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Stanley Cohen, MD: Hello. I'm Dr Stan Cohen. Welcome to Medscape's InDiscussion series on psoriatic arthritis. It's my pleasure to have one of my old friends and colleagues with us today, Dr Arthur Kavanaugh. He's a professor of medicine at the University of California, San Diego, and director of the Center for Innovative Therapy and the USCD Division of Rheumatology, Allergy, and Immunology. Today we're going to be discussing the updated GRAPPA guidelines. So, Artie, welcome. It's really great to have you here today and to talk with you.
Arthur Kavanaugh, MD: Thanks very much, Stan. It's always good to interact with you, and it's a such a great topic. Thank you for having me.
Cohen: Artie, I've known you for a long time. I know you were a young whippersnapper, and I was a little older whippersnapper. You're a wonderful researcher and educator. How did you get involved in psoriatic arthritis, which is really what we're talking about in the new treatment recommendations? What was the impetus to lead you into that discipline?
Kavanaugh: Oh, it's interesting. If you think of the history and, of course, Stan, you were intimately involved in this with the development of the new drugs for rheumatoid arthritis. And once we had the tumor necrosis factor (TNF) inhibitors and they were successful, they really changed the approach to rheumatoid arthritis. So a couple of us sitting around — myself and my friends Bruce Kirkham, who is in the UK, and Christian Antoni, who is in Erlanger, Germany, at a meeting — we were just talking about how we see psoriatic arthritis patients and why don't we think about using these new therapies for psoriatic arthritis? At that time, as you remember, Stan, psoriatic arthritis was kind of the "redheaded stepchild" of rheumatology, where we treated it like we treated rheumatoid arthritis. We kind of ignored the skin and didn't do much else. We said, "Well, let's do this." We did an investigator-initiated study with infliximab, the three of us and some colleagues. It worked fantastically, as we know now. It turns out that at that same time, Phil Mease in Seattle was doing an investigator-initiated study of etanercept in psoriatic arthritis. Dafna Gladman has been interested in psoriatic arthritis for a very long time and she was excited by these new developments. A bunch of people — I'm going to leave some out — but especially Phil Helliwell, in Leeds in the UK, who is working with a number of people, including Will Tillett, on developing assessments in diagnostic criteria and classification criteria and outcomes in psoriatic arthritis. So, all of that came together once we said, "Boy, these studies are fantastically positive." And, as happens with positive data, you all of a sudden realize, Oh my gosh, we don't know really how to evaluate all the different domains of PsA. That was the impetus to put GRAPPA together.
Cohen: Well, it's really interesting, Artie, because I would say in the clinic we see many more psoriatic arthritis patients these days than we actually see rheumatoid arthritis patients. And I think that has a lot to do with the efforts of dermatologists to try to recognize which patients may have musculoskeletal complaints and refer them to us. We're talking about GRAPPA, which is the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Give me a little of the history. When did you guys start as an organization? How do you decide when new recommendations need to be considered and what kind of staffing do you have and funding that allows you to continue to put out these wonderful treatment recommendations?
Kavanaugh: The studies I was talking about that showed the success were starting in the very late nineties, 1999, and those studies were done in the early 2000s. And that was about the time when we started talking about forming GRAPPA. And one of the early initiatives was to say, "You know what, we want to put out some recommendations based on all these data that were accumulating about treatment options for patients with psoriatic arthritis." That was really the start of it. Treatment recommendations were part and parcel of our goals from the start. Since then, we've evolved and grown into actual study designs and looking at different aspects of the different domains of disease, but still the recommendations are something that's near and dear to our heart. We put out initial recommendations in the late 2000s and a version was done in 2015. Of course, as you know, Stan, being so involved with a lot of these studies, there's just so much new data, so many new mechanisms of action, so many new treatment approaches, so many considerations of tolerability and safety and co-morbidity. The field is changing so fast, we felt we really needed to do it again, and we finished it just last year. Even though those are done, there's new data since then. It's really an ongoing process and we've been fortunate to have GRAPPA get support from a lot of pharma. Of course, there has been a big interest in psoriatic arthritis, as there is in psoriasis, over the years. So, our interests have converged and really, I think, helped drive the whole field forward.
Cohen: And so, looking at the authors on the recent recommendations, you have obviously clinicians, researchers, dermatologists, rheumatologists. You have patients as well. I see you also have members from industry. Is that correct?
Kavanaugh: The paper does include the patients, and that's a very important part of it. They really give us the reality check. Sometimes we'll get off on something and the patients will bring us back to the reality of, Hey, we need to do this to be able to make this something that's really useful. One of the things that's been true of GRAPPA from the start is that it's dermatologists and rheumatologists, and that's been fun. It's been a real strength of the organization because those different domains, the musculoskeletal domains and the dermatologic domains, are very important. We're certainly very cognizant of not only conflicts but also the appearance of any conflict. So, pharma is not involved with the recommendation formation process at all.
