Simple Summary Since B cells have been linked to multiple sclerosis (MS) and its progression as well as T cells, the second-generation anti-CD20 recombinant humanized monoclonal antibody ocrelizumab has been approved for MS treatment. Although ocrelizumab efficiently depletes B cells in peripheral blood, some B cells and CD20 negative plasma cells persist in lymphatic organs, and their survival is regulated by the B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) system. Moreover, ocrelizumab may result in higher infectious risk. Herein, we investigated plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated people with (pw) MS at baseline, at 6 months and at 12 months after starting the treatment, comparing the above-mentioned findings with a control group. At baseline, plasma levels of all three cytokines were higher compared to the control group. In pwMS, the longitudinal assessment showed a significant increase in plasma BAFF levels and a significant reduction in plasma APRIL and CD40L. Moreover, when stratifying pwMS according to the onset of an infectious event during the 12-month follow-up period, significantly higher plasma BAFF levels were found at all time-points in the group with an infectious event than in the group without an infectious event. Hence, BAFF may have a role as a marker of immune dysfunction and infectious risk. Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too. Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (p < 0.0001), APRIL (p = 0.0223) and CD40L (p < 0.0001) levels compared to HD. Compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 (p < 0.0001 and p < 0.0001, respectively). Whereas plasma APRIL and CD40L levels were decreased at T12 (p = 0.0003 and p < 0.0001, respectively). When stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups-with (14) and without an infectious event (24)-higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). Conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk
