This transcript has been edited for clarity.
Stanley Cohen, MD: I am Dr Stanley Cohen and welcome to Medscape's InDiscussion series on psoriatic arthritis. This is episode 3 of the second season. Today we'll be discussing the treatment paradigm for psoriatic arthritis and looking at the role of methotrexate and other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) among this plethora of treatments that we have for psoriatic arthritis. When I was preparing for these podcasts, I was reviewing the literature and ran across a couple articles by our guest today, Caylib Durand, and he has written some very educational papers on the new treatment recommendations for psoriatic arthritis and the role of methotrexate and csDMARDs in comparison to biologics. So, I'm going to introduce Dr Durand. He is a clinical lecturer in the division of rheumatology at the University of Calgary Cumming School of Medicine and a rheumatologist at the Peak Medical Clinic. It's my pleasure to have you with us today, Caylib. Welcome to InDiscussion. Tell me a little bit about you. I know you're a clinical researcher and also a clinician. Tell me what you do in that beautiful part of the world up in Calgary.
Caylib Durand, MD, PhD: I am a community researcher and community rheumatologist. I also focus on systemic sclerosis. But I obviously see a lot of psoriatic arthritis and a lot of spondylarthritis. We have several rheumatologists in our group, and we're involved in some of the clinical trials here in Canada, so a busy practice like everyone else, really.
Cohen: I've run across a paper that you've written recently with a colleague for the Medical Exchange Expert Report where you were discussing the upcoming new Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. Talk to me about GRAPPA, what they are, how they work, and how they do their systematic literature review and come up with treatment recommendations. Then I'll pick your brain about how you would make treatment decisions for a particular patient.
Durand: Psoriatic arthritis obviously is a bit more of a challenging autoimmune disease to treat. The GRAPPA recommendations are very important because there are 6 different domains, which is why psoriatic arthritis is a bit more challenging. Their goal is to review the literature that is out there and keep it up to date. And these are the latest recommendations that they've done in 2021. And they also used the GRADE evaluation of that literature, which is also very important because it makes it a bit more relevant. It does a good critical review of the literature and then integrates that into recommendations for rheumatologists to move forward with treating their psoriatic arthritis patients. And given the complexity with the six different domains, having the GRAPPA recommendations is very important.
Cohen: They do a wonderful job, and this will be the 2021 update (published in 2022) from the 2016 recommendations. A tremendous amount of new literature has come from clinical trials that have occurred over the last 6 years, which are informing us on how we approach our patients. I've spent most of my career in rheumatoid arthritis and certainly do have many type of inflammatory arthritis clinical trials and research and publications. But there are so many different therapies for psoriatic arthritis, it's confusing. So, let's take a look at a typical patient. A 34-year-old gentleman presents. He's had psoriasis for about 15 years. He has an [affected] body surface area of 4%, so moderate psoriasis. He's been treated with topical therapies by his dermatologist. Within the last year, he developed oligoarticular complaints, some swelling in a knee, wrist pain, and has developed dactylitis on the second toe on his right foot. He is a new patient. He has elevated acute phase reactants. His labs are otherwise unremarkable. As we would expect, he's seronegative for rheumatoid factor and ACPA, because he has psoriatic arthritis. How would you approach this new patient with inflammatory arthritis and long-standing psoriasis based on the GRAPPA recommendations? One of the first questions is, do you consider this mild versus moderate to severe disease? Does that impact your decision-making about what direction you're going to go? Or do you have a go-to therapy from the get-go?
Durand: The GRAPPA guidelines are very helpful. But in clinical practice, as you know, the logistics don't always allow us to follow the recommendations as we'd really like. On that note, in this patient — three domains … it sounds like they have some reasonable disease activity. Yes, the disease activity really is important to us. But unfortunately, where I practice, I can't get a biologic first-line therapy, so there’s more of the practical logistics of getting patients on therapies. In this case, which does actually follow a lot of the GRAPPA recommendations, we would be looking at starting conventional synthetic DMARDs (csDMARDS) for sure. And my go-to would be methotrexate, at least a good dose of 20-25 mg. And we usually start subcutaneously — we go big or go home, so to speak. And if they respond, that's great. If not, we escalate very quickly. That way, we don't have that disease activity around for a long time.
Cohen: Will you cycle through more than one csDMARD in a patient like this or, if you put them on methotrexate and they have a modest response, will you move on to leflunomide or sulfasalazine or will you move on to a more targeted therapy?
