Small-molecule therapies in paediatric atopic dermatitis: current landscape and future perspectives

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by complex immune dysregulation, barrier dysfunction, and intense pruritus. While biologic therapies targeting type 2 cytokines have significantly improved outcomes in moderate-to-severe disease, small molecule agents have emerged as a complementary and increasingly sophisticated therapeutic strategy. These compounds act predominantly at the intracellular level, modulating key signaling pathways involved in immune activation and epidermal homeostasis.
This review provides an updated overview of currently approved and investigational small molecules for pediatric AD, including phosphodiesterase 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, aryl hydrocarbon receptor (AhR) modulators, sphingosine-1-phosphate receptor (S1PR) modulators, histamine H4 receptor antagonists, and emerging transcriptional regulators such as STAT6 inhibitors and degraders. PDE4 inhibitors represent the first successful class of intracellular immunomodulators in dermatology, offering steroid-sparing options particularly in mild-to-moderate disease. JAK inhibitors provide rapid and robust clinical responses in moderate-to-severe AD, though safety considerations require careful patient selection. Novel approaches targeting upstream T-cell signaling (e.g., ITK inhibition), dual kinase pathways, or transcriptional hubs such as STAT6 reflect a shift toward more precise modulation of type 2 inflammation. In contrast, S1PR modulators and H4 receptor antagonists have thus far shown limited clinical efficacy in AD despite strong biological rationale.
Collectively, small molecules are reshaping the therapeutic landscape of AD by expanding options beyond extracellular cytokine blockade. Future positioning will depend on balancing efficacy, selectivity, long-term safety, and patient phenotype, with the potential for increasingly personalized, mechanism-driven treatment strategies.

EPIDEMIOLOGY, CLINICAL IMPACT, AND DIAGNOSTIC FRAMEWORK

Atopic dermatitis (AD) is the most common skin disease in children in Italy and represents the leading cause of pediatric dermatology visits in developed countries. It is also the most prevalent chronic inflammatory skin disorder in childhood ¹.

A retrospective Italian study conducted between 2006 and 2012 estimated a prevalence of 8.5% among children aged 0-14 years, corresponding to approximately 600,000 affected individuals, with an increasing trend compared to previous years ². More recent international data indicate a prevalence ranging from 10% to 20% among children in Western European countries ³.

In adults, the prevalence is approximately half that observed in pediatric populations, with Italian estimates ranging between 3.4% and 4.4% (approximately 1.7-2.2 million adults) ⁴. These figures are consistent with European surveys reporting an adult prevalence of 4.4% ⁵.

Overall, current estimates suggest that 2.3-2.8 million individuals in Italy are affected by AD, with higher prevalence in children than in adults. These data underscore the substantial clinical and socio-economic burden of the disease and justify the ongoing research efforts aimed at optimizing its management.

Over the past decade, AD treatment has undergone significant evolution with the introduction of biologic therapies and novel small molecules, which now represent key components of current and future therapeutic strategies, including in pediatric populations. These agents have substantially reshaped the management of both mild-to-moderate and moderate-to-severe disease.

In this review, we first outline the most recent European guidelines (EADV/EAACI) for the management of pediatric atopic eczema and subsequently focus on the current evidence regarding small molecules and their potential positioning within the therapeutic algorithm.

DIAGNOSIS AND ASSESSMENT OF AD SEVERITY

The diagnosis of atopic dermatitis is primarily clinical and based on the well-established Hanifin-Rajka criteria ⁶. It relies on the evaluation of lesion morphology and distribution (which vary according to age), the chronic-relapsing course of the disease, and the exclusion of alternative dermatoses. Subjective symptoms, particularly pruritus and associated sleep disturbance, represent key components of disease burden and are integral to both diagnosis and severity assessment.

The availability of reliable quantitative tools to assess severity of AD and therapeutic response is essential in pharmacologic research. The most widely validated instruments include (Tab. I):

• Eczema Area and Severity Index (EASI): evaluates objective clinical signs and body surface involvement. It does not include patient-reported symptoms such as pruritus. EASI represents the most commonly used endpoint in trials for moderate-to-severe AD and is considered the gold standard in registration studies, where outcomes such as EASI-50, EASI-75, and EASI-90 (representing 50%, 75%, or 90% improvement from baseline) are assessed ⁷.
• SCORing Atopic Dermatitis (SCORAD): combines objective signs, disease extent, and subjective symptoms (pruritus and sleep disturbance). Although less frequently used as a primary endpoint compared with EASI, it remains particularly relevant in pediatric populations, where sleep impairment is a key clinical parameter ⁸.
• Investigator’s Global Assessment (IGA): an ordinal clinician-reported measure of overall disease severity. It provides a rapid and global evaluation and is often used as a co-primary endpoint in registration trials (IGA 0/1 with ≥2-point improvement).
• Worst Pruritus/Peak Pruritus Numerical Rating Scale (WP/PP-NRS): a standardized measure of itch intensity. In clinical trials, a reduction of ≥4 points is generally considered the minimum clinically important difference (MCID).
• Children’s Dermatology Life Quality Index (CDLQI), Infants’ Dermatitis Quality of Life Index (IDQoL), and Dermatology Life Quality Index (DLQI): assess the impact of AD on quality of life in children, infants, and adults, respectively.

Contemporary research evaluates AD severity as a multidimensional construct integrating lesion severity (EASI/IGA), itch intensity (NRS), and quality-of-life impairment (DLQI/CDLQI). These measures will serve as the framework for the analysis and comparison of studies evaluating novel small molecules.

Based on the above-mentioned scoring systems, three categories of disease severity can be identified, although clinical trials often simplify classification into two main groups:

• Mild-to-moderate and
• Moderate-to-severe: defined by extensive skin involvement (body surface area ≥10%) and/or significant clinical severity (EASI ≥16 or IGA ≥3), associated with substantial pruritus and functional impairment, inadequately controlled despite optimized topical therapy.

The European Academy of Dermatology and Venereology (EADV) guidelines, updated in February 2025, are based on the concept of stepped-up care, which provides a gradual intensification of therapy according to disease severity, progressing from mild to more severe forms. This escalation corresponds to a transition from exclusively topical treatment to systemic oral therapy in more advanced cases ⁹.

Given the chronic nature of AD, maintenance therapy represents the foundation of the therapeutic pyramid. Additional treatments are introduced during eczema flares (reactive therapy) in mild disease, while a proactive approach aimed at long-term relapse prevention may be adopted in moderate cases. Systemic immunosuppression is reserved for severe disease.

Cornerstones of maintenance therapy include regular use of emollients (basic or “plus” formulations which are enriched with functional non-pharmacologic ingredients), appropriate skin cleansing, and avoidance of relevant allergens in sensitized individuals.

Acute flares are managed with topical corticosteroids (TCS) of appropriate potency depending on the anatomical site, along with topical calcineurin inhibitors (TCI), and, in selected cases, wet-wrap therapy. The initial reactive phase typically involves daily topical application, followed by a proactive phase characterized by gradual tapering to intermittent regimens (commonly weekend therapy), which has been shown to reduce relapse rates.

Failure to achieve adequate control or early relapse despite optimized topical management defines moderate-to-severe AD and warrants consideration of systemic therapy. Available options include biologic agents (dupilumab, lebrikizumab, nemolizumab), Janus kinase inhibitors (abrocitinib, baricitinib, upadacitinib), and conventional immunosuppressants (cyclosporine, azathioprine, methotrexate). Treatment selection is multifactorial and takes into account disease severity, patient age, immunologic profile, presence of atopic comorbidities (allergic rhinitis, asthma, eosinophilic esophagitis), and overall benefit-risk assessment.

In pediatric populations, safety considerations are predominant. The use of broad systemic immunosuppression during immune system maturation has raised both clinical and ethical concerns. This has driven the development of more targeted therapies that are capable of selectively modulating disease-specific pathways while preserving physiological immune processes.

An in-depth review of biologic therapies has previously been published in this journal and readers are referred to it for further discussion ¹⁰. The present review focuses on the pharmacologic paradigm of small molecules in the treatment of AD.

PATHOGENESIS AND PHARMACOLOGICAL TARGETS IN AD

AD is a chronic inflammatory skin disorder characterized by acute and chronic eczematous lesions associated with intense pruritus. Two major pathogenic models have been proposed. The outside-in hypothesis identifies epidermal barrier dysfunction as the initial trigger of the inflammatory cascade, whereas the inside-out theory attributes primary immune dysregulation as the driving force of disease. These mechanisms are not mutually exclusive; rather, they are tightly interconnected and reinforce each other within a self-perpetuating loop commonly referred to as the itch-scratch cycle.

Recently, advances in immunobiology have also introduced the concept of endotypes, defined as patient subgroups characterized by distinct molecular and immunologic profiles. Two principal endotypes have been described: extrinsic and intrinsic, with the former accounting for approximately 80% of cases and the latter for about 20% ¹¹.

Extrinsic Endotype

This form typically presents with earlier onset and often greater clinical severity. The inflammatory response is predominantly Th2-driven and mediated by key cytokines:

• IL-4 and IL-13: act synergistically, with IL-4 promoting Th2 differentiation and IgE class switching, while IL-13 contributing to peripheral tissue inflammation, barrier dysfunction, and tissue remodeling.
• IL-5: plays a central role in eosinophil maturation, activation, and survival, and is associated with peripheral eosinophilia.
• IL-31: often referred to as the “itch cytokine,” directly stimulates sensory neurons and amplifies cutaneous inflammation.

