Alexis Ogdie, MD, on Adverse Effects of Methotrexate in PsA

Dr Ogdie discusses her research into the differences in reactions to methotrexate and tumor necrosis factor inhibitors among patients with psoriatic arthritis and rheumatoid arthritis.

Alexis Ogdie, MD, is a rheumatologist and an associate professor of medicine and of epidemiology at the Hospital of the University of Pennsylvania.

TRANSCRIPT:

Welcome to this podcast from the Rheumatology and Arthritis Learning network. I'm your moderator, Rebecca Mashaw and today we're delighted to have with us Dr. Alexis Ogdie, who is an associate professor of medicine and epidemiology at the University of Pennsylvania. She's going to talk to us about her recent research into the side effects of methotrexate and tumor necrosis factor inhibitors, and the differences in tolerability among patients with psoriatic arthritis and rheumatoid arthritis.

Good morning and thanks for joining us, Dr. Ogdie.

Dr Ogdie: Good morning. Thanks so much for having me.

RALN: The objective of your study was to examine the prevalence of side effects with these 2 therapies, methotrexate and TNFis, among patients with psoriatic arthritis and rheumatoid arthritis. What led you to investigate this topic?

Dr Ogdie: Well, several years ago I was thinking in clinic that we prescribed methotrexate as first-line therapy in psoriatic arthritis at the time, and I'd have a patient come in with rheumatoid arthritis who was on methotrexate say and they feel just fine, they tolerate the side effects or they’re like it’s not so bad. And they were feeling pretty good. But then the patients with psoriatic arthritis come in and tell you about how the side effects were really bothersome. They really couldn't tolerate it, and so it kept leading me to question whether or not there was a real difference, because we were at the time questioning whether or not methotrexate really is a good treatment for psoriatic arthritis. So in this particular study we examined those side effects, and the differences of prevalence over the course of a number of years of follow-up among patients with psoriatic arthritis, and then patients with rheumatoid arthritis in the FORWARD database.

RALN: Can you give us a brief overview of your research? How many patients did you study in these groups? What was that length of time, and what kind of criteria did you use for inclusion?

Dr Ogdie: Great question. We took 116 patients with psoriatic arthritis and 4247 with RA, and they were all newly initiated on methotrexate. This dataset was initiated initially as a rheumatoid databank, and then they started to roll in psoriatic arthritis patients. So there weren't as many patients on these medicines with psoriatic arthritis, at least as compared to rheumatoid arthritis.

But in addition to those methotrexate initiators, we also wanted to follow TNFi initiators just as a comparison group to look at side effects, and we identified 124 new initiators of a TNF inhibitor that had psoriatic arthritis, and 4361 that had rheumatoid arthritis, and then we followed them all for 1 year after the time they initiated their therapy and the outcome of interest was whether or not they reported a side effect. So there was an opportunity to report on each questionnaire what medicine you were taking, what medicines you had been taking, or if you'd stopped in your medicines, and whether or not you had had any side effects. And then we examined the types of side effects that people recorded.

In addition, we also looked at things like did the patient report on a symptom set—nausea, vomiting, hair, loss, diarrhea those kinds of things—among those patients who had initiated methotrexate, and among those patients who had initiated a TNF inhibitor.

RALN: So let's talk about your primary findings. How did these 2 groups of patients differ?

Dr Ogdie: Well, first of all, in terms of just baseline characteristics, they do differ a little bit as well; overall, patients with psoriatic arthritis actually had similar age to those with rheumatoid arthritis. The RA patients that initiated a TNF inhibitor were a little younger than them, and the patients who initiated methotrexate who had RA were a little bit older than the patients with psoriatic arthritis.

In general the BMI for patients with psoriatic arthritis was higher than the patients with rheumatoid arthritis. And then duration of disease was fairly similar, but fairly long for both groups of patients, slightly less for those patients who were initiating a TNF inhibitor, as you might expect.

And then, in terms of proportion to reporting side effects. Reporting side effects was similar among TNF inhibitor initiators between PsA and RA. So overall 22% and 24% of patients reported a side effect to a TNF inhibitor. When he looked at the methotrexate initiators, there were differences. Patients with psoriatic arthritis, 44% of them reported a side effect of methotrexate compared to 29% who had RA. So a bigger difference in reporting side effects to methotrexate.

And then, if you drill down to like what kinds of symptoms were patients reporting, it’s the kind of things you would think of on methotrexate – so nausea, for example, some hair loss, headaches, fatigue, so general things that you would expect on methotrexate. But the patients with psoriatic arthritis were reporting this more often.

In general we found that patients with psoriatic arthritis were just overall reporting more symptoms across the board. So whether they were methotrexate users or TNF inhibitors in most cases at least, patients with psoriatic arthritis reported more symptoms.

