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.).

Similarities and differences in peripheral itch and pain pathways in atopic dermatitis.

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of µ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.

A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council.

BACKGROUND: Janus kinase inhibitors (JAKinibs) have the potential to dramatically alter the landscape of atopic dermatitis (AD) management due to their promising efficacy results from phase 3 trials and rapid onset of action. However, JAKinibs are not without risk, and their use is not appropriate for all AD patients, making this a medication class that dermatologists should understand and consider when treating patients with moderate-to-severe AD. OBJECTIVE: This consensus expert opinion statement from the International Eczema Council (IEC) provides a pragmatic approach to prescribing JAKinibs, including choosing appropriate patients, dosing, clinical and lab monitoring, as well as long-term use. METHODS: An international cohort of authors from the IEC with expertise in JAKinibs selected topics of interest and were formed into authorship groups covering 10 subsections. The groups performed topic-specific literature reviews, consulted up-to-date adverse event (AE) data, referred to product labels and provided analysis and expert opinion. The manuscript guidance and recommendations were reviewed by all authors as well as the IEC Research Committee. RESULTS: We recommend JAKinibs be considered for patients with moderate to severe AD seeking the benefits of rapid reduction in disease burden and itch, oral administration, and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKinibs, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKinib therapy should be current on vaccinations and we provide a generalized framework for laboratory monitoring, though clinicians should consult individual product labels for recommendations as there are variations among the JAKinib class. Patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in AD patients to assess the durability and safety of continuous long-term use of JAKinibs, combination medication regimens, and the effects of flexible, episodic treatment over time. CONCLUSIONS: The decision to initiate a JAKinib should be shared among patient and provider, accounting for AD severity and personal risk/benefit assessment, including consideration of baseline health risk factors, monitoring requirements and treatment costs.

Abrocitinib Provides Rapid and Sustained Improvement in Skin Pain and Is Associated with Improved Quality of Life Outcomes in Adult and Adolescent Patients with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Skin pain in atopic dermatitis (AD) increases with disease severity and is associated with substantial quality of life (QoL) burden. OBJECTIVES: The aim of the study was to evaluate abrocitinib efficacy on skin pain and QoL in adults and adolescents with moderate-to-severe AD. METHODS: This post hoc analysis included data with abrocitinib administered as monotherapy (pooled phase 2b [NCT02780167] and phase 3 JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]) or in combination with topical therapy (phase 3 JADE COMPARE [NCT03720470] and JADE TEEN [NCT03796676]). Patients received oral, once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 or 16 weeks (JADE COMPARE). Skin pain was rated using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) skin pain Numerical Rating Scale (NRS) item ("How painful was your skin over the past 24 h?") on a scale from 0 (not painful) to 10 (extremely painful). Itch (Peak Pruritus NRS) and QoL (Dermatology Life Quality Index or Children's Dermatology Life Quality Index) were assessed. Least squares mean (LSM) change from baseline was analyzed using mixed-effects repeated measures modeling. RESULTS: A total of 1,822 patients (monotherapy pool, n = 942; JADE COMPARE, n = 595; and JADE TEEN, n = 285) were analyzed. LSM change from baseline in PSAAD skin pain score was significantly greater with abrocitinib versus placebo from week 2 through week 12 or 16 across all 3 study populations and occurred in a dose-dependent manner. A greater proportion of patients achieved a ≥4-point improvement from baseline in PSAAD skin pain score with abrocitinib (200 mg and 100 mg) versus placebo in the monotherapy pool (56% and 38% vs. 12%; week 12), JADE COMPARE (72% and 52% vs. 26%; week 16), and JADE TEEN (51% and 60% vs. 31%; week 12). Additionally, a greater proportion of patients achieved a stringent threshold of skin pain improvement (PSAAD skin pain score <2) with abrocitinib versus placebo. Adults and adolescents who achieved a ≥4-point improvement in skin pain reported greater QoL improvement than those who did not achieve a ≥4-point improvement. A positive correlation (≥0.3) was observed between skin pain and QoL and separately between skin pain and itch across the 3 study populations. CONCLUSION: Abrocitinib as monotherapy or in combination with topical therapy improved skin pain and was associated with improved QoL in both adults and adolescents with moderate-to-severe AD across all evaluated studies.

Chronic Itch Affects Patients' Ability to Experience Pleasure: Anhedonia in Itchy Disorders.

Anhedonia, the reduced ability to experience pleasure, is a prevalent symptom in various psychiatric disorders, but has not been investigated in dermatological conditions, particularly those characterized by chronic itch. This study aimed to examine the prevalence and clinical correlates of anhedonia in patients with chronic itch. A cross-sectional study was conducted in 137 patients with chronic itch, classified according to the International Forum for the Study of Itch (IFSI) classification. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS) and Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS). Itch severity, quality of life, and psychological distress were assessed using the Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), ItchyQoL, and Hospital Anxiety and Depression Scale (HADS), respectively. The mean SHAPS score was 1.0 ± 1.7 points, and the mean ACIPS total score was 76.9 ± 16.2 points. In the study sample, 13.1% of patients were identified as anhedonic, with a higher prevalence observed in those with severe and very severe itch. Anhedonia was significantly correlated with itch severity (R = 0.2, p=0.02 for 24 h VASmean and SHAPS; R = 0.2, p = 0.01 for 24 h VASmax and SHAPS), anxiety symptoms (R = 0.3, p < 0.001 for SHAPS and HADS-anxiety), depression symptoms (R = 0.4, p < 0.001 for SHAPS and HADS-depression), and impairment in quality of life (R = 0.2, p = 0.014 for SHAPS and ItchyQoL). Anhedonia is a significant and prevalent aspect of psychological distress in patients with chronic itch. Addressing this symptom may not only improve patients' overall mental health but also enhance the effectiveness of treatments for chronic itch. Future research is needed to elucidate further the mechanisms underlying the relationship between anhedonia and chronic itch and to develop targeted interventions for this population.

Notalgia Paresthetica Dermatologist Report of Symptom Burden and Treatment: Results from a Physician Survey.

Notalgia paresthetica (NP) is a sensory neuropathy characterized by chronic pruritus, skin pain, and other pathologic sensations affecting the mid-to-upper back. NP may be under-recognized and under-diagnosed, with limited data available on its symptom presentation and treatment patterns. NP-DERM was an internet-based survey of dermatologists (n = 650) from 8 different countries on their perspectives on NP symptoms and current treatment practices. Dermatologists typically treated a median of 12 patients with NP per month. Dermatologists reported that itch (pruritus) was the most common symptom for their patients with NP, followed by hyperpigmentation and sensitive skin. The most burdensome NP symptom was pruritus, followed by burning or hot sensation, and painful or raw skin. The most prescribed treatments included non-medicated skin care, topical corticosteroids, oral antihistamines, medicated topicals, and gabapentin or pregabalin. Physicians reported low satisfaction with available treatments. The most common reason for physicians to discontinue patients' therapy was lack of response.

Validation of a scoring algorithm for the clinician-reported outcome tool 'prurigo activity and severity (PAS)' based on clinical studies of dupilumab in adults with prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians. OBJECTIVES: To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN. METHODS: The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds. RESULTS: The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score. CONCLUSIONS: PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance.

New horizons in dermatological education: Skin cancer screening with virtual reality.

