Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with heterogenous presentation and often immense patient burden. Safe, targeted treatment options are currently limited. This ...focused review of the published literature, including clinical trial results, case reports, and abstracts, as well as presentations from scientific meetings and data from industry press releases, describes the use of topical and systemic Janus kinase (JAK) inhibitors in the treatment of AD. New topical JAK inhibitors include ruxolitinib (JAK1/2) and delgocitinib (pan-JAK). Ruxolitinib cream met all primary and secondary endpoints in phase 3 clinical trials for mild-to-moderate AD with minimal treatment-emergent adverse events. Delgocitinib ointment was recently approved in Japan for pediatric and adult AD. Oral JAK inhibitors include baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective). All 3 met primary and secondary endpoints across numerous trials for moderate-to-severe AD. Treatment-emergent adverse events were mainly mild to moderate and included acne, nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infection and selected laboratory abnormalities. JAK inhibitors hold great promise as the next generation of targeted AD therapy. While their outstanding efficacy is balanced by a favorable safety profile in clinical trials, real-world data are needed to better understand long-term safety, durability, and treatment success.
New treatments in atopic dermatitis Puar, Neha; Chovatiya, Raj; Paller, Amy S
Annals of allergy, asthma, & immunology,
01/2021, Volume:
126, Issue:
1
Journal Article
Peer reviewed
Open access
To discuss the efficacy and safety of novel and emerging topical and systemic therapeutic agents for atopic dermatitis (AD).
The review of the published literature was performed using the PubMed ...database, published abstracts and virtual presentations from scientific meetings, posted results on ClinicalTrials.gov, and data from industry press releases.
Primary manuscripts with trial results, case reports, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on management of AD were selected.
Emerging topical and systemic therapies primarily target the type 2 immune pathway. Moreover, 2 newer targeted medications are now approved by the Food and Drug Administration for both children and adults, crisaborole 2% ointment and dupilumab, with several others in the therapeutic pipeline. New directions in developing topical medications include Janus kinase inhibitors, tapinarof (an aryl hydrocarbon receptor agonist), and agents to correct microbial dysbiosis. In addition to the subcutaneously injected monoclonal antibody targeting the interleukin (IL) 4 receptor (dupilumab), other biologics targeting IL-13, IL-31, IL-33, OX40, and thymic stromal lymphopoietin are currently being tested. Oral Janus kinase inhibitors are showing outstanding efficacy and no serious safety signs, but safety concerns remain.
Given the tremendous burden of AD on physical, mental, and social health, the need is high to develop new, targeted therapies. Advances in our understanding of AD pathogenesis have paved the way toward the development of new therapies that promise to revolutionize our management of AD. Future research will focus on long-term efficacy and safety and creating predictive models for choosing best management options on a personalized basis.
Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The ...pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application. The first highly effective mAb for AD, dupilumab, targets the IL-4/IL-13 receptor and was approved in early 2017 in the United States for moderate-to-severe adult AD. Other biologics similarly inhibit TH2 cytokines (thymic stromal lymphopoietin, IL-4, IL-5, IL-13, and the itch-specific cytokine IL-31 and their receptors) or TH22/TH17 cytokines, levels of which are increased in lesional skin. Orally administered small-molecule inhibitors that suppress inflammation (targeting chemoattractant receptor–homologous molecules expressed on TH2 lymphocytes, PDE4, the histamine 4 receptor, and Janus kinase) or specifically itching (eg, NK1R inhibitors) are also being studied. Comparing biomarkers with individual responses to experimental agents will help to determine subphenotypes within AD that predict prognosis and treatment responses.
Despite extensive discovery about the mutations underlying genetic skin disorders, there have been few therapeutic advances. Better understanding of the molecular changes that may lead to the ...phenotypic manifestations of genetic disorders may lead to the discovery of new pharmacologic interventions. The ichthyoses are characterized by scaling, inflammation, and an impaired epidermal barrier. Recent studies have uncovered T helper type 17 skewing in ichthyotic skin, resembling psoriasis, and high frequencies of IL-17– and IL-22–expressing T cells in blood, correlating with severity and transepidermal water loss. Repurposing systemic T helper type 17/IL-23–inhibitory therapies for psoriasis may prove useful for patients with ichthyosis.
The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly ...understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.
Phosphodiesterase 4 inhibitors Zebda, Rema; Paller, Amy S.
Journal of the American Academy of Dermatology,
March 2018, 2018-03-00, 20180301, Volume:
78, Issue:
3
Journal Article
Peer reviewed
Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy ...reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration–approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.
Background Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. Objective We sought to assess the efficacy and safety of crisaborole ...ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766 ; AD-302: NCT02118792 ). Methods Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. Results More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity. Limitations Short study duration was a limitation. Conclusions Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.
Safe and efficacious topical treatments are needed for atopic dermatitis (AD).
We assessed the safety and efficacy of tapinarof cream (2 concentrations and 2 application frequencies) in patients with ...AD.
A double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients age 12 to 65 years, with body surface area involvement of at least 5% to 35% and an Investigator's Global Assessment score of 3 or higher (moderate to severe) at baseline. Primary end points included an Investigator's Global Assessment score of clear or almost clear (0 or 1) and a minimum 2-grade improvement (treatment success) at week 12. Secondary analyses included a 75% or greater improvement in Eczema Area and Severity Index score, reduction of numeric rating scale (NRS) score for itch from baseline, and other prespecified end points.
The rates of treatment success with tapinarof cream at week 12 were 53% (a concentration of 1% twice daily), 46% (a concentration of 1% once daily), 37% (a concentration of 0.5% twice daily), 34% (0.5% once daily), 24% (vehicle twice daily), and 28% (vehicle once daily). The rate with a concentration of 1% twice daily (53%) was statistically significantly higher than the rate with vehicle twice daily (24%). Treatment success was maintained for 4 weeks after the end of tapinarof treatment. The rate of treatment-emergent adverse events was higher with tapinarof (93 of 165 56%) than with vehicle (34 of 82 41%), and the events were mild to moderate in intensity.
Large confirmation trials are needed.
Tapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.
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