Topical Management of Plaque Psoriasis—A Review and Case Series Discussion with Focus on Aryl Hydrocarbon Receptor Modulation

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J Clin Aesthet Dermatol. 2023;16(9 Suppl 1):S3-S12

by Matthew Bruno, PA-C, Bruce Strober, MD, PhD, and James Q. Del Rosso, DO

Supported by—Dermavant Sciences Inc., Long Beach, California

Jointly sponsored by—Matrix Medical Communications, West Chester, Pennsylvania;
Ciné-Med, Woodbury, Connecticut

Instructions for CME credit can be found after the reference section of this article

ABSTRACT: While corticosteroids and a limited number of nonsteroidal agents have formed the basis for United States Food and Drug Administration (FDA)-approved topical treatments of plaque psoriasis, there remains a need for efficacious nonsteroidal topical therapies in patients with psoriasis who cannot tolerate, do not respond well to, or wish to avoid topical corticosteroid therapy. Aryl hydrocarbon receptor (AhR) modulation has been shown to be an effective mechanism of action in the topical treatment of psoriasis. Currently there is only one FDA-approved, nonsteroidal, topical AhR modulating agent for the treatment of psoriasis. This educational activity seeks to broaden the treatment knowledge of the practicing dermatology community and inform them on the use of topical AhR modulating therapy as an addition to the advancing treatment armamentarium for patients with psoriasis.

Introduction

Psoriasis is a common, chronic immune-mediated disease that is estimated to affect three percent of adults in the United States.¹ There are multiple subtypes of psoriasis, of which plaque psoriasis is the most common.²

Plaque psoriasis manifests with well-demarcated, erythematous, scaly, pruritic lesions. Bothersome itch and cosmetic disfigurement associated with visible plaques contribute to significant psychosocial burdens and quality of life impairment for patients with psoriasis.^3,4

The pathogenesis of psoriasis involves T helper (Th)17, Th22, and Tregulatory (Treg) cells, along with dysfunction of the interleukin (IL)-23/IL-17A pathway.^2,5 Various triggers can induce dendritic cells to release proinflammatory cytokines, including IL-23, tumor necrosis factor-alpha (TNF- α), and IL-12. These mediators activate the IL-23 and/or IL-22 pathway leading to differentiation of Th17 and/or Th22 cells and release of cytokines (TNF-α, interferon-γ, IL-17, and IL-22) that induce inflammation and hyperproliferation of keratinocytes. Impaired skin barrier function and oxidative stress are also thought to play a role in the development of inflammation in psoriasis.

A broadened understanding of the pathogenesis of psoriasis has led to significant advances in its treatment, including the development of several targeted systemic biologic and small molecule agents. Most patients with plaque psoriasis, however, have mild, localized disease and are candidates for topical therapy.^6,7 Topical medications also have an important role in management of more severe plaque psoriasis because even the more effective biologics do not usually result in complete clearance, especially indefinitely; as a result, many of these patients exhibit some persistent plaques that are often treated with adjunctive topical therapy ⁸

Conventional topical therapies. Steroidal therapies. Corticosteroids have been a mainstay of topical treatment for plaque psoriasis for over five decades, and availability in a variety of potencies and vehicle formulations enables use of corticosteroids to treat plaques of varying severity and at different anatomic locations. However, the potential for local adverse effects, including skin atrophy, striae, folliculitis, telangiectasia, and purpura, limit the extent of body surface area (BSA), duration, and site of use of topical corticosteroids, especially middle-to higher potency agents.⁶

Nonsteroidal therapies. The most commonly used nonsteroidal topical alternatives in the treatment of psoriasis include vitamin D analogues, which are available as single formulations or fixed combinations with a corticosteroid; tazarotene as a monotherapy or in combination with a corticosteroid; and topical calcineurin inhibitors ([TCIs] pimecrolimus and tacrolimus, used off-label).Topical crisaborole, a phoshodiesterase-4 (PDE4) inhibitor (used off-label) has also been investigated in psoriasis.⁹ All these medications do exhibit drawbacks that can limit their utility. For example, vitamin D analogues can be slow in their onset of effect as monotherapies, are less effective than corticosteroids, and can cause local skin tolerability reactions, including burning, pruritus, peeling, dryness, and erythema, on lesional and perilesional skin in up to 35 percent of users.⁶ Irritating adverse effects are also an issue with topical tazarotene, especially with certain formulations and at higher concentrations; irritating adverse effects may also occur with TCIs.⁶ In addition, the boxed warning in the labeling for TCIs that cautions about the potential for malignancies with long-term intermittent use may make some patients and/or caregivers fearful about using those products, despite receiving clinician reassurance that multiple studies have found little-to-no evidence for such risks.^10,11

Newer additions to topical therapy. Side effects of the conventional topical therapies, complicated regimens, inadequate efficacies, and dislike of the cosmetic properties of some products contribute to the problem of therapeutic nonadherence that compromises treatment success. Thus, a need has remained for safe, effective, and well-tolerated nonsteroidal topical medications for patients with psoriasis who do not respond well to, do not tolerate, or wish to avoid existing options. Newer topical nonsteroidal therapies may replace these existing options as being logical initial choices in many cases. In 2022, the United States (US) Food and Drug Administration (FDA) approved two new nonsteroidal topical therapies for the treatment of plaque psoriasis—tapinarof cream 1% and roflumilast cream 0.3%.

