Ocrelizumab Treatment Modulates B-Cell Regulating Factors in Multiple Sclerosis

Abstract

Background and ObjectivesAntibodies to CD20 efficiently reduce new relapses in multiple sclerosis (MS), and ocrelizumab has been shown to be effective also in primary progressive MS. Although anti-CD20 treatments efficiently deplete B cells in blood, some B cells and CD20−plasma cells persist in lymphatic organs and the inflamed CNS; their survival is regulated by the B cell–activating factor (BAFF)/A proliferation-inducing ligand (APRIL) system. The administration of a soluble receptor for BAFF and APRIL, atacicept, unexpectedly worsened MS. Here, we explored the long-term effects of ocrelizumab on immune cell subsets as well as on cytokines and endogenous soluble receptors comprising the BAFF-APRIL system.MethodsWe analyzed immune cell subsets and B cell–regulating factors longitudinally for up to 2.5 years in patients with MS treated with ocrelizumab. In a second cohort, we determined B-cell regulatory factors in the CSF before and after ocrelizumab. We quantified the cytokines BAFF and APRIL along with their endogenous soluble receptors soluble B-cell maturation antigen (sBCMA) and soluble transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (sTACI) using enzyme-linked immunosorbent assays (ELISAs). In addition, we established an in-house ELISA to measure sTACI-BAFF complexes.ResultsOcrelizumab treatment of people with MS persistently depleted B cells and CD20+T cells. This treatment enhanced BAFF and reduced the free endogenous soluble receptor and decoy sTACI in both serum and CSF. Levels of sTACI negatively correlated with BAFF levels. Reduction of sTACI was associated with formation of sTACI-BAFF complexes.DiscussionWe describe a novel effect of anti-CD20 therapy on the BAFF-APRIL system, namely reduction of sTACI. Because sTACI is a decoy for APRIL, its reduction may enhance local APRIL activity, thereby promoting regulatory IgA+plasma cells and astrocytic interleukin (IL)-10 production. Thus, reducing sTACI might contribute to the beneficial effect of anti-CD20 as exogenous sTACI (atacicept) worsened MS.Classification of EvidenceThis study provides Class IV evidence that endogenous sTACI in blood and CSF is decreased after ocrelizumab treatment.

Histologic manifestations of ocrelizumab‐associated intestinal and hepatic injury in patients with multiple sclerosis

“…It has been postulated that anti-CD20 antibodies may not have a similar effect on mucosal Bcells and their precursors when compared to circulating B-cells, thereby renewal and preservation of intestinal mucosal plasma cells. [36][37][38] Only rare case reports of ocrelizumab-associated hepatitis have been reported. In Phase III clinical trials on ocrelizumab, serum liver enzyme elevations were noted in 1%-2% of the patients.…”

Evaluation of BAFF, APRIL and CD40L in Ocrelizumab-Treated pwMS and Infectious Risk

“…Upon longitudinal evaluation of the cytokine plasma levels in pwMS, plasma BAFF levels significantly increased across all time-points, whereas reduction in plasma APRIL and CD40L were observed. These temporal dynamic patterns may be reconducted to their different roles and activity on various B cell maturation phases [ 55 , 56 , 57 ]. BAFF specifically induces survival and maturation of naïve B cells, promoting B cell homeostasis [ 56 , 58 ].…”

“…BAFF specifically induces survival and maturation of naïve B cells, promoting B cell homeostasis [ 56 , 58 ]. During anti-CD20 treatment, the majority of cells that respond to BAFF stimulation are depleted [ 59 ]; thus, the increase in plasma BAFF levels could be due to either the lack of cells with receptors for BAFF, especially BAFF-R, or due to a feedback mechanism with the purpose of promoting B cell repopulation [ 57 , 60 , 61 , 62 , 63 ]. Moreover, MS induces a state of constant and intense immunoactivation, which may lead to immune dysfunction and, eventually, premature exhaustion [ 8 , 64 ].…”

“…In these conditions, BAFF is involved in the vicious cycle of persistent immunoactivation and may be uncontrollably increased [ 17 ]. The increase in plasma BAFF during anti-CD20 therapy has been documented in several reports about Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Sjögren syndrome and, recently, in MS too [ 57 , 60 , 61 , 62 , 63 ].…”

Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

“…Indeed, while anti‐CD20 therapies ablate pathogenic IL‐6‐producing B cells, reconstituting B cells after therapy were reported to show increased production of anti‐inflammatory IL‐10 [5, 157, 158]. The increase of IL‐10‐producing B cells might be the result of increased BAFF levels upon treatment with CD20‐depleting therapies, as it has been reported in MS [159] and different rheumatoid diseases [160]. Importantly, elevated BAFF levels are associated with IgA subclass switching and clonal expansion in immune‐mediated diseases, such as ANCA‐associated vasculitis [144], underlining the pivotal role of BAFF for regulatory IgA + B cell functioning.…”