Q: What are the chief safety and tolerability concerns with commonly used agents for RA, and how do you talk with patients about the major concerns related to DMARDs?

It is very common that when we, as rheumatologists, suggest to patients that we advance their therapy, typically by initiating newer biologic agents, that the first questions patients have are related to side effects. There is a very important pivot that clinicians should take when approaching this subject, and that is to first discuss the potential efficacy of these agents to achieve the goal of disease remission. This is because we all believe that the potential gains from efficacy are greater than the potential for negative effects. I begin my conversation with patients by explaining that the reasons for advancing therapy are to reduce clinical symptoms, prevent damage, prevent deformities, prevent disability, preserve function, control the systemic inflammation and associated comorbidities, and prolong life. Those are all very strong messages. 

The other side of the coin is to explain that side effects are, in fact, potential side effects, and there are 2 types. There are tolerability issues that include side effects such as nausea, rash, and headache—things that can be mildly to extremely uncomfortable for patients but do not inflict serious acute or long-lasting harm. Tolerability issues occur in a minority of patients—perhaps 5% to 25%, depending on the individual drug, studies, and populations of those studies. Then there are more serious issues such as serious infectious events (eg, pneumonia), cancer, and other possibilities, and those occur in a much smaller number of patients. So, by example, the risk of actually not having a serious infection in 1 year is likely over 90% to 95%, and stating it that way helps to frame the conversation.

The actual bad guy, or the 800 lb gorilla in the room, as Jack Cush, MD, at Baylor University states, is the disease itself. Because the disease is present right now, it is not a future possibility. And the disease has the potential to cause very significant harm—both physiologically and as it relates to quality of life and happiness. So, framing things in this way may help the patient to understand these considerations from a more accurate perspective.

I agree with Dr Tesser. Another 800 lb gorilla in the room is the challenge for patients to sort out risks versus benefits, and direct-to-consumer advertising from pharmaceutical companies may complicate this. Only 2 countries allow it: the United States and New Zealand. While I am in favor of disease state education and nonbranded commercials, I think that all of these commercials tend to contribute to the obfuscation of risks and benefits for patients, with risks of severe and/or fatal side effects presented along with images of a person smiling and skipping across the lawn. So, how are patients supposed to process this? A really important role for advanced practitioners in the health care setting is to help patients navigate through this messaging about drug safety and efficacy.

You are absolutely right. And how many patients actually can do all of those things? Well, it depends on when their disease started and on their whole cycle of treatment initiation. Not every patient can achieve remission, and I do not know many patients with RA who can actually achieve drug-free remission.

However, to begin to address the question about chief concerns for the various agents, there are certainly concerns related to pregnancy. We know that methotrexate is a problem. In animal models, it is an abortifacient, and it is associated with deformities, low birth weight, and lowered fertility. However, it is interesting to note that it appears in registry studies, where exposure to methotrexate has inadvertently taken place during the first trimester, that outcomes may not be as poor as one would think. We know that leflunomide is a problem as well. Although it is not a known abortifacient drug, there are concerns related to pregnancy, and this is despite the emergence of data suggesting that it may be quite safe, especially during investigations with teriflunomide, which is a major metabolite of leflunomide that is approved for treatment of multiple sclerosis. Nonetheless, there are pregnancy warnings and washout recommendations for leflunomide. And clearly, no one wants to be in the situation in which the patient is taking either of these drugs when she becomes pregnant.

We have learned that the biologics do not have the same safety concerns as methotrexate—and I am neither saying that the biologics are safe nor that they are unsafe during pregnancy. However, we now have at least 1 anti–tumor necrosis factor (anti-TNF) agent, certolizumab pegol, that has provided updated labeling information to include additional data on pregnancy and lactation: 2 studies conducted during the 3rd trimester of pregnancy showed that placental transfer of certolizumab pegol was negligible in most infants at birth, and low in other infants at birth. Pharmacokinetic data also showed minimal transfer of certolizumab pegol to breast milk from mother to infant. It was nice to see the labeling information updated to reflect these findings. So, we may have a preferred agent during pregnancy, but many people will have already stayed on a different anti-TNF agent or another biologic agent, and we have to think about the other agents as well. We try to get data from the Organization of Teratology Information Specialists (OTIS) registry in RA. All companies are encouraged to set up a registry through OTIS when a new product is approved, but the data are limited. We have not truly resolved the other issue of potential for risk when the father has been exposed to an RA medication; however, it seems that, generally, we do not have to worry as much about paternal exposure.

Dr Kay:
The major challenge in managing the pregnant patient with RA is that both methotrexate and leflunomide are contraindicated during the several months prior to conception and during pregnancy. Thus, treating RA during this period is challenging since the only effective drugs that are safe in this setting are azathioprine, hydroxychloroquine, and prednisone. However, RA may go into remission during pregnancy. Although an association between TNF inhibition and VATER/VACTERL congenital anomalies has been suggested, no increased rate of major congenital anomalies was identified in a prospective, observational study that compared 83 anti-TNF agent–exposed pregnancies to 86 disease-matched pregnancies not exposed to these medications. We do not know much about the reproductive effects of the newer agents, so we must use them with caution during pregnancy.