Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

Epidemiology of prurigo nodularis in England: a retrospective database analysis.

BACKGROUND: Prurigo nodularis is a debilitating skin condition that is classified as rare by the Genetic and Rare Diseases Information Center (GARD) and the National Organization for Rare Diseases (NORD). There are currently no estimates of the prevalence of prurigo nodularis in England. OBJECTIVES: We aimed to address this data gap by describing the epidemiology of prurigo nodularis in a representative dataset derived from the English National Health Service. METHODS: The study utilized data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data. Patients with a diagnosis of prurigo nodularis were selected by clinical code in the primary care or inpatient datasets. Case definition was based on a minimum of two distinct diagnoses to maximize specificity. Point prevalence was calculated for the midpoint of 2018 and incidence rates from 2008 to 2018 were presented. For those classified as incident cases, demographic and clinical characteristics were reported. In sensitivity analyses the case definition was modified to relax the multiple diagnosis criteria and to restrict cases to those diagnosed within a maximum of 4 or 10 years of the midpoint prevalence date. RESULTS: Overall, 11 656 patients within the dataset had at least one prurigo nodularis diagnosis. Following application of the relevant inclusion criteria, 2743 patients formed the point prevalent cohort; the estimated prevalence was 3·27 patients per 10 000 population [95% confidence interval (CI) 3·15-3·40]. In sensitivity analyses the estimated prevalence ranged from 2·24 (95% CI 2·14-2·34) to 6·98 (95% CI 6·80-7·16). Incidence over the study period was 2·88 per 100 000 patient-years. Comorbidity was relatively high in this population, notably for atopic dermatitis (52·2%), depression (41·1%) and anxiety (35·4%). CONCLUSIONS: This study supports the NORD/GARD classification of prurigo nodularis as a rare disease with a prevalence of 3·27 patients per 10 000 population, which equates to 18 471 patients living with the disease in England in 2018. The relatively high prevalence of comorbidity observed for these patients may increase the complexity of management.

The effect of water hardness on atopic eczema, skin barrier function: A systematic review, meta-analysis.

BACKGROUND: Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life. OBJECTIVE: To review the literature on the relationship between the effect of water hardness (high calcium carbonate; CaCO3 ) on (a) the risk of developing AE, (b) the treatment of existing AE and (c) skin barrier function in human and animal studies. DESIGN , DATA SOURCES AND ELIGIBILITY CRITERIA: We systematically searched databases (MEDLINE, Embase, Cochrane CENTRAL, GREAT and Web of Science) from inception until 30/6/2020. Human and animal observational and experimental studies were included. The primary outcomes were risk of AE and skin barrier function. Studies were meta-analysed using a random effects model. Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Sixteen studies were included. Pooled observational data from seven studies on 385,901 participants identified increased odds of AE in children exposed to harder versus softer water (odds ratio 1.28, 95% CI 1.09, 1.50; GRADE certainty: very low). Two mechanistic studies in humans reported higher deposition of the detergent sodium lauryl sulphate in those exposed to harder versus softer water. Two randomized controlled trials comparing water softeners with standard care did not show a significant difference in objective AE severity with softened water (standardized mean difference 0.06 standard deviations higher, 95% CI 0.16 lower to 0.27 higher; GRADE certainty: moderate). CONCLUSIONS & CLINICAL RELEVANCE: There was a positive association between living in a hard water (range: 76 to > 350 mg/L CaCO3 ) area and AE in children. There is no evidence that domestic water softeners improve objective disease severity in established AE. There may be a role of water hardness in the initiation of skin inflammation in early life, but there is a need for further longitudinal and interventional studies.

The Sleep Disturbance Numerical Rating Scale: Content Validity, Psychometric Validation, and Meaningful Within-Patient Change in Prurigo Nodularis.

