Use of TNF Blockers May Raise Skin Cancer Risk

NEW YORK — The greatest malignancy risk in patients receiving tumor necrosis factor antagonists is skin cancer, Dr. Jeffrey Greenberg said at a rheumatology meeting sponsored by New York University.

However, data conflict as to how great malignancy risk is overall for these patients.

Two years ago, a widely noted systematic review and meta-analysis found a threefold increased risk for malignancy in patients with rheumatoid arthritis (RA) treated with infliximab or adalimumab (JAMA 2006;295:2275–85). The meta-analysis included nine randomized, placebo-controlled trials, with 3,493 RA patients who received an active drug and 1,512 RA patients who received placebo.

In the anti-tumor necrosis factor (TNF) arms of this analysis, there were 10 lymphomas, nine nonmelanoma skin cancers, and 12 assorted other cancers, Dr. Greenberg said. "What was most interesting was the cancers that weren't found in the placebo arms—there were two basal cell cancers and one solid tumor—and that's it," he said, adding that in a group of 1,500 RA patients, 8–10 malignancies would be expected.

Aside from the lower-than-expected rates of malignancy in the placebo arms, the meta-analysis had other limitations, according to Dr. Greenberg of New York University, New York, who is chief scientific officer of the Consortium of Rheumatology Researchers of North America (CORRONA).

Among these limitations were the exclusion of etanercept; the association of higher-than-usual doses of infliximab with most malignancies; and the fact that the investigators used a per-patient analysis rather than person-years of drug exposure. Their approach assumes equal time exposure for placebo and the anti-TNF drugs, and four of the nine trials had higher placebo dropout rates.

"Patients on placebo who drop out are not followed for long periods of time looking for malignancies, so of course they are going to have fewer events," he added.

However, a different picture is emerging from observational studies and RA registries in the United States and Europe. In three Swedish registries—one prevalent cohort that included 53,067 patients, one incident cohort that included 3,703 patients, and one TNF antagonist-treated cohort of 4,160 patients—RA patients treated with TNF blockers had a tripled lymphoma risk, compared with the general population. However, after adjustment for sex, age, and disease duration, the lymphoma risk among TNF antagonist-treated patients was no higher than in the other RA cohorts (Ann. Rheum. Dis. 2005;64:1414–20).

In a report from the National Data Bank for Rheumatic Diseases, when RA patients were compared with the general population from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, there was no increased rate of cancer overall, but lymphoma and melanoma were increased, with both having standardized incidence ratios of 1.7. However, only nonmelanoma skin cancer and melanoma were increased among patients on biologics, with odds ratios of 1.5 and 2.3, respectively. No other malignancy was significantly associated with biologic use (Arthritis Rheum. 2007;56:2886–95).

Data from the British Biologics Register also found no increase in malignancy rate, with an adjusted incidence rate ratio (IRR) of 0.7 for patients treated with anti-TNF agents, compared with those treated with nonbiologic disease-modifying antirheumatic drugs.

And in CORRONA, which includes 15,000 RA patients, the adjusted IRR for skin cancer was 2.10, whereas that for lymphoma was 0.74 and that for all cancers was 1.05, according to Dr. Greenberg.

"I think the take-home message of the observational studies is that it's the nonmelanoma skin cancers and possibly the melanomas that are the greatest concern, not the lymphomas," he said.

However, the discrepancy between the findings of the meta-analysis and those of the observational studies remains to be explained, Dr. Greenberg said.

"Frankly, I think they could not be more conflicting. It may be that there is a group of patients with subclinical neoplasms, including lymphomas, that any immunosuppressive or immunomodulatory treatment may unmask or accelerate. We probably should be screening for these cancers more aggressively regardless of treatment," he said.