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Stanley Cohen, MD: Hi. I'm Dr Stanley Cohen, and welcome to Medscape's InDiscussion series on psoriatic arthritis. This is episode 6 of the second season.
Today, we will discuss an update on novel therapeutics in clinical trials, discussing a more refractory-type patient. Today, I'm pleased to introduce my guest, Dr Allan Gibofsky. Dr Gibofsky is a professor of medicine, healthcare policy, and research at Weill Cornell Medicine, attending rheumatologist and co-director of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery, and attending physician at NewYork-Presbyterian Hospital and Memorial Sloan Kettering Cancer Center. Besides all those accolades and titles, Allan is a longtime friend and colleague and a well-recognized expert in clinical rheumatology and inflammatory arthritis. Welcome, Allan.
Allan Gibofsky, MD, JD: Thank you, Stan. Good to be with you.
Cohen: I'm glad to have you today. This is a really a very interesting subject. One of the things we struggle with is how to manage patients with refractory disease. Also, we're very curious about what's on the horizon that might be added to our armamentarium for the treatment of these patients with psoriatic arthritis. But before we launch into a case that you've prepared for us, I'm just curious. I've known you a long time, but I've never actually asked you the question: How did you get into rheumatology? What was the impetus for you becoming a rheumatologist, an academic rheumatologist?
Gibofsky: As a medical student, I was interested in studying transplant antigens. There is kidney disease in my family and my father had a transplant, and as you know, so did I. And that was what I wanted to do. I wanted to go into nephrology and study the HLA system and its relationship to determining whether grafts would survive. And the year that I graduated was the landmark observation that HLA B27 was associated with ankylosing spondylitis. There I was at Cornell at a fork in the road. Do I study rheumatology, or do I study transplant nephrology? And it just turned out that the chief of rheumatology, Dr Charles Christian, was just such a charismatic individual that it was like the Pied Piper. And I went into rheumatology and never looked back.
Cohen: You know, Dr Christian was certainly a giant in our field, and it's always amazing — it's the mentors who really provide us the path that we choose. That's fascinating. So let's talk about the case that you prepared today.
Gibofsky: I want to discuss with you a patient, J.D. He's a 45-year-old White man referred for evaluation of pain in multiple small joints, and his primary care physician thought he had rheumatoid arthritis. For the past 6 months, he was managed by the primary care physician with nonsteroidals, none of which really gave him any significant relief. In the month before he came to our unit, he had increasing difficulty putting on and wearing shoes because by his reports, several toes on his feet were becoming swollen and tender.
There was no family history of arthritis. There was no family history of inflammatory bowel disease. Interestingly, there was no family history of skin disease. But when we finally got to see him, his general physical exam was normal, but he had swollen metacarpophalangeal (MCP) joints on both hands, bilateral wrist tenderness, and swelling and pain across the arches of the feet. I noted a scaly rash in his natal cleft and umbilicus, and he had a body surface area of this rash of about 2%.
It was clear to me that no one had ever looked at these areas and asked him about them. And very often our busy schedules, we don't take the time to disrobe the patient completely, because had he been disrobed, at least the association may have been made in the mind of whoever was seeing him previously. In any event, we did some preliminary lab studies, and we had some lab studies that he came with. He had a normal chemistry profile; he had a normal complete blood cell count (CBC). He had a slightly elevated erythrocyte sedimentation rate of 30. His rheumatoid factor was negative, his anti–cyclic citrullinated peptide (CCP) was negative, he had a positive antinuclear antibody (ANA) titer, and he had a C-reactive protein (CRP) level of 8. The upper limit of normal in our lab was 5, and he had a normal serum uric acid level.
I then proceeded to get some imaging studies, and x-rays of his hands and feet. It was clear both from the radiologist's report and from my inspection that he had extensive soft-tissue swelling with earlier relative changes of the MCP and distal interphalangeal (DIP) joints, which were consistent with psoriatic arthritis. At that point, I let him continue on the ibuprofen, which was what he was taking (the last nonsteroidal tried), and I started him on methotrexate. He came back to me after several weeks saying that he really hadn't gotten any better in terms of either his pain or swelling.
Cohen: I think it's a fascinating case, a great teaching case. I'm sure you use this with your students and your fellows. The fact that you searched his body for one or two patches of psoriasis, which most people don't do; the seronegativity; and then the soft-tissue changes and erosive changes making the diagnosis.
I'm really curious, as we talk launch into therapeutic decision-making for psoriatic arthritis: You have multiple options. we have the GRAPPA group, I understand their new recommendations will be out shortly. You chose methotrexate initially, and I know there's been controversy about the role of methotrexate. For years, many people did not feel that methotrexate was particularly effective for psoriatic arthritis. Tell me a little bit about your choice of methotrexate initially rather than going to a biologic or targeting a synthetic disease-modifying antirheumatic drug (DMARD).