Tapinarof is a first-in-class aryl hydrocarbon receptor (AhR) modulating agent that is indicated for use in adults, is applied once daily, and carries no warnings, precautions, or contraindications and no restrictions regarding severity of plaque psoriasis, anatomic site, or duration of use.¹² Roflumilast is a selective PDE-4 inhibitor indicated for use in patients aged 12 years or older that is also recommended to be applied once daily, carries no warnings or precautions, and also has no restrictions regarding severity of plaque psoriasis, anatomic site, or duration of use.¹³ Although roflumilast is the first topical PDE-4 inhibitor approved for the treatment of plaque psoriasis, it is not the first PDE-4 inhibitor approved for dermatologic use. Oral apremilast was approved for psoriatic arthritis and moderate-to-severe plaque psoriasis in 2014, for oral ulcers of Behcet’s disease in 2019, and for all severity levels (mild-to-severe) of plaque psoriasis in 2021; crisaborole ointment was first approved for treatment of atopic dermatitis in 2016.

This educational activity seeks to broaden the treatment knowledge of the practicing dermatology community and inform them on the use of topical AhR modulating therapy with tapinarof as an addition to the expanding treatment armamentarium for plaque psoriasis.

Topical AhR modulating therapy in the treatment of plaque psoriasis

Role of the AhR in skin health and disease. The AhR is a cytoplasmic transcription factor activated by a variety of exogenous ligands.¹⁴ It is found in immune cells and various tissues throughout the body, including in keratinocytes, sebocytes, fibroblasts, melanocytes, endothelial cells, Langerhans cells, and lymphocytes in the skin.^14,15 Interest in the AhR as a therapeutic target for managing psoriasis derives from knowledge that AhR signaling plays an important role in maintaining skin homeostasis via effects on T-helper 17 (Th17) and Th22 cell differentiation, T regulatory (Treg) cells, production of cytokines (IL-10, IL-17, IL-21, IL-22), expression of skin barrier protein genes, and antioxidant effects.^14,16

Topical tapinarof. Mechanisms of action. Tapinarof is a naturally derived polyphenol AhR ligand that is thought to improve psoriasis through activities involving immune modulation, normalization of the skin barrier, and reduction of oxidative stress.^14,16 Specifically, results of in-vitro studies show that tapinarof decreased production of proinflammatory Th17 cytokines, increased expression of skin barrier protein genes (filaggrin and loricrin), and reduced the activity of tissue-resident memory T cells are thought to contribute to emergence of recurrent psoriasis (Figure 1).^14,17 Tapinarof has also demonstrated antioxidant activity that appears to be mediated in part by activation of the AhR nuclear factor erythroid 2-related factor 2 pathway and also via direct antioxidant activity.^14,16

Tapinarof psoriasis clinical trials. A 12-week, Phase II, randomized, double-blind, vehicle-controlled, dose-finding study investigating different concentrations and application frequencies of tapinarof cream for the treatment of plaque psoriasis enrolled 227 adults with 1- to 15-percent BSA involvement (excluding the scalp) and a Physicians Global Assessment (PGA) score of 2 or higher (mild to severe).¹⁸ The primary endpoint analysis showed that the percentage of patients achieving a PGA score of 0 (clear) or 1 (almost clear) at Week 12 with at least a 2-point improvement from baseline PGA was significantly greater in the group using tapinarof cream 1% once daily compared to the two control groups applying vehicle (56% vs. 11% and 5%, respectively). Clinical efficacy appeared to improve modestly with twice-daily application of tapinarof cream 1%, but the once-daily regimen was investigated in the Phase III trials because it was expected to be associated with better patient adherence. In the Phase II study, there were no serious adverse events judged to be related to use of tapinarof. Folliculitis (13%) and contact dermatitis (5%) were the most frequent adverse events in a pooled analysis of all tapinarof treatment groups, with most cases rated as mild or moderate in severity, which did not often lead to discontinuation of treatment.

PSOARING 1 and PSOARING 2, the Phase III pivotal trials investigating tapinarof cream 1%, enrolled a total of 1,025 patients who were randomized 2:1 to treatment with tapinarof or vehicle once daily.¹⁹ Eligible patients were aged 18 to 75 years with a baseline PGA from 2 (mild) to 4 (severe) and affected BSA from 3 to 20 percent (excluding scalp, palms, soles, fingernails, or toenails). At entry, about 80 percent of participants had a PGA of 3 (moderate), and overall mean affected BSA was about 7.8 percent.