BACKGROUND: Technological advances in the field of virtual reality (VR) offer new opportunities in many areas of life, including medical education. The University of Münster has been using VR scenarios in the education of medical students for several years, especially for situations that are difficult to reproduce in reality (e.g., brain death). Due to the consistently positive feedback from students, a dermatological VR scenario for skin cancer screening was developed. OBJECTIVES: Presentation and first evaluation of the skin cancer screening VR scenario to determine to what extent the technical implementation of the scenario was evaluated overall by the students and how their subjective competence to perform a skin cancer screening changed over the course of the teaching unit (theory seminar, VR scenario, theoretical debriefing). METHODS: Students (n = 140) participating in the curricular pilot project during the 2023 summer term were surveyed throughout the teaching unit using several established questionnaires (System Usability Scale, Simulation Task-Load-Index, Realism and Presence Questionnaire) as well as additional questions on cybersickness and subjective learning. RESULTS: (i) The use of VR is technically feasible, (ii) students evaluate the VR scenario as a useful curricular supplement, and (iii) from the students' subjective perspective, a good learning outcome is achieved. Although preparation and follow-up appear to be important for overall learning, the greatest increase in subjective competence to perform a skin cancer screening is achieved by the VR scenario. CONCLUSIONS: Technically feasible and positively evaluated by students, VR can already be a useful addition to dermatology education, although costs are still high. As a visual discipline, dermatology offers special opportunities to create VR scenarios that are not always available or comfortable for patients in reality. Additionally, VR scenarios guarantee the same conditions for all students, which is essential for a high-quality education.

Responder analysis using clinically meaningful thresholds: Post hoc analyses from randomized dupilumab clinical trials in patients with prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an intensely pruritic disease characterized by itchy nodules on the trunk/extremities; it is often accompanied by skin pain and sleep disruption with negative impacts on the quality of life (QoL). The patient-reported outcome (PRO) instruments, Worst Itch-Numeric Rating Scale (WI-NRS), Skin Pain-NRS, Sleep-NRS and Dermatology Life Quality Index (DLQI) have been psychometrically validated and the clinically meaningful within-patient improvement thresholds (responder definition) have been established through data pooled from the two Phase-3 trials (PRIME, NCT04183335 and PRIME2, NCT04202679) of dupilumab in adults with PN uncontrolled on topical therapies. OBJECTIVES: To estimate the proportion of dupilumab-treated patients (vs. placebo) achieving clinically meaningful improvement in itch, skin pain, sleep and QoL, either alone or in combination, from the data pooled from PRIME and PRIME2 trials. METHODS: The patient-level data pooled from the two Phase-3 trials (N = 311) were used for this post hoc analysis. Thresholds of clinically meaningful within-patient improvement in PRO instrument scores from baseline at Week 24 used for defining responders were 4 (WI-NRS and Skin Pain-NRS), 2 (Sleep-NRS) and 9 points (DLQI). The proportion of dupilumab-treated patients, versus placebo, achieving the thresholds, and the time taken to achieve the thresholds were evaluated for the individual and combination of PROs. RESULTS: Responder rates were significantly higher with dupilumab, versus placebo at Week 24 for WI-NRS (58.8% vs. 19.0%, p < 0.0001), Skin Pain-NRS (49.7% vs. 20.9%, p < 0.0001), Sleep-NRS (42.5% vs. 23.4%, p < 0.0001) and DLQI (64.7% vs. 22.8%, p < 0.0001). Proportion of patients achieving simultaneous improvement in symptoms and QoL (24.8% vs. 6.3%, p < 0.0001) were significantly higher in dupilumab-treated patients versus placebo. The time needed for achieving clinically meaningful improvement in symptoms were significantly lower in dupilumab-treated patients, versus placebo. CONCLUSIONS: Significantly greater proportion of dupilumab-treated patients with PN, versus placebo, demonstrated clinically meaningful improvements in PRO measures of symptoms and QoL.

Clinical aspects and management of chronic itch.

Chronic pruritus (CP) (ie, itch that persists for more than 6 weeks) poses significant challenges to patients' health and quality of life. It is a common reason for visits to dermatologists and general practitioners and can be caused by a range of conditions, including systemic diseases such as chronic kidney disease or liver diseases, malignancies, neuropathic conditions, and dermatoses such as atopic dermatitis. CP often does not develop in parallel with the course of the disease and can become an entity of its own, which must be treated with antipruritic drugs, even if the underlying cause is already under therapy. Depending on the etiology of CP, different pathways in the pathogenesis have been analyzed recently, following which new treatments have been developed and tested in randomized controlled trials. This article discusses the recent results of these studies and highlights how best to manage health care for patients with CP.

