Ocrelizumab effect on humoral and cellular immunity in multiple sclerosis and its clinical correlates: a 3-year observational study

Abstract

Objective: We aim to evaluate 3-year effects of ocrelizumab (humanized anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS)) on lymphocytes, neutrophils and immunoglobulins: (1) when compared with pre-infusion assessment; (2) over the course of treatment; and (3) possible clinical correlates of the observed immunological modifications.

Methods: This real-world observational cohort study has been conducted on prospectively collected data from 78 MS patients (mean age 47.8 ± 10.5 years; females 48.7%) commencing on ocrelizumab from 2018, with mean follow-up of 36.5 ± 6.8 months. Clinical data and blood samples were collected every three months. Total lymphocyte count and subpopulations were assessed on peripheral blood using flow cytometry. Serum immunoglobulins were evaluated with nephelometry.

Results: When compared with pre-infusion values, we observed reduction of total, CD19 and CD20 lymphocyte counts; however, after the first infusion, their levels remained substantially stable. Over time we observed a progressive reduction of CD8 lymphocytes, while no changes were observed for CD4, CD27, CD3CD27, and CD19CD27. After the first infusion, we observed reduction in IgG, which further decreased during the follow-up. Higher probability of EDSS progression was associated with reduced modulation of CD8 lymphocytes.

Interpretation: Ocrelizumab affects both humoral and cellular immune responses. Disability progression over the follow-up was associated with lower CD8 cytotoxic T-lymphocyte reduction. Changes in humoral response are immediate and sustained, while modulation of cellular immunity occurs progressively through regular re-treatment, and is related to clinical stability.

Keywords: Immunoglobulins; Lymphocytes; Multiple sclerosis; Ocrelizumab.

Fig. 1

Flow cytometry gating strategy. The dot plots show the subsequent gates that were drawn to analyze the lymphocytes. SSC-Area and FSC-Area were plotted to exclude debris and to identify viable cells, among which the lymphocyte region was defined (a). Then, FSC-Area and FSC-Height were used to exclude doublets (b). From this region of lymphocyte singlets, plots were constructed to define lymphocyte subpopulations based on CD expression (e.g., CD3 + CD4 + in c, CD3 + CD8 + in d)

Fig. 2

Laboratory changes over time. Profile plots show changes in total lymphocyte count (a), CD19 lymphocytes (b), CD20 lymphocytes (c), CD4 lymphocytes (d), CD8 lymphocytes (e), CD27 lymphocytes (f), IgG (g), IgM (h) and IgA (i)