Development and Psychometric Validation of a Patient-Reported Outcome Measure to Assess the Signs and Symptoms of Chronic Hand Eczema: The Hand Eczema Symptom Diary (HESD).

INTRODUCTION: Chronic Hand Eczema (CHE) is an inflammatory skin disease of the hands. The Hand Eczema Symptom Diary (HESD) is a new patient-reported outcome measure of worst severity of core CHE signs/symptoms. This study aimed to evaluate content and psychometric validity of the HESD. METHODS: The HESD was developed based on the literature and concept elicitation interviews. Qualitative cognitive debriefing interviews were conducted with CHE patients to assess relevance and understanding of items, response options and recall period. Psychometric properties of the HESD (item performance, dimensionality, reliability, validity, responsiveness and estimation of meaningful change thresholds) were then assessed, first using data from a phase 2b trial (NCT03683719), and confirmed using data from the first 280 participants completing the 16-week treatment phase of a phase 3 trial (NCT04871711). RESULTS: Cognitive debriefing supported item refinement and removal of items and confirmed all items were well understood and relevant to patients. Item properties and dimensionality analyses in the phase 2b data supported removal of additional items, resulting in the 6-item HESD included in the phase 3 trial. Unidimensionality was supported by inter-item correlations (all > 0.70) and Rasch analysis. Internal consistency (Cronbach's alpha = 0.96) and test-retest reliability (Intraclass Correlation Coefficient > 0.89) results were very strong. Construct validity was supported by moderate correlations with concurrent measures (0.53-0.64) and significant differences between severity groups (p < 0.001). Large effect sizes for mean change scores in participants that improved and significant differences between change groups indicated the ability to detect change. Anchor-based analyses supported within-individual responder definitions of ≥ 4-points for improvements in 7-day average HESD scores. CONCLUSION: The HESD is the first CHE-specific, patient-reported outcome measure of CHE signs/symptoms developed and validated in line with regulatory guidance. This article provides evidence of strong content validity and psychometric validity and shows improvements of ≥ 4 points on 7-day average HESD scores represent clinically meaningful, important changes. TRIAL REGISTRATION: NCT03683719, NCT04871711.

Validation of the Investigator Global Assessment of Chronic Hand Eczema (IGA-CHE): a new clinician reported outcome measure of CHE severity.

The Investigator Global Assessment of Chronic Hand Eczema (IGA-CHE) is a novel Clinician-Reported Outcome measure that allows investigators to assess cross-sectional CHE global disease severity using clinical characteristics of erythema, scaling, lichenification/hyperkeratosis, vesiculation, oedema, and fissures as guidelines for overall severity assessment. This study aimed to evaluate the psychometric properties of the IGA-CHE for use as an outcome measure in CHE clinical trials and clinical practice. Psychometric analyses were performed using data from a sample of 280 patients with moderate to severe CHE from a phase 3 trial of delgocitinib cream, pooled across treatment groups. Test-retest reliability results were moderate to strong with kappa coefficients ranging from 0.63 to 0.76. Correlations with measures assessing related concepts were moderate or strong (range 0.65-0.72) and exceeded a priori hypotheses, providing evidence of convergent validity. Known-groups validity was supported by statistically significant differences between severity groups (< 0.001). Within-group effect sizes were consistently larger for improved groups compared to stable groups, providing evidence of ability to detect change. Anchor-based analyses generated within-subject meaningful change estimates ranging from - 0.8 to - 2.3. A correlation weighted average suggested a single value of - 1.7 in change from baseline. These findings provide evidence the IGA-CHE scale has strong reliability, construct validity, and ability to detect change, supporting its use as an endpoint in CHE clinical trials and clinical practice. Based on the evidence, 2-level changes in IGA-CHE score are considered a conservative meaningful change threshold; however, findings also indicate 1-level change in IGA-CHE scores reflects a clinically meaningful improvement for patients.Clinical trial registration: NCT04871711.

Safety, efficacy, and pharmacokinetics of delgocitinib ointment in infants with atopic dermatitis: A phase 3, open-label, and long-term study.