Interleukin Profiling in Atopic Dermatitis and Chronic Nodular Prurigo.

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.

Chronic Prurigo.

Chronic prurigo (CPG) is a neuroinflammatory dermatosis characterized by prolonged pruritus lasting more than 6 weeks, pruriginous skin lesions, and repeated scratching. Patients with CPG suffer significantly from psychological distress and a marked impairment in their quality of life. The most common subtype of CPG is chronic nodular prurigo (CNPG, also called prurigo nodularis). In addition to the clinical features of CPG and the burden of disease, this CME article provides an overview of the significant advances in understanding the pathophysiology, including the associated therapeutic options for CPG. Dupilumab is the first approved therapy for moderate and severe CNPG to date from the European Medicines Agency (EMA) and the US Food & Drug Administration (FDA). It also highlights other agents currently being studied in Phase II and Phase III clinical, randomized, placebo-controlled trials. These include biologics such as nemolizumab (anti-IL-31-RA-mAb), vixarelimab/KPL-716 (anti-Oncostatin-M receptor ß-mAb), and barzolvolimab/CDX-0159 (anti-KIT-mAb), as well as Janus kinase inhibitors such as povorcitinib/INCB054707 and abrocitinib, and opioid modulators such as nalbuphine.

Validation of the German Pruritus Questionnaire for the systematic assessment of chronic pruritus.

BACKGROUND: Chronic pruritus is a clinically heterogeneous symptom that manifests itself with varying duration, intensity, or quality. To date, there is no validated German-language instrument that systematically assesses the relevant parameters. With the support of the Pruritus Research Working Group (Arbeitsgemeinschaft Pruritusforschung, AGP), a questionnaire for the assessment of chronic pruritus (AGP questionnaire) was developed in 2008. The subsequently revised instrument, now called the German Pruritus Questionnaire, records pruritus-specific parameters such as localization, course, intensity and quality, anamnestic data on the general state of health, sociodemographic data, quality of life, and coping methods. It is to be validated in the study presented here. PATIENTS AND METHODS: The questionnaire was used in 366 patients with chronic pruritus of different etiologies from Germany (University Hospitals Heidelberg, Münster, Mainz, Erlangen, Giessen, private practice Bad Bentheim, TU Munich, Wiesbaden Kidney Center), Austria (Graz University Hospital) and Switzerland (Aarau Cantonal Hospital). RESULTS: The reliability for repeated completion (retest reliability) with regard to localization, first occurrence, and concomitant diseases showed high values for Cohen's kappa (> 0.8). The data on the retest reliability of the pruritus characteristics showed lower values (< 0.7). With regard to the measurability of practically relevant changes (change sensitivity), medium to strong effect sizes were found (0.09-0.19). A statistically significant differentiation of the pruritus etiologies based on the recorded parameters was not possible. CONCLUSIONS: The German Pruritus Questionnaire allows a comprehensive and structured recording of patient- and clinician-reported, relevant dimensions of chronic pruritus of different etiologies. Further adaptation and development are planned.

Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis. METHODS: We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18. RESULTS: A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms. CONCLUSIONS: Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.).

Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis.

BACKGROUND: Poor sleep quality is associated with increased mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis. This post hoc analysis of Phase 3 studies (3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing haemodialysis, who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1/-2) or placebo (N = 425, KALM-1/-2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D itch scale (5­D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥ 3-point, versus < 3-point WI-NRS improvement using SQ-NRS in Study 3105 (mean [95% confidence interval]: -5.2 [-5.6, -4.8] vs -1.5 [-2.0, -1.0]) and 5-D SDQ in KALM-1/-2 (-1.8 [-2.1, -1.6] vs -0.8 [-1.1, -0.4]). SQ-NRS and WI-NRS scores correlated strongly at baseline and Week 12 in Study 3105 (Spearman correlation coefficient: 0.77 and 0.84, respectively). Correlations were also observed between 5-D SDQ and WI-NRS scores in Study 3105 and KALM­1/­2. CONCLUSIONS: In patients undergoing haemodialysis with moderate-to-severe CKD-aP, itch reduction with intravenous difelikefalin was associated with improved sleep quality. As disturbed sleep may contribute to mortality and morbidity in CKD-aP, difelikefalin may help to address a major clinical burden by improving sleep quality, secondary to itch relief.

