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This article discusses the burden of atopic dermatitis (AD), a chronic inflammatory skin disease that affects both children and adults. The incidence of AD is increasing globally, and it has a significant impact on quality of life. Current treatments have limitations, and there is a need for improved topical medications. Tapinarof, a nonsteroidal topical medication, has shown promise in clinical trials for patients with AD, including children as young as 2 years old. Targeting the aryl hydrocarbon receptor (AhR) may offer a novel therapeutic strategy for AD. The document provides a list of references and citations for further research on atopic dermatitis, covering various topics related to the condition and its treatment. [Extracted from the article]

Introduction/Background Atopic dermatitis (AD) has different clinical presentations, pathophysiology, comorbidity frequencies, and genetic profiles in adult-onset vs childhood-onset disease. Based on these differences, it is plausible that treatment response would also be different between adult- and childhood-onset AD. Lebrikizumab, a novel, high affinity monoclonal antibody, selectively targeting IL-13 with high affinity and slow dissociation rate, has been approved in the EU, UK, and Japan and is under investigation in the US and elsewhere for the treatment of moderate-to-severe AD. Objectives To evaluate the Week-16 efficacy of lebrikizumab monotherapy by age of AD onset in adults and adolescents with moderate-to-severe AD from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), identically-designed, randomized, double-blind, placebo-controlled phase 3 trials. Methods In ADvocate1 and ADvocate2, eligible patients were randomly allocated 2:1 to receive lebrikizumab 250 mg or placebo every 2 weeks. The date of AD onset was collected, and age of onset was calculated accordingly. Patients were stratified by age of AD-onset as ≤2, >2-to-<18, and ≥18 years. Efficacy was assessed at Week 16 with the proportion of patients with Investigator's Global Assessment score of 0 or 1 with ≥2-point improvement (IGA 0,1; the trials' primary endpoint); ≥75% (EASI 75) and ≥90% (EASI 90) improvement in the Eczema Area and Severity Index from baseline; ≥4-point Pruritus Numeric Rating Scale (NRS) improvement from baseline (with baseline score ≥4), and percentage change in total EASI from baseline. Data from patients who received topical or systemic rescue medication or discontinued treatment due to lack of efficacy were imputed as nonresponders or set to baseline values. Data from patients who discontinued treatment for other reasons were set to missing and analyzed by multiple imputation. This was a post-hoc analysis conducted on the modified, pooled intent-to-treat population. Treatment-by-age subgroup interaction was assessed with logistic regression. Binary outcomes were analyzed by the Cochran-Mantel-Haenszel method, and continuous outcomes were analyzed with ANCOVA. Results At baseline, the numbers of patients treated with lebrikizumab and placebo, respectively, were 215 and 117 in the ≤2 years AD-onset subgroup, 178 and 103 in the >2-to-<18 years subgroup, and 171 and 67 in the ≥18 years subgroup. At baseline, the percentages of patients with ≥1 atopic comorbidity were 81% in the ≤2 years subgroup, 74% in the >2-to-<18 years subgroup, and 58% in the ≥18 years subgroup. At Week 16, treatment-by-age subgroup interactions were not significant at the 0.10 level for IGA 0,1; EASI 75; EASI 90; and Pruritus NRS 4-pt improvement. Within each subgroup, a higher proportion of lebrikizumab-treated compared with placebo-treated patients (p<0.001) achieved IGA 0,1 responses (≤2 years: 41% vs. 12%; >2-to-<18 years: 35% vs. 12%; ≥18 years: 38% vs. 12%), EASI 75 responses (≤2 years: 57% vs. 17%; >2-to-<18 years: 51% vs. 16%; ≥18 years: 58% vs. 20%), and EASI 90 responses (≤2 years: 38% vs. 10%; >2-to-<18 years: 32% vs. 9%; ≥18 years: 33% vs. 8%). Additionally, the least-squares mean percentage change from baseline in total EASI score for lebrikizumab and placebo, respectively, was -65% and -26% in the ≤2 years subgroup, -60% and -26% in the >2-to-<18 years subgroup, and -63% and -30% in the ≥18 years subgroup (p<0.001 for lebrikizumab vs. placebo in all subgroups). The proportion of lebrikizumab-treated patients who reported ≥4-point improvement in Pruritus NRS from baseline (baseline ≥4) was greater compared with placebo-treated patients ([N]; ≤2 years: 43% [201] vs. 11% [108]; >2-to-<18 years: 41% [161] vs. 14% [96]; ≥18 years: 45% [154] vs. 12% [60]; p<0.001). Conclusions Regardless of age of AD onset, lebrikizumab was associated with significant improvements in AD signs and symptoms compared with placebo over 16 weeks of treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Adults with atopic dermatitis (AD) commonly report adult-onset disease. AD is associated with different genetics, lesion morphology and distribution, and symptoms by age of onset. Yet little is known about possible differences in treatment efficacy between adults with adult-onset or childhood-onset AD. Methods: We evaluated the efficacy of dupilumab by age of AD onset in adults with moderate-to-severe AD, using pooled data from the LIBERTY AD SOLO 1 and 2 studies (NCT02277743, NCT02277769). Results were stratified based on self-reported age of AD onset, divided into four age subgroups: 0–4, 5–9, 10–19, and over 20 years. Results: This analysis included 460 patients treated with placebo and 457 treated with dupilumab 300 mg every 2 weeks (q2w), with a mean patient age of 38 years. Most patients (53.2%) reported AD onset at 0–4 years, with 14% at 5–9 years, 13.4% at 10–19 years, and 18.5% at 20 years or older. Dupilumab significantly improved AD signs and symptoms over 16 weeks compared with placebo, regardless of age of onset. Dupilumab treatment resulted in a significantly greater proportion of patients achieving Eczema Area and Severity Index (EASI)-50, EASI-75, and EASI-90 (50%, 75%, and 90% improvement from baseline EASI, respectively), and clear or almost clear skin (Investigator's Global Assessment score 0 or 1) across all age-of-onset subgroups compared with placebo. In addition, EASI improvements were significant across all anatomical regions in all subgroups. Weekly average peak pruritus Numerical Rating Scale and Dermatology Life Quality Index also improved consistently and significantly with dupilumab versus placebo, regardless of age of onset. Conclusion: Despite possible differences in presentation and progression of AD linked to age of onset, dupilumab showed similar significant and sustained improvements in AD signs, symptoms, and quality of life in adults compared with placebo, over 16 weeks of treatment. Trial Registration: LIBERTY AD SOLO 1: NCT02277743; LIBERTY AD SOLO 2: NCT02277769. Infographic available for this article. Plain Language Summary: Atopic dermatitis (AD, also known as eczema) is a skin disease with itchy, red rashes. AD often develops during childhood, but can also start in adulthood. Depending on the age it starts, AD may have different triggers and appearance, and might require different treatment. A medicine called dupilumab, which targets two proteins that cause inflammation, has provided benefit in children and adults with AD. We wanted to know if the age at which AD starts (during infancy, childhood, adolescence, or adulthood) impacts the improvement of dupilumab in adult patients. We looked at 917 adults, who participated in two studies taking dupilumab or a dummy treatment (placebo) every 2 weeks for 4 months. We compared four groups of patients with different ages of AD onset. The results showed that dupilumab compared with the placebo reduced skin lesions, relieved itch, and improved quality of life in a similar way in all adults, regardless of whether their disease started earlier or later in life. In the four groups, dupilumab reduced skin lesions across all areas of the body. Together with the previously reported safety data, our results support the use of dupilumab in adults with moderate-to-severe AD, irrespective of age of disease onset. Infographic: [ABSTRACT FROM AUTHOR]

