Exploring Definitions and Predictors of Severe Asthma Clinical Remission after Biologic Treatment in Adults.

Rationale: There is no consensus on criteria to include in an asthma remission definition in real life. Factors associated with achieving remission after biologic initiation remain poorly understood. Objectives: To quantify the proportion of adults with severe asthma achieving multidomain-defined remission after biologic initiation and identify prebiologic characteristics associated with achieving remission that may be used to predict it. Methods: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1 year before and after biologic initiation. A priori-defined remission cutoffs were: 0 exacerbations/yr, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted FEV1 ⩾ 80%. Remission was defined using two (exacerbations + LTOCS), three (+control or +lung function), and four of these domains. The association between prebiologic characteristics and postbiologic remission was assessed by multivariable analysis. Measurements and Main Results: A total of 50.2%, 33.5%, 25.8%, and 20.3% of patients met criteria for two-, three- (+control), three- (+lung function), and four-domain remission, respectively. The odds of achieving four-domain remission decreased by 15% for every additional 10 years of asthma duration (odds ratio, 0.85; 95% confidence interval, 0.73-1.00). The odds of remission increased in those with fewer exacerbations per year, lower LTOCS daily dose, better control, and better lung function before biologic initiation. Conclusions: One in five patients achieved four-domain remission within 1 year of biologic initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission after biologic treatment, indicating that biologic treatment should not be delayed if remission is the goal.

Expert opinion on diagnosis and management of Severe Asthma in low and middle income countries (LMIC) with focus on India.

OBJECTIVE: In this document, 9 Indian experts have evaluated the factors specific to LMICs when it came to Severe Asthma (SA) diagnosis, evaluation, biologic selection, non-biologic treatment options, and follow-up. DATA SOURCES: A search was performed using 50 keywords, focusing on the Indian/LMICs perspective, in PubMed, Cochrane Library, and Google Scholar. The key areas of the search were focused on diagnosis, phenoendotyping, non-biological therapies, selecting a biologic, assessment of treatment response, and management of exacerbation. STUDY SELECTIONS: The initial search revealed 1826 articles, from these case reports, observational studies, cohort studies, non-English language papers, etc., were excluded and we short-listed 20 articles for each area. Five relevant articles were selected by the experts for review. RESULTS: In LMICs, SA patients may be referred to the specialist for evaluation a little late for Phenoendotyping of SA. While biologic therapy is now a standard of care, pulmonologists in LMICs may not have access to all the investigations to phenoendotype SA patients like fractional exhaled nitric oxide (FeNO), skin prick test (SPT), etc., but phenotyping of SA patients can also be done with simple blood investigations, eosinophil count and serum immunoglobulin E (IgE). Choosing a biologic in the overlapping phenotype of SA and ACO patients is also a challenge in the LMICs. CONCLUSIONS: Given the limitations of LMIC, it is important to select the right patient and explain the potential benefits of biological therapy. Non-biologic add-on therapies can be attempted in a resource-limited setting where biological therapy is not available/feasible for patients.

Multicenter Canadian case series of pediatric patients less than 12 years of age with moderate-to-severe atopic dermatitis treated with dupilumab.

BACKGROUND: Dupilumab is approved for moderate-severe atopic dermatitis (AD) in patients aged ≥6 months by the US Food and Drug Administration and Health Canada; however, there are little real-world data because providers have limited practical experience with this recently approved therapy. OBJECTIVES: To describe the real-world effectiveness and safety in patients aged <12 years with moderate-severe AD currently receiving or previously having received dupilumab. METHODS: A multicenter retrospective study was conducted at six Canadian sites. Cases were divided into Group 1 ≤2 years old, Group 2 >2 to <6 years old, and Group 3 ≥6 to <12 years old. Medical history and details of dupilumab treatment were collected. The primary outcome was to measure the improvement in eczema area and severity index. Secondary outcomes examined included the children's dermatology life quality index/infant's dermatitis quality of life, peak pruritus numerical rating scale, and delay to dupilumab access for patients who were considered off-label for dupilumab due to their age. RESULTS: Sixty three pediatric patients (37 males) with moderate-to-severe AD were included; the mean age was 6.4 years old (range: 2-11) when dupilumab treatment was started. Overall, 75% (36/48) achieved EASI-75% and 71% (34/48) achieved EASI-90. EASI-75 and EASI-90 were achieved in 90% (17/19) and 73% (12/19) in patients <6 years old, and 76% (22/29) and 59% (17/29) in patients >6 years old, respectively. No serious adverse events were reported. CONCLUSIONS: Dupilumab is safe and effective for patients under the age of 12. However, even for experienced providers, access to the medication was challenging.

