Frontiers in Immunology · Oct 30, 2026
TNF Inhibitor Therapy is associated with an Increase in Absolute Lymphocyte Count that is in turn Associated with Lower Mortality Across the Spectrum of Immune Mediated Inflammatory Diseases
By Lenche Kostadinova, Brigid Wilson, Hinnah Siddiqui et al.
Introduction: We previously observed lower absolute lymphocyte count (ALC) associates with greater subsequent mortality in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and TNF-inhibitor (TNFi) therapy initiation associates with an increase in the ALC, that in turn associates with lower mortality. We investigated the pathway and disease specificity of these findings over a range of Immune Mediated Inflammatory Diseases (IMID) and biologic and targeted synthetic (b and ts) disease modifying anti-rheumatic drug (DMARD) therapies. Methods: Using the VA Corporate Data Warehouse, we identified patients that initiated TNF, JAK, IL12/23, IL23, IL17, IL6 or costimulation (abatacept) inhibitor therapy 2017-2022, with ALC before and 3-24 months after therapy initiation. We evaluated change in ALC and overall mortality among patients with documented diagnoses of RA, Psoriasis (PsO), Inflammatory Bowel Disease (IBD), or Ankylosing Spondylitis (AS) at drug initiation. Results: Among 31,416 patients with a bDMARD or tsDMARD drug initiation, ALC increased by a mean of 0.23 x103 cells/µl (95% CI=0.22- 0.24) in the 22,471 patients with TNFi initiation. Comparing ALC values post-drug initiation and adjusting for baseline ALC, demographics, comorbidities, conventional DMARD use, chronic steroid use, and IMID diagnosis, we found patients with TNFi had significantly higher ALCs than those initiating any other drug classes (paired ALC differences of 0.18-0.29 x103 cells/µl, p < 0.001 for six comparisons). In survival models predicting all-cause mortality and adjusting for age ,race, sex, ethnicity, Charlson comorbidity index, concordant cDMARD and chronic steroid medication, we found TNFi use, greater baseline ALC, and increased ALC at follow-up associated with greater survival. Conclusion: TNFi therapy associated with an increase in the ALC across a range of IMID, and this associates with lower subsequent mortality after adjustment for age, sex, and Charlson comorbidity index. Whether the TNFi-induced increase in ALC is mechanistically responsible for improved longevity or is a prognostic biomarker remains to be determined.