¹University of Central Florida/HCA Healthcare Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA
^* Co-first authors

Conflict of interest: None.
Funding sources: None.
Disclaimer: This research was supported in whole or in part by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Abstract:
Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin. Several factors can precipitate SD development, such as colonization of Malassezia, sebocyte activity, impaired immunity, and environmental influences. Topical antifungals, corticosteroids, and calcineurin inhibitors are the current mainstay treatment of SD. Recent clinical trials have validated the efficacy of non-steroidal roflumilast 0.3% foam for the treatment of SD. In this review, we analyze the safety and efficacy profile of roflumilast 0.3% foam.

Keywords: seborrheic dermatitis, treatment, roflumilast, PDE-4 inhibitor

Introduction

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder most commonly affecting areas rich in sebaceous glands, such as the scalp, face, axilla, and groin.¹ While clinical presentations may differ, typical findings include erythematous, pruritic plaques and patches with a yellow, greasy appearance.^1,2 This condition can significantly impact quality of life due to activity limiting symptoms and emotional distress exacerbated by cosmetic ramifications.³ SD affects approximately 5% of the global population, whereas its non-inflammatory counterpart, dandruff, likely impacts closer to 50%.⁴ Despite such high prevalence, the pathogenesis and exact mechanisms via which these yeasts cause inflammation have yet to be fully elucidated.

Malassezia is a part of the human microbiome, interacting with the innate and acquired skin immune system. Innate immunity plays a critical role in initiating the initial immune response against Malassezia.⁵ Sensitization to Malassezia can cause a type I hypersensitivity reaction leading to redness, itching, and scaling.⁶ Further studies point towards Malassezia causing an irritant, non-immunogenic stimulation of the immune system, leading to complement activation and a localized increase in NK1+ and CD16+ cells.^7,8

Currently, there are many mainstay treatments for SD. Due to the underlying mechanism of Malassezia proliferation, most commonly topical antifungals are used for long-term treatment and topical corticosteroids and calcineurin inhibitors for short-term treatment (Table 1).¹ Due to the chronicity of SD, ongoing maintenance therapy is often necessary to achieve low recurrence rates of visible signs of the condition, as well as alleviate associating symptoms, such as pruritus.

Table 1

Phosphodiesterase-4 (PDE-4) inhibitors, including roflumilast, represent a significant advancement in the treatment of SD and other inflammatory conditions. These drugs work by inhibiting the PDE-4 enzyme, which plays a role in modulating inflammatory responses by breaking down cyclic adenosine monophosphate (cAMP).^9,10 Elevated levels of cAMP result in reduced inflammation, making PDE-4 inhibitors effective in managing various ongoing inflammatory disorders such as chronic obstructive pulmonary disease (COPD) and asthma.¹⁰ In dermatology, PDE-4 inhibitors have received regulatory approval in the US and Canada for plaque psoriasis, psoriatic arthritis, atopic dermatitis and, most recently, SD. They have shown promise in off-label treatment of a myriad of other inflammatory skin conditions. Apremilast is an oral PDE-4 inhibitor FDA-approved for psoriasis and psoriatic arthritis in patients ≥6 years of age. Crisaborole is a topical PDE-4 inhibitor, currently FDA-approved for atopic dermatitis in patients ≥3 months of age. Roflumilast has also demonstrated safety and efficacy in managing chronic inflammatory skin conditions, with the regulatory approval status in the US and Canada summarized in Table 2. Compared to currently available PDE-4 inhibitors, apremilast and crisaborole, used to treat skin disease, roflumilast has demonstrated greater selectivity and potency.^9,10

Table 2

Herein, the review will focus on the treatment of SD with a particular emphasis on roflumilast 0.3% foam.

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE-4.⁹ Inhibition of PDE-4 leads to an increase in cAMP and subsequent decrease in pro-inflammatory mediators such as interleukin (IL)-17, IL-23, tumor necrosis factor alpha, and interferon gamma.¹⁰

