Background/Purpose: Rheumatoid factors (RFs), antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis (RA) but also can arise in other inflammatory conditions and infections. In turn, infections, such as respiratory infections, correlate with RA development. Recently, RFs with reactivity to citrullinated and homocitrullinated IgG peptides were discovered in RA, but were not found in other autoimmune diseases. Similar to other infections, RFs have been reported in COVID-19, but RA-specific RFs, which perhaps could suggest a greater risk for RA, have not been evaluated. The purpose of this study was to determine if RA-specific RFs develop post-COVID-19.

Methods: Sera from adults with COVID-19 (~5 weeks post-symptom resolution), with seropositive RA, and age- and sex-matched controls (n=20) were used in ELISA to evaluate IgA, IgM, and IgG binding to the native, citrullinated (B), and homocitrullinated (J) forms of peptides beginning at amino acid positions 11, 80, 167, 202, 219, and 289 of IgG1 (Uniprot P01857) with results compared to controls by Kruskal-Wallis with Dunn’s multiple comparisons tests. Also, using a threshold based on the highest control subject Ig binding signal, the percent positive for each antibody/peptide combination was compared by Fisher’s exact test for RA and COVID-19 versus controls. P< 0.05 was considered significant.

Results: As expected, IgG binding to 75% of the citrulline- or homocitrulline-containing peptides and IgA binding to 50% of these peptides was increased in RA compared to controls. No peptides had increased IgM binding in RA. Also, no peptides had increased IgA, IgM, or IgG binding in COVID-19, although there was a trend towards increased IgG binding to IgG1-80J in COVID-19 (p=0.056). When analyzed based on percent positivity, significantly more COVID-19 subjects were positive for IgG binding to IgG1-80J and IgG1-219J compared to controls (45% and 30% vs. 0%, respectively). Also, significantly more COVID-19 subjects were positive for IgA binding to IgG1-11, IgG1-167, and IgG1-167J compared to controls (30%, 25%, and 25% vs 0% respectively). Many of these IgA and IgG binding values were minimally elevated in COVID-19, but some COVID-19 subjects had Ig binding >10x higher than controls for these peptides.

Conclusion: While RFs that bind to citrulline- and homocitrulline-containing IgG epitopes are primarily restricted to RA, some COVID-19 patients generate antibodies that bind to a few of these epitopes in the native or homocitrullinated form. Longitudinally evaluating reactivity against these IgG and related epitopes, as well as joint symptoms, could provide important insights into how immune tolerance is regained or further lost on a path towards RA following a viral infection.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rheumatoid-arthritis-specific-rheumatoid-factors-develop-in-some-covid-19-patients/