Next Article in Journal
Exploring the Antimicrobial and Pharmacological Potential of NF22 as a Potent Inhibitor of E. coli DNA Gyrase: An In Vitro and In Silico Study
Next Article in Special Issue
Efficacy and Safety of JAK1 Inhibitor Abrocitinib in Atopic Dermatitis
Previous Article in Journal
Increased Sensitivity of Computed Tomography Scan for Neoplastic Tissues Using the Extracellular Vesicle Formulation of the Contrast Agent Iohexol
Previous Article in Special Issue
OX40-OX40L Inhibition for the Treatment of Atopic Dermatitis—Focus on Rocatinlimab and Amlitelimab
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis

UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli—IRCCS, 00168 Rome, Italy
Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(12), 2767;
Submission received: 4 November 2022 / Revised: 4 December 2022 / Accepted: 6 December 2022 / Published: 10 December 2022
(This article belongs to the Special Issue New and Emerging Target-Oriented Drugs for Atopic Dermatitis)


Topical agents that are currently available for the treatment of atopic dermatitis may represent a valid approach in the management of mild or mild–moderate cases, whereas they are often supplemented with systemic therapies for handling more complex or unresponsive cases. The most used compounds include topical corticosteroids and calcineurin inhibitors, although their use might be burdened by side effects, poor response, and low patient compliance. Consequently, new innovative drugs with higher efficacy and safety both in the short and long term need to be integrated into clinical practice. A deeper understanding of the complex pathogenesis of the disease has led to identifying new therapeutic targets and to the development of innovative therapeutics. This narrative review aims to collect data on selected promising topical drugs that are in an advanced stage of development.

1. Introduction

Atopic dermatitis (AD) is an immune-mediated skin disease with a chronic relapsing course, characterized by eczematous lesions often associated with intense itching. It represents the most frequent inflammatory skin disease, with a worldwide prevalence ranging from 5–10% in children and 1–3% in adults [1,2]. Globally, an increased incidence of AD is emerging in Western industrialized countries as well as in low-income areas [3,4]. AD onset occurs before the first year of life, in approximately 50% of cases, and in 85% before the fifth year, while in 5% of individuals AD persists beyond adolescence [5]. Adult-onset AD accounts for 25% of all cases in adulthood [6].
The pathogenesis of the disease is complex, involving environmental and genetic factors, resulting in an altered immune response, impaired epidermal barrier function, along with cutaneous dysbiosis.
Clinical manifestations of AD are heterogeneous with various phenotypes that have been described [7]. Typical features include symmetrical, erythematous, and scaly papules or plaques, involving flexural areas, face, neck and distal extremities in adolescent and adults [8,9]. The pivotal symptom is chronic itching resulting in lichenification and excoriation, along with an increased risk of superimposed infections and a profound negative impact on the patient’s quality-of-life (QoL), also affecting sleep. Indeed, AD is associated with a high incidence of sleep disturbances, depression, and attention-deficit/hyperactivity disorder (ADHD), and frequently causes social isolation and work impairment [10,11]. Patients with AD present increased rates of comorbidities, such as cardiometabolic, neuropsychiatric, and malignant disorders [12]. Besides the negative impact on QoL, affecting both patients and their caregivers, AD is also associated with an unfavorable economic burden. Daily skin management is highly time-consuming, and direct and indirect economic efforts for therapeutic management may be particularly burdensome.
Multiple therapeutic options are currently available, ranging from topical approaches for mild disease (emollients, topical corticosteroids, and calcineurin inhibitors) to phototherapy and systemic agents for moderate-to-severe cases. Choosing between these therapies depends on the clinical features of AD lesions (erythema, papulation/edema, excoriation, and lichenification), the extent of skin involvement, the patient’s reported symptoms, preferences, and the physician’s experience [13,14].
Topical corticosteroids (TCS) still represent the major therapy for most patients with mild or localized AD, as they exert anti-inflammatory, antiproliferative, and vasoconstrictive effects by downregulating the genes encoding proinflammatory cytokines. These drugs, although effective, are burdened by potential side effects such as skin atrophy, telangiectasias, and striae, in case of prolonged use. Appropriate choice of potency and vehicle for TCS should be considered to optimize the patient’s compliance and minimize adverse events.
Topical calcineurin inhibitors (TCI) are steroid-sparing drugs, including tacrolimus 0.03% and 0.1% ointment, and pimecrolimus 1% cream. They act through the blockade of T cell activation by inhibiting IL-2 and IFN-γ synthesis. The most frequent adverse events include skin burning and itching that usually reduce over time. TCIs have a satisfactory efficacy and safety profile.
Because of new topical agents recently approved or currently in the pipeline for AD (Figure 1 and Figure 2), this review aimed to collect data on their safety and efficacy, conducting a search in the published literature through 20 September 2022 that included original articles (i.e., case reports, case series, and randomized controlled trials) using the PubMed database, and clinical trial data published on The terms used for the PubMed search were as follows: “Atopic dermatitis” AND “topical treatment”, OR “target therapy”, OR “topical JAK inhibitors”, OR “pipeline”, OR “crisaborole”, OR “Aryl hydrocarbon Receptor modulator”, OR “PDE4 inhibitors”, OR “skin microbiome”.
The authors selected articles that outlined pivotal and novel insights into AD, with special regard to topical treatments.

2. AD Pathogenesis

AD is characterized by a multifactorial pathophysiology, resulting from the complex interaction between genetic factors, environmental influences, immunological system dysregulation, and the impairment of skin barrier function.
The complex immunological activation includes cells belonging to type 2 inflammatory cells, such as T helper 2 cells (Th2), T cytotoxic 2 cells (Tc2), type 2 innate lymphoid cells (ILC2s), mast cells and eosinophils, and other immunologic pathways driven by Th22, Th17/IL-23, and Th1 cytokines [15], depending on various factors, such as disease stage and ethnicity [16]. Activated type 2 inflammatory cells promote the release of proinflammatory cytokines, mainly interleukin (IL)-4, IL-13, IL-31, mediating skin inflammation, pruritus, and antigen-specific IgE production by B cells and plasma cells.
Overall, most of the soluble mediators involved in the pathogenesis of AD exert their effects upon binding to specific transmembrane receptor and activation of the downstream intracellular Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Four isoforms of JAK, all with tyrosine kinase (TYK) activity, are currently known: JAK1, JAK2, JAK3, and TYK2 [17]. Following the interaction between the ligand and its specific receptor, activation of associated JAKs occurs, which phosphorylate the intracellular domain of the receptor, creating a docking site for STATs. STATs translocate into the nucleus and modulate the transcription of target genes involved in cell proliferation, differentiation, and activation [18]. AD is associated with increased signaling through all four JAKs [19], although the ultimate effect of the activation of this pathway depends on the isoform being activated. For instance, IL4 and IL13 mainly induce the activation of JAK1 and JAK3, and subsequently of STAT6.
Due to the crucial role of the activation of the JAK/STAT pathway in AD pathogenesis, its inhibition through JAK inhibitors (JAKi) represents a current target of recently approved drugs, and several others are in the pipeline, with encouraging results (Table 1 and Table 2) [20].
Interestingly, although AD has been traditionally considered a T cell-mediated disease, recent evidence has pointed to the role of B cells and humoral immunity in its pathogenesis [21]. Activated B cells are thought to contribute to AD pathophysiology through their differentiation into plasma cells secreting IgE antibodies as well as acting as antigen-presenting cells (APC), activating the T cell-mediated immune responses [22]. Both IL-4 and IL-13, the two key cytokines in AD pathogenesis, can directly act on B cells and induce a selective class-switch production of IgE [23]. High serum levels of IgE were indeed reported in AD patients and correlated with AD severity [24]. Furthermore, a newly described subset of B cells, exerting a negative regulation on immune responses through IL-10 production (Breg cells), have been shown to play a role in AD pathogenesis [25]. Notably, levels of IL-10-producing B cells in peripheral blood have been reported to be significantly lower in AD patients than in healthy individuals, suggesting that depletion of this cell population may contribute to AD inflammation and severity [26]. Finally, the role of B cells in AD pathogenesis has also been suggested by some reports describing an improvement of AD lesions in patients treated with rituximab, an anti-CD20 monoclonal antibody that depletes CD20+ B cells [27].