BACKGROUND: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established. METHODS: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to <24 months received 0.25% or 0.5% of delgocitinib ointment twice daily for 52 weeks in an open-label uncontrolled manner. Topical corticosteroids were allowed to apply for worsening AD during the treatment period at the investigators' discretion. RESULTS: A total of 22 infants were enrolled. Adverse events (AEs) were reported in 21 (95.5%) infants and were mostly mild. No treatment-related AEs were reported. The Modified Eczema Area and Severity Index (mEASI) score continuously decreased until week 4, and the score reduction was maintained until week 52. The mean percent changes in the mEASI score from baseline were -73.5% at week 4, -81.7% at week 28, and -81.9% at week 52. Delgocitinib was not detected in the plasma of most infants (68.2%-95.2%). CONCLUSIONS: Delgocitinib ointment is well tolerated and effective for up to 52 weeks when applied to Japanese infants with AD.

Topical treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD prescription topical treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s). RESULTS: The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. CONCLUSIONS: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.

Inhibidores de JAK en dermatitis atópica, nuevas perspectivas / Janus Kinase Inhibitors in Atopic Dermatitis: New Perspectives

La vía Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) es esencial en la señalización final de una gran mayoría de interleucinas (IL) fundamentales en la patogénesis de la dermatitis atópica (DA). El bloqueo transversal que consiguen los inhibidores de JAK a través de la inhibición intermitente de las acciones de múltiples citoquinas, permite modular la inflamación Th2, la disfunción de barrera epidérmica y la señalización del prurito. Sin embargo, esa inhibición amplia también puede asociarse con una mayor variedad de efectos adversos. En este artículo se revisan los inhibidores de JAK recientemente aprobados en la DA —baricitinib, upadacitinib y abrocitinib—, así como otros emergentes o en desarrollo como gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib y cerdulatinib. El bloqueo de la señalización de diversas citoquinas relevantes en esta dermatosis, compleja patogénicamente y con una expresión fenotípica heterogénea, a través de los inhibidores de JAK, ha supuesto una revolución en el tratamiento de la DA (AU)

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is an essential final step in the signaling process of most interleukins with a critical role in the pathogenesis of atopic dermatitis. By achieving broad, intermittent inhibition of the activity of multiple cytokines, JAK inhibitors help modulate T helper 2 cell–mediated inflammation, epidermal barrier dysfunction, and itch signaling. This comprehensive blockade, however, can result in a wider range of adverse effects. We review a number of JAK inhibitors that have been recently approved for use in atopic dermatitis, such as baricitinib, upadacitinib, and abrocitinib, as well as others that are currently in the pipeline or under development, such as gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib, and cerdulatinib. The use of JAK inhibitors to block the signaling of numerous cytokines with a critical role in the pathogenesis of atopic dermatitis has revolutionized the treatment of this pathogenically complex, phenotypically heterogeneous skin disease (AU)

[Translated article] Janus Kinase Inhibitors in Atopic Dermatitis: New Perspectives / Inhibidores de JAK en dermatitis atópica, nuevas perspectivas

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is an essential final step in the signaling process of most interleukins with a critical role in the pathogenesis of atopic dermatitis. By achieving broad, intermittent inhibition of the activity of multiple cytokines, JAK inhibitors help modulate T helper 2 cell–mediated inflammation, epidermal barrier dysfunction, and itch signaling. This comprehensive blockade, however, can result in a wider range of adverse effects. We review a number of JAK inhibitors that have been recently approved for use in atopic dermatitis, such as baricitinib, upadacitinib, and abrocitinib, as well as others that are currently in the pipeline or under development, such as gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib, and cerdulatinib. The use of JAK inhibitors to block the signaling of numerous cytokines with a critical role in the pathogenesis of atopic dermatitis has revolutionized the treatment of this pathogenically complex, phenotypically heterogeneous skin disease (AU)