The primary endpoint was met in both PSOARING 1 and PSOARING 2 studies: the percentage of patients achieving a PGA score of 0 or 1 at Week 12, with a 2-point or greater improvement from baseline, was significantly higher in the tapinarof groups (35.4% and 40.2%, respectively) compared to the vehicle groups (6.0% and 6.3%, respectively) (P ≤0.001 for both comparisons). Tapinarof demonstrated superiority, compared to vehicle, by Week 4 in both studies, indicating a rapid onset of therapeutic benefit.

Statistically significant differences (P<0.001) favoring tapinarof versus vehicle were also achieved in secondary efficacy endpoint analyses looking at Psoriasis Area and Severity Index-75 percent (PASI-75) responder rates at Week 12, percentage of patients achieving a PGA score of 0 or 1 at Week 12, and mean change in BSA from baseline to Week 12 (Table 1). In addition, patients using tapinarof benefited from rapid, clinically meaningful, and statistically significant improvement in itch.²⁰ Patient-reported outcomes of quality of life using the Dermatology Life Quality Index (DLQI) questionnaire and symptom severity using the Psoriasis Symptom Diary were consistently better in the tapinarof groups compared to control, although the studies were not designed to analyze statistical significance for these outcomes.¹⁹ A series of post-hoc analyses showed that the efficacy of tapinarof cream 1% was clearly apparent regardless of baseline disease severity or demographic characteristics.^19,21

Tapinarof cream 1% was well-tolerated and had a good safety profile. The most common adverse events in PSOARING 1 and PSOARING 2 that occurred at a rate of two percent or higher in the tapinarof groups compared to the vehicle group were folliculitis (23.5% and 17.8% vs. 1.2% and 0.6%, respectively) and contact dermatitis (5.0% and 5.8% vs. 0% and 0.6%, respectively). Among patients using tapinarof, the only severe adverse event was a Grade 3 folliculitis, and in both trials, rates of discontinuation for folliculitis and contact dermatitis in the tapinarof groups were low (0.9% to 1.8% and 1.5% to 2.0%, respectively). There were no serious adverse events judged to be related to tapinarof. Local tolerability was favorable, including application to areas of sensitive skin, as assessed by patient ratings of burning, stinging, and itching and investigator ratings of irritation, including at sensitive skin sites.

Patients who completed PSOARING 1 and PSOARING 2 were eligible to enroll in PSOARING 3, an open-label, 52-week extension study of tapinarof cream 1%.²² Of 833 patients who were eligible to participate in PSOARING 3, 763 patients (91.6%) enrolled. Patients with a PGA score of 0 stopped treatment and were followed for relapse defined as PGA score of 2 or greater. Patients with a PGA of 1 or greater used tapinarof once daily and stopped treatment if they achieved PGA of 0. In PSOARING 3, 40.9 percent of patients achieved a PGA score of 0 at least once. Follow-up of patients who entered PSOARING 3 with a PGA score of 0 or who achieved complete clearance during the study and then discontinued tapinarof showed the medication had a prolonged remittive effect for a mean total duration of 130 days, defined as the number of days until plaque psoriasis returned from a PGA score of 0 (clear) to a PGA score of 2 (mild).

No new safety issues for tapinarof emerged during the long-term study.²² Rates of folliculitis and contact dermatitis, the severity of these reactions, and the rates for discontinuation related to folliculitis and contact dermatitis were similar to those observed during PSOARING 1 and PSOARING 2. Patient satisfaction with treatment was high, with nearly 86 percent of patients agreeing that they could easily manage their psoriasis with tapinarof.

Tapinarof cream 1% was also found safe and effective for treating patients with extensive plaque psoriasis in a Phase IIa clinical trial.²³ This 28-day maximal use study enrolled 21 patients with a PGA score of at least 3 and affected BSA that ranged from 20.5 to 46.0 percent. Plasma assays showed systemic exposure to tapinarof was minimal and decreased over time, a phenomenon that the investigators postulated might be attributable to treatment-related skin barrier function repair.

Case Discussions

The following cases (from case files of author MB) and expert discussions (authors MB, BS, and JDR) provide “real-world” insights on the use of topical tapinarof cream 1% in the treatment of psoriasis

Case 1—A cancer patient seeking nonsteroidal topical treatment for psoriasis. A 63-year-old man presented with a 30-plus year history of psoriasis involving both knees (Figures 2A and 3B). His affected BSA was two percent and PGA score was 2 (mild). Itch severity rated by the patient with a 11-point Numeric Rating Scale (NRS) was 5 out of 10 (0=no itch,10=unbearable itch). The patient was treated previously with systemic biologics that were discontinued six years ago when he was diagnosed with malignant melanoma with multiple organ metastases. He was undergoing experimental therapy for his cancer with interferon injections every six weeks, and after every injection he would experience a psoriasis flare, usually appearing as plaques on his elbows and knees. At presentation, the patient indicated that he wanted to continue avoiding systemic therapies for psoriasis and preferred avoiding topical corticosteroids.