3. Recently Approved Topical Drugs for AD

3.1. Crisaborole

Crisaborole is a specific inhibitor of phosphodiesterase 4 (PDE4), an enzyme that plays a key role in regulating proinflammatory cytokine production. Indeed, PDE4, through degradation of cyclic adenosine monophosphate (cAMP), results in the inhibition of protein kinase type A (PKA) and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T cells (NFAT), with a subsequent increase in specific cytokines such as (TNF)-alpha, IL-5, IL-10, and IL-2 [28,29]. This molecular process would explain the importance of PDE4 in the pathogenesis of AD, and therefore the therapeutic relevance of its inhibition.
Crisaborole 2% ointment was originally approved in 2016 by the Food and Drug Administration (FDA), for the treatment of moderate-to-severe AD in children ≥2 years old, and in March 2020 it obtained a therapeutic extension for patients aged >3 months [30,31].
The efficacy and safety of crisaborole were assessed in a large patient cohort enrolled in two randomized, double-blind, vehicle-controlled, phase III trials (AD-301; AD-302), including a total of 1522 patients ≥ 2 years of age with mild-to-moderate AD. The primary endpoint, meant as Investigator’s Static Global Assessment (IGSA) 0/1 at day 29, was achieved by a higher percentage of patients in the crisaborole arm vs. control (AD-301: 32.8% vs. 25.4%, p = 0.038; AD-302: 31.4% vs. 18.0%, p = 0.001).
Earlier reduction in itch emerged in patients treated with crisaborole compared with placebo (pooled data, 1.37 vs. 1.70 days, p = 0.001) [32]. This improvement in itch sensation was maintained throughout the duration of the study and confirmed by a subsequent analysis of the phase III trials performed by Yosipovitch et al. (56.6% vs. 39.5%; p < 0.001) [33,34]. Crisaborole also demonstrated a satisfactory safety profile, with 10.3% of enrolled patients developing adverse events, including AD (3.1%), application-site pain (2.3%), and application-site infection (1.2%).
A phase IV open-label study (CrisADe CARE 1) evaluated the efficacy and safety of crisaborole in patients aged 3–24 months with mild-to-moderate AD, and the primary endpoint (IGSA 0/1) was met by 30.2% of patients, with a mean percentage change in the Eczema Area and Severity Index (EASI) score of −57.5% [35].

3.2. Delgocitinib

The nonselective pan-JAKi, delgocitinib, in ointment formulation, was approved in Japan in 2020 for the treatment of AD [36]. The randomized, double-blind, phase III trial included Japanese patients ≥16 years with moderate-to severe AD. Participants were randomized in a 1:1 ratio to delgocitinib 0.5% ointment or vehicle twice daily for four weeks. The modified EASI (mEASI)-75 was achieved by 26.4% of delgocitinib-treated patients, compared with 5.8% in the placebo group (p < 0.01). The mEASI is a modified measure that excludes the assessment of untreated body areas in the study. Efficacy data were confirmed in a 52-week extension study [37,38]. Similarly to mEASI, IGA and itch numeric rating scale (NRS) scores were significantly reduced in the delgocitinib arm compared with the placebo.
Side effects were reported in 69% of patients, the most common adverse events were being nasopharyngitis (25.9%) and contact dermatitis (4.5%). Comparable efficacy data were obtained from a phase III trial enrolling patients aged 2–15 years. Patients applied delgocitinib 0.25% ointment for four weeks, with a favorable safety profile [39]. Delgocitinib cream (LEO242549) is currently being tested in a phase III trial for the treatment of chronic hand eczema (CHE), whereas the investigation for AD has been discontinued in both Europe and USA [40].

3.3. Ruxolitinib

Ruxolitinib 1.5% cream selectively inhibits JAK1 and JAK2, and was approved by the FDA in September 2021 for short-term and noncontinuous chronic treatment of mild-to-moderate AD in immunocompetent patients ≥12 years [41].
Two parallel, randomized, double-blind, phase III clinical trials (Topical Ruxolitinib Evaluation in Atopic Dermatitis: TRuE-AD1 and TRuE-AD2), investigated the efficacy and safety of topical ruxolitinib 0.75% and 1.5% cream for 8 weeks. A total of 1249 mild-to-moderate AD patients aged ≥12 years with a baseline IGA 2/3 and body surface area (BSA) of 3–20%, were enrolled in the study. In both trials, a greater number of patients achieved an IGA 0/1 and an improvement of ≥ 2 grades compared with baseline using ruxolitinib at 0.75% (50% TRuE-AD1, 39.0% TRuE-AD2) or 1.5% (53.8%, 51.3%) compared with the vehicle group (15.1%, 7.6%) [41]. A rapid and prolonged amelioration of itch was detected using ruxolitinib 1.5% or 0.75% cream in both the TRuE-AD1 and TRuE-AD2 trials. A rapid efficacy in reducing pruritus was also supported by a recent subanalysis derived from TRuE-AD trial program data [42].
Ruxolitinib was generally well tolerated in both treatment arms, with nasopharyngitis being the most common adverse event reported, whose incidence was significantly higher (3% and 2.6%) in ruxolitinib arms compared with placebo (0.8%) [43]. Treatment-related adverse events included folliculitis at the application site and acne.
The efficacy of ruxolitinib was also assessed among adolescents, demonstrating an EASI ≥ 90% improvement (EASI-90) in 41.5% of patients applying 0.75% cream, 39.1% for 1.5% ruxolitinib cream, and 7% for placebo, with a safety profile in line with previous trial outcomes [44].
A recent pooled analysis proved similar efficacy in terms of IGA 0/1 achievement in the Black or African American population, and as a global improvement across all body areas [45,46].
Several studies are currently ongoing, specifically a phase III, double-blind, randomized, vehicle-controlled study followed by a long-term safety extension period in children with AD (age ≥2 years to <12 years) (TRuE-AD3). A phase III, open-label, one-year safety study of ruxolitinib cream in adolescents with AD (age ≥12 < 18 years) is not yet recruiting. Localized facial and/or neck AD efficacy and safety will be investigated in a phase II trial, actively recruiting.

4. New Emerging Topical Treatments for AD in the Pipeline

4.1. Aryl Hydrocarbon Receptor Modulating Agents

Aryl hydrocarbon Receptor (AhR) is a ligand-dependent receptor that acts as a transcription factor, and it is expressed on the surface of several immune cells and epithelial cells, including the skin, intestine, and lungs. Several molecules, both endogenous and exogenous, can act as AhR ligands, leading to its activation. AhR is involved in the transcriptional regulation of multiple genes implicated in the immune response, cellular apoptosis, proper functioning of anti-inflammatory regulatory T cells (Tregs), pro-inflammatory cytokine suppression, and keratinocytes terminal differentiation [47]. A deeper understanding of the molecular processes mediated by AhR has made it possible to develop a targeted therapy for this pathway.
Tapinarof 1% cream (GSK2894512 cream, WBI-1001, or BenvitimodTM) is an AhR modulating agent for topical use, under development for the treatment of AD and psoriasis [48,49]. A phase IIb, double-blind, vehicle-controlled randomized study included adolescents and adults (aged 12–65 years) with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily for 12 weeks, with a four-week treatment-free follow-up [50,51]. The percentage of patients achieving IGA response was higher for all tapinarof groups than for the vehicle at each visit by week 2 and maintained throughout the follow-up period. Tapinarof 1% cream-treated patients demonstrated higher response rates than the 0.5% group. At the last observation, IGA response rates were 53% (1% twice daily; p = 0.008) and 37% (0.5% twice daily; p = 0.240) vs. 24% (vehicle twice daily). At week 12, the mean change in EASI score was significantly higher in all tapinarof groups than in the vehicle group, and this was evident as early as week 1: 73% (1% twice daily; p < 0.001) and 66% (0.5% twice daily; p < 0.004) vs. 38% (placebo twice daily). Tapinarof was well tolerated, with most adverse events evaluated as mild or moderate, mainly represented by folliculitis. Phase III clinical trial programs (ADORING 1 and ADORING 2) are two 8-week, parallel studies currently ongoing in children aged ≥2 years and adults with moderate-to-severe AD, and will be followed by an open-label, 48-week extension study (ADORING 3) [52].

