Misti Paudel, PhD, on Difficult-to-Treat Rheumatoid Arthritis

Dr Paudel reviews research she and colleagues conducted to validate the EULAR definition of difficult-to-treat rheumatoid arthritis, and differences among patients with difficult-to-treat RA versus those with controlled disease.

Misti Paudel, PhD, is an assistant professor of medicine and researcher at Brigham and Women's Hospital in Boston, Massachusetts.

TRANSCRIPT:

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your host, Rebecca Mashaw.

Today I'm talking with Misti Paudel, Ph.D., assistant professor of medicine at Brigham and Women's Hospital in Boston. She conducts research on a variety of subjects, including rheumatoid arthritis. She recently presented a paper at EULAR on difficult to treat patients with rheumatoid arthritis. And this will be coming out soon in the Journal of Rheumatology. She’s going to tell us about these patients and how best to work with them to achieve the best outcomes. Thank you for joining us.

Dr Paudel: My pleasure. Thank you for inviting me to be here.

Q: What led you to initiate this research?

Dr Paudel: We were particularly interested in understanding the underlying reasons why some subset of patients with RA cycle through multiple RA therapies without observing any substantial improvement in their condition and then progress to the state of becoming difficult to treat. And we thought EULAR’s definition published back in 2021 was a much-needed step forward in being to correctly identify and characterize this really complex and interesting subset of RA patients.

So for this study in particular we really wanted to implement that algorithm in a cohort that we have access to, validate it, and then estimate the prevalence of difficult-to-treat RA.

Q: Tell us a little more about that EULAR definition of difficult-to-treat RA.

Dr Paudel: Absolutely. As I mentioned it was proposed back in 2021, and it was based on recommendations of a task force that did a survey of the literature. And they also took into consideration results from an international survey of rheumatologists.

The definition they came up with has 3 essential components. And for any particular patient to be classified as difficult to treat, they have to meet all 3. And that's key.

So the first one is treatment failure, which they define as failure on at least 2 or more biologic DMARD therapies after failing conventional DMARD therapy. Second condition is persistent disease activity, and they provided multiple different subcomponents or ways in which a patient could meet that criterion. And then the third component is that either the rheumatologist or the patient has to perceive that the signs or symptoms are problematic.

The definition was meant to be a little broad, as well. Like I mentioned, for that persistent disease activity second component there are multiple subcriteria. Most of those align with what we would consider undercontrolled or active disease, like having an elevated DAS-28 or CDAI score, not being able to taper off of glucocorticoids, having radiographic progression or erosions, having extra-articular manifestations, those types of things.

But then there's this other criterion that they felt really strongly about including that was a patient with RA who has on all of those above-mentioned things pretty well controlled disease but still is reporting symptoms or signs that are impacting their quality of life. It’s a little bit of a heterogenous but very important definition.

Q: Would you describe the parameters of your own research? How did you go about this study? What all did that involve?

Dr Paudel: Sure. So we used data from the BRASS Registry, which is the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study. It enrolled around a little over 1500 adults with established RA, had annual visits with a rheumatologist, and interim assessments about every 6 months or so.

And for each of EULAR's criteria, we constructed a definition using data from BRASS, also prioritizing measures that we thought would be generally available in other studies, because replication is important. We had to make some decisions on the components of the definition that were a little bit less clearly defined, such as that patient with well-controlled disease, but having signs or symptoms that are problematic, that's a little bit less clearly defined. And we walk through our decision-making process for all of those in our paper.

And then we also constructed a subgroup or a comparison group, rather, of participants who were biologic-DMARD experienced but did not meet the definition of difficult-to-treat RA, and we matched them 2 to 1 to every difficult-to-treat patient. And we matched on study visit.

Q: And what were your findings?

Dr Paudel: So in terms of prevalence, across the entire cohort of about 1581 participants, we saw a prevalence rate of 14.4 per 100 persons. And when we narrowed down to participants that were biologic-experienced, this prevalence rate increased to 22.3 for 100 persons. When you look at the literature for difficult-to-treat RA, the prevalence is reported to be pretty broadly varying from, I think I've seen 5 all the way up to 34% or per 100 persons. But most of the studies do seem to hone in on this range of like 14 to 17 % or so, which is right where we landed for the most part.

