Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer.
OBJECTIVE
Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs.


OBJECTIVE
To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC.


METHODS
In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012.


METHODS
Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery.


METHODS
A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models.


RESULTS
Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95% CI, 0.76-2.44), respectively.


CONCLUSIONS
Methotrexate use is associated with an increased risk of a second NMSC. Anti-TNF use may increase the risk of a second NMSC when used with methotrexate for RA. Further long-term studies are required before one can conclude that thiopurine and/or anti-TNF do not increase the risk of a second NMSC in patients with IBD.
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia2Division of Gastroenterology, University of Pennsylvania, Philadelphia.
Frank I
FI
Scott
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia3Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Ronac
R
Mamtani
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia4Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia.
Colleen M
CM
Brensinger
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia.
Kevin
K
Haynes
Department of Dermatology, University of Pennsylvania, Philadelphia.
Zelma C
ZC
Chiesa-Fuxench
Department of Epidemiology, University of Alabama at Birmingham.
Jie
J
Zhang
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham.
Lang
L
Chen
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham.
Fenglong
F
Xie
Department of Epidemiology, University of Alabama at Birmingham.
Huifeng
H
Yun
Division of Gastroenterology, University of Pennsylvania, Philadelphia.
Mark T
MT
Osterman
Department of Epidemiology, University of Alabama at Birmingham.
Timothy
T
Beukelman
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia5Department of Dermatology, University of Pennsylvania, Philadelphia.
David J
DJ
Margolis
Department of Epidemiology, University of Alabama at Birmingham7Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham.
Jeffrey R
JR
Curtis
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia2Division of Gastroenterology, University of Pennsylvania, Philadelphia.
James D
JD
Lewis
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy; D001685:Biological Factors / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology* / Q000209:etiology / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D001685:Biological Factors; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha