Associations of Circulating Cytokines and Chemokines With Cancer Mortality in Men With Rheumatoid Arthritis.
To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA).



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.



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.



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.
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.
Bryant R
BR
England
VA Palo Alto Health Care System and Stanford University, Palo Alto, California.
Jeremy
J
Sokolove
VA Palo Alto Health Care System and Stanford University, Palo Alto, California.
William H
WH
Robinson
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.
Geoffrey M
GM
Thiele
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.
Apar K
AK
Ganti
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha.
Harlan
H
Sayles
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, and National Data Bank for Rheumatic Diseases, Wichita, Kansas.
Kaleb
0000-0002-5350-3934
K
Michaud
Denver VA Medical Center and University of Colorado, Denver.
Liron
L
Caplan
Denver VA Medical Center, University of Colorado, and Denver Health Medical Center, Denver, Colorado.
Lisa A
LA
Davis
VA Salt Lake City Health Care System and University of Utah School of Medicine, Salt Lake City.
Grant W
GW
Cannon
VA Salt Lake City Health Care System and University of Utah School of Medicine, Salt Lake City.
Brian
B
Sauer
Iowa City VA Health Care System and University of Iowa, Iowa City.
Namrata
N
Singh
Dallas VA Medical Center and University of Texas Southwestern Medical Center, Dallas.
E
0000-0002-4947-2741
E
Blair Solow
Dallas VA Medical Center and University of Texas Southwestern Medical Center, Dallas.
Andreas M
AM
Reimold
Washington DC VA Medical Center and Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC.
Gail S
GS
Kerr
Portland VA Health Care System and Oregon Health and Sciences University, Portland.
Pascale
P
Schwab
Philadelphia VA Medical Center and University of Pennsylvania, Philadelphia.
Josh F
JF
Baker
Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha. tmikuls@unmc.edu.
Ted R
TR
Mikuls
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000276:immunology*; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000401:mortality; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality; D008223:Lymphoma / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000401:mortality; D010456:Peptides, Cyclic / Q000276:immunology; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000276:immunology / Q000401:mortality; D012042:Registries; D012215:Rheumatic Nodule / Q000453:epidemiology / Q000276:immunology; D012217:Rheumatoid Factor / Q000276:immunology; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology; D013851:Thinness / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D014493:United States Department of Veterans Affairs
D018925:Chemokines; D016207:Cytokines; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002097:C-Reactive Protein; D012217:Rheumatoid Factor