Researchers set out to answer a pressing question: Is it safe for rheumatoid arthritis (RA) patients who have had cancer in the past to use a biologic drug rather than a traditional disease-modifying antirheumatic drug (DMARD), like methotrexate, to control their disease? Their answer, detailed in a study recently published online in the journal Rheumatology, is reassuring. They found that patients with a previous malignancy who later took certain biologics did not appear to have an increased risk of cancer after an average of five years, compared to those who took a traditional DMARD.
The immune system is at the root of the problem in people with RA. Instead of defending the body from unwanted invaders, like viruses and bacteria, and watching out for mutations that may turn into cancer, the faulty immune system creates inflammation and directs attacks on the joints and organs. Biologic medications (and some traditional DMARDs) control the disease and its damage by interrupting the rogue immune activity at specific points in the process.
The concern has been that tamping down the immune system – especially by inhibiting tumor necrosis factor (TNF), a molecule that conducts immunosurveillance of tumors – to protect the joints and organs also decreases its ability to protect the body from cancer, adding a greater risk than that associated with the disease. For people who have already had cancer, the question is more urgent: Would biologics cause a recurrence of cancer?
Researchers in the United Kingdom identified 425 people who had had cancer out of a large, national, database of 18,000 RA patients. The patients were taking either a traditional DMARD or one of two types of biologics – an anti-TNF drug, such as adalimumab (Humira), etanercept (Enbrel) or infliximab (Remicade) – or the B-cell inhibitor rituximab (Rituxan). (Interestingly, in addition to being used to treat RA, rituximab is sometimes used to treat certain cancers, including lymphomas.).
They found that over an average follow-up of five years, 101 patients out of the 425 total developed new cancers. New cancers were defined as new primary cancers, local recurrences and metastases. A deeper analysis showed that those who had been taking a biologic drug – whether an anti-TNF or the B-cell inhibitor — had approximately half the risk of developing a new cancer as those who were on a traditional DMARD.
Are Biologics Safer than DMARDs?
Lead author Lucía Silva-Fernández, MD, clinical research fellow at the Arthritis Research UK Centre for Epidemiology at the University of Manchester, warns against jumping to the conclusion that one treatment is more or less likely to increase cancer risk. She says the study was not a randomized, control trial but rather reflects routine clinical practice. That means patients were not assigned a treatment randomly; instead, their rheumatologists chose treatments for them, presumably in consideration of their risk of cancer recurrence.
“In this scenario, doctors would only prescribe biologics to those patients with an estimated low risk of recurrence,” Dr. Silva explains. This results in what is called a “treatment selection bias” where the healthier patients receive biologics and those with a higher risk of recurrence stay on DMARDs, she notes. “This different baseline risk is probably the most likely explanation for the difference in the rate of recurrence.”
Dr. Silva is also careful about characterizing her team’s findings as definitive, noting that they are far from it. “We cannot conclude from this study that biologics are not associated with cancer,” she says, nor that biologics are appropriate for everyone who has had cancer. “But it is reassuring to see that we can trust the way doctors [in the U.K.] select patients with prior cancer for a biologic treatment, as it does not increase the rate of incident malignancies.”
Treatment Guidelines in the U.S.
In the United States, the American College of Rheumatology (ACR) treatment guidelines for RA have evolved regarding recommendations for using biologics in patients with a history of cancer. The 2015 guidelines recommend the use of traditional DMARDs over biologics in cases of skin cancer and the B-cell inhibitor ritixumab over any of the anti-TNFs for people who had had cancer of the lymph system, such as a lymphoma. For patients previously treated for solid tumors, the guidelines make the “same recommendations as in patients without this condition” – meaning there are no special considerations beyond those for patients in the general population.
But the ACR guidelines underscore that most of these recommendations are based on expert opinion because there is a lack of high-quality scientific evidence. As a result, the recommendations are labeled “conditional” – as opposed to “strong” – recommendations.
Robert S. Katz, MD, a rheumatologist and professor of medicine at Rush Medical College, in Chicago, says many patients have cancer concerns when he recommends a biologic to treat their arthritis, so he welcomes this research. “It is good to hear and good for patients to understand. It’s not the last word and it’s not a perfect study but it is helpful,” Dr. Katz says.
Elaine Husni, MD, vice chair in the Department of Rheumatic & Immunologic Diseases at Cleveland Clinic, agrees that research on this topic is needed because patients have so many questions about it. “This has been a topic that many of my patients raise,” she says. “Luckily, these malignancies are rare so there are low numbers of events. But that makes it hard to make conclusions.”
More Studies Still Needed
This latest study, which is an extension of an earlier study published in Arthritis Care & Research in 2010, builds on a growing body of research on this topic. By increasing the average follow-up time by three years, it is now the largest and longest study to date to address this question.
But it has limitations. Researchers did not have details of how aggressive the original cancer was in participants or what treatment they initially received for their cancers. There was also no typical control group. The researchers say that reflects routine clinical practice because there is no situation in which patients with active arthritis don’t receive treatment. That’s why the study focused on comparing anti-TNFs, rituximab and DMARDs (the standard of care for RA).
Dr. Katz says the message for patients is: If you have had a malignancy, your rheumatologist shouldn’t make your treatment decision alone. He recommends the patient, the rheumatologist, the oncologist and family members all work together to come to a consensus on how to best proceed with your RA treatment, given your cancer history and current needs.
Author: Jennifer Davis for the Arthritis Foundation