The patient was prescribed tapinarof cream 1%, applied once daily to affected areas. He was contacted for follow-up by phone after 72 hours and reported no side effects. At a return visit two weeks after starting tapinarof, the patient again reported having no adverse events. Plaque elevation was reduced (Figures 2C and 3D), PGA score was 1 (almost clear), and NRS improved to 4. The patient stopped using tapinarof once he achieved complete clearance, and his psoriasis remained clear for 90 days while he continued to receive his interferon injections.

Case 1 expert panel discussion. Matthew Bruno, PA-C: This gentleman wanted to use a topical nonsteroidal medication for his psoriasis because he was concerned that a systemic medication or an absorbed topical corticosteroid would negatively impact his cancer or its treatment. Tapinarof cream was an appealing option because of data showing that its absorption is negligible in most patients and it lacks systemic adverse effects, but also considering evidence that it can be associated with a prolonged remittive effect.^19,22,23 All patients with psoriasis would like to achieve clearance and a durable remission off therapy, and those outcomes would be especially valued by this patient, considering the burdens from his medical diagnoses and related treatments.

The patient described the response to tapinarof as similar to what he experienced in the past using clobetasol ointment, but he was very happy that the benefit was achieved with a nonsteroidal applied once daily and that its effects persisted when he was off therapy, eliminating his need for return visits for dermatologic care.

Bruce Strober, MD, PhD: I have been using tapinarof in patients such as this whose low BSA involvement makes them candidates for topical therapy, and tapinarof is a particularly good choice for this patient who wanted to avoid corticosteroids. People with cancer are an important subgroup of patients with psoriasis. They may be experiencing stress from their cancer diagnosis, and its treatment can be a trigger for psoriasis flares.²⁴ Having psoriasis as a comorbidity and dealing with its treatment can compound psychological and emotional stress in these patients. I think too often patients with cancer are denied appropriate intervention for psoriasis due to concerns about how the medication might affect their cancer or its treatment. This case is remarkable in showing how tapinarof met this patient’s objectives of avoiding any systemic or topical corticosteroid therapy for his psoriasis and providing a remittive effect. Not only was the patient very happy, but success stories like his can be very emotionally gratifying for us as providers who empathize with our patients’ suffering.

James Q Del Rosso, DO: Dr. Strober, are there medications that have been linked to psoriasis flares or that make psoriasis more refractory to treatment?

Bruce Strober, MD, PhD: Interferons, beta-blockers, lithium, and antimalarials, including hydroxychloroquine, are among the drugs that have been most commonly reported to induce or exacerbate psoriasis.²⁵However, I discount the supposed risk with hydroxychloroquine. Hydroxychloroquine has been used for decades to treat psoriatic arthritis, and psoriasis flares are nonexistent among the patients I have seen using hydroxychloroquine for that purpose.

Case 2—A patient with localized, treatment-refractory plaques. A 37-year-old man (Fitzpatrick Skin Type IV) presented with psoriasis of the left knee that was diagnosed 10 months earlier. Affected BSA was one percent, PGA was 2 (mild), and NRS for itch was 4 out of 10. The patient was especially bothered by the psoriasis because he enjoyed being outdoors and wearing shorts.

He was started on fixed combination calcipotriene/betamethasone dipropionate cream 0.005%/0.064%, but this was discontinued after two weeks when the patient reported no improvement (Figure 3A). He was switched to tapinarof cream 1% once daily. At his return visit four weeks later, the patient reported that he had stopped using tapinarof one week earlier because he was satisfied with the response (Figure 3B). PGA and NRS scores were 0 at follow-up.

Case 2 expert panel discussion. James Q Del Rosso, DO: This case raises a few points. First, it is often stated in older textbooks that itch is not a common feature of psoriasis, but that is not true and it can be very bothersome for some patients.⁴ Second, we know that lack of adherence can underlie treatment failure. So, when patients return for follow-up and say, as this patient did, that their medication is not working, are there specific questions you ask to tease out poor adherence as the reason?

Matthew Bruno, PA-C: If I ask patients to tell me how they used their treatment, I am still challenged to know whether they are answering truthfully. With some exceptions, when patients say that they applied their treatment every day as directed, I generally assume they used it about half as much as they were supposed to. I was somewhat doubtful about this patient’s adherence with his calcipotriene/betamethasone because I expected his psoriasis would have been somewhat improved after 14 days, even if he had used the medication less often than directed.

