Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16weeks compared to placebo. Objectives: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment. Methods: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep). Results: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders. Conclusions: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD. ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2). [ABSTRACT FROM AUTHOR]

Background Poor sleep quality is associated with higher 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 (HD). This post hoc analysis of the Phase 3 difelikefalin studies (Study 3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in individuals with CKD-aP improved sleep quality. Methods Itch intensity was assessed in patients undergoing HD 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 and -2) or placebo (N  = 425, KALM-1 and -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 (5-D 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 and -2 [–1.8 (–2.1, −1.6) vs −0.8 (–1.1, −0.4)]. SQ-NRS and WI-NRS scores were highly correlated at both 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 KALM-1 and -2. Conclusions In patients undergoing HD 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. Trial Registration KALM-1 (NCT03422653), KALM-2 (NCT03636269), Study 3105 (NCT03998163). [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: 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 β‐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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction Patients with prurigo nodularis (PN) often report high disease burden with substantial impact on quality of life. Patient Global Impression of Change (PGIC) and Severity (PGIS) are patient self-assessment measures that quantify their experience of disease during treatment. Dupilumab has recently been approved as the first systemic treatment for PN in the US and Europe. Objectives: To evaluate patient-reported global impression of disease severity improvement in dupilumab-treated patients with PN during the LIBERTY-PN PRIME and PRIME 2 trials. Materials & Methods: PRIME and PRIME2 were randomized, double-blind, multicenter, parallel-group, 24-week, phase 3 trials in adults with PN with ≥20 nodules and severe itch, inadequately controlled with topical prescription therapies or for whom these are inadvisable. Patients received 300 mg dupilumab subcutaneously (600 mg loading dose; n = 153) or matched placebo (n = 158) every 2 weeks. In this analysis, data from the two studies were pooled. Patient satisfaction was assessed in the overall placebo group, overall dupilumab-treated group, and those treated with dupilumab who did not achieve the stringent multicomponent endpoint (n = 99) of ≥4-point improvement from baseline in Worst Itch Numerical Rating Scale (WI-NRS, range: 0-10) and an Investigator's Global Assessment PN Stage (IGA PN-S, score range: 0-4) score 0 or 1 (clear or almost clear; ≤5 nodules) at Week (W) 24. Endpoints include proportion of patients achieving: PGIC (range: 0-6) scores of 0 or 1 (very much better or moderately better) at W12, and W24; and PGIS (range: 1-4) score of 1 or 2 (none or mild) at baseline, W12, and W24. Safety was also assessed. Results: Baseline demographic and clinical characteristics were generally similar between groups. In the overall dupilumab and placebo groups, baseline mean (SD) WI-NRS scores were 8.6 (0.9) and 8.4 (1.1), respectively; 32.7% and 34.2% had an IGA PN-S score of 4 (remaining patients had IGA PN-S 3); and mean (SD) PGIS scores were 3.7 (0.5) and 3.7 (0.5) respectively. In dupilumab multicomponent endpoint non-responders, mean (SD) WI-NRS score was 8.6 (0.9). 35.4% and 64.6% had an IGA PN-S score of 4 and 3 respectively; and mean (SD) PGIS score was 3.7 (0.5). At W12, 68.0% vs 38.0% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIC 0 or 1, while 55.6% of dupilumab multicomponent non-responders achieved this endpoint (P = 0.0099 vs placebo). At W24, this increased to 74.5% vs 32.9% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieving PGIC 0 or 1, and 61.6% of multicomponent non-achievers (P < 0.0001 vs placebo). At W12, 51.6% vs 22.2% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIS 1 or 2, while 40.4% of multicomponent non-responders achieved the endpoint (P = 0.0027 vs placebo). At W24, 61.4% vs 24.1% (P < 0.0001 vs placebo) of dupilumab-treated vs placebo-receiving patients achieved PGIS 1 or 2, while 44.4% of multicomponent non-responders achieved the endpoint (P = 0.0025 vs placebo). Safety findings were consistent with the known dupilumab safety profile. Conclusions: While not all patients achieved the stringent multicomponent endpoint within the 24-week treatment period during PRIME and PRIME 2 trials, around half of the dupilumab-treated patients still reported significantly more improvement in disease severity and satisfaction with therapy. Overall safety was consistent with the known dupilumab safety profile. [ABSTRACT FROM AUTHOR]

The article discusses the results of two phase III clinical trials, ADvocate1 and ADvocate2, which examined the efficacy and safety of lebrikizumab monotherapy in patients with moderate-to-severe atopic dermatitis (AD). The trials found that lebrikizumab significantly improved patient-reported itch and reduced sleep loss due to itch. The improvements in itch and sleep loss were observed as early as the first few days of treatment and were consistent with previous studies on lebrikizumab. The study was funded by Dermira, a subsidiary of Eli Lilly and Company, and medical writing assistance was provided by ProScribe–Envision Pharma Group. [Extracted from the article]