INTRODUCTION: Sleep is often disturbed in patients with prurigo nodularis (PN). To address the lack of validated patient-reported outcome (PRO) measures for quantifying sleep disturbance in PN, we evaluated the Sleep Disturbance Numerical Rating Scale (SD NRS) as a single-item PRO measure for quantifying sleep disturbance in PN. METHODS: Adults with PN participated in qualitative interviews, which included concept elicitation and cognitive debriefing of the SD NRS. The SD NRS was evaluated psychometrically using data from a phase 2 randomized trial in adults with PN (NCT03181503). Other PRO assessments included the Average Pruritus (AP) NRS, AP Verbal Rating Scale (VRS), peak pruritus (PP) NRS, PP VRS, and Dermatology Life Quality Index (DLQI). Reliability, validity, and responsiveness of the SD NRS were evaluated, and meaningful within-patient change was estimated from qualitative interview responses and quantitative trial data. RESULTS: All interview participants (N = 21) experienced sleep disturbance and most (95%) understood the SD NRS as intended. The SD NRS demonstrated test-retest reliability based on intra-class correlation coefficients for itch-stable participants of 0.87 for the AP VRS and 0.76 for the PP VRS. At baseline, Spearman's rank-order correlation coefficients were moderate to strong (0.3-0.8) between the SD NRS and the AP NRS, AP VRS, PP NRS, PP VRS, and DLQI. Known-groups validity was demonstrated by higher (worse) SD NRS scores in participants with worse scores on the AP NRS, AP VRS, PP VRS, and DLQI. Improvements in SD NRS scores were greater in participants classified as "improved" versus "worsened/unchanged" on the anchor PROs. A 2- to 4-point decrease on the 11-point SD NRS scale was identified as a meaningful within-patient change. CONCLUSION: The SD NRS is a well-defined, reliable, and valid PRO measure that can be used in daily practice and clinical trials to capture sleep disturbance in adults with PN.

Patients with the skin disease prurigo nodularis often sleep badly because their skin is very itchy in the evening and at night. In assessing the effectiveness of new treatments for prurigo nodularis, it is useful to know whether patients sleep better when taking them. Here, we tested whether the "Sleep Disturbance Numerical Rating Scale" (SD NRS), a tool for measuring sleep, can be used by patients with prurigo nodularis. The SD NRS asks patients to score their sleep loss during the previous night on a scale of 0 ("no sleep loss") to 10 ("I did not sleep at all"). When we interviewed 21 patients with prurigo nodularis, 19 of them had problems falling asleep and 18 of them woke up every night. Most of the patients found the SD NRS easy to use. To further explore whether the SD NRS is suitable for patients with prurigo nodularis, we also analyzed data from a European clinical study in which patients with prurigo nodularis received nemolizumab, a new treatment being developed for the disease. Patients completed the SD NRS each morning during the clinical study. We found that the SD NRS has the necessary properties to be useful for assessing sleep on a daily basis. We also determined that a 2- to 4-point decrease on the SD NRS scale would represent a meaningful improvement in sleep for patients with prurigo nodularis. We conclude that the SD NRS is a useful tool for assessing sleep in prurigo nodularis patients participating in clinical studies.

Patient Perspectives on Living With Severe Prurigo Nodularis.

Importance: Because of a paucity of qualitative research on prurigo nodularis (PN), the symptoms and impacts of PN that are most important to patients are poorly understood. Objective: To explore patients' perspectives on their PN symptoms and to understand the impacts of the condition. Design, Setting, and Participants: One-on-one qualitative telephone interviews were held with English-speaking US adults aged 18 years or older with a confirmed diagnosis of PN, severe pruritus, and moderate to severe sleep disturbance. Participants were recruited via patient associations, patient panels, and social media posts. Interviews took place between September 10, 2020, and March 16, 2021. Main Outcomes and Measures: The main symptoms of PN and their impacts on quality of life were identified by content analysis of deidentified interview transcripts. Results: A total of 21 adults with PN (mean [SD] age, 53.1 [11.8] years; 15 [71%] female; 2 African American or Black patients [10%], 1 Asian patient [5%], and 18 White patients [86%]; of these, 1 patient [ 5%] had Hispanic or Latino ethnicity) participated in the interviews. All participants reported itch, pain associated with PN, bleeding or scabbing, and dry skin. Other frequently reported symptoms included lumps or bumps (95%), having a crust on the skin (95%), burning (90%), stinging (90%), lesions or sores (86%), skin discoloration (86%), and raw skin (81%). Of the 17 participants who indicated what their worst symptoms were, 15 (88%) identified itching as the worst or 1 of the worst symptoms. The most frequently reported impacts of PN for quality of life were changes in sleep (100%), daily life (100%), feelings or mood (95%), relationships (95%), social life (81%), and work or school (71%). Overall, the worst impact of PN was its association with impaired feelings or mood. Conclusions and Relevance: This qualitative study suggests the importance of itching, sleep disturbance, and other symptoms and impacts of PN. This information can be used to guide end point selection in clinical trials and to inform patient-centric decision-making in clinical practice.

Assessing Response in Atopic Dermatitis: A Systematic Review of the Psychometric Performance of Measures Used in HTAs and Clinical Trials.