Gibofsky: Well, if I had my druthers, I would probably not use methotrexate and go right to a biologic or targeted synthetic. I think the evidence is clear that that's the way to go in treating chronic disease. But we often have issues with access that you can't get these biologics in many instances until the patient has been designated a failure of methotrexate. So we often have to start methotrexate, anticipating that is not going to be the agent of choice in a patient like this — but [we start it] in order to get past that first hurdle that the managed cost companies always put in our way.
Cohen: Though there have been recent studies from NICE and others that suggest that at least in about 50% of patients, depending on what outcome you look at, methotrexate may be beneficial for a period. Not as effective as etanercept monotherapy in combination, but some people do respond.
Gibofsky: But the key thing there is for a period of time. Now you're dealing with younger patients whom you know are probably going to outlive you if not in practice, then in lifespan. You want to get them on the earliest and most aggressive therapy that they need in order to achieve the most optimal outcome.
Cohen: All right. So let's continue. The patient took methotrexate without relief. What were your next thoughts on the patient?
Gibofsky: In the back of my mind are always things like the GRAPPA guidelines. When you're dealing with a patient like this, and having taken methotrexate with an inadequate response for 3 months, he would be considered now a patient with peripheral arthritis, with an inadequate response to DMARDs and also to methotrexate. And the recommendations are multiple. There's a recommendation for PD4 inhibitors and other conventional synthetic DMARDs, like sulfasalazine and oral corticosteroids. These are, if you drill down, only conditional recommendations. We often like to differentiate between those recommendations that are strong and those recommendations that are conditional.
Now, of the choices that we have, we have a strong recommendation for either a tumor necrosis factor (TNF) inhibitor at that point or for a JAK inhibitor. But you know quite well that given where we are with the JAK inhibitors — maybe we can talk about this a little bit later — you really can't get a JAK inhibitor until you've tried at least one TNF inhibitor.
In this instance, I elected to go after his inadequate response to methotrexate to a TNF inhibitor so that I could set the stage for whatever direction I wanted to go after the TNF inhibitor.
Cohen: So, a couple of questions about your decision-making at this point. Did you continue the methotrexate or, as we often do in a rheumatoid arthritis patient, at this point make a switch?
Gibofsky: In this patient, I stopped the methotrexate. He didn't feel it was doing him any good. I didn't feel it was doing him any good. And quite honestly, as you well know, Stan, of all the medications that we use in rheumatology, methotrexate is the one the patients love to hate. They have great difficulty with it. And even when they're tolerating it, they don't feel that's what's working for them, because most of the time we have to switch them to something else anyway. To the extent that patients are not eager to continue something, I'm not at all upset when they say, can I stop this? And I go, sure, why not?
Cohen: There's been numerous clinical trials and long-term experience. [On the basis of the] observational registry data on the benefits of TNF inhibitors and psoriatic arthritis, can you differentiate any of the TNF inhibitors from one another? Is there any go-to TNF inhibitor for you with psoriatic arthritis?
Gibofsky: I'll answer the first question, which is I'm not sure that any of the clinical data that we have differentiates them. As you yourself pointed out in many instances as well as others, in the absence of head-to-head studies, you can't look at one drug study's submission and another drug study's submission and say, oh, well, this one had an American College of Rheumatology (ACR) score of 26 and this one had an ACR of 22; therefore, the first one must be better because the number was higher. You can't do that in the absence of a head-to-head study. That's a long-winded way of saying that of the five TNF inhibitors that we have, I'm not sure that there's any real difference in terms of efficacy. Sure, you can differentiate between how often you give them, the route of administration, and the ease of comfort of the injecting device. But other than that, I think you pay your money and you take your choice. Or more often, the insurance company pays its money and tells you which choice it's going to be. And it's unusual that I'm going to fight that battle at this point among the TNF inhibitors.
My go-to drug, because I have the most experience with it and the most comfort with it, is adalimumab in this class. But if the patient said, I can't get adalimumab, I have to take one of the four others. I'm not going to die on that hill.
Cohen: That's great. So the patient was started on a TNF inhibitor. What happened at that point?
Gibofsky: The patient was started on a TNF inhibitor, and he came back several weeks later. I see them about every 3 months.
Cohen: I've got it.