To address the need for long‐term efficacy and patient‐reported outcomes (PROs) data for patients with atopic dermatitis (AD) treated with baricitinib 2 mg, a study was conducted to evaluate the efficacy of baricitinib 2 mg in adult patients with moderate‐to‐severe AD. Data presented here provided efficacy and outcomes data for patients treated for 52 weeks. Patients who participated in the originating study, BREEZE‐AD5 (NCT03435081), and met additional eligibility criteria could enroll in the multicenter, open‐label, Phase 3, long‐term extension study BREEZE‐AD6 (NCT03559270). Patients received baricitinib 2 mg for the duration of BREEZE‐AD6. In BREEZE‐AD6, the proportion of patients who achieved a 75% improvement in the Eczema Area and Severity Index (EASI75) and validated Investigator Global Assessment for AD (vIGA‐AD™) of 0 (clear) or 1 (almost clear) were assessed through 52 weeks, in addition to several PROs. At week 52, the proportion of patients treated with baricitinib 2 mg daily achieving EASI75 was 48.6% (70/144), and 31.3% (45/144) of patients achieved a vIGA‐AD score of 0 or 1 (clear or almost clear). Improvements in PROs such as SCORing Atopic Dermatitis (SCORAD, itch and sleep) scores, Dermatology Life Quality Index (DLQI) total score, and DLQI ≤5 response were observed, and these responses were sustained through 52 weeks. Long‐term efficacy of baricitinib in patients with AD was demonstrated by both clinician and patient‐reported outcome measures. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense itch and eczematous skin lesions that can impact individuals at any age across any area of the body. There is a need for safe treatments for AD that provide rapid itch relief and skin clearance and that are suitable for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor, which is approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe AD. The current analysis assessed the long-term safety for up to 4 years of upadacitinib 15 and 30 mg in adolescents and adults with moderate-to-severe AD, using integrated data from three ongoing global pivotal phase 3 studies. The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1 : 1 : 1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg or placebo once daily alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1 : 1 to receive either upadacitinib 15 or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). A total of 2693 adults and adolescents (upadacitinib 15 mg, 1340; upadacitinib 30 mg, 1353) who received at least one dose of upadacitinib were included in the integrated analysis. Treatment-emergent adverse events of special interest (AESI) were analysed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Upadacitinib was well tolerated by both adults and adolescents. For all patients, rates of AESIs were similar at the 1-year analysis and up to 4-year analysis for upadacitinib (15 mg/30 mg) for: serious infections, 2.3 and 2.2/2.8 and 2.8; opportunistic infections, 1.6 and 1.8/1.9 and 2.4; active tuberculosis, <0.1/<0.1 at both time points; herpes zoster, 3.5 and 3.1/5.2 and 5.8; nonmelanoma skin cancer (NMSC), 0.3 and 0.4/0.4 and 0.3; malignancy excluding NMSC, 0.1 and 0.4/0.5 and 0.3; and adverse events leading to death, 0 and 0/<0.1 and <0.1. Rates of adjudicated major adverse cardiovascular events (MACE) were 0.1 and <0.1/<0.1 and <0.1, and for venous thromboembolic events (VTE) were <0.1 for both doses at the 1-year analysis and up to 4-year analysis. Rates of gastrointestinal perforations were 0 for both doses at both timepoint analyses. Rates of serious infections remain low (<3.0 E/100 PY). Based on the integrated analysis of long-term safety data for up to 4 years, rates of AESIs remained low throughout a longer duration of treatment with upadacitinib 15 or 30 mg among adults and adolescents with moderate-to-severe AD. No new safety risks were observed. Findings of the current safety analysis continue to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 4 years of treatment. [ABSTRACT FROM AUTHOR]

Background: The relationship between atopic dermatitis (AD) severity, sleep disturbance (SD), and health-related outcomes is not fully elucidated. Objective: The aim of the study was to determine the prevalence of SD in adult AD and its relationship with AD severity and health outcomes among the US population. Methods: A cross-sectional, US population–based survey study of 2893 adults was performed. Results: Among adults meeting the UK Diagnostic Criteria for AD, 255 (40.7%) reported 1 or more, 67 (11.1%) reported 3 to 4, and 57 (9.5%) reported 5 to 7 nights of SD in the past week; 475 (79.7%) reported at least some trouble sleeping in the past 3 days. Moderate and severe Patient-Oriented Scoring AD, Patient-Oriented Eczema Measure, and Numeric Rating Scale–itch and Numeric Rating Scale–skin pain scores were associated with more severe SD compared with those without AD. More frequent and severe SDs were associated with higher Dermatology Life Quality Index, lower 12-item Short-Form Health Survey, and higher Hospital Anxiety and Depression Scale (HADS) scores. Significant mediation by SD severity was observed between Patient-Oriented Eczema Measure and Numeric Rating Scale–itch with Dermatology Life Quality Index, 12-item Short-Form Health Survey physical and mental component scores, HADS-anxiety and HADS-depression scores, diagnosed anxiety, and heart disease. Conclusions: Atopic dermatitis and AD severity are associated with SDs. Sleep disturbances considerably impact quality of life and other health outcomes in adults with AD. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α‐subunit of interleukin (IL)‐4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. Methods: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non‐lesional skin of adults and adolescents with moderate‐to‐severe AD over the course of 16‐week treatment with dupilumab and compared those values with that of matched healthy volunteers. Results: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL‐4/IL‐13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non‐hydroxy fatty acids and C18‐sphingosine and increased the level of esterified omega‐hydroxy fatty acid‐containing ceramides) and increased ceramide chain length in lesional as well as non‐lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. Conclusions: Inhibition of IL‐4/IL‐13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

Abrocitinib, a once-daily, oral Janus kinase 1 selective inhibitor, was shown to be an effective treatment for moderate-to-severe atopic dermatitis in phase 2 b/3 monotherapy trials. These analyses included data for Investigator's Global Assessment responder (clear [0] or almost clear [1] with ≥2-grade improvement) and nonresponder patients with moderate-to-severe atopic dermatitis who received abrocitinib (200 mg or 100 mg) or placebo in three abrocitinib monotherapy trials (phase 2 b, NCT02780167; two phase 3, NCT03349060/JADE MONO-1 and NCT03575871/JADE MONO-2). Outcomes measuring skin clearance, itch, and quality of life were evaluated. Both nonresponders (n = 548) and responders (n = 260) treated with abrocitinib had rapid and clinically meaningful improvement in skin clearance, itch, and quality of life compared with placebo. Patients with moderate-to-severe atopic dermatitis treated with abrocitinib who did not achieve an Investigator's Global Assessment 0/1 response at week 12 still experienced rapid, clinically meaningful improvements across several other validated measures of efficacy and quality of life. NCT02780167, NCT03349060, NCT03575871 [ABSTRACT FROM AUTHOR]

