Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib ...compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12–17 years) and adults (aged 18–75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index EASI score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis vIGA-AD score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 clear or 1 almost clear with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 70% of 281 patients) and upadacitinib 30 mg (227 80% of 285 patients) groups than the placebo group (46 16% of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% 95% CI 46·4–60·2 for the upadacitinib 15 mg group; 63·4% 57·1–69·8 for the upadacitinib 30 mg group) and Measure Up 2 (166 60% of 276 patients in the upadacitinib 15 mg group and 206 73% of 282 patients in the upadacitinib 30 mg group vs 37 13% of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% 39·9–53·9 for the upadacitinib 15 mg group; 59·6% 53·1–66·2 for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 48% patients) and upadacitinib 30 mg (177 62% patients) groups than the placebo group (24 8% patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% 33·2–46·4 for the upadacitinib 15 mg group; 53·6% 47·2–60·0 for the upadacitinib 30 mg group) and Measure Up 2 (107 39% patients in the upadacitinib 15 mg group and 147 52% patients in the upadacitinib 30 mg group vs 13 5% patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% 27·8–40·2 for the upadacitinib 15 mg group; 47·4% 41·0–53·7 for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 7% of 281 patients in the upadacitinib 15 mg group, 49 17% of 285 patients in the upadacitinib 30 mg group, and six 2% of 281 patients in the placebo group in Measure Up 1; 35 13% of 276 patients in the upadacitinib 15 mg group, 41 15% of 282 patients in the upadacitinib 30 mg group, and six 2% of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 9% patients, 38 13% patients, and 20 7% patients; 19 7% patients, 17 16% patients, and 12 4% patients), nasopharyngitis (22 8% patients, 33 12% patients, and 16 6% patients; 16 6% patients, 18 6% patients, and 13 5% patients), headache (14 5% patients, 19 7% patients, and 12 4% patients; 18 7% patients, 20 7% patients, and 11 4% patients), elevation in creatine phosphokinase levels (16 6% patients, 16 6% patients, and seven 3% patients; nine 3% patients, 12 4% patients, and five 2% patients), and atopic dermatitis (nine 3% patients, four 1% patients, and 26 9% patients; eight 3% patients, four 1% patients, and 26 9% patients).
Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit–risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
AbbVie.
Sleep disturbances are associated with poor health outcomes in adults. However, little is known about the sleep disturbances that occur in adult eczema. We studied the association between adult ...eczema and sleep disturbance and their impact on overall health and health care utilization. We used the 2012 National Health Interview Survey, a cross-sectional questionnaire of 34,613 adults. Eczema was associated with higher odds of fatigue (odds ratio (95% confidence interval): 2.97 (2.65–3.34)), regular daytime sleepiness (2.66 (2.34–3.01)), and regular insomnia (2.36 (2.11–2.64)), even after controlling for sleep duration, history of allergic disease, sociodemographics, and body mass index. There were significant interactions between eczema and fatigue, sleepiness, and insomnia as predictors of poorer overall health status, number of sick days, and doctor visits, such that eczema and each of the sleep symptoms were associated with higher odds of poorer outcomes than either eczema or sleep symptoms alone. Latent class analysis was used and identified five classes of fatigue, sleep disturbances, and allergic disorders. Two classes had high probabilities of eczema: one with high probabilities of asthma, hay fever, food allergy, and multiple sleep symptoms and the other with intermediate probability of insomnia alone. Future studies are warranted to better characterize sleep loss in eczema and develop strategies for treatment and prevention.
As human skin hosts a diverse microbiota in health and disease, there is an emerging consensus that dysregulated interactions between host and microbiome may contribute to chronic inflammatory ...disease of the skin. Neonatal skin is a unique habitat, structurally similar to the adult but with a different profile of metabolic substrates, environmental stressors, and immune activity. The surface is colonized within moments of birth with a bias toward maternal strains. Initial colonists are outcompeted as environmental exposures increase and host skin matures. Nonetheless, early life microbial acquisitions may have long-lasting effects on health through modulation of host immunity and competitive interactions between bacteria. Microbial ecology and its influence on health have been of interest to dermatologists for >50 years, and an explosion of recent interest in the microbiome has prompted ongoing investigations of several microbial therapeutics for dermatological disease. In this review, we consider how recent insight into the host and microbial factors driving development of the skin microbiome in early life offers new opportunities for therapeutic intervention. IMPACT: Advancement in understanding molecular mechanisms of bacterial competition opens new avenues of investigation into dermatological disease. Primary development of the skin microbiome is determined by immunological features of the cutaneous habitat. Understanding coordinated microbial and immunological development in the pediatric patient requires a multidisciplinary synthesis of primary literature.