Cohen: I can see that from the quality of the recommendations. So, Artie, go over the domains. Were these domains included in the original recommendations or were they something that has evolved over time — why the decision to use domains and stratify our therapeutic options by domains?
Kavanaugh: That's a great point. I think domains are one of the differences in psoriatic arthritis. I think I'd point this out to medical students as a reason they should be a rheumatologist. For instance, you see a chart and it says rheumatoid arthritis. You're going to go in there and examine the joints. But when you see psoriatic arthritis on a chart, you get to go in there and say, do they have peripheral arthritis (which can be like rheumatoid arthritis)? Do they have skin psoriasis? Do they have nail psoriasis in addition to peripheral arthritis? Do they have axial disease? We had the core domains with those, and we also had dactylitis and enthesitis. We had core domains from the start and that arose organically from discussions about what is important to patients. Every patient is different, as you know well, and some people have a lot of skin involvement and just a little bit of enthesitis. Other people have horrible peripheral arthritis and one patch of skin. And the approach to the patients, therefore, is different based on differential efficacy of our various mechanisms of action across those different domains. Most recently, we added inflammatory bowel disease (IBD). We talked about IBD because it's certainly important in a subset of patients with psoriatic arthritis; and iritis or interior uveitis, which is also common in these diseases and important to patients. In these most recent recommendations, what we did is make them individual domains as opposed to just a comorbidity. We had considered it in the previous version because there is so much data on those domains of disease. They were raised to the level of domain. It gets tricky because a lot of the data for axial spondyloarthritis (SpA), as well as the data for IBD and iritis, may not come specifically from PsA. We try to recognize that and say, Well, there's a bunch of studies in IBD and this is what they've come to in terms of treatments that work or don't work. We're going to recognize that. We're talking about IBD and we're not making recommendations for GI doctors by any means, but IBD concomitant involvement is so important, and it affects treatments and decisions. We certainly include them.
Cohen: I think that's an important advance in the recommendation. Your group uses the GRADE-informed methodology, which is the Grading of Recommendations, Assessment, Development and Evaluations methodology. Tell the group and folks listening, how do you come up with a strong recommendation or a conditional recommendation? Do you guys sit together and vote and if you have 90% agree and 10% disagree it's strong, or if it's 60/40 — how do you come up with the strong recommendation? Or just remind me is the GRADE methodology utilized to come up with those recommendations?
Kavanaugh: Absolutely. The GRADE recommendations are sort of the latest thing of treatment recommendations or guidelines. We like to stick to the word "recommendations" because "guidelines" has legal implications in certain jurisdictions. GRADE is meant to make guidelines — the process calls, of course, for a strict literature review. That's the basis of any sort of guidelines. Then we try to answer the PICO questions, the patients, the interventions, the complications and the other considerations that are there, and say, What do we have that is going to say it speaks to the efficacy and tolerability of the different agents? GRADE works well in a very simplistic manner if you strictly apply it. A two-by-two table is where GRADE has great utility. For example, you might want to know what the best hypertensive drug is for a person with diabetes and you say beta-blockers vs ACE inhibitors — you have data that speaks to that directly. Well, psoriatic arthritis is so heterogeneous it would lead to a myriad of two-by-two tables. That's why we say it's a GRADE-informed process. A strong condition is — and you can see in the GRADE definitions — this is something supported by the evidence that most people would choose in a given situation. Conditional is where there's a need for more opinion, perhaps because of the heterogeneity of disease. We do talk about this and discuss in the GRAPPA group. What we've done is take apart the individual domains, and they are tackled by a group, a dozen or two dozen people. They look at the literature and discuss where they're thinking and the different mechanisms that can be used, and come up with the ratings. Those inform the overall outline for the treatment recommendations.
Cohen: That's good to know. So, with the new updated recommendations, what's new? We talked already about uveitis and IBD, including them in the domains. But it looks like you have tackled the upcoming interesting summer we're about to have with biosimilars and also the issue of tapering of therapy. That's been a huge topic of discussion, which you've been involved in in rheumatoid arthritis, and also in discussing psoriatic arthritis. Talk to me about what's new with the recommendations.
