James Song, MD

Topicals are the mainstay of treatment for patients with plaque psoriasis (PsO) of any disease severity.

 Since 1997, corticosteroids, retinoids, and vitamin D analogues have been the only active ingredients used in topical therapies for PsO; new formulations introduced since then have featured changes in the vehicle components or in combinations of active ingredients. Many of these formulations have limitations on duration of use and body areas on which they can be applied due to the potential for certain adverse effects (AEs). Patients may need to use multiple different topical agents at a time, which increases the likelihood of medication misuse and nonadherence. The 2022 approvals of the tapinarof cream, 1% (VTAMA®; Dermavant Sciences) (an aryl hydrocarbon receptor agonist) and roflumilast cream, 0.3% (Zoryve®; Arcutis Biotherapeutics), (a phosphodiesterase-4 [PDE4] inhibitor) for treatment of plaque PsO has provided 2 new options for safe, effective, and well-tolerated steroid-free topical therapies with the potential to simplify management for patients.

As an aryl hydrocarbon receptor agonist, tapinarof uses a novel mechanism of action to downregulate expression of T helper type 17 cytokines that drive inflammation in PsO, normalize skin barrier function, and increase antioxidant activity.

 In the pivotal phase 3 PSOARING 1 (NCT03956355) and PSOARING 2 (NCT03983980) trials, researchers found that a Physician’s Global Assessment (PGA) score of 0 or 1 with a 2-grade reduction was achieved by a considerably greater proportion of groups given once-daily tapinarof compared with the respective vehicle groups at 12 weeks (PSOARING 1: 35.4% vs 6.0%; adjusted difference, 29.4 percentage points; relative rate, 5.8; 95% CI, 2.9-11.6; 

 < .001; PSOARING 2: 40.2% vs 6.3%; adjusted difference, 33.9 percentage points; relative rate, 6.1; 95% CI, 3.3-11.4; 

 Among 312 patients who achieved PGA 0 at least once during the vehicle-controlled and/or the open label extension period, the median time to relapse (defined as PGA 2 or greater) was an unprecedented 4 months. Additionally, patients treated with tapinarof, 1%, cream who had a Peak Pruritus Numerical Rating Scale (PP-NRS) score of at least 4 points at baseline experienced at least a 4-point reduction as early as 2 weeks, which continued to increase to 60.7% and 56.9% by 12 weeks, compared to just 43.2% and 29.6% of patients in the vehicle groups, demonstrating rapid and robust itch reduction.

In the 40-week, open-label safety study (PSOARING 3), participants continued the tapinarof cream until they had complete skin clearance, after which the patients held application of the cream. The duration to symptom recurrence was measured, and a durable remittive effect was observed. On average, the median remittive duration was approximately 4 months, and some remained symptom-free for up to 8 to 9 months. In addition, the trial results showed a durable response out to 52 weeks without evidence of tachyphylaxis.

Overall, tapinarof demonstrated good local tolerability. In the PSOARING 1 and PSOARING 2 trials, respectively, contact dermatitis was experienced by 5% and 5.8% of the patients who received tapinarof vs 0.6% and no patients who received the vehicle; one of these cases in PSOARING 2 was a severe adverse event. Folliculitis was reported in 23.5% and 17.8% in the tapinarof-treated groups vs 1.2% and 0.6% in the vehicle groups. Most cases of folliculitis were mild to moderate with only 1 grade 3 event that was reported during the PSOARING 1 trial; therapy was discontinued due to folliculitis in 1.8% and 0.9% of patients.

Folliculitis presentation includes keratotic papules, pustules, and milia and varies among patients; it was generally limited to the site of application. In the authors’ experience, this appears to occur more frequently in hair-bearing areas. Treatments for folliculitis include temporary interruption of tapinarof, antibiotics, urea, retinoids, salicylic acid, or topical corticosteroids; however, many cases resolved even without any treatment. Educating patients about the potential for this AE and how it may be managed is important to ensure patient adherence.

