<p>Managing difficult-to-treat rheumatoid arthritis (RA) requires a nuanced approach. Understanding the difference between inflammatory and noninflammatory pain, effective methotrexate use, and fostering strong doctor-patient relationships are key. In this article, RA experts explore strategies for improving patient outcomes, providing personalized care, and addressing the structural demands of a busy practice.</p>

I do not like to use the word “refractory” and instead prefer to use “difficult-to-treat RA,” as I am not sure that all these patients are truly refractory. In the Leeds study, researchers identified several hundred patients who met the European Alliance of Associations for Rheumatology (EULAR) definition of difficult-to-treat RA, and 43% of people who met the definition of difficult-to-treat RA did not have synovitis on ultrasound. So, their disease activity was likely being driven by noninflammatory pain. When I see difficult-to-treat patients in my own practice, I am frequently performing advanced imaging to determine whether they have active synovitis. These patients may not need another biologic or targeted therapy; what they may need is better pain control.

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I think that we, as rheumatologists, help create some of the difficult-to-treat scenarios when we take patients with RA off the combination regimen that they used originally to control their disease. If they are on a monoclonal antibody in combination with methotrexate, they often will need to remain on some dose of methotrexate to maintain response. A lot of patients who may have been on adalimumab or abatacept, for example, flare after getting tapered off their methotrexate. They are not flaring because the drug does not work; they are likely flaring because they developed antibodies against the monoclonal therapy, and we created that situation by stopping their methotrexate. I think that one of the things we need to do better is tell the patient why they are on methotrexate, which is an education-related issue.

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We also need to emphasize that corticosteroids are not the patient’s “friend” long-term, although we all use them. We need to lower the prednisone dose as much as possible and even try to avoid it in the first place, unless the patient cannot function. Even on low-dose prednisone, the issue in older patients is skin fragility, and we also have to think about the risk of hyperpigmentation, cataracts, osteoporosis, infection, and cardiovascular disease. Patients on prednisone can experience some improvement in pain and swelling, but they are really risking a lot of toxicity from even a couple of milligrams a day.

Long ago, it was difficult to define nonresponse in RA because we had nothing other than corticosteroids available for treatment. Therefore, patients stayed on those drugs for longer periods regardless of response, since they often would not want to stop taking them because they would be afraid of losing whatever benefits they were experiencing. Now, since there are so many other drugs available, the definition of refractory or nonresponse gets confusing because, as new medications are coming on the market, the criteria for assessing nonresponse have changed. Over many years and decades of seeing patients with RA, it often seems that the clinical criteria for defining a treatment-refractory patient are based on whatever other drugs are available. One always has to keep this in mind. In addition, one always needs to be aware of the not-uncommon scenario of when the patient is not actually taking their medications because of a fear of side effects but is not telling their physician. So, regarding this issue of the difficult-to-treat patient, we need to ask, “Where’s the difficulty coming from?” It may be that not listening to the patient is creating the problem and is preventing the development of that trusting relationship in which patients are able to reveal what is truly going on.

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I recently asked a colleague at Mayo Clinic what his referral population for refractory or difficult-to-treat RA looks like. He told me that, when talking to his patients who are referred to him from all over the country, he discovered that the problem is not that they have refractory disease (since the disease is usually quiet), but rather that they are not able to communicate their personal pain and functional needs effectively with their treating rheumatologist. Is this because they do not get enough time to do so? Or is it because there is a more fundamental failure of the doctor-patient relationship and not the medications? This scenario is responsible for 50% of the consultations that he gets at Mayo Clinic. I see the same thing at my practice.

In clinical practice, we see patients who say that they have tried “a bunch of medications” and nothing is really working for them. The first thing that you have to sort out is: Are the medications not working because they are truly not addressing the underlying inflammatory disease, or are they not working because the patient is experiencing noninflammatory pain? We can use an ultrasound or magnetic resonance imaging to figure that out.

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Somewhere in the range of 20% to 25% of people with RA have significant pain that is not inflammatory. So, it is not going to be addressed by the latest biologic, but it may respond to something like duloxetine or pregabalin that can better address the pain component. For me, the first step is to talk to the patient and help them understand that I know they are not making it up. It is real pain, but there may be a different driver to that pain, and we need to come up with a different way of managing it.

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It comes back to the doctor-patient relationship and communication. For years, we said, “Methotrexate is so well tolerated,” yet there are many people who just feel awful the day they take it each week, but we do not listen to them or ask about it. The discussion that I often have with patients involves me saying, “You need to take some methotrexate, but let’s put you on a dose that isn’t going to make you feel sick. And we’re doing it because we want to maintain the efficacy of the other medications that you’re taking.”

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However, if you are in a managed environment as a clinician, the problem is that your appointments are so tight, and, with the use of electronic medical records, the amount of time that you actually have with the patient ends up being approximately 15 minutes. It does not take that long to examine joints, to be quite honest. It does, however, take a while to talk to patients, so we need to do a better job of figuring out how to use our 15 to 20 minutes of time efficiently.