A systematic review of genetic associations, autoantibody profiles, and research gaps of peptidyl arginine deiminases type 2 (PAD2) and PAD4 in rheumatoid arthritis.

Peptidylarginine deiminases (PAD) 2 and 4 are pivotal enzymes in the pathophysiology of RA, owing to their involvement in protein citrullination, which produces autoantigens recognised by anti-citrullinated protein antibodies (ACPAs). Genetic variations in PADI2 and PADI4, along with autoantibodies targeting these enzymes, have been identified as significant contributors to the susceptibility and heterogeneity of RA. This systematic review with narrative synthesis consolidates existing evidence on the correlations between PADI2/PADI4 polymorphisms and the risk of RA, alongside the prevalence and clinical implications of anti-PAD2 and anti-PAD4 autoantibodies, with particular emphasis on identifying research deficiencies in underrepresented communities. A thorough literature review of PubMed, Web of Science, Scopus, Embase, and Google Scholar was performed until March 2024 for studies examining PADI2/PADI4 genetics or anti-PAD antibodies in patients with RA. No geographical or linguistic restrictions were applied. Forty-two genetic studies and 18 autoantibody studies were included. PADI4 polymorphisms exhibit notable relationships with RA in Asian populations (pooled odds ratio 1.23, 95% confidence interval 1.16-1.31); however, the results are equivocal among Europeans. A protective PADI2 variation (rs1005753) was discovered in Southeast Asians (OR = 0.87 (95% CI =0.77-0.99)). Anti-PAD4 antibodies (18-35% prevalence) were correlated with severe erosive disease, whereas anti-PAD2 antibodies (∼18.5% prevalence) were correlated with milder disease. No studies pertaining to genetics or autoantibody profiles in African populations were found. Substantial advancements have been made in understanding PAD2 and PAD4 in Asian and European populations. The lack of data from African populations constitutes a significant research gap that necessitates immediate focus to guarantee the equitable implementation of biomarkers and therapeutic strategies.