Dupilumab-Treated Patients with Asthma in the Real World: The RAPID Global Registry.

BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma. OBJECTIVES: The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients. METHODS: RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter. PLANNED OUTCOMES: Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded. CONCLUSION: RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04287621.

Baseline Demographics and Severity and Burden of Atopic Dermatitis in Adult Patients Initiating Dupilumab Treatment in a Real-World Registry (PROSE).

INTRODUCTION: Dupilumab was initially approved in 2017 as the first biologic therapy for atopic dermatitis (AD). We characterized adults with AD initiating dupilumab in a real-world setting in the USA/Canada. METHODS: PROSE is an ongoing, longitudinal, prospective, observational, multicenter registry of patients with AD initiating dupilumab per country-specific prescribing information. We report baseline data (day of first dupilumab injection) for patients enrolled from April 2018 through July 2019. RESULTS: Among 315 patients (mean age 42.5 years, 55.2% female), the median AD duration was 17.0 years; 65.4% reported a history of type 2 inflammatory comorbidities (e.g., allergic rhinitis, asthma), and 93.3% reported treatment(s) for AD in the previous year, including topical corticosteroids (90.8%), systemic corticosteroids (36.2%), and nonsteroidal systemic therapies (14.0%). In total, 89.2% had an Overall Disease Severity score of 3 (moderate) or 4 (severe). Other mean disease severity scores included the following: Eczema Area and Severity Index 16.9 (range 0-72), body surface area affected 26.8%, Patient-Oriented Eczema Measure 18.5 (range 0-28), Dermatology Life Quality Index 12.7 (range 0-30), and pruritus Numerical Rating Scale score 6.9 (range 0-10). CONCLUSION: Patients initiating dupilumab have longstanding moderate-to-severe AD with significant disease burden and frequent type 2 comorbidities. GOV IDENTIFIER: NCT03428646.

Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma.

BACKGROUND: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases. METHODS: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline. RESULTS: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups. CONCLUSIONS: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.).

Immunogenicity of Botulinum Toxin Formulations: Potential Therapeutic Implications.

Botulinum neurotoxins (BoNTs) are proteins produced by bacteria of the Clostridium family. Upon oral ingestion, BoNT causes the neuroparalytic syndrome botulism. There are seven serotypes of BoNT (serotypes A-G); BoNT-A and BoNT-B are the botulinum toxin serotypes utilized for therapeutic applications. Treatment with BoNT injections is used to manage chronic medical conditions across multiple indications. As with other biologic drugs, immunogenicity after long-term treatment with BoNT formulations may occur, and repeated use can elicit antibody formation leading to clinical nonresponsiveness. Thus, approaching BoNT treatment of chronic conditions with therapeutic formulations that minimize stimulating the host immune response while balancing patient responsiveness to therapy is ideal. Immunogenicity is a clinical limitation in many settings that use biologic drugs for treatment, and clinically relevant immunogenicity reduction has been achieved through engineering smaller protein constructs and reducing unnecessary formulation components. A similar approach has influenced the evolution of BoNT formulations. Three BoNT-A products and one BoNT-B product have been approved by the Food and Drug Administration (FDA) for therapeutic use: onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB; a fourth BoNT-A product, daxibotulinumtoxinA, is currently under regulatory review. Additionally, prabotulinumtoxinA is a BoNT-A product that has been approved for aesthetic indications but not therapeutic use. Here, we discuss the preclinical and clinical immunogenicity data that exist within the scientific literature and provide a perspective for considering immunogenicity as a key factor in choice of BoNT formulation.

A phase 3 study evaluating the safety and efficacy of a pediatric dose of mometasone furoate with and without formoterol for persistent asthma.