Unlike other available PDE4 inhibitors, roflumilast has 3 major anchoring points that bind to the PDE4 enzyme, which drastically increases the potency (as assessed in vitro) compared with that of other PDE4 inhibitors. In the phase 3 DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389) trials, considerably greater proportions of patients given roflumilast achieved the primary end point of Investigator’s Global Assessment (IGA) scale (clear or almost clear status and at least a 2-grade improvement from baseline) at 8 weeks compared to those given the vehicle (DERMIS-1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3-46.9]; DERMIS-2: 37.5% vs 6.9%; difference, 28.8% [95% CI, 20.8-36.9]).

 Additionally, significant improvements in IGA success with roflumilast were observed as early as 4 weeks after start of treatment (DERMIS-1: 20.6% vs 2.3%; difference, 19.3% [95% CI, 13.5-25.1]; 

 < .001; DERMIS-2: 19.1% vs 5.3%; difference, 13.5% [95% CI, 7.2-19.9]; 

Additional findings from the DERMIS-1 and -2 trials showed that roflumilast was also beneficial for patients with intertriginous psoriasis. Compared with use of the vehicle treatment, roflumilast treatment significantly improved intertriginous IGA scores at 6 weeks among patients having an intertriginous IGA score of 2 or more at baseline (DERMIS-1: 56.6% vs 22.2%; difference, 41.0% [95% CI, 20.1-61.8]; 

 = .005; DERMIS-2: 57.8% vs 13.8%; difference, 40.5% [95% CI, 18.7-62.2]; 

 = .004), leading to the inclusion of intertriginous psoriasis in the US prescribing label.

Regarding safety, nonsteroidal options have traditionally been associated with tolerability issues. Findings from the DERMIS-1 and -2 trials indicated that application site pain was infrequent, and nearly 99% of patients reported no signs of irritation at 4 and 8 weeks.

 Additionally, the rates of diarrhea and headache, which are commonly associated with oral PDE4 inhibitors, were low (diarrhea, 2.8%-3.5%; headache, 1.0%-3.8%) and mild or moderate in severity; no events involving diarrhea required interruption or discontinuation of treatment.

Given the difficult of treating intertriginous PsO, a topical nonsteroidal option that is effective, safe, and well tolerated when used in these areas is particularly valuable. The ability to use roflumilast, 0.3%, cream on multiple areas of the body, including difficult-to-treat areas like the elbows and sensitive areas like the skin folds, can simplify treatment options for appropriate patients.

Roflumilast has a trademarked drug delivery formulation (HydroARQ Technology™) that does not contain propylene glycol, a potential irritant and allergen, and includes a proprietary hydrophilic emulsifier (Crodafos™ CES) found in many other popular cosmeceuticals, resulting in an elegant cream that is well tolerated and compatible with most other skin care products.

 Educating patients about the formulation’s novel mechanism of action and the well-tolerated vehicle may provide reassurance in patients who have had a negative experience with previous PDE4 inhibitors or topical agents.

Use of roflumilast in a foam vehicle has also been studied for scalp and body PsO. In a phase 2b study (NCT04128007), use of this formulation yielded an achievement of scalp-IGA clear or almost clear and a 2-grade or more improvement from baseline to week 8 in 59.1% of patients vs 11.4% of those given vehicle, with significant effects observed as early as week 2.5 Roflumilast foam was also well tolerated; there was no evidence of irritation in 96% or more of patients based on investigator-rated tolerability and mild or no sensation in 94% or more on patient-rated tolerability.

 Due to the anionic nature of the Crodafos CES emulsifying wax, roflumilast foam is repulsed by the natural negative charge of the hair, allowing it to selectively target the scalp skin while avoiding the hair shaft. This is particularly advantageous for patients with tightly coiled hair who may be more susceptible to hair shaft breakage from harsh ingredients.