This endotype is frequently associated with elevated total and specific IgE levels, peripheral eosinophilia, and loss-of-function mutations in the filaggrin gene, which impair barrier integrity and predispose to Staphylococcus aureus colonization. It is also closely linked to the so-called atopic march ¹¹.

Intrinsic Endotype

The intrinsic form generally presents later in life and is associated with a milder phenotype. The inflammatory response is predominantly Th1/Th17-mediated, driven by IFN-γ and IL-17. Serum IgE levels are typically normal, and systemic allergic sensitization is absent. Relative preservation of the epidermal barrier reduces susceptibility to bacterial colonization and allergic comorbidities.

Of note, this endotypical classification reflects relative predominance immunological responses and Th2, Th1, and Th17 pathways may coexist and interact, contributing variably to the clinical phenotype of AD.

THERAPEUTIC TARGETS OF CONVENTIONAL AND BIOLOGIC THERAPIES IN ATOPIC DERMATITIS

We briefly review the principal therapeutic targets of conventional treatments used for eczematous flares.

Corticosteroids

Topical corticosteroids have represented the cornerstone of AD management for more than four decades, owing to their rapid anti-inflammatory, immunosuppressive, and antipruritic effects during acute flares.

Corticosteroids bind cytoplasmic glucocorticoid receptors (GR), which translocate to the nucleus upon activation and regulate gene transcription by suppressing pro-inflammatory pathways, primarily through inhibition of NF-κB and AP-1.

This results in:

• suppression of Th2 cytokines (IL-4, IL-5, IL-13);
• inhibition of inflammatory mediators such as prostaglandins and leukotrienes;
• reduced activation and chemotaxis of immune cells (T lymphocytes, macrophages, dendritic cells, mast cells, eosinophils);
• cutaneous vasoconstriction;
• antiproliferative effects beneficial in chronic lichenified lesions.

Short courses of systemic corticosteroids may be used as rescue therapy, although their efficacy is generally inferior to cyclosporine and long-term use is limited by safety concerns ⁹.

Cyclosporine

Cyclosporine is currently employed as second-line systemic therapy in severe AD. It inhibits T-cell activation by blocking calcineurin signaling and preventing activation of nuclear factor of activated T cells (NFAT).

Consequently, it reduces:

• IL-2 production (critical for T-cell clonal expansion);
• Th2 cytokines (IL-4, IL-5, IL-13);
• IFN-γ and TNF-α, involved in chronic inflammation.

Due to its rapid onset of action, cyclosporine is often considered a rescue therapy. However, long-term use is limited by its narrow therapeutic index and the need for close monitoring of blood pressure and renal function. Compared with biologics such as dupilumab, cyclosporine demonstrates faster onset but lower long-term drug survival ⁹.

Topical Calcineurin Inhibitors

Tacrolimus ointment and pimecrolimus cream provide a steroid-sparing option, particularly for sensitive areas (face, neck, intertriginous regions, genital skin).

Calcineurin inhibitors inhibit T-cell activation by binding to FKBP-12, forming a complex that blocks calcineurin activity and prevents NFAT activation, thereby reducing cytokine transcription.

Their main limitations include transient local burning and the presence of a boxed warning, although long-term malignancy risk has not been conclusively demonstrated ¹².

TARGETED BIOLOGIC THERAPIES

Pharmacologic development has progressively shifted toward selective inhibition of Th2-driven inflammation in moderate-to-severe AD.

Biologic agents, which are subcutaneously administered monoclonal antibodies, selectively neutralize key cytokines:

• Dupilumab: fully human IgG4 monoclonal antibody targeting the IL-4 receptor α subunit, inhibits IL-4 and IL-13 signaling;
• Tralokinumab: IgG4 monoclonal antibody selectively neutralizes IL-13;
• Lebrikizumab: high-affinity IgG4 antibody targeting soluble IL-13 and prevents IL-13Rα1/IL-4Rα signaling complex formation;
• Nemolizumab: antibody targeting the IL-31 receptor α chain, primarily aimed at rapid itch reduction ⁹.

TOWARD INTRACELLULAR TARGETING

Advances in the understanding of atopic dermatitis pathogenesis, together with the need for more versatile therapeutic options beyond subcutaneously administered biologics, have driven the development of small molecules targeting intracellular pathways, and are available in both topical and oral formulations.

These agents act by directly modulating intracellular signaling cascades involved in inflammatory responses, allowing broader yet mechanistically selective inhibition of disease-driving pathways.

The following sections will review the main representatives of this therapeutic class, beginning with agents that are currently approved and available in clinical practice.

JANUS KINASE INHIBITORS

The Janus kinase family consists of four cytoplasmic tyrosine kinases—JAK1, JAK2, JAK3, and TYK2. These enzymes are essential for signal transduction downstream of type I and type II cytokine receptors, which lack intrinsic enzymatic activity. Such receptors mediate the effects of multiple cytokines, including several interleukins (such as IL-2, IL-4, IL-6, IL-7, IL-12, and IL-23), interferons (IFN-α, IFN-β, IFN-γ), and growth factors like GM-CSF. Cytokine engagement induces receptor-associated JAK activation, leading to phosphorylation of STAT proteins. Once phosphorylated, STATs form dimers and translocate to the nucleus, where they regulate transcriptional programs that control cell proliferation, differentiation, survival, and immune responses ¹³.

Pharmacologic inhibition of the JAK-STAT pathway results in a broad attenuation of cytokine signaling, including key mediators implicated in atopic dermatitis pathogenesis such as IL-4 and IL-1 (central drivers of type 2 inflammation), IL-31 (a major contributor to pruritus), IFN-γ and IL-22 (involved in epidermal hyperplasia).

Clinical efficacy

Clinical trials consistently demonstrate:

• Rapid onset of action, particularly in reducing pruritus (often within days);
• Significant improvement in objective severity scores (EASI responses);
• Oral and topical formulations, allowing tailored systemic or localized treatment;
• Broad anti-inflammatory activity with potential utility across overlapping inflammatory dermatoses, sharing immunopathogenic pathways (e.g., prurigo nodularis, chronic hand eczema, hidradenitis suppurativa, psoriasis, vitiligo, alopecia areata) ^14,15.

However, their mechanism of broad immune modulation also underlies important safety considerations.

Limitations and safety concerns

• Increased risk of upper respiratory tract infections and herpes zoster with potential for opportunistic infections ¹⁶.
• Reported associations with venous thromboembolism (VTE) and major adverse cardiovascular events (MACE). Interestingly, a recent real-world study reported a slightly increased risk of pulmonary embolism and deep venous thrombosis among patients with AD treated with JAK inhibitors compared to dupilumab and methotrexate, but no significantly elevated risk of myocardial infarction or stroke ¹⁷.
• Requirement for thrombotic risk assessment at baseline and periodic laboratory monitoring.
• Regulatory boxed warnings, reflecting concerns derived partly from data in other immune-mediated diseases. In a recent meta-analysis exploring the risk of malignancy associated with JAK inhibitors across different disease indications, they were associated with a higher incidence of cancer, though rare, compared to TNF inhibitors but not placebo or methotrexate ¹⁸.

For these reasons, JAK inhibitors are generally reserved for patients with moderate-to-severe AD who are candidates for systemic therapy, particularly when rapid disease control is clinically desirable.

Currently available or investigational JAK inhibitors in AD differ in selectivity and formulation:

• Selective JAK1 inhibitors (oral): upadacitinib, abrocitinib, ivarmacitinib;
• Dual JAK1/JAK2 inhibitor (oral): baricitinib;
• Pan-JAK/SYK inhibitor: gusacitinib;
• Extended-spectrum inhibitors (e.g., ITK/JAK3 inhibition): soquelitinib, ATI-2138;
• Topical agents: ruxolitinib (JAK1/JAK2) and delgocitinib (pan-JAK).

From a mechanistic standpoint, greater selectivity (e.g., JAK1-focused inhibition) may theoretically reduce off-target adverse effects, whereas pan-JAK inhibition may provide broader cytokine suppression at the cost of potentially increased systemic risk.

Given the expanding therapeutic landscape and the immunologic overlap between AD and other inflammatory dermatoses, JAK inhibitorsthat are effective in related conditions may represent future therapeutic extensions. Nevertheless, long-term pharmacovigilance and real-world safety data remain essential to better define their optimal positioning in clinical practice.

UPADACITINIB

Upadacitinib is an oral selective JAK1 inhibitor with high target specificity and potent immunomodulatory activity. Upadacitinib received EMA approval in 2021 and FDA approval in 2022 for moderate-to-severe AD in adults and adolescents aged ≥12 years who are candidates for systemic therapy. It is administered once daily at doses of 15 mg or 30 mg.

Clinical efficacy and safety

The Phase 3 trials Measure Up 1(NCT03569293), Measure Up 2 (NCT03607422), and AD Up (NCT03568318) evaluating upadacitinib 15 mg (UPA15) and 30 mg (UPA30) in adults and adolescents with moderate-to-severe AD, demonstrated:

• High rates of EASI-75 responses versus placebo with sustained efficacy over longer-term extension studies. At week 140, EASI-75 was achieved by 85.5%/90.5% (UPA15/UPA30; integrated MeUp1/2) and 81.5%/90.0% (UPA15/UPA30; AD Up) of patients.
• Significant improvements in IGA 0/1. At week IGA 0/1 was achieved by 56.6%/64.4% (UPA15/UPA30; integrated MeUp1/2) and 52.0%/56.8% (UPA15/UPA30; AD Up) of patients.
• Marked and rapid reduction in pruritus, with some patients reporting improvement within 48 hours. Over 60% of patients across all three studies achieved PP-NRS4 at week 140.
• Safety profiles consistent with 16-week and 52-week analyses ¹⁹. Adverse events are consistent with the JAK inhibitor class. The most commonly reported include: acne, upper respiratory tract infections/nasopharyngitis, headache, dose-dependent herpes zoster, creatine phosphokinase (CPK) elevations, while serious adverse events are uncommon.

Head-to-head data of daily upadacitinib 30 mg versus biweekly dupilumab 300 mg (Heads Up trial, NCT03738397) showed faster and greater early skin clearance (EASI-75 at week 16; 72.4% for upadacitinib and 62.6% for dupilumab) (62.6%) and itch reduction as early as week 1 (mean 32.0% vs. 8.9%; P < .001), though long-term positioning requires individualized risk assessment.

Positioning: Upadacitinib represents one of the most efficacious systemic options for moderate-to-severe AD, particularly when: rapid disease control is required, severe pruritus dominates the clinical picture or biologic therapy is contraindicated, ineffective, or not tolerated. However, careful patient selection and long-term pharmacovigilance remain essential.

ABROCITINIB

Abrocitinib is an oral selective JAK1 inhibitor characterized by high affinity for JAK1 and substantially lower activity against JAK2, JAK3, and TYK2, supporting its classification as a JAK1-preferential agent ²⁰.

Abrocitinib received FDA approval in 2022 and EMA approval shortly thereafter for the treatment of moderate-to-severe AD in adults and adolescents aged ≥12 years who are candidates for systemic therapy. It is administered once daily at doses of 100 mg or 200 mg. The drug is rapidly absorbed, reaching peak plasma levels within approximately one hour, and is primarily metabolized via the CYP2C19 and CYP2C9 pathways, supporting convenient once-daily dosing ²¹.

Clinical efficacy

Abrocitinib showed long-term efficacy (at 48 weeks) and safety (at ~4 years) in adults and adolescents with moderate- to- severe atopic dermatitis (AD) in several phase 3 trials. Data from adolescents in JADE MONO- 1 (NCT03349060), MONO- 2 (NCT03575871), TEEN (NCT03796676), REGIMEN (NCT03627767; safety analysis only), and the extension trial, EXTEND (NCT03422822), treated with abrocitinib (200, 100 mg) demonstrated:

• Significant and sustained improvements in EASI-75 and higher-level responses at week 112: EASI- 75 (85% and 83%), EASI- 90 (62% and 60%) ²².
• Achievement of IGA 0/1 in a substantial proportion of patients: IGA 0/1 (57%, 57%).
• Rapid pruritus reduction; frequently within the first 24–48 hours and at week 2, PPNRS4 (57% and 35% versus placebo 7%) and PPNRS0/1 (6% and 22% versus 0%, respectively) ²³.
• Safety in long-term follow-up (JADE EXTEND trial): Incidence rates of TEAEs (Treatment-Emergent Adverse Events) and TEAEs leading to discontinuation of treatment were numerically higher with abrocitinib 200 mg compared with 100 mg (TEAEs IR [95% CI]; 5.47 [3.69-7.80] vs. 3.45 [1.89-5.80] and for those leading to discontinuation IR 6.78 [4.80-9.31] vs. 5.39 [3.38-8.16]); however, the overlapping 95% confidence intervals indicate that the difference between the two different dosages was not statistically robust ²². Adverse events are generally consistent with the JAK inhibitor class. The most frequently reported include: nausea (particularly at treatment initiation), headache, acne, upper respiratory tract infections, transient platelet count reductions, lipid elevations. Baseline and periodic laboratory monitoring (CBC and lipid profile) is recommended ²⁴.

Head-to-head comparisons with dupilumab (JADE COMPARE) showed faster itch relief with abrocitinib 200 mg at week 2, highlighting its potential utility when rapid symptom control is a priority ²⁵.

Positioning: Abrocitinib represents an effective systemic option for moderate-to-severe AD, particularly in adolescents with severe pruritus requiring rapid control, who have had inadequate response to biologics and who prefer oral therapy. The 100 mg dose may offer a more favorable benefit-risk balance in patients with cardiovascular or thrombotic risk factors, whereas the 200 mg dose may be considered when maximal efficacy is needed and the risk profile allows it.

BARICITINIB

Baricitinib is an oral JAK1/JAK2 inhibitor approved for the treatment of moderate-to-severe AD in adults eligible for systemic therapy.

Baricitinib received FDA approval in 2021 for adult patients and is approved by the EMA and the Italian Medicines Agency (AIFA) for the treatment of moderate-to-severe AD in adult and pediatric patients aged 2 years and older. It is administered once daily at doses of 2 mg or 4 mg. The drug shows rapid absorption (peak concentration approximately 1 hour post-dose) and is primarily eliminated unchanged via renal excretion, with minimal CYP-mediated metabolism. This pharmacokinetic profile supports predictable exposure and convenient once-daily administration ^26,27.

Clinical efficacy

The BREEZE-AD phase 3 program evaluated baricitinib both as monotherapy and in combination with topical corticosteroids. Key findings include:

• Significant improvement in EASI-75 and IGA responses versus placebo with greater efficacy observed with the 4 mg dose and long standing results (IGA 0/1 at week 16 /week 68 45.7%/47.1% (4 mg) and 46.3%/59.3% (2 mg)) ²⁸.
• Reduction in pruritus and sleep disturbance.
• Safety analysis derived from 8 trials (All-bari A) with a duration of up to 200 weeks and a maximum exposure of 4.6 years of therapy, showed rates of MACE, DVT/PE, malignancies and serious infections within ranges of background rates in patients with AD ²⁹. Minor adverse events were generally consistent with the others JAK inhibitor class. Baseline and periodic laboratory evaluation is recommended.

However, network meta-analyses comparing oral JAK inhibitors suggests a decreasing scale of effectiveness, respectively, for upadacitinib, abrocitinib and baricitinib ³⁰.

Positioning: The 2 mg dose may offer a more favorable benefit-risk balance in patients with comorbid cardiovascular or thrombotic risk factors, whereas the 4 mg dose provides enhanced efficacy when disease severity warrants more intensive control. Compared with newer selective JAK1 inhibitors, baricitinib may offer slightly lower peak efficacy.

RUXOLITINIB

Ruxolitinib is a topical JAK1/JAK2 inhibitor approved for the treatment of mild-to-moderate AD ³¹. In 2022, ruxolitinib 1.5% cream received regulatory approval from FDA for short-term and non-continuous treatment of mild-to-moderate AD. Its topical formulation allows targeted cutaneous action with minimal systemic exposure, differentiating it from oral JAK inhibitors in terms of safety considerations ³².

Clinical efficacy

Two phase 3 studies (TRuE-AD1/TRuE-AD2) have shown:

• Significant improvement in Investigator’s Global Assessment (IGA) responses (at week 8, 1.5% ruxolitinib cream vs. vehicle 50.6% vs. 14.0%) and EASI-75 (60.9% vs. 34.9%).
• Rapid reduction in pruritus from day two with NRS4 (52.1% vs. 17.4%; P=0.009) ³³.
• Favorable tolerability with consistent short-term efficacy. The most commonly reported adverse events are mild application-site burning or stinging, transient erythema, and occasional local acneiform reactions ³⁴.

Positioning: Ruxolitinib cream represents an important non-steroidal topical option for: mild-to-moderate AD inadequately controlled with emollients, patients intolerant to or concerned about long-term corticosteroid use, sensitive areas (e.g., face, intertriginous regions), and situations where rapid pruritus control is needed without systemic exposure. Its targeted topical activity, rapid onset of action, and favorable tolerability profile position it as a valuable alternative to topical corticosteroids and calcineurin inhibitors within the evolving therapeutic algorithm of AD.

DELGOCITINIB

Delgocitinib is a topical pan-JAK inhibitor developed for the treatment of mild-to-moderate AD. Unlike selective JAK inhibitors, delgocitinib provides wider cytokine modulation at the local level, while maintaining minimal systemic exposure due to its topical formulation ³⁵. Delgocitinib was first approved in Japan in 2020 as the first topical JAK inhibitor for AD (≥16 years), with a pediatric formulation subsequently approved for children aged 2-16 years. In 2023, the EMA approved a 2% cream formulation for adults with moderate-to-severe chronic hand eczema refractory to topical corticosteroids ³⁶.

