Episode 6: Emerging and Novel Therapeutics in the Management of PsA – Medscape

This transcript has been edited for clarity.

Elaine Husni, MD, MPH: Welcome to this Medscape InDiscussion episode six. We're going to talk about emerging and novel therapeutics in the treatment of psoriatic arthritis. I'm particularly excited today because we have Dr Ana-Maria Orbai, who's both a friend and colleague. She is an assistant professor of medicine in the division of rheumatology at the Johns Hopkins University School of Medicine. And she also directs the psoriatic arthritis program at her institution. It is definitely a treat to have her here and to talk about some really interesting new therapeutics in psoriatic arthritis. Before I begin, I'd love to ask Ana-Maria, do you recall one of any of your first experiences with a psoriatic arthritis patient and what made you interested to become an expert in this field?

Ana-Maria Orbai, MD, MHS: First of all, thank you, Dr Husni, for the generous introduction. It's my pleasure to be here. Yes, of course I recall starting with psoriatic arthritis. We didn't have much in the beginning. We were still following in the footsteps in terms of both the framework for evaluating our patients as well as the therapy choices. Since then, the clinical data have expanded. We have a lot of new therapeutics. We have head-to-head trials, so there are many more treatment choices than before, and there is the possibility of adapting the treatment to the patient's own presentation and psoriatic disease phenotype. It's a very exciting time for psoriatic disease.

Husni: I agree. I remember when you and I were going to these meetings national meetings there'd be these huge exhibits for rheumatoid arthritis (RA) and these little exhibits for psoriatic arthritis. And now we're on equal footing. It's fun to see how it's exploded. I wanted to start off with a case if that is okay with you. He's a 46-year-old construction worker. He had longstanding psoriasis, using topicals for a long time. He had an episode of dactylitis in his second toe, and he was placed on methotrexate. Unfortunately, he didn't really like the way that it made him feel so he's really been on and off of methotrexate throughout the year or two. But luckily, his dactylitis did subside after a while. A few months later, he did have some worsening skin, mostly pretty classic plaque psoriasis, on his extensor surfaces his elbows and knees. He was started on a tumor necrosis factor (TNF) inhibitor and noticed that his skin really cleared up and that it was doing pretty well. That takes us to about 6 months before his visit with me. Why he went to see me is that he found it really difficult because he has to wear these special shoes at work these construction shoes and he's noticed a lot of pain by his heel to the point where it was really difficult for him to bend down. He was really having a hard time at work. His current rheumatologist did some x-rays and some bloodwork and said that everything was pretty normal. So he was getting a little frustrated and he wanted to see if there's anything better than adalimumab, which he was on for his psoriatic arthritis, or if there was something else going on. But he just really was quite debilitated at work. So I wanted to talk to you to see how you might approach this particular patient in terms of whether or not he should stay on and be more compliant with the methotrexate along with the adalimumab. Would you consider switching and maybe talking about some of the emerging treatments that may be better in a patient like this?

Orbai: Very interesting case for sure. A common scenario in our clinics is where patients may do well initially, or the disease may be controlled for them to continue on their current therapy. But then new symptoms emerge. In your case, it sounds like it's the lower extremities. We're hearing about pain, wearing boots, standing at work. So I am thinking, without examining the patient, just imagining and thinking: It either could be arthritis, MTPs, tarsus, ankles, subtalar joint, or with heel pain, plantar fascia pain, right? Could this be enthesitis or could these be combined? It's very common for our treatments to lose efficacy over time. It sounds like he's been on this treatment for 1 year. It's not uncommon for it to lose efficacy, especially since methotrexate was on and off. This could be one case where antidrug antibodies could have been developed, and that's why the biologic no longer works. Or maybe the psoriatic arthritis just figured another way to become active, going around adalimumab. I would definitely look into switching the medication fronts for this patient, also considering the patient's preference. It sounds like he's not very enthusiastic about continuing methotrexate in the first place, so maybe we should work with that as well and think, What else do we have in our toolkit? The first mechanism of action that comes to mind and for which we have head-to-head trials with adalimumab, would be interleukin (IL)-17 inhibition. While we have used this and we're familiar with this mechanism of action first for several years now, we have an emerging IL-17 pathway inhibitor, which is a dual inhibitor of IL-17A and -F, bimekizumab. We've all seen it, the phase 2b trial results with bimekizumab, and we're awaiting the phase 3 results. This pathway would definitely be of consideration.