INTRODUCTION: Assessing treatment response is key to determining treatment value in atopic dermatitis (AD). Currently, response is assessed using various clinician- or patient-reported measures and response criteria. This variation creates a mismatch of evidence across trials, hindering the ability of clinicians, regulators, and payers to compare the efficacy of treatments. This review identifies which measures and criteria are used to determine response in clinical trials and health technology assessments (HTAs). Moreover, it systematically reviews the psychometric performance of those measures and criteria to understand which perform best in capturing patient-relevant symptoms and treatment benefits. METHODS: A scoping review of clinical trials and HTAs in AD identified the following measures for inclusion: the Eczema Area and Severity Index (EASI), the Investigator's Global Assessment (IGA), the Dermatology Life Quality Index (DLQI) and the Peak Pruritus Numerical Rating Scale (PP-NRS). A systematic search was performed in MEDLINE and Embase to identify studies testing the psychometric performance of these measures in adults or adolescents with AD. RESULTS: A lack of consistency in the assessment of response was observed across clinical trials and HTAs. Important gaps in psychometric evidence were identified. No content validations of the EASI and IGA in AD were found, while some quantitative studies suggested that these measures fail to capture itch, a core symptom. The PP-NRS and DLQI performed well. No studies compared the performance of different response criteria. CONCLUSION: Content validation of the PP-NRS confirmed the importance of itch as a core symptom and treatment priority in AD; however, itch is not well covered in the EASI or IGA. Including the PP-NRS in clinical trials and HTAs will better capture patient-relevant benefit and response. Although various response criteria were used, no studies compared the performance of different criteria to inform which were most appropriate to compare treatments in clinical trials and HTAs.

The assessment of treatment response is important in determining treatment value in atopic dermatitis (AD). This study aimed to identify which outcome measures and criteria are used to determine treatment response in clinical trials and health technology assessments (HTAs). The psychometric performance of identified outcome measures and criteria was then systematically reviewed to understand which perform best in capturing patient-relevant symptoms and treatment benefits in AD. The review identified and included the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI) and Peak Pruritus Numerical Rating Scale (PP-NRS) as response measures. Lack of consistency in how response is assessed across clinical trials and HTAs makes it difficult for clinicians and payers to compare the efficacies and cost-effectivenesses of different treatments and to make optimal treatment decisions. The review found that content validity (the extent to which a measure covers those symptoms and treatment benefits which are important to patients) was not assessed for EASI and IGA. EASI and IGA are often used to assess response in clinical trials and HTAs, but they miss key elements of the patient-relevant disease impact and treatment benefit, including itch. Treatments leading to improvements in missed symptoms (e.g. itch) will be undervalued using EASI and IGA, decreasing the chances of regulatory approval and reimbursement. Moreover, response criteria used in clinical trials and HTAs are sometimes adopted in prescriber settings. Here, if response assessment does not capture patient-relevant benefit, patients' access to tailored treatment may be restricted due to the perceived non-response.

Incident Comorbidity, Resource Use, and All-Cause Mortality Associated with Prurigo Nodularis: A United Kingdom Retrospective Database Analysis.

We described comorbidity, resource utilization, and mortality for patients with prurigo nodularis (PN) using data from the Clinical Practice Research Datalink. Patients with incident PN (2008-2018) were selected and matched to controls. Of 2,416 patients with PN, 2,409 (99.7%) were matched to controls. Prevalence of atopic dermatitis (relative risk [RR] = 2.571; 95% confidence interval [CI] = 2.356-2.806), depression (RR = 1.705; 95% CI = 1.566-1.856), anxiety (RR = 1.540; 95% CI = 1.407-1.686), coronary heart disease (RR = 1.575; 95% CI = 1.388-1.787), chronic kidney disease (RR = 1.529; 95% CI = 1.329-1.759), and type 2 diabetes mellitus (RR = 1.836; 95% CI = 1.597-2.111) was significantly higher for patients with PN. Subsequent risk of atopic dermatitis (hazard ratio = 6.58; 95% CI = 5.17- 8.37), depression (hazard ratio = 1.61; 95% CI = 1.30-1.99), and coronary heart disease (hazard ratio = 1.37; 95% CI = 1.09-1.74) were significantly increased. Resource utilization was increased in all settings: incidence rate ratio = 1.48 (95% CI = 1.47-1.49) for primary care, incident rate ratio = 1.80 (95% CI = 1.75-1.85) for inpatients, incident rate ratio = 2.15 (95% CI = 2.13-2.18) for outpatients, and incidence rate ratio = 1.32 (95% CI = 1.27-1.36) for accident and emergency. Respective cost ratios were 1.78 (95% CI = 1.67-1.90), 1.52 (95% CI = 1.20-1.94), 2.34 (95% CI = 2.13-2.58), and 1.55 (95% CI = 1.33-1.80). Total primary and secondary healthcare costs were £2,531 versus £1,333, a cost ratio of 1.62 (95% CI = 1.36-1.94). The adjusted hazard ratio for mortality was 1.37 (95% CI = 1.14-1.66). Patients with PN had significantly increased rates of comorbidity, healthcare resources utilization, and mortality compared with matched controls.

