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.

Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

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).

Sickle cell bone disease and response to intravenous bisphosphonates in children.

Children with sickle cell disease (SCD) have the potential for extensive and early-onset bone morbidity. This study reports on the diversity of bone morbidity seen in children with SCD followed at three tertiary centers. IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. INTRODUCTION: To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with SCD. METHODS: We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises, or stroke attributed to IV bisphosphonate therapy. CONCLUSION: Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.

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.

Pioneering global best practices in atopic dermatitis: results from the atopic dermatitis quality of care initiative.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by unrelenting pruritus and recurrent eczematous lesions. It affects up to 15% of children and adolescents and up to 5% of adults, and confers a high and multifactorial burden to patients, families and society. With increasing awareness of this substantial burden, AD has become a priority for healthcare systems. AIM: The Atopic Dermatitis Quality of Care (ADQoC) initiative set out to describe good practices for addressing the challenges that impede the management of AD. METHODS: The initiative carried out a literature review and surveyed 32 expert care centres, catalogued findings, and analysed and elucidated global challenges to AD care along with good practice implementations that can address them. RESULTS: The four challenges to quality care for AD are: (i) misconceptions about AD; (ii) delayed referral and access to AD specialists; (iii) poor patient access to AD treatments and poor adherence to medications; and (iv) managing the complexity of AD and its comorbidities. The initiative highlighted 5 of 10 good practice implementations as high priority for any AD care centre to focus on: (i) clinical assessment and diagnosis; (ii) a structured multidisciplinary care team; (iii) monitoring and evaluating care quality; (iv) patient education and communication; and (v) collaboration and exchange with patient groups. CONCLUSION: These implementations can provide benefits for patients, healthcare providers and the healthcare system. They directly contribute to the efficacy of treatment, improved healthcare provider efficiency, improved education for patients and healthcare providers, and improved costs to healthcare systems. The initiative was launched on https://atopicdermatitiscare.kpmg.co.uk/ to provide an easy-to-use educational platform.

Employing the theory of planned behaviour to design an e-cigarette education resource for use in secondary schools.

BACKGROUND: An extended version of the theory of planned behaviour (TPB) was used to inform the design of a framework for an educational resource around e-cigarette use in young people. METHODS: A sequential exploratory design was employed. In Phase 1, elicited behavioural, normative and control beliefs, via 7 focus groups with 51 participants, aged 11-16 years, identified salient beliefs around e-cigarette use. These were used to construct a questionnaire administered to 1511 young people aged 11-16 years, which determined predictors of e-cigarette use and ever use. In Phase 2, sociodemographic variables, e-cigarette knowledge, access, use, marketing and purchasing of e-cigarettes and smoking behaviour were also gathered. The composite findings from Phase 1 and 2 informed the design of a post primary educational resource in Phase 3 around e-cigarette use. RESULTS: Current e-cigarette use was 4%, with almost 23% reporting ever use, suggesting current use is stable but experimentation may be increasing in this cohort. Sociodemographic variables, knowledge of e-cigarettes, smoking behaviour and TPB variables (direct and indirect measures of attitudes, subjective norm, and perceived behavioural control) accounted for 17% of the variance in current e-cigarette use, with higher intentions to use e-cigarettes within the next month, having the strongest impact on use (p < 0.001), followed by self-efficacy (p = 0.016). Sociodemographic and TPB variables accounted for 65% of the variance in intentions to use e-cigarettes in the next month; current e-cigarette use (p < 0.001), more positive attitudes (p < 0.001), stronger social influence (p < 0.001), higher self-efficacy (p < 0.001), higher control beliefs (p < 0.001) and greater motivation to use e-cigarettes (p < 0.001) were the main predictors of intentions. Phases 1 and 2 informed the mapping of key predictors of intentions and use of e-cigarettes onto the Theoretical Domains Framework, which identified appropriate intervention functions and behaviour change techniques. CONCLUSIONS: This paper is the first to bridge the theoretical-practice gap in an area of significant public health importance through the development of a framework for a novel theory driven school-based educational resource aimed at reducing experimentation and uptake of e-cigarette use in young people.

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.

Mass Equilibration and Fluctuations in the Angular Momentum Dependent Dynamics of Heavy Element Synthesis Reactions.

Mass and angle distributions for the ^{52}Cr+^{198}Pt and ^{54}Cr+^{196}Pt reactions (both forming ^{250}No) were measured and subtracted, giving new information on fast quasifission mass evolution, and the first direct determination of the dependence of sticking times on angular momentum. TDHF calculations showed good agreement with average experimental values, but experimental mass distributions unexpectedly extended to symmetric splits while the peak yield remained close to the initial masses. This implies a strong role of fluctuations in mass division early in the collision, giving insights into the transition from fast energy dissipative deep-inelastic collisions to quasifission.

Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician-reported signs (Eczema Area and Severity Index, EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVES: To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long-term control and itch intensity. METHODS: A face-to-face consensus meeting was held in Tokyo, Japan (8-10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules. RESULTS: It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale (NRS)-11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.

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.

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.

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.

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.

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.

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).

Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema clinical trials. Previous consensus meetings have agreed upon preferred instruments for clinician-reported signs (Eczema Area and Severity Index - EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure - POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVE: To complete the core outcome set for atopic eczema by agreeing upon core outcome instruments for the domains of quality of life, long-term control and itch intensity. METHODS: Face-to-face consensus meeting held in Tokyo, Japan (8th to 10th April, 2019) including 74 participants (47 healthcare professionals/methodologists, 14 patients, 13 industry representatives), from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using pre-defined consensus rules. RESULTS: It was agreed by consensus that quality of life should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children, and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale(NRS)-11 past 24 hours was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in atopic eczema is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.