In terms of validating EULAR’s definition, we did find that when we applied this algorithm, we identified a subset of patients with RA who had not achieved disease targets and very much seems to pass the face validity test that we are honing in on a population of RA patients who are failing multiple treatments and continuing to not do well.

Q: You mentioned in your article that the team observed a lot of differences in demographics, comorbidity, and RA disease activity between patients who were difficult to treat and those who were not.  Can you explain a little more about that? Tell us what kind of differences you saw.

Dr Paudel: Yeah, so we observed pretty similar patterns as to what's been reported in the literature and other attempts to look at difficult-to-treat RA, in that these patients were proportionally more female, they had a younger age at a diagnosis or RA onset, greater BMI, and a greater prevalence of depression, CVD, greater prevalence of using prednisone at the time that they became difficult to treat, and a lower prevalence of using methotrexate also at the time they became difficult to treat. And this is in comparison to that comparison group that we matched them to.

Q:  Did you come to any conclusions based on those demographics?

Dr Paudel: Not really in terms of that. I mean, we weren't really looking to make a conclusion one way or another. We were just interested to see how these patients differ from those that we can say are not difficult to treat.

Q:  I was just wondering… you said that those that were difficult to treat were less likely to have been treated with methotrexate. And I wondered if that might factor into progression of their arthritis to the point that it became difficult to treat.

Dr Paudel: Probably most likely that is a factor. Not really— I think it would be interesting for future research to look at the patient experience of how they become difficult to treat. And I, you know, probably I agree, not taking methotrexate is because they failed on it.

Q: Because that's typically the first line drug, isn't it?

Dr Paudel: It is, yeah. It is.

Q: You also noted that varying EULAR subcriteria resulted in a range of prevalence rates for difficult to treat RA. What kind of subcriteria are we talking about there?

Dr Paudel: Yeah, So I mentioned that in the literature, it's been reported that the prevalence is quite broad, ranging from like 5 to 34%.  A lot of the drivers as to why that is, is because different definitions are being applied. So one of the things that we wanted to do was to try to apply different subcriteria of EULAR's definition to match kind of what's been used in the literature, to understand what impact that has on the prevalence of difficult-to-treat RA. We saw the greatest prevalence when we used the first criteria of DMARD failure only; that prevalence was 17.5 per 100 persons in the general cohort. And then in the biologic experience that was 27 per 100 persons, so higher than when using all of the criteria together, clearly.

We got the lowest prevalence when we combined DMARD failure criteria with either radiographic progression or that well-controlled disease but still having symptoms that impact quality of life criteria. So that prevalence was 1.6 to 7.2 per 100 persons, respectively.

Q: When you mentioned these patients who have well-controlled disease, but they're still having issues, what kinds of problems are they expressing to their caregivers? What is affecting their quality of life?

Dr Paudel: I didn't dive into that too much, but in our study, how we defined those patients were that they didn't meet any of the other persistent disease activity criteria, such as, you know, their DAS 28 wasn't, you know, looking at active disease. They didn't have extra-articular manifestations. They didn't have radiographic progression. They weren't on glucocorticoids at a high dose. But they had a RAPID 3 score that was high. And RAPID 3 was how we defined that particular criterion.

Q: What kind of additional research might you have planned?

Dr Paudel: So we are continuing to try to validate this definition in alternative cohorts and studies. We're interested in, you know, diving in and parsing out, you know, the heterogeneity that's in the definition. So understanding these patients that are having complaints that impact their quality of life, but no evidence of active disease on other measures.

We're interested in looking at risk factors, causal mechanisms of how someone becomes difficult to treat. So that's the pathway that that we're focused on.

Q: That will be a very interesting topic, too, is what makes someone become difficult to treat. And I imagine it's multiple failures with multiple therapies. But why? Why does that happen? And that's of course the answer to that is something that everybody would hope to be able to finally come to.

Any last thoughts for clinicians who are working face-to-face with these difficult to treat RA patients? What would you advise them?

Dr Paudel: I would advise that I think there's still a lot more that we need to learn about this challenging and interesting subgroup of patients with RA, including everything we've talked about of the causal mechanisms—how do they arrive there, and then what do we do about it? How do we make it better for them? I don't think I have specific treatment recommendations right now because the science isn't quite there yet. But don't give up on them. Keep trying. There's something that will work for them.

Q: Well, I appreciate you taking the time to talk with us today and I'll look forward to hearing more from you in the future.

Dr Paudel: Thank you.