Pathotype-Specific Expression of Granzyme-Perforin Pathway Genes and Their Association With Clinical Disease Activity in Early Rheumatoid Arthritis and in a Randomized Clinical Trial.

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease. We examined gene expression of five granzymes (GZMs), perforin (PRF-1), and serglycin (SRGN) from tissues derived from pathobiology of early arthritis cohort (PEAC) and phase 4 randomized controlled trial in anti-TNF inadequate responder patients with RA (R4RA). Information regarding gene expression of GZMs, PRF-1, and SRGN in synovium and blood pathotypes and their correlations with disease activity scores with 28 joints (DAS28)-erythrocyte sedimentation rate and with DAS28-C-reactive protein in early RA (eRA) is lacking. To determine the expression of these genes in synovium and blood pathotypes, we analyzed bulk RNA-sequencing data. The percentage of CD8+ T cells was determined in synovium, and the presence of Porphyromonas gingivalis was examined in synovium. The expression of GZM A, B, H, K, M, PRF-1, and SRGN was significantly higher in the lymphoid pathotype in the PEAC and R4RA synovium. The percentage of CD8 T cells was low, and minor speckles (Ag-reactivity) of P. gingivalis Ag were detected in eRA synovium. Rituximab and tocilizumab treatment in R4RA decreased the expression of all GZMs, PRF-1, and SRGN in the synovium. In conclusion, components of the GZM-PRF-1 pathway are upregulated in RA and may play a mechanistic role.