Exploring the role of anti-citrullinated protein antibodies in rheumatoid arthritis and in disease heterogeneity

Rheumatoid arthritis (RA) is a complex autoimmune disorder marked by persistent joint inflammation, synovial inflammation, cartilage damage, and bone erosion, leading to progressive joint deformities and functional decline. Central to RA pathogenesis are autoantibodies, particularly anti-citrullinated protein antibodies (ACPAs), which target citrullinated proteins and trigger immune responses. ACPAs, presenting years before clinical symptoms manifest, serve as specific markers for early diagnosis and predicting disease progression, joint damage, and severity. This review examines the role of ACPAs in RA, focusing on their involvement in disease onset, progression, and the impact of epitope spreading on disease heterogeneity. The activation of peptidyl arginine deiminase (PAD) enzymes, especially PAD2 and PAD4, plays a crucial role in RA development by catalyzing citrullination, leading to hypercitrullination in synovial fluid (SF). Genetic polymorphisms in PAD4 contribute to RA susceptibility by influencing enzyme activity and the conversion of arginine to citrulline. Environmental factors like smoking further activate PAD enzymes, promoting immune responses that drive RA. ACPAs, produced through somatic hypermutation, play a pivotal role in disease onset and progression. These autoantibodies initiate signaling by binding to citrullinated proteins on cell surfaces and forming immune complexes that activate Fc receptors, which are further amplified by rheumatoid factors (RFs). This process enhances inflammation and immune cell recruitment, contributing to early subclinical synovial inflammation. Epitope spreading accelerates disease progression, and PAD inhibitors, targeting citrullination, are being explored as potential therapeutic options for RA and other autoimmune diseases.