B cell synovitis and clinical phenotypes in rheumatoid arthritis: relationship to disease stages and drug exposure

OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsies, demographic and clinical data were collected from two RA cohorts (n=329): treatment-naïve early-RA (n=165) and TNF-inhibitor inadequate responders (TNFi-IR) established-RA (n=164). Synovial tissue underwent H&E and immunohistochemistry staining and semi-quantitative assessment for the degree of synovitis (0-9) and of CD20+ B cell infiltrate (0-4). B cell scores were validated by digital image analysis (DIA) and B cell lineage-specific transcript analysis (RNA-seq) in the early RA (n=91) and TNFi-IR (127) cohorts. Semi-quantitative CD20 scores were applied to classify patients as B cell rich (≥ 2) or poor (< 2). RESULTS: Semi-quantitative B cell scores correlated with DIA quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of early-RA and 47.7% of TNFi-IR established-RA (p=0.025). B cell-rich patients showed higher levels of disease activity and sero-positivity for RF and ACPA in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semi-quantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses. We demonstrate an ongoing B cell-rich synovitis in a larger proportion of patients with established RA that does not seem to be captured by standard clinimetric assessment.