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1.
JAAD Int ; 5: 19-32, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34816131

RESUMO

Introduction: Pruritus is a common symptom across various dermatologic conditions, with a negative impact on quality of life. Devices to quantify itch objectively primarily use scratch as a proxy. This review compares and evaluates the performance of technologies aimed at objectively measuring scratch behavior. Methods: Articles identified from literature searches performed in October 2020 were reviewed and those that did not report a primary statistical performance measure (eg, sensitivity, specificity) were excluded. The articles were independently reviewed by 2 authors. Results: The literature search resulted in 6231 articles, of which 24 met eligibility criteria. Studies were categorized by technology, with actigraphy being the most studied (n = 21). Wrist actigraphy's performance is poorer in pruritic patients and inherently limited in finger-dominant scratch detection. It has moderate correlations with objective measures (Eczema and Area Severity Index/Investigator's Global Assessment: rs(ρ) = 0.70-0.76), but correlations with subjective measures are poor (r2 = 0.06, rs(ρ) = 0.18-0.40 for itch measured using a visual analog scale). This may be due to varied subjective perception of itch or actigraphy's underestimation of scratch. Conclusion: Actigraphy's large variability in performance and limited understanding of its specificity for scratch merits larger studies looking at validation of data analysis algorithms and device performance, particularly within target patient populations.

2.
J Invest Dermatol ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34757070

RESUMO

Itch compromises quality of life, but most itch assessments focus only on itch intensity. We aimed to develop and validate a comprehensive PROMIS (Patient Reported Outcomes Measurement Information System®) pediatric measure for itch symptoms and itch impact, defined as the effect specifically of itch on physical, mental, and social health, all of which can affect life quality. After literature review, concept elicitation and cognitive interviews with parents and children with itch, and repeated content-expert review, an item pool was generated and refined. The pool was calibrated with data from 499 pruritic children using exploratory and confirmatory factor analyses, item response theory, and item fit analysis. The resultant 45-item bank, PROMIS Itch Questionnaire - Child (PIQ-C), showed good convergent and discriminant validity in 181 children 8-17 years of age, discriminating children with different levels of severity, and was responsive to change. Strong correlations (rho>.60) were observed with pain and sleep measures, and moderate correlations with other pediatric PROMIS measures. PIQ-C comprehensively measures itch intensity and burden, providing an itch-specific alternative for assessing life quality. The independent calibration of each item/question allows for flexibility in generating short-forms or computerized adaptive testing for efficient use in research and office practice.

3.
J Am Acad Dermatol ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34756933

RESUMO

BACKGROUND: Patients with atopic dermatitis (AD) are considered at increased risk of developing other type 2 inflammatory diseases. However, real-world evidence based on large commercially insured pediatric populations in the United States is scarce. OBJECTIVE: To use a large claims database (IBM MarketScan 2013-2017) in the United States to assess prevalence and incidence of type 2 inflammatory diseases in pediatric patients with AD. METHODS: Pediatric patients with AD were matched 1:1 to patients without AD. Prevalence was assessed for conjunctivitis, rhinitis, urticaria, asthma, eosinophilic esophagitis, and chronic rhinosinusitis/nasal polyps at the 12 months' post-index date (the first AD diagnosis date for patients with AD; a randomly selected outpatient visit for control patients). The incidence of other type 2 inflammatory diseases post-index was assessed among patients 0-2 years of age. RESULTS: A total of 244,776 AD and matched non-AD patients were selected. The prevalence and incidence of type 2 inflammatory diseases were higher among patients with AD. Overall, the prevalence more than doubled for asthma, eosinophilic esophagitis, urticaria, and rhinitis, and increased with AD severity. LIMITATIONS: AD identification was based on billing diagnoses; the observation period was only 12 months; and the study was limited to commercially insured patients. CONCLUSION: The burden of type 2 inflammatory diseases in pediatric patients with AD is substantial, highlighting the need to optimize management of AD and its numerous associated morbidities.

4.
Pediatr Dermatol ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34647354

RESUMO

BACKGROUND/OBJECTIVES: Psoriasiform eruptions after initiation of dupilumab have been previously described in adults. This report details the risk of developing or unmasking psoriasiform eruptions after initiation of dupilumab in children. METHODS: Records of patients ≤18 years of age with atopic dermatitis who developed psoriasiform dermatitis during treatment with dupilumab were reviewed retrospectively. RESULTS: Six children, 4-18 years of age, on dupilumab for severe atopic dermatitis developed new-onset psoriasiform dermatitis at a median duration of 8 months (range, 6-12 months) after dupilumab initiation. Typical locations of psoriasis were involved (face, scalp, trunk, and extensor extremities). The majority showed clearance or near clearance with the use of medium-strength to potent topical corticosteroid ointments and 83% continued use of the dupilumab. A 7th patient had psoriasis, in addition to severe atopic dermatitis, and the psoriasis was unmasked by its failure to respond to dupilumab. CONCLUSION: Although unusual, psoriasiform lesions can appear during effective treatment with dupilumab for atopic dermatitis, potentially reflecting a shift toward cutaneous IL-23/TH 17 pathway activation with dupilumab-induced suppression of type 2 immunity.

5.
J Am Acad Dermatol ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34634382

RESUMO

BACKGROUND: Accurate diagnosis of epidermolysis bullosa (EB) has significant implications for prognosis, management, and genetic counseling. OBJECTIVE: To describe diagnostic testing patterns and assess diagnostic concordance of transmission electron microscopy (TEM), immunofluorescence mapping (IFM), and genetic analysis for EB. METHODS: A retrospective cohort included patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2004, to July 8, 2019. Tests concluding the same EB type (EB simplex, junctional EB, dominant dystrophic EB, and recessive dystrophic EB) were considered concordant; those concluding different EB types were considered discordant; and those with nonspecific/nondefinitive results were equivocal. RESULTS: A total of 970 diagnostic tests were conducted from 1984 to 2018 in 771 patients. Genetic analyses were performed chronologically later than IFM or TEM (P < .001). The likelihood of undergoing genetic analysis was greater for junctional EB and recessive dystrophic EB, and the same for dominant dystrophic EB as compared with EB simplex. TEM results in 163 patients were equivocal (55%), concordant (42%), and discordant (3%). IFM results in 185 patients were equivocal (54%), concordant (42%), and discordant (4%). LIMITATIONS: Retrospective design. CONCLUSIONS: Diagnostic testing has shifted in favor of genetic analysis. TEM and IFM frequently offer equivocal findings when compared to the specificity afforded by genetic analysis.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34536413

RESUMO

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

7.
J Am Acad Dermatol ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474079

RESUMO

BACKGROUND: The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity. OBJECTIVE: To develop an AA severity scale based on expert experience. METHODS: A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development. RESULTS: Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale. LIMITATIONS: The scale is a static assessment intended to be used in clinical practice and not clinical trials. CONCLUSION: The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease.

8.
Br J Clin Pharmacol ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34378230

RESUMO

AIMS: Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A used in the treatment of adult and paediatric patients with moderate-to-severe psoriasis. This analysis evaluated the pharmacokinetics (PK) of ixekizumab and the exposure-efficacy relationship in paediatric patients aged 6 to <18 years with psoriasis. METHODS: Population PK and exposure-efficacy models were developed. The models used data from paediatric patients with psoriasis participating in the Phase 3 IXORA-PEDS trial in which patients were dosed according to weight categories. The exposure-efficacy model is a Psoriasis Area and Severity Index (PASI) time course model using data up to Week 12, a co-primary efficacy endpoint. RESULTS: A 2-compartment population PK model describes the PK of ixekizumab in paediatric patients with the effect of body weight incorporated on clearance and volume terms using an allometric relationship. The weight category-based dosing ensured that ixekizumab mean trough serum concentrations in paediatric patients with psoriasis (3.20-3.33 µg/mL) were within the range of concentrations observed in adult patients with psoriasis (mean [standard deviation]: 3.48 [2.16] µg/mL) administered an efficacious dosing regimen. The observed PASI response rates at Week 12 in paediatric patients (91.9/81.8/52.5% for PASI75/90/100) are well predicted by the final exposure-efficacy model and response rates are similar or higher than those achieved in adults (86.2/66.6/35.0% for PASI75/90/100). CONCLUSION: This analysis is the first to describe the PK and exposure-efficacy relationship of ixekizumab in paediatric patients with psoriasis. The analyses support the selection of the weight category-based ixekizumab dosing regimens approved for use in paediatric patients with psoriasis.

9.
Dermatol Ther (Heidelb) ; 11(5): 1643-1656, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34427891

RESUMO

INTRODUCTION: In phase III trials in adolescents and children with atopic dermatitis (AD), dupilumab significantly decreased global disease severity. However, the effects of dupilumab on the extent and signs of AD across different anatomical regions were not reported. Here we characterize the efficacy of dupilumab in improving the extent and signs of AD across four different anatomical regions in children and adolescents. METHODS: A post hoc subset analysis was performed using data from two randomized, double-blind, placebo-controlled, international multicenter, phase III trials of dupilumab therapy in adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD and children aged ≥ 6 to < 12 years with severe AD. Endpoints included mean percentage change in Eczema Area and Severity Index (EASI) signs (erythema, edema/papulation, excoriation, lichenification) and extent of AD (measured by percentage of body surface area [% BSA] involvement) from baseline to week 16 across four anatomical regions (head and neck, trunk, upper extremities, lower extremities). RESULTS: Dupilumab improved both the extent and severity of AD signs across the four anatomical regions. Improvements were shown to be similar across the four anatomical regions for % BSA involvement and for reduction in EASI signs. Improvements in all signs were seen early, within the first 4 weeks of treatment, and were sustained through week 16, across all regions. CONCLUSIONS: In pediatric patients 6 years of age and older, treatment with dupilumab resulted in rapid and consistent improvement in the extent and signs of AD across all anatomical regions. CLINICALTRIALS. GOV IDENTIFIERS: LIBERTY AD ADOL (NCT03054428) and LIBERTY AD PEDS (NCT03345914). Does dupilumab provide improvement in atopic dermatitis across all anatomical regions in children and adolescents? (MP4 48,385 kb).

10.
Pediatr Dermatol ; 38(5): 1237-1242, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34448248

RESUMO

CARD14-associated papulosquamous eruption (CAPE) is a proposed term that encompasses features ranging from psoriasis to pityriasis rubra pilaris (PRP) in association with CARD14 mutations. The early onset of the disease, prominent facial involvement, family history of an autosomal dominant trait, and poor response to conventional treatment are characteristics of CAPE that distinguish it from classical psoriasis and PRP. We describe the clinical features, family history, and response to therapy in three unrelated children with CAPE and compare these characteristics with those of previously described pediatric patients. Testing for CARD14 mutations in children with early onset of features of psoriasis or pityriasis rubra pilaris and resistance to conventional therapy should be considered.


Assuntos
Exantema , Pitiríase Rubra Pilar , Proteínas Adaptadoras de Sinalização CARD/genética , Criança , Guanilato Ciclase , Humanos , Proteínas de Membrana , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/tratamento farmacológico , Pitiríase Rubra Pilar/genética
11.
J Allergy Clin Immunol ; 148(4): 927-940, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34437922

RESUMO

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.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Administração Oral , Administração Tópica , Dermatite Atópica/imunologia , Humanos
12.
Paediatr Drugs ; 23(5): 515-527, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34462864

RESUMO

BACKGROUND: Previous studies of dupilumab in adolescents and adults with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful adverse changes in laboratory parameters. OBJECTIVE: The aim of this study was to assess laboratory outcomes in children aged 6-11 years with severe AD in a randomized, placebo-controlled, phase III trial of dupilumab. METHODS: Children aged 6-11 years with severe AD were randomized 1:1:1 to 16 weeks of dupilumab 300 mg every 4 weeks, 100 or 200 mg every 2 weeks, or matching placebo, all with concomitant topical corticosteroids (TCS). Blood samples were collected at baseline and Weeks 4, 8, and 16; urine samples were collected at baseline and Weeks 4 and 16. RESULTS: Of 367 patients enrolled in the study, 362 were included in the safety analysis, 351 completed study treatment, and 4 withdrew due to treatment-emergent adverse events not related to laboratory abnormalities. Both dupilumab + TCS groups showed overall trends toward increases in mean blood levels of eosinophils and alkaline phosphatase, and decreases in mean blood levels of platelets, neutrophils, and lactate dehydrogenase levels, without corresponding mean changes in the placebo + TCS group. None of these changes were associated with symptoms or clinically meaningful adverse outcomes, and none led to treatment modification. No clinically significant changes or trends were observed for other measured laboratory parameters. CONCLUSION: There were no clinically meaningful adverse changes in routine laboratory parameters attributable to treatment with dupilumab + TCS. Changes in platelet counts and lactate dehydrogenase levels likely reflect reduced inflammation. These results confirm similar findings in adults and adolescents, and suggest that there is no need for routine laboratory monitoring of children aged 6-11 years treated with dupilumab + TCS for severe AD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03345914. Does treatment with dupilumab require routine laboratory monitoring in 6- to 11-year-old children with severe atopic dermatitis? (MP4 180482 kb).


Assuntos
Dermatite Atópica , Adolescente , Adulto , Anticorpos Monoclonais Humanizados , Criança , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Humanos , Laboratórios , Índice de Gravidade de Doença , Resultado do Tratamento
14.
Clin Pharmacol Ther ; 110(5): 1318-1328, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34270797

RESUMO

Dupilumab demonstrated efficacy with an acceptable safety profile in two randomized, double-blind, placebo-controlled, parallel-group, phase III trials in adolescents (12-17 years; LIBERTY AD ADOL) and children (6-11 years; LIBERTY AD PEDS) with atopic dermatitis (AD) treated for 16 weeks. Here, we present the pharmacokinetic profiles and exposure-response (E-R) relationships of dupilumab that guided the posology in these populations. A total of 251 adolescent patients with moderate-to-severe AD were randomized to subcutaneous dupilumab monotherapy every 2 weeks (q2w; 200 mg q2w, baseline weight < 60 kg; 300 mg q2w, ≥ 60 kg), dupilumab 300 mg every 4 weeks (q4w; non-weight tiered), or placebo; 367 children with severe AD were randomized to dupilumab q2w (100 mg q2w, baseline weight < 30 kg; 200 mg q2w, ≥ 30 kg), dupilumab 300 mg q4w, or placebo. Children received concomitant topical corticosteroids in addition to dupilumab, and loading doses were administered at the start of therapy. Mean dupilumab trough concentrations at week 16 for weight subcategories in each dosing regimen were compared with adult exposures for the approved dupilumab 300 mg q2w regimen. Positive E-R relationships were demonstrated between dupilumab trough concentrations and AD outcome measures across patient populations and regimens; no relationship was observed with treatment-emergent conjunctivitis. Based on these analyses, a weight-tiered posology was proposed for adolescents (200/300 mg q2w in patients 30-< 60 kg/≥ 60 kg) and children (300 mg q4w in patients 15-< 30 kg, 200 mg q2w in patients 30-< 60 kg) with moderate-to-severe AD.

15.
Artigo em Inglês | MEDLINE | ID: mdl-34111454

RESUMO

BACKGROUND: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). CONCLUSIONS: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

16.
Sci Adv ; 7(18)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33931455

RESUMO

Itch is a common clinical symptom and major driver of disease-related morbidity across a wide range of medical conditions. A substantial unmet need is for objective, accurate measurements of itch. In this article, we present a noninvasive technology to objectively quantify scratching behavior via a soft, flexible, and wireless sensor that captures the acousto-mechanic signatures of scratching from the dorsum of the hand. A machine learning algorithm validated on data collected from healthy subjects (n = 10) indicates excellent performance relative to smartwatch-based approaches. Clinical validation in a cohort of predominately pediatric patients (n = 11) with moderate to severe atopic dermatitis included 46 sleep-nights totaling 378.4 hours. The data indicate an accuracy of 99.0% (84.3% sensitivity, 99.3% specificity) against visual observation. This work suggests broad capabilities relevant to applications ranging from assessing the efficacy of drugs for conditions that cause itch to monitoring disease severity and treatment response.

