Expanding the Topical Therapeutic Landscape for Atopic Dermatitis: A Systematic Review

J Clin Aesthet Dermatol. 2026;19(3):20–30.

by Joshua Burshtein, MD; Sara Nahon, MS; Diego Ruiz Dasilva, MD; and Graham Litchman, DO, MS

Dr. Burshtein is with the Department of Dermatology at the University of Illinois-Chicago, Chicago, Illinois. Ms. Nahon is with the University of Illinois, College of Medicine at Chicago, Chicago, Illinois. Dr. Dasilva is with Forefront Dermatology and Eastern Virginia Medical School, Virginia Beach, Virginia. Dr. Litchman is with the Department of Dermatology at Touro University Nevada, and Vivida Dermatology, Las Vegas, Nevada.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Burshtein and Ms. Nahon declare no conflicts of interest relevant to the content of this article. Dr. Dasilva is a consultant and/or speaker for AbbVie, Arcutis, Dermavant, Galderma, Janssen, LEO Pharma, Lilly, Pfizer, Sanofi & Regeneron, UCB, and Verrica. Dr. Litchman has served as a research investigator, clinical advisor, or speaker for AbbVie, Arcutis, Bristol Meyers Squibb, Castle Biosciences, Dermavant, Galderma, Novartis, Pfizer, Sanofi/Regeneron, Taketa, and UCB.

ABSTRACT: Background: Atopic dermatitis (AD) is a common chronic inflammatory disease. Despite its global prevalence, the current standard of care has remained unchanged for many years. Historically, first-line agents include topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs). However, these agents have significant limitations, including local and systemic adverse effects. In the last several years, novel topical therapeutic agents have been approved by the United States Food and Drug Administration (FDA) and more are being developed. Objective: The present review aims to summarize these topical therapeutic advances and report their efficacy and safety relative to the existing armamentarium. Methods: Three searches were conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews guidelines. These included electronic searches of FDALabel (without date restriction) and PubMed and ClinicalTrials.gov (between April 8, 2020 and April 8, 2025). Results: A total of 52 nongeneric, prescription topical therapeutic agents are currently approved by the FDA for AD, the majority of which are TCS (n=11; 52.4%) and TCIs (n=4; 19.0%). There have been several agents with novel mechanisms of action (n=3; 7.6%) approved by the FDA in recent years, including Janus kinase (JAK) inhibitors, nonsteroidal aryl hydrocarbon receptor (AhR) modulators, and phosphodiesterase 4 (PDE4) inhibitors. Conclusion: In the last 5 years, important innovations in the therapeutic landscape of AD have emerged. Treatments include novel JAK inhibitors, AhR modulators, and PDE4 inhibitors. Adopting these therapies as part of clinical care can improve patients’ therapeutic outcomes and quality of life. Keywords: Atopic dermatitis, topical treatments, corticosteroids, nonsteroid, adverse effects, novel therapies

Introduction

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin conditions worldwide, with millions of adults and children affected globally.¹ Historically, first-line therapy includes moisturizers and emollients to maintain skin hydration and barrier function, as well as topical corticosteroids (TCS).² In AD, low- to mid-level potency TCS are recommended as initial therapy, which can be raised to a higher potency in moderate-to-severe cases.³ However, TCS are associated with many known cutaneous and systemic adverse effects (AE). Other historical topical therapies that do not contain corticosteroids include tacrolimus and pimecrolimus, topical calcineurin inhibitors (TCI), and crisaborole, a phosphodiesterase 4 (PDE4) inhibitor. These treatments have more favorable safety profiles and can be effective for anatomically sensitive areas (eg, face, eyelids).⁴ Recent advancements in the therapeutic landscape have markedly transformed the management of AD, offering more targeted, effective, and personalized options than were previously available.