Clinical efficacy

Phase 3 trials QBA4-1 and QBA4-2 delgocitinib 0.5% ointment demonstrated:

• Significant improvement in mEASI (modified EASI) scores versus vehicle at 4 weeks 10.9% and at 24 weeks (22.7%);
• Sustained efficacy with long-term use up to 52 weeks (mEASI 27.5%);
• Consistent improvement in inflammatory lesions and pruritus;
• Favorable tolerability profile with minimal systemic absorption and reported adverse events including nasopharyngitis, headache, mild local reactions. No significant systemic safety signals have emerged in long-term studies ³⁷.

A Japanese Phase 3 pediatric trial demonstrated significant IGA reduction compared to vehicle (-39.3% vs. +10.9%, P <.001) at week 4 and through week 56 ³⁸. Its broad cytokine inhibition may be particularly relevant in patients with mixed inflammatory phenotypes beyond classic Th2 dominance.

Positioning: In clinical practice, delgocitinib represents a valuable steroid-sparing option for mild-to-moderate AD, particularly when broader local cytokine suppression is desired and long-term topical therapy is needed.

IVARMACITINIB

Ivarmacitinib is an oral highly selective JAK1 inhibitor characterized by very strong affinity for JAK1 and markedly lower activity against other JAK isoforms ³⁹. Ivarmacitinib was approved in China in April 2025 for adults with moderate-to-severe AD who are inadequately controlled with, or intolerant to, topical or other systemic therapies.

Clinical efficacy

In the Phase 3 QUARTZ3 trial (NCT04875169), once-daily ivarmacitinib demonstrated significant clinical benefit in adolescents and adults with moderate-to-severe AD. Key findings included:

• Higher rates of IGA clear/almost clear status compared with placebo at week 16 (42%). Both the 4 mg and 8 mg doses showed clinically relevant improvements, supporting a favorable benefit-risk balance in systemic candidates.
• Robust EASI-75 responses at week 16 (66%).
• Sustained efficacy through 52 weeks.
• Meaningful symptom reduction, including pruritus.
• Common side effects: upper respiratory tract infections, creatine phosphokinase (CPK) elevations, folliculitis. No unexpected safety signals emerged in trial populations, though long-term real-world data remain limited ⁴⁰.

Positioning: Given its high JAK1 selectivity and favorable efficacy profile, ivarmacitinib represents an emerging systemic option within the expanding oral JAK inhibitor landscape. Its ultimate positioning relative to established agents such as upadacitinib and abrocitinib will depend on broader international approvals and comparative long-term safety data.

EMERGING JAK-INHIBITORS

Lepzacitinib (ATI-1777) is a topical JAK1/JAK3 inhibitor formulated as an ethyl ester prodrug designed to ensure potent local activity while minimizing systemic exposure through rapid metabolic inactivation. In Phase 2 studies, the 2% formulation demonstrated reductions in modified EASI scores of -75%, compared to -42% in the vehicle group with good local tolerability. Its prodrug design may offer a safety advantage over other topical JAK inhibitors, although long-term data are still limited ⁴¹.

Jaktinib (gecacitinib) is an oral pan-JAK inhibitor, originally developed for myelofibrosis, that exerts broad suppression of JAK-STAT signaling. The Phase 2 trial NCT04539639 of the 50 mg twice-daily dose demonstrated significant clinical responses at week 12, including EASI-50 (80.9% vs. 54.5% with placebo) and EASI-75 improvements. No serious adverse events were described. As with other systemic kinase inhibitors, long-term safety monitoring will be critical to define its place relative to more selective JAK1 inhibitors ⁴².

Gusacitinib (ASN002) is an oral dual JAK/SYK inhibitor that combines inhibition of multiple JAK isoforms with blockade of spleen tyrosine kinase (SYK), thereby targeting both adaptive and innate immune signaling. Early-phase trials study (NCT03654755) showed rapid and sustained clinical improvements in moderate-to-severe AD. By extending beyond selective JAK inhibition, gusacitinib may provide broader immunomodulation, particularly relevant in complex inflammatory phenotypes. Long-term safety remains to be clarified ^43,44.

INTERLEUKIN-2–INDUCIBLE T-CELL KINASE (ITK) INHIBITORS

Soquelitinib is an oral covalent inhibitor of interleukin-2–inducible T-cell kinase (ITK), acting upstream at the level of T-cell receptor signaling. By preferentially suppressing Th2 cytokines (IL-4, IL-5, IL-13), it represents a mechanistically distinct approach compared with JAK inhibitors ⁴⁵. Early-phase 1 trial NCT06345404 suggest meaningful EASI improvement with 200 mg BID dose reducing EASI scores by 64.8% at day 28 versus 34.4% for placebo. The drug showed favorable short-term tolerability with no dose-limiting toxicities ⁴⁶.

ATI-2138 is a first-in-class oral covalent inhibitor targeting both ITK and JAK3, thereby modulating T-cell activation and cytokine signaling simultaneously. Phase 1 trials in healthy volunteers showed good tolerability up to 80 mg and dose-dependent inhibition of IL-2 and IFN-γ production, supporting further development in Th2-driven diseases ⁴⁷.

STAT6 DIRECTED THERAPIES

Mechanism of action

STAT6 is a pivotal transcription factor downstream of IL-4 and IL-13 signaling, orchestrating Th2-driven immune responses central to atopic dermatitis (AD) and other allergic conditions. Upon cytokine binding, receptor-associated JAK activation leads to STAT6 phosphorylation, dimerization, nuclear translocation, and transcription of pro-inflammatory genes involved in type 2 inflammation.

While JAK inhibitors indirectly modulate STAT6 activation, they act broadly on multiple cytokine pathways, raising concerns about off-target effects. Direct inhibition of STAT6 has historically been challenging due to structural features such as its almost flat SH2 binding pocket (key for dimerization STAT-STAT) and high homology within the STAT family ⁴⁸.

Recent advances in targeted protein degradation have renewed interest in STAT6 as a therapeutic target. Proteolysis-targeting chimeras (PROTACs) promote ubiquitination and proteasomal degradation of STAT6, enabling functional silencing of this key transcription factor rather than simple enzymatic inhibition. This approach may offer a novel, orally available strategy to selectively disrupt IL-4/IL-13 signaling in AD ⁴⁹. However, STAT6-degrader (KT 621, NX 3911) and STAT6-inhibitors (REX-8756) remain in early clinical development, and their future role will depend on demonstrating sustained efficacy and long-term safety in larger trials.

STAT6 directed molecules

KT-621 is an oral targeted protein degrader that promotes selective proteasomal elimination of STAT6 rather than enzymatic inhibition. In a Phase 1 clinical trial (NCT06673667), it achieved >90% STAT6 degradation in peripheral blood and complete degradation in blood and skin at higher doses at doses exceeding 50 mg, with favorable tolerability. Ongoing trials in AD will clarify its clinical potential ⁵⁰.

NX-3911 is another investigational oral STAT6 degrader that induces selective STAT6 elimination. Preclinical models demonstrated rapid STAT6 degradation, effective inhibition of type 2 inflammation, and therapeutic benefit in AD and asthma animal models. Clinical development is forthcoming ⁵¹.

In contrast, REX-8756 is a first-in-class oral, reversible STAT6 inhibitor that blocks phosphorylation and activation of STAT6 by targeting its SH2 domain, without degrading the protein. Preclinical data show sustained inhibition of Th2 gene expression and efficacy comparable to IL-4/IL-13 biologics in experimental animal models ⁵².

PHOSPHODIESTERASE-4 INHIBITORS

Mechanism of action

Phosphodiesterase 4 (PDE4) is an intracellular enzyme responsible for degrading cyclic adenosine monophosphate (cAMP), a key second messenger involved in immune and inflammatory regulation. PDE4 is widely expressed in immune cells, including T and B lymphocytes, eosinophils, mast cells, macrophages, and neutrophils, as well as in skin cells such as keratinocytes and endothelial cells. Four PDE4 subtypes (PDE4A-D) generate multiple isoforms with different tissue distributions, but their high structural similarity makes isoform-selective inhibition challenging ⁵³.

In AD, PDE4 activity is increased, leading to reduced intracellular cAMP levels. Lower cAMP promotes activation of pro-inflammatory pathways, including NF-κB signaling, and enhances the production of cytokines such as IL-4 and IL-13, central drivers of type 2 inflammation.

PDE4 inhibitors counteract this process by preventing cAMP degradation. Elevated cAMP activates protein kinase A (PKA), which suppresses pro-inflammatory mediator release (e.g., TNF-α, IFN-γ, IL-12) and promotes anti-inflammatory cytokines such as IL-10 ⁵⁴. Through this shift in intracellular signaling balance, PDE4 inhibition dampens cutaneous inflammation, contributing to reductions in erythema, pruritus, and lesion severity. Overall, PDE4 inhibitors act as intracellular immunomodulators that rebalance inflammatory signaling rather than directly targeting individual cytokines.

Current molecules

Among oral PDE4 inhibitors, apremilast is approved for plaque psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease, reflecting its systemic anti-inflammatory activity mediated through cAMP modulation.

Roflumilast, initially developed as an oral therapy for severe chronic obstructive pulmonary disease, has more recently been formulated for topical use in dermatology and approved for plaque psoriasis, seborrheic dermatitis, and AD, highlighting its tissue-specific therapeutic adaptability.

In the dermatologic setting, topical PDE4 inhibitors such as crisaborole and difamilast have expanded non-steroidal options for mild-to-moderate atopic dermatitis, providing local anti-inflammatory effects with minimal systemic exposure.