Introduction Roflumilast is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a nonsteroidal, once-daily cream for treatment of atopic dermatitis (AD). Methods We present pooled results from two identical phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600) of roflumilast cream 0.15%. Patients aged ≥6 years with mild to moderate AD were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) cream once-daily for 4 weeks. The primary endpoint was validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) Success (Clear/Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4. Patient-reported outcomes (PROs) were evaluated using the Worst Itch-Numeric Rating Scale (WI-NRS), SCORing AD (SCORAD), Patient-Oriented Eczema Measure, Dermatology Life Quality Index/Children's Dermatology Life Quality Index, and the Dermatitis Family Impact questionnaire. Safety and tolerability were also evaluated. Results At Week 4, more roflumilast- than vehicle-treated patients achieved vIGA-AD Success (31.3% vs. 14.1%, P<0.0001), WI-NRS Success (≥4-point improvement on WI-NRS in patients aged ≥12 years with baseline WI-NRS ≥4; 31.9% vs. 16.6%, P<0.0001); and WI-NRS of 0/1 (in patients with baseline WI-NRS ≥2; 28.8% vs 18.5%, P=0.0087). At Week 4, roflumilast-treated patients improved more than vehicle-treated on the pruritus and sleep components of SCORAD (least squares mean percentage change −48.2% vs. −27.8%; [P<0.0001] and −47.9% vs. −22.9% [P<0.05], respectively). Differences favoring roflumilast were also seen for other secondary endpoints, including quality of life of the patient and family. Safety and local tolerability were favorable. Conclusion Once-daily, nonsteroidal roflumilast cream 0.15% improved PROs in patients with AD. [ABSTRACT FROM AUTHOR]

Introduction: Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, is indicated in the European Union and Japan for treatment of moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. In the ongoing, placebo-controlled, phase 3 trial BREEZE-AD5, once-daily oral baricitinib 2-mg monotherapy improved disease in moderate-to-severe AD patients who had an inadequate response or intolerance to topical corticosteroids. This post-hoc analysis aimed to identify responders to baricitinib 2 mg, using a proposed clinical tailoring approach based on baseline body surface area (BSA) affected and early clinical improvement, in BREEZE-AD5. Methods: Classification and regression tree method was used to evaluate baseline predictors for the proportion of patients achieving ≥ 75% improvement in Eczema Area and Severity Index (EASI75) at week 16 among baricitinib 2-mg-treated patients. Two-by-two contingency tables evaluated the association between early response, defined as ≥ 50% improvement in BSA or ≥ 3-point improvement in Itch Numeric Rating Scale from baseline at weeks 4 or 8, and response at week 16 for the proportion of patients achieving EASI75, validated Investigator Global Assessment for AD (vIGA-AD) score of 0 or 1, or ≥ 4-point improvement in Itch (Itch ≥ 4), respectively. Missing data were imputed as non-responder. Results: At week 16, EASI75 and vIGA-AD (0,1) were achieved by 37.5% and 31.7% of baricitinib 2-mg-treated patients with baseline BSA 10–50% compared with 9.5% and 4.8% with BSA > 50%. Early response in skin inflammation or itch at week 4 was associated with corresponding EASI75, vIGA-AD (0,1), and Itch ≥ 4 of 55.4%, 48.2%, and 39.3% at week 16, while early response at week 8 was associated with 66.7%, 56.1%, and 42.1% of patients achieving these endpoints. Conclusion: Baseline BSA of 10–50% and early clinical improvement after 4 or 8 weeks of baricitinib 2-mg treatment may identify patients most likely to benefit from long-term baricitinib 2-mg therapy. Clinical Trial Registration: NCT03435081. Plain Language Summary: Baricitinib is a medication that helps a dysregulated immune system readjust. This leads to improvements in the inflammatory disease atopic dermatitis (AD). Baricitinib is approved for adults with moderate-to-severe AD in over 40 countries. In the ongoing study BREEZE-AD5, baricitinib 2 mg improved moderate-to-severe AD in patients who previously did not respond to or could not tolerate topical corticosteroids. Understanding which patients are likely to benefit most from a medication can improve patient experience with treatment. It can also ensure that only patients who are likely to benefit from a medication are exposed to it. This analysis aimed to identify patients who are most likely to benefit from baricitinib 2 mg in BREEZE-AD5, using an approach based on baseline body surface area (BSA) affected and early clinical improvement. We showed that patients with moderate-to-severe AD affecting between 10% and 50% of their BSA account for the majority of patients who respond to baricitinib 2 mg after 16 weeks of treatment. Clinical assessment of skin inflammation or itch in patients after 4–8 weeks of initiation of baricitinib 2-mg treatment further improved the ability to identify patients who are most likely to benefit from long-term therapy. This proposed clinical tailoring approach of baseline BSA of 10–50% and early clinical improvement after 4 or 8 weeks of baricitinib 2-mg treatment may allow for the treatment of patients who are most likely to respond to therapy, and rapid decision on discontinuation of treatment for those who are not likely to benefit from baricitinib 2 mg. [ABSTRACT FROM AUTHOR]

Introduction/Background Type 2 inflammatory cytokines interleukin 4 (IL-4) and IL-13 play an important role in skin barrier disruption in atopic dermatitis (AD). Filaggrin and ceramides play a crucial role in skin barrier integrity. Loss of function mutations in the FLG gene are associated with the impaired skin barrier function and more severe AD.1,2 FLG mutations only affect a minority of AD patients; however, increased IL-4 and IL-13 cytokines are a common cause of reduced filaggrin expression in patients with AD, independent of FLG genotype. Objectives: To explore whether dupilumab treatment improves skin barrier function in patients with or without FLG mutations. Methods: In the BArrier function and LIpidomics STudy in Atopic Dermatitis (BALISTAD; NCT04447417), a 16-week study in patients with AD aged 12 to 65 years, adult patients with AD received dupilumab 300 mg every 2 weeks; adolescent patients with AD received dupilumab 200 mg every 2 weeks if their baseline weight was <60 kg and 300 mg if =60 kg. FLG mutations were evaluated in DNA from blood samples of consenting patients with AD and healthy volunteers. Transepidermal water loss (TEWL) was assessed longitudinally after 5 skin tape strippings (STS) from AD lesions (n = 26) and from the skin of healthy participants (n =26) (age: 12 to 63 years) over a 16-week course of dupilumab treatment. Quantitative N(C18) S-ceramide analysis of STS samples collected on Days 1, 15, 29, 57, and 85, and at Week 16 from AD lesions and from the skin of healthy participants was performed using liquid chromatography tandem mass spectrometry. Results: At baseline, mean TEWL after 5 STS (TEWL5) was significantly higher in AD lesional skin than healthy skin (p<0.0001). The mean TEWL5 in AD lesions in subjects with FLG mutations (n = 6/19) was significantly higher at baseline than in AD subjects without mutations (P < 0.0001). Dupilumab treatment significantly reduced TEWL5 in AD lesional skin as early as Week 2 with a progressive decrease through Week 16 (P < 0.0001). Reduction in mean TEWL5 was similar from Week 2 to Week 16 in AD patients with and without FLG mutations. At Week 16, TEWL5 was comparable to healthy skin in the lesional skin of AD patients with and without FLG mutations (P > 0.05). AD skin lesions had increased levels of N(C18)S-ceramides at baseline (P < 0.0001); but no differences were noted in subjects with or without FLG mutations (P > 0.05). Dupilumab treatment significantly reduced levels of N(C18)S-ceramides in AD lesional skin as early as Week 2 with a progressive decrease through Week 16 (P < 0.0001). Dupilumab treatment decreased levels of N(C18)S-ceramides in STS samples similarly in subjects with and without FLG mutations from Week 2 to Week 16. Conclusions: Dupilumab treatment normalizes TEWL5 and decreases levels of N(C18)S-ceramides in AD lesional skin of subjects with and without FLG mutations. [ABSTRACT FROM AUTHOR]