Kavanaugh: Sure. The things you mentioned were definitely not in the previous versions. Interestingly, biosimilars, as you know, sort of popped on the horizon. We have not had that much use of them here in the US. We have a couple of IV biosimilars, but we've not had the subQ and that's about to change. Timewise, it ended up being very fortunate that we covered it. We had discussed this as a group in GRAPPA earlier and came up with an approach to biosimilars. This is the first time it's really getting a wide airing to say, What would you think of a biosimilars? What should a patient think of them? What should the provider think of them? And the issues therein. Because GRAPPA is international, and the biosimilars are available in many countries worldwide. Regarding tapering, we always love to have more data and it's, of course, incredibly important to patients. We thought it might be nice to have some sort of an outline to say what could and could not be considered in the most sublime approach to tapering. And that is not driven by monetary considerations or monetary considerations alone, but what could be possible for the patient. And then, of course, the newer therapies. So, the IL-23s — these have, of course, a tremendous amount of new information available to them. A hot issue that we haven't quite fully addressed yet is the spine — axial arthritis. Or is ankylosing spondylitis a condition distinct from spinal arthritis in PsA or axSpA (axial spondylarthritis)? There's been debate about that. There's some suggestion that the IL-23 and the IL-12/23 inhibitors do not work in ankylosing spondylitis. There's some dissonance about whether they could work in people who have axial arthritis who have PsA. There are some studies that are ongoing to address that . Look for that in the next series of recommendations.
Cohen: Real good. Going back to the biosimilars, I wasn't aware of this, but we're going to have a biosimilar adalimumab on the market within the next month, and then in the summer we're going to have, at a minimum, another six or seven biosimilar adalimumabs. We're going to have, I think, overnight nonmedical switching by insurance companies. And I think it's going to create a tremendous dilemma for providers who are going to be — may be — informed or may not be informed about the switch, and patients are going to have a new box show up at their house with a different name on it. It's going to be so helpful to have professional organizations such as GRAPPA at least come out with a position statement about them and also raise the issues. We know what a single switch, or two or three switches will do, but we'll have to see what multiple switches will do. I was intrigued by the tapering position statement, looking at the voting of the patients vs the physicians. As far as agreement on the various position statements about tapering, a joint decision between the patient and the provider, and about concerns about reactivation of disease, the physicians or clinicians agree 92% of the time; with patients, not so much — 72%. I'm not sure. What is your interpretation? That patients don't want to taper their therapy? They're afraid to taper their therapy? Do you think they didn't agree with the evidence that was provided?
Kavanaugh: I think that people, especially if you ask them a question specifically, tend to be conservative. If they're doing well, I think in answer to a question like this, they would probably say, "You know what? They're doing well, leave it alone, and let me continue as I've been doing." But as we both know in the clinic, it's very often the patients who are driving this. And, you know, you say, "Mrs Jones, you're taking this every 2 weeks." And she says, "Well, Dr Cohen, not quite every 2 weeks. I'm out to every 3.5 weeks now and I'm doing okay." And, you know, there are many more anecdotes than there are great data to inform it. It's a bit of a fuzzy area because we have studies showing that some people can taper and do great, some people can stop — a small percentage of them — and do great, but we don't know who those people are, a priori. We do not know enough to be able to say "You have a pretty good chance of tapering and you're going to do great." We don't know the characteristics of the patient, so we need more data to really inform that.
Cohen: I was also interested in that methotrexate was somewhat escalated as an option. It previously had been discounted by many people in the psoriasis/psoriatic arthritis field, but the data from the SEAM study looking at methotrexate monotherapy vs etanercept monotherapy plus methotrexate did suggest that in contrast to what a lot of people believed, it did have some impact on enthesitis and dactylitis. If I'm correct, you guys did move this up somewhat more conditional and strong because there was no placebo group to compare to. But at least it's on the board again for us old guys who are still using methotrexate.
Kavanaugh: Right, yeah, and you know we tried to keep it strictly based on the evidence and tried to avoid, "Well, what would you do?" in terms of sequencing and things like that. And as you said, that was great evidence from the SEAM study. There are people who really dislike methotrexate; there are people who have used it forever. But the data are the data and I think rather than get into any opinions or feelings about how to sequence therapy in the absence of a lot of head-to-head studies, we just list the things that had been shown to be possible and where they are effective. And that's how methotrexate, the data, got better. And so, overall, the place of it in the sequence looked better.
Cohen: To finish up, I see that your group did recommend a research agenda, which is so important and so frustrating in rheumatology. The lack of precision medicine in inflammatory arthritis was one of the things you highlighted. And the other fascinating question is why some patients with psoriasis develop psoriatic arthritis. I know there's quite a bit of basic work going on in that as well. Overall, I think that you and your group did a phenomenal job. I appreciate you being with us today to discuss the process and also the new recommendations. Thank you a great deal for joining us. Again, this is Dr Stanley Cohen for InDiscussion. Thank you for listening to our podcast today.
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Resources
Etanercept Treatment of Psoriatic Arthritis: Safety, Efficacy, and Effect on Disease Progression
GRADE: An Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations
US Welcomes First Adalimumab Biosimilar, Amjevita
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Cite this: Rundown: What Changed in the GRAPPA Guidelines for Psoriatic Arthritis? - Medscape - Mar 28, 2023.
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