Clinical Trials

Phase 2¹¹

The Phase 2a study design was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily roflumilast 0.3% foam. A total of 226 participants aged 18 or older were enrolled in the 8-week trial conducted at 24 sites in the US and Canada with a clinical diagnosis of SD for a 3-month long duration and affecting less than 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. Roflumilast 0.3% foam demonstrated a statistically significant increase in treatment success, with 104 participants (73.8%) achieving an Investigator Global Assessment (IGA) score of 0 or 1, compared to its vehicle. At week 8, 50 individuals (35.5%) attained an IGA score indicating clearance, while 54 patients (38.3%) achieved an IGA score signifying almost clear skin. In comparison, the vehicle group exhibited lower rates of improvement, with only 10 patients (15.2%) reaching clearance and 17 patients (25.8%) achieving almost clear status. Roflumilast patients exhibited significantly higher rates of erythema success, defined as an overall erythema score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline, compared to those treated with the vehicle. At weeks 2, 4, and 8, respective absolute differences were 16.6% (95% Confidence Interval (CI): 6.4%-24.8%), 25.2% (95% CI: 13.1%-34.9%), and 23.5% (95% CI: 9.6%-35.0%). Similar results were noted for scaling success, defined as overall scaling score of 0 (clear) or 1 (almost clear) plus a 2-grade improvement from baseline. Statistically significant differences at weeks 2, 4, and 8: absolute differences were 11.8% (95% CI: -0.3% to 21.8%), 20.4% (95% CI: 6.8%-31.8%), and 28.8% (95% CI: 14.4%-41.0%), respectively. Overall, roflumilast 0.3% foam exhibited good tolerability, with a low occurrence of adverse events.

Phase 3¹²

The Phase 3 trial design was a parallel-group, double-blinded, vehicle-controlled, multicenter (50 centers) study with participants aged ≥9 years who were clinically diagnosed with SD affecting up to 20% body surface area, including the scalp, face, trunk, and/or intertriginous areas. 457 patients were randomly assigned in a 2:1 ratio to roflumilast (n = 304) or vehicle (n = 153). The primary endpoint was an IGA score of 0 (clear) or 1 (almost clear) and a ≥2-point improvement from baseline by week 8. The secondary endpoints included IGA success by weeks 2 and 4 and a ≥4-point improvement on the Worst Itch Numeric Rating Scale score (WI-NRS).

During this 8-week trial, a statistically significant amount of roflumilast treated patients (79.5%) achieved IGA success compared with vehicle (58.0%; P < 0.001). Roflumilast also demonstrated success at weeks 2 and 4, with percentages of IGA success of 43.0% versus 25.7% (P < 0.001) and 73.1% versus 47.1% (P < 0.001). At week 8, a higher percentage of patients treated with roflumilast (62.8%) achieved WI-NRS success compared to those treated with the vehicle (40.6%: P < 0.001), with improvement observed within 48 hours after the first application, respectively (Table 3).

Table 3

Safety and Tolerability

Overall, roflumilast 0.3% foam was well tolerated, and had similar rates of adverse events (AE) as the vehicle. During all phases of the study, there were no treatment emergent adverse events (TEAEs) reported as a direct result of roflumilast 0.3% foam treatment.^11,12 The most prevalent adverse reactions, observed in ≥1% of subjects across both Phase 2 and Phase 3 study groups included nasopharyngitis (1.5%), nausea (1.3%), and headache (1.1%).^11,12 Less frequent AEs included application site pruritus, application site pain, and diarrhea.^11,12 There were no significant differences between groups noted in clinical laboratory assessments. Vital signs, body weight, and body mass index indicated no clinically meaningful variations.¹² Moreover, evaluations for depression, suicidal ideation, and behavior revealed no safety concerns.¹²

Contraindications

Contraindications include individuals with a known hypersensitivity to roflumilast or any of the components in the formulation, as this can lead to severe allergic reactions. Additionally, patients with moderate to severe liver impairment (Child-Pugh B or C) should not use roflumilast, as it may exacerbate liver dysfunction.¹³ The coadministration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 may increase roflumilast systemic exposure and result in increased adverse reactions.¹³ It should be noted that no formal drug-drug interaction studies were done with topical roflumilast and these recommendations are based on oral roflumilast, which has a much greater bioavailability.

Regulatory Approval

The roflumilast 0.3% foam formulation was approved by the US FDA in December of 2023 and Health Canada in October 2024 for the treatment of SD in individuals aged ≥9 years.¹⁴ The medication is to be applied once daily to the affected areas, with the duration determined by the healthcare provider. One pressurized can of roflumilast 0.3% foam (60 g) contains 3 mg roflumilast per 1 g.