Limitations of the Current Standard of Care

TCS are associated with numerous AEs, including skin atrophy, tachyphylaxis, permanent striae on the groin, inner thigh, and underarms, telangiectasias,⁵ delayed wound healing,⁶ perioral dermatitis, steroid acne, induction or exacerbation of rosacea, hypertrichosis, contact dermatitis, hypopigmentation, potential topical steroid withdrawal, and increased susceptibility to infections.⁷ Systemic adverse effects can also arise due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to hormonal dysregulation (caused by adrenal insufficiency), which can escalate to iatrogenic Cushing’s disease.⁷ Additionally, TCS can lead to hyperglycemia, particularly in individuals with pre-existing diabetes. Avascular necrosis has also been reported. Other rare systemic adverse effects include ocular defects (glaucoma, cataracts), electrolyte imbalances (edema, hypertension, hypocalcemia), and metabolic defects (osteopathy, decreased growth rate).⁸ A recent expert consensus panel determined that the use of long-term TCS is associated with significant AEs as well as notable medicolegal risks for clinicians prescribing these medications.⁸ While the adverse effects of TCI are milder than TCS, they also present with both local and systemic adverse effects. Local AEs include irritation (burning, itching, stinging),⁹ erythema,¹⁰ photosensitivity, and increased risk for skin infections and folliculitis.¹¹ The main theoretical systemic side effect of long-term TCI is lymphoma and skin cancers, for which there is a boxed warning.¹²

In the last decade, new insights into the mechanism of disease for AD have ignited research into finding new disease-specific therapeutic options for patients. As a result, several novel topical therapies have been approved by the United States (US) Food and Drug Administration (FDA) or are undergoing clinical trials. These advanced targeted topical therapies are reported to be safe and effective for treating AD.⁸ Currently, limited literature critically analyzes these novel topical therapeutics relative to the existing armamentarium of topical therapies. The present review seeks to provide an overview of novel and upcoming topical therapies in
the pipeline.

Methods

FDALabel. A query was launched using the FDALabel website with the following criteria:

• • Labeling Types: “HumanRX” and “Human OTC”
  • Labeling Section: “Simple search” for “atopic dermatitis” within “1 indications and usage”
  • Routes of Administration: “Topical”

This search generated 109 results. Results were filtered to include marketing categories New Drug Application (NDA) only (ie, excluding Abbreviated NDA, NDA Authorized Generic, OTC Monograph Final, and Unapproved drug other). This left 21 results, for which AD approval dates were manually confirmed using a public search engine. Missing drug classes were manually added.

PubMed. A literature review was conducted on PubMed. The review was based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines¹³ and Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews guidelines.¹⁴ An electronic search of PubMed between April 8, 2020 and April 8, 2025 using the terms (“Atopic Dermatitis” AND “Topical”) AND (“systematic review” OR “meta-analysis”) was conducted.

Inclusion criteria. Studies published in English, between April 8, 2020 and April 8, 2025, and available in full text were included.

Exclusion criteria. Preprints and studies examining nontopical delivery mechanisms, probiotics, non-FDA–approved or over-the-counter (OTC) treatments/home remedies, indications other than AD, nonapproved drugs in the last 5 years, pediatric patients, or nonhuman participants were excluded.

ClinicalTrials.gov. A search on ClinicalTrials.gov was conducted to understand the volume and classes of compounds in the pipeline for future novel therapeutic applications. A search was launched using the following criteria: Atopic Dermatitis | Completed studies | Adult (18 – 64) | Interventional studies | Studies with results | Study completion from April 8, 2020 to April 8, 2025.

Inclusion criteria. Studies published in English, between April 8, 2020 and April 8, 2025, and available in full text were included.

Exclusion criteria. Preprints and studies examining nontopical delivery mechanisms, terminated trials, non-FDA–approved or OTC treatments/home remedies, indications other than AD, or pediatric participants were excluded.

Results

FDALabel. TCS represented the largest share of the available 21 NDA approvals (n=11; 52.4%), followed by TCIs (n=4; 19.0%). Several agents with novel mechanisms of action were identified, including Janus kinase (JAK) inhibitors (4.8%), nonsteroidal aryl hydrocarbon receptor (AhR) modulators (4.8%), and PDE4 inhibitors (9.5%) (Figure 1; Table 1; Table 2). Three agents (7.6%) were approved by the FDA in the last 5 years (Table 2).