Introduction/Background As symptoms of atopic dermatitis (AD) can wax and wane over time, disease control is better represented by consistency of response over a long treatment duration rather than at a single time point. Objective To evaluate the proportion of pediatric patients achieving and maintaining mild or no itch (defined by a SCORing Atopic Dermatitis (SCORAD) itch visual analog scale (VAS; 0-10 over last 3 days) score of lower than 4) across 5 visits during a 52-week open label extension trial of dupilumab. Methods: Patients who previously participated in 16-week trials and were aged 0.5-5 years (LIBERTY AD PRESCHOOL; NCT03346434), 6-11 years (LIBERTY AD PEDs; NCT03345914), and 12-17 years (LIBERTY AD ADOL; NCT03054428), were subsequently enrolled in the phase 3, open-label extension trial, LIBERTY AD PED-OLE (NCT02612454). Patients were treated with 300 mg q4w or 200/300 mg q2w (body weight <60 or ≥60 kg, respectively). In this analysis, patients with a SCORAD itch VAS score of greater than 4 at OLE baseline, were assessed for the maintenance of SCORAD itch VAS lower than 4, at 5 timepoints: Weeks 4, 16, 28, 40, and 52. Results: In 763 patients, 400 patients with a SCORAD itch VAS score of greater than 4 were assessed. Mild or no itch was achieved in at least 4 of 5 timepoints in most patients aged 0.5-5 years (55/110; 50%), 6-11 years (76/148; 51%), and 12-17 years (73/142; 51%). Across these age groups, over 65% maintained this response for at least 3 of 5 timepoints. Safety was consistent with the known dupilumab safety profile in patients with atopic dermatitis. Conclusions: Most pediatric patients achieved improvement in itch, maintained during 1 year of treatment with dupilumab. Results were consistent for infants/preschoolers, children, and adolescents. [ABSTRACT FROM AUTHOR]

Introduction/Background Atopic dermatitis (AD) is an inflammatory skin disease associated with atopic comorbidities, including asthma, food allergy, hay fever, and allergic conjunctivitis. Tralokinumab, a high-affinity monoclonal antibody that specifically targets IL-13, is indicated for the treatment of moderate-to-severe AD. Objectives: To assess the impact of atopic comorbidities on the efficacy and safety of tralokinumab vs. placebo for moderateto-severe AD in patients age ≥12 years. Methods: This post-hoc analysis presents data from the adult trials ECZTRA 1 and 2 (NCT03131648 and NCT03160885 pooled; 300 mg tralokinumab every 2 weeks [Q2W] vs. placebo) and ECZTRA 3 (NCT03363854; 300 mg tralokinumab Q2W vs. placebo, both plus TCS as needed), and the ECZTRA 6 adolescent trial (NCT03526861; pooled 150 mg and 300 mg tralokinumab Q2W vs. placebo). Tralokinumab-treated patients received a loading dose. Proportion of patients achieving IGA 0/1 and EASI-75 at Week 16 according to patient-reported current or past atopic comorbidity are presented as observed regardless of rescue medication use; missing data were imputed as non-responders. Results: In total 2,223 patients were included across four trials. Among patients in ECZTRA 1 and 2, 50.5% reported history of asthma, 38.5% food allergy, 53.8% hay fever, and 33.5% allergic conjunctivitis, while 19.8% reported no atopic comorbidities and 79.3% reported ≥1 atopic comorbidity. Proportions of patients in ECZTRA 3 and 6 reporting history of atopic comorbidities were largely similar, although more adolescent patients reported food allergy. In all subgroups at Week 16, higher proportions of patients receiving tralokinumab vs. placebo achieved EASI-75. In ECZTRA 1 and 2, response rates among patients in each subgroup were asthma: 35.3% vs. 12.8%, food allergy: 33.2% vs. 14.7%, hay fever: 36.8% vs. 16.5%, allergic conjunctivitis: 34.8% vs. 12.7%, none: 34.6% vs. 20.5%; and ≥1 atopic comorbidity: 35.5% vs. 15.2% (P<0.05 for all). A similar pattern of response was observed in ECZTRA 3 and 6, and for IGA 0/1 across trials. EASI-75 response rates for tralokinumab-treated patients were consistent across patients with different numbers of atopic comorbidities. Safety across subgroups was consistent with the safety profile of tralokinumab observed overall in adults and adolescents. Conclusions: 16 weeks of tralokinumab treatment improved AD signs and symptoms in adult and adolescent patients with and without atopic comorbidities, regardless of type or number of atopic comorbidities. The safety profile of tralokinumab was consistent between patients with and without atopic comorbidities. [ABSTRACT FROM AUTHOR]

