Rheumatoid Factor as a Potentiator of Anti–Citrullinated Protein Antibody–Mediated Inflammation in Rheumatoid Arthritis

Abstract

Objectives The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) is well described in rheumatoid arthritis (RA). However, the mechanisms underlying the potential interaction between these two distinct autoantibodies has not been well defined. We sought to evaluate the epidemiologic and molecular interaction of ACPA and RF with both disease activity as well as measures of RA-associated inflammation. Methods In a cohort of 1,488 Veterans with RA, measures of disease activity and levels of serum cytokines and multiplex ACPA were compared between the double-negative (aCCP-/RF-), ACPA-positive and RF-negative (aCCP+/RF-), ACPA-negative and RF-positive (aCCP-/RF+), or double-positive (aCCP+/RF+) subgroups. Studies were additionally performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA-ICs in the presence or absence of monoclonal IgM RF, and TNFα production measured as readout of macrophage activation. Results Compared with the double negative (as well each single positive) subgroup, the aCCP+/RF+ subgroup exhibited higher disease activity, serum CRP, and inflammatory cytokines (all P<0.001). In vitro stimulation of macrophages by ACPA-ICs induced increased cytokine production with the addition of monoclonal IgM RF as compared to ACPA-ICs alone (P=0.003) Conclusions The combined presence of ACPA and IgM RF mediates increased proinflammatory cytokine production in vitro, and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM RF enhances the capacity of ACPA-ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA-ICs in RA.

Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans

“…However, this is the first study, to our knowledge, to demonstrate meaningful differences in RF concentration between current and former cigarette smokers as manifested by a corresponding reduced level of disease activity. Thus, the correlation of RF titre with smoking status suggests it to be a potential driver of autoantibody-mediated inflammation and supports recent work by our group and others demonstrating the capacity for RF to potentiate the inflammatory capacity of ACPA immune complexes [26,27].…”

The value of rituximab treatment in primary Sjögren's syndrome

“…Following B cell repopulation, RF levels rise again and this rise can predict relapse of clinical symptoms [5,12]. Similar to findings in rheumatoid arthritis (RA), combined presence of RF and disease-specific autoantibodies (anti-SS-A/Ro, anti-SS-B/La) may result in higher disease activity in pSS as well [13]. The mechanism behind this synergistic effect is unknown, but crosslinking and/or stabilization of immune complexes, consisting of autoantigens and autoantibodies, by RF is likely involved.…”

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

“…Of note, the concordant presence of IgM RF and ACPA, which occurs in a very large majority of patients, was very recently reported to associate with increased disease activity (69). Even more recently, it was reported that an increase in RF titer enhanced the size and number of erosions in ACPA + but not ACPA 2 patients (70).…”