Multiple sclerosis (MS) is a chronic, autoimmune disease of the central nervous system (CNS) characterized by consistent myelin and axonal damage that is mediated by autoreactive B- and T-cells. The role of B-cells in MS involves different cellular functions, including the production of autoantibody, antigen presentation to autoreactive T-cells and secretion of pro-inflammatory cytokines. Recent advances have led to the development of mAbs that effectively deplete B cells and target pathways essential for B-cell development. The pivotal role of B-cells in MS immunopathogenesis has been reinforced by the development of B cell-depleting monoclonal antibody (mAb), ocrelizumab that target the CD20 receptor on cells of the B cell lineage.
Ocrelizumab, is a humanized anti-CD20 mAb licensed on 2017, depletes circulating immature and mature B-cells through different way. Despite its clinical and radiological efficacy, ocrelizumab may increase the risk of reactivation of latent pathogenic viruses and contracting de novo infections, as result of a profound alteration of the immune response.
Given the infectious complications and the increasing use of ocrelizumab in MS, is necessary to identify predictive biomarkers that can provide better clinical management of patients and avoid possibly infectious adverse.
B cell activating factor (BAFF) and proliferation-inducing ligand (APRIL) are important cytokines involved in B-cell survival and activation. Moreover, CD40L is a costimulatory molecule involved in productive B-cell activation, antibody production, and isotype class switching.
The aim of the study is to evaluate the role of BAFF, APRIL and CD40L, as biomarkers of infectious risk during ocrelizumab treatment.
The infectious risk under DMTs has become one of the most important setting in the clinical management of MS patients. Balance of the overall risk versus benefit should be continuously evaluated and monitored in order to avoid possibly adverse events. Ocrelizumab is the only DMT approved by the US Food and Drug Administration (FDA) both for relapsing-remitting (RR) and primary progressive (PP) form in MS. Patients under ocrelizumab treatment showed significant improvements and this makes ocrelizumab a new milestone in MS therapy. The efficacy and safety profile of ocrelizumab seems to be higher than its homologue rituximab. However, as we learned by rituximab, long-lasting B-cell depletion may increases the infection risk (Gea-Banacloche, 2010).
Increased plasma BAFF levels during rituximab therapy have been reported in patients with Sjögren's syndrome and systemic lupus erythematosus (Seror et al. 2007; Lavie et al., 2007).
A recent study evaluated plasma BAFF and APRIL levels in rituximab-treated patients with rheumatoid arthritis. The authors suggested that the dysregulation of these cytokines due to rituximab-induced B-cell depletion may associate with an increased susceptibility to infections (Gutierrez et al., 2019).
Finally, CD40L is a costimulatory molecule involved in productive B-cell activation, antibody production, and isotype class switching. The important role of CD40L co-operates with various cytokines to induce B-cell activation and proliferation (Gardell et al., 2017).
In our study plasma BAFF, APRIL and CD40L levels will be evaluated before and during ocrelizumab treatment in MS patients. The comparison between MS patients before starting ocrelizumab and healthy donors may give a deeper insight of these three cytokines role in MS. The longitudinal evaluation of plasma BAFF, APRIL and CD40L levels during ocrelizumab treatment could clarify the involvement and relationship with the clinical outcome of MS patients. This approach is intended to identify early biomarkers of infection in order to improve the management of MS treatment and increase the safety profile of ocrelizumab.