4.2. Phosphodiesterase 4 Inhibitors

The intracellular enzyme PDE4 plays a major role in AD pathogenesis and its inhibition may represent a valuable therapeutic strategy. In addition to crisaborole, a topical anti-PDE4 agent, other topical PDE4 inhibitors are in clinical development. Topical application avoids the typical gastrointestinal adverse events related to systemic administration.
Roflumilast cream (ARQ-151) is a highly potent PDE-4 inhibitor. Its efficacy and safety are under investigation for both plaque psoriasis (phase III study) and mild-to-moderate AD [53].
A four-week, phase II proof-of-concept study involved 136 AD patients ≥ 12 years, randomized to roflumilast 0.15%, 0.05%, or placebo. The primary endpoint, represented by the absolute change from baseline in EASI score at week 4, was not achieved.
Two parallel, double-blind, vehicle-controlled phase III trials (Integument-1 and Integument-2), undertaken in February 2021, evaluated patients ≥6 years, with AD involving >3% BSA, treated once daily with roflumilast 0.15% for 4 weeks [54,55].
A phase III trial (Integument-PED) is currently investigating the application of roflumilast 0.05%, in patients between 2 and 5 years of age, with a total of 650 patients enrolled, posing as primary outcome IGA success, defined as vIGA-AD score 0/1 and 2-grade improvement from baseline at week 4 [56]. Results from phase III trials are not yet available.
Difamilast is a topical selective PDE4 inhibitor tested in two phase III trials that have been recently completed in Japan for both adult and pediatric populations [57]. In the first one, patients aged 15–70 years with an IGA of 2/3, treated with difamilast ointment 1% or placebo twice daily for four weeks, were included. The percentage of patients on difamilast therapy who achieved an IGA 0/1 score at week 4 was higher than the placebo group (38.46% vs. 12.64%, respectively, p < 0.0001). At week 4, EASI-75 was obtained in 42.86% of difamilast-treated patients vs. 13.19% of placebo (p < 0.0001), while EASI-90 was observed in 24.73% vs. 5.49%, respectively (p < 0.0001) [58].
Treatment-emergent adverse events were observed in 32 (28%) of difamilast-treated patients vs. 51 (28%) of the placebo arm, and the most frequently encountered were AD (1% difamilast 3.8%; vehicle 12.1%) and nasopharyngitis (1% difamilast 4.9%; vehicle 3.8%). The main treatment-emergent adverse event that led to treatment discontinuation was AD worsening (1% difamilast: 3.8%; placebo: 9.3%).
The efficacy and safety of difamilast 0.3% and 1% on a pediatric population were evaluated in a randomized, double-blind, vehicle-controlled phase III study. Patients between 2 and 14 years of age with IGA 2/3 were enrolled and randomized in three arms: difamilast 0.3% (n = 83), difamilast 1% (n = 85), or vehicle (n = 83) applied twice daily, for 4 weeks. The primary endpoint was the percentage of patients with an IGA of 0/1 and an improvement by at least two grades at week 4. Success rates in IGA scores at week 4 were higher in the active arms (44.6% and 47.1% vs. 18.1%). Therapeutic success, meant as EASI 75, at week 4 was detected in 43.4% of the difamilast 0.3% group and 57.7% of the difamilast 1% group vs. 18.1% of the vehicle group. The favorable safety profile resulting from this study is comparable to that previously established [59,60].
A phase III, multicenter, open-label, uncontrolled study evaluating the efficacy and safety of difamilast ointment in infants younger than two years of age is currently ongoing. At the end of 2021, difamilast ointment received approval in Japan for the treatment of AD patients ≥2 years [61].
An additional agent named LEO 29102 selectively blocks the PDE4D isoform [62]. A phase II proof-of-concept and dose-finding study enrolled 183 patients, splitting them into differently-dosed arms and comparing LEO 29102 with pimecrolimus and placebo.
However, due to the lack of statistical significance in terms of both pruritus and EASI reduction compared to baseline, the drug development was discontinued [63].
The evaluation of the efficacy and safety of lotamilast (RVT-501/E6005) was the aim of two Japanese clinical trials in adult and pediatric populations with mild–moderate AD [64,65]. Seventy-eight adults were randomized to lotamilast 0.2% or vehicle for 4 weeks followed by an extension period of 8 weeks. The evaluation of clinical efficacy showed an improvement, although not statistically significant, in the treated group compared to placebo, in terms of EASI score, Severity Scoring Atopic Dermatitis (SCORAD)-objective, SCORAD-C (visual analog scales for pruritus and sleep loss), and itch NRS.
Regarding the extension study, the group receiving topical E6005 for 12 weeks showed significant score reductions from baseline for EASI (p = 0.030), SCORAD-objective (p < 0.001), and SCORAD-C (p = 0.038).
In pediatric patients, a greater decrease in severity score was obtained in the lotamilast-treated group compared to the vehicle (−45.94% vs. −32.26%), although not statistically significant.
A multicenter, randomized, vehicle-controlled, double-blind, phase II trial involving adult and adolescent subjects with mild-to-moderate AD was designed to evaluate safety, efficacy, and pharmacokinetics of 0.2% and 0.5% concentrations of RVT-501, but results are not yet available [66].
A phase II clinical study is currently underway to study the efficacy and safety of Hemay808 at various concentrations (1%, 3%, 7%) for the treatment of adults with mild-to-moderate AD.
A phase IIa, randomized, double-blind, vehicle-controlled, parallel group study recently published the results of a group analysis concerning the efficacy and safety of PF-07038124 ointment in adult patients, with mild-to-moderate AD or plaque psoriasis. The study enrolled 104 participants, 70 for the AD group and 34 for plaque psoriasis, randomized to PF-07038124 0.01% or placebo. Active-arm AD participants achieved a mean percent change from baseline to week 6 in EASI score of −74.9% vs. −35.5% in the placebo group (p = 0.0004). A total of 44.4% of AD patients in the treatment group achieved an IGA 0/1 or two-point reduction at week 6 compared with baseline (vs. placebo, 8.8%).

4.3. JAK Inhibitors

In addition to the topical JAKi already approved, others are currently under investigation.
Cerdulatinib (DMVT-502) simultaneously blocks all JAKs and spleen tyrosine kinase (SYK) [67]. A phase Ib, single-center, double-blind study evaluated the safety and efficacy of cerdulatinib 0.37% gel and its molecular effects on lesional skin in adults with mild-to-moderate AD. Mean EASI scores decreased significantly from baseline to day 14, with a mean change of −2.6. Adverse events were generally mild, occurring in 8/10 cerdulatinib-treated patients, and headache was the most common adverse event reported. To investigate the effects of the drug on epidermal thickness, cell infiltration, and gene expression, lesional skin biopsies were obtained at baseline and after 14 days of treatment. The results showed a reduction in both epidermal thickness and expression of key inflammatory markers, and a decrease in inflammatory dendritic cell infiltration [68].
ATI-1777 (JAK1/3 inhibitor) completed a phase IIa trial with positive results, as shown by preliminary released data [69]. During a 4-week treatment period, 50 adults with moderate-to-severe AD were randomized in a 1:1 ratio of ATI-1777 2.0% topical solution or placebo applied twice daily. A 74.4%-reduction in the mEASI score from baseline to week 4 emerged in subjects applying ATI-1777 (vs. 41.4% of placebo; p <0.0001), with minimal systemic exposure. Improvements in itch and BSA reduction were also observed. Subsequently, a phase IIb, multicenter, randomized, double-blind, vehicle-controlled study was performed to determine the safety, tolerability, pharmacokinetics, and efficacy of ATI-1777 in patients aged 12–65 years old with moderate-to-severe AD.
ATI-502 (JAK1/3 inhibitor) was evaluated in an 8-week phase IIa safety and tolerability study in adults with moderate-to-severe AD [70]. No other trials are ongoing.
SHR0302 is a highly selective JAK1 inhibitor, investigated in both oral and topical formulations [71]. A phase II/III, randomized, double-blind, vehicle-controlled, seamless study is ongoing to evaluate the efficacy and safety of topical SHR0302 at different doses in adult and adolescent patients with mild-to-moderate AD.
Brepocitinib (JAK1/TYK2), completed a phase IIb vehicle-controlled trial with a primary endpoint meant as the change from baseline in EASI score at week 6, with different drug concentrations. Brepocitinib 1% QD and 1% BID treatment arms achieved a statistically significant difference compared to the placebo at week 6. The safety profile appeared favorable [72].
Other topical JAKi, namely, jaktinib (pan-JAKi), and CEE321 (pan-JAKi), are currently under clinical investigation and the results are not yet available.
Tofacitinib is a JAK1/3 inhibitor [73] whose topical efficacy was investigated in a phase IIa trial with encouraging results (82% EASI reduction vs. 30%; prompt improvement of pruritus) and a good safety profile [74]. However, the clinical trial program was discontinued.

