Rheumatoid arthritis and risk of lung cancer: Meta-analysis and Mendelian randomization study

Observational studies suggest that rheumatoid arthritis (RA) may be associated with lung cancer (LC) risk, while the evidence is inconsistent. We conducted a meta-analysis and a Mendelian randomization study to investigate the association and causality between RA and the LC risk. We conducted a systematic search of cohort studies and performed a meta-analysis (PROSPERO ID CRD42020159082) to calculate the relative risks (RRs) and their 95% confidence intervals (95%CIs). Subgroup analyses based on sex and initiation year of follow-up were carried out. E‐values of each study were calculated to evaluate if existing studies were sensitive to unmeasured confounding. Furthermore, we investigated the correlation between genetically predisposed RA and LC risk using summary statistics from the International Lung Cancer Consortium (11,348 cases and 15,861 controls) and 90 RA-related single nucleotide polymorphisms from European and East Asian descent as instrumental variables. A two-sample Mendelian randomization (MR) analysis was performed to detect the findings based on LC and histological subtypes. Sensitivity analyses were performed to test the robustness of our findings. In the meta-analysis of 11 cohort studies involving 183,888 patients, an increased risk of LC was observed among RA patients (RR = 1.44, 95%CI = 1.31–1.57). Subgroup analyses suggested that male patients have a relatively higher LC risk than female patients, and an increased incidence of LC in RA patients was found from 1950 to 2010. Conversely, in the MR analysis, we found that genetically predisposed RA was associated with a decreased risk of LC overall, while neither causally associated with the risk of lung adenocarcinoma nor squamous cell lung cancer. Nevertheless, genetically predisposed RA was associated with a decreased LC risk among the East Asian population, but not in Europeans. These results were robust against extensive sensitivity analyses. Our meta-analysis suggested that although RA was associated with a relatively higher LC risk, the causal relationship between genetically predisposed RA and LC risk was not supported by the MR study. Further studies are warranted to elucidate the possible association between RA and the risk of LC, as well as its underlying mechanisms.