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

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 <i>GZMs</i>, <i>PRF-1</i>, and <i>SRGN</i> 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 <i>Porphyromonas gingivalis</i> was examined in synovium. The expression of <i>GZM A</i>, <i>B</i>, <i>H</i>, <i>K</i>, <i>M</i>, <i>PRF-1</i>, and <i>SRGN</i> 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 <i>P. gingivalis</i> Ag were detected in eRA synovium. Rituximab and tocilizumab treatment in R4RA decreased the expression of all <i>GZMs</i>, <i>PRF-1</i>, and <i>SRGN</i> in the synovium. In conclusion, components of the GZM-PRF-1 pathway are upregulated in RA and may play a mechanistic role.