4.4. Skin Microbiome Modulating Agents

The role of the cutaneous microbiome is known as a pathogenetic factor contributing to AD, and therapeutic interventions on the microbiome would likely lead to clinical benefits for patients with AD. Current research is focused on the development of topical drugs capable of restoring its composition, via bacterial replacement and microbiome transplantation (Table 2) [75,76].
FB-401 is a compound under development that combines three chains of Roseomonas mucosa, a Gram-negative bacterium that appears predominant in AD patients’ skin. Its activity seems to be related to the activation of tissue repair systems and anti-inflammatory activity via Toll-like receptor 5 (TLR5) and tumor necrosis factor receptor (TNFR) [75].
A randomized, double-blind, placebo-controlled, 16-week phase II trial was designed to evaluate the efficacy and safety of FB-401 in children and adults with AD. Despite the encouraging results obtained (60% of adults showed a 50% reduction in the SCORAD values, 90% of pediatric patients achieved EASI50) [77], the phase II study was discontinued due to the lack of a statistically significant difference in achieving the primary outcome (EASI 50, 58% in FB-401 patients vs. 60% in placebo; p = 0.7567).
AD-like skin inflammation was triggered in mice models by certain strains of Staphylococcus aureus isolated from patients with severe AD. Topical application of a lyophilized human-derived strain of Staphylococcus hominis A9 (ShA9) should inhibit S. aureus overgrowth and toxin production, allowing nonpathogen, commensal microbiome to proliferate [78]. To assess the safety, mechanism of action, and potential therapeutic efficacy of ShA9, a randomized, double-blind, vehicle-controlled phase I study was designed. The study drug was applied for one week on the forearm skin of 54 adults with S. aureus cultured-positive AD. No serious adverse events were reported in the ShA9-treated arm, compared with the placebo. Overall, adverse events were mild and fewer in the active arm (p = 0.044). No significant difference between the two groups was observed in terms of clinical efficacy assessed through the EASI score and SCORAD. Another phase 1 open-label study is currently recruiting participants with moderate-to-severe AD to assess the survival of skin-transplanted ShA9 on lesional and non-lesional AD skin [79]. All patients will receive the study compound and the vehicle on their arm.
Nitrosomonas eutropha (B244), an ammonia-oxidizing bacteria (AOB), produces nitric oxide, which has anti-inflammatory and vasodilator capabilities, and nitrite, with anti-infective activity [80]. It also downregulates the production of IL-4, IL-5, IL-13, and IL-31 [72]. B244 is frequently deficient in the skin, so the aim of this novel potential compound is to re-establish the normal composition of the cutaneous microbiome. Phase II trials have been completed both on atopic dermatitis and pruritus, with promising results and no safety issues.
Niclosamide (ATx201) is an investigational drug delivered topically and designed to reduce colonization by S. aureus, known to be linked to disease severity and progression. A randomized, double-blind, placebo-controlled phase II trial investigated ATx201 ointment 2% applied twice daily in patients with mild-to-severe AD [81]. The study drug reduced S. aureus colonization (94.4% success rate vs. 38.9%, p = 0.0016) and significantly increased Shannon diversity in the skin microbiome at day 7.
Omiganan pentachloride is a synthetic indolicidin analog peptide that inhibits S. aureus overgrowth and exerts anti-inflammatory effects [82], tested in a phase II study with the aim of assessing its pharmacodynamics, tolerability, and efficacy [83]. Although the compound was effective in reducing the proliferation of S. aureus, the 28-day treatment was not associated with an amelioration of clinical manifestations in patients with mild-to-moderate AD.

4.5. Other Novel Therapies in the Pipeline

Currently, many other topical compounds are in the pipeline for AD with distinct mechanisms of action, and some promising molecules in the later stage of development are discussed below. Among these, it is worth mentioning the liver X receptors (LXRs), ligand-activated nuclear transcription factors, with a central role in maintaining skin barrier homeostasis and regulating the immune response.
The LXR-β agonist, VTP-38543 cream, was investigated in a double-blind, placebo-controlled phase II study including 104 patients with mild-to-moderate AD, at different concentrations (0.05%, 0.15%, and 1.0%) applied twice daily for 28 days. The aim of this study was to evaluate its safety, tolerability, and clinical efficacy, assessed by SCORAD, IGA score, and EASI. Thirty-three patients underwent skin biopsy prior to and after treatment to examine the cutaneous expression of biomarkers [84]. The drug was safe and well tolerated. Skin biopsies demonstrated an improvement in the skin barrier, with an increased expression of mRNA encoding for loricrin and profilaggrin, reduced epidermal thickness, and nonsignificant reduction in Th2/Th17 markers.
Another LXR-β agonist, ALX 101, completed its phase IIb study, but the results are not yet available [85].
BEN-2293, a pan-tropomyosin receptor kinase (pan-TRK) antagonist, is currently under investigation in a double-blind, placebo-controlled phase I/II proof-of-concept study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of the topical ointment (0.25% or 1% concentration) [86].
AMTX-100 is a cell-penetrating nuclear transport modifier (NTM), effective in modulating the transport of transcription factors (NF-κB, NFAT, AP-1, and STAT1) that regulate the expression of genes involved in the production of inflammatory cytokines and chemokines (TNFα, IL-1β, IL-6, IL-17, etc.) [87]. A two-part, phase I/IIb, multicenter, double-blind, randomized, vehicle-controlled trial has been designed to evaluate the safety and efficacy of topically applied AMTX-100 in adults with mild-to-moderate disease.
Another frontier that is currently being explored is focused on the covalent inhibition of Bruton tyrosine kinase (BTK), a key intracellular signaling factor involved in immune responses [88]. The presently approved drugs within this class have oncological indications and lead to the irreversible inhibition of BKT. Topical PRN473 showed sustained and potent reversible inhibition of BTK along with low systemic exposure in preclinical studies. Its mechanisms of action include downregulation of signaling for BCR, Fc receptors, and specifically inhibited IgE (FcεR)-mediated mast cell and basophil activation, IgG (FcγR)-mediated monocyte activation, and reduced neutrophil migration [89]. PRN473 is being explored for the treatment of AD in a phase IIa trial.
AKP-11 is a topical highly selective Spingosine-1-Phosphate receptor subtype-1 (S1PR1) modulator. Sphingosine 1-phosphate (S1P) is a ceramide-derived lipid via ceramidase and sphingosine kinase activity. S1P binds to high-affinity G-protein-coupled receptors, S1RPs, modulating cell proliferation and differentiation, proinflammatory cytokine production, proper skin barrier function, migration, and degranulation of endothelial, epithelial, nervous, and immune cells [90]. AKP-11, via its modulation of S1PR1, proved to be safe and well-tolerated in two phase-1 studies in subjects with psoriasis and AD. Its efficacy and safety will be evaluated in phase II trials in patients with AD and prurigo nodularis.

5. Discussion

Despite TCS and TCI remain the mainstay of the topical approach for AD in a real-world setting, novel topical agents are being developed in order to fulfill important unmet needs represented by (i) the limited number of compounds with immunomodulant mechanisms that could represent a valid alternative strategy to corticosteroids; (ii) efficacy of therapeutic options that could be comparable with corticosteroids; and (iii) ease of use through innovative and different formulations that could enhance patients’ adherence and optimize drug delivery (i.e., nanomolecules). A deeper understanding of AD pathogenesis has led to the development of topical compounds targeting different molecules, mainly involved in the regulation of the abnormal immune and inflammatory response, homeostasis of the skin barrier, and modulation of the cutaneous microbiome. The most promising ones include AhR, PDE4, JAK/STAT inhibitors, and skin microbiome modulating factors.
Tapinarof 1% cream, an AhR modulator that acts as a transcription factor, has successfully completed phase IIb trials, proving to be highly effective and well tolerated in patients affected by moderate-to-severe AD. It is currently under development in a phase III program, which also involves pediatric subjects aged ≥2 years.
Several PDE4 inhibitors are in the pipeline following FDA approval for crisaborole 2% ointment, for AD patients aged ≥ 3 months. Difamilast recently received manufacturing and marketing approval in Japan for the treatment of both adults and children with mild-to-moderate disease, after positive results achieved in phase III trials.
JAK inhibitors, available in both topical and oral formulations, are proving to be highly effective agents in the management of AD. In addition to the approved ruxolitinib and delgocitinib, several other compounds are in late-stage development phases.
Multiple strategies for restoring the skin microbiome have been proposed and this therapeutic approach, one of the most interesting future directions in the AD pipeline. Despite the considerable interest in AD, the pathogenic relevance of skin dysbiosis in AD remains unclear, and, therefore, the pharmacological potentiality of these drugs is not fully established.
Although some limitations of the therapeutic approach in terms of long-term use might be foreseen (low patients’ adherence due to a daily time-consuming approach), the future topical agents may offer promising perspectives regardless of whether advantages over the currently available topical compounds, such as higher efficacy, long-lasting effect after treatment withdrawal, and a marked reduction in side effects related to the long-term, will be demonstrated.