Collectively, these approvals support the concept of “PDE4 inhibitor-responsive dermatoses” ⁵⁵. Rather than targeting a single cytokine axis, PDE4 inhibition rebalances inflammatory networks, accounting for its therapeutic breadth across different immune-mediated diseases.

CRISABOROLE

Crisaborole is a topical boron-based phosphodiesterase 4 (PDE4) inhibitor developed for the treatment of mild-to-moderate AD. Its benzoxaborole structure enhances selective binding to the PDE4 active site by interacting with catalytic metal ions, thereby stabilizing enzyme inhibition and reducing cAMP degradation ⁵⁶. Through this mechanism, crisaborole increases intracellular cAMP levels and attenuates pro-inflammatory signaling.

Crisaborole was the first PDE4 inhibitor approved for AD, receiving FDA approval in 2016 (initially for patients ≥2 years, later expanded to ≥3 months) and EMA approval in 2020. Later withdrawal by the EMA in 2022 was due to commercial considerations. It is available as a 2% ointment for topical use in adults and pediatric patients from 3 months of age with BID application.

Clinical efficacy and safety

The Phase 3 clinical trials AD-301 (NCT02118766), AD-302 (NCT02118792) and later studies have demonstrated:

• Significant improvement in disease severity scores in mild-to-moderate AD with IGA 0/1 score at week 4 AD-301 vs. vehicle of 51.7% vs. 40.6% (P = .005), and AD-302 vs. vehicle 48.5% vs. 29.7% (P<.001) ⁵⁷.
• Rapid reduction of inflammation and improvement in skin barrier function ⁵⁸.
• Consistent efficacy across diverse racial and ethnic populations ⁵⁹.
• Favorable outcomes in infants and young children with minimal systemic exposure.
• Good safety profile with the most common adverse event being mild, transient application-site pain. Serious adverse events have not been observed in clinical trials, and systemic absorption is minimal ⁶⁰.

According to the Cochrane review by Lax et al., phosphodiesterase-4 inhibitors demonstrate lower efficacy compared to medium- to high-potency TCS, tacrolimus 0.1%, and JAK inhibitors which rank among the most effective short-term treatments for AD. In the comparison between potent TCS and crisaborole 2%, the odds ratio was approximately 6.10 (95% CI 3.00-12.41) in favor of corticosteroids.

In the non-severe subgroup, difamilast and ruxolitinib ranked higher than roflumilast and crisaborole, highlighting variability in efficacy even within the same pharmacologic class.

When compared with pimecrolimus, PDE4 inhibitors showed similar efficacy (OR ≈ 1.02), but were less effective than tacrolimus 0.1% and moderate-to-potent TCS.

Importantly, the Cochrane analysis did not demonstrate superior cutaneous tolerability of PDE4 inhibitors compared with pimecrolimus. Although PDE4 inhibitors were more frequently associated with application-site burning compared to vehicle, this did not translate into higher rates of treatment discontinuation ⁶¹.

Positioning: Crisaborole represents a well-established non-steroidal topical option for mild-to-moderate AD, particularly suitable for: pediatric patients, including infants, sensitive anatomical areas, and long-term steroid-sparing strategies.

ROFLUMILAST

Roflumilast is a highly potent and selective PDE4B/D inhibitor that suppresses type 2 cytokine-driven inflammation by preventing cAMP degradation. Its binding to the catalytic domain of PDE4 closely mimics cAMP interaction, explaining its strong inhibitory activity.

While roflumilast was initially developed as an oral therapy for severe chronic obstructive pulmonary disease, topical formulations have enabled its use in dermatology. Topical administration achieves high cutaneous concentrations with minimal systemic exposure, supported by a stratum corneum reservoir effect that allows sustained local activity ⁶². Roflumilast is FDA-approved in topical formulations for mild-to-moderate AD (≥2 years, from October 2025), plaque psoriasis and seborrheic dermatitis.

Clinical efficacy and safety

Clinical trials in mild-to-moderate AD have shown:

• Significant improvement in EASI scores compared with vehicle
• Higher rates of IGA success
• Rapid reduction in pruritus and improvement in sleep and quality of life
• Consistent efficacy across pediatric and adult populations ⁶³.

The Phase 3 trials INTEGUMENT-1 and -2 confirmed superior outcomes of roflumilast cream 0.15%, applied once daily versus vehicle in patients aged ≥6 years (IGA 0/1 and ≥2-grade improvement of 31.3% vs. 14.1% of vehicle) ⁶⁴, while the INTEGUMENT-PED study demonstrated efficacy, in children aged 2-5 years, of roflumilast cream 0.05% applied once daily (IGA 0/1 and ≥2-grade improvement of 25.4% vs. 10.7% of vehicle; EASI-75 39.4% vs. 20.6% and WI-NRS Success 35.3% vs. 18.0%; improvement in pruritus within 24 h after the first application [nominal p = 0.0014]). Topical roflumilast is generally well tolerated at all timepoints, with application-site stinging/burning reported by ≤ 0.7% of caregivers of patients in the roflumilast group ⁶³.

Positioning: Roflumilast represents a valid non-steroidal topical option within the PDE4 inhibitor class. Compared with earlier topical PDE4 inhibitors, it appears to provide stronger clinical efficacy while maintaining a favorable safety profile.

DIFAMILAST

Difamilast (OPA-15406) is a topical PDE4 inhibitor structurally characterized by a 3,4-dialkoxyphenyl group that contributes to high binding affinity within the PDE4 catalytic site. Preclinical studies demonstrated potent activity in models of allergic and chronic dermatitis, with efficacy exceeding that of crisaborole in some experimental settings. Importantly, topical administration results in minimal systemic absorption, reducing the risk of systemic adverse effects, such as nausea and diarrhea, associated with oral PDE4 inhibition ⁶⁵.

Difamilast has been approved in Japan since 2021 for the treatment of AD in patients aged ≥2 years (0.3% and 1% ointment formulations, applied twice daily) and in February 2026 the FDA also approved it (Adquey), for the treatment of mild to moderate AD in patients 2 years and older.

Clinical efficacy and safety

Several trials demonstrated its efficacy in adults:

• In a Phase 3 trial, difamilast 1% ointment showed significantly better outcomes than vehicle (IGA 0/1 at week 4: 38.46 vs. 12.64%) with substantially improved EASI scores. Difamilast was well-tolerated with adverse events being mild or moderate ⁶⁶.
• Similarly, a meta-analysis of 5 randomized controlled trials supported these findings, reporting significant improvements in IGA and EASI scores at week 4. No significant differences in treatment-related adverse events were noted between difamilast and vehicle, confirming the treatment’s safety ⁶⁷.
• Difamilast has also been evaluated in pediatric and adolescent populations with AD:
• A Phase 2 trial evaluated with either difamilast (0.3% or 1%) or a vehicle ointment twice daily for 4 weeks in 73 Japanese pediatric patients with AD, aged 2-14 years; the drug was well tolerated, with no serious events reported and efficient in reducing IGA, EASI,and pruritus score from baseline, compared to the vehicle group ⁶⁸.
• A recent Phase 3, long-term, open-label study in Japanese infants with AD aged 3 to <24 months, evaluated difamilast 0.3% and 1% ointment showing response in the IGA score of 56.1% at week 4, and 75.6% at week 52. The response rate in EASI-75 was 82.9% at week 4, and maintained at 80.5% at week 52. Adverse events were reported in 41 (100.0%) infants, most of which were mild or moderate in severity (nasopharyngitis in 82.9% and gastroenteritis in 46.3%). Difamilast was demonstrated to be effective up to 52 weeks and well tolerated, indicating a new useful treatment option for this population ⁶⁹.

Positioning: Difamilast represents a pediatric-focused non-steroidal topical option within the PDE4 inhibitor class. Compared with earlier agents, it demonstrates consistent efficacy. Minimal systemic absorption supports its safety profile in children, especially in mild-to-moderate AD requiring long-term steroid-sparing therapy.

APREMILAST

Apremilast is an oral PDE4 inhibitor approved in the United States for psoriatic arthritis, moderate-to-severe plaque psoriasis, and oral ulcers in Behçet’s disease. Although primarily developed for psoriasis, several Phase 2 trials in adults with moderate-to-severe AD demonstrated modest reductions in EASI scores, with greater efficacy observed at higher doses. In a Phase 2 trial, participants were randomized to receive either placebo, 30 mg of apremilast twice daily (APR30), or 40 mg twice daily (APR40). At week 12, among 185 patients, the APR40 group showed significant improvements in EASI (-31.6%) compared to APR30 (-11.0%) and placebo. However, APR40 was associated with increased adverse events, including gastrointestinal symptoms and cases of cellulitis, limiting further development in AD, especially in the pediatric population ⁷⁰.

Positioning: Apremilast illustrates the systemic potential of PDE4 inhibition, but its clinical impact in AD appears limited compared with newer targeted agents.

ORISMILAST

Orismilast is an oral PDE4 inhibitor targeting PDE4B and PDE4D isoforms, with relative selectivity over other subtypes. In a Phase IIb randomized trial (Adesos trial, NCT05469464) in adults with moderate-to-severe AD, oral orismilast (20, 30, or 40 mg) demonstrated rapid pruritus reduction and clinical improvement by 2 weeks. Adverse events were consistent with the PDE4 inhibitor class, predominantly gastrointestinal (nausea and diarrhea), and generally manageable ⁷¹.

