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.

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.

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.

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.

Body dysmorphia in common skin diseases: results of an observational, cross-sectional multicentre study among dermatological outpatients in 17 European countries.

BACKGROUND: Body dysmorphic disorder (BDD) is a common psychiatric disorder associated with high costs for healthcare systems as patients may repeatedly ask for different, often not effective, interventions. BDD symptoms are more prevalent in patients with dermatological conditions than in the general population, but there are no large sample studies comparing the prevalence of BDD symptoms between patients with dermatological conditions and healthy skin controls. OBJECTIVES: To compare the prevalence of BDD symptoms between patients with different dermatological conditions and healthy skin controls and to describe sociodemographic, physical and psychological factors associated with BDD symptoms to identify patients who may have a particularly high chance of having this condition. METHODS: This observational, cross-sectional, comparative multicentre study included 8295 participants: 5487 consecutive patients with different skin diseases (56% female) recruited among dermatological outpatients at 22 clinics in 17 European countries, and 2808 healthy skin controls (66% female). BDD symptoms were assessed by the Dysmorphic Concern Questionnaire. Sociodemographic data and information on psychological factors and physical conditions were collected. Each patient was given a dermatological diagnosis according to ICD-10 by a dermatologist. The study was registered with number DRKS00012745. RESULTS: The average participation rate of invited dermatological patients was 82.4% across all centres. BDD symptoms were five times more prevalent in patients with dermatological conditions than in healthy skin controls (10.5% vs. 2.1%). Patients with hyperhidrosis, alopecia and vitiligo had a more than 11-fold increased chance (adjusted Odds Ratio (OR) > 11) of having BDD symptoms compared with healthy skin controls, and patients with atopic dermatitis, psoriasis, acne, hidradenitis suppurativa, prurigo and bullous diseases had a more than sixfold increased chance (adjusted OR > 6) of having BDD symptoms. Using a logistic regression model, BDD symptoms were significantly related to lower age, female sex, higher psychological stress and feelings of stigmatization. CONCLUSIONS: Clinical BDD symptoms are significantly associated with common dermatological diseases. As such symptoms are associated with higher levels of psychological distress and multiple unhelpful consultations, general practitioners and dermatologists should consider BDD and refer patients when identified to an appropriate service for BDD screening and management.

Healthcare Utilization and Treatment Patterns in Patients with Chronic Prurigo and Chronic Pruritus in Germany.

BACKGROUND: To date, there have been no large studies describing real-world treatment of chronic prurigo (CPG) and pruritus (CPR) in Germany. OBJECTIVE: To determine the healthcare utilization, treatment patterns, and costs associated with CPG and CPR in Germany. METHODS: Retrospective analysis using anonymized claims data (German DAK-Gesundheit), based on a 40% sample of all insured adults of the DAK-Gesundheit on December 31, 2010 (N = 2,006,003). RESULTS: Patients with CPR (prevalence 2.2%) most commonly visited general medicine/general practitioners (GPs, 80.1%), followed by gynecologists (66.1%) and dermatologists (51.1%). Patients with CPG (prevalence 0.2%) most commonly visited dermatologists (85.7%), GPs (78.1%), and ophthalmologists (47.2%). Of adult patients, 44% received at least one drug prescription. Two thirds of patients with a drug prescription received ≥1 topical drug (66.2%), and 54.3% ≥1 systemic drug (total costs of approximately EUR 550,000 and 2,500,000, respectively). Of patients with CPG, 33.8% received ≥1 systemic and 45.1% ≥1 topical drug prescription (costs of approximately EUR 360,000 vs. 105,000). Of patients with CPR, 23.5% received ≥1 systemic and 28.6% ≥1 topical drug prescription (costs of approximately EUR 2,000,000 vs. 500,000). Of patients with CPG, 5.8% received ≥1 phototherapy application vs. 1.2% of patients with CPR. CONCLUSIONS: These findings reflect the reality of care and can form a basis for the identification of overuse, underuse, and misuse in order to design CPG and CPR healthcare more effectively and efficiently.

Introduction of a Specific Dermatological Rehabilitation Programme for Patients with Chronic Pruritus: A Pilot Study.