6. Conclusions

The topical approach is a cornerstone in the therapeutic armamentarium for AD but consists of a limited number of agents. A better understanding of AD pathogenesis is leading to the identification of therapeutic targets and, thus, the development of new drugs that could expand the opportunity to manage AD manifestations with multiple lines of topical compounds. Furthermore, a greater variety of topical compounds would allow tailoring the topical therapeutic approach, enabling the implementation of precision medicine in the daily management of AD patients.

Author Contributions

Conceptualization, A.C. andf L.M.P.; writing—original draft preparation, L.M.P.; writing—review and editing, A.C., M.M., and L.C.; supervision, K.P. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Nutten, S. Atopic dermatitis: Global epidemiology and risk factors. Ann. Nutr. Metab. 2015, 66, 8–16. [Google Scholar] [CrossRef] [PubMed]
  2. Weidinger, S.; Beck, L.A.; Bieber, T.; Kabashima, K.; Irvine, A.D. Atopic dermatitis. Nat. Rev. Dis. Primers 2018, 4, 1. [Google Scholar] [CrossRef] [PubMed]
  3. Mei-Yen Yong, A.; Tay, Y.K. Atopic dermatitis. Racial and Ethnic differences. Dermatol. Clin. 2017, 35, 395–402. [Google Scholar] [CrossRef] [PubMed]
  4. Laughter, M.R.; Maymone, M.B.C.; Mashayekhi, S.; Arents, B.W.M.; Karimkhani, C.; Langan, S.M.; Dellavalle, R.P.; Flohr, C. The global burden of atopic dermatitis: Lessons from the Global Burden of Disease Study 1990-2017. Br. J. Dermatol. 2021, 184, 304–309. [Google Scholar] [CrossRef] [PubMed]
  5. Kowalska-Olędzka, E.; Czarnecka, M.; Baran, A. Epidemiology of atopic dermatitis in Europe. J. Drug Assess. 2019, 12, 126–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Sacotte, R.; Silverberg, J.I. Epidemiology of adult atopic dermatitis. Clin. Dermatol. 2018, 36, 595–605. [Google Scholar] [CrossRef]
  7. Lee, H.H.; Patel, K.R.; Singam, V.; Rastogi, S.; Silverberg, J.I. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J. Am. Acad. Dermatol. 2019, 80, 1526–1532.e7. [Google Scholar] [CrossRef]
  8. Silverberg, N.B. Typical and atypical clinical appearance of atopic dermatitis. Clin. Dermatol. 2017, 35, 354–359. [Google Scholar] [CrossRef]
  9. Torres, T.; Ferreira, E.O.; Gonçalo, M.; Mendes-Bastos, P.; Selores, M.; Filipe, P. Update on Atopic Dermatitis. Acta Med. Port. 2019, 2, 606–613. [Google Scholar] [CrossRef] [Green Version]
  10. Silverberg, J.I.; Gelfand, J.M.; Margolis, D.J.; Boguniewicz, M.; Fonacier, L.; Grayson, M.H.; Simpson, E.L.; Ong, P.Y.; Chiesa Fuxench, Z.C. Patient burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study. Ann. Allergy Asthma Immunol. 2018, 121, 340–347. [Google Scholar] [CrossRef]
  11. Drucker, A.M.; Wang, A.R.; Qureshi, A.A. Research gaps in quality of life and economic burden of atopic dermatitis: The National Eczema Association burden of disease audit. JAMA Derm. 2016, 15, 873–887a. [Google Scholar] [CrossRef] [PubMed]
  12. Ungar, B.; Garcet, S.; Gonzalez, J.; Dhingra, N.; Correa da Rosa, J.; Shemer, A.; Krueger, J.G.; Suarez-Farinas, M.; Guttman-Yassky, E. An Integrated Model of Atopic Dermatitis Biomarkers Highlights the Systemic Nature of the Disease. J. Investig. Dermatol. 2017, 137, 603–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Wollenberg, A.; Barbarot, S.; Bieber, T.; Christen-Zaech, S.; Deleuran, M.; Fink-Wagner, A.; Gieler, U.; Girolomoni, G.; Lau, S.; Muraro, A.; et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: Part I. J. Eur. Acad. Dermatol. Venereol. 2018, 32, 657–682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Beck, L.A.; Thaçi, D.; Hamilton, J.D.; Graham, N.M.; Bieber, T.; Rocklin, R.; Ming, J.E.; Ren, H.; Kao, R.; Simpson, E.; et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N. Engl. J. Med. 2014, 371, 130–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Brunner, P.M.; Guttman-Yassky, E.; Leung, D.Y. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J. Allergy Clin. Immunol. 2017, 139, S65–S76. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Brunner, P.M.; Guttman-Yassky, E. Racial differences in atopic dermatitis. Ann. Allergy Asthma Immunol. 2019, 122, 449–455. [Google Scholar] [CrossRef] [Green Version]
  17. Shreberk-Hassidim, R.; Ramot, Y.; Zlotogorski, A. Janus kinase inhibitors in dermatology: A systematic review. J. Am. Acad. Dermatol. 2017, 76, 745–753.e19. [Google Scholar] [CrossRef] [PubMed]
  18. Villarino, A.V.; Kanno, Y.; O’Shea, J.J. Mechanisms and consequences of JAK-STAT signaling in the immune system. Nat. Immunol. 2017, 18, 374–384. [Google Scholar] [CrossRef] [PubMed]
  19. O’Shea, J.J.; Kontzias, A.; Yamaoka, K.; Tanaka, Y.; Laurence, A. Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. 2013, 72 (Suppl 2), ii111–ii115. [Google Scholar] [CrossRef]
  20. Chovatiya, R.; Paller, A.S. JAK inhibitors in the treatment of atopic dermatitis. J. Allergy Clin. Immunol. 2021, 148, 927–940. [Google Scholar] [CrossRef]
  21. Egbuniwe, I.; Karagiannis, S.N.; Nestle, F.O.; Lacy, K.E. Revisiting the role of B cells in skin immune surveillance. Trends Immunol. 2015, 36, 102–111. [Google Scholar] [CrossRef] [PubMed]
  22. LeBien, T.W.; Tedder, T.F. B lymphocytes: How they develop and function. Blood 2008, 112, 1570–1580. [Google Scholar] [CrossRef] [PubMed]
  23. Saunders, S.P.; Ma, E.G.M.; Aranda, C.J.; De Lafaille, M.A.C. Non-classical B Cell Memory of Allergic IgE Responses. Front. Immunol. 2019, 10, 715. [Google Scholar] [CrossRef] [PubMed]
  24. Tokura, Y. Extrinsic and intrinsic types of atopic dermatitis. J. Dermatol. Sci. 2010, 58, 1–7. [Google Scholar] [CrossRef] [PubMed]
  25. Suga, H.; Sato, S. Il-10–producing regulatory b cells in skin diseases. J. Cutan. Immunol. Allergy 2019, 2, 68–74. [Google Scholar] [CrossRef] [Green Version]
  26. Yoshihara, Y.; Ishiuji, Y.; Yoshizaki, A.; Kurita, M.; Hayashi, M.; Ishiji, T.; Nakagawa, H.; Asahina, A.; Yanaba, K. IL-10–Producing Regulatory B Cells Are Decreased in Patients with Atopic Dermatitis. J. Investig. Dermatol. 2019, 139, 475–478. [Google Scholar] [CrossRef] [Green Version]
  27. Simon, D.; Hösli, S.; Kostylina, G.; Yawalkar, N.; Simon, H.-U. Anti-CD20 (rituximab) treatment improves atopic eczema. J. Allergy Clin. Immunol. 2008, 121, 122–128. [Google Scholar] [CrossRef]
  28. Jimenez, J.L.; Punzón, C.; Navarro, J.; Muñoz-Fernández, M.A.; Fresno, M. PDE4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J. Pharmacol. Exp. Ther. 2001, 299, 753–759. [Google Scholar]
  29. Woo, T.E.; Kuzel, P. Crisaborole 2% Ointment (Eucrisa) for Atopic Dermatitis. Skin Ther. Lett. 2019, 24, 4–6. [Google Scholar]
  30. Bieber, T. Atopic dermatitis: An expanding therapeutic pipeline for a complex disease. Nat. Rev. Drug Discov. 2022, 21, 21–40. [Google Scholar] [CrossRef]
  31. Paller, A.S.; Tom, W.L.; Lebwohl, M.G.; Blumenthal, R.L.; Boguniewicz, M.; Call, R.S.; Eichenfield, L.F.; Forsha, D.W.; Rees, W.C.; Simpson, E.L.; et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J. Am. Acad. Dermatol. 2016, 75, 494–503.e6. [Google Scholar] [CrossRef] [Green Version]