Positioning: Orismilast represents a next-generation oral PDE4 inhibitor with promising antipruritic effects, although long-term comparative data are still needed.

PF-07038124

PF-07038124 is a topical, boron-based selective PDE4B2 inhibitor designed using a “soft-drug” strategy, allowing rapid metabolic inactivation upon systemic absorption to minimize systemic exposure ⁷². In a Phase 2a study in mild-to-moderate AD and plaque psoriasis, once-daily topical application of PF-07038124 0.01% ointment led to substantial reductions in EASI (-74.9%) and PASI (-4.8) scores by week 6, compared with vehicle (-35.5% and 0.1, respectively), with no significant local tolerability concerns ⁷³.

Positioning: PF-07038124 represents an investigational topical PDE4 inhibitor combining high local efficacy with a favorable safety strategy aimed at reducing systemic risk.

LOTAMILAST (E6005, RVT-501)

Lotamilast is a selective topical PDE4 inhibitor characterized by a quinazoline core structure ⁷⁴. Beyond anti-inflammatory activity, preclinical data suggest additional antipruritic effects, including inhibition of PAR2-mediated itch pathways, reduction of leukotriene B4 production, and attenuation of C-fiber nerve signaling ⁷⁵.

Clinical efficacy and safety

In a Phase 2 trial in Japanese adults with AD, the drug was well-tolerated with no serious adverse events. At 4 weeks, significant improvements were observed in the EASI, SCORAD, and pruritus scores compared to the vehicle group. Longer treatment for an additional 8 weeks showed further significant reductions in these scores, supporting its efficacy over longer periods ⁷⁶.

An exploratory study in Japanese children with mild-to-moderate AD treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks showed it to be safe and well-tolerated. The 0.2% E6005 group showed higher treatment success compared to vehicle (IGA response 34.4% vs. 20.0%) and decreased pruritus score (-37.5% vs. -6.7%) ⁷⁷.

Positioning: Lotamilast may offer dual anti-inflammatory and antipruritic benefits, potentially interrupting the itch-scratch cycle in the pediatric AD population.

HSK44459

HSK44459 is a selective PDE4B inhibitor under clinical development, designed to provide anti-inflammatory and anti-fibrotic effects with improved tolerability compared with non-selective PDE4 inhibitors. Structural details remain undisclosed.

A Phase 2 randomized, placebo-controlled trial (NCT06996912) is ongoing to evaluate its safety and efficacy in adults with AD ⁷⁸.

Positioning: HSK44459 represents a precision PDE4 subtype-targeting strategy, aiming to enhance benefit-risk balance within the PDE4 inhibitor class.

ARYL HYDROCARBON RECEPTOR MODULATING AGENTS

Mechanism of action

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/PAS family. It functions as a sensor of environmental, microbial, dietary, and metabolic signals and plays a central role in maintaining immune and epithelial homeostasis ⁷⁹.

In the skin, AhR activation promotes epidermal differentiation and barrier integrity by upregulating structural proteins such as filaggrin (FLG), loricrin, and involucrin. Beyond keratinocyte biology, AhR modulates innate and adaptive immune responses, influencing cytokine production, antimicrobial peptide expression, and the balance between regulatory and effector T-cell subsets ^80,81.

In atopic dermatitis (AD), dysregulated AhR signaling has been associated with altered cytokine profiles, particularly increased IL-22 production from Th22 cells ⁸². Elevated IL-22 contributes to impaired keratinocyte differentiation and epidermal hyperplasia, worsening barrier dysfunction ⁸³.

AhR activity also intersects with IL-17–mediated pathways, which may further promote keratinocyte proliferation and chronic inflammation. Thus, pharmacologic modulation of AhR aims to restore epidermal differentiation and rebalance inflammatory signaling, rather than simply suppressing immune activation ⁸⁴.

TAPINAROF

Tapinarof (3,5-dihydroxy-4-isopropyl-trans-stilbene) is a topical AhR modulator derived from a bacterial metabolite. Its lipophilic structure supports effective dermal penetration, and it is formulated as a 1% cream, with once daily application regimen, approved in the United States down to 2 years of age ⁸⁵.

Clinical efficacy

Tapinarof was tested in adult and pediatric populations:

• A Phase 2b trial in adolescents and adults with AD evaluated the efficacy and safety of tapinarof 1% cream twice daily. The study revealed IGA 0/1 in 53% of tapinarof group (compared to 24-28% in the vehicle group) with significantly higher rates of EASI-75 and a ≥3-point improvement in pruritus. Common adverse events included folliculitis, headache, and upper respiratory infections ⁸⁶.
• Tapinarof cream 1% once daily demonstrated significant efficacy in patients from the age of 2 years with AD in the ADORING 1 and 2 (NCT05014568, NCT05032859) Phase 3 trials. Treatment was well tolerated, including on sensitive skin areas, with improvement of symptoms and quality of life and no-to-minimal burning/stinging and itching, from first application through Week 8 ⁸⁷.

Concerns about the long-term risks of AhR activation, including a potential link to squamous cell carcinoma remain unconfirmed in clinical practice ⁸⁷.

Positioning: Tapinarof represents a novel non-steroidal topical option for mild-to-moderate AD that combines barrier restoration with immune modulation. Unlike PDE4 or JAK inhibitors, AhR modulation promotes epidermal differentiation while rebalancing inflammatory signaling, positioning it as a mechanistically distinct alternative within the expanding topical therapeutic landscape.

HISTAMINE H4 RECEPTOR ANTAGONISTS

Mechanism of action

The histamine H4 receptor (H4R), identified in 2000, is the most recently characterized histamine receptor subtype and plays a central role in immune and allergic inflammation. It is expressed in multiple immune cells and in the skin, particularly within the epidermis, suggesting involvement in pruritus modulation, immune activation, and barrier-related responses.

Given its dual role in itch signaling and inflammatory regulation, H4R has been explored as a potential therapeutic target in atopic dermatitis, asthma, and allergic rhinitis ⁸⁸. Several H4R antagonists have advanced into clinical development; however, translation from preclinical promise to clinical efficacy has proven challenging.

JNJ-39758979

JNJ-39758979 was the first oral H4R antagonist evaluated in humans. Early studies demonstrated rapid reduction of histamine-induced itch in healthy volunteers, supporting its mechanistic relevance in pruritus.

However, in a Phase 2a trial (NCT01497119) in adults with moderate AD, the study was terminated prematurely after cases of agranulocytosis occurred. These events were attributed to reactive metabolites rather than direct H4R blockade, leading to discontinuation of the program ⁸⁹.

Positioning: Although proof-of-concept for antipruritic activity was established, safety concerns halted further development.

ADRIFORANT (ZPL389)

Adriforant is an oral H4R antagonist with demonstrated preclinical anti-inflammatory and antipruritic effects. In murine models, it reduced histamine-induced itch and attenuated dermatitis severity. Despite promising in vitro and animal data, a phase 2 clinical trial (NCT03948334) in AD failed to meet primary efficacy endpoints ⁹⁰.

Positioning: These results suggest that isolated H4R antagonism may be insufficient to achieve clinically meaningful disease control in AD.

IZUFORANT (LEO 152020 / JW1601)

Izuforant is an oral H4 receptor inverse agonist designed to combine antipruritic and anti-inflammatory effects. In a phase 2, placebo-controlled trial (NCT05117060) in moderate-to-severe AD, it did not demonstrate statistically significant improvement in EASI scores compared with placebo. Following these findings, the development program was discontinued ^91,92.

Positioning: Clinical outcomes further underscore the limited therapeutic impact of selective H4R targeting in AD.

SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR MODULATORS

Mechanism of action

Sphingosine-1-phosphate receptor (S1PR) modulators act by initially activating S1P receptors, followed by receptor internalization and functional downregulation, ultimately suppressing S1P-mediated lymphocyte trafficking. This mechanism reduces immune cell egress from lymphoid tissues and dampens inflammatory responses.

Fingolimod, approved in 2010 for relapsing-remitting multiple sclerosis, established proof of concept for S1PR targeting in immune-mediated disease. Interest has since extended to inflammatory skin disorders, including AD. However, systemic immunomodulation and potential off-target effects, particularly cardiovascular concerns, remain important considerations ⁹³.

ETRASIMOD

Etrasimod is an oral selective modulator of S1PR1, S1PR4, and S1PR5. It has been evaluated in moderate-to-severe AD in a Phase 2 trial with daily doses of 1 mg and 2 mg over 12 weeks. While the primary endpoint (EASI-75) was not met, modest clinical signals were observed with the 2 mg dose. Safety was generally acceptable, with no major safety concerns reported ⁹⁴. A subsequent phase 2/3 trial in treatment-resistant AD was terminated early due to lack of efficacy ⁹⁵.

Positioning: Despite biological plausibility, clinical benefit in AD appears limited.

