Elevated Immune Response to Gut Bacterial Protein Associated with Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) and those at-risk of developing RA had higher levels of antibodies against a gut protein expressed by Prevotella copri (Pc) when compared with a control group, according to a study published in Arthritis & Rheumatology.¹ Results indicate a potential role for Pc in the evolution of preclinical RA and the pathogenesis of synovitis.

“Manifestation of systemic autoantibodies in serum prior to inflammation in joints, the well-established primary tissue target of the disease, suggests initiation of the autoimmune process elsewhere,” investigators stated. “Mucosal sites such as the periodontium, lungs, gut, and vaginal tract have garnered attention as initiating sites for the autoimmune process in RA. Recent developments in the identification and categorization of bacterial commensals and pathobionts at mucosal sites have helped to advance our understanding of the immune consequences when dysbiosis exists.”

Participants were chosen from the multicenter, longitudinal Studies of Etiology of Rheumatoid Arthritis (SERA) study. At-risk participants, patients with early RA (< 1 year), those with established RA, and healthy controls were included in the study. Serum levels of immunoglobulin A (IgA) and immunoglobulin G (IgG) anti-Pc-p27 were analyzed and compared with controls. Anti-Pc-p27 antibodies were evaluated in participants stratified by RA-related autoantibody status. Questionnaires evaluated demographics, history of disease in the participant as well as their family, and environmental exposures, both past and present. A 68-joint examination was performed in the at-risk patients and control participants to confirm the absence of RA and confirm the presence of inflammatory arthritis (IA) in those who transitioned to disease.

Patients with RA had significantly higher levels of IgA anti-Pc-p27 antibodies and trended towards higher levels of IgG anti-Pc-p27 antibodies when compared with matched controls. Patients with early RA had higher median values of IgG anti-Pc-p27 when compared with those with established RA. However, median values of IgA anti-Pc-p27 were statistically significantly higher in participants with established RA when compared with matched controls.

In autoantibody specific analyses, participants at-risk of developing RA with anti-cyclic citrullinated peptide (CPP) autoantibodies were more likely to present with an increased level of IgG anti-Pc-p27; however, this did not carry over to those with rheumatoid factor (RF). Patients with RA who were CCP+/RF+ reported significantly increased levels of IgA anti-Pc-p27 antibodies and a trend toward levels of IgG anti-Pc-p27 antibodies when compared with the control group.

The Pc immune response was recognized based on reactivity with only 1 protein, Pc-p27, which may have limited the ability to detect reactivity with this microbe and negatively impacted the significance in some adjusted analyses. Further, pathogenesis of this protein may have only had immunologic relevance in a subset of patients with RA. It remains unclear as to why those with the most significant IgA response to Pc-p27 was seen in patients with established RA instead of those with early RA. However, investigators were able to show statistically significant associations with IgA anti-Pc-p27 antibody responses in patients with RA and higher levels of IgG anti-Pc-p27 in the CCP+ at-risk participants, as well as those with early RA.

“Our hope is that these findings can help to further elucidate the complex etiologic role of bacterial commensals in people who are at-risk of developing RA and in those with RA so that targeted therapies can be developed with the goals of providing better treatment and ultimately, prevention of the disease,” corresponding investigator Jennifer A. Seifert, MPH, of the University of Colorado Denver, concluded.

Reference:

Seifert JA, Bemis EA, Ramsden K, et al. Association of antibodies to Prevotella copri in anti-CCP-positive individuals at-risk for developing rheumatoid arthritis and in those with early or established rheumatoid arthritis [published online ahead of print, 2022 Oct 19]. Arthritis Rheumatol. 2022;10.1002/art.42370. doi:10.1002/art.42370