Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress.

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease representing a major source of global disability burden. Disease-modifying therapies are showing promise in chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease with method and timing of initial treatment impacting long-term disease outcomes. Whether disease-modifying therapies, specifically those used as an early interventional approach, impacts disease course and comorbidity development in AD is not well-understood. We reviewed the progress in disease modification strategies, emphasizing early intervention approaches in common (or proto-typical) inflammatory diseases. Although more common in other fields, disease modification approaches are becoming increasingly investigated in dermatology, though studies in AD are lacking. Despite significant limitations in ongoing and completed studies, early data are promising and suggest that both the choice and timing of early intervention approach can affect long-term disease course and comorbidity development. To best improve AD patient outcomes, more research is needed to further explore the impact of early disease-modifying therapies. Future studies should focus on identifying the most effective approaches and extend the early results to a more inclusive set of comorbidities and longer-term outcomes.

Optimizing maintenance therapy in responders to abrocitinib induction: A post hoc analysis of JADE REGIMEN.

BACKGROUND: Treatment optimization may require dosing flexibility. The Phase 3 JADE REGIMEN trial (NCT03627767) evaluated maintenance of abrocitinib 200 mg-induced response in patients with moderate-to-severe atopic dermatitis (AD) randomly assigned to subsequent maintenance with continuous-dose abrocitinib (200 mg), reduced-dose abrocitinib (100 mg) or placebo. Maintenance with continuous-dose abrocitinib was associated with a stronger prevention of disease flares, but also with a higher occurrence of adverse events, compared with the reduced dose. OBJECTIVE: This post hoc analysis of JADE REGIMEN aimed to identify predictors of not flaring during the maintenance period and to generate tools that can be used to assess probability of not flaring. METHODS: Data were analysed from patients who responded to abrocitinib 200 mg induction therapy (12 weeks) and were randomly assigned to receive abrocitinib (200 mg or 100 mg) or placebo in the 40-week maintenance period. Demographic and baseline disease characteristics and level of response to induction were evaluated for association with not flaring using logistic regression. Parameters with a significant (p < 0.15) interaction with the treatment arm were fitted into a multivariable regression model, which was used to assess probability of not flaring. RESULTS: Lower percentage body surface area affected at baseline (p = 0.09), absence of prior exposure to systemic agents (p = 0.02) and greater percentage change in EASI from baseline to randomization (p < 0.001) were identified as predictors of not flaring with abrocitinib. In both abrocitinib arms, percentage change in EASI from baseline to end of induction (Week 12) was the major contributor to the probability of not flaring in the maintenance period. CONCLUSIONS: Maintenance of response using reduced-dose abrocitinib 100 mg may be feasible for patients with lower baseline disease severity and strong response to abrocitinib 200 mg induction treatment.

Effect of upadacitinib on atopic hand eczema in patients with moderate-to-severe atopic dermatitis: Results from two randomized phase 3 trials.

BACKGROUND: Approximately 60% of patients with atopic dermatitis have involvement of the hands adding to the burden of disease. OBJECTIVE: This analysis aims to evaluate the effect of upadacitinib monotherapy on atopic hand eczema in patients with moderate-to-severe AD over 16 weeks in the Measure Up 1 and 2 studies. METHODS: Data from patients (ages 12-75) randomized 1:1:1 to receive upadacitinib 15 mg, 30 mg, or placebo once daily in the Measure Up 1 and 2 studies were analysed for impact on atopic hand eczema assessed using the Hand Eczema Severity Index (HECSI). The percent change from baseline in HECSI score was a prespecified additional endpoint at all visits. The proportion of patients with at least a 75% improvement in HECSI score (HECSI 75) was evaluated post hoc. RESULTS: Patients treated with upadacitinib 15 mg or 30 mg experienced greater improvement in HECSI score compared with placebo as early as Week 1, which was maintained through Week 16. At Week 16, the mean change from baseline in HECSI score for patients receiving upadacitinib 15 mg, 30 mg, and placebo was -68%, -74%, and -15% in Measure Up 1 and -68%, -74% and +21% (positive change indicates worsening for placebo) in Measure Up 2, respectively. A greater proportion of upadacitinib-treated patients achieved HECSI 75 compared with placebo at all timepoints beginning at Week 1 through Week 16. CONCLUSIONS: Upadacitinib 15 mg and 30 mg monotherapy provided rapid and sustained improvement in atopic hand eczema compared with placebo through Week 16 in patients with moderate-to-severe AD. At Week 16, the observed mean improvements in HECSI score in upadacitinib-treated patients were clinically meaningful based on previous interpretability studies. These results suggest that upadacitinib may be an effective treatment option for atopic hand eczema in patients with moderate-to-severe AD.