IL-4 and IL-13, not eosinophils, drive type 2 airway inflammation, remodeling and lung function decline.

RATIONALE: Type 2 (T2) asthma is characterized by airflow limitations and elevated levels of blood and sputum eosinophils, fractional exhaled nitric oxide, IgE, and periostin. While eosinophils are associated with exacerbations, the contribution of eosinophils to lung inflammation, remodeling and function remains largely hypothetical. OBJECTIVES: To determine the effect of T2 cytokines IL-4, IL-13 and IL-5 on eosinophil biology and compare the impact of depleting just eosinophils versus inhibiting all aspects of T2 inflammation on airway inflammation. METHODS: Human eosinophils or endothelial cells stimulated with IL-4, IL-13 or IL-5 were assessed for gene changes or chemokine release.Mice exposed to house dust mite extract received anti-IL-4Rα (dupilumab), anti-IL-5 or control antibodies and were assessed for changes in lung histological and inflammatory endpoints. MEASUREMENTS AND MAIN RESULTS: IL-4 or IL-13 stimulation of human eosinophils and endothelial cells induced gene expression changes related to granulocyte migration; whereas, IL-5 induced changes reflecting granulocyte differentiation.In a mouse model, blocking IL-4Rα improved lung function by impacting multiple effectors of inflammation and remodeling, except peripheral eosinophil counts, thereby disconnecting blood eosinophils from airway inflammation, remodeling and function. Blocking IL-5 globally reduced eosinophil counts but did not impact inflammatory or functional measures of lung pathology. Whole lung transcriptome analysis revealed that IL-5 or IL-4Rα blockade impacted eosinophil associated genes, whereas IL-4Rα blockade also impacted genes associated with multiple cells, cytokines and chemokines, mucus production, cell:cell adhesion and vascular permeability. CONCLUSIONS: Eosinophils are not the sole contributor to asthma pathophysiology or lung function decline and emphasizes the need to block additional mediators to modify lung inflammation and impact lung function.

Predicting dupilumab treatment outcome in patients with primary diffuse type 2 chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis with a type 2 inflammatory pattern (T2CRS) is believed to be restricted to the nose and sinuses and associated with polyps, without clear serologic markers. Dupilumab is a promising new therapy in difficult to treat T2CRS. No factors are known to predict dupilumab treatment outcome. METHODS: Patients undergoing dupilumab treatment were assessed clinically to report ultra-short- and short-term outcome up to 90 days. Serum samples were taken on day 0 and 30 days of treatment, and proteomic analyses were performed using Olink®. The results were compared with healthy controls (HC). The aim was to identify clinical and serological markers associated with a treatment response to dupilumab. Confirmation of predictive parameters was evaluated in a prospective cohort of 20 T2CRS patients. RESULTS: Thirty patients were included, 80% of which were treatment responders. SinoNasalOutcomeTest-20 (SNOT-20) scores and the total nasal polyp score improved significantly (p < .05) on Day 7. An improvement of 2.5 points at the first visit was associated with a favorable outcome with a sensitivity of 86%. Proteomic analyses revealed significant changes compared with HC. Furthermore, we could identify OPG in the serum of dupilumab-treated patients that may serve as a predictor of the clinical outcome of dupilumab treatment. The predictive value of OPG was confirmed in the second cohort. CONCLUSION: Clinical response after 1 week of treatment with dupilumab is highly associated with a favorable outcome. High sensitivity proteomic analyses can identify T2CRS-specific dysregulated proteins in serum. Serum OPG may serve as a predictor for dupilumab treatment outcome before the initiation of any therapy.

Interactions between Malassezia and New Therapeutic Agents in Atopic Dermatitis Affecting Skin Barrier and Inflammation in Recombinant Human Epidermis Model.

Several studies have reported the pathogenic role of Malassezia in atopic dermatitis (AD); the significance of Malassezia's influence on AD needs to be further investigated. Dupilumab, a monoclonal antibody to anti-Interleukin (IL) 4Rα, and ruxolitinib, a Janus kinase (JAK)1/2 inhibitor, are the first approved biologics and inhibitors widely used for AD treatment. In this study, we aimed to investigate how Malassezia Restricta (M. restricta) affects the skin barrier and inflammation in AD and interacts with the AD therapeutic agents ruxolitinib and anti-IL4Rα. To induce an in vitro AD model, a reconstructed human epidermis (RHE) was treated with IL-4 and IL-13. M. restricta was inoculated on the surface of RHE, and anti-IL4Rα or ruxolitinib was supplemented to model treated AD lesions. Histological and molecular analyses were performed. Skin barrier and ceramide-related molecules were downregulated by M. restricta and reverted by anti-IL4Rα and ruxolitinib. Antimicrobial peptides, VEGF, Th2-related, and JAK/STAT pathway molecules were upregulated by M. restricta and suppressed by anti-IL4Rα and ruxolitinib. These findings show that M. restricta aggravated skin barrier function and Th2 inflammation and decreased the efficacy of anti-IL4Rα and ruxolitinib.

