depleted by systemic anti-CD20. Accordingly, one strategy currently being explored to eradicate CNS-established B cells more efficiently is intrathecal (IT) administration of anti-CD20 in patients with progressive MS. In this issue of Neurology ® Neuroimmunology & Neuroinflammation, Svenningsson …