Introduction/Background Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by intense itch and eczematous skin lesions, impacting individuals at any age. There is a need for AD treatments that provide rapid itch relief and skin clearance that are safe for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor approved in multiple countries for the treatment of moderate-to-severe AD in adults and adolescents. Objectives: We evaluated the long-term safety for up to 5 years of upadacitinib 15 mg and 30 mg use in adolescents and adults with moderate-to-severe AD, based on the results of integrated data from three ongoing global pivotal Phase 3 studies. Materials & Methods: The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal Phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1:1:1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily alone (Measure Up 1 and 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 mg or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1:1 to receive either upadacitinib 15 mg or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). Results: A total of 2683 patients (2154 adults, 529 adolescents) who received at least 1 dose of upadacitinib (15 mg, 1337; 30 mg, 1346) were included in the integrated analysis. Treatmentemergent adverse events of special interest (AESI) were analyzed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Rates of AESIs were similar at the 1-year analysis and up to 5-year analysis for upadacitinib for: serious infections, 15 mg, 2.3 (1 yr) and 2.2 (5 yrs)/30 mg, 2.8 (1 yr) and 2.6 (5 yrs); opportunistic infections, 15 mg, 1.6 (1 yr) and 1.7 (5 yrs)/30 mg, 1.9 (1 yr) and 2.2 (5 yrs); active tuberculosis, <0.1 at both timepoints for both doses; herpes zoster, 15 mg, 3.5 (1 yr) and 3.1 (5 yrs)/30 mg, 5.2 (1 yr) and 5.5 (5 yrs); non-melanoma skin cancer (NMSC), 15 mg, 0.3 (1 yr) and 0.4 (5 yrs)/30 mg, 0.4 (1 yr) and 0.3 (5 yrs); malignancy excluding NMSC, 15 mg, 0.1 (1 yr) and 0.3 (5 yrs)/30 mg, 0.5 (1 yr) and 0.4 (5 yrs); gastrointestinal perforations, 15 mg, 0 at both time points/30 mg, 0 (1 yr) and <0.1 (5 yrs); adjudicated major adverse cardiovascular events (MACE), 15 mg, 0.1 (1 yr) and 0.2 (5 yrs)/30 mg, <0.1 at both timepoints; adjudicated venous thromboembolic events (VTE), <0.1 for both doses at 1 year and 0.1 for both doses at 5 years. Rates of adverse events leading to death were: 15 mg, 0 (1 yr) and <0.1 (5 yrs)/30 mg, <0.1 at both timepoints. Rates of serious infection at both timepoints and doses remained low (<3.0 E/100PYs). Upadacitinib was well-tolerated by both adults and adolescents. Conclusions: The integrated analysis of long-term safety data for up to 5 years indicates that rates of AESIs remained low throughout treatment with upadacitinib 15 mg or 30 mg among adults and adolescents with moderate-to-severe AD. There were no new safety risks. The current safety analysis continues to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 5 years of treatment, including over 7000 years of patient exposure. [ABSTRACT FROM AUTHOR]

Introduction Roflumilast cream 0.15% is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a non-steroidal, once-daily treatment for atopic dermatitis (AD). Objectives: Here, pooled results from two identical Phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587 and INTEGUMENT-2: NCT04773600) are presented. Methods: Patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of Mild or Moderate were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) once daily for 4 weeks. Results: A significantly greater percentage of roflumilast-versus vehicle-treated patients achieved the primary endpoint, vIGA-AD Success (Clear or Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4 (31.3% vs. 14.1%; P<0.0001). Significant differences favoring roflumilast were observed for multiple secondary endpoints at Week 4: percentage of patients achieving vIGA-AD of Clear or Almost Clear (41.1% vs. 21.4%; P<0.0001), percentage achieving 75% reduction in EASI (42.7% vs. 20.6%; P<0.0001), and percentage with baseline Worst Itch-Numeric Rating Scale ≥4 achieving a 4-point reduction (31.9% vs. 16.6%; P<0.0001). Improvement in itch was reported as early as 24 hours. Both groups had low incidences of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation. Local tolerability was favorable, with >90% of patients reporting no or mild sensation across both treatment groups at all timepoints. Conclusions: Once-daily roflumilast cream 0.15% provided improvement across multiple efficacy endpoints by Week 4 with favorable safety and tolerability in patients aged ≥6 years with AD in two Phase 3 trials. [ABSTRACT FROM AUTHOR]

Optimal management of atopic dermatitis requires a comprehensive assessment of response to treatment in order to inform therapeutic decisions. In a realworld setting, successful response to atopic dermatitis treatment is measured by sustained improvements in signs, symptoms, and quality of life. Post-hoc analyses of a 1-year, randomized, double-blinded, placebocontrolled trial (NCT02260986) of dupilumab with concomitant topical corticosteroids in 421 adults with moderate-to-severe atopic dermatitis (of whom 315/106 received placebo/dupilumab (of whom 315 received placebo and 106 received dupilumab) was performed to assess the proportion of responders to dupilumab through a multidimensional composite endpoint. At 6-months, 80.2% of dupilumab-treated vs 40.0% placebo patients (p < 0.0001) achieved improvement in signs (Eczema Area and Severity Index ≤ 7), symptoms (worst itch score ≤ 4), or quality of life (Dermatology Life Quality Index ≤5), representative of minimal/clear atopic dermatitis. All 3 endpoints, indicative of no/minimal atopic dermatitis, were achieved by 44.3% of dupilumab-treated vs 10.2% placebo patients (p < 0.0001) and sustained through 1 year. Dupilumab treatment provided sustained clinically meaningful improvement in signs, symptoms, and quality of life in adults with moderate-to-severe atopic dermatitis. [ABSTRACT FROM AUTHOR]

Background: Laboratory testing is typically required for patients with atopic dermatitis (AD) treated with systemic immunosuppressants. A previous analysis of laboratory outcomes in randomized, double-blinded, placebo-controlled clinical trials of dupilumab in adults with moderate-to-severe AD found no clinically important changes in hematologic, serum chemistry, and urinalysis parameters, supporting the use of dupilumab without routine laboratory monitoring. Objective: The aim was to assess laboratory results in adolescents with moderate-to-severe AD treated with dupilumab in a phase 3, randomized, double-blind, placebo-controlled trial. Methods: Adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD were randomized 1:1:1 to subcutaneous dupilumab 200/300 mg every 2 weeks (q2w) (200 mg for patients < 60 kg at baseline; 300 mg for patients ≥ 60 kg at baseline); dupilumab 300 mg every 4 weeks (q4w); or placebo for 16 weeks. Laboratory evaluations included hematology, serum chemistry, and urinalysis parameters. Results: Of 251 patients enrolled in the study, 250 received treatment and were included in the analysis. 4.7%, 2.4%, and 4.8% of patients receiving placebo, dupilumab 200/300 mg q2w, and dupilumab 300 mg q4w, respectively, had laboratory abnormalities reported as treatment-emergent adverse events, none of which prompted discontinuation of study treatment or study withdrawal. Mean eosinophil counts were elevated at baseline in all treatment groups. Patients in both dupilumab regimens, but not the placebo group, showed mild transient increases in mean eosinophil counts above baseline that returned to near-baseline values by week 16. Mean levels of lactate dehydrogenase trended towards the upper limit of normal at baseline and decreased with treatment; greater decreases were seen in dupilumab-treated patients than placebo-treated patients. There were no meaningful changes in other laboratory parameters, and none of the laboratory abnormalities were clinically significant. Conclusion: No clinically meaningful changes in laboratory parameters were seen in adolescents, similar to that observed in adults. The findings of this study indicate no routine laboratory monitoring is required in this population prior to or during dupilumab treatment. Trial Registration: ClinicalTrials.gov: NCT03054428. 6vz_jLtTkCJ6tzGx5HdiGv Video abstract: Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized Placebo-Controlled Phase 3 Clinical Trial (MP4 175137 KB) [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis is a chronic inflammatory condition with substantial burden and limited treatment options for adolescents with moderate-to-severe disease. Significantly more patients treated with dupilumab vs. placebo achieved Investigator's Global Assessment 0/1 at week 16. Objective: The objective of this study was to assess the impact of dupilumab treatment vs. placebo on the achievement of clinically meaningful improvements in atopic dermatitis signs, symptoms and quality of life. Methods: R668-AD-1526 LIBERTY AD ADOL was a randomized, double-blinded, parallel-group, phase III clinical trial. Two hundred and fifty-one adolescents with moderate-to-severe atopic dermatitis received dupilumab 300 mg every 4 weeks (q4w; n = 84), dupilumab 200 or 300 mg every 2 weeks (q2w; n = 82), or placebo (n = 85). A post-hoc subgroup analysis was performed on 214 patients with Investigator's Global Assessment > 1 at week 16. Measures of atopic dermatitis signs, symptoms, and quality of life were assessed. Clinically meaningful improvement in one or more of three domains of signs, symptoms, and quality of life was defined as an improvement of ≥ 50% in Eczema Area and Severity Index, ≥ 3 points in Peak Pruritus Numerical Rating Scale, or ≥ 6 points in the Children's Dermatology Life Quality Index from baseline. Results: Of patients receiving dupilumab q2w, 80.5% [66/82] experienced clinically meaningful improvements in atopic dermatitis signs, symptoms, or quality of life at week 16 (vs. placebo, 20/85 [23.5%], difference 57.0% [95% confidence interval 44.5–69.4]; q4w vs. placebo, 53/84 [63.1%], difference 39.6% [95% confidence interval 25.9–53.3]; both p < 0.0001). Results were similar in adolescents with Investigator's Global Assessment > 1 at week 16 (q2w, 46/62 [74.2%] vs. placebo, 18/83 [21.7%], difference 52.5% [95% confidence interval 38.5–66.6]; q4w, 38/69 [55.1%] vs. placebo, difference 33.4% [95% confidence interval 18.7–48.1]; both p < 0.0001). Conclusions: Dupilumab provided clinically meaningful improvements in signs, symptoms, and quality of life in adolescents with moderate-to-severe atopic dermatitis among patients with Investigator's Global Assessment > 1 at week 16. Treatment responses should be interpreted in the context of such clinically relevant patient-reported outcome measures. Trial Registration: ClinicalTrials.gov; NCT03054428. Adolescents with atopic dermatitis: does dupilumab improve their signs, symptoms, and quality of life? (MP4 212916 kb) [ABSTRACT FROM AUTHOR]