La vía Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) es esencial en la señalización final de una gran mayoría de interleucinas (IL) fundamentales en la patogénesis de la dermatitis atópica (DA). El bloqueo transversal que consiguen los inhibidores de JAK a través de la inhibición intermitente de las acciones de múltiples citoquinas, permite modular la inflamación Th2, la disfunción de barrera epidérmica y la señalización del prurito. Sin embargo, esa inhibición amplia también puede asociarse con una mayor variedad de efectos adversos. En este artículo se revisan los inhibidores de JAK recientemente aprobados en la DA —baricitinib, upadacitinib y abrocitinib—, así como otros emergentes o en desarrollo como gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib y cerdulatinib. El bloqueo de la señalización de diversas citoquinas relevantes en esta dermatosis, compleja patogénicamente y con una expresión fenotípica heterogénea, a través de los inhibidores de JAK, ha supuesto una revolución en el tratamiento de la DA (AU)

Small molecule protein kinase inhibitors approved by regulatory agencies outside of the United States.

Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.

Janus Kinase Inhibitors in Atopic Dermatitis: New Perspectives. / Inhibidores de JAK en dermatitis atópica, nuevas perspectivas.

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is an essential final step in the signaling process of most interleukins with a critical role in the pathogenesis of atopic dermatitis. By achieving broad, intermittent inhibition of the activity of multiple cytokines, JAK inhibitors help modulate T helper 2 cell-mediated inflammation, epidermal barrier dysfunction, and itch signaling. This comprehensive blockade, however, can result in a wider range of adverse effects. We review a number of JAK inhibitors that have been recently approved for use in atopic dermatitis, such as baricitinib, upadacitinib, and abrocitinib, as well as others that are currently in the pipeline or under development, such as gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib, and cerdulatinib. The use of JAK inhibitors to block the signaling of numerous cytokines with a critical role in the pathogenesis of atopic dermatitis has revolutionized the treatment of this pathogenically complex, phenotypically heterogeneous skin disease.

Topical and systemic JAK inhibitors in hand eczema - a narrative review.

INTRODUCTION: Hand eczema is a chronic inflammatory skin disease characterized by significant prevalence and impact on patients' Quality of Life (QoL). Because of its complex and diverse clinical picture, HE management requires patient-specific treatment which may constitute a challenge. First described in the 1990s, Janus kinase inhibitors (JAK inhibitors) state a group of modern therapeuticals, which exhibit good bioavailability and are well tolerated by patients in both - topical and systemic - routes of administration. They are an immunomodulating small molecules, impacting JAKs' enzymatic activity. AREAS COVERED: This review provides a summary of available data concerning JAK inhibitors' use in HE patients, regarding also clinical trials for the HE treatment. EXPERT OPINION: Recent studies are introducing JAK inhibitors as an alternative for other topical and systemic therapies in HE patients. Treatment targeting specific immune pathways enables precise management and extends range of potential therapeutic options. Despite early promising results, future studies need to evaluate JAK inhibitors' safety, potential risks and benefits resulting from the treatment, as well as impact of the therapy on patients' QoL.

A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata.

Alopecia areata/AA is an autoimmune cause of nonscarring hair loss. The pathogenesis of AA involves many immune axes, including Th1/Th2 pathways. Delgocitinib is a pan-Janus kinase/JAK inhibitor that broadly blocks pro-inflammatory cytokines and has been effective in other inflammatory skin conditions. Recent human studies/reports have shown that use of some systemic JAK inhibitors led to hair regrowth, suggesting this medication class as a potential therapy for AA. However, topical treatment is desirable due to potential systemic side effects. To assess the efficacy and safety of topical delgocitinib in AA, we conducted a double-blind, randomized, vehicle-controlled clinical trial in 31 moderate-to-severe AA patients that were randomized 2:1 to receive delgocitinib ointment 30 mg/g (n = 20) or ointment vehicle (n = 11) for 12 weeks. The primary endpoint was change in severity of Alopecia Tool/SALT score from baseline to week 12. The secondary endpoint included safety profile by reported adverse events. Twenty-three subjects completed the trial, with eight discontinuing mostly due to voluntary withdrawal. Ten patients receiving delgocitinib ointment and three patients receiving vehicle showed SALT score improvements after 12 weeks, but the mean percent SALT improvement at week 12 compared to baseline between the two arms was not significant (p = 0.92). Our study suggests that delgocitinib ointment is not effective in moderate-to-severe AA, likely due to its inability to penetrate sufficiently deeply into the dermis of the scalp, but larger studies are necessary to assess whether a different formulation of topical JAK inhibitors may be suitable to treat mild or more localized forms of AA.