Discussion

Current first-line therapies for SD typically include topical antifungals and topical steroids (Table 1). These treatments are often readily available and affordable, leading to their widespread use. While these are effective in many cases, some individuals require a combination of multiple topicals for control which contributes to patient non-compliance due to complex treatment regimens.⁴ Moreover, these treatments may be ineffective in some individuals and can be associated with poor tolerability due to various AEs such as local skin reactions, burning, pruritus, and blistering.⁴

Roflumilast 0.3% foam provides an additional non-steroidal anti-inflammatory treatment option in those who have failed first-line therapies or prefer a once daily treatment regimen. It marks the first regulatory approved medication for SD with a novel mechanism of action in over two decades. This foam is uniquely formulated in a water-based emollient formula without skin irritating fragrances or alcohols such as, propylene glycol, polyethylene glycol, isopropyl alcohol, or ethanol.¹⁴ It is reported to be the first-in-class drug formulated with a novel emulsifier that lacks ceramide stripping properties. The hydrating features of the vehicle itself may add to its therapeutic effect. Moreover, the non-irritating, non-steroidal formula enables use anywhere on the body, including the eyelids and genitalia. The non-greasy foam formulation lends itself to use on hairy scalps.

Roflumilast may improve adherence and tolerance due to its once daily application, potent formulation, and minimal AEs. Its greater selectivity for PDE-4 than apremilast and crisaborole, likely contributes to its low side effect profile. Few patients reported stinging, burning, application site reactions, or application site pain with roflumilast.¹² Data from key trials reported IGA success, defined as IGA of 0 (clear) or 1 (almost clear) plus ≥2-point improvement from baseline in 80% of participants, with some reaching IGA success as early as weeks 2 and 4.¹² Pruritus, measured via the WI-NRS, improved as early as 48 hours after application. These results are in-line with other first-line therapies (Table 3).

With the continual push for more effective and safer therapies, roflumilast appears to be a useful agent added to the SD armamentarium.

Conclusion

Due to its minimal AEs and favorable tolerability, the novel roflumilast 0.3% foam offers a safe treatment for the erythema, scaling, and pruritus caused by SD. Its once daily application and potent formulation provides a convenient and effective treatment for SD. This treatment highlights the importance of continued advancement in the development of innovative therapies for SD as it is essential to improve outcomes and enhance the quality of life for individuals affected by this condition.

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¹John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic, inflammatory disease with heterogeneous clinical features. The pathogenesis of PsA involves a complex interplay of genetic, immunologic, and environmental factors, leading to the activation of the immune system and subsequent inflammation. Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23/T helper 17 pathway in the disease process. Guselkumab, a novel IL-23 inhibitor, has emerged as a promising therapeutic option for PsA, offering an alternative to conventional therapies and other biologics. This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Keywords: psoriatic arthritis, guselkumab, treatment, efficacy, psoriasis, arthritis

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that will develop in about 30% of individuals with psoriasis. The condition is characterized by a wide range of clinical features, making it complex and diverse in its presentation. The pathogenesis of PsA involves a multifaceted interaction between genetic, immunologic, and environmental factors, which leads to immune system activation and subsequent inflammation.¹

Currently, there are no specific diagnostic criteria or tests for PsA. Diagnosis is typically based on the presence of inflammatory musculoskeletal symptoms in joints, entheses, or the spine, alongside skin and/or nail psoriasis, and the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The progression from psoriasis to PsA may occur in stages, although the underlying mechanisms remain unclear. Interestingly, the severity of musculoskeletal inflammation does not always correlate with the severity of skin or nail psoriasis, a phenomenon likely influenced by genetic variability, particularly in the human leukocyte antigen (HLA) region.¹

Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23 (IL-23)/T helper 17 (Th17) pathway in the disease process. Guselkumab is a human monoclonal antibody that selectively binds to the p19 subunit of IL-23, thereby inhibiting its interaction with the IL-23 receptor. By blocking IL-23 signaling, guselkumab prevents the activation and proliferation of Th17 cells, which are pivotal in the pathogenesis of PsA. Th17 cells produce several pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the inflammation and joint damage observed in PsA. By targeting IL-23, guselkumab effectively reduces the levels of these downstream cytokines, thereby attenuating the inflammatory response and improving clinical outcomes in patients with PsA.²

Guselkumab has been approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) for the treatment of adult patients with active psoriatic arthritis and moderate-to-severe psoriasis (PSO) who are candidates for systemic therapy. Additionally, the EMA has approved guselkumab for the treatment of active psoriatic arthritis in adults who have had an inadequate response to, or are intolerant of, previous disease-modifying antirheumatic drug (DMARD) therapy.²

This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Methods

Our search focused on English-language literature concerning clinical trials of guselkumab in adults with psoriatic arthritis. We conducted a search in the Medline database via PubMed up until September 1, 2024, using the MeSH terms “guselkumab” AND “psoriatic arthritis.” This search yielded 177 results. We excluded books, meta-analyses, reviews, and systematic reviews, narrowing our focus to clinical trials and randomized controlled trials, resulting in 30 trials. Out of these, we included 9 trials and excluded 10 due to integrated analysis of multiple trials, 7 due to duplication, and 4 due to a focus on topics other than PsA.