Treatment With Dupilumab in Patients With Atopic Dermatitis: Systematic Review and Meta-Analysis.

Atopic dermatitis (AD) is a type 2 chronic skin disorder associated with systemic and psychosocial comorbidities decreasing the quality of life for many patients. Dupilumab, a human monoclonal antibody that blocks interleukins IL-4 and IL-13, is a recently added systematic treatment option with an emerging evidence base. Here, we assessed the safety and efficacy of dupilumab in patients with AD. We conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials evaluating the safety and efficacy of dupilumab on AD-related outcomes including clinical symptoms, quality of life and adverse events (AE). Subgroup analysis was further performed in adults and children/adolescents. Fourteen trials were included: twelve in adults (n = 3,817) and two in children/adolescents (n = 618). Dupilumab decreased the Eczema Area Severity Index (EASI) score [standardized mean difference (SMD) = -0.98; 95% confidence interval (95% CI) = (-1.09, -0.88)], the percent change difference in Scoring Atopic Dermatitis (SCORAD) [mean difference (MD) = -31.56, 95% CI = (-33.75, -29.36)], and in pruritus Numeric Rating Scale (pNRS) [MD = -29.24, 95% CI = (-32.11, -26.37)]. It also achieved a reduction of at least ≥75% in the EASI score [Risk Ratio (RR) = 2.89, 95% CI = (2.47, 3.38)], the Investigator's Global Assessment (IGA) score ≤1 [RR = 3.47, 95% CI = (2.96, 4.06)] and eight additional endpoints with no signs of increased AE compared to placebo. In subgroup analysis, the results were concordant for both groups. Dupilumab improved clinical symptoms and quality of life in adults and children/adolescents with a safety profile comparable to placebo.

Dupilumab for prurigo nodularis: Case series and review of the literature.

Dupilumab is a recombinant complete human monoclonal antibody modulating the signaling of interleukin-4 and interleukin-13 pathways and has been approved for the treatment of moderate/severe atopic dermatitis. Here, we present three cases of prurigo nodularis treated off-label with dupilumab, and a review of the existing literature. All patients in this study had longstanding severe disease and had tried multiple treatment modalities. They were treated with dupilumab at an initial dose of 600 mg subcutaneously, followed by 300 mg every 2 weeks. Systematic literature searches were performed to identify literature describing the evaluation of the effect of treatment with dupilumab in prurigo nodularis. The physician's assessment of the patients revealed a good or excellent response to the treatment with dupilumab. Patients were evaluated after treatment for 4 and 7 months. Treatment was generally well-tolerated; one in three patients reported dry eyes. Four studies with a total of 11 patients (range: 1-4) were identified by the literature search. Complete response was noted in all 11 patients. Treatment with dupilumab appears to be safe and well-tolerated with clinical benefit in recalcitrant prurigo nodularis. Larger randomized and controlled trials using validated outcome measures are needed before dupilumab could be applied in clinical settings.

Biologicals in the Treatment of Pediatric Atopic Diseases.

The management of atopic diseases such as severe asthma, severe atopic dermatitis, and severe food allergy in childhood is challenging. In particular, there are safety concerns regarding the use of high-dose corticosteroids. The recent development of biologicals and their approval for the treatment of children offer a new, very promising, and more personalized therapy option. Omalizumab, mepolizumab, and dupilumab are currently approved as add-on treatments of severe asthma in children and have been shown to be effective in improvement of asthma control and reduction of exacerbations. Dupilumab is the only biological approved for the treatment of atopic dermatitis in adolescents so far. It has been demonstrated to significantly improve symptoms of atopic dermatitis.However, safety data for biologicals used in atopic diseases in children and adolescents are still very limited. Biologicals are generally considered to be safe in adults. These data are often extrapolated to children. Additionally, data for long-term use are lacking. Thus, the safety profiles of those biologicals cannot yet be conclusively assessed.

Antibody therapy for the management of severe asthma with eosinophilic inflammation.