Systemic treatments often require laboratory monitoring. Here we report 52-week laboratory safety data for dupilumab-treated children aged 6 months to 5 years with moderate-to-severe AD. LIBERTY AD PED-OLE (NCT02612454) is an open-label extension study of children aged 6 months to <18 years with moderate-to-severe AD. This analysis includes hematologic and chemistry laboratory parameters in children aged 6 months to 5 years treated with dupilumab every 4 weeks (q4w; 200 mg: ≥5 to <15 kg; 300 mg: ≥15 to <30 kg). Of the 180 patients enrolled, 122 (67.8%) completed up to 16 weeks and 30 (16.7%) completed up to 52 weeks. Mean (SD) eosinophil counts increased slightly from baseline [1.15 × 109/L (1.18) ] to Week 16 [1.5 × 109/L (1.91)], but then decreased below baseline by Week 52 [0.80 × 109/L (0.64)]. Mean (SD) platelet counts were relatively stable with a modest decrease from baseline [388.7 × 109/L (102.51)] to Week 52 [356.1 × 109/L (107.48)]. Chemistry parameters remained within the normal reference ranges. One patient (0.6%) reported a mild case of anemia, and one patient (0.6%) reported a mild case of thrombocytopenia, which were resolving and resolved at the time of this interim analysis, respectively. Overall safety was consistent with the known dupilumab safety profile. No clinically meaningful changes in hematologic and chemistry parameters were observed during 52 weeks of dupilumab treatment. As with adults, adolescents and older children, routine laboratory monitoring is unnecessary in children aged 6 months to 5 years with moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long‐term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD. [ABSTRACT FROM AUTHOR]

Introduction: The impact of crisaborole ointment, a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD), on quality of life (QoL) was assessed in two identically designed phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792, both at http://www.clinicaltrials.gov).Methods: In both studies, patients aged ≥ 2 years with mild to moderate AD per the Investigator’s Static Global Assessment were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. QoL was assessed using the Children’s Dermatology Life Quality Index (CDLQI) (2-15 years), the Dermatology Life Quality Index (DLQI) (≥ 16 years), and the Dermatitis Family Impact Questionnaire (DFI) (parents/caregivers/family of patients aged 2-17 years). Established QoL score severity bands provided clinical context.Results: Greater mean improvement in QoL was observed in crisaborole-treated patients than in vehicle-treated patients at day 29 [mean change from baseline (∆BL), CDLQI: − 4.6 vs. − 3.0; P < 0.001; DLQI: − 5.2 vs. − 3.5; P = 0.015]. At baseline, more than half the patients had a “moderate effect” or higher of AD on QoL. At day 29, there was a trend toward more crisaborole- than vehicle-treated patients having “small effect” to “no effect”, The QoL of parents/caregivers/family improved more for crisaborole-treated than for vehicle-treated patients (∆BL, DFI: − 3.7 vs. − 2.7; P = 0.003).Conclusion: Crisaborole treatment results in clinically meaningful improvement in QoL for patients and their parents/caregivers/families.Trial Registration: AD-301: http://www.clinicaltrials.gov, NCT02118766; AD-302: http://www.clinicaltrials.gov, NCT02118792.Funding: Anacor Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc., New York, NY. [ABSTRACT FROM AUTHOR]

The consequences of atopic dermatitis reach beyond the skin and past childhood. Patients with atopic dermatitis are at risk of developing allergic comorbidities, but less is known about the associations between atopic dermatitis and non-allergic conditions. Understanding these non-allergic comorbidities has the potential to improve patient outcomes and to help mitigate the cost and burdens associated with these conditions. Atopic dermatitis is associated with cutaneous bacterial infections, more severe forms/courses of cutaneous viral infections, and extra-cutaneous infections. Atopic dermatitis is also associated with several mental health comorbidities particularly attention-deficit hyperactivity disorder, anxiety, and depression. Data are largely inconsistent for specific cancers, but atopic dermatitis appears to protect against malignancy overall; severe long-term atopic dermatitis is associated with adult lymphomas. Atopic dermatitis may also be associated with obesity, cardiovascular disease, and autoimmune disease, particularly alopecia areata and gastrointestinal immune-mediated disorders. Although the causative mechanisms underlying these associations are poorly understood, treating physicians should be aware of associations in seeking to alleviate the burden for patients with atopic dermatitis. [ABSTRACT FROM AUTHOR]

