Rheumatoid arthritis (RA) is an autoimmune illness marked by inflammation and synovial hyperplasia. Because of the local presence of immune complexes in the joints, autoantibodies in seropositive RA suggest that complement system activation might have a pathophysiologic function. For a study, researchers sought to look through the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression in synovium and blood. Using multiplex immunohistochemistry labeling, investigators also sought to identify the biodistribution of specific complement activation proteins and inhibitors from individuals in the Accelerating Medicines Partnership (AMP) RA/SLE research. For the complement genes C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1, there were substantial positive correlations between particular complement gene mRNA expression levels in the synovium and DAS28-ESR in the PEAC trial. DAS28-ESR is also strongly negatively correlated with Colec12, C5, C6, MASP-1, CFH, and MCP. The synovium showed strong positive connections between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A, and FcγR3A. Notably, after six months of treatment with the DAS28-ESR, CFHR4 synovial expression was strongly associated, suggesting a role in poor therapeutic responses. The failure of C5/C5aR inhibitors to provide significant effect in clinical studies in individuals with RA might be due to the negative correlation of C5 RNA expression in the synovium. Multiplex immunohistochemistry investigations of early RA synovium indicated strong evidence of localized abnormalities in activation and inhibitory components, indicating that local complement activation was likely to occur.