Pharmacodynamics of Janus kinase inhibitors for the treatment of atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is the most common inflammatory skin disorder. Despite the high disease burden, the therapeutic options are limited and their efficacy in controlling AD might be partially satisfactory. AREAS COVERED: Most of the key mediators in AD pathogenesis act through the JAK/STAT signaling pathway, which represents a valid therapeutic target. The first generation of JAK inhibitors, namely tofacitinib and ruxolitinib, inhibit multiple JAKs, whereas newer JAK inhibitors show more selective inhibitory effects for specific JAKs. The aim of this review was to discuss the role of the JAK/STAT pathway in AD and its inhibition, with a special focus on pharmacodynamic properties. EXPERT OPINION: JAK inhibitors have different selectivity for various JAK molecules, which influences their pharmacodynamics, efficacy, and safety profile. Since many key cytokines in AD signal through JAK1, the selective JAK1 inhibition may be effective, avoiding the concomitant inhibition of JAK2- and JAK3-dependent pathways could be associated with additional safety issues. Therefore, selective JAK1 inhibitors may represent promising therapeutic agents for AD, as they might prevent off-target effects of JAK inhibitors, especially related to the hematologic profile.

Current emerging and investigational drugs for the treatment of chronic hand eczema.

INTRODUCTION: Chronic hand eczema (CHE) is a highly prevalent, burdensome condition associated with functional impairment. Currently, topical therapeutics are the mainstay of CHE management. However, many cases are refractory to existing topical therapeutics, and the few existing systemic options are often limited in efficacy and by their side effect profiles. AREAS COVERED: Following a brief overview of CHE pathogenesis and existing treatments, this review will outline the mechanisms and available data on emerging and investigational drugs currently being studied in clinical trials for the treatment of CHE. EXPERT OPINION: Immunomodulatory drugs such as topical and systemic JAK inhibitors and Th2-targeting antibodies such as dupilumab are currently under investigation for CHE treatment, with early promise. Management of CHE will likely move toward more targeted treatments through clinical trials and away from broad immunosuppressants such as cyclosporine and methotrexate, which have previously been investigated for CHE and have more side effects. In coming years, CHE patients may benefit from a wider range of both topical and systemic therapeutics that target immune pathways relevant to the various CHE subtypes.

[Development of new topical substances for the treatment of atopic dermatitis]. / Entwicklung von neuen topischen Substanzen zur Therapie der atopischen Dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. In everyday clinical practice, about 80% of patients present with mild to moderate disease, which is usually treated with topical therapy. Topical anti-inflammatory therapy thus continues to be the standard of care in addition to the basic therapy. Topical glucocorticoids (TGC) and topical calcineurin inhibitors (TCI) are two potent approved substances that are available. In addition to newly developed systemic therapies for moderate to severe AD, there are also new therapeutic approaches in anti-inflammatory topical treatment. Topical Janus kinase inhibitors show a high therapeutic effect. However, only delgocitinib and ruxolitinib have so far been approved for topical administration in Japan and the USA since 2021. Crisaborole, a phosphodiesterase 4 inhibitor, also received approval in the USA. Other phosphodiesterase inhibitors are currently being investigated in clinical trials. Interesting results of clinical studies give hope for further substances and therapeutic approaches.

Real-world efficacy of proactive maintenance treatment with delgocitinib ointment twice weekly in adult patients with atopic dermatitis.

Previous studies have shown the efficacy of delgocitinib (DEL) ointment, a topical Janus kinase inhibitor, against atopic dermatitis (AD). However, there is no available information regarding the efficacy of DEL ointment in maintaining remission. Data of patients with AD who received remission maintenance therapy twice weekly with DEL or topical corticosteroid (TCS) on the affected skin of each upper limb were extracted from the medical records. Efficacy was assessed based on changes in pruritus numerical rating scale (NRS) score, stratum corneum hydration (SCH), erythema index (EI). Of 25 patients, four patients (16%) had eczema flare-ups on the TCS side and eight patients (32%) on the DEL side. The extent of change in each parameter between TCS- and DEL-treated areas of the skin did not differ significantly. The mean changes in the NRS and EI showed a slight improvement on the side treated with TCS and were slightly worse on the side treated with DEL. However, the SCH of the DEL group was maintained, while that of the TCS group worsened. TCS is more likely to be effective than DEL in terms of remission maintenance therapy. However, topical DEL is as effective as topical steroid in the maintenance therapy of AD in dry skin patients.

