Autoreactive B cells remain active despite clinical disease control in rheumatoid arthritis

Abstract

Background: Autoimmune diseases (AIDs) are frequently hallmarked by the presence of autoreactive B cell responses which are involved in disease pathogenesis. However, the dynamics of such responses and their relation to clinical disease activity in humans is poorly understood. Rheumatoid arthritis (RA), a prototypic chronic AID, is hallmarked by B cell responses directed against citrullinated proteins.

Objective: To determine the relation between the activity of the anti-citrullinated protein antibody (ACPA) B cell response and clinical disease activity in ACPA⁺ patients with RA.

Methods: Expression of B cell activation markers by ACPA⁺, tetanus toxoid (TT)⁺ and ACPA^- memory B cells (MBCs) from peripheral blood of ACPA⁺ RA patients receiving different treatments was analyzed by flow cytometry. Results were correlated to clinical disease activity.

Results: Compared to TT⁺ and ACPA^- MBCs, ACPA⁺ MBCs displayed a highly activated phenotype as evidenced by increased expression of Ki-67, CD86, CD80, CD19 and CD20 and reduced expression of CD32. The activated phenotype of ACPA⁺ MBCs did not associate with clinical disease activity in a cross-sectional analysis of RA patients treated with various therapeutic agents. Also, in a longitudinal analysis of patients treated with Janus kinase (JAK) inhibitors, ACPA⁺ MBCs retained their activated phenotype despite effective control of inflammation and clinical disease.

Conclusion: ACPA⁺ MBCs remain active despite clinical disease control in patients with RA across a range of interventions. This persistent activity indicates the absence of immunological remission and might explain why ACPA⁺ patients rarely reach sustained drug-free remission and frequently flare upon drug tapering.

Keywords: Anti-citrullinated protein antibodies; Autoimmunity; Autoreactive B cells; B cell activation; Immunological disease activity; Rheumatoid arthritis.