PubMed. Fifteen results matched the search criteria on PubMed and were filtered down to 8 (Figure 1; Table 3). Advanced targeted topical agents such as JAK inhibitors, AhR modulators, and PDE4 inhibitors were found to have efficacy for the treatment of AD with low rates of AEs.^15–18

ClinicalTrials.gov. There were 119 results that were reduced to 31 trials upon secondary manual review (Figure 1; Table 4). Several novel JAK inhibitors were deemed safe and efficacious, including delgoticinib and ruxolitinib, while others failed to meet endpoints (ARQ-252).^19–26 Two phase 3 (crisaborole and roflumilast) and one phase 2 (difamilast) trials for PDE4 inhibitors demonstrated statistically significant results.^27–29 Other mechanisms of action were also examined with mixed findings and some AEs.^30–35 For example, a phase 2 clinical trial for an interleukin 1 receptor-associated kinase 4 (IRAK4) inhibitor did not demonstrate statistically significant improvement relative to vehicle, ending development for that compound.³⁶ Finally, 6 phase 3 trials were used to approve the agents tapinarof, roflumilast, and ruxolitinib (Table 2).^{23,24,37–41}

Five studies (NCT04871711, NCT04872101, NCT05259722, NCT03683719, NCT04949841) examined delgoticinib, a JAK inhibitor, in phase 3 trials (DELTA1, DELTA2, and DELTA3) for the indication of chronic hand eczema (CHE).^{20, 25,26,42,43} Difamilast (PDE4 inhibitor) was another compound that was thoroughly investigated (NCT03961529).⁴⁴

Discussion

Nonsteroidal AhR modulator. The AHR/AHR-nuclear translocator (ARNT) system is a sensitive sensor for exogenous and endogenous small–molecule chemicals.⁴⁵ AhR expression has been shown to be increased in AD skin.⁴⁶ Once activated, the AhR/ARNT axis strengthens skin barrier function and accelerates epidermal terminal differentiation by upregulating filaggrin expression.⁴⁵ The FDA initially approved the first AhR modulator, tapinarof cream 1%, for plaque psoriasis in May 2022 and for AD in December 2024 in adults and children as young as 2 years. Two double-blind, randomized, vehicle-controlled phase 3 trials (NCT05014568, NCT05032859) were conducted.³⁷ A total of 407 and 406 patients were randomized in ADORING 1 and 2, respectively. A significantly higher proportion of patients treated with tapinarof achieved a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 with at least a 2-grade improvement from baseline at Week 8 compared to those receiving the vehicle: 45.4% in the tapinarof arm compared with 13.9% with vehicle in ADORING 1 (P<0.0001) and 46.4% vs 18.0% in ADORING 2 (P<0.0001).³⁷ A greater proportion of patients treated with tapinarof achieved at least 75% improvement in the Eczema Area and Severity Index (EASI 75) at Week 8 compared to the vehicle group: 55.8% of tapinarof-treated patients vs 22.9% for vehicle in ADORING 1 (P<0.0001) and 59.1% vs 21.2% in ADORING 2 (P<0.0001).³⁷ Patients reported rapid and significant reductions in pruritus with tapinarof treatment compared to the vehicle.³⁷ Common AEs (occurring in ≥5% of patients) included folliculitis, headache, and nasopharyngitis.³⁷ Treatment-emergent adverse events (TEAEs) were reported in 70% of patients compared to 38% with vehicle, and these events were primarily mild or moderate in severity.³⁷ Notably, fewer patients discontinued treatment due to AEs in the tapinarof group compared to the vehicle group.³⁷