Results

The included studies primarily consisted of double-blind, randomized, placebo-controlled Phase 3 trials that evaluated the efficacy of guselkumab in patients with PsA (Table 1). Across these trials, guselkumab demonstrated significant efficacy in achieving American College of Rheumatology (ACR) response criteria at various time points:

Table 1

ACR20 Response

Guselkumab consistently showed superior results compared to placebo. For instance, Deodhar et al. reported that 59% of patients treated with guselkumab every 4 weeks and 52% treated every 8 weeks achieved ACR20, compared to 22% in the placebo group.³ Similar trends were observed in other studies, with response rates ranging from 44% to 76% for guselkumab, significantly higher than the placebo groups, which ranged from 20% to 33%.^4-7

ACR50 and ACR70 Responses

Some trials also assessed higher response thresholds. McInnes et al. observed ACR50 and ACR70 responses in 48-56% and 30-36% of patients, respectively, in the guselkumab-treated groups.⁸ Ritchlin et al. noted that 33% and 31% of patients achieved ACR50 at week 24 in the every-4-weeks and every-8-weeks groups, respectively, compared to 14% in the placebo group. ACR70 responses were achieved by 13-19% of guselkumab-treated patients, compared to 4% in the placebo group.⁹

Additional Outcomes

Beyond ACR responses, trials such as Curtis et al. and Orbai et al. assessed work productivity and patient-reported outcomes, showing significant improvements in these domains among patients treated with guselkumab. Improvements in presenteeism, work productivity, non-work activity, and Patient-Reported Outcomes Measurement Information System® (PROMIS)-29 scores were all more substantial in guselkumab groups compared to placebo, with improvements continuing through week 52 after placebo patients were switched to guselkumab.^10,11

These results highlight the efficacy of guselkumab in improving clinical outcomes in PsA patients, particularly in achieving ACR response criteria and enhancing patient-reported outcomes.

Discussion

In the management of PsA, the primary objective of pharmacological treatment is to enhance patients’ health-related quality of life. This is achieved by alleviating symptoms, preventing structural joint damage, and restoring normal function and daily activities. A significant reduction in inflammation is crucial to reaching these goals. Within this therapeutic landscape, guselkumab offers several distinct advantages over other biologics, particularly tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors.

TNF inhibitors are commonly used in PsA treatment, but their efficacy in managing skin symptoms can be variable, and they are associated with a higher risk of certain adverse events (AEs), such as infections and demyelinating diseases. IL-17 inhibitors, including secukinumab and ixekizumab, are effective for both skin and joint manifestations but may increase the risk of inflammatory bowel disease. In contrast, guselkumab specifically targets the IL-23 pathway, offering a more focused modulation of the immune response in PsA. This targeted inhibition may lead to fewer offtarget effects and a more favorable safety profile, particularly concerning infections and autoimmune-related AEs. Additionally, guselkumab has shown efficacy in patients who have not responded adequately to TNF inhibitors, making it an invaluable option for this challenging subset of patients.¹²

The safety profile of guselkumab has been thoroughly evaluated in both clinical trials and post-marketing surveillance. Across these studies, the incidence of AEs was comparable between guselkumab and placebo groups, with the most common being nasopharyngitis, upper respiratory tract infections, and headaches. Serious adverse events were infrequent and occurred at similar rates across treatment groups. Importantly, guselkumab did not increase the risk of serious infections, malignancies, or major cardiovascular events, which supports its suitability for long-term use.

Overall, guselkumab emerges as a promising therapeutic option for PsA, particularly for patients who require an alternative to TNF inhibitors or those concerned with the safety profiles of currently available biologics. Its focused mechanism of action, combined with a robust safety profile, positions guselkumab as an effective and well-tolerated treatment in the ongoing effort to improve patient outcomes in PsA.

Conclusion

Guselkumab represents a significant advancement in the treatment of PsA, providing a novel mechanism of action with robust clinical efficacy and a favorable safety profile. The evidence from RCTs and real-world studies supports its use in a broad range of patients, including those who are biologic-naïve and those with previous biologic exposure. As the understanding of the IL-23/Th17 pathway continues to evolve, guselkumab and other IL-23 inhibitors are likely to play an increasingly important role in the management of PsA, offering patients new hope for improved disease control and quality of life. Future research should focus on long-term outcomes, comparative effectiveness with other biologics, and the identification of biomarkers to personalize treatment strategies for patients with PsA.

References

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