Upadacitinib for moderate-to-severe atopic dermatitis: Stratified analysis from three randomized phase 3 trials by key baseline characteristics.

BACKGROUND: Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease with different clinical phenotypes based on factors such as age, race, comorbidities, and clinical signs and symptoms. The effect of these factors on therapeutic responses in AD has only been scarcely studied and not for upadacitinib. Currently, there is no biomarker predicting response to upadacitinib. OBJECTIVES: Evaluate the efficacy of the oral Janus kinase inhibitor upadacitinib across patient subgroups (baseline demographics, disease characteristics and prior treatment) in patients with moderate-to-severe AD. METHODS: Data from phase 3 studies (Measure Up 1, Measure Up 2 and AD Up) were utilized for this post hoc analysis. Adults and adolescents with moderate-to-severe AD were randomized to receive once daily oral upadacitinib 15 mg, upadacitinib 30 mg or placebo; patients enrolled in the AD Up study received concomitant topical corticosteroids. Data from the Measure Up 1 and Measure Up 2 studies were integrated. RESULTS: A total of 2584 patients were randomized. A consistently greater proportion of patients achieved at least 75% improvement in the Eczema Area and Severity Index, a 0 or 1 on the validated Investigator Global Assessment for Atopic Dermatitis, and improvement in itch (including an achievement of a reduction of ≥4; and score of 0/1 in Worst Pruritus Numerical Rating Scale) with upadacitinib compared with placebo at Week 16, regardless of age, sex, race, body mass index, AD severity, body surface area involvement, history of atopic comorbidities or asthma, or previous exposure to systemic therapy or cyclosporin. CONCLUSIONS: Upadacitinib had consistently high skin clearance rates and itch efficacy across subgroups of patients with moderate-to-severe AD through Week 16. These results support upadacitinib as a suitable treatment option in a variety of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2) and NCT03568318 (AD Up).

Conjunctivitis in adult patients with moderate-to-severe atopic dermatitis: results from five tralokinumab clinical trials.

BACKGROUND: Tralokinumab, a fully human IgG4 monoclonal antibody that specifically binds with high affinity to interleukin-13, effectively reduces moderate-to-severe atopic dermatitis (AD) when given every 2 weeks. The incidence of conjunctivitis is elevated vs. placebo, but severity and aetiology have not been examined. OBJECTIVE: To analyse conjunctivitis data recorded in five randomized, placebo-controlled trials of tralokinumab in adult patients with moderate-to-severe AD. METHODS: Overall, 2285 adults with AD were studied up to 16 weeks. Cochran-Mantel-Haenszel weights were applied to calculate the adjusted incidence of adverse events. RESULTS: The incidence of conjunctivitis was higher (7·5%) with tralokinumab than with placebo (3·2%). Most events were mild or moderate in severity, and 78·6% and 73·9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1·4%) events led to the permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline AD, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. LIMITATIONS: This analysis reports events up to week 16 only, with limited confirmation of conjunctivitis and its aetiology by an ophthalmologist, and insufficient reporting of ophthalmic treatments. CONCLUSIONS: Treatment with tralokinumab was associated with an increased incidence of conjunctivitis vs. placebo, but these cases were mostly mild and transient.

Facial erythema in patients with atopic dermatitis treated with Dupilumab - a descriptive study of morphology and Aetiology.

BACKGROUND: The development of dermatitis on face and neck, which was not described in phase 3 clinical trials, has been reported in the literature in patients treated with dupilumab. Little is known regarding the causes or defining features of the facial dermatitis. OBJECTIVES: We conducted surveys of consecutive patients with AD on dupilumab to describe its clinical features, morphology and aetiology. METHODS: A multi-centre prospective cohort study was conducted from 1 January 2020, to 31 December 31 2020. A total of 162 patients under dupilumab treatment were asked to complete a questionnaire and patients were evaluated by dermatologists. RESULTS: Of all 162 patients, 137 (84.6%) patients reported pre-existing facial dermatitis prior to dupilumab therapy. One hundred and twenty-one (88.3%) patients with pre-existing facial dermatitis reported improvement of their facial dermatitis with dupilumab therapy, nine (6.6%) patients reported no change after the treatment and seven (4.3%) patients of them got worse after the treatment (exacerbation group). Of 25 patients who reported no pre-existing active facial dermatitis, six (24%) patients reported new-onset facial erythema after the starting dupilumab therapy (new-onset group). A large proportion of the patients in both the exacerbation (86%) and new-onset groups (67%) had a history of facial TCS use. Both groups showed similar clinical manifestations and distribution with few differences. CONCLUSIONS: The vast majority of patients treated with dupilumab in academic institutions from Korea and the United States experienced improvement in their facial dermatitis with dupilumab therapy. A small proportion of patients had new onset and exacerbation. Although the mechanisms of this adverse event remain unclear, steroid withdrawal should be considered as a diagnosis of the erythema in some patients.

Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).

BACKGROUND: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. METHODS: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. RESULTS: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. CONCLUSIONS: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Measurement properties of patient-reported outcome measures for eczema control: a systematic review.

Atopic eczema (herein referred to as 'eczema') is a skin disease characterized by remitting and relapsing symptoms. The Harmonising Outcome Measures for Eczema (HOME) initiative was developed to establish a core outcome set (COS) for eczema to be measured for all future eczema trials. The core outcome set for atopic eczema clinical trials includes the domain for patient-reported eczema control, but a review of the validation of available eczema control instruments was lacking. We aimed to review the literature and systematically assess the measurement properties of validated patient-reported outcome instruments that capture eczema control. PubMed and Ovid EMBASE were searched up to 24 January 2020 for any study that reported on PROM instrument development or validation. The COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria were used to assess the quality of eligible studies. We screened 12 036 titles and abstracts and 58 full texts. A total of 12 papers were included, reporting on seven PROMS. These were assessed with respect to development, reliability, construct validity and responsiveness. Two instruments, Recap of Atopic Eczema (RECAP) and the Atopic Dermatitis Control Tool (ADCT), have been developed and validated to a sufficient standard to support their recommendation as patient-reported outcome instruments for measuring control of atopic eczema as part of the HOME Core Outcome Set.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

A phase 2, open-label study of single-dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy.

BACKGROUND: Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6-17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk-benefit profile in younger children remains a significant unmet need. OBJECTIVES: To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ≥6 months to <6 years. METHODS: This open-label, multicenter, phase 2, sequential, two-age cohort, two-dose level study (LIBERTY AD PRE-SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4-week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low-to-medium potency topical corticosteroids was allowed. RESULTS: Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose-proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by -44.6% and -49.7% (older cohort) and -42.7% and -38.8% (younger cohort), and mean Peak Pruritus NRS scores by -22.9% and -44.7% (older cohort) and -11.1% and -18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. CONCLUSIONS: Single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non-linear, consistent with previous studies in adults and adolescents.

Validation of five patient-reported outcomes for atopic dermatitis severity in adults.

BACKGROUND: Structured patient-reported outcomes of atopic dermatitis (AD) severity are not standardized in clinical practice. OBJECTIVES: To determine the construct validity, internal consistency, cross-cultural validity and floor or ceiling effects of multiple AD severity assessments. METHODS: This is a cross-sectional, population-based study of 2893 adults, including 602 adults who met a modified set of U.K. diagnostic criteria for AD. AD severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) and its objective and subjective components, and numerical rating scale (NRS)-itch. Quality of life was assessed using Short-Form (SF)-12 mental and physical health scores, Short-Form Six Dimensions (SF-6D) health utility scores and Dermatology Life Quality Index (DLQI). Mental health was assessed with the Hospital Anxiety and Depression Scale (HADS). RESULTS: PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM all had moderate-to-strong correlations with each other and DLQI, fair-to-moderate correlations with HADS-anxiety and HADS-depression, and inverse correlations with SF-12 mental component score and SF-6D (Pearson correlations, P < 0·001). All scores showed good criterion validity as judged by anova and receiver operator characteristics. PO-SCORAD, PO-SCORAD objective subscore and POEM had similarly good internal consistency (Cronbach's alpha = 0·84, 0·82 and 0·86); the PO-SCORAD subjective subscore was less internally consistent (alpha = 0·57). All scores showed potentially poor cross-cultural validity as demonstrated by uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity for multiple items. There were floor effects for POEM, but not for the other assessments. CONCLUSIONS: PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM appear to be valid for assessing AD severity in clinical practice. What's already known about this topic? Few studies have demonstrated the validity of the atopic dermatitis severity assessments Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), PO-SCORAD subscores, numerical rating scale (NRS)-itch and Patient-Oriented Eczema Measure (POEM). What does this study add? This study demonstrates that PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all had good construct validity in the assessment of atopic dermatitis severity in adults. Only POEM demonstrated floor effects. What are the clinical implications of this work? PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all appear to have sufficient validity to be used as assessments of atopic dermatitis severity in clinical practice.