Gibofsky: He did have some improvement in his skin rash, but his skin rash, as I indicated earlier, was not his major problem because many instances he wasn't aware of it, but his joint pain really hadn't improved. In addition, the toes on his feet hadn't improved. One of his toes, in fact, had developed almost a sausage-like appearance. And for the first time, he began complaining of pain in his heel, particularly at the Achilles insertion. That suggested to me that I could perhaps change the dose a little bit of this agent, maybe add back his methotrexate. But again, I really didn't think that that was going to continue to get him the optimal outcome.
Cohen: At that point, how was your decision made? This is where we face a dilemma with these patients with somewhat refractory disease. We have multiple ways we can go: interleukin (IL)-17 inhibitors, IL-23 inhibitors. It's like you said: a second TNF inhibitor, or we use a JAK inhibitor at this point and an IL-12/23 inhibitor. What do you use? What's in your bag that you use to inform you or to take that next step? What class of therapy are you going to go to at this point?
Gibofsky: In this instance, I went to an IL-17 inhibitor. I've been impressed with the data on secukinumab in particular on its effect on enthesitis and dactylitis, and since those were the areas of his disease, the domains of his disease that were giving him the most trouble, I thought, sure, why not. Of the choices I had, I'll go with that one. So I put him on secukinumab.
Cohen: Okay. And again, as monotherapy. How did he do after that initiation of treatment?
Gibofsky: He tolerated the drug well. He didn't have any intolerance or safety issues with the drug. But he was really complaining that he still had joint pain, that he was still having difficulty getting into his shoes, and he asked me to try something else. When we had so few agents, we kept a patient on an agent longer than we do now. And I think patients were willing to stay on agents longer than they are now, when they know they have multiple choices. For me, about 3 or 4 months is the decision point. When the patient comes in with no real improvement after a good trial, and I'm convinced that the patient is adherent and they're not just conning me and having secondary gain issues to try and enjoy poor health, as it is, for other reasons, then I'll try something else. So, I put this patient on abatacept. I put this patient on risankizumab. I was considering other agents as well. That's where he is most recently.
Cohen: I know a number of our colleagues will take a look at the therapies. It seems that the IL-23 inhibitors have become the treatment of choice for dermatologists because of their safety profile. And you also agree that the safety profile of all of our therapies does look quite robust, probably one of the best.
Gibofsky: Yeah, I do. But I do agree that there seems to be this dichotomy between skin and joint and that the dermatologists like an IL-12/23 inhibitor because it does improve skin more than it does joint. I think we've been less improved with IL-12/23 inhibitors for joint than it is for skin, and we are rheumatologists. So, if a patient's primary problem is their joint, I'm not as convinced that an IL-12/23 inhibitor is the way to go. If their skin is their primary problem, then the IL-12/23 inhibitor may be a better way to go.
So just to step back a bit. One of the first questions I ask the patient is, you've got psoriatic arthritis. What's more important to you to clear up: the psoriasis or the arthritis? Which is giving you the greater impairment in your quality of life: your psoriasis or your arthritis? Because if it turns out that they say, if you can clear my skin, I can deal with the joint pain I have, that's one decision point. Whereas if they say, if you can just take care of my joints so I can function, I can deal with the skin problems I have, that's another. I think that often helps us determine what we're going to be using. This patient really never went above 4% or 5% body surface area. I really thought that the IL-12/23 inhibitors were not going to be my primary way of going. I might keep them for or when nothing else worked, but I was going to go down some other roads.
Cohen: So the other option after the TNF inhibitor failure [is a JAK inhibitor], and as we know, the US FDA has come out with basically a restriction on all immune-mediated inflammatory diseases that we really should not use JAK inhibitors until a TNF inhibitor has failed. You could have gone to just tofacitinib or upadacitinib. What are your thoughts on the four clinical trials, two for tofacitinib and the two from upadacitinib, both of which compared the conventional synthetic DMARD (csDMARD) in incomplete responders: tofacitinib, upadacitinib, and adalimumab. And then they also had studies in biologic incomplete responders. What's your take on those particular therapies at this point, as far as where they fit in in the armamentarium?
Gibofsky: Before I answer that, I want to say one thing: This is a young man who did not have any cardiovascular (CV) risk factors. He's not a smoker. He doesn't have any previous episodes. He's quite clean when it comes to CV [factors]. So I'm not convinced that the restrictions on the targeted synthetics — in particular, upadacitinib and tofacitinib — by the FDA as a result of the study in rheumatoid arthritis in patients over 50 with one risk factor would necessarily apply to this patient. I think that this would be a patient I would like to get on a JAK inhibitor, and that's why I went to the TNF earlier in my discussion, in my armamentarium.