  32. Yosipovitch, G.; Gold, L.F.; Lebwohl, M.G.; Silverberg, J.I.; Tallman, A.M.; Zane, L.T. Early Relief of Pruritus in Atopic Dermatitis with Crisaborole Ointment, A Non-steroidal, Phosphodiesterase 4 Inhibitor. Acta Derm. Venereol. 2018, 98, 484–489. [Google Scholar] [CrossRef] [PubMed]
  33. Schlessinger, J.; Shepard, J.S.; Gower, R.; Su, J.C.; Lynde, C.; Cha, A.; Ports, W.C.; Purohit, V.; Takiya, L.; Werth, J.L.; et al. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to <24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1). Am. J Clin. Dermatol. 2021, 21, 275–284. [Google Scholar] [CrossRef] [Green Version]
  34. Dhillon, S. Delgocitinib: First approval. Drugs 2020, 80, 609–661. [Google Scholar] [CrossRef] [PubMed]
  35. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Kaino, H.; Nagata, T. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol. 2020, 82, 823–831. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Murata, R.; Kaino, H.; Nagata, T. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J. Dermatol. 2020, 47, 114–120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Nakagawa, H.; Nemoto, O.; Igarashi, A.; Saeki, H.; Murata, R.; Kaino, H.; Nagata, T. Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle- controlled study and a subsequent open-label, long-term study. J. Am. Acad. Dermatol. 2021, 85, 854–862. [Google Scholar] [CrossRef]
  38. Worm, M.; Bauer, A.; Elsner, P.; Mahler, V.; Molin, S.; Nielsen, T.S.S. Efficacy and safety of topical delgocitinib in patients with chronic hand eczema: Data from a randomized, double-blind, vehicle-controlled phase IIa study. Br. J. Dermatol. 2020, 182, 1103–1110. [Google Scholar] [CrossRef] [Green Version]
  39. Incyte Announces US FDA Approval of Opzelura (Ruxolitinib) Cream, a Topical Jak Inhibitor, for the Treatment of Atopic Dermatitis (Ad). Published 21 September 2021. Available online: (accessed on 13 September 2022).
  40. Papp, K.; Szepietowski, J.C.; Kircik, L.; Toth, D.; Eichenfield, L.F.; Leung, D.Y.M.; Forman, S.B.; Venturanza, M.E.; Sun, K.; Kuligowski, M.E.; et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double- blind studies. J. Am. Acad. Dermatol. 2021, 85, 863–872. [Google Scholar] [CrossRef]
  41. Blauvelt, A.; Szepietowski, J.C.; Papp, K.; Simpson, E.L.; Silverberg, J.I.; Kim, B.S.; Kwatra, S.G.; Kuligowski, M.E.; Venturanza, M.E.; Sun, K.; et al. Ruxolitinib cream rapidly decreases pruritus in atopic dermatitis: Pooled results from two phase 3 studies. In Proceedings of the AAD VMX 2021, Online, 23–26 April 2021. Poster 26884. [Google Scholar]
  42. Eichenfield, L.F.; Simpson, E.L.; Siegfried, E.C.; Kuligowski, M.E.; Venturanza, M.E.; Sun, K.; Paller, A.S. Efficacy and safety of ruxolitinib cream among adolescents with atopic dermatitis: Pooled results from two phase 3 studies. In Proceedings of the AAD VMX 2021, Online, 23–26 April 2021. Poster 27633. [Google Scholar]
  43. Eichenfield, L.F.; Stein Gold, L.F.; Chiesa Fuxench, Z.C.; Venturanza, M.E.; Brar, K.K. Safety and efficacy over 8 weeks and disease control over 52 weeks with ruxolitinib cream among Black or African American patients with atopic dermatitis: Pooled results from two phase 3 studies. In Proceedings of the 2022 American Academy of Dermatology Annual Meeting, Boston, MA, USA, 25–29 March 2022. Abstract: 34794. [Google Scholar]
  44. Simpson, E.L.; Bissonnette, R.; Stein Gold, L.F.; Chiesa Fuxench, Z.C.; Venturanza, M.E.; Silverberg, J.I. Efficacy of ruxolitinib cream for the treatment of atopic dermatitis by anatomic region: Pooled analysis from two randomized phase 3 studies. In Proceedings of the 2022 American Academy of Dermatology Annual Meeting, Boston, MA, USA, 25–29 March 2022. Abstract: 34587. [Google Scholar]
  45. Trikha, P.; Lee, D.A. The role of AhR in transcriptional regulation of immune cell development and function. Biochim Biophys Acta Rev. Cancer 2020, 1873, 188335. [Google Scholar] [CrossRef]
  46. Furue, M.; Hashimoto-Hachiya, A.; Tsuji, G. Aryl hydrocarbon receptor in atopic dermatitis and psoriasis. Int. J. Mol. Sci. 2019, 20, 5424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Smith, S.H.; Jayawickreme, C.; Rickard, D.J.; Nicodeme, E.; Bui, T.; Simmons, C.; Coquery, C.M.; Neil, J.; Pryor, W.M.; Mayhew, D.; et al. Tapinarof is a natural AhR agonist that resolved skin inflammation in mice and humans. J. Investig. Dermatol. 2017, 137, 110–119. [Google Scholar] [CrossRef] [PubMed]
  48. Paller, A.S.; Stein Gold, L.; Soung, J.; Tallman, A.M.; Rubenstein, D.S.; Gooderham, M. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis. J. Am. Acad. Dermatol. 2021, 84, 632–638. [Google Scholar] [CrossRef] [PubMed]
  49. Peppers, J.; Paller, A.S.; Maeda-Chubachi, T.; Wu, S.; Robbins, K.; Gallagher, K.; Kraus, J.E. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 2019, 80, 89–98.e3. [Google Scholar] [CrossRef]
  50. Dermavant Announces First Patient Dosed in ADORING, Its Pivotal Phase 3 Clinical Program for Tapinarof for the Topical Treatment of Atopic Dermatitis—Dermavant. Published 9 September 2021. Available online: (accessed on 14 September 2022).
  51. Gooderham, M.J.; Kircik, L.H.; Zirwas, M.; Lee, M.; Kempers, S.E.; Draelos, Z.D.; Ferris, L.; Jones, T.M.; Proulx, E.S.; Bissonnette, R.; et al. The safety and efficacy of roflumilast cream 0.15% and 0.05% in atopic dermatitis: Phase 2 proof-of-concept study. Br. J. Dermatol. 2021, 184, e56–e87. [Google Scholar] [CrossRef]
  52. Bethesda (MD): National Library of Medicine (US). Identifier NCT04773587, Trial of PDE4 Inhibition with Roflumilast for the Management of Atopic Dermatitis (INTEGUMENT-I). Available online: (accessed on 14 September 2022).
  53. Bethesda (MD): National Library of Medicine (US). Identifier NCT04773600, Trial of PDE4 Inhibition with Roflumilast for the Management of Atopic Dermatitis (INTEGUMENT-II). Available online: (accessed on 14 September 2022).
  54. Bethesda (MD): National Library of Medicine (US). Identifier NCT04845620, Trial of PDE4 Inhibition with Roflumilast for the Management of Atopic Dermatitis (INTEGUMENT-PED). Available online: (accessed on 14 September 2022).
  55. Kleinman, E.; Laborada, J.; Metterle, L.; Eichenfield, L.F. What’s New in Topicals for Atopic Dermatitis? Am. J. Clin. Dermatol. 2022, 23, 595–603. [Google Scholar] [CrossRef]
  56. Saeki, H.; Ito, K.; Yokota, D.; Tsubouchi, H. Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial. J. Am. Acad. Dermatol. 2022, 86, 607–614. [Google Scholar] [CrossRef]
  57. Saeki, H.; Ito, K.; Yokota, D.; Tsubouchi, H. Difamilast, a selective phosphodiesterase 4 inhibitor, ointment in pediatric patients with atopic dermatitis: A phase III randomized double-blind, vehicle-controlled trial. Br. J. Dermatol. 2021, 186, 40–49. [Google Scholar] [CrossRef]