Atopic dermatitis (eczema) is a chronic inflammatory disorder that is associated with other chronic diseases (eg, asthma), major quality-of-life impairment, sleep disturbance, and the use of potent ...topical and sometimes systemic corticosteroids, all of which might affect growth in childhood and adolescence. However, previous smaller-scale studies found conflicting results.
To determine whether eczema is associated with short stature.
We used data from 9 US population-based studies, including the National Survey of Children's Health (2003-2004 and 2007-2008), National Health Interview Survey (children's health, 2008-2012; adult health, 2010 and 2012), and National Health and Nutrition Examination Survey (2003-2004 and 2005-2006). Participants included 264 326 children and adolescents and 83 511 adults.
History of eczema.
Percentiles of height for age and sex in children and height in adults. We constructed multivariate survey linear or logistic regression models for individual studies with Box-Cox transformed or dichotomized height, respectively. Pooled analyses used generalized linear mixed models.
Overall, eczema was not associated with significant differences of height (continuous or <5th or <25th percentiles) in any of the studies or in the pooled analyses. We found a significant interaction by age, such that eczema was associated with shorter stature at 12 to 13 but not 14 to 15 or 16 to 17 years of age or in adulthood. Moderate to severe eczema was associated with shorter stature (continuous and <25th percentile). In particular, short stature (<5th percentile) was associated with eczema only when accompanied by an indicator of insufficient sleep (ie, 0 to 3 nights of sufficient sleep per week) (1.3% of children with eczema) but was not associated with asthma, hay fever, or use of prescription medication. The interaction between eczema and insufficient sleep remained significant at 10 to 11 years of age (P = .003) but not at other ages (P > .08 for all).
Eczema is not associated with short stature overall. However, a small subset of children and adolescents with severe eczema accompanied by prominent insufficient sleep may have potentially reversible vertical growth impairment.
Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both ...cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities.
Background Little is known about the epidemiology of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in children. Objective We sought to determine the morbidity, mortality, and ...comorbid health conditions of SJS and TEN in US children. Methods This was a cross-sectional study of the 2009 to 2012 Nationwide Inpatient Sample, which contains a representative 20% sample of all US hospitalizations. Sociodemographics, inflation-adjusted cost, length of stay, comorbidities, and mortality were analyzed using descriptive statistics and multivariate regression analyses. Results The incidences of SJS, SJS-TEN, and TEN were a mean 5.3, 0.8, and 0.4 cases per million children per year in the US, respectively. Prolonged length of stay and higher costs of care (SJS: 9.4 ± 0.6 days, $24,947 ± $3171; SJS-TEN: 15.7 ± 1.5 days, $63,787 ± $8014; TEN: 20.4 ± 6.3 days, $102,243 ± $37,588) were observed compared with all other admissions (4.6 ± 0.1 days, $10,496 ± $424). Mortality was 0% for SJS, 4% for SJS-TEN, and 16% for TEN. In regression models, predictors of mortality included renal failure (adjusted OR aOR 300.28, 95% confidence interval CI 48.59->999.99), malignancy (aOR 54.33, 95% CI 9.40-314.22), septicemia (aOR 30.45, 95% CI 7.91-117.19), bacterial infection (aOR 20.38, 95% CI 5.44-76.36), and epilepsy (aOR 5.56, 95% CI 1.37-26.2). Limitations Data regarding treatment were not available. Date of diagnosis of comorbidities was not present, precluding temporal analysis. Conclusions Pediatric SJS/TEN poses a substantial health burden in the United States.
Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, ...approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.
To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.
A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.
Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).
Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.
A total of 251 patients were randomized (mean SD age, 14.5 1.7 years; 148 59.0% male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 53.6%; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).
In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.
ClinicalTrials.gov identifier: NCT03054428.
Children with severe atopic dermatitis (AD) have limited treatment options.
We report the efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD ...inadequately controlled with topical therapies.
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.
Both the q4w and q2w dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + 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. Conjunctivitis and injection-site reactions were more common with dupilumab + TCS than with placebo + TCS.
Short-term 16-week treatment period; severe AD only.
Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.
Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.
To ...analyze blood inflammatory proteins of early pediatric AD.
Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD.
In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11).
Different baseline expression levels in healthy pediatric vs adult samples.
Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.
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