BACKGROUND/OBJECTIVE: The study of autoantibody isotypes in autoimmune diseases has been useful for identifying clinically relevant endotypes. Here, we studied the prevalence and clinical significance of different isotypes and IgG subclasses of anti-peptidylarginine deiminase 4 (PAD4) autoantibodies in individuals with rheumatoid arthritis (RA). METHODS: Anti-PAD4 antibody types were determined by ELISA in 196 RA subjects and 64 healthy controls. We investigated associations of anti-PAD4 antibodies and clinical outcomes. Relevant features were confirmed using an independent RA cohort. RESULTS: Anti-PAD4 IgG1, IgG2, IgG3, IgG4, IgA, and IgE antibodies were more frequent in patients with RA than healthy controls (P<0.001 for all). Anti-PAD4 IgG1, IgG3 and IgE were associated with distinct features. Anti-PAD4 IgG1 was predictive of progressive radiographic joint damage (OR 4.88, P=0.005), especially in RA patients without baseline joint damage (40% vs. 0%, P=0.003) or in those negative for anti-CCP and/or rheumatoid factor (OR 32, P=0.009). IgG1 was also associated with higher levels of C-reactive protein (P=0.006) and IL-6 (P=0.021). RA patients with anti-PAD4 IgG3 had higher baseline joint damage (mean SHS 13 vs. 7, P=0.046), while those with anti-PAD4 IgE had higher DAS28 scores (mean 4.0 vs. 3.5, P=0.025), more frequent rheumatoid nodules (31% vs. 16%, P=0.025) and interstitial lung disease (glass ground opacification) (24% vs. 9%, P=0.014). Joint damage associations of anti-PAD4 IgG1 antibodies were corroborated in an independent RA cohort. CONCLUSION: Anti-PAD4 IgG1, IgG3 and IgE antibodies identify discrete disease subsets in RA, suggesting that heavy chain usage drives distinct effector mechanisms of anti-PAD4 antibodies in RA.