Associations between rheumatoid arthritis and skin cancer: A bidirectional two-sample Mendelian randomization study

To the Editor: Chronic inflammation has the capacity to induce gene mutations and DNA damage, which can lead to tumorigenesis.1Greten F. Grivennikov S. Inflammation and cancer: triggers, mechanisms, and consequences.Immunity. 2019; 51: 27-41Abstract Full Text Full Text PDF PubMed Scopus (1794) Google Scholar Consequently, the relationship between chronic inflammatory diseases and tumors is a subject of significant interest in research. Rheumatoid arthritis (RA), as a chronic autoimmune inflammatory disease, has established the relationship between RA, biologic disease-modifying antirheumatic drugs (bDMARDs), and skin cancer. Observational studies have indicated that the utilization of bDMARDs in RA could elevate the risk of nonmelanoma skin cancer (NMSC).2Raaschou P. Simard J. Asker Hagelberg C. Askling J. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden.BMJ. 2016; 352: i262Crossref PubMed Scopus (96) Google Scholar However, the precise factors responsible for the increased risk of skin cancer remain unknown. Mendelian randomization (MR) employs genetic variation as a natural experiment to study associations between exposure and outcome, with the advantage of being less likely to be affected by confounding factors or reverse causation than observational studies. Here, we conducted a bidirectional MR analysis to investigate the associations between RA and skin cancer. Fig 1 illustrates the study design and data sources3Okada Y. Wu D. Trynka G. et al.Genetics of rheumatoid arthritis contributes to biology and drug discovery.Nature. 2014; 506: 376-381Crossref PubMed Scopus (1600) Google Scholar in a schematic diagram. Detailed information regarding the specific analysis methods employed in this study can be found in the Supplementary Materials method, available via Mendeley at https://doi.org/10.17632/tt37566yvz.1. Genetic liability to RA was associated with a decreased risk of NMSC and cutaneous melanoma (CM), demonstrating odds ratios of 0.74 (βivw = −0.30, PIVW = 0.021) and 0.94 (βivw = −0.05, PIVW = 0.015), respectively (Fig 2). The reverse MR analysis did not reveal any significant associations. In subsequent analyses, we observed that the protective genetic association was in basal cell carcinoma (BCC) (βivw = −0.04, PIVW = 0.007) but not in squamous cell carcinoma (βivw = −0.10, PIVW = 0.279). Additionally, our findings from the validation data set indicated that there might not be a significant correlation between RA and CM (βivw = −0.0005, PIVW = 0.053). The heterogeneity test revealed the presence of heterogeneity in the analysis (RA vs NMSC; RA vs BCC). Therefore, we employed the random-effects model as the main method to address the heterogeneity. No significant evidence of horizontal pleiotropy was detected as indicated by the MR‒Egger intercept. The enrichment analysis revealed that the genetic protective effect of RA on BCC was primarily enriched in the Th17 differentiation pathway. Supplementary Materials, available via Mendeley at https://doi.org/10.17632/tt37566yvz.1 provide further detailed information on additional results.Fig 2Forest plots for the associations of genetic susceptibility to RA with different Mendelian randomizations of CM and NMSC. Reverse MR: IVW method. CM, Cutaneous melanoma; IVW, inverse-variance weighted; MR, Mendelian randomization; NMSC, nonmelanoma skin cancer; RA, rheumatoid arthritis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our investigation unveils a unidirectional association whereby RA exerts a protective effect against NMSC, particularly BCC. Notably, this conclusion differs from the findings of previous observational studies. The present study shows that there may not be a significant association between RA and CM, which aligns with the results of previous meta-analyses.4Esse S. Mason K. Green A. Warren R. Melanoma risk in patients treated with biologic therapy for common inflammatory diseases: a systematic review and meta-analysis.JAMA dermatology. 2020; 156: 787-794Crossref PubMed Scopus (41) Google Scholar Recent investigations have revealed that Hedgehog signaling blockade facilitates the conversion of Tregs into pathogenic Th17 cells.5Hinshaw D. Benavides G. Metge B. et al.Hedgehog signaling regulates treg to Th17 conversion through metabolic rewiring in breast cancer.Cancer Immunol Res. 2023; 11: 687-702Crossref PubMed Scopus (5) Google Scholar Interestingly, BCC is driven by aberrant Hedgehog signaling. We postulate that in RA patients, Th17 cell differentiation may be associated with Hedgehog pathway suppression, thereby conferring a protective effect on BCC. In summary, patients with RA should be notified that the disease itself may not inherently increase the risk of developing skin cancer. However, educating RA patients receiving bDMARDs about skin cancer signs, the significance of regular self-examination, and the importance of sun protection is still imperative. None disclosed. Genetic association estimates for rheumatoid arthritis, melanoma and nonmelanoma skin cancer were obtained from data sets from the IEU Open GWAS project. Genetic association estimates for basal cell carcinoma and squamous cell carcinoma were obtained from data sets from the FinnGen release 9 project. The authors thank all investigators for sharing these data. Fig 1 was created by a biorender. Enrich analysis used by the Enrichr database.