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Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease.Recent advances in understanding of the complex phenotype and mechanisms underlying atopic dermatitis (AD) have revealed multiple new potential targets for pharmacological intervention. Here, Bieber reviews therapeutic strategies and assesses the expanding pipeline for the therapy of AD, highlighting the potential for a precision medicine approach to the management of this complex disorder.

Progress in understanding of the mechanisms underlying chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis vulgaris, has led to new treatment options with the primary goal of alleviating symptoms. In addition, this knowledge has the potential to inform on new strategies aimed at inducing deep and therapy-free remission, that is, disease modification, potentially impacting on associated comorbidities. However, to reach this goal, key areas require further exploration, including the definitions of disease modification and disease activity index, further understanding of disease mechanisms and systemic spillover effects, potential windows of opportunity, biomarkers for patient stratification and successful intervention, as well as appropriate study design. This Perspective article assesses the opportunities and challenges in the discovery and development of disease-modifying therapies for chronic inflammatory skin disorders.Current treatments for the two most common chronic inflammatory skin disorders, atopic dermatitis and psoriasis, are mainly limited to the alleviation of symptoms. Here, Bieber discusses opportunities and strategies for the discovery and development of interventions aimed at inducing remission of these disorders and their associated comorbidities, assessing key issues that must be addressed to reach this goal.

In patients with prurigo nodularis, a severely pruritic skin disorder, the subcutaneously administered interleukin-31 receptor antibody nemolizumab was tested in a 12-week, phase 2 trial. The intensity of itching and overall severity of the disorder were more greatly reduced with nemolizumab than with placebo.

In a trial comparing abrocitinib with placebo and dupilumab, IGA and EASI-75 responses were better with abrocitinib than with placebo at 12 weeks. Itch response at 2 weeks was better with the 200-mg dose of abrocitinib than with dupilumab, but neither abrocitinib dose differed significantly from dupilumab in most other key secondary end-point comparisons at week 16.

In two 16-week, placebo-controlled trials enrolling adults with moderate-to-severe atopic dermatitis, dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, was effective in controlling the signs and symptoms of atopic dermatitis. Atopic dermatitis is a chronic, relapsing inflammatory skin disease that is characterized by the up-regulation of type 2 immune responses (including those involving type 2 helper T cells), 1 , 2 an impaired skin barrier, and increased Staphylococcus aureus colonization. 3 , 4 In patients with moderate-to-severe atopic dermatitis, skin lesions can encompass a large body-surface area and are frequently accompanied by intense, persistent pruritus, which leads to sleep deprivation, symptoms of anxiety or depression, and a poor quality of life. 5 – 7 For patients with moderate-to-severe atopic dermatitis, topical therapies have limited efficacy, and systemic treatments are associated with substantial toxic effects. Thus, there . . .

Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (−74% [SE 5·16]), 300 mg every 2 weeks (−68% [5·12]), 200 mg every 2 weeks (−65% [5·19]), 300 mg every 4 weeks (−64% [4·94]), 100 mg every 4 weeks (−45% [4·99]); placebo (−18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. Sanofi and Regeneron Pharmaceuticals.

Cutaneous lupus erythematosus (CLE) is an interferon (IFN) -driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Lesional skin of patients with different CLE subtypes and healthy controls ( = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed using an established lupus-prone mouse model. Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE models and also improves skin lesions in lupus-prone TREX1 -mice markedly. IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 -mouse model and appears to be a promising therapeutic approach for CLE patients.

Background Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p  < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p  < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p  < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25 bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control. Impaired interleukin-2 production and regulatory T cell dysfunction is implicated in multiple autoimmune diseases. Here, in two phase lb trials, the authors show that rezpegaldesleukin, a Treg-selective pegylated IL-2, is safe and improves symptoms in patients with atopic dermatitis or psoriasis.