Assessing the need for routine safety testing for patients being treated with dupilumab for moderate-to-severe atopic dermatitis.

Atopic dermatitis (also known as AD or eczema) is a common skin disease that can cause intense and persistent itching and rashes. Skin creams or ointments are not suitable or effective for some patients with moderate-to-severe AD. In these patients, oral (taken by mouth) or injected medications may be required. Some of those oral or injected treatments could be toxic and often have unwanted side effects, especially when used for a longer period of time, so patients must be regularly tested to see whether those treatments are harming their blood or organs. Dupilumab is a newer injectable drug for treating moderate-to-severe AD. Dupilumab specifically targets key molecules in the body that cause AD. Dupilumab has been tested for up to one year in more than 2000 patients enroled in placebo-controlled clinical trials. During those trials, patients provided blood and urine samples for laboratory testing while they were being treated with dupilumab or placebo (dummy drug). In this paper, the authors from Germany and the U.S.A, analysed how blood cells, blood chemistry, and urine chemistry changed during treatment, to check whether dupilumab is safe to use without the need for regular laboratory tests. After performing many routine laboratory tests on patients' blood and urine, they found that there were no clinically important changes in test results that could be linked to dupilumab. They concluded that patients using dupilumab for moderate-to-severe AD do not need routine laboratory testing. This is a summary of the study: Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS).

Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS).

BACKGROUND: Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications. OBJECTIVES: To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). METHODS: Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. RESULTS: Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. CONCLUSIONS: There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with dupilumab. Our data support the use of dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

The patient-reported disease burden in adults with atopic dermatitis: a cross-sectional study in Europe and Canada.

BACKGROUND: Cross-sectional data on patient burden in adults with atopic dermatitis (AD) from real-world clinical practice are limited. OBJECTIVE: This study compared patient-reported burden associated with adult AD across severity levels from clinical practices in Canada and Europe. METHODS: This study included adults (18-65 years) diagnosed with AD by dermatologists, general practitioners or allergists. Participants categorized as mild (n = 547; 37.3%), moderate (n = 520; 35.4%) or severe (n = 400; 27.3%) based on Investigator's Global Assessment completed a questionnaire that included pruritus and pain numerical rating scales, Patient-Oriented-Scoring of Atopic Dermatitis (PO-SCORAD) itch and sleep visual analogue scales, Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). Participants were also stratified by inadequate efficacy/intolerance/contraindication to cyclosporine [Cyclo; n = 62 (4 mild, 18 moderate, 40 severe)] and any systemic immunomodulatory agent [IMM; n = 104 (13 mild, 31 moderate, 60 severe)] and compared with the severe group excluding participants identified as Cyclo/IMM. RESULTS: Age was similar across severity groups; the proportion of women was higher in the mild group relative to severe (61.2% vs. 50.5%; P < 0.001). Compared with moderate and mild, participants with severe AD had more comorbidities, higher itch and pain severity, worse sleep and higher levels of anxiety and depression (all P < 0.001). Mean ± SD DLQI score among participants with severe AD (16.2 ± 6.9) showed a large effect on quality of life that was higher than those with moderate (10.2 ± 6.3) and mild (5.5 ± 4.9) (both P < 0.001). The burden among Cyclo and IMM subgroups was generally similar to that of participants with severe AD. CONCLUSIONS: Adults with AD reported a substantial burden across multiple domains that was significantly higher in those with severe disease. The burden among participants in the Cyclo/IMM subgroups was similar to those with severe AD.

Symptoms and diagnosis of anxiety and depression in atopic dermatitis in U.S. adults.