Incorporating Novel Topical Agents Into Clinical Practice

While topical corticosteroids will continue to be an important option in our topical armamentarium, novel nonsteroidal topicals such as tapinarof and roflumilast can address some of the limitations associated with topical corticosteroids. Furthermore, these agents could simplify the treatment regimen because of both their once-daily application versus the twice-daily frequency required by many other topical agents and their effectiveness, safety, and tolerability across a wide range of body areas. No direct comparative studies have been conducted between tapinarof or roflumilast, yet each of these agents has unique characteristics that should be considered when choosing treatment for a given patient.

Both of the pivotal studies were conducted as monotherapy, yet the product label allows for tapinarof and roflumilast to be used together with other therapeutic agents. Prescribing a topical corticosteroid in addition to tapinarof or roflumilast may benefit patients who want a more rapid response. Patients on a systemic treatment with residual disease may also benefit from adding tapinarof or roflumilast. Educating patients on the mechanism of action and setting specific expectations on the timeline for a therapeutic response is particularly important to improve treatment adherence.

Faculty presenters: Eingun James Song, MD, FAAD; and Kimberly Gutowsy Baker, MSN, FNP-C

. This article was reviewed, edited, and approved by Dr Song, Ms Gutowsy Baker, and Dr Stein Gold.

Lebwohl MG, Stein Gold L, Strober B, et al. Phase 3 trials of tapinarof cream for plaque psoriasis. 

. 2021;385(24):2219-2229. doi:10.1056/NEJMoa2103629

FDA approves Dermavant’s VTAMA (tapinarof) cream, 1% for the treatment of plaque psoriasis in adults: first topical novel chemical entity launched for psoriasis in the U.S. in 25 years. Press release. 

. Updated May 24, 2022. Accessed December 14, 2023. https://www.dermavant.com/u-s-fda-approves-our-novel-topical-treatment-for-adults-with-plaque-psoriasis/

FDA approves Arcutis’ ZORYVE (roflumilast) cream 0.3% for the treatment of plaque psoriasis in individuals age 12 and older. Press release. Arcutis Biotherapeutics. Updated July 29, 2022. Accessed December 14, 2023. https://www.arcutis.com/fda-approves-arcutis-zoryve-roflumilast-cream-0-3-for-the-treatment-of-plaque-psoriasis-in-individuals-age-12-and-older/

Lebwohl MG, Kircik LH, Moore AY, et al. Effect of roflumilast cream vs vehicle cream on chronic plaque psoriasis: the DERMIS-1 and DERMIS-2 randomized clinical trials. 

. 2022;328(11):1073-1084. doi:10.1001/jama.2022.15632

Strober B, Stein Gold L, Bissonnette R, et al. One-year safety and efficacy of tapinarof cream for the treatment of plaque psoriasis: Results from the PSOARING 3 trial. 

. 2022;87(4):800-806. doi:10.1016/j.jaad.2022.06.1171

Kircik LH, Alonso-Llamazares J, Bhatia N, et al. Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study. 

. 2023;189(4):392-399. doi:10.1093/bjd/ljad182

Articles

This publication was developed independently by MJH Life Sciences Global Medical Affairs. Support for the thought leaders meeting and the publication was provided by Arcutis Biotherapeutics, Inc; The Bristol Myers Squibb Company; Janssen Global Services, LLC; and UCB, Inc.

New Topical Agents for Treatment of Plaque Psoriasis

Dermatologists end their discussion on seborrheic dermatitis (SD), highlighting key takeaways for patients and clinicians on managing this condition.

Beyond Skin Deep: Validating and Transforming SD Patient Care

 As we kind of wrap things back around, we’ve all been in practice for a good amount of time. I think we all have kind of a unique perspective on treating patients with seborrheic dermatitis. I’m just wondering, based on the information that you’ve seen, based on your own clinical practice and any clinical trials, if you could think about some kind of a pearl that you would give to our viewers to take home, maybe to make us all a little bit better in our prescribing or our understanding the needs of a seborrheic dermatitis patient. Adelaide, I’m going to start with you, talking about children, is [there] some special way to communicate or [do] you know some special kernel of truth that you’ve learned in treating a seborrheic dermatitis pediatric patient?