Chronic pruritus is a common symptom, associated with several severe medical conditions, great psychological burden, and reduced quality of life. It also poses socio-economic challenges concerning patients' work loss and healthcare costs. In Germany, medical rehabilitation programmes represent an integral part of the medical care of patients with chronic inflammatory skin diseases. However, such programmes play only a rudimentary role in the treatment of other dermatological diseases, such as dermatological oncology, genetic skin diseases, and chronic pruritus. Therefore, a specific antipruritic dermatological rehabilitation programme was developed in cooperation between the Department of Dermatology of the Medical Rehabilitation Center Bad Bentheim and the Center for Chronic Pruritus of the University Hospital of Muenster, Germany. This prospective study compared short-term patient-reported outcomes (n = 121) at the beginning and end of the rehabilitation programme. The majority of subjects had chronic pruritus on primary diseased, inflamed skin. Significant improvements in pruritus intensity (p ≤ 0.001), quality of life (p ≤ 0.001), anxiety symptoms (p ≤ 0.001) and depression (p ≤ 0.001), as well as an overall patient-relevant benefit (Patient Benefit Index 2.6 ± 1.06) and treatment-related patients' satisfaction, were shown. This suggests that implementation of this standardized rehabilitation programme for treatment of patients with chronic pruritus was successful.

S2k guideline: Diagnosis and treatment of chronic pruritus.

Pruritus is a cross-disciplinary leading symptom of numerous diseases and represents an interdisciplinary diagnostic and therapeutic challenge. In contrast to acute pruritus, chronic pruritus (CP) is a symptom of various diseases that is usually difficult to treat. Scratching and the development of scratch-associated skin lesions can alter the original skin status. In the presence of an itch-scratch-cycle, even secondary diseases such as chronic prurigo can develop. Chronic pruritus leads to considerable subjective suffering of those affected, which can result in restrictions on the health-related quality of life such as sleep disturbances, anxiety, depressiveness, experience of stigmatization and/or social withdrawal up to clinically relevant psychic comorbidities. Medical care of patients should therefore include (a) interdisciplinary diagnosis and therapy of the triggering underlying disease, (b) therapy of the secondary symptoms of pruritus (dermatological therapy, sleep promotion, in the case of an accompanying or underlying psychological or psychosomatic disease an appropriate psychological-psychotherapeutic treatment) and (c) symptomatic antipruritic therapy. The aim of this interdisciplinary guideline is to define and standardize the therapeutic procedure as well as the interdisciplinary diagnosis of CP. This is the short version of the updated S2k-guideline for chronic pruritus. The long version can be found at www.awmf.org.

Chronic Pruritus of Unknown Origin: Clinical Profile and Disease-Related Burden.

Chronic pruritus of unknown origin is established when no underlying origin for pruritus can be determined. This retrospective cohort study aimed to determine the clinical profile and disease-related burden of chronic pruritus of unknown origin. A total of 263 patients (female/male: 154/109, median age 55 years) were included. Moderate to severe itch intensities were recorded (median average itch: 5.5/10, n = 200; median worst itch: 7.5/10, n = 199). In most cases pruritus lasted longer than 1 year (77.6%), occurred daily (68.2%), occurred in attacks (72.8%), and was often accompanied by dysaesthesias, such as burning, tingling and stinging. Quality of life was moderately impaired, while 22.2% and 12.4% of patients showed pathological anxiety and depression scores. Scratch lesions were associated with higher intensities of itch and greater impairment of quality of life, while women were more burdened by the disease than men. Chronic pruritus of unknown origin may occur at any age and the majority of patients endure severe itch with substantial disease-related burden.

Hand Pruritus: Clinical Profile, Functional Impairment and Disease-related Burden in a Prospective Cohort Study of 395 Patients.

Human hands are complex structures essential for a variety of functions in everyday life. This study prospectively investigated the clinical features of hand pruritus and the resulting functional impairment and disease-related burden in 395 patients with chronic pruritus (210 females, median age 59 years). Moderate to very severe hand pruritus was reported by 91.2% of patients, while 79% perceived additional sensory symptoms, such as burning, pain or tingling. A long duration of pruritus occurred in most cases (>6 months: 71.4%). A considerable proportion of patients showed moderate to severe impairment in the use of their hands (40.2%), performance of daily activities (65.0%) and quality of life (45.2%). Disease severity and burden is particularly high when both the palms and the backs of the hands are affected, and when pain is present simultaneously. Pruritus located on the hands is impairing and burdensome due to the functional relevance of the hands in everyday life.

Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials.