Another notable facet of this case is that it highlights the real-life situation where patients self-treat, deciding on their own when to stop and when to start using their psoriasis medications. With that in mind, I like that tapinarof is available in a single concentration and can be used on any anatomic site for any duration without restrictions. When prescribing a super potent corticosteroid, we must be concerned about whether the patient is using the medication more frequently than prescribed, for a longer duration than directed, or at a sensitive skin site where it was not intended to be used.

James Q Del Rosso, DO: As a corollary to your comment, because patients have been cautioned so much about the appropriate use of corticosteroids, it is important to educate them about how tapinarof is different. Otherwise they might assume tapinarof carries the same restrictions as the corticosteroids they used in the past.

Bruce Strober, MD, PhD: When I prescribe tapinarof, I always tell patients it is not a steroid, it should be used once a day, and it can be used anywhere on the body and for as long as it is needed. It is very liberating for patients to not have to worry about the safety issues that are associated with corticosteroids.

James Q Del Rosso, DO: Looking at the follow-up images for this patient, there appears to be some darkening of the skin, which I believe might be postinflammatory hyperpigmentation or a friction-induced change. Are there any concerns about pigmentary changes using tapinarof in skin of color patients?

Bruce Strober, MD, PhD: Tapinarof has been used in patients of all skin types without causing any type of dyschromia, but postinflammatory hyperpigmentation can be seen after psoriasis clears when skin of color patients are treated with any medication. Sometimes patients mistake the darkening for persistent disease.

James Q Del Rosso, DO: Fair-skinned patients may have some residual erythema at sites where the psoriatic plaque resolved, and we may be challenged to know if the redness is just post-treatment sequela or a sign of active inflammation requiring ongoing treatment. Because tapinarof has no restrictions on duration of use, we can feel comfortable allowing patients to continue using tapinarof, and we don’t have to be too concerned about determining the cause of the redness.

Case 3—A patient with moderate psoriasis and significant itch. A 69-year-old man presented with a nine-year history of plaque psoriasis involving both elbows (Figure 4A) and his distal lower legs. Affected BSA was 11 percent, PGA score was 3 (moderate), and NRS score for itch was 8 out of 10. Previous treatments included clobetasol ointment 0.05%, calcipotriene 0.005%, fluocinonide 0.1%, halobetasol propionate foam 0.05%, and halobetasol/tazarotene lotion 0.01%/0.045%. The patient had also been treated with tumor necrosis factor-alpha (TNF-α) inhibitors (etanercept and adalimumab) for psoriatic arthritis, but had stopped taking these on his own. When he came back for a visit, it was decided to reinstate biologic therapy. While waiting for lab results and authorization from insurance, the patient was provided with samples and a prescription for tapinarof cream 1%, with instructions to apply it once daily to the psoriasis plaques.

The patient did not return for his scheduled two-week follow-up visit. When contacted a week later, the patient reported that he had been using tapinarof twice daily and had stopped after just two weeks because he was satisfied with the response. Photos taken by the patient of his elbows showed significant clearing after one week with further improvement at Week 2 (Figures 4B and 5C). When he was seen at four weeks, the plaque on the left elbow had resolved and the right elbow showed minor scale and erythema (Figure 4D).

Case 3 expert panel discussion. Matthew Bruno, PA-C: I was impressed by the rapidity of the response in this case because while the elbow plaques were not that severe, they were thick and resistant to multiple previous treatments. The patient was using tapinarof twice daily, which might explain why his plaques cleared faster than I expected. Whereas some patients given a corticosteroid for their psoriasis might use it less often than instructed because they fear the side effects, perhaps this individual applied tapinarof twice daily because he was anxious to achieve clearing and understood that tapinarof had a favorable safety profile. Alternatively, maybe a twice-daily regimen had become habitual for him after using medications that way in the past. Regardless of the explanation, a message of this case is that we may need to reinforce to patients that tapinarof should be used just once daily.

James Q Del Rosso, DO: This patient is representative of the many patients we see whose psoriasis is not cleared completely by systemic therapy. That situation can particularly occur if the patient is being treated for psoriatic arthritis, because for some systemics, the recommended dose for psoriatic arthritis is lower than the dose recommended for plaque psoriasis.

Matthew Bruno, PA-C: Tapinarof gives us a useful adjunct to address persistent plaques in these cases without having to modify the systemic regimen.

Bruce Strober, MD, PhD: Because this patient had psoriatic arthritis with psoriasis affecting 11-percent BSA, I would have started him on an anti-IL-17 or anti-IL-23 agent that would cover both his skin and joint disease. Whether they are comfortable treating psoriatic arthritis themselves or choose to work in a co-management relationship with a rheumatologist, dermatology clinicians need to be sure that patients with psoriatic arthritis receive treatment for their joint disease.