 Well, I think one of the first things I do is I reassure them that it is a treatable problem and that we have tools that will be helpful. And we also have on the horizon some medicines which I’m always proud to say that I’ve had a small role in bringing forward hopefully to the market, and they’ll be coming soon, and I’ll update them as we go along. I think addressing it front and center as a medical problem for which we have treatments and hopefully, soon, better treatments is reassuring. The other thing I say is we take this seriously. I’ve had too many patients come in and say [that] the doctor barely looked then they left the room. “I got a prescription, but then what do I do?” They don’t feel that they’re really feeling validated, so [as] I do often with many disease states I say [that] we take this seriously, and they tell me how grateful they are to hear somebody say that.

 Adelaide, I think I’m taking that home. I want to tell my patients from now, “I take this very, very seriously,” because I think I want to be heard as a patient. I want you to hear what I’m saying and understand that this is important to me even if it doesn’t look like it’s so terrible; I want I want my physician to hear me and understand what I’m saying. James, thoughts on anything that you can give us to take home?

 Just to validate the patient’s concerns and the impact that it has on her life. [Telling them,] “Hey, it’s OK for you to feel this way about your condition. It’s not too trivial, and [I] take it very seriously.” I also thinking establishing that this is a condition that we’re going to be able to treat. It’s not a cure, but we’re going to treat this. We have really good treatments now on the horizon that could really help you get to the place you want to be.

 I think it’s important not to make judgments based on how their seborrheic dermatitis may appear. It’s important to ask patients about their symptoms. In particular, I really focus on asking about their itch. I’ve been surprised so many times. And I think seborrheic dermatitis is just one of those diseases where itch can be a significant burden. You should ask them about it. And now we have the emergence of [a] novel therapeutic that can reduce itch so quickly.

 It’s so interesting because I ask all of my atopic dermatitis patients, talk to me about your itch. That’s so easy because it’s so quick, and I can write it down. I don’t have to do a whole EASI [Eczema Area and Severity Index] score. I can ask them about their itch, do an overall IGA, or investigator’s global assessment. I’ve learned that itch is very important for my psoriasis patients. So now I try to ask my patients [about it]; not [that] everybody itches, but a significant number of psoriasis patients do itch. But I haven’t always asked my seborrheic dermatitis patients about their itching. I think that we could all kind of take that back, and maybe that will make us even better in terms of understanding their burden and being able to monitor it a little bit closer.

 I think all of you said it best, but I would take it a step further and just make them unravel it and remind them of the itch, the dryness, the epidermal changes of scale, the redness, and then bring it back to why are we treating with all these different components of cleansing, moisturizing, and the active ingredient. But also make them think about the marathon and not the sprint, not just making [it] go away quickly, but making things stay away and the safety of giving them things that will do that.

 I think these are all such critical points. What I’m hearing from all of you, who are some of the best clinicians out there, is validating that they have a real medical condition and that they deserve appropriate therapy, that we hear them, we have new options that are available, we can help to simplify the treatment regimen, we can give them something that’s safe, effective, [and] well tolerated, and we can help them in this journey. My goal always is to make them not think about their skin. If they want to think about it in a good way, that’s great, if they’re happy with their skin, that’s great. I want you to live your life and your skin goes with you, but your skin should not be the center of how you live your life, trying to hide the flake, trying to hide the redness, trying to not scratch. I think this is really, really critical. I’ve learned a lot from my colleagues and from talking to each one of you. I think we have some really interesting information. I want to thank each of you for participating today, I’d like to thank the audience for joining us. I hope that you’ve all been able to take home some kernels of truth, and I’d like to thank you all for watching this HCPLive 

Transcript was AI-generated and edited for clarity. 