Chronic prurigo is a pruritic disease characterized by the development of pruriginous lesions due to scratching. The number of lesions is representative of the stage of the disease, while the presence of excoriations reflects the scratching activity. Aim of this study was to validate a new developed tool for the objective assessment of chronic prurigo. Investigator's Global Assessment scales for stage and activity were completed for 187 patients with chronic prurigo, who also reported patient-reported outcomes for itch intensity and quality of life. To assess the reliability and objectivity of the Investigator's Global Assessment, 5 independent raters completed the Investigator's Global Assessment scales for 8 patients twice. The scores increased with increased intensity of pruritus. The Investigator's Global Assessment stage scales correlated strongly with each other (Kendall's-tau-b 0.62) and moderately with the Investigator's Global Assessment activity scale (Kendall's-tau-b 0.47). Intra-rater test-retest reliability was excellent for all items, while the congruence among raters was very good for Investigator's Global Assessment - chronic prurigo activity (Kendall's W 0.84) and good for Investigator's Global Assessment stage scales (Kendall's W 0.747). Investigator's Global Assessment - chronic prurigo stage and activity are thus the best Investigator's Global Assessment instruments for use in assessing chronic prurigo.

Chronic Nodular Prurigo: A European Cross-sectional Study of Patient Perspectives on Therapeutic Goals and Satisfaction.

Chronic nodular prurigo is characterized by recalcitrant itch. Patient perspectives on therapeutic goals, satisfaction with therapy and efficacy of therapeutic regimens for this condition are unknown. This questionnaire study examined these issues in 406 patients with chronic nodular prurigo from 15 European dermatological centres. Improvements in itch, skin lesions and sleep were the most important goals. Emollients, topical corticosteroids and antihistamines were the most frequently used treatments, while a minority of patients were prescribed potent medications, such as systemic immunosuppressants and gabapentinoids. Most patients were not satisfied with their previous therapy (56.8%), while 9.8% did not receive any therapy despite having active disease. A substantial number of respondents (28.7%) considered none of the therapeutic options effective. Although chronic nodular prurigo is a severe disease, most patients were not treated with potent systemic drugs, which may contribute to the high levels of dissatisfaction and disbelief in available therapies. Specific guidelines for chronic nodular prurigo and the development of novel therapies are necessary to improve care.

Diagnostic and treatment algorithm for chronic nodular prurigo.

Chronic nodular prurigo (CNPG) is a subtype of chronic prurigo, also called prurigo nodularis, and a chronic skin condition characterized by intensely pruritic nodular lesions. Although the exact cause of CNPG is unknown, it appears to result from a repetitive itch-scratch cycle induced by neuronal sensitization to chronic pruritus. CNPG is associated with an underlying dermatologic condition in about half of patients, and it can also be attributed to systemic, neurologic, psychogenic, or unknown causes. For most patients, multiple underlying causes are identified. Patients with CNPG often experience impaired quality of life, sleep disturbance, anxiety, and depression. To encourage consistent and accurate diagnosis and treatment of CNPG across regions, we are proposing a diagnostic and treatment algorithm that includes initial assessment of core symptoms, detailed dermatologic history and clinical examination, patient-reported outcomes, diagnostic workup, and recommended therapies. This information is supplemented with photographs to illustrate clinical appearance and disease severity. Because CNPG is often multifactorial and it can take months to years for lesions to heal, interdisciplinary cooperation and long-term management are important.

Analysis of 325 Patients with Chronic Nodular Prurigo: Clinics, Burden of Disease and Course of Treatment.

Chronic nodular prurigo presents with multiple pruriginous nodules and severe pruritus. This study aims to explore the treatment course and regimens in patients with chronic nodular prurigo and to analyse predictive factors contributing to therapeutic success. A total of 325 patients with chronic nodular prurigo (male 37.5%) were analysed concerning demographic data, pruritus intensity, medical history, psychological impairment, quality of life, treatment duration, regimens and outcome. These parameters were compared with 325 sex- and age-matched patients with chronic pruritus on non-lesional skin. Treatment success was dependent on duration and regime of treatment and independent of age, sex and initial itch intensity. Non-responders displayed a higher percentage of inflamed nodules, a higher portion of excoriated nodules and a higher impairment of quality of life and mood factors before initiation of treatment. Gabapentinoids and immunosuppressants proved to be the most successful therapeutic agents. Compared with patients with chronic pruritus, those with chronic nodular prurigo needed longer duration of therapy.

Challenges in Clinical Research and Care in Pruritus.

