Treatment of Refractory Rheumatoid Arthritis

Philip J. Mease, MD; Jon T. Giles, MD, MPH


November 16, 2023

This transcript has been edited for clarity.

Philip J. Mease, MD: Hello. I'm Dr Philip Mease. I'm a rheumatologist and director of rheumatology research at Swedish Medical Center in Seattle. I'm joined by Dr Jon Giles, who is a rheumatologist and researcher from Columbia University in New York City. Our topic today is how to treat patients with refractory or difficult-to-treat rheumatoid arthritis, a problem which faces all of us as rheumatologists on a weekly basis as well as patients who are on their fourth or fifth biologic agent to try to control their rheumatoid arthritis.

John, tell us about your experience on a day-to-day basis with these kinds of patients and who they are.

Jon T. Giles, MD, MPH: There really is a variety of patients. It's not one-size-fits-all. They're the patients who always do partially well on any agent that they're on, but they never quite get over the finish line of low disease activity or remission. Then there are the patients who are truly refractory to most therapies — they just don't respond to anything. We're always sort of waiting for the next thing to come out on the market so we can try that.

And then there are the other patients who have intolerances to medications, or they have particular comorbidities where we can't use all of the variety of medications that we would like to use. So it really is a mixed bag of patients, and each one is different in their own way.

Mease: One of the issues that we face is that we really don't have a good definition for what is refractory disease. We kind of know what it is. It's a patient who's complaining of pain and fatigue. It's a patient who might have some swollen joints or elevated CRP, for example. But there's really not necessarily a codified definition, at least in the United States.

There have been efforts to try to come up with a definition, including a EULAR task force. I think some of the items that they indicated were quite helpful, including a patient who was not in a state of low disease activity as measured by DAS28, a patient who had signs and symptoms of progressive disease, swollen joints, elevated CRP; they were on steroids and you couldn't get their prednisone down below 7.5 mg. And they had evidence of rapid progression on imaging, such as either x-ray or more sensitive measures like ultrasound.

So this gives us a little bit of a footing or foundation. And these are all patients who had failed at least two different mechanisms of action of drug and were still in this state. Obviously, clinicians need some guidance like this.

John, what are some of the approaches that you take in dealing with this issue?

Giles: There are a number of approaches. For me, the first is to try to figure out where the symptoms are coming from. Are we dealing with overlying fibromyalgia? Are we dealing with osteoarthritis that may be on the part of the patient or on the part of me being confused for the rheumatoid arthritis disease activity? That's where objective measures — looking at swollen joints, getting ultrasound, MRI sometimes — come in, in order to really figure out what we're dealing with and make sure that this is really rheumatoid arthritis that's active.

Another approach may be revisiting the medications that they've been on. Did they really fail those medications? Did we give them enough time? And this includes medications that the patient may have been on in the remote past, maybe even before I saw them.

Maybe they were given only a month on a TNF inhibitor — another option — and then they abandoned that and moved on. And maybe if we revisit that class we could get some improvement. The other question is, do they have rheumatoid arthritis at all? Occasionally we've encountered patients who are only seen to respond to glucocorticoids, and they don't have rheumatoid arthritis, especially if they're seronegative. Sometimes we see that there is some polyarticular calcium pyrophosphate deposition disease, maybe a polymyalgia rheumatica overlay, and rethinking the diagnosis can help us move in a direction that's more helpful for the patient.

Mease: You bring up an important point about establishing whether this is really rheumatoid arthritis that's active. One of my subjects of research is the issue of concomitant fibromyalgia. We find that in large cohorts of patients with rheumatoid arthritis, psoriatic arthritis, axial psoriatic arthritis, and so on, upwards of 20% of patients will have concomitant fibromyalgia, and that various measures — such as the DAS28, or the DAPSA score in psoriatic arthritis — will be almost twice as severe in patients with concomitant fibromyalgia.

So we need to take this into account, this contextual factor, this important comorbidity, when we're doing shared decision-making with our patients, and think about treating the fibromyalgia in parallel with the rheumatoid arthritis.

Let's say that we've got a patient in front of us who has truly refractory disease — elevated CRP, elevated vector scores, and so forth. We are in a fix; we've already tried two TNF inhibitors. We've tried a JAK inhibitor. We've tried an IL-6 inhibitor. What do we do? In some instances, we are, at least for brief periods of time if not ongoing, now experimenting with combining either two biologics or a biologic and an oral targeted synthetic DMARD. When we're choosing the combination, we're really thinking about safety in the back of our minds. We're trying to pair, say, a drug that has a slightly lower rate of serious infection with one that has a standard rate of serious infection for that particular class.

We tell the patients quite clearly, "This is off-label, this hasn't been studied in terms of safety. So if you develop signs of infection, we want to know right away."

But there are also situations where we can pair with another physician from a different discipline. For example, in psoriatic arthritis, we can pair with a dermatologist who will prescribe one medication and we'll prescribe another.

Jon, what do you all end up doing with this kind of situation?

Giles: I think we do all of those approaches. And I think we also sometimes underestimate the value of the nonbiologics in these patients as well. Just because a patient has failed multiple biologics and a JAK inhibitor does not mean that a nonbiologic may not be effective for them, especially if we can combine them. And so going back and revisiting, adding on hydroxychloroquine — will the leflunomide work for these patients if they've never tried it? By continuing the mechanism of action of the biologic that worked best for them, often we can get a lot of improvement in these patients without having to go into uncharted territory.

Mease: And besides medications, of course, bringing in other members of the team — physical therapists, occupational therapists, psychologists — to try to improve.

Jon, thanks so much for this conversation. I learned a lot and I hope those in the audience did too.


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