Videos

Experts discuss the profound impact of seborrheic dermatitis on a patients' well-being, examining the common misconceptions and diagnostic delays.

Silently Struggling: Discussing the Unseen Burdens of SD

 I think what we’re understanding is, this is a condition that is highly prevalent. It is symptomatic, it’s itchy, it can be painful. It’s emotionally devastating because people are judged. And we wonder if our patients are paranoid because they say, I’m not getting the promotion that I want. I was not picked to be the one to present. But the truth is, we’ve seen studies where people are being judged based on their skin conditions. And you mentioned earlier this Harris study. This did involve a lot of seborrheic dermatitis patients. Do these patients know that they have a skin disease, or do they think that they just have a little dandruff and that this is not something that deserves medical treatment?

 Great question, Linda. I think one of the challenges is that there’s very little out there on education for seborrheic dermatitis. So many patients don’t actually realize this is a medical condition that could be potentially treated. They look it up online, to Neal’s point, they’re like, “Is this psoriasis? Is this eczema?” And they realize that seborrheic dermatitis can actually affect areas outside of the scalp. A lot of these patients, they do feel embarrassed, but they also feel like sometimes maybe it’s not serious enough to bring up to a health care provider, even though that Harris poll data showed it has such a profound impact on quality of life. So it’s a tough situation to be in.

 And I think as dermatologists, we don’t necessarily understand the journey that these patients have gone through. They ask dermatologists, well, how long do you think it takes for the diagnosis to be made? And they estimate maybe a year and a half or so. And then, as you mentioned, you ask the patients, and they say it takes between 3 and 4 years to make that diagnosis. In the meantime, these people are walking around without the care that they need. I think we really [owe] it to our patients to ask them a little bit more about their journey and what they’re going through.

 I think part of that equation, too, is the perception. Again, we talked before about [how] they just think it’s dry skin. They think it’s bad hygiene. They blow it off to things that they can correct at home. But I think the other population that deserves that, again, we mentioned before about the neurological patients, the HIV and the AIDS patients, they don’t realize that’s a significant part of their disease. And I don’t think they’re getting the treatment that they probably should be getting because I don’t think it’s identified as serious enough.

 Yes, many patients think that it’s a hygiene problem. I’ve heard parents say about the children, we just can’t get them to wash his hair enough or we can’t get them to use the shampoo that I put there for them. And so there are a lot of misconceptions here. And I think also some patients feel like they should be able to go to their local pharmacy and treat themselves. The failure of recognition of its medical condition or that a dermatologist can be so impactful in getting them better, it’s just not part of the everyday regimen that we see. So our outreach has to be better.

 I agree. I have seen so many teenage patients who come in. When you have seborrheic dermatitis, no matter what you do, I think your hair looks dirty because it’s flaky. You ask patients about hairstyles, and that impacts both men and women. I have one patient who’s actually grown his beard and his hair long and he said, I will kind of shave and trim it up once I don’t have this problem because by wearing the hair really long and keeping the beard, it covers a lot of the redness, the scaling and everything else. It’s embarrassing.

 Well, you wonder too how many physicians outside of dermatology are just also sending that message to them, saying, “Well, that’s just dry skin. It’ll go away. Shower once a day, shower twice a day.” So some of it’s not just on the dermatologist and the patient. I mean, there’s probably some disconnect somewhere where people aren’t getting treated.

 And I think education is so important, because unfortunately, if you shower 2 or 3 times a day, you’re going to end up having a worse problem. You’re not going to make the seborrheic dermatitis any better. It’s going to be really, really a significant problem. So I think what we’ve identified here is the fact that this is a major problem. I tell people, I could walk out into the waiting room today and find people with seborrheic dermatitis. You are not alone. It’s so common. And, unfortunately, I think this is something that our patients cannot necessarily handle on their own. For those with the most mild [cases], I think it’s appropriate, certainly, to try an over-the-counter product, try a medicated shampoo, see how it does. But I think what we’ve learned from the polls and our patients and actually doing these trials is that this is very prevalent. We’re not diagnosing it when it’s there in front of us, necessarily, if we’re not looking for it and the patient’s not complaining about it. And the patient doesn’t necessarily think about telling us about it. So there’s a lot going on. I’m glad we have a new option. It sounds like we don’t have a whole lot more on the horizon at this point, but fortunately we do have something that is safe and effective.