Durand: From a practical standpoint, if they're not fully responding, I will usually use leflunomide. That’s not because I wouldn't love to dose escalate something faster. It is actually a requirement for some of our reimbursement processes that we have to try at least two of those before we can move on. Unfortunately, as much as we would love to be able to do what the recommendations are in GRAPPA guidelines, we do have some restrictions here from the reimbursement cost perspective. So yes, with leflunomide and sulfasalazine; I tend to use more of leflunomide, as I just find I have less drug-drug interactions with that.
Cohen: I know there was a recent presentation at EULAR about a combination of leflunomide and methotrexate in psoriatic arthritis, and we had a great deal of experience with that in rheumatoid arthritis back in the late 1990s. It was a very good combination for rheumatoid arthritis. Leflunomide is a quirky drug with a significant adverse event profile and needs close monitoring. The combination works very well together but you need to certainly monitor the liver very closely. Have you had any experience with the combination in certain times?
Durand: Tons. I use it quite often. Usually what I'll do is if the patient is tolerating methotrexate quite well and it seems to have gotten them a decent disease response, maybe not 100% but a good response, I'll add half a dose of leflunomide, so 10 mg. I tend to find I rarely get the liver enzyme elevation or any bone marrow suppression. I've had significantly more problems with sulfasalazine plus methotrexate compared to leflunomide.
Cohen: That’s interesting. I assume none of us are using a loading dose of leflunomide anymore — that's pretty much gone by the wayside. The other oral therapy that we've had prior to the JAK inhibitors recently has been apremilast. The data in psoriatic arthritis are modest: there are some patients that respond. Does it fit into your treatment paradigm or is it something that you use infrequently?
Durand: I use it very rarely. We have such better options out there going forward for psoriatic arthritis that cover more needs, to be quite honest. I don't usually use a lot of apremilast.
Cohen: We see our dermatology colleagues using it quite a bit. And I'm always amazed when they can get combination therapy and we'll have a patient on a TNF inhibitor and they'll somehow figure out how to add apremilast. And we had the same problems in the United States that you have north of the border, with step therapies and restrictions and so forth. Let's say you didn't have the restriction. You didn't have to go through one or two csDMARDs initially. In which patient would you say, "I just can't do this — this is not right. I've got to be much more aggressive." Is it the degree of psoriasis they have? Is it the load of inflammatory synovitis that they have? What would be your thought process if the world was a wonderful place to be and we could do whatever we wanted to do?
Durand: By far, disease severity would be the major deciding factor there. And I absolutely agree. I have patients who have head-to-toe psoriasis and it's really frustrating when I'm stuck having to do these steps in between. I would love to get them right on to a biologic therapy … an anti-TNF or an anti-IL-17. Then it would also be the number of domains involved. If you have a patient walking in the door and they've got five out of the six domains for psoriatic arthritis, that really makes me want to escalate therapy very quickly and get them on to what I think is the ideal drug. Don't get me wrong, methotrexate and leflunomide … they're good drugs and they've been shown to work. But it's definitely not going to be what you need and it's not going to be what you're going to get remission with in those severe or moderate to severe psoriatic arthritis patients.
Cohen: I think the clinical trial, where Phil Mease was the first author, the SEAM-PsA trial, was very helpful to all of us because there was a lot of controversy about whether methotrexate worked at all in psoriatic arthritis. You could talk to different opinion leaders, and that clearly showed that it is not as effective as etanercept or a combination, but it worked in 50% of people in terms of ACR20 and about 20% to 25% had a PASI 75. I think there is a role for csDMARDs and, again, because of the step edits we have to use, I've learned the lesson the hard way. I'm a lot older than you. I do stay away from methotrexate in morbidly obese patients. I thought it was not a problem based on my review of the literature. But some of my patients who have been on it for 20 or 30 years who are morbidly obese came down with liver issues. I think it is a concern. So, let's take patients as you put them on methotrexate and you add leflunomide. They still have active disease. You can move on to the next step. You have TNF inhibitors, you have IL-17 inhibitors, you have IL-23 inhibitors, and you have JAK inhibitors. Walk me through your thought process in a patient like this who has moderate skin disease and still has ongoing synovitis — what would be your choice for next steps?