BMS-986166

BMS-986166 is an oral prodrug of an active S1PR1 modulator designed to improve cardiac safety relative to earlier S1P-targeting agents ⁹⁶. Preclinical studies demonstrated anti-inflammatory effects in AD models, including reduced skin inflammation and immune cell infiltration. The compound advanced to a Phase 2 clinical trial (NCT05014438) in moderate-to-severe AD. However, limited participant numbers restrict the interpretability of results ⁹⁷.

Positioning: While preclinical rationale is strong, clinical development in AD remains uncertain.

SCD-044 (VIBOZILIMOD)

SCD-044 (vibozilimod) is an oral selective S1PR1 agonist investigated for plaque psoriasis and AD ⁹⁸. In Phase 2 trials for plaque psoriasis (NCT04566666) and AD (NCT04684485), it showed acceptable safety and expected reductions in circulating lymphocyte counts, confirming biological activity. However, the compound failed to achieve significant improvements in PASI-75 and EASI-75 compared with placebo. Following these negative efficacy outcomes, development was discontinued ⁹⁹.

Positioning: Clinical data suggest that S1PR1 modulation alone may not provide sufficient therapeutic impact in AD.

CONCLUSION

Table II provides a comprehensive overview of the new small molecule therapies for AD. The therapeutic landscape of AD has entered an era of increasingly refined intracellular modulation. Beyond biologic cytokine blockade, small molecules now target multiple levels of immune signaling, from second messengers to transcription factors and lymphocyte trafficking pathways.

Topical small molecules have expanded the non-steroidal therapeutic options for mild-to-moderate AD, offering targeted anti-inflammatory activity with minimal systemic exposure. Among them, topical JAK inhibitors (ruxolitinib, a JAK1/JAK2 inhibitor; delgocitinib, a pan-JAK inhibitor), PDE4 inhibitors and Ahr modulating agents differ in mechanism and clinical impact.

Topical JAK inhibitors act directly on cytokine receptor signaling pathways that are central to AD, resulting in more rapid and clinically pronounced reductions in pruritus and lesion severity compared with PDE4 inhibitors, which modulate inflammation indirectly through cAMP signaling. Ruxolitinib, in particular, has demonstrated fast itch relief and meaningful improvement in clinical endpoints, while delgocitinib provides broader cytokine inhibition and sustained efficacy. PDE4 inhibitors generally show more modest efficacy, but remain useful as steroid-sparing options in mild disease. Unlike PDE4 or JAK inhibitors, AhR modulator (Tapinarof) combines barrier restoration with immune modulation, expanding topical therapeutic landscape.

All three classes exhibit favorable safety profiles, due to limited systemic absorption, with mostly mild application-site reactions. In current practice, topical JAK inhibitors are often preferred when rapid symptom control is needed, whereas PDE4 inhibitors are frequently positioned in milder phenotypes or maintenance strategies.

To date, topical small molecules with pediatric approval for mild-to-moderate atopic eczema include: Ruxolitinib (≥12 yrs USA and UE, ≥2 yrs Japan), delgocitinib (≥2 yrs Japan), crisaborole (≥3 months USA, ≥2 yrs Canada, Israel and Australia), roflumilast (≥2 yrs USA), difamilast (≥2 yrs USA and Japan), and tapinarof (≥2 yrs USA).

For systemic treatment of moderate-to-severe AD, JAK inhibitors have demonstrated that deeper and faster disease control can be achieved by directly interfering with cytokine receptor signaling. Among oral small molecules, selective JAK1 inhibition currently provides the highest efficacy, with a descending gradient from upadacitinib to abrocitinib to baricitinib. However, long-term safety, risk stratification, and patient selection remain pivotal to optimal positioning.

To date pediatric oral approved small molecules for moderate-severe atopic eczema are: upadacitinib (≥12 yrs USA, UE, Italy), abrocitinib (≥12 yrs USA, UE, Italy), and baricitinib (≥2 yrs USA, UE, Italy).

Emerging strategies aim for greater specificity. Dual kinase inhibitors (e.g., JAK/SYK) and ITK-targeting agents seek to modulate upstream T-cell activation, while STAT6 inhibitors and degraders directly silence the central transcriptional hub of IL-4/IL-13 signaling. Together, these approaches reflect a shift from broad pathway suppression toward precision targeting of type 2 inflammation. In contrast, H4 receptor antagonists and S1P receptor modulators, despite strong biological rationale, have shown limited or inconsistent clinical efficacy in AD, underscoring the complexity of disease pathogenesis and the need for pathway-relevant intervention.

Overall, the future of small molecules in AD lies in balancing three key dimensions: (1) depth of efficacy, (2) selectivity of immune modulation, and (3) long-term safety and tolerability. As intracellular targeting becomes more sophisticated, therapeutic decisions will likely evolve toward phenotype-driven and risk-adapted strategies that integrate mechanism of action with individual inflammatory profiles. The next phase of innovation will clarify whether highly selective transcriptional targeting can match, or surpass, the benchmark established by cytokine-directed biologics, potentially redefining systemic therapy in AD.

Funding

This research received no external funding.

Conflict of interest statement

The authors declare no conflict of interest.

Authors’ contributions

Conceptualization, F.M and A.G.; Resources F.M, L.P. and A.G., Methodology, F.M and A.G; Writing-Original Draft Preparation F.M, L.P. and A.G.; Writing-Review & Editing F.M, and A.G.; Supervision, A.G.

History

Received: February 28, 2026

Published: March 27, 2026

Figures and tables

TABLE I. Key clinical instruments for assessing atopic dermatitis severity and trial endpoints.

Instrument	Mild	Moderate	Severe	Score Range / Notes	Role in Clinical Trials
EASI (Eczema Area and Severity Index)	0-7	7.1-21	>21	Total score 0-72; assesses objective signs and body surface area	Primary endpoint (e.g., EASI-75, EASI-90)
SCORAD (SCORing Atopic Dermatitis)	<25	25-50	>50	Total score 0-103; includes pruritus and sleep disturbance	Less frequently used as primary endpoint
IGA (Investigator’s Global Assessment, 0-4 scale)	2 = Mild	3 = Moderate	4 = Severe	Ordinal clinician-reported global severity scale	Regulatory co-primary endpoint (IGA 0/1 with ≥2-point improvement)
Pruritus NRS (Numerical Rating Scale)	1-3	4-6	7-10	Total score: 0-10; MCID: ≥4-point reduction	Secondary endpoint; itch burden assessment
DLQI (Dermatology Life Quality Index, adults)	2-5	6-10	>10	Total score 0-30	Secondary endpoint; quality-of-life impact
CDLQI (Children’s Dermatology Life Quality Index, 4-16 yrs)	2-6	7-12	>13	Total score 0-30	Secondary endpoint; pediatric QoL impact
IDQoL (Infants’ Dermatitis Quality of Life Index, 0-4 yrs)	2-5	6-10	>10	Total score 0–30	Secondary endpoint; caregiver-reported QoL impact

TABLE II. Comprehensive overview of novel small molecules in atopic eczema. Agents approved for pediatric use are highlighted in green.