Evaluating topical JAK inhibitors as a treatment option for atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin condition mediated by cytokines that utilize the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling cascade. Topical JAK inhibitors are an emerging alternative in the treatment of AD. AREAS COVERED: This expert review presents an overview of the underlying molecular pathophysiology of AD, current standards of care, and evaluation of the efficacy and safety of topical JAK inhibitors. A PubMed database search was utilized with a focus on the evidence from double-blind, randomized Phase I, II, and III clinical trials published between January 2015 and July 2021. EXPERT OPINION: Current topical therapies for AD are efficacious but limited by their adverse side effects. Long-term topical corticosteroid use leads to loss of pigmentation, striae, and skin atrophy. Patients may be concerned about topical calcineurin inhibitors' black box warning of increased risk of malignancy. Topical crisaborole, a phosphodiesterase four inhibitor, is limited by application site burning. Topical ruxolitinib is a JAK inhibitor comparable to triamcinolone in efficacy without the adverse effects seen with long-term topical corticosteroid use. Although topical JAK inhibitors have promising efficacy and safety profiles, poor medication adherence common to topical treatments may limit their utility in a clinical setting.

Innovation in the treatment of atopic dermatitis: Emerging topical and oral Janus kinase inhibitors.

Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions. The knowledge on the pathogenesis of AD is driving the development of new drugs. From the research results, it has been revealed that Th2 cell-mediated immunity, skin barrier dysfunction, and pruritus cause a vicious cycle of AD. On the other hand, the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway are one of the essential signaling pathways in various inflammatory diseases including AD. In particular, TSLP, IL-4, IL-13 and IL-22 occupy an important position for Th2 cell-mediated immune reaction. Moreover, experimentally pan-JAK inhibitor suppress the STAT3 activation and improved the skin barrier function. Furthermore TSLP, IL-4, IL-13 and IL-31 contribute a lot to chronic pruritus of AD, and transmitted via JAK-STAT pathway. Therefore, JAK inhibitors are promising candidates for the treatment of severe AD. Here we review clinical trials of topical dergocitinib; a pan-JAK inhibitor, ruxolitinib; a JAK1 and JAK2 inhibitor, and tofacitinib; a JAK1, JAK2, and JAK3 inhibitor and oral baricitinib; a JAK1 and JAK2 inhibitor, abrocitinib and upadacitinib; JAK1 inhibitor. Significant improvements in the symptoms were obtained by each drug with low frequency of adverse events. In particular, oral JAK inhibitors have the ability to improve the pruritus and skin symptoms quickly. Therefore, the emergence of these topical and oral JAK inhibitors would be regarded as an innovation in the treatment of atopic dermatitis.

Delgocitinib in atopic dermatitis.

Delgocitinib ointment is a newly approved topical medication for the treatment of atopic dermatitis (AD). AD usually has onset in early childhood and is a common, often chronic relapsing inflammatory skin condition that affects all age groups. AD has a large impact on patients' quality of life including physical health and emotional impacts. Conventional management of AD consists of phototherapy and treatments that comprise corticosteroids (both topically and systemically), topical calcineurin inhibitors (tacrolimus and pimecrolimus) or systemic immunosuppressants like ciclosporin. New targeted therapies for AD, including interleukin (IL)-4/13 inhibitors, Janus kinase (JAK) inhibitors and IL-13 inhibitors have been introduced for both topical and systemic use. In this review, we give an overview of the use of delgocitinib, the first topical JAK inhibitor to be approved for AD, including its preclinical pharmacology, pharmacokinetics and metabolism, safety, existing clinical trials and future directions.