Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis.

Objective: To determine whether antibodies against peptidyl arginine deiminase type 4 (PAD-4) are present in the preclinical phase of rheumatoid arthritis (RA) and to compare the timing and extent of their appearance with those of other preclinical autoantibodies.

Methods: Prediagnosis serum samples from 83 patients with RA were evaluated for the presence of anti-PAD-4 antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, and rheumatoid factor. In addition, a control cohort (n = 83) matched by age, sex, race, number of serum samples, and duration of serum storage was tested for the presence of anti-PAD-4 antibody to determine its sensitivity and specificity for the subsequent development of RA.

Results: Fifteen of 83 patients with RA (18.1%) had at least 1 prediagnosis sample positive for anti-PAD-4. One of 83 control subjects (1.2%) had at least 1 positive sample, resulting in a sensitivity and specificity of 18.1% and 98.8%, respectively, of anti-PAD-4 for the future development of RA. The mean duration of anti-PAD-4 positivity prior to clinical diagnosis was 4.67 years. Anti-PAD-4 positivity was associated with anti-CCP positivity (odds ratio 5.13 [95% confidence interval 1.07-24.5]). In subjects with prediagnosis samples that were positive for both antibodies, anti-CCP positivity predated anti-PAD-4 positivity in 9 of 13 cases (69%).

Conclusion: Autoantibodies to PAD-4 are present during the preclinical phase of RA in a subset of patients and are associated with anti-CCP positivity. Further exploration is needed regarding the timing of appearance and disease-related effects of PAD-4 autoimmunity.