We do have a couple of head-to-head studies. I'm not sure, for example, how well the ones we've seen have been powered to look at head-to-head against adalimumab, as opposed to adalimumab as a reference arm compared with placebo. Certainly, we did have the SPIRIT head-to-head trial, which was done for ixekizumab — which of course doesn't answer your question because that's not a targeted synthetic. But we do have the one of upadacitinib vs adalimumab, and I would have to check — Stan, please correct me — I'm not sure that was powered to look at that.
Cohen: It was that the tofacitinib was not [powered as a head-to-head against adalimumab], but [upadacitinib was] a noninferiority trial. Fifteen to 30 mg was noninferior. Thirty milligrams was superior, but that's not the approved dose. Right.
So they [tofacitinib and upadacitinib] clearly are effective. And in most of those patients, about half had insignificant psoriasis. Most had very minimal psoriasis. One of the questions, before we talk about what's on the horizon, is that I see dermatologists not infrequently adding apremilast to other treatments, and I'm always confused by that because I can never get them approved and haven't used combination therapy. Have you had any experience or seen any studies that have confirmed that there's added efficacy, that there are synergism benefits in combining therapies in psoriatic arthritis?
Gibofsky: I've not seen those data. I know that I've had a handful of patients who I have on a biologic, and they're also seeing the dermatologist and the dermatologist is prescribing apremilast. Certainly, I don't have any experience, nor have I seen patients on combined biologic therapy, because even in psoriatic arthritis, I think that remains the "thou shalt not" as it is in rheumatoid arthritis. But I just came from a conference last weekend where my rheumatology colleagues were talking about how they get their dermatology colleagues to prescribe apremilast. And it gets paid for, because if they try and do apremilast and another biologic, it will not be.
Cohen: That's interesting. What's new on the horizon? What can we expect in the next few years as far as therapies in clinical trials presently?
Gibofsky: There are a couple. Obviously there's bimekizumab, which is probably the closest one. The trials for bimekizumab have been done extensively, and that's likely to be seen in the next 12-18 months. There were some technical issues regarding its approval in psoriasis, which was studied first, and that resulted in a temporary hold from the FDA until those facility inspection issues could be resolved. But the plan was to get bimekizumab [approved] in psoriasis and then in psoriatic arthritis. I think that's likely to happen.
Deucravacitinib is on the horizon again, something that may appear first in psoriasis and then psoriatic arthritis. Deucravacitinib is a tyrosine kinase 2 (TYK2) inhibitor, which people think is a different mechanism of action. But in the world of rheumatology, we know TYK2 is part of the family of JAKs and virtually every review paper ever written begins with a sentence either in the first paragraph or in the second one: There are four members of the JAK family — JAK1, JAK2, JAK3, and TYK2. Given that, many think — and I'm among them — that when the FDA looks at TYK2, they're very likely to classify it among the JAK family and impose many of the same restrictions on where TYK2 inhibitors can be placed in the therapeutic armamentarium after TNF inhibitors.
There are a few others, but not entirely ready for prime time. There was a phase 2 study of an agent called izokibep. I think that's how to pronounce it. It's a novel IL-17 agent that is a small protein with a high affinity for IL-17. But I think bimekizumab, deucravacitinib, isokibep are probably the next three that we're likely to see.
Cohen: A quick question as we're wrapping up: With bimekizumab, do you think inhibiting IL-17A and IL-17F is going to provide a substantial difference from the other IL-17 inhibitors?
Gibofsky: I don't know. I was asked this question yesterday and I said, I need to see the data. You know, these stories are great, but we have stories for everything in our discipline. We love the stories. But at the same time, we call our body of knowledge literature because it's so much litter in it. I love to be convinced that inhibiting both is better than just inhibiting one. But I'm going to wait to see the data and then, better yet, a head-to-head trial.
Cohen: Thank you, Allan. This has been terrific. I think it's wonderful to work through a refractory-type patient and talk about the multitude of therapies that we have. And it's certainly a lot better than it was a few years ago, when we were a little younger. Thank you for your time. Much appreciated.
Today we've had Dr Gibofsky discuss a refractory disease case and let us know what's coming down the pike as far as potential new therapies in this discipline of psoriatic arthritis. I want to thank you so much for joining us for episode 6, which is our final episode. And this is Dr Stanley Cohen, for InDiscussion.
Listen to additional seasons of this podcast.
Resources
GRAPPA Treatment Recommendations: 2021 Update
Methotrexate in Psoriasis and Psoriatic Arthritis
Psoriatic Arthritis Medication
Three JAK Inhibitors Get Boxed Warnings, Modified Indications
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Cite this: What's Next in Psoriatic Arthritis: Clinical Trials, Novel Therapeutics, and Refractory Disease - Medscape - Nov 16, 2022.
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