Husni: I agree with you. A common scenario is where somebody does really well on a biologic and the expectations are here, right? When they start to have that waxing and waning course or any new symptoms and you elegantly pointed out that enthesitis could be playing a huge role because we are not seeing lots of changes on x-ray over time or bloodwork. Yet, he's having interference for some of his work and daily activities, which really makes us wonder about some of these other manifestations of psoriatic arthritis, such as enthesitis, as you brought up. This is where some of these new treatments for me become really interesting because now we're no longer just looking at general efficacy for psoriatic arthritis. We are really raising the bar and looking at different manifestations clinical presentations of the disease. I would love to hear a little bit more on some of these early studies on bimekizumab. What is your conclusion to some of these early trials?

Orbai: We could start with the psoriasis trials where we've seen much higher efficacy with inhibiting the dual pathway, and I am very hopeful that we can expect the same augmented effect in in the psoriatic musculoskeletal disease as well. I am very much looking forward to the phase 3 trial results. From the phase 2b trial, we saw that on the ACR 50 outcome, about 50% of the patients achieved this higher bar of efficacy. We also noted that although the primary outcome was selected at 12 weeks in this phase 2b trial, there was evidence that the magnitude of responses increased over time through weeks 16 and 20 of therapy. I think that's very exciting. For enthesitis, many of the results in the phase 2b trial were exploratory simply due to sample size and looking at multiple doses. For enthesitis, improvement in the MASES enthesitis score, were numerically higher than placebo, which is very encouraging. It does make sense that an IL-17 inhibitor would work better for enthesitis because we know that enthesitis is mediated through the IL-23 and IL-17 axes. I definitely look forward to seeing outcomes specifically on enthesitis with this new mechanism of action.

Husni: I agree. The ability to have outcome measures now, whether its MASES scores, has really elevated the way that we look at trials coming because I'm not just looking at joint and skin count now, I'm curious about dactylitis, enthesitis, axial involvement, and the ability for certain subsets of these therapeutics to work on some manifestations and not others. I do find enthesitis to be a little bit harder overall because the physical exam sometimes is difficult. Then, in addition, trying to understand the different outcome measures that they're using for enthesitis and whether or not this would be good in our patients. But nonetheless, so happy to see data coming out in head-to-head trials. I'm really looking forward to phase 3 and getting some more information on this drug. I really think that it'll make some difference in our field and I'm excited that new options are still coming out. The next issue I wanted to talk about are oral agents that you and I are familiar with from RA but yet are getting approved in psoriatic arthritis, and those are the JAK inhibitors. As you know, we probably have some more initial comfort in the RA world as they were approved their first. But now, we're seeing some safety challenges. I'd love to hear how you think about the JAK inhibitors in psoriatic arthritis.

Orbai: Indeed, safety is very important; in the psoriatic program, we have it lined up right with efficacy. I always talk to my patients about the balance being on just enough medicine to get us to the treatment goals while staying safe. That could be one medicine or a combination, depending on how active the psoriatic disease is. But safety is an important discussion with the recent data on JAK inhibitors. We know that in Europe, there's the recommendation to not prescribe these drugs to people older than age 65 because of the concern for risk for infection, heart disease, and thrombosis. Data from the safety studies taught us about increased risk. Interestingly, with the JAK inhibitor mechanism compared with the TNF inhibitor mechanism, which I think is very relevant for practice, there is an increased risk for heart disease as well as cancer. Clinicians were prepared to notice this increased risk on the basis of our knowledge of the mechanism of action. I don't think it's that surprising to us. To see those data, though, is very important and helps us put the mechanism of action in the context of our clinic. We have patients of different ages with different risk, and I think it's very, very important to tailor therapies to each of our patients. For example, I would agree that maybe in patients with certain comorbidities, you'd have to think twice about prescribing a JAK inhibitor, right? Somebody with a history of deep vein thrombosis (DVT) or with known cardiovascular disease that frequently happens in psoriatic arthritis probably should not be on a JAK inhibitor unless we had no other choice. If we had to do that, then I would definitely tighten the monitoring and the management of the additional risk factors. Somebody who may be a cancer survivor, obviously we wouldn't challenge with that mechanism of action, and we have other options which I would prioritize first.

Husni: Those are really interesting points. The initial enthusiasm was that this was oral, and there was some mindset that oral is always safer than injections. At least that's how some of my patients have been looking at this. The excitement at the beginning was the method of taking this and allowing more freedom for these patients. But then the labeling change really gave us pause to say, "Okay, maybe there are subsets that should avoid JAK inhibitors." We also saw such great efficacy, as I'm sure you did in RA. I don't think I was ready to let it go completely. But in my practice now, I probably reserve it for the younger age group, and in the older than 50-55 age group, I tend not to use the JAK inhibitors as freely as I probably did before some of these safety concerns. This past American College of Rheumatology (ACR) meeting had some really interesting new data that were really trying to quantify this risk rather than just saying risk/no risk. So, I think there's more to come. I don't think I'm ready to give up, but I have taken a pause, like you said, in these certain, more vulnerable groups. But I do think having an oral option that does work for the joints is really exciting because that's sometimes where I find some of the newer mechanisms fall in the joint space, and I am looking for something.

