Mendelian randomization identifies multiple immune cell surface markers as potential causal contributors and drug targets in rheumatoid arthritis

Objective Although biologic therapies targeting cytokines have revolutionized the treatment of rheumatoid arthritis, immune cell surface markers remain underexplored as therapeutic targets. We combined Mendelian randomization with clinical evidence to identify causal immune cell phenotypes as potential causal contributors to rheumatoid arthritis and as candidate drugs and therapeutic targets. Methods We analyzed genome-wide association study summary statistics from rheumatoid arthritis cohorts (discovery: 12,555 cases/240,862 controls; replication: 14,361 cases/43,923 controls) as well as 731 immune cell traits. The primary analysis used inverse-variance weighted Mendelian randomization. Clinical trial evidence was further used to explore the therapeutic potential of identified targets. Associations with p < 0.05 were considered nominally significant, while Bonferroni correction was applied to determine statistical significance (p < 6.83 × 10 −5 ). Results Analysis of the discovery cohort identified 92 nominally associated immune phenotypes, with 10 surviving multiple testing correction. Replication analysis showed 88 nominal associations, with 4 passing the correction. Meta-analysis revealed suggestive evidence for 17 phenotypes. Five immune markers (CD28, CD27, CX3CR1, CD3, and human leukocyte antigen (HLA)-D-related (DR)) emerged as potential diagnostic and therapeutic targets, supported by clinical trial evidence. Conclusions This study identified immune biomarkers as potential diagnostic and therapeutic targets for rheumatoid arthritis, providing a framework for prioritizing targetable pathways beyond cytokine blockade and offering new therapeutic avenues.