Over the past few decades, the dermatologic care of inflammatory skin conditions has been transformed through the growing use of small molecules disease-modifying anti-rheumatic drugs (DMARDs) and targeted biologic therapies. However, alongside the tremendous benefits offered by these therapeutic agents are concerns regarding potential adverse effects, in particular associated risks of cancer development. The controversial relationship between immunosuppressive medications frequently used in dermatologic practice and increased cancer risk is a concern which emerging research aims to mitigate. According to data recently published in Dermatologic Therapy, these agents are not significantly associated with certain cancer subtypes yet warrant caution as there is not enough research in the field.
Examining Cancer Risk and Immunosuppressant Use
A team of researchers conducted a systematic review of online trial databases including studies focused on the evaluation of cancer risk among patients being treated with immunosuppressant agents for inflammatory cutaneous conditions. Their research aims to improve current guidance and the counseling of patients with dermatologic diseases who are considering these therapeutics as treatment pathways.
In their review, the study’s authors included research that reported drug type, study cohort characteristics, and cancer outcomes The primary outcome of interest was the occurrence of cancer as related to immunosuppressant exposure, expressed as a standardized incident ratio, relative risk, or odds ratio. Wherever possible, study outcomes were standardized into the number needed to harm (NNH) per year, or the number of patients that needed to be treated by a drug for 1 year in order for 1 case of a specific malignancy to occur.
Rates of cancer within the participating cohorts were compared with rates observed in the general population as reported by the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program Cancer Statistics Review. Immunosuppressant agents were classified as: thiopurines, tumor necrosis factor inhibitors (TNFis), topical calcineurin inhibitors, mycophenolate motefil, and methotrexate (MTX). Finally, the research team stratified results by both drug class and malignancy type.
Cancer Risk and Numbers Needed to Harm
Their review revealed that the association of thiopurine with lymphome, non-melanoma skin cancer, and urinary tract cancer was well-documented in several studies of rheumatoid arthritis and inflammatory bowel disease. Across most cancer subtypes, the number needed to harm was high.
In order for 1 case of lymphoma to occur, 3,572 patients would need to receive thiopurine; meanwhile, in the general population the NNH for lymphoma was estimated at 4,171. Thiopurine was not significantly associated with an increased risk for primary breast cancer, recurrent breast cancer, melanoma, or colorectal cancer. Only for non-melanoma skin cancer was the NNH very low, at 132 patients among those receiving thiopurine compared with between 80 and 3,000 in the general population depending on baseline risk factors.
On the other hand, tumor necrosis factor inhibitors were linked to a slightly increased risk for non-Hodgkin’s lymphoma. The NNH reported by a 2017 study was 9,058 during 1 year. In the untreated population, the NNH for non-Hodgkin’s lymphoma was 10,630. At the same time, the results of TNFis with other lymphomas, non-melanoma skin cancer, and melanoma were inconclusive. They were not associated with Hodgkin’s lymphoma, breast cancer, colorectal cancer, prostate cancer, lung cancer, or overall cancer incidence.
Researchers found that few studies are available regarding the risks associated with methotrexate and topical calcineurin inhibitors. They reported that 2 studies seemed to suggest an increased risk of lymphoma as a result of methotrexate use although, neither of the trials employed an appropriate comparison cohort. Lymphoma in methotrexate users may result from the combined effect of the agent with arthritic conditions and not from MTX use alone. The effect of MTX on lung cancer risk was also unclear. Furthermore, although topical calcineurin inhibitors come with a warning about potential lymphoma risk, no research to date has demonstrated an actual link between the compound and lymphoma.
Other studies included in the review reported no link between topical calcineurin inhibitors and the risk of melanoma or non-melanoma skin cancers. At this time, no studies are able to define the correlation between the risk of cancer and mycophenolate motefil use, underscoring more research is needed in this subject area.
Clinical Implications
The results of the literature review explore the potential safety concerns associated with immunosuppressant agents. Although both thiopurine and TNFis demonstrated some statistically significant associations with cancer risks, only for non-melanoma skin cancers was the NNH below 500-patients-per-year. Meanwhile, for other malignancies the NNH is estimated at thousands of patients receiving care with no reported incidence of cancer.
“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,” the 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.”
The latest review adds clinical context to the level of risk associated with immunosuppressants by establishing a number needed to harm that estimates the number of patients a provider would need to treat with any given agent in 1 year to cause 1 adverse outcome over that time.
However, due to a general lack of data, these results cannot be interpreted conclusively. Further research is needed to clarify the long-term cancer risk in patients using immunosuppressant agents. As such, the researchers highlight the importance of caution and carefully weighing the risks associated with the potential benefits of treatment on an individual basis before prescribing these agents.
