Assessing Cancer Risk Associated With Immunosuppressive Agents in Dermatology

Cancer risks associated with immunosuppressant agents commonly used in dermatology were outlined in study data published in Dermatologic Therapy. Although disease-modifying antirheumatic drugs (DMARDs) and biologic therapies are frequent first-line treatments for inflammatory dermatologic disorders, concerns remain about their potential role in increased cancer risk. The present review sought to assess the risk for cancer by subtype in broad categories of immunosuppressing drugs.

In July 2020, investigators conducted a systematic review of online trial databases for studies evaluating cancer risk among patients receiving immunosuppressants for inflammatory skin conditions. Studies that reported drug type, study cohort characteristics, and cancerous outcomes were included. The outcome of interest was the occurrence of cancer following immunosuppressant exposure, expressed as a standardized incident ratio, relative risk, or odds ratio. When possible, study outcomes were standardized into a number needed to harm (NNH) per year, or the number of patients needed to be treated by the drug during 1 year in order for 1 case of specific malignancy to appear. Cancer rates in study cohorts were compared with rates in the general population, determined using the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program Cancer Statistics Review. Results were stratified by drug class and malignancy type.

Immunosuppressant drugs were classified as follows: thiopurines; tumor necrosis factor inhibitors (TNFis); methotrexate (MTX); topical calcineurin inhibitors; and mycophenolate motefil. The association of thiopurine with lymphoma, nonmelanoma skin cancer (NMSC), and urinary tract cancer was well-documented in several studies of rheumatoid arthritis and inflammatory bowel disease. However, the NNH was high across most cancer subtypes: for lymphoma, 3572 patients would need to receive thiopurine in order for 1 case of lymphoma to occur. In the general population, the NNH for lymphoma was estimated at 4171. Only for NMSC was the NNT very low, at 132 among those receiving thiopurine. NNH in the general population ranged from 80 to more than 3000, depending on baseline risk factors. Thiopurine was not substantially associated with risk for primary breast cancer, recurrent breast cancer, melanoma, or colorectal cancer.

TNFis were associated with slightly increased risk for non-Hodgkin’s lymphoma, according to data from a 2017 study. The NNH during 1 year was 9058: nearly 10,000 patients would need to receive TNFis in order for a case of NHL to occur. In the untreated population, the NNH for non-Hodgkin’s lymphoma was 10,630. Results were inconclusive regarding the association of TNFis with other lymphomas, NMSC, or melanoma. TNFis were not associated with Hodgkin’s lymphoma, breast cancer, colorectal cancer, prostate cancer, lung cancer, or overall cancer incidence.

Few studies were available regarding risks associated with MTX and topical calcineurin inhibitors. The investigators found 2 studies that suggested that lymphoma risk may be increased with MTX use, although neither study used an appropriate comparison cohort. Lymphoma in MTX users may be a result of the combined effect MTX and arthritic conditions, rather than MTX alone. Similarly, the effect of MTX on melanoma and lung cancer was unclear. And although topical calcineurin inhibitors come with a black box warning about potential lymphoma risk, no studies have demonstrated an actual link between the active agent and lymphoma. Other studies found no link between topical calcineurin inhibitors and risk of melanoma or NMSC. No studies were available for the risks associated with mycophenolate motefil.

Results from this review outline the potential safety concerns surrounding immunosuppressant agent use. Although thiopurine and TNFis had some statistically significant associations with cancer risks, only for NMSC was the NNH below 500 patients-per-year. For other malignancies, thousands of patients are projected to receive care with no incidence of cancer. As such, the benefits of treatment must be carefully weighed against the risks. These results should be interpreted with caution, the researchers noted, given the lack of available data. Further long-term studies are needed to better assess long-term cancer risk in patients using immunosuppressants.

“For most extracutaneous malignancies, large observational studies did not reveal an increased incidence of tumors, including breast, colorectal, prostate, and lung, which make up the overwhelming majority of cancers,” investigators wrote. “By understanding and communicating the concept of NNH, physicians can begin to better define acceptable risks of treatment of impactful and debilitating but not necessarily life-threatening skin diseases.”

Reference

Daugherty TT, Swerlick RA. Clinical context for cancer risk of immunosuppressive agents used in dermatology [published online October 20, 2020]. Dermatol Ther. doi: 10.1111/dth.14433