Orbai: We don't know everything about these drugs. For example, I'll tell you about a case of a 30-year-old man with psoriatic arthritis. He had comorbid irritable bowel disease (IBD) and he was bed-bound because of arthritis of the hips, and in between infections and his flares, there was no question about hip replacement. I completely ran out of medications in his case, and then we decided: Well, you are on DVT prophylaxis because you're pretty much bedbound let's try a JAK inhibitor. And that was what basically got him out of bed. And now he's exercising. Things are not perfect, but we have MRIs that have shown that his synovitis in his hips improved. So there's definitely a nuance in how people respond to these therapies and what's driving the disease at target tissue level. As long as we learn how to use these drugs and subset our patients, then we can manage the risks. The problem is when we have to go blindly with recommending first-line, second-line, third-line the one-size-fits-all approach won't work. And that's what our problem is because we try to have a pattern that will suit everyone, and that's just not real life.

Husni: It's not just the science, but it's the art of medicine, right? Even though the science tells us this is all approved for psoriatic arthritis and efficacious, we know that it's still the art of delivering these meds in the right patients at the right time.

Last but not least, I do have to talk about the IL-23 inhibitors because they obviously have been around in the psoriasis space, and they've been very comfortable with them. We now have the first IL-23 approved, guselkumab, for psoriatic arthritis. I just recently heard of risankizumab being approved for psoriatic arthritis. It is exciting that data are coming out with the joints. I'd love to hear your take on whether you've been using a lot of IL-23 inhibitors and when to use them in patients with psoriatic arthritis.

Orbai: I have been and it's so exciting to now have two because insurance coverages are so different. Having two choices allows us to cover more patients if these drugs are needed. IL-23s are very convenient in terms of dosing. It's very attractive to have a loading dose 4 weeks apart and then maintenance treatment with an injection that patients get every 8 or every 12 weeks. So great dosing flexibility. I'm trying to start them early on. Maybe I just diagnosed a patient with psoriatic arthritis. Maybe we just started methotrexate and we're weighing whether we go up on the methotrexate or whether we start something else. When patients are in the moderate, low disease activity level after my first intervention, adding an IL-23 inhibitor to their baseline methotrexate, for example, makes me less worried for risk for infection. This could be an easy add-on that I'm trying to implement earlier on in clinic, and I've had good results with this strategy and patients like the convenience of this injection. Not to mention that some patients come back and tell me, "Doctor, the next day or 2 days after this injection, my skin stopped itching." It's nice to have an initial effect which gives the patients optimism that the rest of the goals will be achieved. So it's very exciting to have these.

Husni: I couldn't agree more that in addition to getting excited about new classes, we have some unmet needs to learn how to really get better at giving this to the right patient at the right time. I always look forward to seeing you at our meetings, and I'm sorry that we haven't been able to see each other in person, but it's really nice to have you on this podcast. I would love to ask you the same question that I ask everybody who joins me. Are you up for that? If you were cooking in your kitchen, what are the first three ingredients for a successful treatment for patients with psoriatic arthritis?

Orbai: My first is aligning with the patient's goals. Our patients walk into our office. They need help with concerns. They are concerned that this is never going to go away. That they are never going to be able to get their real life back. Or maybe they are concerned to go on a drug that may have all these serious side effects trying to assess what's bothering them the most. What's their most important goal and fear it's very important. And then once we're aligned, the rest of the ingredients: having the specialty center, which allows me to consult with other specialists like dermatologists, colleagues in cardiology, colleagues in the Inflammatory Bowel Disease Center, which are common conditions and comorbidities that our patients come with. Having that framework of a specialized center is very helpful because I can lean on my colleagues with cases that are more complicated. The third ingredient is making sure that we have the discussion with the patient that this is a long journey that we're embarking on: It's going to involve monitoring and assessing whether we are at treatment target, and it's a team approach. We will always adjust the plan and are working together in getting them where they want to be.

Husni: Well, thanks to Ana-Maria, those are really great pearls of wisdom. It was really a joy to have you. Thank you for taking time out to talk with us.

Orbai: Thank you. My pleasure.

2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis

EULAR Recommendations for the Management of Psoriatic Arthritis With Pharmacological Therapies: 2019 Update

Treatment Guidelines in Psoriatic Arthritis

Bimekizumab in Patients with Active Psoriatic Arthritis: Results From a 48-Week, Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Phase 2b Trial

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Episode 6: Emerging and Novel Therapeutics in the Management of PsA - Medscape