  58. Otsuka Pharmaceutical Co., Ltd. Otsuka’s Moizerto® Ointment Granted Approval in Japan as a Treatment for Atopic Dermatitis. 2021. Available online: (accessed on 14 September 2022).
  59. Felding, J.; Sørensen, M.D.; Poulsen, T.D.; Larsen, J.; Andersson, C.; Refer, P.; Engell, K.; Ladefoged, L.G.; Thormann, T.; Vinggaard, A.M.; et al. Discovery and early clinical development of2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]- 2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J. Med. Chem. 2014, 57, 5893–5903. [Google Scholar] [CrossRef]
  60. LEO 29102 Cream in the Treatment of Atopic Dermatitis. Available online: (accessed on 15 September 2022).
  61. Furue, M.; Kitahara, Y.; Akama, H.; Hojo, S.; Hayashi, N.; Nakagawa, H.; JAPANESE E6005 Study Investigators. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: Results of a randomized, vehicle-controlled, multicenter clinical trial. J. Dermatol. 2014, 41, 577–585. [Google Scholar] [CrossRef]
  62. Nemoto, O.; Hayashi, N.; Kitahara, Y.; Furue, M.; Hojo, S.; Nomoto, M.; Shima, S.; Japanese E6005 Study Investigators. Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial. J. Dermatol. 2016, 43, 881–887. [Google Scholar] [CrossRef] [PubMed]
  63. Study of RVT-501 in Adult and Adolescent Subjects with Atopic Dermatitis. Available online: (accessed on 15 September 2022).
  64. Guo, A.; Lu, P.; Coffey, G.; Conley, P.; Pandey, A.; Wang, Y.L. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. Oncotarget 2017, 8, 12953–12967. [Google Scholar] [CrossRef] [PubMed]
  65. Piscitelli, S.C.; Pavel, A.B.; McHale, K.; Jett, J.E.; Collins, J.; Gillmor, D.; Tabolt, G.; Li, R.; Song, T.; Zhang, N.; et al. A phase 1b, randomized, single-center trial of topical cerdulatinib (DMVT-502) in patients with mild-to-moderate atopic dermatitis. J. Investig. Dermatol. 2021, 141, 1847. [Google Scholar] [CrossRef]
  66. Aclaris Therapeutics Announces Positive Preliminary Topline Data from Phase 2a Trial of ATI-1777 for Moderate to Severe Atopic Dermatitis. Available online: (accessed on 12 September 2022).
  67. Smith, S.; Bhatia, N.; Shanler, S.D.; DeMoor, R.; Schnyder, J. Safety of ATI-502, a novel topical JAK1/3 inhibitor, in adults with moderate to severe atopic dermatitis (AD): Results from phase 2a, open-label trial. J. Am. Acad. Dermatol. 2020, 83, AB170. [Google Scholar] [CrossRef]
  68. Zhao, Y.; Zhang, L.; Ding, Y.; Tao, X.; Ji, C.; Dong, X.; Lu, J.; Wu, L.; Wang, R.; Lu, Q.; et al. Efficacy and Safety of SHR0302, a Highly Selective Janus Kinase 1 Inhibitor, in Patients with Moderate to Severe Atopic Dermatitis: A Phase II Randomized Clinical Trial. Am J Clin. Dermatol. 2021, 22, 877–889. [Google Scholar] [CrossRef]
  69. Landis, M.N.; Arya, M.; Smith, S.; Draelos, Z.; Usdan, L.; Tarabar, S.; Pradhan, V.; Aggarwal, S.; Banfield, C.; Peeva, E.; et al. Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: A phase IIb, randomised, double-blind, vehicle-controlled, dose-ranging, and parallel-group study. Br. J. Dermatol. 2022, 187, 878–887. [Google Scholar] [CrossRef]
  70. Ghoreschi, K.; Jesson, M.I.; Li, X.; Lee, J.L.; Ghosh, S.; Alsup, J.W.; Warner, J.D.; Tanaka, M.; Steward-Tharp, S.M.; Gadina, M.; et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 2011, 186, 4234–4243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Bissonnette, R.; Papp, K.A.; Poulin, Y.; Gooderham, M.; Raman, M.; Mallbris, L.; Wang, C.; Purohit, V.; Mamolo, C.; Papacharalambous, J.; et al. Topical tofacitinib for atopic dermatitis: A phase IIa randomized trial. Br. J. Dermatol. 2016, 175, 902–911. [Google Scholar] [CrossRef]
  72. Callewaert, C.; Knödlseder, N.; Karoglan, A.; Güell, M.; Paetzold, B. Skin microbiome transplantation and manipulation: Current state of the art. Comput. Struct. Biotechnol. J. 2021, 19, 624–631. [Google Scholar] [CrossRef]
  73. Paller, A.S.; Kong, H.H.; Seed, P.; Naik, S.; Scharschmidt, T.C.; Gallo, R.L.; Luger, T.; Irvine, A.D. The microbiome in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2019, 143, 26–35. [Google Scholar] [CrossRef] [Green Version]
  74. Myles, I.A.; Castillo, C.R.; Barbian, K.D.; Kanakabandi, K.; Virtaneva, K.; Fitzmeyer, E.; Paneru, M.; Otaizo-Carrasquero, F.; Myers, T.G.; Markowitz, T.E.; et al. Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid- mediated TNF-related epithelial repair. Sci. Transl. Med. 2020, 12, eaaz8631. [Google Scholar] [CrossRef] [PubMed]
  75. Forte Biosciences, Inc. Announces First Patient Dosed in the Clinical Trial of FB-401 for the Treatment of Children and Adults with Atopic Dermatitis. Available online: (accessed on 12 September 2022).
  76. Nakatsuji, T.; Hata, T.R.; Tong, Y.; Cheng, J.Y.; Shafiq, F.; Butcher, A.M.; Salem, S.S.; Brinton, S.L.; Rudman Spergel, A.K.; Johnson, K.; et al. Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nat. Med. 2021, 27, 700–709. [Google Scholar] [CrossRef] [PubMed]
  77. Targeted Investigation of Microbiome Elimination (TIME-1). Available online: (accessed on 14 September 2022).
  78. Maura, D.; Elmekki, N.; Goddard, C.A. The ammonia oxidizing bacterium Nitrosomonas eutropha blocks T helper 2 cell polarization via the anti-inflammatory cytokine IL-10. Sci. Rep. 2021, 11, 14162. [Google Scholar] [CrossRef] [PubMed]
  79. Todd Krueger Discusses AOBiomes’ Positive Results from Phase 2b Trial for Both Pruritus (Itch) and Appearance of Atopic Dermatitis (Eczema). Available online: (accessed on 14 September 2022).
  80. Weiss, A.; Delavenne, E.; Matias, C.; Lagler, H.; Simon, D.; Li, P.; Hansen, J.U.; Dos Santos, T.P.; Jan, B.; Priemel, P.; et al. Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double-blind, placebo-controlled Phase 2 trial. Clin. Transl. Med. 2022, 12, e790. [Google Scholar] [CrossRef]
  81. Javia, A.; Misra, A.; Thakkar, H. Liposomes encapsulating novel antimicrobial peptide Omiganan: Characterization and its pharmacodynamic evaluation in atopic dermatitis and psoriasis mice model. Int. J. Pharm. 2022, 624, 12204. [Google Scholar] [CrossRef]
  82. Niemeyer-van der Kolk, T.; Buters, T.P.; Krouwels, L.; Boltjes, J.; de Kam, M.L.; van der Wall, H.; van Alewijk, D.C.J.G.; van den Munckhof, E.H.A.; Becker, M.J.; Feiss, G.; et al. Topical antimicrobial peptide omiganan recovers cutaneous dysbiosis but does not improve clinical symptoms in patients with mild to moderate atopic dermatitis in a phase 2 randomized controlled trial. J. Am. Acad. Dermatol. 2022, 86, 854–862. [Google Scholar] [CrossRef]
  83. Czarnowicki, T.; Dohlman, A.B.; Malik, K.; Antonini, D.; Bissonnette, R.; Chan, T.C.; Zhou, L.; Wen, H.C.; Estrada, Y.; Xu, H.; et al. Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial. Ann. Allergy Asthma Immunol. 2018, 120, 631–640.e11. [Google Scholar] [CrossRef]
  84. A Study in Subjects with Moderate Atopic Dermatitis. Available online: (accessed on 14 September 2022).
  85. A First-in-Human PoC Study with BEN2293 in Patients with Mild to Moderate Atopic Dermatitis. Available online: (accessed on 14 September 2022).
