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Hard Conversations: DMARDs and Malignancy

Cancer is the most difficult disease modifying antirheumatic drug (DMARD) risk to discuss with patients. Few warnings could scare people away from a drug faster than the words “may increase risk of cancer,” yet the risks (even when substantiated) have all been low and may be counterbalanced by the benefits of disease control. Today I would like to discuss a few relevant pathways as a means to describe my overall approach to counseling about this risk. 

First and foremost, we must grapple with the fact that some of our drugs have a well-substantiated risk of cancer.

The Janus kinase (JAK) inhibitor tofacitinib notoriously failed to demonstrate non-inferiority to TNF inhibitors in the ORAL SURVEILLANCE study, with a cited number needed to harm of 55 patients over 5 years (ie for every 55 patients treated with a JAK instead of a TNF, 1 cancer would be caused). This risk has not been substantiated in multiple low-quality observational studies and in 1 high quality observational study, but the FDA has rightly affixed a black box warning to all of the marketed JAK inhibitors. 

Less widely discussed but no-less consequential is a risk of non-basal cell skin cancers with methotrexate. The CIRT trial, which evaluated methotrexate against placebo for cardiovascular disease, observed 4 additional cases per 1,000 person years of exposure. Yet I find this wholly unconvincing as a risk that would affect my prescribing. First, the risk is small and in a cancer-type that could be mitigate-able with a regular visit to a dermatologist. Second, the study compared methotrexate use to placebo among patients without autoimmune disease. I strongly suspect that uncontrolled disease activity would pose a greater risk to the total health of my patients. I do encourage dermatologic evaluations for patients on methotrexate but this finding has not otherwise changed my practice. 

The success of JAK inhibitors against tofacitinib may be surprising given the widely discussed risk of lymphoma from TNFs. Shortly after it arose, this was debunked in a large observational dataset and has been soundly refuted since. Despite the science being relatively clear on this question, patients routinely ask me about this risk and I spend an inordinate amount of time in clinic reassuring them that it should not affect their use of TNF inhibitors. It should be noted that many people who have received TNF inhibitors have developed lymphoma, but this is likely because (1) we have given hundreds of thousands of patients TNF inhibitors and (2) autoimmunity itself increases the risk of lymphoma. I do not believe that TNFs cause lymphoma.

More recently, a fellow and I published a reply to the recently published study of perisolimab for rheumatoid arthritis. Perisolimab is a novel stimulator of the PD-1 pathway. Anyone paying attention to oncology would immediately recognize that this flies in the face of recent oncologic progress, which has used the inhibition of PD-1 to great effect. Perisolimab poses a theoretical risk of cancer that seems prohibitive to me, and I would counsel patients to be wary of it until long term post-marketing studies have been conducted. Unfortunately, our regulatory system has not been designed to adequately address risks of this nature. The risk of malignancy with tofacitinib, for instance, was largely unrecognized in the trials that informed the 2012 regulatory approval, and thousands of patients received tofacitinib without being adequately counseled. 

How then should we counsel patients about DMARDs and malignancy? I recommend the following strategies: 

  1. Transparency. All patients considering any of the JAK inhibitors should be informed of this risk.
  2. Courage. When the data says that a risk does not exist, stand behind the data. I tell patients that the risk of malignancy for TNF inhibitors has been unsubstantiated and that it should not influence prescribing.
  3. Caution. Novel mechanisms present novel risks. I would prefer the devil I know (JAKs) to the devil yet-to-be-studied (perisolimab).
  4. Compassion. Rheumatoid arthritis is difficult enough already. Concerns about malignancy are justified and patients need informed and compassionate advice about how to navigate this area. 


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Mike Putman is an Assistant Professor of Medicine at the Medical College of Wisconsin, where he is the Medical Director of the Vasculitis Program and maintains an active practice in general rheumatology. He is involved in education and currently serves as the Associate Program Director for Rheumatology, Associate Program Director for Internal Medicine, and medical school co-director for Hematology and Immunology. His research interests include clinical trials in vasculitis, “big data” epidemiology, and meta- research. He is also an Associate Editor of the journal Rheumatology and hosts the Evidence Based Rheumatology podcast.