Background Exploration of the mechanism underlying the delay of development of clinical signs of seropositive rheumatoid arthritis (RA) observed after B cell directed therapy in individuals at risk of developing autoantibody positive RA may offer insights into the mechanism of disease and may assist the development of preventive strategies.
Objectives To explore the effects of a single infusion of rituximab (anti-CD20 antibody) on the observed delay of the onset of clinically manifest arthritis in individuals at risk of developing autoantibody positive RA.
Methods In a study of 81 subjects positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) with arthralgia who never had clinically manifest arthritis and never used disease-modifying antirheumatic drugs, a 55% reduction of the risk of developing arthritis was observed 12 months after receiving a single iv infusion of 1000 mg rituximab when compared to placebo. In this group there was a delay in the development of arthritis of 12.0 months (12 months placebo vs 24 rituximab group) at the 25% quartile (75% free of arthritis) of the cumulative arthritis-free survival. Explorative analysis of disease-related biomarkers was performed in subgroups to better understand the mechanisms of the observed delay of clinical disease onset.
Results Baseline levels of ESR (mm/h; HR 1.03; p=0.016), the total number of B cells in peripheral blood (HR 1.48; p=0.047), the presence of anti-alpha-enolase 1 (anti-CEP1) antibodies (HR 3.71; p=0.004) and the percentage of regulatory B cells (HR 1.04; p=0.002) were related to arthritis development over time. Importantly, genetic analysis of 100 RA associated SNPs showed that the top SNP associated with arthritis development in the rituximab-treated group (OR=7, MAF in cases 60% compared to 17% in unaffected) was in the PLCL2 gene, described to play a role in B cell signaling1. In individuals treated with rituximab, B cell numbers and subtypes mainly of the memory and regulatory compartment as well as serum levels of IgM-RF (p<0.0001), IgA-RF (p=0.003), total IgM (p=0.001), and anti-CCP (p=0.035) showed statistically significant changes over time compared to individuals who received placebo. Exploratory analysis showed trends for multiple biomarkers in the B cell compartment that appeared predictive of the development of arthritis.
Conclusions A single infusion of 1000 mg rituximab significantly affects B cell numbers and subsets of memory and regulatory B cells as well as a reduction of disease-related antibodies and immunoglobulin levels in individuals at risk of RA. The changes coincide with a decrease in risk and a delay in development of arthritis in this population. PLCL2 gene polymorphism was associated with arthritis development in rituximab-treated individuals.
Takenaka K, Fukami K, Otsuki M, Nakamura Y, Kataoka Y, Wada M, Tsuji K, Nishikawa S, Yoshida N, Takenawa T. Role of phospholipase C-L2, a novel phospholipase C-like protein that lacks lipase activity, in B-cell receptor signaling. Mol Cell Biol. 2003 Oct;23(20):7329–38.
Disclosure of Interest None declared
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