Frequency and Clinical Significance of Elevated IgG4 in Rheumatoid Arthritis: A Systematic Review

Abstract

Immunoglobulin (Ig)G4 is a unique protein molecule and its role in autoimmune diseases remains elusive and controversial. Accumulating evidence suggests a pathogenic role of IgG4 in rheumatoid arthritis (RA). Rheumatoid factors (RF) in RA can recognize the Fc domains of IgG4 to form RF-IgG4 immune complexes that may activate the complement system leading to synovial injury. The aim of this article was to systematically review the literature from the past 2 decades to determine the frequency of elevated IgG4 and its clinical significance in RA. We comprehensively searched the Pubmed, Scopus, and Web of Science databases with the following terms: “IgG4”, “rheumatoid arthritis”, and “immunoglobulin G4”, and scrutinized all of the relevant publications. Based on the selection criteria, 12 studies were incorporated, which involved a total of 1715 RA patients. Out of 328 subjects from three studies, the pooled frequency of elevated non-specific IgG4 was 35.98%. There was a significant positive correlation between the IgG4 levels and the RA disease activity based on DAS-28 measurements (r = 0.245–0.253) and inflammatory markers, i.e., erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (r = 0.262–0.389). Longitudinal studies that measured the serial levels of IgG4 consistently showed a decline in the concentrations (up to 48% less than baseline) with disease modifying anti-rheumatic drug (DMARD) treatment. Current evidence suggests that serum IgG4 levels are significantly elevated in RA compared to the general population. This review indicates that IgG4 is a promising biomarker of disease activity and tends to decline in response to DMARD therapies. Biologic therapies have revolutionized the therapeutic armamentarium of RA in the recent decade, and IgG4 appears to be a potential treatment target.

Fc proteoforms of ACPA IgG discriminate autoimmune responses in plasma and synovial fluid of rheumatoid arthritis patients and associate with disease activity

“…Given the fact that IgG4 are generally relatively poor activators of complement and Fcγ receptors (FcγRs) [51], the absence of a correlation in ACPA seems plausible. The finding that total IgG4 levels correlated with mentioned inflammatory markers is supported by a significant but relatively weak correlation of these two factors in a recent meta-study and is worth further investigation [53]. Next to subclasses, we assessed IgG sequence variations (allotypes) and monitored their relative abundance per subclass.…”

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

“…However, in some RA models, IL‐4‐deficient mice were protected from severe disease. In addition, IL‐4 also activates B cells and induces isotype switching to IgG4, which dominates autoantibodies found in RA sera 178 . Therefore, the role of IL‐4 in RA and other autoimmune diseases, like systemic lupus erythematosus (SLE), is complex and depends upon genetic background, the type of eliciting antigen, and the relative role of autoantibodies in pathogenesis.…”

“…In addition, IL-4 also activates B cells and induces isotype switching to IgG4, which dominates autoantibodies found in RA sera. 178 Therefore, the role of IL-4 in RA and other autoimmune diseases, like systemic lupus erythematosus (SLE), is complex and depends upon genetic background, the type of eliciting antigen, and the relative role of autoantibodies in pathogenesis. Further delineation of IL-4/-13 in autoimmune disorders will inform the design and validation of clinical therapies to treat these diseases.…”

Autoimmune diseases presenting with IgG4 related lesions at atypical sites - a tale of two cases with literature review

“…Blocking IL6 by tocilizumab has been shown to reduce IgG4 ACPA antibodies, but not IgG1 ACPA antibodies, indicating the potential in uence of IL-6 on the production of IgG4 anti-CCP antibodies in RA. (9) Sakthiswary et al (10) recently completed a systematic review of nineteen studies where serum IgG4 in RA was assessed. They showed that elevated IgG4 level was positively correlated with increased disease activity (measured by DAS28-ESR ) and in ammatory markers.…”