Two recent Japanese phase 3 studies evaluating tapinarof cream, 1%, for AD shared similar efficacy endpoints. In the ZBB4-1 randomized, double-blind, vehicle-controlled trial, the primary endpoint was the proportion of patients who achieved an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with at least a 2-grade improvement at Week 8; this was reached by 20.24% of tapinarof-treated patients vs 2.24% on vehicle (P=0.0007).⁴⁷ EASI 75 was achieved by 40.3% in the tapinarof group vs 4.3% on vehicle (P<0.0001).⁴⁷ In the open-label, 52-week ZBB4-2 study, sustained efficacy was observed, with IGA success rates of 28.1% at Week 16, 32.3% at Week 24, and 41.3% at Week 52. EASI 75 response rates increased over time from 53.3% at Week 16 to 76.6% at Week 52.⁴⁷ Across both trials, most AEs were mild or moderate. Common AEs included folliculitis, acne, and headache, and no new safety concerns were identified over the 52-week treatment period.⁴⁷

JAK inhibitors. The JAK/signal transducer and activator of transcription (STAT) pathway is a significant cell signaling pathway involved in cytokine production, well characterized for mediating the inflammatory immune response, among other functions.⁴⁸ It facilitates the production of inflammatory cytokines interleukin (IL) 4, IL-5, IL-13, and IL-31, which drive the activation of helper T-cell 2 cell-mediated immunity, a pathway crucial for the pathogenesis of AD.⁴⁹ Blocking this inflammatory pathway has been shown to alleviate symptoms of AD.^48,49 Regarding topical agents, research has indicated promise for both first-generation and second-generation JAK inhibitors for AD, including studies on delgocitinib (a pan-JAK inhibitor), ruxolitinib (a JAK1/JAK2 inhibitor), tofacitinib (a pan-JAK inhibitor), ifidancitinib (a JAK1/JAK3 inhibitor), upadacitinib (a JAK1 inhibitor), and brepocitinib (a TYK2/JAK1 inhibitor).^48,49

Most recently, two phase 3 trials for ruxolitinib (TRuE-AD1 and TRuE-AD2) involving patients aged ≥12 years with mild-to-moderate AD found promising results.⁴⁰ At Week 8, 53.8% to 54.5% of patients using ruxolitinib cream, 1.5%, twice daily achieved Investigator’s Global Assessment–Treatment Success (IGA–TS), defined as a score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline, compared to 11.5% to 15.1% in the vehicle group.⁴⁰ Additionally, 61.8% to 62.0% achieved EASI 75 vs 24.6% to 29.6% with vehicle.⁴⁰ Treatment over 52 weeks resulted in 74.1% to 77.8% of patients achieving IGA 0 or 1.⁴¹ AEs were mostly mild; the most common were nasopharyngitis and application site reactions.⁴⁰ After 1 year of treatment, only 7.4% experienced treatment-related AEs.⁴¹

Delgocitinib, a topical pan-JAK inhibitor, was approved in Japan in January 2020 for the treatment of AD in patients aged 16 years and older. In the US, delgocitinib received FDA approval for the treatment of moderate to severe CHE in adults in July 2025. In the European Union, delgocitinib cream received approval in September 2024 for the treatment of moderate to severe CHE in adults.

A phase 2B randomized, double-blind, vehicle-controlled study evaluated the efficacy and safety of brepocitinib, 1%, in adults with mild-to-moderate AD over 6 weeks.⁵⁰ Patients treated with brepocitinib 1% twice daily achieved a 75% reduction in EASI scores at Week 6, compared to a 47.6% reduction in the vehicle group.⁵⁰ Once-daily applications of brepocitinib 1% and 3% resulted in EASI score reductions of 70.1% and 67.9%, respectively, vs 44.4% in the once-daily vehicle group.⁵⁰ A 90% reduction in EASI score (EASI 90) was observed in 27.0% to 41.7% of patients using brepocitinib, compared to 10.8% in the once-daily vehicle group and 8.3% with the twice-daily vehicle.⁵⁰ Topical brepocitinib was well tolerated, with no serious treatment-related AEs reported. The most common adverse effects were mild application site reactions.⁵⁰