Abstract: Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices). [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a type 2 inflammatory disease characterized by elevations in several biomarkers including serum IgE—a key downstream mediator in the type 2 adaptive immune response. Patients with moderate-to-severe AD were enrolled for 16 weeks in any of six randomized, placebo-controlled, phase 3 studies: in LIBERTY AD PRESCHOOL, (NCT03346434 part B) patients aged 6 months to 5 years were treated with dupilumab 200/300 mg every 4 weeks (q4w) + topical corticosteroids (TCS; n = 83) or placebo + TCS (n = 79); in LIBERTY AD PEDS (NCT03345914), patients aged 6–11 years were treated with dupilumab + TCS [100/200 mg q2w (n = 122), 300 mg q4w (n = 122)] or placebo + TCS (n = 123); in LIBERTY AD ADOL (NCT03054428), patients aged 12–17 years were treated with dupilumab [200/300 mg q2w (n = 82), 300 mg q4w (n = 83)] or placebo (n = 85); and in LIBERTY AD CHRONOS/SOLO1/SOLO2 (NCT02260986/NCT02277743/NCT02277769, pooled), patients aged ≥18 years were treated with dupilumab [300 mg q2w (n = 563),300 mg qw (n = 781) ] or placebo (n = 775). The TCS were allowed in CHRONOS only. At Week 16, dupilumab treatment significantly (P < 0.0001) reduced median total serum IgE levels [kU/L (IQR)] compared with placebo in patients aged 6 months to 5 years [843 (207–3300) vs. 3625 (540.5–8585)], 6–11 years [1519 (532–3808) vs. 3862 (1166–9999)], 12–17 years [1391 (436–2842) vs. 4569 (800.5–10000)] and ≥18 years [1340 (229–4360) vs. 3722 (555–10000)]. Dupilumab treatment reduced total serum IgE levels in patients aged 6 months and older with moderate-to-severe AD. Overall safety was consistent with the known dupilumab safety profile. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis ( AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety. Methods This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected. Results Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years ( N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar. Conclusions This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD) may complicate the clinical course of atopic dermatitis (AD), and patch testing remains the criterion standard for diagnosing ACD. To date, there have been no guidelines or consensus recommendations on when and how to patch test individuals with AD. Failure to patch test when appropriate may result in overlooking an important and potentially curable complicating comorbidity. In this article, we present consensus recommendations regarding when to perform patch testing in the AD patient, best practices, and common pitfalls. Patch testing should be considered in AD patients with dermatitis that fails to improve with topical therapy; with atypical/changing distribution of dermatitis, or pattern suggestive of ACD; with therapy-resistant hand eczema in the working population; with adult- or adolescent-onset AD; and/or before initiating systemic immunosuppressants for the treatment of dermatitis. A suggested patch testing algorithm for AD patients is provided. [ABSTRACT FROM AUTHOR]

Atopic dermatitis ( AD) is a distressing dermatological disease, which is highly prevalent during infancy, can persist into later life and requires long-term management with anti-inflammatory compounds. The introduction of the topical calcineurin inhibitors ( TCIs), tacrolimus and pimecrolimus, more than 10 yr ago was a major breakthrough for the topical anti-inflammatory treatment of AD. Pimecrolimus 1% is approved for second-line use in children (≥2 yr old) and adults with mild-to-moderate AD. The age restriction was emphasized in a boxed warning added by the FDA in January 2006, which also highlights the lack of long-term safety data and the theoretical risk of skin malignancy and lymphoma. Since then, pimecrolimus has been extensively investigated in short- and long-term studies including over 4000 infants (<2 yr old). These studies showed that pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use. Unlike topical corticosteroids, long-term TCI use does not carry the risks of skin atrophy, impaired epidermal barrier function or enhanced percutaneous absorption, and so is suitable for AD treatment especially in sensitive skin areas. Most importantly, the studies of pimecrolimus in infants provided no evidence for systemic immunosuppression, and a comprehensive body of evidence from clinical studies, post-marketing surveillance and epidemiological investigations does not support potential safety concerns. In conclusion, the authors consider that the labelling restrictions regarding the use of pimecrolimus in infants are no longer justified and recommend that the validity of the boxed warning for TCIs should be reconsidered. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an important chronic or relapsing inflammatory skin disease that often precedes asthma and allergic disorders. New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies. Patients with AD have a unique predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. Measures directed at healing and protecting the skin barrier and addressing the immune dysregulation are essential in the treatment of patients with AD, and early intervention may improve outcomes for both the skin disease as well as other target organs. [ABSTRACT FROM AUTHOR]

Background: MAS063DP (Atopiclair™) is a topical cream approved for symptomatic relief in the treatment of atopic and contact dermatitis. Methods: This was a multicenter, randomized, double-blind, vehicle-controlled study in adults with mild-moderate atopic dermatitis. Patients were given MAS063DP or vehicle (2:1) three times per day to areas affected by atopic dermatitis for up to 50 days. A patient global assessment change from baseline was determined at days 8, 22, 36, and 50. Patient total body pruritus (visual analog scale) and patient opinion on treatment acceptability were also assessed. Results: A total of 218 patients (active: n = 145, vehicle: n = 73) were enrolled. At Day 22, 77% of patients on MAS063DP had a patient global assessment of good improvement or better versus 21% on vehicle (p<0.0001, chi-squared test). Similarly, more patients had improvement in itch over their total body on MAS063DP than on vehicle (p<0.0001). Conclusion: MAS063DP treatment results in patient-perceived improvements in mild-moderate atopic dermatitis. [ABSTRACT FROM AUTHOR]

Successful strategies for managing atopic dermatitis require an accurate diagnosis, identification and elimination of exacerbating factors including irritants and allergens, adequate hydration of the skin, control of pruritus and infections, and appropriate use of topical antiinflammatory and other medications. Proper patient education increases the chances of successful therapy. [ABSTRACT FROM AUTHOR]

Atopic eczema (AE) is a chronic inflammatory skin disease characterized by pruritus, dry skin and an ongoing course of exacerbations and remissions. AE is a common disorder in children with a worldwide cumulative prevalence of 15–20% in this age group. AE has a strong familial predisposition. While AE is a complex disease with multiple gene involvement, recent interest has focused on genes involved in skin barrier/epidermal differentiation and in immune response/host defense. Recent developments and future directions on pathogenesis, diagnosis, natural course and prognosis are discussed. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a chronic, inflammatory condition affecting up to 20% of children. Here, we report the long-term extension study of previously published pivotal phase III studies with pimecrolimus cream 1%. Two identical, 26-week studies (6-week, double-blind, followed by 20-week, open-label phases) were conducted in children aged 2 to 17 years with atopic dermatitis. Pooled efficacy and safety analyses were performed. At day 43, 34.8% pimecrolimus-treated patients versus 18.4% in the vehicle group (p < 0.001) were clear/almost clear (Investigators’ Global Assessment 0/1) of disease, with significant differences (p < 0.05) between treatment groups for all double-blind visits in all parameters. Pimecrolimus was significantly more effective (based on the Eczema Area and Severity Index) in treating the face and neck versus the rest of the body (p < 0.0001) and versus vehicle (p < 0.0001) in the double-blind phase. Disease control was sustained in the pimecrolimus group throughout the whole study. Patients treated with vehicle during the double-blind phase experienced rapid, marked improvement when switched to pimecrolimus in the open-label phase. The incidence of adverse events was low and comparable between treatment groups. In conclusion, pimecrolimus cream 1% is effective and well tolerated in the long-term control of children with mild to moderately severe atopic dermatitis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a common, chronic, relapsing inflammatory skin disease frequently affecting infants and children. The worldwide prevalence of atopic dermatitis is estimated to be 5–20% of the paediatric population. First-line therapy has generally consisted of dry skin care, avoidance of triggers, application of topical corticosteroids, and administration of antihistamines and oral antibacterials. Topical corticosteroids improve the lesions of atopic dermatitis; however, concern on the part of physicians and patients regarding adverse effects has led to reluctance to utilise topical corticosteroids early and especially for prolonged periods. Topical immunomodulators (TIMs), including tacrolimus ointment and pimecrolimus cream, were recently introduced for the treatment of atopic dermatitis. Clinical data show that TIMs are effective in atopic dermatitis, yet do not cause the significant adverse effects associated with topical corticosteroids. Questions remain regarding the place of TIMs as a treatment for atopic dermatitis and how to use them most effectively, from both therapeutic and pharmacoeconomic standpoints. Specifically, two major issues remain unresolved: (i) how TIMs measure up to other therapies, especially topical corticosteroids; and (ii) how members of the TIM drug class compare against each other. Previous research has established that atopic dermatitis has a significant impact on quality of life (QOL) and carries a substantial economic burden. Some studies have also measured the utility of various atopic dermatitis disease states. While there is a need for further research, early economic studies provide evidence that TIMs positively affect the QOL of patients and families. In certain patients, TIMs may be cost effective and have an acceptable incremental cost utility compared with topical corticosteroids. Making cost-effectiveness comparisons between tacrolimus and pimecrolimus is challenging because there are limited head-to-head comparative data. Given currently available efficacy data, the results of one study suggest that tacrolimus may be more cost effective than pimecrolimus in paediatric patients with moderate atopic dermatitis. The full economic and QOL benefits of both agents are yet to be completely understood. The studies reviewed herein are the first to delineate the pharmacoeconomic benefits of TIMs in atopic dermatitis, and lay the foundation for future analyses. TIMs represent an exciting advance in the treatment of atopic dermatitis. Additional research will help determine the proper place of TIMs among the current array of therapeutic options for atopic dermatitis. [ABSTRACT FROM AUTHOR]