Janus kinase inhibitors
Formulazione	Drug	Mechanism	Age in trials	Dose in trials	Efficacy Endpoints	Adverse Effects	Drug approval	Indication
Oral	Upadacitinib	JAK1 inhibitor	≥12 yrs	15 mg or 30 mg, once daily	Measure Up 1: EASI-75 achieved by 70% (15 mg) and 80% (30 mg) vs. 16% on placebo Measure Up 2: EASI-75 achieved by 60% (15 mg) and 73% (30 mg) vs. 13% on placebo	Very common: acne, upper respiratory infections, nasopharyngitis, headache, elevated CPK Common: neutropenia, herpes simplex/zoster, lab changes (CPK, liver enzymes) dose-dependent but generally mild	FDA, EMA, AIFA ≥12 yrs	Moderate-severe AD
	Abrocitinib	JAK1 inhibitor	≥12 yrs	100 mg or 200 mg, once daily	JADE MONO-1, MONO-2, COMPARE: EASI-75 at week 12 achieved in 40-69% of patients with 100 mg JADE EXTEND: at week 48 (200 mg vs. 100 mg): IGA 0/1 52% and 39%, EASI-75 82% and 67%, NRS ≥-4 point 68% and 51%	Very common: headache, nausea, acne, nasopharyngitis, herpes simplex, elevated CPK, vomiting, dizziness, abdominal pain Common: infections, hematologic lab changes, diarrhea, conjunctivitis	FDA, EMA, AIFA ≥12 yrs	Moderate-severe AD
	Baricitinib	JAK1/JAK2 inhibitor	≥2 yrs	2 mg or 4 mg, once daily	BREEZE-AD: EASI-75 at week 16 achieved in 13% (1 mg) and 24% (2 mg)	Very common: nasopharyngitis Common: headache, upper respiratory tract infections, herpes simplex	FDA, EMA, AIFA ≥2 yrs	Moderate-severe AD
	Ivarmacitinib	JAK1 inhibitor	≥12 yrs	4 mg or 8 mg	QUARTZ3: EASI-75 at week 16 achieved in 66%	Common: upper respiratory infections, increased CPK levels, and folliculitis	China adults	Moderate-severe AD
	Gusacitinib	JAK/SYK inhibitor	≥18 yrs	40-60-80 mg	Phase I/IIb (NCT03654755) trials: significant improvement in pruritus and EASI at 4 weeks	Common: upper respiratory tract infection, headache, nausea, and nasopharyngitis	/	/
	Jaktinib	Pan-JAK inhibitor	≥18 yrs	50-75-100 mg BID	Phase 2 trial (NCT04539639): EASI-75 64.4%, 65.1% and 71.4% of the Jaktinib 50-75-100 mg group IGA response in 24.4%, 41.9%, and 35.7% respectively	Generally well tolerated, with adverse events mostly mild to moderate	/	/
Topical	Ruxolitinib	JAK1/JAK2 inhibitor	≥2 yrs	1.5% cream, twice daily	TRuE-AD1: EASI-75 at week 8 achieved by 56.0% (0.75%), 62.1% (1.5%) TRuE-AD2: EASI-75 at week 8 achieved by 51.5% (0.75%), 61.8% (1.5%) TRuE AD3 (2-11 yrs): at week 4, through week 52, reduction in affected BSA and IGA	Common: nasopharyngitis, upper respiratory tract infection, headache, application site burning, application site pruritus	FDA, EMA ≥12 yrs Japan ≥2 yrs	Mild-moderate AD
	Delgocitinib	pan-JAK inhibitor	≥6 months	2%, 0.5%, and 0.25% ointment	QBA4-1: mEASI-75 at week 4 achieved by 10.9% and at week 24 by 22.7% QBA4-2: mEASI-75 at week 52 achieved by 27.5% Pediatric trials: at week 4 IGA0/1 mild AD 46.2% (0.25% ointment), 71.4% (0.5% ointment) and 7.7% (vehicle); moderate-severe AD 19%, 20% and 0% respectively	Common: nasopharyngitis, contact dermatitis, acne, application site folliculitis	Japan ≥2 yrs	Mild-moderate AD
	Lepzacitinib	JAK1 and JAK3 inhibitor	≥18 yrs	0.5%, 1.0%, and 2.0% solutions twice daily	Phase IIa trial (NCT04598269.): In moderate-severe AD, at 4 weeks: EASI reduction 75% (2% solution), compared to 41% in the vehicle group	Adverse events comparable to vehicle	/	/
Interleukin-2-inducible T-cell kinase (ITK) inhibitors
Oral	Soquelitinib	ITK inhibitor	≥18 yrs	200 mg BID	Phase I trial (NCT06345404): in moderate-severe AD, reduced EASI scores by 64.8% at day 28 vs. 34.4% for placebo	No significant adverse events reported	/	/
	ATI-2138	ITK and JAK3 inhibitor	≥18 yrs	Up to 80 mg	Phase I trials: good tolerability, linear pharmacokinetics, and dose-dependent inhibition of IL-2 and IFNγ	No significant adverse events reported	/	/
STAT6 Directed Therapies
Oral	KT-621	STAT6 degrader	≥18 yrs	Up to 800 mg	Phase I clinical trial (NCT06673667): over 90% STAT6 degradation in blood at doses ≥ 6.25 mg, with complete degradation in blood and skin observed at doses exceeding 50 mg	No serious adverse events	/	/
	REX-8756	Reversible, STAT6 inhibitor	/	/	Preclinical studies: complete and durable inhibition of STAT6 Phosphorylation, with suppressed inflammatory gene expression In animal models reduced type 2 inflammatory biomarkers with therapeutic efficacy comparable to anti-IL-4/IL-13 biologics	Favorable tolerability	/	/
	NX-3911	STAT6 degrader	/	/	In preclinical studies: fast and effective degradation of STAT6 in blood and skin tissues, with complete suppression of IL-4/IL-13-driven inflammatory pathways In animal models: efficacy in type 2-mediated diseases	/	/	/
Phosphodiesterase 4 Inhibitors
Topical	Crisaborole	PDE4 inhibitor	≥3 months	2% ointment BID	AD-301: at week 4, mild AD IGA0/1 51.7% vs. 40.6% of vehicle AD-302: at week 4, mild AD IGA0/1 48.5% vs. 29.7% of vehicle	Application site pain	FDA ≥3 months Canada, Israel and Australia ≥2 yrs	Mild-to-moderate AD
	Roflumilast	PDE4B/D inhibitor	≥2 yrs	0.15% and 0.05% cream once daily	INTEGUMENT-1 IGA 0/1 and ≥2 point improvement 32.0% vs. 15.2% of vehicle. At week 4 EASI-75 43.2% vs. 22.0% of vehicle INTEGUMENT-2 : IGA 0/1 and ≥2 point improvement 28.9% vs. 12.0% of vehicle. At week 4 EASI-75 42.0% vs. 19.7% of vehicle INTEGUMENT-PED (2-5 years) : IGA 0/1 and ≥2 points improvement 25.4% vs. 10.7% of vehicle; EASI-75 39.4% vs. 20.6% and WI-NRS success 35.3% vs. 18.0% of vehicle; improvement in pruritus within 24 h after the first application	Mild: rash and application site pain	FDA ≥2 yrs	Mild-to-moderate AD.
	Difamilast	PDE4B/D inhibitor	≥3 months	0.3% or 1% ointment	Phase III trial: IGA 0/1 at week 4: 38.46 vs. 12.64% of vehicle Phase III trial (3-24 months): IGA 0/1 and ≥2 point improvement 56.1% at week 4, and 75.6% at week 52. EASI-75 82.9% at week 4, and 80.5% at week 52	Mild to moderate: application-site reactions (folliculitis, contact dermatitis, acne, pruritus, and pain/burning)	≤ 2 yrs nasopharyngitis, gastroenteritis Japan and FDA ≥2 yrs	Mild-to-moderate AD
	PF-07038124	PDE4B2 inhibitor	≥18 yrs	0.01% ointment once daily	Phase IIa study: At week 6 greater reductions in EASI (-74.9%) than vehicle (-35.5%)	No local application site reactions	/	/
	Lotamilast	PDE4 inhibitor	≥2 yrs	0.01%-0.5% ointment	Phase II trial: at week 4, significant improvement in EASI and pruritus scores Trial on pediatric patients (NCT03415282): all week 2, improved lesion severity and pruritus	No serious adverse events	/	/
	HSK44459	PDE4B inhibitor	≥18 yrs	/	Phase II clinical trial (NCT06996912): ongoing	/	/	/
Oral	Orismilast	PDE4B/D inhibitor	≥18 yrs	20, 30, or 40 mg	Phase IIb trial (Adesos trial, NCT05469464): all doses showed rapid and significant pruritus reduction by week 2	Common: diarrhea and nausea	/	/
	Apremilast	PDE4 inhibitor	≥18 yrs	20, 30 or 40 mg BID	Phase II trial: EASI score reduction at 3 month: 20 mg: -19%, 30 mg: -39% Phase II trial: EASI score reduction at 3 month: 40 mg: -31.6%, 30 mg: -11%.	Common : nausea, diarrhea, headache, and nasopharyngitis	/	/
Aryl Hydrocarbon Receptor (AhR) Modulating Agents
Topical	Tapinarof	AhR modulator	≥2 yrs	1% cream once daily	A phase IIb trial: over 75% improvement in EASI and a ≥3-point improvement in pruritus Phase III ADORING 1-2 trials: significantly improved efficacy with moderate-to-severe AD, including children over 2 years old Phase II trial head-to-head over Tacrolimus 0.1%: at week 6, IGA 0/1: tapinarof 62.1% vs. 58.6% tacrolimus	Common: folliculitis, headache, and upper respiratory infections (Concerns about the long-term risks of AhR activation, including squamous cell carcinoma remain unconfirmed in clinical practice)	FDA ≥2 yrs	Mild-moderate AD
Histamine H4 Receptor Antagonists
Oral	JNJ-39758979	H4R antagonist	≥18 yrs	100 and 300 mg	Phase IIa trial (NCT01497119): study was terminated early after two participants developed agranulocytosis	Agranulocytosis	/	/
	Adriforant	H4R antagonist	≥18 yrs	30 and 50 mg	Phase II trial (NCT03948334): failed to meet efficacy endpoints	/	/	/
	Izuforant	H4R inverse agonist	≥18 yrs	/	Phase II trial (NCT05117060): failed to meet efficacy endpoints	/	/	/
Sphingosine-1-Phosphate Receptor (S1PR) Modulators
Oral	Etrasimod	Modulator of S1P R 1, 4, and 5	≥18 yrs	1 mg or 2 mg	Phase II trial: no statistically significant reduction in EASI-75 score, but some efficacy of the 2 mg dose for secondary endpoints Phase II/III trials: failed to meet at interim efficacy endpoints and was terminated	No serious adverse events reported	/	/
	BMS-986166 (Branebrutinib)	S1P1R modulator	≥18 yrs	/	Phase II clinical trial (NCT05014438): limited participant numbers restrict the interpretability of results	/	/	/
	SCD-044 (Vibozilimod)	Selective S1PR1 agonist	≥18 yrs	/	Phase II trial (NCT04684485): no significant improvements in PASI-75 or EASI-75 at week 16 vs. placebo	No serious adverse events reported	/	/
CCR4 (C-C chemokine receptor type 4) antagonist
Oral	RPT193	CCR4 antagonist	≥18 yrs	/	Phase Ia/Ib trial: drug was well tolerated with no serious adverse events	None	/	/