Cost-effectiveness and Quality of Specialized and Routine Care in a German Cohort of Patients with Chronic Pruritus.

Chronic pruritus is a prevalent interdisciplinary symptom with a strong influence on health-related quality of life. Patients need extensive diagnostics and long-term treatment. This retrospective and prospective cohort study compared routine and university-based specialized care in terms of cost-effectiveness and patient benefit. Direct medical and non-medical costs and patient-reported outcomes (PRO; pruritus intensity, quality of life, treatment needs and benefits) were assessed. Data analyses were conducted using descriptive methods and non-parametric statistical tests. A total of 300 adult patients (54.3% female) participated in the study. Six months after the treatment start in a specialized German pruritus care unit, the total costs were significantly reduced (mean total costs 686 € vs 433 € per patient per half year (total cohort); p < 0.001; mean out-of-pocket costs 198 € vs 124 € per half year (total cohort), p < 0.001). Pruritus intensity (numerical rating  scale 5.3 vs 3.7, p < 0.001), quality of life (Dermatology Life Quality Index 8.9 vs 5.7, p < 0.001) and patient benefit (Patient Benefit Index Pruritus 1.2 vs 2.1, p < 0.001) improved significantly (total  cohort). The results of this study show, that treatment of chronic pruritus patients in a specialized itch centre leads to an improvement in patient  benefit and reduces the economic burden at the same time.

Perceived Stigmatization among Dermatological Outpatients Compared with Controls: An Observational Multicentre Study in 17 European Countries.

Perceived stigmatization places a large psychosocial burden on patients with some skin conditions. Little is known about the experience of stigmatization across a wide range of skin diseases. This observational cross-sectional study aimed to quantify perceived stigmatization and identify its predictors among patients with a broad spectrum of skin diseases across 17 European countries. Self-report questionnaires assessing perceived stigmatization and its potential predictors were completed by 5,487 dermatology outpatients and 2,808 skin-healthy controls. Dermatological diagnosis, severity, and comorbidity were clinician-assessed. Patients experienced higher levels of perceived stigmatization than controls (p < 0.001, d = 0.26); patients with psoriasis, atopic dermatitis, alopecia, and bullous disorders were particularly affected. Multivariate regression analyses showed that perceived stigmatization was related to sociodemographic (lower age, male sex, being single), general health-related (higher body mass index, lower overall health), disease-related (higher clinician-assessed disease severity, presence of itch, longer disease duration), and psychological (greater distress, presence of suicidal ideation, greater body dysmorphic concerns, lower appearance satisfaction) variables. To conclude, perceived stigmatization is common in patients with skin diseases. Factors have been identified that will help clinicians and policymakers to target vulnerable patient groups, offer adequate patient management, and to ultimately develop evidence-based interventions.

Comorbidities, healthcare resource utilization & treatment pattern among patients with prurigo nodularis, compared to a benchmark in Germany: A real-world evidence claims data study.

