Presence of Autoantibodies Targeting the Shared Epitope in Rheumatoid Arthritis and Psoriatic Arthritis

Eduard Graell Martinez^1,2*Juan Francisco Delgado De La Poza^2,3*Antonio Domingo Gomez^1,2Maria García-Marique^1,2Menna Rusiñol^1,2Albert Rodrigo²Antoni Berenguer-Llergo²Jordi Gratacos^1,2Joan Calvet^1,2

• ¹Rheumatology Department. Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA). Universitat Autònoma de Barcelona, Sabadell, Spain
• ²Inflammatory Joint Diseases, Bone Metabolism, and Systemic Autoimmune Diseases Research Group. Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Sabadell, Spain
• ³Immunology Laboratory, Clinical Laboratories Service. Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA). Universitat Autònoma de Barcelona. Sabadell, Spain., Sabadell, Spain

Abstract Introduction Rheumatoid arthritis (RA) is an autoimmune disease marked by the production of autoantibodies (AAb) against citrullinated proteins/peptides (ACPA). The shared epitope (SE) in the HLA-DRB1 gene is a major genetic risk factor for RA and has been linked to ACPA production, particularly in individuals exposed to environmental triggers such as smoking. However, the role of the SE itself, especially in its citrullinated form, as a target of humoral immunity in RA remains underexplored. Methods We analyzed autoantibodies against SE-containing peptides (SE-AAb) in 150 RA patients, 62 patients with psoriatic arthritis (PsA), and 204 healthy controls. HLA-DRB1 polymorphisms associated with the SE (QKRAA, QRRAA, RRRAA) were evaluated by PCR-SSO. IgG reactivity against native, citrullinated, and carbamylated SE peptides, in linear and cyclic conformations, was assessed using a custom ELISA. Results SE-AAb were detected in RA patients with frequencies ranging from 26.0% to 45.3%, depending on peptide conformation and post-translational modification, with the highest positivity observed against citrullinated SE peptides. Antibodies against cyclated citrullinated SE peptides were present in 45.3% of RA patients, compared with 21.6% of healthy controls. PsA patients also showed SE-AAb positivity, with frequencies ranging from 17.7% to 35.5%, displaying a pattern largely similar to RA. No significant association was observed between SE-AAb positivity and SE genetic carriage, and SE-AAb presence was not associated with clinical features of RA. Conclusion SE-AAb are present in RA patients, particularly against citrullinated SE peptides, but are not specific to RA, as similar reactivity is observed in PsA. The presence of these autoantibodies is independent of SE genetic carriage, suggesting that inflammatory conditions rather than genetic SE status may contribute to their generation. Further studies are needed to clarify the clinical relevance of SE-AAb in RA pathogenesis.