One of the characteristic features of asthma is chronic airway inflammation typically with eosinophil infiltration. Most asthmatics can be treated successfully with conventional treatment appropriate for their severity, but in some severe cases, asthma cannot be well controlled even with thorough treatment and this condition is known as 'refractory asthma'. To overcome severe refractory asthma, a new therapeutic strategy with biologics has been developed based on the knowledge of molecular mechanisms of airway inflammation in asthma, induced by the condition of high Th2-type responses and activation of eosinophils as well as allergic reactions. Humanized anti-human IgE antibody (anti-IgE; omalizumab) was the first biological preparation approved for treating asthma. Based on clinical evidence, treatment with anti-IgE (anti-IgE therapy) has been accepted as a new therapeutic approach for severe allergic asthma in adults since 2009 and in children since 2012 and has been shown to have ~60% efficacy. More recently, a humanized anti-IL-5 antibody (anti-IL-5; mepolizumab) was launched in June 2016 and has attracted great interest due to its potential effects. Several clinical studies are also ongoing to evaluate the biological preparations targeting IL-5 receptor α (IL-5Rα), IL-4 receptor α (IL-4Rα), which is shared by IL-4 and IL-13, thymic stromal lymphopoietin (TSLP) and IL-33. The new strategy with biologics targeting eosinophilic airway inflammation might open a new array for us to overcome severe refractory asthma in the future.

Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial.

BACKGROUND: Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma. OBJECTIVES: We sought to evaluate the induction of sustained tolerance to allergen when anti-IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response. METHODS: In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti-IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4, and facilitated antigen binding. RESULTS: Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti-IL-4. Treatment with anti-IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4-producing cell counts (P < .01). Both active treatment arms led to induction of dual IL-4/IL-10-producing cells during the pollen season. CONCLUSION: The combination of anti-IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH2 responses might translate into clinical benefit.

Low Serum IL-18 Levels May Predict the Effectiveness of Dupilumab in Severe Asthma.

Objective Dupilumab, a monoclonal antibody specific for the human interleukin (IL)-4 receptor α, is used to treat severe asthma, especially in patients with elevated blood eosinophil counts and fractional exhaled nitric oxide (FeNO). The therapeutic response to dupilumab is highly variable. In this study, we explored new serum biomarkers to accurately predict the effect of dupilumab and examine the effect of dupilumab based on changes in the clinical parameters and cytokine levels. Methods Seventeen patients with severe asthma treated with dupilumab were enrolled. Responders, defined as those with a >0.5-point decrease in the Asthma Control Questionnaire (ACQ) score after 6 months of treatment, were included. Results There were 10 responders and 7 non-responders. Serum type 2 cytokines were equivalent between responders and non-responders; the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9±51.0 pg/mL; non-responders, 323.4±122.7 pg/mL, p=0.013). The cut-off value of IL-18 at 230.5 pg/mL could be used to distinguish non-responders from responders (sensitivity 71.4, specificity 80.0, p=0.032). Conclusion A low baseline serum IL-18 level may be a useful predictor of an unfavorable response to dupilumab in terms of the ACQ-6.

Effect of biologic therapies on quality of life in severe asthma: Findings from the PRISM study.

Background: Anti-type 2 (T2) biologic therapies (biologics) improve exacerbation rates, lung function, and asthma-related quality of life (QoL) in patients with severe T2 asthma. However, studies comparing different biologics are lacking. We evaluated the QoL in patients with severe asthma comprehensively and compare the efficacy of different T2-directed biologics using QoL questionnaires. Methods: We compared the QoL between severe and mild-to-moderate asthma and between severe asthma with and without biologics treatment. Data of mild-to-moderate were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea, and data of severe asthma were collected from the Precision Medicine Intervention in Severe Asthma. We included 183 patients with severe asthma treated with T2 biologics or conventional therapy between April 2020 and May 2021 and assessed QoL of them using the Questionnaire for Adult Korean Asthmatics (QLQAKA), Severe Asthma Questionnaire (SAQ), and EuroQoL-5Dimensions (EQ-5D) at baseline and 6 months. Results: The EQ-5D index (0.803) of severe asthma was lower than that of other chronic diseases representing a worse QoL. The scores for all questions of QLQAKA, except "cough," were lower (less control) in the severe asthma group than in the mild-to-moderate asthma group at baseline and 6 months (P < 0.05). The total scores and subscores of all domains of the QLQAKA, SAQ, and EQ-5D improved significantly 6 months after biologic therapy but not after conventional therapy. The total QLQAKA, SAQ, and EQ-5D scores improved after 6 months in the anti-IL-5 (P < 0.05) and anti-IL-4/IL-13 (P < 0.05) treatment groups with no significant difference between groups (P > 0.05). Conclusion: QoL was worse in severe asthma than in mild-to-moderate asthma and other chronic diseases. T2 biologics equally improved QoL in patients with severe asthma.

