AUTHOR=Chen Ding-Qiang , Xu Wen-Bin , Que Zhi-Qiang , Xiao Ke-Yi , Sun Nai-Kun , Cai Di-Xin , Feng Jin-Yi , Rui Gang 

TITLE=Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment

JOURNAL=Frontiers in Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1368346

DOI=10.3389/fmed.2024.1368346

ISSN=2296-858X

ABSTRACT=Objective
Interleukin-6 (IL6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, more and more evidence is revealing the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study is aimed at evaluating the potentially therapeutic utility of IL6R-targeted approaches in AS.
Methods
C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association studies (GWAS) data was used as the primary outcome of drug-targeted MR analyses to test the relationship between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposure and outcome to examine results for stability.
Results
According to the IVW results, IL6R inhibitors significantly reduced the risk of AS, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, P = 5.12×10-08), ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, P = 6.25×10-15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, P = 1.25×10-06), ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, P = 7.81×10-09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy.
Conclusion
This MR analysis result further validate that the IL6 pathway may contribute to the pathogenesis of AS and that inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.