Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease both clinically and biologically. Currently, the relationship between molecular drivers of disease in RA and therapeutic outcome is poorly understood, and advances are needed if improved drugs targeted to subsets of disease are to be developed. Using a combination of gene expression, histologic, and cellular analysis of RA synovial samples, different pathological phenotypes within the rheumatoid synovium have been defined with distinct underlying gene expression profiles and histological features. A myeloid biology-dominated synovial subset had a more robust response to anti-TNFα therapy. Further, using differential gene expression in synovium to nominate systemic biomarker candidates, pre-treatment assessment of serum biomarkers indicated that different RA patient populations optimally respond to anti-TNFα therapy as compared with anti-IL6R therapy. Of note, patients with a low inflammatory synovial subset showed poor clinical response to therapy. These data underscore the importance of disease heterogeneity in RA, and provide a path forward for the identification and validation of systemic biomarkers that predict response to targeted therapies.
Disclosure of Interest M. Townsend Shareholder of: Roche, Employee of: Genentech/Roche