Type 2 severe asthma: pathophysiology and treatment with biologics.

INTRODUCTION: The hallmark of most patients with severe asthma is type 2 inflammation, driven by innate and adaptive immune responses leading to either allergic or non-allergic eosinophilic infiltration of airways. The cellular and molecular pathways underlying severe type 2 asthma can be successfully targeted by specific monoclonal antibodies. AREAS COVERED: This review article provides a concise overview of the pathophysiology of type 2 asthma, followed by an updated appraisal of the mechanisms of action and therapeutic efficacy of currently available biologic treatments used for management of severe type 2 asthma. Therefore, all reported information arises from a wide literature search performed on PubMed. EXPERT OPINION: The main result of the recent advances in the field of anti-asthma biologic therapies is the implementation of a personalized medicine approach, aimed to achieve clinical remission of severe asthma. Today this accomplishment is made possible by the right choice of the most beneficial biologic drug for the pathologic traits characterizing each patient, including type 2 severe asthma and its comorbidities.

Exploring Definitions and Predictors of Response to Biologics for Severe Asthma.

BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.

Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway in Atopic Dermatitis: How Can We Choose?

Atopic dermatitis (AD) is an immune-mediated skin disorder with a chronic-relapsing course and a multifactorial pathogenesis. In contrast to the traditional concept of AD as solely a type 2 immune-activated disease, new findings highlight the disease as highly heterogeneous, as it can be classified into variable phenotypes based on clinical/epidemiological or molecular parameters. For many years, the only therapeutic option for moderate-severe AD was traditional immunosuppressive drugs. Recently, the area of systemic therapy of AD has significantly flourished, and many new substances are now marketed, licensed, or in the last step of clinical development. Biological agents and small molecules have enriched the therapeutic armamentarium of moderate-to-severe AD, such as dupilumab, tralokinumab, lebrikizumab (monoclonal antibodies targeting the IL-4/13 pathway), abrocitinib, upadacitinib, and baricitinib (JAK inhibitors). Indeed, the AD treatment paradigm is now split into two main approaches: targeting the IL-4/13 axis or the JAK/STAT pathway. Both approaches are valid and have strong evidence of preclinical and clinical efficacy. Therefore, the choice between the two can often be difficult and represents a major challenge for dermatologists. Indeed, several important factors must be taken into account, such as the heterogeneity of AD and its classification in phenotypes, patients' comorbidities, age, and personal preferences. The aim of our review is to provide an overview of the clinical and molecular heterogeneities of AD and to explore the factors and parameters that, in clinical practice, may help inform clinical decision-making.

Dupilumab Demonstrates Rapid Onset of Response Across Three Type 2 Inflammatory Diseases.

BACKGROUND: Type 2 inflammatory diseases often coexist in patients. Dupilumab targets type 2 inflammation and has demonstrated treatment benefits in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) with an acceptable safety profile. OBJECTIVE: This post hoc analysis across five phase 3 studies in patients with moderate to severe AD or asthma, or severe CRSwNP, evaluated time of onset and duration of the treatment response. METHODS: Patients received subcutaneous dupilumab 200/300 mg or placebo. Assessments included the Eczema Area and Severity Index, Peak Pruritus Numerical Rating Scale, and Dermatology Life Quality Index in AD; pre-bronchodilator FEV1, daily morning peak expiratory flow, and symptom scores in asthma; and University of Pennsylvania Smell Identification Test, daily nasal congestion, and loss of smell scores in CRSwNP. RESULTS: At week 2 after the initiation of dupilumab versus placebo, 67.8% versus 36.5% of AD patients achieved a clinically meaningful benefit (Eczema Area and Severity Index: 50% or greater improvement; Peak Pruritus Numerical Rating Scale: 3 point or greater improvement; or Dermatology Life Quality Index: 4 point or greater improvement) (P < .001). Moreover, 61.6% versus 39.9% of asthma patients achieved improvements in pre-bronchodilator FEV1 of 100 mL or greater and 48.8% versus 26.3% achieved 200 mL or greater improvement (both P < .001); 33.2% versus 5.6% of CRSwNP patients regained a sense of smell (P < .001). Treatment effects further improved or were sustained to the end of treatment. CONCLUSIONS: Clinically meaningful responses were achieved rapidly after the first dupilumab dose in AD, asthma, or CRSwNP and were sustained throughout treatment (see Video in this article's Online Repository at www.jaci-inpractice.org).