So it leads you to wonder, why is that? I think there's a few things. One is obesity does play a role. We did try to adjust for obesity, and that did decrease the difference between the groups a little bit. It might be that our patients with psoriatic arthritis are more obese, and maybe that's either not allowing it to work as well or making them more sensitive to it. It's not quite clear.

I think the other thing from a clinical experience is that if you are responding well to a medicine, you're less likely to be burdened by the side effects. So if it's making a big difference for you, I think that you're probably less likely to reach out and report those symptoms. And I think that in general what we see is that it doesn't feel like methotrexate does as much as in psoriatic arthritis as it does for that patient with rheumatoid arthritis. And again, that's not what we tested here, but just one hypothesis about why you might see more side effects to methotrexate.

RALN: Your article states that, and I'm quoting here, “while prior studies and of methotrexate they focused on who hepatotoxic effects and comparisons of treatment persistence in psoriatic disease or RA.” You compared the treatment burden from the patient's perspective from these 2 most common therapies. Would you describe how you define treatment burden, and the difference between how clinicians may define it, and how patients experience it? And why does it matter?

Dr Ogdie: Yeah, that's a great question. Actually, we have a follow-up paper that will be coming out soon on exactly that topic. In the same question, we just did more of a patient deep dive. When we think about side effects, we think about what's in the label, or what you know when we look at updates, and we see these are the things of the medicine can cause, and we look at the frequencies of those. And that's what we're looking at in the clinical trials and all that data comes from clinical trials.  But the ontologies using clinical trials are really derived from medication studies in oncology, for example.

So these are things that you know they are important side effects. But when the patient has a burden of the side effect that means something different. So if you have really bad nausea and diarrhea, you know it's just a line for us on a checkmark that you're having that, but it can prevent people from going out, from being social or doing the things they want to do.

Or if you're constantly thinking about all right, I’ve got a plan for that day when I take my methotrexate, so the next day I can just be okay to be out of commission, which is what a lot of patients tell us. That's really meaningful. It's really impacting how they're living their life. And so I think when we collect side effects in trials, we're not really doing a good job of saying, How meaningful is that to the patient? How is that impacting the patient’s life?

And so what we are trying to get at with some of these studies that we've started to really re-examine how is burden measured. And then, when we're thinking about new therapies and we're comparing among therapies, we want to make sure that we're comparing the burden as well, so patients get a better understanding of that.

RALN: That was one of my questions—how do you think these findings should be taken into account in clinical practice?

Dr Beatty: So in our subsequent paper that will be coming soon, that we presented to ACR a couple of years ago, we essentially asked patients that—what does this mean to you when you have these different side effects, and how bothersome are they? And you know, I think it means engaging that patient when they're coming in with a side effect and they're saying nausea or diarrhea, or for infusions. Actually, that can be great burden, somebody that's driving to the center, for example. So really understanding what the patients’ needs and wants are, and how those side effects are impacting their life. And even though it may be working, then maybe that's not worth it to the patient, if they are having to rearrange their lifestyle just to account for the medication. There's so many medicines out there now that we shouldn't have to make them do that. So I think, being open to that conversation is one way to kind of put these into action. I think a longer-term goal is to think about how we put into clinical trials these measures, so that we know what patients are experiencing from the new medicines that are being tested.

RALN: Now that you've looked at methotrexate and TNFis, are you looking at additional research into how other therapies are tolerated, and the treatment burden of such therapies as IL-23s or JAK inhibitors?

Dr Ogdie: That's a great question. We have not; what we've done mainly in the subsequent papers is come up with a conceptual model for what it means to have treatment burden, and how we might think about different categories of treatment burden, for example. So I think that we have not applied that going forward, as something will be interested in doing after we get this next set out.

RALN: Any last thoughts for practicing rheumatologists who are trying to choose the right therapies for their patients, in particular for psoriatic arthritis, considering this apparent increased sensitivity, whatever may be lying behind that.

Dr Ogdie: That's a great question. So I think that, interestingly enough, since we initiated this study, things have changed a lot, and patient and providers often will go directly to a biologic now, as is part of the ACR/NPF guidelines. The guidelines were happening just as we were doing this study back in 2019. So I think that things are changing. But I think that side effects and treatment burdens, it is important to assess that every visit, and we do that. But I think it's not just asking the question, but leaving the mind open to asking the next question, which is, How is this impacting you and then figuring out the best regimen for the patient.

RALN: Thanks very much for talking with us this morning, and we'll look forward to talking to you again later, when the second paper comes out.

Dr Ogdie: That sounds great. Thank you so much for your time. Have a good rest of day.