PDE4 inhibitors. Roflumilast cream, 0.15%, was approved by the FDA for AD in patients aged 6 years and older in 2024. Clinical trials showed a significantly greater proportion of patients treated with roflumilast cream achieved vIGA-AD success at Week 4 compared to those receiving the vehicle cream.^38,54 Of the patients treated with roflumilast, 42% achieved EASI 75 at Week 4, compared to 19.7% in the vehicle group (P<0.0001).^38,54 Those treated with roflumilast also had a higher rate of achieving IGA success (32.0% vs 15.2%, P<0.001).³⁸ Further, 30.2% of patients treated with roflumilast experienced a ≥4-point reduction in Worst Itch Numeric Rating Scale at Week 4 vs 12.4% in the vehicle group (P<0.01).^38,54 Roflumilast cream was well tolerated, with most TEAEs being mild-to-moderate in severity.^46,47 Serious AEs were experienced by 0.9% of patients, and 1.4% to 1.8% discontinued roflumilast due to any TEAE at 4 weeks.^38,54 The most common TEAEs included headache, nausea, vomiting, diarrhea, and upper respiratory tract infection.³⁸

Difamilast is another PDE4 inhibitor approved in Japan for AD. A phase 3 randomized, double-blind, vehicle-controlled study assessed the efficacy of difamilast ointment, 1%, applied twice daily for 4 weeks in adult patients with mild-to-moderate AD.⁴⁴ At Week 4, 38.46% of patients achieved IGA 0 or 1 with a ≥2-grade improvement from baseline, compared to 12.64% in the vehicle group (P<0.0001).⁴⁴ The difamilast group had statistically significant improvements across EASI reductions, including 58.24% vs 25.82% achieving at least 50% improvement in EASI (P<0.001), 42.86% vs 13.19% for EASI 75 (P<0.0001), and 24.73% vs 5.49% for EASI 90 (P<0.0001), respectively.⁴⁴ Additionally, a significant mean percent change in overall EASI score from baseline was observed for the difamilast group compared with vehicle at Week 1 (–32.6% vs –10.4%, respectively; P<0.0001) and was sustained until Week 4 (–49.1% vs –10.5%, respectively; P<0.0001).⁴⁴ TEAEs were mostly mild or moderate and occurred less frequently in the difamilast group than in the vehicle group.⁴⁴

Conclusion

The therapeutic landscape for AD has been transformed through development of new, advanced targeted therapies. Short- and long-term use of TCS have substantial AEs, prompting a search for novel mechanisms of action to address this significant unmet need. Advanced agents have been introduced in the last five years using mechanisms such as JAK inhibition, PDE4 inhibition, and AhR modulation. Collectively, these advances mark a new era in the treatment of AD, offering more precise, effective, and safe options tailored to the disease’s immunologic complexity. Incorporating these therapies into treatment protocols may substantially improve disease management and patient quality of life.

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63. A study to learn about the study medicine (PF-07038124) in patients with mild-to-moderate atopic dermatitis or mild-to-severe plaque psoriasis. Updated October 2, 2024. https://clinicaltrials.gov/study/NCT05375955
64. Safety and efficacy of ARQ-252 cream in subjects with chronic hand eczema. Updated April 5, 2024. https://clinicaltrials.gov/study/NCT04378569
65. Open-label multisite extension trial in subjects who completed the DELTA 1 or DELTA 2 trials. Updated April 8, 2025. https://clinicaltrials.gov/study/NCT04949841
66. Safety and efficacy of a topical scalp treatment for dry scalp conditions in children and adult. Updated February 24, 2025. https://clinicaltrials.gov/study/NCT03830177
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68. Tapinarof for the treatment of atopic dermatitis in children and adults (DMVT-505-3102). Updated September 2, 2025. https://clinicaltrials.gov/study/NCT05032859
69. Long term extension study of tapinarof cream, 1% for subjects with atopic dermatitis. Updated August 13, 2025. https://clinicaltrials.gov/study/NCT05142774