OBJECTIVE: RA patients develop autoantibodies against a spectrum of antigens but their clinical significance is unclear. Using the phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA.

METHODS: This study was conducted using a validated electronic medical record (EMR) RA cohort from 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all ICD-9 codes for each subject and grouped them using a published method into disease categories (PheWAS codes). We tested for the association of each autoantibody grouped by targeted protein with PheWAS codes. For significant associations (false discovery rate [FDR] ≤0.1), we reviewed 50 medical records of subjects with each PheWAS code to determine the positive predictive value (PPV).

RESULTS: We studied 1006 RA subjects, mean age 61.0 years (SD 12.9) and 79.0% female. There were 3,568 unique ICD-9 codes grouped into 625 PheWAS codes; 206 PheWAS codes with a prevalence ≥3% were studied. PheWAS identified 24 significant associations of autoantibodies to epitopes at FDR≤0.1. Associations with the strongest associations and highest PPV for PheWAS code included autoantibodies against fibronectin with obesity (p=6.1x10^-4 , PPV 100%), and fibrinogen with pneumonopathy (p=2.7x10^-4, PPV 96%). The latter included diagnoses for cryptogenic organizing pneumonia and obliterative bronchiolitis.

CONCLUSION: We demonstrated the application of a bioinformatics method, the PheWAS, to screen for clinical significance of RA-related autoantibodies. PheWAS identified potential significant links between variations in levels of autoantibodies and comorbidities of interest in RA. This article is protected by copyright. All rights reserved.