James Q Del Rosso, DO: Psoriatic arthritis should be considered in all patients with psoriasis, and it is important to diagnose psoriatic arthritis early, when patients may be experiencing just joint tenderness or stiffness, rather than waiting until they have developed swollen painful joints. However, patients with psoriasis may think they should only discuss skin issues with their dermatology clinician and thus fail to mention joint complaints. What questions do you ask to screen for psoriatic arthritis?

Bruce Strober, MD, PhD: I ask about swollen or tender joints and a personal or family history of psoriatic arthritis. In addition, I ask about stiffness lasting more than 30 minutes in the morning or after another period of inactivity, heel pain, joint pain causing nighttime awakening, Achilles tendonitis, carpal tunnel issues, golf or tennis elbow, low back pain, neck stiffness, and limited range of motion. My suspicion for psoriatic arthritis is raised if a patient reports two or three of those problems.

James Q Del Rosso, DO: I also look for nail or scalp psoriasis because those manifestations are often associated with psoriatic arthritis.²⁶

Matthew Bruno, PA-C: Thinking that a patient with a swollen toe from dactylitis was misdiagnosed, I scan the medication history for any gout treatments, and I palpate for enthesitis.

Case 4—A patient with severe intertriginous psoriasis. A 55-year-old man presented with plaque psoriasis newly involving both axillae (Figures 5A and B). Eight years earlier, he was diagnosed with plaque psoriasis that developed elsewhere on his body and was controlled with topical corticosteroids prescribed by the patient’s primary care physician. At presentation, this patient’s affected BSA was two percent (1% for each axilla), and his PGA score was 4 (severe), considering his NRS score for itch was 9 out of 10.

The patient had attempted to treat his intertriginous disease with some over-the-counter products, and had used a topical antifungal agent prescribed by his primary care physician without improvement. He was started on tapinarof cream 1% once daily. After two weeks, PGA and NRS scores were both 1 (Figures 5C and D). Treatment in the intertriginous area was well tolerated. The patient reported having no stinging or burning from tapinarof.

Case 4 expert panel discussion. Matthew Bruno, PA-C: This gentleman was the first patient I treated with tapinarof for intertriginous psoriasis, and I was very impressed by the efficacy and lack of side effects. As another consideration, I knew that this patient traveled a lot for work, so I expected that he might not be able to come back to the office soon if he developed a flare. Because tapinarof has no restrictions on application site, area, or duration, I was very comfortable prescribing a 60gm tube to the patient and allowing him to use the medication as needed. I told him he could use tapinarof if the axillary psoriasis recurred and for plaques that developed at other intertriginous sites, including the intergluteal cleft or genital area. He then mentioned that he had used tapinarof successfully to treat some dry scaly areas that had developed behind and inside his ears.

James Q Del Rosso, DO: Patients might not tell us about intertriginous psoriasis if it involves the groin, genital area, or inframammary folds or they may think that the redness is from irritation or something other than psoriasis. Therefore, patients with visible psoriasis should always be asked whether they have redness or a rash anywhere else on the body. Intertriginous psoriasis was effectively treated by tapinarof in its pivotal trials and by roflumilast in its pivotal trials in which the protocol was designed to separately evaluate the response to intertriginous disease.^19,27

Bruce Strober, MD, PhD: Patients with axillary psoriasis may have psoriasis in other intertriginous sites or involving nonintertriginous skin. If the patient is deemed appropriate for topical therapy, one of the newer nonsteroidals, tapinarof or roflumilast, can be an ideal choice because they are convenient once-daily medications that can be used anywhere on the body. That said, I would have also considered treating this patient with a topical calcineurin inhibitor. I think that, generally, topical treatments can be particularly effective for intertriginous disease because intertriginous skin is relatively thin and natural occlusion occurs after topical application, therefore allowing for better drug absorption. I would not use calcipotriene nor do I use it in any situation because it can be very irritating and we have more effective options.

Case 5—A patient with treatment-refractory head and scalp psoriasis. A 79-year-old woman was diagnosed with psoriasis of the scalp, ears, and neck two years prior to presentation. At presentation, her BSA was nine percent, PGA score was 3 (moderate), and NRS for itch was 7 out of 10. Previous treatments prescribed by another clinician included clobetasol scalp solution 0.005% and several systemic medications, including methotrexate, which caused nephrotic injury. She was then switched to tildrakizumab, but did not achieve any improvement in BSA or PGA after 16 weeks. Upon obtaining clearance from the nephrologist, the patient started apremilast 30mg daily, but had only minimal improvement after one year. The patient did not want to be treated with a TNF-α inhibitor, and consideration was given to starting guselkumab. While waiting for authorization from her insurance, she was provided with samples and a prescription for tapinarof cream 1% and began using it once daily.

