Anti-TNF Medications Linked to Nonmelanoma Skin Cancer in Rheumatoid Arthritis Patients

Alice Goodman

October 21, 2009

October 21, 2009 (Philadelphia, Pennsylvania) — Patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) medications are at increased risk of developing nonmelanoma skin cancer, particularly basal and squamous cell skin cancers, compared with those treated with traditional disease-modifying anti-rheumatoid drugs (DMARDs), although the risk is modest, according to 2 large retrospective studies presented here at American College of Rheumatology (ACR) 2009. The studies had different populations and methods, but came to the same conclusion.

The first study, reported by Prabha Ranganathan, MD, from the Division of Rheumatology at Washington University in St. Louis, Missouri, was based on a retrospective cohort of 16,829 RA patients, from the Veterans Affairs database, enrolled on the basis of ICD-9 codes between October 1, 1998 and September 30, 2006. Patients were divided into 2 groups: those receiving nonbiologic medications and those receiving anti-TNF medications. The researchers in this federally funded study sought to determine the incidence of nonmelanoma skin cancer and melanoma skin cancer.

"Our study suggests that RA patients with risk factors for skin cancer who are being treated with biologic therapy should be monitored more closely for the development of skin cancer," she said. "These findings are not a contraindication for the use of anti-TNF medications."

Of 16,829 patients, 3096 were treated with anti-TNF medications. The incidence of nonmelanoma skin cancer was 25.9 per 1000 patient-years in patients receiving anti-TNF medications and 19.6 per 1000 patient-years in those receiving nonbiologic DMARDs, representing a 34% increased risk for those receiving the anti-TNF agents (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.15 - 1.58; P < .0001). Factors associated with an increased risk for nonmelanoma skin cancer were age (being older), sex (being male), use of steroids, previous malignancy, and duration of RA therapy.

Dr. Ranganathan said that 6.9% of patients receiving RA drug therapy for 1 to 6 months had a nonmelanoma skin cancer, whereas those receiving drug therapy for more than 5 years had an incidence of 12.1%.

The association between anti-TNF therapy and melanoma was less robust than for nonmelanoma skin cancer. The incidence of melanoma was 3.7 per 1000 patient-years in patients receiving anti-TNF drugs and 2.6 per 1000 patient-years in those receiving nonbiologic DMARDs. The risk was increased by 50% for those receiving anti-TNF drugs (HR, 1.5; 95% CI, 1.01 - 2.24; < .05). Risk factors for melanoma included a history of malignancies.

Dr. Ranganathan said that the correlation between ICD-9 codes and medical records was good for nonmelanoma skin cancers but not as good for melanoma, so these results regarding melanoma should be interpreted with more caution.

A second large observational study, based on the British Biologics Registry, which has collected data on all RA patients in the United Kingdom since 2001, found a trend toward an increased risk for nonmelanoma skin cancer in patients receiving anti-TNF therapy, compared with those receiving traditional DMARD therapy. The risk was increased for anti-TNF therapy 70% in patients who had not been previously diagnosed with nonmelanoma skin cancer, although this difference did not reach statistical significance.

"Although the trend was for increased risk with anti-TNF therapy, the absolute risk was low. RA patients should be closely monitored for suspicious skin lesions, because they have about a 2 times higher risk of developing nonmelanoma skin cancer than the general population, and a higher risk than those treated with DMARDs," said Kimme l. Hyrich, MD, senior lecturer at the University of Manchester in the United Kingdom and lead author of the study.

The registry comprised 16,000 patients: 11,757 consecutive anti-TNF-treated patients and 3515 biologic-naïve subjects with active RA treated with conventional DMARD therapy. The researches found 221 incidents of nonmelanoma skin cancer: 175 in 149 patients receiving anti-TNF drugs and 46 in 40 patients receiving DMARDs.

The strongest predictor of nonmelanoma skin cancer was previous nonmelanoma skin cancer. Age, being male, and steroid use were also associated with increased risk. When patients with previous nonmelanoma skin cancer were excluded from the analysis, the fully adjusted HR was 1.7 for anti-TNF vs DMARD therapy (95% CI, 0.9 - 3.4).

The risk was greatest for infliximab, Dr. Hyrich added.

Careful Monitoring Warranted

Commenting on both studies, Allan Gelber, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, said that "even though these are observational studies, I would not call these data preliminary, since they are based on tens of thousands of patients and comprise a rich dataset."

"The data presented here cautions the treating physician to be vigilant about monitoring RA patients for skin cancer. These studies provide data on skin cancers. Nonmelanoma is a relatively innocuous cancer. We should continue to use biologics in patients who fail on DMARDs, but we need to monitor for early signs of skin cancer," Dr. Gelber concluded.

Dr. Ranganathan, Dr. Hyrich, and Dr. Gelber have disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2009: Abstract 1379. Presented October 20, 2009.


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