BACKGROUND: Prurigo nodularis (PN) is a rare chronic inflammatory skin disease with a high disease burden, but data on clinical and economic burden are still scarce. OBJECTIVE: To describe the real-world epidemiologic, clinical and therapeutic characteristics and related economic burden of patients with PN compared to a benchmark population in Germany. METHODS: This retrospective study was based on an excerpt of German Statutory Health Insurance data of patients with an initial PN diagnosis between 2012 and 2016. PN cohort contained no record of PN in eight quarters before the index quarter and was followed up for eight quarters (unless deceased). Benchmark cohort without PN was calculated using direct standardization and 1:1 matching to PN cohort. RESULTS: Out of 4,536,002 insured patients, 2309 incident patients with PN were identified and matched to the benchmark cohort out of 3,018,382 patients without PN. Patients were mostly between 45 and 80 years when diagnosed with PN. Higher comorbidity rates were reported for PN than benchmark, with a rising disease burden at follow-up. Most patients with PN (91.3%) were diagnosed outpatient and had >50% more outpatient visits than the benchmark cohort. Hospitalization rates were higher in PN (53.9%) versus benchmark (35.1%), yielding twice longer mean hospital stays for PN (12 days) compared to benchmark (6 days) (p < 0.001). The most common initial therapy for patients with PN was topical corticosteroids (47.6%); ≥10% of patients were treated with antidepressants, antihistamines or systemic corticosteroids. Therapy rates were higher for PN compared to benchmark (p < 0.001). Mean initial costs were twofold higher in PN versus benchmark for outpatient, inpatient and drugs. During follow-up, an increase of >70% in mean PN costs compared to benchmark was identified for outpatient, inpatient and concomitant treatments (p < 0.001). CONCLUSION: This study highlights the significantly higher clinical and economic burden incurred by PN compared to benchmark patients in Germany, reflecting the unmet medical need for PN.

Upadacitinib treatment withdrawal and retreatment in patients with moderate-to-severe atopic dermatitis: Results from a phase 2b, randomized, controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to upadacitinib oral treatment is not fully characterized. OBJECTIVES: Assess the effect of upadacitinib withdrawal on skin clearance and itch improvement in adult patients with moderate-to-severe AD and evaluate the kinetics of recovery on rescue treatment. METHODS: Data from a phase 2b randomized, placebo-controlled trial (NCT02925117) of upadacitinib in patients with moderate-to-severe AD were analysed. Patients were randomized 1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg or placebo, and then at Week 16, patients were re-randomized 1:1 to receive the same dose of upadacitinib (upadacitinib 30 mg for patients initialized to placebo) or placebo. From Week 20, those who experienced loss of response defined as Eczema Area and Severity Index <50% improvement from baseline (EASI 50) received rescue treatment with upadacitinib 30 mg. RESULTS: Patients who withdrew from upadacitinib experienced a rapid loss of skin clearance response, while those who switched from placebo to upadacitinib gained response. Loss of skin clearance response occurred within 4 weeks and worsening of itch occurred within 5 days. In patients who originally received placebo or a lower dose of upadacitinib leading to a loss of EASI response, rescue treatment with upadacitinib 30 mg resulted in rapid recovery or improvement of both skin and itch responses; most patients who were re-randomized to placebo achieved EASI 75 and IGA 0/1 by 8 weeks of rescue treatment. No new safety risks were observed. CONCLUSIONS: Continuous treatment with upadacitinib is suggested to maintain skin clearance and antipruritic effects.

International Dermatology Outcome Measures (IDEOM) - Report from the 2022 Annual Meeting.

BACKGROUND: The International Dermatology Outcome Measures (IDEOM) is a non-profit organization dedicated to the advancement of evidence-based, consensus-driven outcome measures in dermatological diseases. Researchers and stakeholders from various backgrounds collaborate to develop these objective benchmark metrics to further advance treatment and management of dermatological conditions. SUMMARY: The 2022 IDEOM Annual Meeting was held on June 17-18, 2022. Leaders and stakeholders from the hidradenitis suppurativa, acne, vitiligo, actinic keratosis, alopecia areata, itch, cutaneous lymphoma, and psoriatic disease workgroups discussed the progress of their respective outcome-measures research. This report summarizes each workgroup's updates from 2022 and their next steps as established during the 2022 IDEOM Annual Meeting. J Drugs Dermatol. 2023;22(12):1153-1159 doi:10.36849/JDD.7615.