Durand: A couple of factors play into that. One, definitely, is patient preference. Patients like to be involved in that decision-making process. We actually give them a couple of options, ones that are definitely reasonable within that scope. I tend to like the IL-17s; the data look good. The newer data coming out for the IL-23s are good, although maybe not as great as we'd like for some of the really aggressive inflammatory arthritis components. I don't usually have a drug that I'm particularly trying to get the patient on, per se, but I'll give them two or three options. I tend to get better buy-in with that because patients, at least in Canada, have been more reluctant to go on some of the advanced therapies. They've seen the news, they've seen some of the safety data, and they've seen and heard about the JAKs with the risks that are potentially there. And then obviously, the co-morbidities of those patients, as you were talking about — obesity, heart disease, really significant melanoma, skin cancer, or other cancer malignancies — can play a role in what we'd be looking at for therapies going forward. So, it really comes down to trying to find just the right drug for that patient, where we think we can get the best disease response but trying to reduce the risk as much as possible. It's really a risk-benefit talk that I have with them.
Cohen: Basically, it is shared decision-making, which is so important. Do you stratify when you look at these therapies as far as more skin disease, less joint disease, or vice versa? Does that impact your decision as to what you can do next?
Durand: Yes. We have some of that data nuance coming out of the clinical trials, showing that certain drugs will be a bit better for skin if that's what the heavier weighting is in that domain. And some are better for inflammatory arthritis. So that definitely plays a role. Enthesitis and dactylitis are, by far, more challenging to treat. I have a lot of patients, for instance, with nail psoriasis; it drives them crazy and it's really extensive. And so that can really direct you to which therapy you want to use.
Cohen: Going back to the nails before we launch in the next discussion, I noticed in your manuscript that you talked about topical JAK inhibitors for the nails. Have you had experience with ruxolitinib? I am curious. I have not yet.
Durand: Interestingly enough, our dermatologists are a little bit more advanced than the rheumatologists, so we do lean on our colleagues in that field a bit more. I have compounded a few of the JAKs. It's a little bit harder to get right now, which is a supply issue. But we do have access to a compounding pharmacy, and they have been using that on occasion. Usually, though, we're moving on to more advanced systemic therapy. And we don't start with that per se. It's more of those challenging cases where we can't or they don't want to progress to that biologic.
Cohen: How do you monitor your patients in clinic? For old guys like me, it was the gestalt method of walking in the room and saying, "I don't see any swollen joints. The skin's better. Hey, everything's cool." Do you measure and look for minimal disease activity as an outcome? Or are you using the DAS or ACR20? What do you do in the clinic when you're monitoring your patients?
Durand: We definitely do swollen and tender joint [counts] and use that in calculations of the DAS. We would like to use other things but restriction is more from our insurance payers. They want a specific disease outcome, so they're a little bit behind on minimal disease activity scores and things like that. We have to cater to them a little bit. But obviously you're right. Your gut feeling when you walk in the room … you know when your patients are not looking well and they're not in remission, even though their criteria or their scores look fine. So that plays a role in whether we're escalating therapy or moving forward.
Cohen: So, you end up putting the patient on an IL-17; again, the skin gets a lot better but the joints don’t get a lot better. And, at that point, you're going to have three IL-17s soon … you actually have three and you may have four if you count brodalumab … and then you have other therapies. What we lack in rheumatology and desperately need are treatment biomarkers. I'm not aware of any biomarker in psoriatic arthritis that we can use in the clinic other than stratification of the skin and joints. Is that correct?
Durand: Yes. Essentially, if you're lucky enough to have a CRP [C-reactive protein], that seems to correlate with disease, and that's the best we get. But other than that, you're right, it's more or less based on clinical presentation.
Cohen: In a particular patient who's failed on IL-17, what would you do next? We're in shared decision-making with the patient. It would just be an empirical decision — one of the options A, B, or C.
Durand: It really depends. If they have some response and then they lose response, it makes me discuss with them whether we want to try the same class and see how that goes, because there's evidence that that should be a reasonable option. But if they're a complete failure and we got nothing in terms of controlling their disease, I emphasize that we should probably switch classes altogether, and usually the patients are on board with that. I always give them the option but at that point they're usually looking and wanting to be on a different drug anyway when they're not doing well.
Cohen: For the patient with psoriatic arthritis who has iritis — do you have any go-to treatments or treatments that you avoid in that particular patient?
Durand: My go-tos would definitely be the TNFs, in particular any of the adalimumab biosimilars or golimumab (Simponi) or certolizumab pegol (Cimzia), because we've seen good data for uveitis in those three drugs. Obviously, the ones to avoid are those that don't look like they're necessarily treating uveitis. I mean, we don't have a lot of uveitis data for the IL-17s. I don't think it [an IL-17 inhibitor] causes it, but I'm not sure it's actually treating it. And that goes for etanercept and some of the others that are in that category.
