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Atopic dermatitis is a heterogeneous disease and resists classification. In this review, we discuss atopic dermatitis nomenclature and identify morphologic phenotypes, which will facilitate correct diagnoses and development of treatment strategies. We support using the term ‘atopic dermatitis’ rather than eczema, because it describes the allergic background and inflammation (‘itis’) as drivers of the disease. Atopic dermatitis has many morphologic manifestations that vary by topographic area affected, age, or race and require consideration in differential diagnosis. Different phenotypes based on morphology and topographic location, ethnicity, and age are discussed. A better-defined phenotype identification for atopic dermatitis will facilitate earlier and correct diagnosis of this complex condition and inform selection of the most appropriate treatment choice in an era in which targeted therapies may generate more individualized patient care.

Background For children aged 6–11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. Objectives This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). Methods Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required. Results Data for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response. Conclusions Consistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6–11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit. Trial Registration ClinicalTrials.gov Identifier NCT02612454. Plain Language Summary Atopic dermatitis (AD) is a chronic disease that causes recurrent inflamed and rough skin rashes with itching and often soreness. In children with AD, treatment with a medication called dupilumab has shown improvements in their disease and quality of life. But most clinical trials of dupilumab in children have only lasted for 16 weeks. We investigated the effect of dupilumab in children treated for a longer time. The 321 children (aged 6–11 years) who were included in this study had taken part in a clinical trial of dupilumab because they had severe AD. They were treated with either dupilumab or a placebo (a dummy treatment) for 16 weeks. When that trial ended, they were then all treated with dupilumab for up to a year. Their average AD severity continued to get steadily better over a year of extended treatment, with almost all children reaching 50% skin improvement compared with their AD before treatment. Many children reached a point where their skin was clear or almost clear of AD for a period, and following the rules of the study they stopped taking dupilumab. In many of them, their AD slowly returned without treatment. But if they started to take dupilumab again, their AD improved, and some could even achieve skin clearance again. Over the longer term, the safety of dupilumab was similar to what was seen with short-term treatment. This study showed that children with AD aged 6–11 years benefited from receiving dupilumab for a longer period of time.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. Children with severe AD have a multidimensional disease burden characterized by skin lesions, itching, frequent infections, sleep deprivation, and a high rate of comorbidities. These impact the mental health and overall quality of life of not only the children but also of their parents and caregivers. There are few effective available treatment options for young children with severe AD that are suitable for long-term use. Due to their adverse effects, practice guidelines consider systemic agents inappropriate for this age group, although they are still used off-label in extreme cases. The biologic dupilumab has recently been approved for children aged 6-11 years with severe (EU) and moderate-to-severe (USA) AD, offering hope to this population of patients with a high unmet clinical need. The purpose of this review is to describe the unmet needs of AD patients aged 6-11 years prior to dupilumab approval and to summarize existing clinical data supporting dupilumab's safety and efficacy in these children.

Introduction Atopic dermatitis (AD) is heterogeneous in distribution pattern and clinical features. This analysis assessed the effect of dupilumab on the extent and severity of AD across various signs (erythema, edema/papulation, excoriation, lichenification) in different anatomical regions (head and neck, trunk, upper extremities, lower extremities) in patients aged 6 months to 5 years. Methods In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo with concomitant low-potency topical corticosteroids (TCS) every 4 weeks for 16 weeks. Changes in AD signs across anatomical regions were assessed using unweighted Eczema Area and Severity Index (EASI) body region scores. Results Overall, 162 patients were randomized to dupilumab ( n  = 83) or placebo ( n  = 79). A significant improvement in least squares mean EASI area score was seen by week 2 in all four anatomical regions ( P  < 0.0001 for dupilumab vs. placebo) and sustained throughout treatment. Least squares mean EASI sign scores in erythema, excoriations, and infiltration/papulation showed significant improvement by week 2 in all regions ( P  < 0.001), while lichenification showed significant improvement in all regions by week 4 ( P  < 0.001). Conclusion Dupilumab use with concomitant low-potency TCS treatment resulted in rapid and consistent improvement in AD signs in all anatomical regions, in patients aged 6 months to 5 years with moderate-to-severe AD. Trial Registration ClinicalTrials.gov Identifier: NCT03346434 Part B.

Introduction The Patient-Oriented Eczema Measure (POEM) assesses patient-reported frequency of atopic dermatitis (AD) symptoms, while the Children’s Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on health-related quality of life (HRQoL) in children. There is currently no threshold for clinically meaningful within-person change in POEM or CDLQI scores in adolescents. Here we empirically derive within-person thresholds of meaningful within-person change in POEM and CDLQI scores in adolescents with moderate-to-severe AD. Methods Data were used from a phase 3, randomized, double-blind, placebo-controlled trial of dupilumab in adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD. Anchor-based methods were employed using the mean change in POEM and CDLQI scores from baseline to week 16 linked with a 1-point improvement in Patient Global Assessment of Disease (PGAD), a score of “a little better” on the Patient Global Assessment of Treatment effect (PGAT), a 50–74% improvement from baseline in the Eczema Area and Severity Index (EASI-50–74), and a 1-point improvement in Investigator’s Global Assessment (IGA) score. Results A mean change of − 7.8 and − 5.6 in the POEM score was associated with PGAD and PGAT anchors, respectively. EASI-50–74 was associated with a mean change in POEM score of − 8.2, while the IGA anchor was associated with a mean change of − 7.9 in POEM score. The mean changes in CDLQI score associated with PGAD and PGAT anchors were − 6.4 and − 6.6, respectively, while CDLQI mean scores changed by − 8.3 and − 8.0 for the EASI and IGA anchors, respectively. Conclusion In adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD, a within-person change of 6–8 points in POEM and CDLQI scores, independently, can be considered a reasonable responder threshold for clinically meaningful change in each of the two scales, respectively. Trial Registration ClinicalTrials.gov Identifier: NCT03054428. Funding Sanofi and Regeneron Pharmaceuticals, Inc.

Background Atopic dermatitis (AD) significantly impacts health‐related quality of life (HRQoL) in children and their caregiver(s)/family. Measures to assess HRQoL include the Children's Dermatology Life Quality Index (CDLQI), Infants' Dermatitis Quality of Life Index (IDQoL) and Dermatitis Family Impact (DFI) questionnaire. Currently, there are no established clinically meaningful within‐person change thresholds for these measures in young children (6 months to 5 years) and their caregiver(s)/family. Objectives To determine the clinically meaningful within‐person change thresholds for CDLQI (4–5 years), IDQoL (<4 years) and DFI scores in children aged 6 months to 5 years with moderate‐to‐severe AD and their caregiver(s)/family. Methods Data from the 16‐week, randomised, double‐blind, placebo‐controlled, phase 3 LIBERTY AD PRESCHOOL part B study in children aged 6 months to 5 years were used. The anchor‐based method was used to assess meaningful change thresholds for the three instruments, using the Caregiver Global Impression of Disease (CGID; range: ‘no symptoms’ to ‘very severe’) as the primary anchor, and Caregiver Global Impression of Change (CGIC; range: ‘much better’ to ‘much worse’) as a supportive anchor. Results The mean CDLQI change scores were −6.3 and −9.5 based on CGID 1‐point improvement and CGIC improvement of ‘a little better’, respectively. The mean IDQoL change scores were −5.6 and −3.4 based on the CGID and CGIC anchors. The mean DFI change scores were −7.0 and −6.7 based on the CGID and CGIC anchors. Conclusions Based on primary anchor findings, improvements of ≥6 points on the CDLQI total score for children aged 4–5 years and on the IDQoL total score for children aged <4 years were recommended as the clinically meaningful within‐person change thresholds in children with moderate‐to‐severe AD. A 7‐point improvement on the DFI total score may be considered as the meaningful threshold for the caregiver(s)/family of children aged 6 months to 5 years with moderate‐to‐severe AD. Using an anchor‐based method, clinically meaningful thresholds for measures assessing health‐related quality of life in children with atopic dermatitis (AD) and their caregiver(s)/family were proposed. Improvement of ≥6 points on CDLQI (Children's Dermatology Life Quality Index) and IDQoL (Infants' Dermatitis Quality of Life Index) total score was considered clinically meaningful for children with moderate‐to‐severe AD aged 4–5 years and <4 years, respectively. For their caregiver(s)/family, the suggested threshold is a 7‐point improvement on DFI (Dermatitis Family Impact) total score.

Background Treatment responses may differ between patients with severe versus moderate atopic dermatitis (AD). Objectives To assess dupilumab response by baseline AD severity in adolescent and adult patients with moderate‐to‐severe AD. Methods We assessed dupilumab response by baseline AD severity in 1719 patients aged ≥12 years with moderate‐to‐severe AD from five randomized, double‐blind, placebo‐controlled trials. Patients received subcutaneous placebo or dupilumab as monotherapy (300 mg [adults, adolescents] or 200 mg [adolescents] every 2 weeks; 16 weeks), or with concomitant topical corticosteroids (TCS) (adults; 16/52 weeks). Patients were stratified by baseline Investigator's Global Assessment (IGA) score (3 [moderate]/4 [severe]). Results Dupilumab‐treated patients with moderate AD had numerically higher absolute proportions of patients achieving IGA 0/1 (clear/almost clear) than those with severe AD; risk differences (dupilumab vs. placebo) were 18.9–35.5 for moderate AD and 16.4–34.2 for severe AD. For all other endpoints assessed, no meaningful differences or consistent response patterns between moderate and severe subgroups were observed. Conclusions Dupilumab with or without TCS demonstrated similar efficacy in patients with moderate or severe AD.

Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV ) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).

In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV ) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.).

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8–57.7 for the difference, P  < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3–31.2; P  = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile. ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 . In the LIBERTY-PN PRIME and PRIME2 phase 3 trials, dupilumab, a monoclonal antibody that blocks IL-4 and IL-13 signaling, significantly reduced itch and skin lesions in patients with prurigo nodularis, a chronic inflammatory skin disease.