Transcript was AI-generated and edited for clarity.

Experts discuss the profound impact of seborrheic dermatitis on a patients' well-being, examining the common misconceptions, diagnostic delays, and societal judgments that hinder effective management and necessitate enhanced clinical outreach and patient education.

Dermatologists discuss the realm of emerging therapies for seborrheic dermatitis (SD), emphasizing the importance of breakthrough and failed trials.

Emerging Therapies in Seborrheic Dermatitis

 James, maybe you can talk to us a little bit. We talked about what’s new, and it’s exciting, but is this now the front door to a whole lot of other potential therapeutic options that are being investigated for seborrheic dermatitis?

 Yeah, it’s always really fun when we see just how much or how little we know about a disease or the pathogenesis, and then how they respond to a certain medication, [it] does give us some insights as to what’s actually causing it, right? So, it’s translational research, I guess you could call it. I think the fact that roflumilast foam works so well for seborrheic dermatitis tells you that PDE4 is absolutely a validated target as well as [able to improve] the skin barrier. We do have another PDE4, it’s a novel PDE4 topical that’s being studied, as well as a topical JAK [Janus kinase] inhibitor; this is more of an investigator-initiated trial. But what’s also interesting is that PDT, a photodynamic therapy study that’s being done for seborrheic dermatitis, and that comes off the heels of some positive data we saw with narrowband UVB and red light. I also think it’s worth mentioning negative studies, studies that didn’t pan out. There is an antimicrobial peptide that was used because we did see higher levels of [

] in some patients with seborrheic dermatitis, so it makes sense; let’s use an antimicrobial peptide that has antibacterial, antifungal effect. When they did a proof-of-concept study against ketoconazole and placebo, it just didn’t look all that much better than the placebo, so I think for now we can say that’s probably not the right approach.

 You bring up a really, really interesting point. We all run clinical trials, and I think that the dermatology community kind of takes it as a given, here’s a clinical trial, we run different studies, they meet their end point, we see a lovely delta of the active versus the vehicle, it’s highly statistically significant, yet as you mentioned, these trials don’t always pan out. You can have the best idea, as in this case, this last treatment, the best idea, it makes sense, it’s scientifically rigorous, it, we’re studying the right population, yet it might do well initially, and then when we bring it to those phase 3 clinical trials, it doesn’t work. And so, you have to realize this matters.

 And what it does is it helps us also understand what is driving pathogenesis. If you’re using a microbial modulating agent, and it’s not working, and then we know when you target the inflammation of these cytokines, it works, it kind of tells us what’s primary. So in seborrheic dermatitis, it’s not the microbial alterations, it’s the inflammation that’s primary.

 But you know, we could try to match the mechanisms of the drug to the disease, but if it’s not in the right vehicle, or if the trial end points are flawed, or if the study population don’t meet the criteria, but all of these other variables go back to the entire design of what made the trial not pass.

 And that’s so important, because when we talk about a topical, was the drug absorbed appropriately into the vehicle, does the drug penetrate into the skin in the vehicle where it’s supplied? There are so many different factors that go into it. And then again, tolerability. One should say it’s dissolving great and it gets into the skin, but can I tolerate it? Is it causing a contact dermatitis? Is it causing a problem? Is it causing my skin to dry out? Is it causing my hair to break? These are all those little pieces of the puzzle that kind of go together.

Dermatologists discuss the realm of emerging therapies for seborrheic dermatitis (SD), emphasizing the importance of both breakthrough and failed trials, while highlighting the need for scientific rigor and patient-reported outcomes.