Cohen: And then with the IL-17s, we avoid those in patients who have concomitant inflammatory bowel disease [IBD].
Durand: It's interesting … we don't. Data don't suggest that it [IL-17] causes IBD, it just doesn't treat it. And we've had this conversation multiple times with our GI/IBD colleagues and most of them are actually fine. You talked about the duobiologics. We actually have that opportunity if one clinician is prescribing it vs the other. And we actually have patients on a TNF or an IL-17 and then vedolizumab (Entyvio), for instance. So as long as their GI symptoms are controlled, there don’t seem to be a lot of GI issues with starting an IL-17 to control joints or other domains of psoriatic arthritis.
Cohen: Well, that's fascinating. That's not something that I've seen here in the States very often. But that's interesting that you're doing that.
Durand: Well, I'm not sure it's a recommendation or guideline per se. As you know, these patients are very difficult to treat when you get to that level. And we've had good outcomes so far. Have we published anything on that data? No. But having said that, EULAR and ACR abstracts have been presented on some of that data, and we know that our IBD colleagues have published on that that already.
Cohen: Let's talk about one other subgroup, which is psoriatic spondyloarthropathy. Is there any role for csDMARDs in those patients who predominantly present with axial skeletal disease or a peripheral joint disease?
Durand: For axial spondyloarthritis(AS) sPa, no, I don't think you'll find a rheumatologist here that's going to be using any of the csDMARDs for treating.
Cohen: Are your hands tied in Canada with that patient or you can code them as AS and get them approved for a biologic?
Durand: Yes. We would just label them as an AS, but we have the option of nonradiographic AS or other ways to get that approved for sure, without having to use the csDMARDs.
Cohen: And I assume in Canada you have the same restriction that we have in the States now for JAK inhibitors — patients have to fail a TNF inhibitor is what the FDA came out with here. I don't know what your restriction is in Canada at this point. Most patients with psoriatic spondyloarthropathy or spondyloarthritis are going to be younger, healthy people. They aren't going to be 65 and older and smokers with cardiovascular risk factors. So, JAK inhibitors would be a very reasonable drug for these patients.
Durand: For psoriatic arthritis, we use JAKs quite a bit in the first line. We don't have a restriction. We can use them pretty much in a naive patient going forward. They're usually younger patients and they seem to do very well. And the data support that as well.
Cohen: I think JAK inhibitors are very effective therapies for many of our diseases, and we just need to understand that the mechanism behind the signal that was seen in elderly rheumatoid arthritis patients. Other than vedolizumab (Entyvio) and IL-17, are there any other combinations of biologics that you guys are playing with or using in clinic?
Durand: I guess it's really a close discussion with the gastroenterologist. We've had a few patients on a TNF and JAK combination. IBD doctors seem to really like that combination because it also helps with their IBD, right? So using those therapies that overlap with both diseases, which is nice because obviously that's what we're trying to do. And it also usually allows us to wean down the dose of them to mitigate some of the side effects — risk of infection, for instance, with JAKs at higher doses that they've been using in IBD, or any VTEs [venous thromboembolisms] or malignancy risks or cardiovascular events.
Cohen: That's very interesting about the use of combination therapy, although we know that it is off-label and not approved by the regulatory authorities. I assume this is really for the treatment-resistant patient.
Durand: Correct … we're talking about patients — it’s about 2% — who have overlap with IBD and psoriatic arthritis, so it's not a large patient cohort, and you're right that these aren't your typical patients in clinical trials. They are very difficult [to treat], refractive, and obviously, yes, we don't recommend this unless we're really having a difficult time treating the patient, trying to get them into remission.
Cohen: Certainly understood. Well, thank you. This has been terrific. I appreciate you taking the time to be with us and run through the North America/Canada approach to the management of patients with psoriatic arthritis. And it's been interesting to hear about the role of our old buddies methotrexate and leflunomide in the management of psoriatic arthritis. Thanks again, Caylib, for spending some time with us. I want to thank you so much for joining us for episode 3. I look forward to another great discussion in episode 4. This is Dr Stanley Cohen for InDiscussion.
Durand: Thank you.
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Cite this: Treating Psoriatic Arthritis: The Role of Methotrexate and csDMARDs in Comparison to Biologics - Medscape - Aug 23, 2022.