Chronic pruritus is a frequent global condition. The pathophysiology, underlying aetiology, clinical manifestation, associated burden and response to therapy of chronic pruritus varies from patient to patient, making clinical research and management of this condition challenging. There are still several unmet needs, such as the need to standardize translational research protocols, diagnostic and therapeutic procedures and to enhance the knowledge of the humanistic and economic burden associated with chronic pruritus. Basic and clinical research is of the utmost importance to target these matters. Clinical research has the potential to identify new relevant mechanisms in affected patients, which may lead to identification of novel therapy targets. This article discusses in depth current shortcomings in the daily care of patients with chronic pruritus and the challenges clinical researchers and physicians treating chronic pruritus face in addressing these matters.

Woad extract containing cream improves significantly dry, irritated, and pruritic skin.

Objective of this open, noninterventional, noncontrolled study was to investigate the tolerability and performance of a woad extract containing cream in subjects with dry, pruritic skin after twice daily application over 2 weeks. Assessments included sensorial characteristics, skin condition, pruritus (numeric rating scale [NRS], dynamic pruritus score [DPS]), skin dryness (itch-controlled days [ItchCD], overall dry skin [ODS]), transepidermal water loss (TEWL), skin hydration and quality of life (5PLQ, DLQI). All sensorial characteristics were well perceived (>4), with tolerability (4.77 ± 0.47) and no negative skin feelings (4.73 ± 0.74) achieving the highest scores (0-5 scale). Dry skin and symptoms improved significantly (p < .001) for all variables: NRS (from 4.8 ± 1.74 to 1.83 ± 2.18), ItchCD (from 8.23 ± 4.40 to 4.81 ± 4.07), ODS (from 1.80 ± 0.85 to 0.65 ± 0.65), hydration (23.33 ± 1.33 to 40.70 ± 1.86), and quality of life (5PLQ: from 7.12 ± 4.25 to 4.24 ± 3.67; DLQI: from 5.29 ± 4.79 to 3.00 ± 3.98). The DPS revealed a moderate antipruritic effect. The TEWL decreased slightly (p = .511). No side effects were reported. The study suggests that, the cream is effective, and well tolerated in treating dry, irritated, and pruritic skin.

Exploratory Study of Intracutaneous Histamine Stimulation in Patient Populations with Chronic Pruritus.

Chronic pruritus can be a diagnostic sign of an underlying disease. In the intracutaneous histamine test, histamine (one of the best-known inducers of pruritus) may cause different reaction patterns depending on the underlying disease. The aim of this study was to determine if an intracutaneous injection of histamine can differentiate between the causes of chronic pruritus and thus be used as a diagnostic test in chronic pruritus of unknown aetiology. A total of 140 subjects with chronic pruritus with various dermatological, systemic or neurological diseases were included. The intracutaneous histamine test was performed once on each subject. Erythema, wheal and pruritus intensity were measured and analysed. Significantly greater wheal size was observed in patients with systemic or multifactorial causes. In general, there was a significant correlation between age and wheal size. Also, noticeable differences were found between males and females regarding pruritus and wheal size. In summary, the exact type of chronic pruritus could not be clearly determined based on the results of the intracutaneous histamine test. However, the results provide valuable insights into specific reaction patterns to experimental histamine-induced itch, e.g. sex-specific differences in the neurophysiology of pruritus, which should be considered in future studies.

Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Validation of a Comprehensive Set of Pruritus Assessment Instruments: The Chronic Pruritus Tools Questionnaire PRURITOOLS.

Few studies have validated standard measurement instruments for evaluation of chronic pruritus. The Chronic Pruritus Tools Questionnaire PRURITOOLS assembles a set of instruments for the assessment of pruritus, such as the visual analogue scale (horizontal 100-mm line), numerical rating scale (0-10), verbal rating scale, and information on pruritus quality and improvement during therapy. This study, with 40 subjects, analysed PRURITOOLS regarding convergent validity and test-retest reliability (60 min), followed by a feasibility questionnaire. Test-retest reliability for PRURITOOLS items was excellent (intraclass correlation coefficient 0.84-1). Strong to very strong correlations between the pruritus intensity scales indicated convergent validity. The feasibility questionnaire showed an overall acceptance of PRURITOOLS, and the majority of subjects (82.5%) considered it an appropriate questionnaire to measure pruritus. In conclusion, PRURITOOLS offers validated tools for rapid pruritus assessment in routine care or endpoints of clinical trials.