TNF Inhibitors Linked to Increased Skin Cancer Risk in Long-Term Cohort Study

Long-term tumor necrosis factor alpha inhibitor (TNF-I) therapy was associated with significantly increased risks of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma in patients with chronic inflammatory disease, according to a large retrospective cohort study published online February 16, 2026, in the Journal of the American Academy of Dermatology (JAAD).¹

Investigators at Northwestern University analyzed 56,209 patients treated across dermatology, gastroenterology, and rheumatology clinics between July 1996 and January 2020, comparing 13,377 TNF-I-exposed patients with 42,832 unexposed patients.¹ Adjusted hazard ratios ranged from 1.54 for melanoma to 1.99 for BCC.¹

Long-Term Data Address Prior Uncertainty

Prior studies evaluating TNF-I therapy and cutaneous malignancy have produced conflicting findings because of relatively short follow-up periods, low event rates, and differences in study design. A large 2025 active-comparator study involving 1.8 million patients identified only a modest association with nonmelanoma skin cancer (NMSC) and no significant increase in melanoma risk.² The study included a median follow-up exceeding 8 years, with manual chart verification of every skin cancer diagnosis and TNF-I prescription date to improve diagnostic accuracy.¹

Study Design and Patient Population

Investigators queried the Northwestern Enterprise Data Warehouse for adults with psoriasis or psoriatic arthritis, hidradenitis suppurativa, Crohn disease, ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis or spondyloarthropathy, and uveitis.¹ Patients were classified by exposure to adalimumab, etanercept, infliximab, certolizumab, or golimumab.¹ Median follow-up was 99 months among TNF-I-exposed patients, including 45 months after first exposure, compared with 87 months among unexposed patients.¹

TNF-I Exposure Nearly Doubled Overall Skin Cancer Risk

In multivariable Cox regression adjusted for age, race, sex, smoking status, and disease indication, TNF-I exposure was associated with a significantly higher risk of any cutaneous malignancy (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.65-2.20; P < .001).¹ Risk was also elevated for BCC (aHR, 1.99; 95% CI, 1.66-2.38; P < .001), SCC (aHR, 1.69; 95% CI, 1.36-2.10; P < .001), and melanoma (aHR, 1.54; 95% CI, 1.11-2.14; P = .009).¹ Sensitivity analyses accounting for multiple chronic inflammatory diagnoses, concomitant immunosuppressants, and phototherapy exposure did not change the direction or significance of these associations.¹

Skin Cancer Severity and Safety Considerations With TNF Inhibitors

Despite the higher incidence of skin cancer, TNF-I exposure did not correlate with more aggressive disease at diagnosis.¹ High-risk BCC histologic subtypes occurred in 22% of exposed patients versus 26% of unexposed patients (P = .4), and invasive SCC occurred in 52% versus 48%, respectively (P = .5).¹ Most melanomas were diagnosed as in situ or stage I disease in both groups (88% exposed vs 89% unexposed; P = .7), with superficial spreading remaining the predominant histologic subtype.¹

In disease-specific analyses, the association between TNF-I exposure and skin cancer differed by underlying condition. Relative risk appeared lower among patients with RA and psoriasis/psoriatic arthritis, whereas higher risks were observed in patients with Crohn disease and uveitis.¹ The investigators suggested that immune dysregulation inherent to RA and psoriatic disease may contribute substantially to baseline skin cancer risk, potentially influencing these findings.¹ No unexpected safety signals emerged from the sensitivity analyses.

Study Limitations

The authors acknowledged several limitations, including the retrospective study design and the inability to consistently account for individual skin cancer risk factors such as cumulative ultraviolet exposure, Fitzpatrick skin type, tanning bed use, and dysplastic nevi history.¹

Clinical Implications for Skin Cancer Screening

TNF-I therapy remains a mainstay for many patients with inflammatory bowel disease, RA, and psoriatic disease, even as interleukin-17 and interleukin-23 inhibitors continue to expand the treatment landscape.¹ The authors recommend annual total-body skin examinations for patients receiving TNF-I therapy, consistent with current practice for other immunosuppressed populations.

Ultimately, screening frequency should incorporate individualized risk factors, including age, skin type, UV exposure, total number and history of dysplastic nevi, and personal or family history.¹ — Conor B. Driscoll, MD

Although additional prospective data are needed, the findings support routine skin cancer surveillance in patients receiving TNF-I therapy and underscore the importance of individualized risk assessment when counseling patients about long-term biologic treatment.

References:

1. Driscoll CB, Schwab G, Quan VL, et al. Tumor necrosis alpha inhibitor therapy is associated with increased long-term risk of nonmelanoma skin cancer and melanoma: a retrospective cohort study. J Am Acad Dermatol. 2026;94(6):1723-1730. doi:10.1016/j.jaad.2026.02.035. https://pubmed.ncbi.nlm.nih.gov/41707711/
2. Lauck KC, Ahmed A, Davis MJ, Council ML, Nehal K, Alam M. Cutaneous malignancy after biologic therapy for inflammatory disease: an active comparator, retrospective cohort study. J Am Acad Dermatol. 2025;93:724-732.