Q: What are the strategies for managing patients with RA and previous or comorbid cancer?

Prior to the introduction of anti–tumor necrosis factor (anti-TNF) agents, many patients had active disease that had been uncontrolled for a significant period of time. Data from a Swedish study by Askling, Baecklund, and colleagues indicated that such patients had an increased risk of lymphoma. It has been established that having RA is linked to an increased risk of lymphoma, with an average doubling of the risk compared with the general population. And the degree of risk is strongly associated with how long a patient has had uncontrolled or very active RA. Overall, the increased risk of developing a malignancy in RA appears to be limited largely to lymphoma. There does not appear to be a significantly increased risk of developing other cancer types in patients with RA. Although patients with RA have a higher risk of developing lung cancer, this likely reflects the higher incidence of RA in smokers. Regarding the risk of cancer with biologics (primarily the anti-TNF agents), we have only observational data, but the sole malignancy with an increased risk related to biologic disease-modifying antirheumatic drugs (bDMARDs) is melanoma. Thus, patients with melanoma or a history of melanoma should not receive a bDMARD. The majority of studies have not demonstrated an association between anti-TNF agents and lymphoma risk, and, in a recent analysis by Hellgren, Baecklund, et al, patients with RA who were exposed to anti-TNF agents were not at higher risk of lymphoma than naive patients. Data on the risk of recurrence are difficult to interpret because the evidence is observational and the studies have channeling bias. This means that individuals who have had a previous malignancy will likely receive a different therapy than those without a prior malignancy. Nonetheless, no study has clearly documented a higher risk of recurrences. Finally, the use of immune checkpoint inhibitors has now revealed a higher incidence of immune-related adverse events, most frequently arthralgias and myalgias, but also thyroiditis, colitis, and inflammatory arthritis, among others. Rheumatologists are increasingly called on, in discussions with patients and referring oncologists, to help manage these events. Data are limited on the safety and efficacy of treatments for immune-related adverse events, but glucocorticoids, hydroxychloroquine, and other agents have been used.

I am relatively conservative with regard to patients with previous or comorbid cancer. I strongly counsel my patients with RA who have had previous lymphomas against the use of anti-TNF agents. The data regarding lymphomas in regulatory clinical trials show an increased risk with biologics; however, there is no suggestion of an increased risk from observational databases, and you could argue that there may even be a decreased risk of some malignancies. You also have to consider the fact that RA itself is associated with an increased risk of lymphoma, so there has to be a balance. Overall, I do not worry about new-onset lymphoma in my patients on anti-TNF agents, particularly if they have been taking them for a significant period of time, but I will avoid anti-TNF agents in patients with a previous lymphoma. Data for other malignancies such as breast, colon, and prostate cancers also seem to indicate no increased risk—with the exception of melanomas, where there is a signal that biologics are associated with an increased risk of reactivation. Therefore, I am cautious about using biologics in patients with previous melanoma. For patients with other prior malignancies (eg, several years removed from breast, colon, or prostate cancer), we have an informed discussion during which I present what little data we have, and then we make a decision, although, in general, I am less likely to use biologics in these patients if I do not have to. I will often try to use nonbiologic therapies, but each patient is treated individually. For those with RA who are undergoing treatment for cancer, RA symptoms tend to decrease because most chemotherapy agents also control active RA. For most malignancies, we can take patients off of their RA medication while they are actively receiving chemotherapy. One issue has recently emerged with the increased use of immune checkpoint inhibitors in oncology. That is, what looks like a disease flare in RA, with myalgia and arthralgia, may actually be “checkpoint inhibitor syndrome,” or an untoward effect of checkpoint inhibition. Hydroxychloroquine seems to be effective for those patients with cancer who develop checkpoint inhibitor syndrome.

It is important to remember that there is an increased risk of certain malignancies in patients with RA. In particular, there is an increased risk of lymphoma that is proportional to the degree of disease activity. There is also an increased risk of lung cancer and nonmelanoma skin cancer. It is therefore important for patients with RA to have periodic skin examinations. Regarding treatment-related concerns, there have been warnings about the risk of biologics and incident cancers for the past 20 years, but very little has emerged during this time about any markedly increased risk of malignancy. This is true both for drugs for which there are 3 to 5 years of data and for those for which we have 20 years of data. In general, the observational data sets indicate that, among patients who are cured of their malignancies according to their oncologists, the use of anti-TNF agents does not lead to a higher risk of recurrence compared with those who did not receive anti-TNF agents. As noted earlier, the 1 exception to this is melanoma and possibly nonmelanoma skin cancer. Patients who are felt to be cured of their melanoma nevertheless have an increased risk of recurrence after initiation of anti-TNF agents. Thus, patients with a history of melanoma should not receive an anti-TNF agent. For those with a history of lymphoma or with concurrent lymphoma, rituximab could be considered because it is effective for both RA and lymphoma.