BACKGROUND: The relationship between atopic dermatitis (AD), anxiety and depression in the U.S. adult population is not well established. OBJECTIVES: To determine the relationship of AD and its severity with symptoms and diagnosis of anxiety and depression in U.S. adults. METHODS: A cross-sectional, population-based study of 2893 adults was performed. AD was determined using modified U.K. Diagnostic Criteria. RESULTS: Adults with AD vs. those without AD had higher mean Hospital Anxiety and Depression Scale anxiety (HADS-A) (7·7 vs. 5·6) and depression (HADS-D) (6·0 vs. 4·3) scores and higher prevalences of abnormal (≥ 11) HADS-A (28·6% vs. 15·5%) and HADS-D (13·5% vs. 9·0%) scores. In multivariable linear and logistic regression models controlling for sociodemographics, AD was associated with significantly higher mean HADS-A and HADS-D scores (7·7 and 6·0) and higher odds of abnormal HADS-A [odds ratio (OR) 2·19, 95% confidence interval (CI) 1·65-2·91] and HADS-D scores (OR 1·50, 95% CI 1·04-2·17) (P ≤ 0·03 for all). Mean and abnormal HADS-A and HADS-D scores were increased in moderate and severe/very severe self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring AD (PO-SCORAD), PO-SCORAD itch and sleep (P < 0·0001 for all). All respondents with severe PO-SCORAD, POEM and PO-SCORAD itch had borderline or abnormal HADS-A and HADS-D scores. Adults with AD vs. those without AD had higher prevalence of self-reported healthcare-diagnosed anxiety or depression in the past year (40·0% vs. 17·5%). Many adults with AD who had borderline and/or abnormal HADS-A or HADS-D scores reported no diagnosis of anxiety or depression. CONCLUSIONS: AD is associated with significantly increased anxiety and depression, which may go undiagnosed. What's already known about this topic? Previous studies found higher rates of anxiety and depression in clinical cohorts of patients with atopic dermatitis. What does this study add? This study found dramatically higher rates of anxiety and depression among adults with atopic dermatitis in the U.S. population, which was primarily driven by atopic dermatitis severity. Anxiety and depression often go undiagnosed in adults with atopic dermatitis.

Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the Investigator's Global Assessment: a pooled analysis of data from two phase III trials.

BACKGROUND: In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab. OBJECTIVES: To evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life. METHODS: LIBERTY AD SOLO 1 and 2 were two 16-week, randomized, double-blind trials enrolling adult patients with moderate-to-severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient-Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769. RESULTS: At week 16, 278 of 449 dupilumab q2w-treated patients (median age 36·0 years) and 396 of 443 placebo-treated patients had IGA > 1. Among patients with IGA > 1 at week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (-48·9% vs. -11·3%, P < 0·001), pruritus NRS (-35·2% vs. -9·1%, P < 0·001), affected BSA (-23·1% vs. -4·5%, P < 0·001), POEM score ≥ 4-point improvement (57·4% vs. 21·0%, P < 0·001) and DLQI score ≥ 4-point improvement (59·3% vs. 24·4%, P < 0·001). CONCLUSIONS: In patients with IGA > 1 at week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant dupilumab treatment effects.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

A randomized controlled trial of an emollient with ceramide and filaggrin-associated amino acids for the primary prevention of atopic dermatitis in high-risk infants.

BACKGROUND: Skin barrier dysfunction may precede infantile development of clinical atopic dermatitis (AD). Early-life emollient therapy to enhance barrier function may prevent or modify AD development in high-risk infants. OBJECTIVES: (a) To determine whether daily full-body application of an emollient with ceramide and amino acids (study emollient) can reduce the cumulative AD incidence compared to standard skin care at 1 year of age. (b) To evaluate the study emollient's effect on skin barrier function, natural moisturizing factor and the microbiome using non-invasive biophysical and biochemical techniques. METHODS: We performed a single-centre, investigator-blinded, randomized controlled trial enrolling infants at high risk for AD development determined by family history. The intervention was full-body once-daily application of the study emollient. The control arm was asked to not apply full-body emollient regularly and only use an emollient of their choice for dry skin. The primary outcome was the cumulative incidence of AD diagnosed at 12 months by a blinded investigator. RESULTS: Less than half the target sample size was enrolled (n = 100, goal sample was 208) with 28% lost to follow-up. Across all clinical end points, a numerical trend was observed in favour of the intervention, although not statistically significant likely due to lack of power from under-enrolment. AD was diagnosed in 13.2% vs. 25.0% at 12 months (P = 0.204) and 19.4% vs. 31.0% at 2 years (P = 0.296) in intervention vs. control groups, respectively. There were no significant differences between groups in skin barrier or microbiome assessments. While there were no serious adverse events, there were more cases of reported contact dermatitis in the intervention vs. control arms, 9.3% vs. 4.3%, respectively; however, these events were not related to the study emollient and most mild in severity. CONCLUSION: The observed trends suggest a protective effect of daily study emollient therapy compared to control.