Phenome-Wide Association Study of Autoantibodies to Citrullinated and Noncitrullinated Epitopes in Rheumatoid Arthritis

Objective. Patients with rheumatoid arthritis (RA) develop autoantibodies against a spectrum of antigens, but the clinical significance of these autoantibodies is unclear. Using a phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA. Methods. This study was conducted in a cohort of RA patients identified from the electronic medical records (EMRs) of 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all International Classification of Diseases, Ninth Revision (ICD-9) codes for each subject and grouped them into disease categories (PheWAS codes), using a published method. We tested for the association of each autoantibody (grouped by the targeted protein) with PheWAS codes. To determine significant associations (at a false discovery rate [FDR] of <= 0.1), we reviewed the medical records of 50 patients with each PheWAS code to determine positive predictive values ( PPVs). Results. We studied 1,006 RA patients; the mean +/- SD age of the patients was 61.0 +/- 12.9 years, and 79.0% were female. A total of 3,568 unique ICD-9 codes were grouped into 625 PheWAS codes; the 206 PheWAS codes with a prevalence of >= 3% were studied. Using the PheWAS method, we identified 24 significant associations of auto-antibodies to epitopes at an FDR of <= 0.1. The associations that were strongest and had the highest PPV for the PheWAS code were autoantibodies against fibronectin and obesity ( P = 6.1 x 10(-4), PPV 100%), and that between fibrinogen and pneumonopathy ( P = 2.7 x 10(-4), PPV 96%). Pneumonopathy codes included diagnoses for cryptogenic organizing pneumonia and obliterative bronchiolitis. Conclusion. We demonstrated application of a bio-informatics method, the PheWAS, to screen for the clinical significance of RA-related autoantibodies. Using the PheWAS approach, we identified potentially significant links between variations in the levels of autoantibodies and comorbidities of interest in RA.