OBJECTIVES: Asthma affects over 6 million children in the United States alone. This study investigated the efficacy and long-term safety of mometasone furoate-formoterol (MF/F) and MF monotherapy in children with asthma. MATERIALS AND METHODS: This phase 3, multicenter, randomized controlled trial evaluated metered-dose inhaler twice daily (BID) dosing with MF/F 100/10 µg or MF 100 µg in children, aged 5 to 11 years, with a history of asthma for greater than or equal to 6 months and confirmed bronchodilator reversibility, who were adequately controlled on inhaled corticosteroid/long-acting beta-agonist combination therapy for greater than or equal to 4 weeks. After a 2-week run-in on MF 100 µg BID, eligible patients received 24 weeks of double-blind treatment and were followed for safety up to 26 weeks. The primary efficacy endpoint was the change from baseline in AM postdose 60-minute AUC %predicted FEV1% across 12 weeks of treatment. RESULTS: A total of 181 participants received at least one dose of MF/F (n = 91) or MF (n = 90). MF/F was superior to MF across the 12-week evaluation period, with a treatment advantage of 5.21 percentage points (P < .001). Superior onset of action with MF/F over MF was achieved as early as 5 minutes postdose on day 1. Overall, approximately 50% of participants experienced one or more treatment-emergent adverse events, with fewer occurring in the MF/F group. CONCLUSIONS: In children 5 to 11 years of age with persistent asthma, the addition of F to MF was well tolerated and provided significant, rapid, and sustained improvement in lung function compared with MF alone.

Frequent Versus Infrequent Bathing in Pediatric Atopic Dermatitis: A Randomized Clinical Trial.

BACKGROUND: Studies evaluating bathing frequency in pediatric atopic dermatitis (AD) are limited. Parents of children with AD often receive conflicting information, leading to frustration and confusion. OBJECTIVE: To evaluate efficacy of twice-daily soaking baths, followed by immediate application of an occlusive moisturizer (ie, soak-and-seal [SS]), versus twice-weekly SS baths, in the acute management of pediatric AD. METHODS: We conducted a randomized, single-blind, crossover-controlled trial comparing frequent versus infrequent SS baths, in children 6 months to 11 years of age with moderate-to-severe AD. Children were randomized 1:1 into 2 groups: group 1 underwent twice-weekly SS baths, for 10 minutes or less, over 2 weeks ("dry method" [DM]) followed by twice-daily SS baths, for 15 to 20 minutes, over 2 weeks ("wet method" [WM]). Group 2 did the inverse. Patients received the same moisturizer, cleanser, and low-potency topical corticosteroid (TCS). Primary outcome was AD severity evaluated using the SCORing Atopic Dermatitis (SCORAD) index. Caregiver assessment of AD severity (Atopic Dermatitis Quickscore [ADQ]), quality of life, Staphylococcal aureus colonization, skin hydration, moisturizer, and TCS usage were assessed. RESULTS: Of the 63 children screened, 42 fulfilled inclusion criteria and were randomized. Forty (95%) completed the study. WM decreased SCORAD by 21.2 compared with DM (95% confidence interval [CI], 14.9-27.6; P < .0001). Secondary analysis showed a greater than 30% SCORAD improvement for WM versus DM (McNemar's χ2 = 8.83, df = 1, P = .0030). SCORAD correlated with ADQ (r = 0.66), and ADQ also showed significant improvement with WM decreasing ADQ by 5.8 (95% CI, 1.8-9.7). No other secondary endpoints showed significance. CONCLUSIONS: As an acute treatment intervention, WM is superior to DM at improving disease severity in moderate-to-severe pediatric AD.

Measurement of FeNO with a portable, electrochemical analyzer using a 6-second exhalation time in 7-10-year-old children with asthma: comparison to a 10-second exhalation.

Objective: Fractional exhaled nitric oxide (FeNO) is a valuable tool for assessing Th2 inflammation in children with asthma. Exhalation times of 6 and 10 s meet the current recommendations for assessing FeNO. The 6-s exhalation provides an alternative for 7-10 year olds not able to complete the 10-s exhalation. Methods: We performed a sub-analysis on data from 7-10-year-old children who participated in a previous study which evaluated the agreement of the 6 and 10-s exhalation times in 6-10 year olds with asthma. Agreement between observed FeNO results obtained by both modes was assessed by weighted Deming regression analysis and Bland-Altman plots. Repeatability was also assessed. Results: Repeatability and agreement of the 6 and 10-s exhalations was demonstrated in 7-10 year olds with two measurements in each mode. Mean observed FeNO measurements were 33.59 ppb (SD = 25.804) for 6 s and 32.46 ppb (SD = 25.302) for 10-s exhalation. Paired differences were centered close to 0 ppb (median = 0.50). Conclusions: Children aged 7-10 years can successfully perform FeNO measurements using a portable, electrochemical FeNO analyzer. Measurements from the 6 and 10-s exhalations were repeatable and consistent with a high degree of agreement between one another. Thus, in young children successful FeNO measurements can be obtained in either the 6-s or 10-s mode, providing physicians valuable information on airway inflammation to aid in the diagnosis and treatment of asthma.

Measurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions.

BACKGROUND: Assessment of asthma using clinical measures alone often fails to detect underlying airway inflammation. Fractional exhaled nitric oxide (FeNO) is a recognized biomarker of type 2 airway inflammation in asthma. Measurement of FeNO is instrumental in the assessment and management of patients with corticosteroid-sensitive asthma. OBJECTIVE: To determine the impact of measuring FeNO on asthma management in real-world clinical practices. METHODS: Clinicians from 337 US practices performed a clinical assessment and recorded treatment plans before and after measuring FeNO in 7,901 patients with asthma. Airway inflammation was classified as low, intermediate, or high according to the clinician's usual procedures, including clinical examination, spirometry, and symptoms. Clinicians recorded asthma medication plans, indicating medications to be initiated, continued, or stopped. FeNO measurement was performed, followed by documentation of any change(s) in the treatment plans based on the FeNO value (eg, initiating new medications or changing the dose of or discontinuing existing medications). RESULTS: Clinical assessment was concordant with FeNO measurement in only 56% of cases, matching FeNO more frequently in patients with low inflammation (64%) vs high inflammation (34%). After FeNO measurement, clinicians modified their treatment plan in 31% and altered prescriptions for inhaled corticosteroids in 90% of cases. Inhaled corticosteroids were initiated or their dose increased in 66% of patients with high inflammation but discontinued or their dose decreased in only 9% of patients with low inflammation. CONCLUSION: Measurement of FeNO enabled clinicians to assess underlying airway inflammation, leading to a significant revision of their treatment plans compared with real-world clinical assessment of asthma alone.

Bathing Frequency Recommendations for Children with Atopic Dermatitis: Results of Three Observational Pilot Surveys.

The results from three online surveys of dermatologists, allergists and immunologists, and primary care physicians (PCPs) regarding routine bathing frequency recommendations for children with atopic dermatitis (AD) are presented. The results suggest that PCPs approach bathing frequency differently than specialists, with PCPs recommending daily bathing less than 50% of the time and specialists recommending daily bathing more than 50% of the time. Because there is lack of consensus, studies are needed to evaluate whether bathing frequency makes a clinical difference in the treatment of pediatric AD.

Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates.

Until recently, no point-of-care tool was available for assessing the underlying airway inflammation associated with asthma. Fractional exhaled nitric oxide (FeNO) emerged in the last decade as an important biomarker for asthma assessment and management. Evidence also indicates that FeNO is most accurately classified as a marker of T-helper cell type 2 (Th2)-mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid-responsive airway inflammation. This manuscript evaluates the evidence for FeNO as a predictor of Th2-mediated corticosteroid-responsive airway inflammation and presents the results of a meta-analysis of three adult studies comparing asthma exacerbation rates with FeNO-based versus clinically-based asthma management algorithms, one of which was not included in a 2012 Cochrane meta-analysis. The primary purpose of the updated meta-analysis was to evaluate asthma exacerbation rates. The results demonstrate that the rate of exacerbations was significantly reduced in favor of FeNO-based asthma management (mean treatment difference = -0.27; 95% CI [-0.42, -0.12] as was the relative rate of asthma exacerbations (relative rate = 0.57; 95% CI [0.41, 0.80]). In summary, FeNO has value for identifying patients with airway inflammation who will and will not respond to corticosteroids. Importantly, the use of FeNO in conjunction with clinical parameters is associated with significantly lower asthma exacerbation rates compared with asthma managed using clinical parameters alone. Together these data indicate that FeNO testing has an important role in the assessment and management of adult asthma. Further studies will continue to define the exact role of FeNO testing in adult asthma.

A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.

Alterations in nuclear factor kappa B (NF-kappaB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-kappaB inhibitor IkappaBalpha, one of two phosphorylation sites that are essential for targeting IkappaBalpha for proteasomal degradation and hence for activation of NF-kappaB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-kappaB signaling by functioning as a dominant negative on NF-kappaB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-kappaB in the human immune response.