Why a positive rheumatoid factor test does not always mean rheumatoid arthritis

Rheumatoid factors (RFs) are autoantibodies directed against the tail region of IgG antibodies and are present in a majority of people with rheumatoid arthritis (RA). RF production is commonly assessed to help diagnose RA, but its performance is limited due to low specificity and sensitivity for reasons that have remained unclear. In this issue of the JCI, Hocaoğlu and Sawalha shed light on this matter using extensive phenome-, genome-, transcriptome-, and proteome-wide association analyses of RF-seropositive and -seronegative individuals. They report that RF production was controlled by a genetic signature that included HLA and non-HLA genes and an immune signature reflective of B cell dysregulation but distinct from the genetic and immune signatures associated with RA. These findings explain the limited diagnostic value of RF testing in RA and may help refine the clinical management of RA and development of interventions that prevent or delay disease.