Discusses several treatment options and therapeutic approaches for atopic dermatitis. Classification of topical non-steroidal immunomodulators; Results of clinical trials on the efficacy of steroid medications; Possible therapeutic benefits of the pimecrolimus corticosteroid drug.

Background: The use of expert opinion is widespread in economic studies of healthcare utilisation; however, few studies have attempted to assess the validity of assumptions derived from such sources. Objective: To examine the use of such expert opinion in determining comorbidities associated with atopic dermatitis/eczema (AD/E), which were assessed as part of a recent third-party payer cost-of-illness study. Design: To identify the disease-related comorbidities that would represent costs associated with AD/E, physicians on an expert panel were asked individually and then collectively to group all International Classification of Diseases, 9[sup th] Edition–Clinical Modification (ICD-9-CM) diagnosis codes as ‘most likely’, ‘possibly’ or ‘definitely not’ related to the costs of identifying and treating patients with AD/E. Claims representing $US464 million in payer reimbursements from nearly 125 000 patients with AD/E were identified within two separate claims databases (1997 values). Over 850 ICD-9-CM diagnosis codes were identified in the first-listed position from these claims. For each group of ‘most likely’, ‘possibly’ and ‘definitely not’ related diagnosis codes, prevalence rates were compared within AD/E and non-AD/E populations from the two historical payer claims databases. Adjusted and non-adjusted odds ratios were calculated by comparing prevalence rates between AD/E and non-AD/E patients in the same payer population. Results: The mean prevalence rate of any diagnosis code in the AD/E population was 0.65 ± 1.82% (SD) with a mean odds ratio of 1.81 ± 0.96. Comorbidities considered by the expert panel ‘most likely’ to be associated with AD/E had higher prevalence rates (3.28 ± 3.63%) and odds ratios (2.14 ± 1.14). Comorbidities considered to be ‘possibly’ related to AD/E had prevalence rates and odds ratios of 3.01 ± 5.06% and 1.84 ± 0.82, respectively. Comorbidities considered to be ‘definitely not’ related to AD/E had the lowest prevalence rates (0.45 ± 1.09%) and odds ratios (1.80 ± 0.97). Conclusions: Comparing the result of consensus panels with actual claims histories validated the use of expert opinion in determining comorbidities associated with AD/E. Expert opinion yielded valid results in terms of identifying comorbidities that manifested frequently and disproportionately in the AD/E population. Limited statistical measurements of comorbidities would have been less specific than expert opinion. Future cost-of-illness studies should consider alternative data sources and methodologies to enhance the validity and importance of expert opinion and to corroborate their findings. [ABSTRACT FROM AUTHOR]

Previous studies have shown that both nucleosides and oligonucleotides linked to isologous gammaglobulin suppress anti-nucleic acid antibody production both in vivo and in vitro. The aim of this study was to determine whether one can make a DNA-human gammaglobulin (HGG) conjugate which can inhibit anti-double stranded DNA (dsDNA) antibodies obtained from a heterogeneous population of systemic lupus eruthematosus (SLE) sera. To do so, we constructed conjugates of sonicated dsDNA fragments of 100-400 base pairs covalently linked to HGG with varying degrees of substitution of DNA:HGG. An ELISA inhibition assay was used to determine which conjugate best inhibits the binding of anti-dsDNA antibodies. Conjugate 2, prepared with monomeric HGG (150 kD) with a high degree of substitution (3.72 DNA:HGG) inhibited the binding of anti-dsDNA antibodies from 27 of 31 SLE sera. In addition, this conjugate inhibited the spontaneous formation of anti-dsDNA in vitro by cultured lymphoid cells from selected SLE patients. Together, this data suggests that a 'generic' tolerogen may provide an antigen specific therapy for SLE. [ABSTRACT FROM PUBLISHER]

Background: The Atopic Dermatitis Control Tool (ADCT©) is a brief patient self-administered instrument designed and validated to assess atopic dermatitis (AD) control; six AD symptoms and impacts are evaluated over the past week, including overall severity of symptoms, days with intense episodes of itching, intensity of bother, problem with sleep, impact on daily activities, and impact on mood or emotions. This study assessed the reliability, validity, and responsiveness of the ADCT in a longitudinal context, and provided thresholds to identify meaningful within-person change.Methods: Data were from a prospective, longitudinal patient survey study of real-world effectiveness of dupilumab in patients with AD. Eligible patients completed a baseline survey before starting dupilumab and were followed at Months 1, 2, 3, and 6 post-initiation as they became eligible.Results: Psychometric analyses confirmed internal consistency; Cronbach's α coefficients were consistently above the threshold of 0.70 across each follow-up; item-to-total correlations were above the threshold of r ≥ 0.50. High correlations between the ADCT and the Dermatology Life Quality Index (DLQI) and skin pain supported construct validity, while known-group validity was shown on Patient Global Assessment of Disease (PGAD) overall well-being subgroups with worse AD-related overall well-being having higher mean ADCT total scores at all time points. The ability of the ADCT to detect change was confirmed; the threshold for meaningful within-person change was estimated to be 5 points. Finally, test-retest reliability was confirmed in subgroups of patients with stable PGAD responses.Conclusions: Our findings confirm that the ADCT is a valid and reliable tool for assessing AD control. [ABSTRACT FROM AUTHOR]