  86. Amytrx Therapeutics Emerges from Stealth to Develop Novel Therapies for Inflammatory Diseases with Lead Program AMTX-100 Currently in Clinical Development for Dermatologic Indications. Available online: (accessed on 14 September 2022).
  87. Owens, T.D.; Brameld, K.A.; Verner, E.J.; Ton, T.; Li, X.; Zhu, J.; Masjedizadeh, M.R.; Bradshaw, J.M.; Hill, R.J.; Tam, D.; et al. Discovery of Reversible Covalent Bruton’s Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib). J. Med. Chem. 2022, 65, 5300–5316. [Google Scholar] [CrossRef]
  88. Xing, Y.; Chu, K.A.; Wadhwa, J.; Chen, W.; Zhu, J.; Bradshaw, J.M.; Shu, J.; Foulke, M.C.; Loewenstein, N.; Nunn, P.; et al. Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models. Immunohorizons 2021, 5, 581–589. [Google Scholar] [CrossRef]
  89. Igawa, S.; Ohzono, A.; Pham, P.; Wang, Z.; Nakatsuji, T.; Dokoshi, T.; Di Nardo, A. Sphingosine 1-Phosphate Receptor 2 Is Central to Maintaining Epidermal Barrier Homeostasis. J. Investig. Dermatol. 2021, 141, 1188–1197.e5. [Google Scholar] [CrossRef]
  90. Akaal Pharma Pty Ltd to Develop First-in-Class Topical Treatment for Pruritus in Inflammatory Skin Diseases. Available online: (accessed on 16 September 2022).
Figure 1. Currently approved and emerging topical treatments for atopic dermatitis. Abbreviations: AD, atopic dermatitis; SYK, spleen tyrosine kinase; TYK2, tyrosine kinase 2.
Figure 1. Currently approved and emerging topical treatments for atopic dermatitis. Abbreviations: AD, atopic dermatitis; SYK, spleen tyrosine kinase; TYK2, tyrosine kinase 2.
Pharmaceutics 14 02767 g001
Figure 2. Outline of topical therapeutic strategies and relevant cellular targets in atopic dermatitis. Abbreviations: AhR, aryl hydrocarbon receptor; BTK, Bruton tyrosine kinase; BTKi, Bruton tyrosine kinase inhibitors; cAMP, cyclic adenosine monophosphate; JAK, Janus kinase; JAKi, Janus kinase inhibitors; LXR, liver X receptor; PDE4, phosphodiesterase 4; PDE4i, phosphodiesterase 4 inhibitors; S1PR1, sphingosine-1-phosphate receptor subtype 1; TRK, tropomyosin receptor kinase; TRKi, tropomyosin receptor kinase inhibitors. Created with
Figure 2. Outline of topical therapeutic strategies and relevant cellular targets in atopic dermatitis. Abbreviations: AhR, aryl hydrocarbon receptor; BTK, Bruton tyrosine kinase; BTKi, Bruton tyrosine kinase inhibitors; cAMP, cyclic adenosine monophosphate; JAK, Janus kinase; JAKi, Janus kinase inhibitors; LXR, liver X receptor; PDE4, phosphodiesterase 4; PDE4i, phosphodiesterase 4 inhibitors; S1PR1, sphingosine-1-phosphate receptor subtype 1; TRK, tropomyosin receptor kinase; TRKi, tropomyosin receptor kinase inhibitors. Created with
Pharmaceutics 14 02767 g002
Table 1. Topical treatments in the pipeline for atopic dermatitis in the late stage of development.
Table 1. Topical treatments in the pipeline for atopic dermatitis in the late stage of development.
Agent (Acronym)Inhibition Target/ActivityClinical Development PhaseClinical Trial Identifier
Aryl Hydrocarbon
Receptor Modulating Agents
Tapinarof/benvitimodAhR agonistIIINCT05142774, NCT05014568, NCT05032859
4 Inhibitors
Roflumilast (ARQ-151)PDE4IIINCT04804605, NCT04773600, NCT04845620, NCT04773587
Difamilast (OPA-15406/MM36)PDE4IIINCT05372653, NCT03908970, NCT03911401
Lotamilast (RVT-501/E6005)PDE4IIINCT03394677, NCT02950922
Topical JAK
DelgocitinibPan-JAKApproved in Japan; IIb in EUNCT03725722
RuxolitinibJAK1, JAK2IIINCT04921969, NCT05456529, NCT03745638, NCT03745651
Abbreviations: AhR, aryl-hydrocarbon receptor; PDE4, phosphodiesterase 4; JAK, Janus kinase.
Table 2. Other novel topical therapies currently in phase I/II of development for atopic dermatitis.
Table 2. Other novel topical therapies currently in phase I/II of development for atopic dermatitis.
Inhibition Target/ActivityStudy PhaseClinical Trial
AD SeverityStudy
Age (Years)Primary EndpointStatus
Skin microbiome
modulating agents
IIbNCT04504279Mild to moderate16 weeks≥2EASI50Completed
ShA9Targeted microbiome transplantINCT05177328Moderate to severe24 days18–80Duration of ShA9 survival on the lesional ventral arm skinRecruting
Nitrosomonas eutropha (B244)Nitric oxide donorIIbNCT04490109Mild to moderate4 weeks18–65Mean change in WI-NRSCompleted
Niclosamide (ATx201)Decolonization of S. aureusIINCT04339985Mild to moderate2 weeks12–60Mean change in EASI scoreCompleted
Omiganan pentachlorideAntimicrobial cationic
IINCT03091426Mild to moderate7 weeks18–65Clinical evaluation [oSCORAD]Completed
OthersVTP-38543LXR-β agonistI/IINCT02655679Mild to moderate28 days18–65Number of AEsCompleted
ALX 101LXR-β agonistIINCT03859986Moderate56 days≥12Mean change in EASI score at week 8Unknown
BEN-2293Pan-TRKI/IINCT04737304Mild to moderateNA18–65Safety and tolerabilityRecruiting
HY209GPCR19IINCT04530643Mild to moderate28 days18–65Safety and tolerabilityRecruiting
AMTX-100Nuclear transport modifierI/IIbNCT04313400Mild to moderateNA≥18Maximum tolerable doseActive not recruiting
PRN473BTK inhibitorIIaNCT04992546Mild to moderate42 days18–70Number of AEsRecruiting
Phosphodiesterase 4 InhibitorsHemay-808PDE4IINCT04352595Mild to moderate29 days18–65Change in the EASI score relative to the baselineNA
LEO 29102PDE4IINCT01037881Mild to moderate28 days18–65Mean change in EASI score at week 8Completed
Topical JAK inhibitorsTofacitinibJAK1, JAK3II (discontinued)NCT02001181Mild to moderate28 days18–60Change in the EASI score relative to the baselineCompleted
ATI-1777JAK1, JAK3IIbNCT05432596Moderate to severe28 days12–65Percentage change from baseline in EASI score at Week 4Recruiting
ATI-502JAK1, JAK3II (discontinued)NCT03585296Moderate to severe56 days>18Number of AEsCompleted
Brepocitinib (PF-06700841)JAK1/TYK2IIbNCT03903822Moderate to severe42 days12–75Percentage change from baseline in EASI score at Week 8Completed
JaktinibPan-JAKI/IINCT04435392Mild to moderateNA18–65Proportion of participants achieving PGA response of 0/1Recruting
CEE321Pan-JAKINCT04612062Mild to moderateNA18–65Number of AEsCompleted
Abbreviations: AEs, adverse events; EASI, eczema area severity index; PGAShA9, Staphylococcus hominis A9; LXR, liver X receptors; TRK, tropomyosin receptor kinase; NA, not applicable; GPCR19, G-protein-coupled receptor 19; BTK, Bruton tyrosine kinase. S1PR1, Spingosine-1-Phosphate receptor subtype-1.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Pinto, L.M.; Chiricozzi, A.; Calabrese, L.; Mannino, M.; Peris, K. Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis. Pharmaceutics 2022, 14, 2767.

AMA Style

Pinto LM, Chiricozzi A, Calabrese L, Mannino M, Peris K. Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis. Pharmaceutics. 2022; 14(12):2767.

Chicago/Turabian Style

Pinto, Lorenzo Maria, Andrea Chiricozzi, Laura Calabrese, Maria Mannino, and Ketty Peris. 2022. "Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis" Pharmaceutics 14, no. 12: 2767.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop