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BACKGROUND: Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
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Anticuerpos Monoclonales , Dermatitis Atópica , Adolescente , Adulto , Humanos , Lactante , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Dermatitis Atópica/complicaciones , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Método Doble Ciego , Interleucina-13/antagonistas & inhibidores , Interleucina-13/inmunología , Prurito/tratamiento farmacológico , Prurito/etiología , Prurito/inmunología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Inmunoglobulina G/inmunología , Piel/efectos de los fármacos , Piel/inmunologíaRESUMEN
BACKGROUND: Rademikibart (CBP-201) is a next-generation IL-4 receptor alpha-targeting antibody. OBJECTIVE: We sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis. METHODS: A total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021. RESULTS: The WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (-63.0%; P = .0007), 150 mg Q2W (-57.6%; P = .0067), 300 mg Q4W (-63.5%; P = .0004) versus placebo (-39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no evidence of plateauing by week 16. Significant improvements were also observed in secondary end points, including pruritus. Across the primary and secondary end points, efficacy tended to be comparable with 300 mg Q2W and Q4W dosing. Rademikibart and placebo had similar, low incidence of treatment-emergent adverse events (TEAEs) (48% vs 54%), serious TEAEs (1.8% vs 3.6%), TEAEs leading to treatment discontinuation (1.2% vs 1.8%), conjunctivitis of unspecified cause (2.9% vs 0%), herpes (0.6% vs 1.8%), and injection-site reactions (1.8% vs 1.8%). Although no discontinuations were attributed to coronavirus disease 2019, pandemic-related restrictions likely had an impact on trial conduct. CONCLUSIONS: Rademikibart was efficacious and well tolerated at Q2W and Q4W intervals. Q4W dosing is a more convenient frequency than approved for current therapies.
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Dermatitis Atópica , Eccema , Adulto , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Dermatitis Atópica/complicaciones , Método Doble Ciego , Eccema/complicaciones , Prurito/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated. FUNDING: Kyowa Kirin.
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Dermatitis Atópica , Adulto , Femenino , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Inyecciones Subcutáneas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Persona de Mediana EdadRESUMEN
BACKGROUND: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited. METHODS: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16. RESULTS: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively. CONCLUSIONS: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Administración Oral , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina A/sangre , Inyecciones Subcutáneas , Subunidad alfa del Receptor de Interleucina-4/antagonistas & inhibidores , Janus Quinasa 1/antagonistas & inhibidores , Masculino , Placebos/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Prurito/tratamiento farmacológico , Pirimidinas/efectos adversos , Índice de Severidad de la Enfermedad , Sulfonamidas/efectos adversosRESUMEN
BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has agreed upon the Core Outcome Set (COS) for use in atopic dermatitis (AD) clinical trials, but additional guidance is needed to maximize its uptake. OBJECTIVES: To provide answers to some of the commonly asked questions about using the HOME COS; to provide data to help with the interpretation of trial results; and to support sample size calculations for future trials. METHODS AND RESULTS: We provide practical guidance on the use of the HOME COS for investigators planning clinical trials in patients with AD. It answers some of the common questions about using the HOME COS, how to access the outcome measurement instruments, what training/resources are needed to use them appropriately and clarifies when the COS is applicable. We also provide exemplar data to inform sample size calculations for eczema trials and encourage standardized data collection and reporting of the COS. CONCLUSIONS: By encouraging adoption of the COS and facilitating consistent reporting of outcome data, it is hoped that the results of eczema trials will be more comprehensive and readily combined in meta-analyses and that patient care will subsequently be improved.
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Dermatitis Atópica , Eccema , Humanos , Dermatitis Atópica/tratamiento farmacológico , Eccema/terapia , Predicción , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress. OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD). METHODS: Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials. RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P < .0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < .0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle. LIMITATIONS: Long-term efficacy was not assessed. CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.
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BACKGROUND: Despite high disease burden, systemic treatment options for patients with atopic hand and/or foot dermatitis (H/F AD) are limited. OBJECTIVES: To evaluate efficacy and safety of dupilumab in H/F AD using specific instruments for assessing disease severity on hands and feet. METHODS: In this multicenter phase 3 trial, adults and adolescents with moderate-to-severe H/F AD were randomized to dupilumab monotherapy (regimen approved for generalized AD), or matched placebo. The primary endpoint was proportion of patients achieving Hand and Foot Investigator's Global Assessment score 0 or 1 at week 16. Secondary prespecified endpoints assessed the severity and extent of signs, symptom intensity (itch, pain), quality of life, and sleep. RESULTS: A total of 133 patients (adults = 106, adolescents = 27) were randomized to dupilumab (n = 67) or placebo (n = 66). At week 16, significantly more patients receiving dupilumab (n = 27) than placebo (n = 11) achieved Hand and Foot Investigator's Global Assessment score 0 or 1 (40.3% vs 16.7%; P = .003). All other prespecified endpoints were met. Safety was consistent with the known AD dupilumab profile. LIMITATIONS: Short-term, 16-week treatment period. CONCLUSION: Dupilumab monotherapy resulted in significant improvements across different domains of H/F AD with acceptable safety, supporting dupilumab as a systemic treatment approach for this often difficult to treat condition.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Dermatosis del Pie , Dermatosis de la Mano , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Femenino , Método Doble Ciego , Dermatitis Atópica/tratamiento farmacológico , Adulto , Adolescente , Persona de Mediana Edad , Dermatosis de la Mano/tratamiento farmacológico , Dermatosis del Pie/tratamiento farmacológico , Adulto Joven , Resultado del Tratamiento , EficienciaRESUMEN
BACKGROUND: Atopic dermatitis is a common chronic, relapsing, and remitting inflammatory skin disorder associated with cutaneous dysbiosis. Current treatment options often fail to adequately control the disease and have unfavorable safety profiles. There is a need for new options that address these treatment shortcomings. OBJECTIVE: The aim of the study was to evaluate the efficacy, safety, and tolerability of FB-401, a live therapeutic product of 3 strains of Roseomonas mucosa, compared to matching placebo applied topically 3 times per week to participants ages ≥2 years of age with mild-to-moderate atopic dermatitis. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. The primary outcome was the proportion of participants with 50% improvement in Eczema Area and Severity Index score from baseline at week 16. 154 subjects aged 2 or older with a clinical diagnosis of atopic dermatitis as defined by Hanifin and Rajka criteria with mild or moderate severity were randomized 1:1 via interactive web response system to FB-401 or placebo. RESULTS: The proportion of subjects who achieved the primary outcome was similar between both treatment groups, with no significant treatment group differences observed at any post-baseline visit. The number of treatment-emergent adverse events and the number of subjects with at least one were similar across treatment groups. One serious adverse event not related to treatment was reported. No treatment-emergent adverse events led to treatment discontinuation or study discontinuation. CONCLUSIONS: FB-401 showed an acceptable safety profile but failed to prove superior to placebo in treating children and adults with mild-to-moderate atopic dermatitis.
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Dermatitis Atópica , Adulto , Niño , Humanos , Adolescente , Preescolar , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Administración Cutánea , Inyecciones Subcutáneas , Método Doble CiegoRESUMEN
Treat-to-target (T2T) is a pragmatic therapeutic strategy being gradually introduced into dermatology after adoption in several other clinical areas. Atopic dermatitis (AD), one of the most common inflammatory skin diseases, may also benefit from this structured and practical therapeutic approach. We aimed to evaluate existing data regarding the T2T approach in dermatology, with a specific focus on AD, as well as the views of International Eczema Council (IEC) members on the potential application of a T2T approach to AD management. To do so, we systematically searched for peer-reviewed publications on the T2T approach for any skin disease in the PubMed and Scopus databases up to February 2022 and conducted a survey among IEC members regarding various components to potentially include in a T2T approach in AD. We identified 21 relevant T2T-related reports in dermatology, of which 14 were related to psoriasis, five to AD, one for juvenile dermatomyositis and one for urticaria. In the IEC member survey, respondents proposed treatable traits (with itch, disease severity and sleep problems getting the highest scores), relevant comorbidities (with asthma being selected most commonly, followed by anxiety and depression in adults), recommended specialists that should define the approach in AD (dermatologists, allergists and primary care physicians were most commonly selected in adults), and applicable assessment tools (both physician- and patient-reported), in both adult and paediatric patients, for potential future utilization of the T2T approach in AD. In conclusion, while the T2T approach may become a useful tool to simplify therapeutic goals and AD management, its foundation in AD is only starting to build. A multidisciplinary approach, including a wide range of stakeholders, including patients, is needed to further define the essential components needed to utilize T2T in AD.
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Dermatitis Atópica , Dermatología , Eccema , Adulto , Humanos , Niño , Dermatitis Atópica/tratamiento farmacológico , Prurito , Encuestas y Cuestionarios , Eccema/tratamiento farmacológico , Calidad de VidaRESUMEN
BACKGROUND: Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. OBJECTIVE: We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. METHODS: Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. RESULTS: The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants' exaggerated allergic skin inflammation. CONCLUSIONS: The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.
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Dermatitis Atópica , Eccema , Ratones , Animales , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Células Th2 , Piel/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Prurito/metabolismo , Eccema/metabolismoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities, and Staphylococcus aureus skin colonization and infections. S aureus is thought to play a role in AD severity. OBJECTIVES: This study characterized the changes in the host-microbial interface in subjects with AD following type 2 blockade with dupilumab. METHODS: Participants (n = 71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple time points: S aureus and virulence factor quantification, 16s ribosomal RNA microbiome, serum biomarkers, skin transcriptomic analyses, and peripheral blood T-cell phenotyping. RESULTS: At baseline, 100% of participants were S aureus colonized on the skin surface. Dupilumab treatment resulted in significant reductions in S aureus after only 3 days (compared to placebo), which was 11 days before clinical improvement. Participants with the greatest S aureus reductions had the best clinical outcomes, and these reductions correlated with reductions in serum CCL17 and disease severity. Reductions (10-fold) in S aureus cytotoxins (day 7), perturbations in TH17-cell subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil, and complement pathways (day 7) were also observed. CONCLUSIONS: Blockade of IL-4 and IL-13 signaling, very rapidly (day 3) reduces S aureus abundance in subjects with AD, and this reduction correlates with reductions in the type 2 biomarker, CCL17, and measures of AD severity (excluding itch). Immunoprofiling and/or transcriptomics suggest a role for TH17 cells, neutrophils, and complement activation as potential mechanisms to explain these findings.
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Dermatitis Atópica , Infecciones Estafilocócicas , Humanos , Dermatitis Atópica/genética , Staphylococcus aureus , Anticuerpos Monoclonales Humanizados/uso terapéutico , Piel/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. FINDINGS: Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. INTERPRETATION: Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. FUNDING: Sanofi and Regeneron Pharmaceuticals.
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Dermatitis Atópica , Fármacos Dermatológicos , Adolescente , Adulto , Niño , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina A/uso terapéutico , Preparaciones Farmacéuticas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados UnidosRESUMEN
Atopic dermatitis (AD) is a chronic, inflammatory, intensely pruritic skin disorder associated with significant patient burden. Interleukin (IL)-13 is a cytokine that acts as a driver of immune dysregulation, skin-barrier dysfunction, and microbiome dysbiosis that characterizes AD, and is consistently overexpressed in AD skin. Tralokinumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody that binds specifically to IL-13 with high affinity, thereby inhibiting subsequent downstream IL-13 signaling. Three pivotal phase 3 clinical trials demonstrated that tralokinumab 300 mg every other week, as monotherapy or in combination with topical corticosteroids as needed, provides significant improvements in signs and symptoms of moderate-to-severe AD, as measured by Investigator's Global Assessment 0/1 (clear/almost clear) and Eczema Area and Severity Index-75 at Week 16. Improvements were observed soon after tralokinumab initiation and were maintained over 52 weeks of therapy. Tralokinumab significantly improved patient-reported outcomes such as itch and sleep, and demonstrated a safety profile comparable with placebo; conjunctivitis during tralokinumab therapy was generally mild. Similar results were observed in a phase 3 adolescent trial. The role of IL-13 in the pathophysiology of AD justifies a targeted approach and a wealth of clinical data supports tralokinumab as a new therapeutic option for people with moderate-to-severe AD.
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Dermatitis Atópica , Adolescente , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Interleucina-13 , Anticuerpos Monoclonales Humanizados/efectos adversos , Inyecciones Subcutáneas , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Anticuerpos Monoclonales/uso terapéutico , Inmunoglobulina G , Método Doble CiegoRESUMEN
BACKGROUND: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. METHODS: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. RESULTS: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. CONCLUSIONS: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.
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Asma , Dermatitis Atópica , Eccema , Hipersensibilidad a los Alimentos , Rinitis Alérgica Estacional , Lactante , Humanos , Preescolar , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/epidemiología , Dermatitis Atópica/prevención & control , Emolientes/uso terapéutico , Rinitis Alérgica Estacional/tratamiento farmacológico , Hipersensibilidad a los Alimentos/prevención & control , Asma/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Baricitinib, an oral, selective Janus kinase 1/2 inhibitor, demonstrated long-term efficacy in moderate-to-severe atopic dermatitis in an ongoing double-blind, phase III, long-term extension study, BREEZE-AD3 (NCT03334435). OBJECTIVES: To evaluate the efficacy and safety of downtitration and treatment withdrawal in a substudy of BREEZE-AD3. METHODS: The substudy included patients (N = 526) treated with baricitinib 4â mg or 2â mg at entry into BREEZE-AD3 who achieved a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD®) scale score of 0 (clear), 1 (almost clear) or 2 (mild) at week 52. Patients treated with baricitinib 4â mg were rerandomized to baricitinib 4â mg (continuous dosing), baricitinib 2â mg (downtitration) or placebo (treatment withdrawal, 4-mg cohort), and patients treated with baricitinib 2â mg were rerandomized to baricitinib 2â mg (continuous dosing), baricitinib 1â mg (downtitration), or placebo (treatment withdrawal, 2-mg cohort). After 16 weeks, we assessed the proportion of patients with vIGA-AD® 0/1, vIGA-AD® 0/1/2, vIGA-AD® ≥ 3 (loss of response; criterion to readminister the original baricitinib dose) and for patients who were readministered the original baricitinib dose, we assessed the proportion of patients who recaptured vIGA-AD® 0/1/2 within 16 weeks of treatment readministration (patients in the continuous dosing maintained the same dose). RESULTS: For the continuous dosing, downtitration, and treatment withdrawal groups 51%, 45% and 30% of patients in the 4-mg cohort achieved vIGA-AD® 0/1 and 87%, 61% and 50% of patients achieved vIGA-AD® 0/1/2, respectively. For the 2-mg cohort, the respective proportions of patients were 48%, 42% and 25% for vIGA-AD® 0/1 and 92%, 71% and 45% for vIGA-AD® 0/1/2. The respective proportions of patients with vIGA-AD® ≥ 3 were 39%, 49% and 56% in the 4-mg cohort and 41%, 41% and 64% in the 2-mg cohort. Of those who were readministered the original baricitinib dose, the proportions of patients who recaptured vIGA-AD® 0/1/2 among the continuous dosing, downtitration, and treatment withdrawal groups were 80%, 85% and 88% in the 4-mg cohort and 90%, 56% and 86% in the 2-mg cohort, respectively. CONCLUSIONS: Baricitinib allows flexibility for patients to downtitrate or stop treatment. For patients who downtitrated treatment, the majority maintained efficacy through 16 weeks. Most patients who lost efficacy with downtitration or treatment withdrawal achieved clinically relevant efficacy upon readministration of their original dose.
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Dermatitis Atópica , Inhibidores de las Cinasas Janus , Humanos , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Inhibidores de las Cinasas Janus/efectos adversos , Índice de Severidad de la Enfermedad , Sulfonamidas , Resultado del TratamientoRESUMEN
BACKGROUND: Core outcome sets (COS) are consensus-driven sets of minimum outcomes that should be measured and reported in all clinical trials. COS aim to reduce heterogeneity in outcome measurement and reporting, and selective outcome reporting. Implementing COS into clinical trials is challenging. Guidance to improve COS uptake in dermatology is lacking. OBJECTIVES: To develop a structured practical guide to COS implementation. METHODS: Members of the Harmonising Outcome Measurement for Eczema (HOME) executive committee developed an expert opinion-based roadmap founded on a combination of a review of the COS implementation literature, the Core Outcome Measures in Effectiveness Trials (COMET) initiative resources, input from HOME members and experience in COS development and clinical trials. RESULTS: The data review and input from HOME members was synthesized into themes, which guided roadmap development: (a) barriers and facilitators to COS uptake based on stakeholder awareness/engagement and COS features; and (b) key implementation science principles (assessment-driven, data-centred, priority-based and context-sensitive). The HOME implementation roadmap follows three stages. Firstly, the COS uptake scope and goals need to be defined. Secondly, during COS development, preparation for future implementation is supported by establishing the COS as a credible evidence-informed consensus by applying robust COS development methodology, engaging multiple stakeholders, fostering sustained and global engagement, emphasizing COS ease of use and universal applicability, and providing recommendations on COS use. Thirdly, incorporating completed COS into primary (trials) and secondary (reviews) research is an iterative process starting with mapping COS uptake and stakeholders' attitudes, followed by designing and carrying out targeted implementation projects. Main themes for implementation projects identified at HOME are stakeholder awareness/engagement; universal applicability for different populations; and improving ease-of-use by reducing administrative and study burden. Formal implementation frameworks can be used to identify implementation barriers/facilitators and to design implementation strategies. The effect of these strategies on uptake should be evaluated and implementation plans adjusted accordingly. CONCLUSIONS: COS can improve the quality and applicability of research and, so, clinical practice but can only succeed if used and reported consistently. The HOME implementation roadmap is an extension of the original HOME roadmap for COS development and provides a pragmatic framework to develop COS implementation strategies.
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Eccema , Humanos , Eccema/terapia , Evaluación de Resultado en la Atención de Salud , Consenso , Predicción , Participación de los Interesados , Resultado del Tratamiento , Proyectos de Investigación , Técnica DelphiRESUMEN
BACKGROUND: Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. OBJECTIVES: To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). METHODS: Patients who responded to lebrikizumab 250â mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250â mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. RESULTS: After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. CONCLUSIONS: After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data.
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Dermatitis Atópica , Adulto , Adolescente , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Anticuerpos Monoclonales Humanizados , Resultado del Tratamiento , Inyecciones Subcutáneas , Método Doble Ciego , Índice de Severidad de la Enfermedad , Anticuerpos Monoclonales/efectos adversos , Interleucina-13 , Inmunoglobulina ARESUMEN
BACKGROUND: Few large-scale international studies broadly characterized the burden of atopic dermatitis (AD) across age groups among children and adolescents. OBJECTIVE: To better characterize the AD burden in pediatric subjects by disease severity. METHODS: This cross-sectional, web-based survey of pediatric subjects (6 months to <18 years old) was conducted in 18 countries representing North America, Latin America, Europe, Middle East/Eurasia, and East Asia. Subjects with diagnosed AD were identified based on the International Study of Asthma and Allergies in Childhood criteria and self-/parent-report of ever being told by a physician that they/their child had eczema. AD severity was assessed using Patient Oriented Eczema Measure and Patient Global Assessment. Outcomes included measures of itch, skin pain, sleep, health-related quality-of-life (HRQoL), missed school days, and atopic comorbidities. RESULTS: The survey included 1489 children 6 months to < 6 years; 2898 children 6 to < 12 years; and 3078 adolescents 12 to < 18 years diagnosed with AD. Although the burden of mild AD was substantial, pediatric subjects with moderate or severe AD had more itch, skin pain, sleep problems, and impaired HRQoL, and missed more school days relative to those with mild AD; greater burden was observed among severe relative to moderate AD. At least one atopic comorbidity was present in 92·5% of all respondents. CONCLUSIONS: These results highlight the burden of AD in pediatric subjects especially those with moderate-to-severe disease, and suggest the need for assessments that include the impact of AD on function and daily life.
RESUMEN
BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD. METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored. RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD. CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.
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Dermatitis Atópica , Adolescente , Adulto , Niño , Humanos , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Inyecciones Subcutáneas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
Atopic dermatitis (AD) is a chronic inflammatory skin disease that can significantly decrease quality of life. AD is commonly associated with comorbidities including ocular surface disease (OSD). Conjunctivitis is the most common OSD associated with AD and can increase in incidence with use of monoclonal antibody biologics that target the type 2 inflammatory pathway. The objective of this review is to raise awareness of comorbid OSD in AD patients that dermatologists may encounter, with a focus on conjunctivitis, and equip dermatologists to address mild ocular concerns. We provide background on the subtypes and pathogenesis of comorbid OSD in AD patients and describe OSD associated with type 2 inflammation-inhibiting AD biologics. We also discuss screening and diagnosis, recommended treatment options for dermatologists, and when to refer to an eye care specialist. This multispecialty approach aims to support the overall health of AD patients and provide optimal patient care.