Associations of Circulating Cytokines and Chemokines With Cancer Mortality in Men With Rheumatoid Arthritis

Objective: To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA). Methods: Male participants in the Veterans Affairs RA registry were followed up from the time of enrollment until death or December 2013. Cytokines and chemokines were measured in banked serum obtained at the time of enrollment, using a bead-based multiplex assay, and a previously developed cytokine score was calculated. Vital status and cause of death were determined through the National Death Index. Associations of cytokines with cancer mortality were examined using multivariable competing-risks regression. Results: Among 1,190 men with RA, 60 cancer deaths (30 of which were attributable to lung cancer) occurred over 5,307 patient-years of follow-up. The patients had a mean age of 64.5 years, had established disease (median duration 8.7 years), were seropositive for rheumatoid factor (81%) or anti–cyclic citrullinated peptide antibody (77%), and frequently had a history of smoking (82% current or former). Seven of 17 analytes examined were individually associated with cancer mortality. The cytokine score was associated with overall cancer (subhazard ratio [SHR] 1.42, 95% confidence interval [95% CI] 1.08–1.85) and lung cancer (SHR 1.86, 95% CI 1.57–2.19) mortality in multivariable analyses. Those in the highest quartile of cytokine scores had a >2-fold increased risk of overall cancer mortality (P = 0.039) and a 6-fold increased risk of lung cancer mortality (P = 0.028) relative to the lowest quartile. A synergistic interaction between current smoking and high cytokine score was observed. Conclusion: Serum cytokines and chemokines are associated with cancer and lung cancer mortality in men with RA, independent of multiple factors including age, smoking status, and prevalent cancer.