Baseline and follow-up images from her pre-auricular region and posterior scalp (Figures 6A–F) show significant reduction in plaque elevation after two weeks of treatment. At that time, the patient reported her itch was 60- to 75-percent improved. The plaques continued to resolve with tapinarof treatment, and at Week 4, PGA and NRS scores were 2. Thereafter, the patient traveled out of the country, but she reported that at eight weeks, her scalp was completely clear and she was extremely satisfied with the results, reporting it was the first treatment that had been effective in treating her scalp psoriasis.

Case 5 expert panel discussion. Matthew Bruno, PA-C: Patients were allowed to treat scalp psoriasis in the tapinarof pivotal trials, but scalp disease was not included in assessments of baseline BSA or disease response. This case was interesting for documenting the improvement in scalp disease that had been highly symptomatic and treatment-refractory. The benefit for relieving itch was particularly remarkable to me.

James Q Del Rosso, DO: Improving itch is important for improving quality of life and considering that scratching can worsen psoriasis via a Koebner phenomenon.

Bruce Strober, MD, PhD: Given the scalp involvement and level of severity, I think this patient would be a candidate for systemic treatment. It is impressive that a cream formulation could be used so effectively on hair-bearing sites and even better that it is a nonsteroidal agent. The relief from pruritus might have been the most important outcome for this patient, and even though the psoriasis was not completely cleared, the reduction in scale might have been very meaningful to her because it would have decreased or eliminated any cosmetic concerns she had relating to noticeable flaking in her hair and on her clothes.

James Q Del Rosso, DO: There are no restrictions against using tapinarof to treat scalp psoriasis, and as a once daily treatment, it can be applied at night when it might be less likely to affect the appearance of the hair versus if it had to be applied in the morning too. There are a variety of medications formulated specifically for scalp treatment, but they may contain a lipid for solubilizing the active ingredient, which can make the product somewhat greasy and difficult to wash out. Tapinarof is not a greasy formulation, and none of my patients using it on the scalp have complained about needing anything special for shampooing their hair after using the product. Nevertheless, tapinarof is a cream. Do you have any tips about applying tapinarof to scalp plaques in areas covered by hair?

Matthew Bruno, PA-C: Consistency-wise, tapinarof cream is more like a lotion, which makes it easier to apply to the scalp. If patients are going to treat the scalp, I have them do an application in the office so that they know how much to use, and I instruct them to rub it in well. I try to be sensitive to patients’ cosmetic concerns and preferences for different formulations. This patient was particularly motivated to achieve improvement, and so product aesthetics may have been less of an issue for her. But patients who just have minimal scale and flaking from scalp psoriasis may not be willing to use a product that is greasy and difficult to remove.

Focus on Safety

James Q Del Rosso, DO: The information from all the cases we discussed reinforces the clinical trial results that show tapinarof is safe and well-tolerated. There were very few clinical trial participants who stopped treatment because of an adverse event, and there were essentially no systemic safety signals, even in the long-term extension or maximal use trials.

Folliculitis was the most common adverse event in the clinical trials. What is your experience with folliculitis in patients using tapinarof?

Bruce Strober, MD, PhD: About 1 in 5 patients treated with tapinarof develops folliculitis. I think of this reaction as a nuisance event rather than a safety issue because it is not a serious reaction like hepatic or renal toxicity, and often it resolves while the patient continues using tapinarof. I inform patients about the risk of folliculitis when I prescribe tapinarof. Because they know it might occur and because the folliculitis is usually mild, most patients do not seem bothered if it develops, and they may mention it occurred when I see them for their next visit. Patients will call if the folliculitis is more extensive or severe. Those individuals are asked to come into the office, and depending on what I see, they might be instructed to temporarily stop applying the tapinarof at the site of the folliculitis until the reaction resolves. Generally, the patients I have seen with folliculitis are also responding to their treatment with tapinarof, and if the rash is mild I ask patients if they are okay continuing tapinarof. I recently started a patient on tapinarof monotherapy for psoriasis involving the elbows, knees, and anterior tibial skin. The plaques improved, but a keratosis pilaris-like follicular reaction developed on the knees. The patient was very satisfied with the therapeutic response and thus did not want to interrupt the treatment, and the eruption cleared with ongoing use.

Matthew Bruno, PA-C: Fewer than 10 patients out of the hundreds I have treated with tapinarof for psoriasis developed folliculitis. Most of those patients mentioned the reaction at follow-up and told me that they continued using tapinarof because they were satisfied with their psoriasis improvement and that the “bumps” disappeared after 1 or 2 weeks.

James Q Del Rosso, DO: We know that a variety of topical medications used in dermatology can cause stinging and burning, and sometimes patients discontinue the treatment because of those side effects. Have you had patients using tapinarof complain about stinging or burning?

Bruce Strober, MD, PhD: Rarely, in the clinical trials, there were patients who reported stinging/burning at the application site. In my clinical experience, I have treated one patient who applied tapinarof to the inguinal folds and reported irritation with this use. However, complaints of local irritation at the application sites for tapinarof are very rare.

