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Background: Children with severe atopic dermatitis (AD) have limited treatment options.Objective: We report the efficacy and safety of dupilumab 1 topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies.Methods: In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight \30 kg; 200 mg q2w, baseline weight $30 kg), or placebo; with concomitant medium-potency TCS.Results: Both the q4w and q2w dupilumab 1 TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo 1 TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved $75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved $4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children \30 kg and 200 mg q2w in children $30 kg.

Macrophages serve to maintain organ homeostasis in response to challenges from injury, inflammation, malignancy, particulate exposure, or infection. Until now, receptor ligation has been understood as being the central mechanism that regulates macrophage function. Using macrophages of different origins and species, we report that macrophage elasticity is a major determinant of innate macrophage function. Macrophage elasticity is modulated not only by classical biologic activators such as LPS and IFN-γ, but to an equal extent by substrate rigidity and substrate stretch. Macrophage elasticity is dependent upon actin polymerization and small rhoGTPase activation, but functional effects of elasticity are not predicted by examination of gene expression profiles alone. Taken together, these data demonstrate an unanticipated role for cell elasticity as a common pathway by which mechanical and biologic factors determine macrophage function.

Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov , NCT04327388 ; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 1...

Background Management of moderate-to-severe atopic dermatitis (AD) commonly requires long-term treatment. Objective The aim of this study was to report the safety and efficacy of dupilumab treatment for up to 3 years in adults with moderate-to-severe AD. Methods This ongoing, multicenter, open-label extension study (LIBERTY AD OLE; NCT01949311) assessed dupilumab treatment in adults previously enrolled in dupilumab trials. Patients received dupilumab 300 mg weekly up to 148 weeks. The primary outcome was safety. Results Of 2677 patients enrolled and treated, 347 reached week 148. Mean self-reported drug compliance was 98.2%. Safety data were consistent with previously reported trials (270.1 adverse events [AEs]/100 patient-years; 6.9 serious AEs/100 patient-years) and the known dupilumab safety profile. Common AEs (≥ 5% of patients) included nasopharyngitis, AD, upper respiratory tract infection, conjunctivitis, headache, oral herpes, and injection-site reactions. AD signs and symptoms showed sustained improvements during treatment with mean (standard deviation, mean percentage change from parent study baseline) Eczema Area and Severity Index 1.4 (3.2, − 95.4%) and weekly Pruritus Numerical Rating Scale 2.2 (1.8, − 65.4%) at week 148. Limitations No control arm; fewer patients at later time points; regimen different from the approved 300 mg every 2 weeks dose. Conclusion These safety and efficacy results support dupilumab as a continuous long-term treatment for adults with moderate-to-severe AD. Trial Registration ClinicalTrials.gov: NCT01949311. Video abstract Electronic supplementary material The online version of this article (10.1007/s40257-020-00527-x) contains supplementary material, which is available to authorized users.

Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.

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