Novel systemic therapies in atopic dermatitis: what do we need to fulfil the promise of a treatment revolution?

Patients with atopic dermatitis (AD) who do not adequately respond to topical therapy and phototherapy often need systemic immunomodulatory treatment to control their symptoms. Conventional systemic agents, such as ciclosporin, azathioprine, and methotrexate, have been used for decades, but there are concerns about their safety profile. There are now many novel systemic agents emerging through clinical trials, which may have great potential in the treatment of AD. Despite this, there are very few data comparing the performance of these drugs against each other. The purpose of this article is to review the current systemic therapies in AD and present an indirect comparison of systemic AD treatments using effectiveness and safety data from published randomised controlled trials, highlighting important remaining gaps in knowledge. Although the latest developments in systemic AD treatments are exciting and dearly needed, further work is required before the promise of a therapeutic revolution becomes reality.

Protocol for an outcome assessor-blinded pilot randomised controlled trial of an ion-exchange water softener for the prevention of atopic eczema in neonates, with an embedded mechanistic study: the Softened Water for Eczema Prevention (SOFTER) trial.

INTRODUCTION: Atopic eczema affects 20% of UK children, and environmental factors are important in its aetiology. Several observational studies suggest an increased risk of atopic eczema in children living in hard water areas. The Softened Water for Eczema Prevention pilot trial tests the feasibility of installing domestic ion-exchange water softeners around the time of birth to reduce the risk of atopic eczema in children with a family history of atopy. A further aim is to explore the pathophysiological mechanisms for this in an embedded mechanistic study. METHODS AND ANALYSIS: Multicentre parallel group assessor-blinded randomised controlled pilot trial. Participants are newborn babies (n=80) living in a hard water (>250 mg/L calcium carbonate) area at risk of developing atopic eczema because of a family history of atopy. Participants will be randomised prior to birth in a 1:1 ratio. The intervention group will have an ion-exchange water softener installed prior to birth. The control group will receive their usual domestic hard water supply. Follow-up will be until 6 months of age. Data will be collected at birth (baseline), 1, 3 and 6 months of age. The main outcome is the proportion of eligible families screened who are willing and able to be randomised. Several secondary feasibility and clinical endpoints will also be evaluated, alongside mechanistic outcomes. Data will be analysed on an intention-to-treat basis. There will be no hypothesis testing for the clinical outcomes. Study acceptability will be evaluated through semistructured interviews. ETHICS AND DISSEMINATION: This study has been reviewed and given a favourable opinion by the North West-Liverpool East Research Ethics Committee (Ref: 17/NW/0661). The results of the study will be reported at international conferences and in peer-reviewed scientific journals. We will send participating families a summary of the pilot trial results. TRIAL REGISTRATION NUMBER: NCT03270566.

Development and Validation of an Algorithm to Accurately Identify Atopic Eczema Patients in Primary Care Electronic Health Records from the UK.

Electronic health records hold great promise for clinical and epidemiologic research. Undertaking atopic eczema (AE) research using such data is challenging because of its episodic and heterogeneous nature. We sought to develop and validate a diagnostic algorithm that identifies AE cases based on codes used for electronic records used in the UK Health Improvement Network. We found that at least one of five diagnosis codes plus two treatment codes for any skin-directed therapy were likely to accurately identify patients with AE. To validate this algorithm, a questionnaire was sent to the physicians of 200 randomly selected children and adults. The primary outcome, positive predictive value for a physician-confirmed diagnosis of AE, was 86% (95% confidence interval = 80-91). Additional criteria increased the PPV up to 95% but would miss up to 89% of individuals with physician-confirmed AE. The first and last entered diagnosis codes for individuals showed good agreement with the physician-confirmed age at onset and last disease activity; the mean difference was 0.8 years (95% confidence interval = -0.3 to 1.9) and -1.3 years (95% confidence interval = -2.5 to -0.1), respectively. A combination of diagnostic and prescription codes can be used to reliably estimate the diagnosis and duration of AE from The Health Improvement Network primary care electronic health records in the UK.

Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis.

Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3-4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).

Omalizumab, an Anti-IgE mAb, receives approval for the treatment of chronic idiopathic/spontaneous urticaria.

Omalizumab, an anti-IgE mAb, has recently been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of chronic idiopathic urticaria. Saini et al. (2014) (this issue) report on ASTERIA I, a 40-week randomized, double-blinded, placebo-controlled phase III trial evaluating omalizumab for the treatment of this disease.