Matthew Bruno, PA-C: Benzoic acid is one of the inactive ingredients in tapinarof cream, and it has the potential to cause transient stinging. Therefore, when patients are going to be using tapinarof on a potentially sensitive site, such as intertriginous or excoriated skin, I have them apply a sample of tapinarof during the visit and ask how it feels. Then I have some insight into the context and severity of their reaction if they subsequently call into the office to report stinging and burning.

Conclusion

This article includes a summary of information on the mode of action of AhR modulation and related data with tapinarof, and clinical trial outcomes reported with use of topical tapinarof cream for plaque psoriasis. However, important to note in this article are the case studies, which look at the management of plaque psoriasis in the real world, without the limitations of inclusion and exclusion criteria mandated in the protocols that govern clinical trials. These cases included patients with a variety of individual characteristics, such as comorbid disease states, specific patient concerns, different anatomic sites of involvement with psoriasis, and associated symptoms such as pruritus. The goal of the authors was to provide information on the topical management of plaque psoriasis with a specific focus on topical tapinarof cream, as it is the first available therapy that exhibits the unique mode of action of AhR modulation (agonism). Through the use of case studies, the authors discussed the therapeutic advantages of topical tapinarof therapy, offered suggestions for other potential treatment options, and reviewed their experiences with adverse effects when encountered. Only through sharing of clinical experiences with various therapies can clinicians expand their knowledge beyond what is published in clinical studies.

Acknowledgment

The authors wish to acknowledgment Cheryl K. Guttman, Northbrook, Illinois, for her editorial assistance with the preparation of this article.

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About this CME Activity

Release/expiration. Release Date: 9/1/23; Expiration Date: 9/1/24

Target audience. This activity is designed for dermatologists, nurse practitioners and physician assistants that treat patients with psoriasis and chronic skin conditions. Content will be applicable to physicians of all levels, novice to advanced learner.

Learning objectives. At the completion of this activity, participants should be able to:

Review and differentiate topical treatment options for plaque psoriasis.
Discuss the role of AHR in skin health and chronic skin conditions such as psoriasis.
Define the role of AHR modulation in the treatment of psoriasis.
Describe the indications, mechanisms of action, and potential adverse effects of an FDA-approved topical AHR modulating agent in the treatment of psoriasis.
Identify patients with psoriasis for whom treatment with a topical AHR modulating agent may be beneficial.
Effectively communicate to patients the potential risks and benefits associated with topical AHR modulating therapy.

Activity goal. This activity is designed to address the following core and team competencies: Medical Knowledge, Practice-based Learning, Patient-centered Care, and Teams and Teamwork.

Nonendorsement statement. The provider verifies that sound education principles have been demonstrated in the development of this educational offering as evidenced by the review of its objectives, teaching plan, faculty, and activity evaluation process. The provider does not endorse or support the actual opinions or material content as presented by the speaker(s) and/or sponsoring organization.

Disclosure. The provider adheres to accreditation requirements regarding industry support of continuing medical education. Disclosure of the planning committee and faculty’s commercial relationships will be made known at the activity. Speakers are required to openly disclose any limitations of data and/or any discussion of any off-label, experimental, or investigational uses of drugs or devices in their presentations. – All provider employees, activity planners, and program chairs in control of content have indicated that they have no relevant financial relationships to disclose.

Disclosed Relationships. Matthew Bruno, PA-C: Bristol-Myer Squib, AbbVie, Sanofi-Regeneron, Dermavant, Novan, Ortho Dermatologic, Mayne Pharma, UCB, Pfizer, Verrica– Consultant, Advisor, James Del Rosso, DO: Dermavant – Consultant, Speaker, Researcher; Bruce Strober, MD, PhD: AbbVie, Arcutis, Dermavant, Janssen, Eli Lilly – Consultant, Speaker; Alamar, Almirall, Amgen, Arena, Aristea, Asana, Boehringer Ingelheim, Immunic Therapeutics, Kangpu Pharmaceuticals, Bristol-Myers-Squibb, Connect Biopharma, Evelo Biosciences, Leo – Consultant; CorEvitas – Consultant, Scientific Co-Director, Investigator.

Accreditation. In support of improving patient care, this activity has been planned and implemented by Cine-Med and Matrix Medical Communications. Cine-Med is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Cine-Med designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses and other allied healthcare professionals. All other healthcare professionals will receive a Certificate of Participation. For information on the applicability and acceptance of Certificates of Participation for activities designated for AMA PRA Category 1 Credits™, consult your professional licensing board.

How to claim CME. After reading the entire supplement, learners can claim CME credit by completing a series of assessment questions using the following URL: https://cine-med.com/certificate.php?redirect=tmpp2023. Participants will be able to download or print a certificate once the form has been submitted.

Commercial support. This activity is being supported by an educational grant from Dermavant Sciences, Inc.