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OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis. This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102. Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (−15·0 [95% CI −28·6 to −1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks −48·3 [−62·2 to −34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks −49·7 [−64·3 to −35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks −61·1 [−75·2 to −47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks −57·4 [−71·3 to −43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths. Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated. Kyowa Kirin.

Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).

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.

Using the 2003 National Survey of Children's Health sponsored by the federal Maternal and Child Health Bureau, we calculated prevalence estimates of eczema nationally and for each state among a nationally representative sample of 102,353 children 17 years of age and under. Our objective was to determine the national prevalence of eczema/atopic dermatitis in the US pediatric population and to further examine geographic and demographic associations previously reported in other countries. Overall, 10.7% of children were reported to have a diagnosis of eczema in the past 12 months. Prevalence ranged from 8.7 to 18.1% between states and districts, with the highest prevalence reported in many of the East Coast states, as well as in Nevada, Utah, and Idaho. After adjusting for confounders, metropolitan living was found to be a significant factor in predicting a higher disease prevalence with an odds ratio of 1.67 (95% confidence interval of 1.19–2.35, P=0.008). Black race (odds ratio 1.70, P=0.005) and education level in the household greater than high school (odds ratio 1.61, P=0.004) were also significantly associated with a higher prevalence of eczema. The wide range of prevalence suggests that social or environmental factors may influence disease expression.

Background Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. Objective The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. Methods Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. Results Total exposure in the all-abrocitinib cohort ( n  = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort ( n  = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 10 3 /mm 3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. Conclusion Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. Trial Registries ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822. Video abstract 9D9_BNDjzL2Ft3hvAy42gh Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the Phase II and III clinical trial program (MP4  1,02,272 kb)

Emollients are a mainstay of treatment in atopic dermatitis (AD), a disease distinguished by skin bacterial dysbiosis. However, changes in skin microbiota when emollients are used as a potential AD preventative measure in infants remain incompletely characterized. We compared skin barrier parameters, AD development, and bacterial 16S ribosomal RNA gene sequences of cheek, dorsal and volar forearm samples from 6-month-old infants with a family history of atopy randomized to receive emollients (n = 11) or no emollients (controls, n = 12). The emollient group had a lower skin pH than the control group. The number of bacterial taxa in the emollient group was higher than in the control group at all sites. The Streptococcus salivarius proportion was higher in the emollient versus control groups at all sites. S. salivarius proportion appeared higher in infants without AD compared to infants with AD. A decrease in S. salivarius abundance was further identified in a separate larger population of older children demonstrating an inverse correlation between AD severity at sampling sites and S. salivarius proportions. The decreased skin pH and the increased proportion of S. salivarius after long-term emollient use in infants at risk for developing AD may contribute to the preventative effects of emollients in high-risk infants.

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.

The consequences of atopic dermatitis reach beyond the skin and past childhood. Patients with atopic dermatitis are at risk of developing allergic comorbidities, but less is known about the associations between atopic dermatitis and non-allergic conditions. Understanding these non-allergic comorbidities has the potential to improve patient outcomes and to help mitigate the cost and burdens associated with these conditions. Atopic dermatitis is associated with cutaneous bacterial infections, more severe forms/courses of cutaneous viral infections, and extra-cutaneous infections. Atopic dermatitis is also associated with several mental health comorbidities particularly attention-deficit hyperactivity disorder, anxiety, and depression. Data are largely inconsistent for specific cancers, but atopic dermatitis appears to protect against malignancy overall; severe long-term atopic dermatitis is associated with adult lymphomas. Atopic dermatitis may also be associated with obesity, cardiovascular disease, and autoimmune disease, particularly alopecia areata and gastrointestinal immune-mediated disorders. Although the causative mechanisms underlying these associations are poorly understood, treating physicians should be aware of associations in seeking to alleviate the burden for patients with atopic dermatitis.

Core outcome sets (COSs) are consensus-derived minimum sets of outcomes to be assessed in a specific situation. COSs are being increasingly developed to limit outcome-reporting bias, allow comparisons across trials, and strengthen clinical decision making. Despite the increasing interest in outcomes research, methods to develop COSs have not yet been standardized. The aim of this paper is to present the Harmonizing Outcomes Measures for Eczema (HOME) roadmap for the development and implementation of COSs, which was developed on the basis of our experience in the standardization of outcome measurements for atopic eczema. Following the establishment of a panel representing all relevant stakeholders and a research team experienced in outcomes research, the scope and setting of the core set should be defined. The next steps are the definition of a core set of outcome domains such as symptoms or quality of life, followed by the identification or development and validation of appropriate outcome measurement instruments to measure these core domains. Finally, the consented COS needs to be disseminated, implemented, and reviewed. We believe that the HOME roadmap is a useful methodological framework to develop COSs in dermatology, with the ultimate goal of better decision making and promoting patient-centered health care.

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.