Mark Lebwohl, M.D., reviews evidence pertaining to malignancy risks with biologics and the rationale for avoiding “drug holidays”.
Dermatologists using biologics to treat psoriasis may wonder if it is reasonable to give patients who are doing well a rest from therapy and if patients with a history of cancer can be treated safely.
Dr. Lebwohl“No” is the simple answer to the first question, but the response to the second is more complicated because only some biologics have been associated with cancer development and then only with certain cancers, says Mark Lebwohl, M.D., professor and chairman, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. He discussed these topics at the South Beach Symposium.
The recommendation to avoid drug holidays when using a biologic to treat psoriasis considers several issues. First, results of studies with infliximab (Remicade, Janssen-Biotech), adalimumab (Humira, Abbvie), etanercept (Enbrel, Amgen), ustekinumab (Stelara, Janssen), and certolizumab pegol (Cimzia, UCB) consistently show that when these agents are stopped in responding patients (eg., individuals achieving a PASI-75 response) and restarted as needed, sizeable proportions of patients-between 10% and 37%, depending on the biologic - fail to regain their previous level of control.
Furthermore, it has been shown that episodic treatment with infliximab increases the risk for anti-infliximab antibody formation, and that is a concern because presence of these antibodies is associated with reduced efficacy and increased risk of infusion reactions. Similarly, development of antibodies to adalimumab has been shown to correlate with poorer response to treatment.
Dr. Lebwohl notes there is also a substantial amount of data for TNF-α blockers, some of the IL-17 blockers, and ustekinumab showing that these biologics protect against joint destruction when they are used on a fixed regimen. In addition, findings from analyses of registry data indicate that fixed treatment with TNF-α blockers and perhaps other biologics may be cardioprotective. In a study of patients with psoriasis, those on a TNF-α blocker had a 50% lower risk of myocardial infarction compared with patients on topical treatment.
“We know these systemic benefits occur in patients who stay on their biologics, but we don’t know if they are also present for patients who go off a fixed regimen,” Dr. Lebwohl says. “Considering all of the evidence, stopping and restarting therapy with a biologic is not a good policy.”
Summarizing data on biologics and malignancy, Dr. Lebwohl says that analyses of data from various registries indicate that the TNF blockers-infliximab, etanercept, and adalimumab-are associated with a significantly increased risk of squamous cell carcinoma (SCC) of the skin. Rates of melanoma and lymphoma have also been found to be higher among patients on TNF blockers compared to controls, although the increased risk has not consistently achieved statistical significance, probably because melanoma and lymphoma are relatively uncommon cancers.
“Huge numbers of patients on TNF-α blockers would be needed to have sufficient power to demonstrate a statistically significant difference in event rates,” Dr. Lebwohl explains.
He also cites a study investigating infliximab for treatment of moderate to severe chronic obstructive pulmonary disease that was terminated early because of a significantly increased incidence of cancers in the active treatment group compared with placebo-treated controls. Specifically, rates of lung and head and neck cancers were higher in the infliximab group, and all affected patients had a history of heavy smoking.
“Based on these data, I always caution smokers that there is an increased risk of malignancy with TNF- α blocker treatment, and I try to get them to stop smoking,” Dr. Lebwohl says.
So far, there is no evidence that the TNF-α blockers increase the risk of solid tumors, including breast, colon, and prostate cancer. And, there is also no evidence that ustekinumab, the interleukin-12 and -23 (IL-12/23) antagonist, increases the risk of any kind of cancer. Registry data for patients on the IL-17a antagonist, secukinumab (Cosentyx, Novartis), are more limited. So far, however, there is no indication that its use is associated with the development of any malignancy.
“The absence of an increased risk of malignancies with ustekinumab and secukinumab is consistent with information that cancer risk is also not elevated among people born with genetic defects in the signaling pathways these biologics inhibit,” Dr. Lebwohl says.
Regarding other systemic treatments for psoriasis, methotrexate is clearly associated with an increase in rates of lymphoma, lung cancer, and SCC of the skin, and cyclosporine dramatically increases the risk of lymphomas and SCC of the skin. In contrast, treatment with acitretin decreases the risk of SCC and basal cell carcinoma, while so far, there is no evidence linking apremilast (Otezla, Celgene) with any malignancy risk.
“Although more long-term data are needed, it is not surprising that there is no signal so far for increased cancer risk with apremilast considering that this phosphodiesterase-4 inhibitor does not act as an immunosuppressant,” Dr. Lebwohl says.
Disclosure: The Department of Dermatology at Icahn School of Medicine at Mount Sinai receives research funding from companies that market biologics for treatment of psoriasis, but Dr. Lebwohl has no personal financial interest to disclose.