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Molecular mechanisms of pruritus in prurigo nodularis.

ABSTRACT: Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune network; however, the underlying mechanism remains undetermined. Itch mediators play a key role in pruritus amplification in PN and understanding their action mechanism will undoubtedly lead to the development of novel targeted antipruritic agents. In this review, we describe a series of pruritogens and receptors involved in mediating itching in PN, including cytokines, neuropeptides, extracellular matrix proteins, vasculogenic substances, ion channels, and intracellular signaling pathways. Moreover, we provide a prospective outlook on potential therapies based on existing findings.

SUBMITTER: Shao Y

PROVIDER: S-EPMC10701428 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Molecular mechanisms of pruritus in prurigo nodularis.

Shao Yixin Y Wang Duoqin D Zhu Yiqi Y Xiao Zijing Z Jin Taiyu T Peng Lisi L Shen Yanyun Y Tang Hui H

Frontiers in immunology 20231123

Pruritus is the most common symptom of dermatological disorders, and prurigo nodularis (PN) is notorious for intractable and severe itching. Conventional treatments often yield disappointing outcomes, significantly affecting patients' quality of life and psychological well-being. The pathogenesis of PN is associated with a self-sustained "itch-scratch" vicious cycle. Recent investigations of PN-related itch have partially revealed the intricate interactions within the cutaneous neuroimmune netwo ...[more]

PMID: 38077377

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Project description:Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that is defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history of repeated scratching. Patients with CPG experience a significant psychological burden and a notable impairment in their quality of life. Chronic prurigo of nodular type (CNPG; synonym: prurigo nodularis) represents the most common subtype of CPG. As CNPG is representative for all CPG subtypes, we refer in this review to both CNPG and CPG. We provide an overview of the clinical characteristics and assessment of CPG, the burden of disease and the underlying pathophysiology including associated therapeutic targets. The information provided results from a PubMed search for the latest publications and a database search for current clinical trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using the following terms or combinations of terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab is the first authorized systemic therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for CNPG to date. Topical and systemic agents that are currently under investigation in clinical randomized, placebo-controlled phase II and III trials such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) and the opioid modulator nalbuphine are highlighted. In the last past 15 years, several milestones have been reached regarding the disease understanding of CPG such as first transcriptomic analysis, first terminology, first guideline, and first therapy approval in 2022, which contributed to improved medical care of affected patients. The broad range of identified targets, current case observations and initiated trials offers the possibility of more drug approvals in the near future.

Project description:ImportanceThere is an unmet need for psychometrically sound instruments to measure pruritus associated with prurigo nodularis (PN).ObjectiveTo evaluate the psychometric properties of the itch numeric rating scale (itch NRS), both the Worst Itch Numeric Rating Scale (WI-NRS) and the Average Itch Numeric Rating Scale (AI-NRS).Design, setting, and participantsThis secondary analysis is based on a secondary end point of a phase 2 randomized clinical trial of serlopitant for treatment of pruritus associated with PN. This randomized, double-blind, placebo-controlled study was conducted at 15 sites in Germany. Eligible patients were aged 18 to 80 years and had generalized PN for more than 6 weeks that was refractory to previous antipruritic therapies. Patients were required to have a visual analog scale itch score of 7 or higher at screening. Data were collected from July 2014 to June 2016 and analyzed from June 2016 to January 2017.Main outcomes and measuresThe itch NRS (AI-NRS and WI-NRS) was correlated together with the following measures: the electronic verbal rating scale (eVRS) for itch self-categorization, average itch visual analog scale (AI-VAS), worst itch visual analog scale (WI-VAS), the pruritus-specific quality-of-life rating instrument ItchyQoL, Dermatology Life Quality Index (DLQI), and Prurigo Activity and Severity Score (items 7b and 7a: percentage healed prurigo lesions and percentage of prurigo lesions with excoriations).ResultsThere were 123 participants in this study; the mean (SD) age of participants was 57.3 (11.58) years, and 58 (47.2%) were male. Strong associations (r ≥ 0.5) were observed between itch NRS items (WI-NRS and AI-NRS) and AI-VAS (24 hours) at weeks 2, 4, and 8 (r = 0.72-0.90; P < .001). Similar strong associations were also observed between itch NRS items and WI-VAS (24 hours) and eVRS for itch severity across weeks 2, 4, and 8 (r = 0.65-0.92; all P < .001). Strong correlations were seen between change scores for WI-NRS and WI-VAS and AI-VAS (r = 0.76 and 0.70, respectively; both P < .001). Similar findings were seen for AI-NRS, where correlations between change scores for WI-VAS and AI-VAS were 0.71 and 0.72, respectively (both P < .001). Analyses for the itch NRS items also showed that test-retest reliability was acceptable and provided evidence of acceptable convergent validity based on the eVRS and visit verbal rating score for itch self-categorization, ItchyQoL, and DLQI.Conclusions and relevanceResults from this secondary analysis show that the itch NRS items WI-NRS and AI-NRS have good psychometric properties for pruritus associated with PN and should be considered acceptable tools for assessing pruritus in future clinical trials of PN.Trial registrationClinicalTrials.gov Identifier: NCT02196324.

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Molecular mechanisms of pruritus in prurigo nodularis.

Publications

Molecular mechanisms of pruritus in prurigo nodularis.

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