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

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Abstract
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.