17.
Curr Opin Pediatr ; 33(4): 392-401, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001717

RESUMO

PURPOSE OF REVIEW: To describe new and emerging therapies for pediatric atopic dermatitis (AD). RECENT FINDINGS: Recent investigations have highlighted the importance of type 2 immunity and interrelationships among the skin immune system, epidermal barrier, and microbiome in the pathogenesis of AD, including in infants and children. These discoveries have translated into more targeted therapy. Crisaborole ointment, a topical phosphodiesterase 4 (PDE4) inhibitor, and dupilumab, a subcutaneously injected interleukin (IL)-4 receptor inhibitor, are now Food and Drug Administration-approved. Topical agents under investigation for use in the pediatric population include Janus kinase (JAK) inhibitors, PDE4 inhibitors, an aryl hydrocarbon receptor agonist, an antimicrobial peptide, and commensal skin bacteria. Emerging systemic agents for pediatric AD include biologics targeting IL-13, the IL-31 receptor, and the IL-5 receptor, as well as oral JAK inhibitors. SUMMARY: Increased understanding of AD pathogenesis has resulted in the development of new, more targeted therapies that show promising safety and efficacy results in Phase 2 and 3 clinical trials, although long-term safety remains to be evaluated. AD is a heterogeneous disease and having choices of therapies with different mechanisms of action will allow a broader group of children and adolescents with moderate-to-severe disease to achieve disease control.


Assuntos
Dermatite Atópica , Eczema , Microbiota , Inibidores da Fosfodiesterase 4 , Adolescente , Criança , Dermatite Atópica/tratamento farmacológico , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Pele
18.
Lancet ; 397(10290): 2151-2168, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34023008

RESUMO

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: AbbVie.


Assuntos
Dermatite Atópica/tratamento farmacológico , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Janus Quinase 1 , Inibidores de Janus Quinases/administração & dosagem , Masculino , Pessoa de Meia-Idade
19.
Transl Res ; 236: 87-108, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34029747

RESUMO

Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.


Assuntos
Diabetes Mellitus/patologia , Pele/inervação , Cicatrização , Animais , Denervação , Modelos Animais de Doenças , Humanos , Neuropeptídeos/metabolismo , Células Receptoras Sensoriais/patologia
20.
J Allergy Clin Immunol Pract ; 9(8): 3120-3129.e3, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33991704

RESUMO

BACKGROUND: Atopic dermatitis (AD) causes sleep disturbance but the epidemiology is not known. OBJECTIVE: To estimate the US prevalence of sleep disturbance and its impact on psychological and neurocognitive function. METHODS: We conducted a cross-sectional survey of 180 parent-child dyads with AD using stratified sampling based on disease severity (Patient Oriented Eczema Measure: mild [n = 30), moderate (n = 75) or severe (n = 75]), age, and race (White or Black or African American or other). Symptoms of sleep and psychologic health were assessed using the Patient-Reported Outcome Measurement Information System. To estimate the prevalence of sleep disturbance, we calculated weights using poststratification adjustment making marginal frequencies of AD severity, race, and age similar to marginal frequencies in the 2007 National Survey of Children's Health. Unweighted regression models examined associations with sleep disturbance. RESULTS: In children age 5 to 17 years with AD, we estimated that sleep disturbance occurred in 66.9% (95% confidence interval, 53.3% to 80.5%; 3,116,305 children). The odds of severe sleep disturbance (worse than 95% of US children) were highest in moderate to severe versus mild AD (2.03 [1.00-4.10]; P = .0495; compared with 8.68 [1.82-41.49]; P = .0068). Predictors of parent proxy-reported sleep disturbance were itch intensity (adjusted ß [95% confidence interval] 1.33 [0.62-2.04]) and low income (<$50,000: 6.64 [2.05-11.23]; and $50,000 to less than 100,000: 4.75 [0.35-9.14]). Controlling for disease severity, itch intensity, and significant sociodemographics-parent-proxy, reported sleep disturbance was associated with increased severity of sleep-related impairment, depression, fatigue, and anxiety, in addition to worse inattention and impulsivity. In fully adjusted models, children who self-reported sleep disturbance (T-score ≥60) had increased odds of sleep-related impairment (1.20 [1.11-1.29]), depression (1.13 [1.03, 1.24]), fatigue (1.28 [1.06-1.54]), and anxiety (1.16 [1.02-1.31]). CONCLUSIONS: Sleep disturbance is a common symptom of AD. It affects about 3 million US children and is associated with neuropsychiatric impairment, including depression, anxiety, and inattention. Clinicians should screen for these symptoms in school-aged children, particularly those with moderate to severe AD.


Assuntos
Dermatite Atópica , Eczema , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Dermatite Atópica/epidemiologia , Humanos , Prevalência , Instituições Acadêmicas , Índice de Gravidade de Doença , Sono
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