A systematic review of interleukin-31 inhibitors in the treatment of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is a neuroimmunological skin disease. Severe itching is the most challenging symptom which affects patients' quality of life. T helper 2-derived cytokines, such as interleukin-31 and oncostatin M (OSM), play a crucial role in PN pathogenesis. Nemolizumab and vixarelimab are two biologics acting as IL-31 inhibitors. Vixarelimab also suppresses the OSM activity. This systematic review evaluates the efficacy and safety of nemolizumab and vixarelimab in PN management. METHODS: A systematic search was conducted in PubMed/Medline, Ovid Embase, and Web of Science up to September 17th, 2023. Clinical trials and cohort studies published in English were included. RESULTS: Among a total of 96 relevant records, five were included. The results of four studies with 452 patients using nemolizumab showed that a significantly higher percentage of patients treated with nemolizumab demonstrated a reduction in peak pruritus numerical rating scale (PP-NRS) and investigator's global assessment along with improved sleep disturbance (SD) and quality of life than the placebo group. Moreover, one study administered vixarelimab to 49 PN patients, and their finding illustrated a higher rate of subjects who received vixarelimab experienced ≥ 4-point diminution in worst itch NRS, visual analog scale, healing of representative lesions, and SD quality compared to the placebo group. CONCLUSIONS: IL-31 inhibitors suggest distinct advantages in improving pruritus, sleep quality, and overall quality of life in subjects with moderate-to-severe PN. Further clinical studies are recommended to compare the effectiveness of these biologics to other therapeutic choices.

Development and Validation of a Patient-Reported Outcome Measure to Assess Disease Control in Chronic Prurigo.

Importance: Chronic prurigo (CPG), including prurigo nodularis, is a difficult disease to treat and considerably affects patients' quality of life. Helping patients obtain control of CPG is a major treatment goal. Objective: To develop and validate the Prurigo Control Test (PCT), a tool for assessing disease control in CPG, and to identify a cutoff value for controlled disease to aid treatment decisions. Design, Setting, and Participants: This qualitative study followed the current recommendations for patient-reported outcome measure development in the generation and validation of the PCT. The final PCT was obtained after item generation, followed by reduction and selection, and was then tested for internal consistency and test-retest reliability, convergent validity, known-group validity, screening accuracy, and banding. The item-generation phase resulted in an unselected list of 69 potential PCT items. Impact analysis, interitem correlation, and review for content (face) validity resulted in final set of 5 PCT items. The validation study was performed among patients across 2 expert centers in Germany. Data were analyzed from February 2017 to November 2019. Main Outcomes and Measures: A 5-item PCT with a recall period of 2 weeks was developed. A cutoff value of 10 points or higher was determined as suitable for identifying patients with well-controlled vs poorly controlled CPG. Results: Of the 95 patients included in the validation study, the median (range) age was 63 (19-87) years, 50 patients (53%) were women, and the median (range) disease duration was 72 (9-774) months. The validation study yielded good internal consistency reliability (Cronbach α, 0.86) and a high degree of convergent validity. The PCT demonstrated good known-group validity and could discriminate between patients who differed in prurigo control. Test-retest reliability was high, and the intraclass correlation coefficient was 0.94, indicating excellent reproducibility. Conclusions and Relevance: This qualitative study showed that the PCT is able to assess disease control in patients with CPG. Its retrospective approach, brevity, and simple scoring likely make the PCT suitable for clinical practice and trials.

Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments.

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.

A critical review of dupilumab for adult patients with prurigo nodularis.

INTRODUCTION: Prurigo nodularis (PN) is a chronic inflammatory skin condition that presents with pruritus and hyperkeratotic nodules. These symptoms impact patients' quality of life and mental health. Treating prurigo nodularis is challenging, and many of the available topical and systemic therapies have limited efficacy and a myriad of adverse effects. AREAS COVERED: In this article, we discuss the use of dupilumab for adult patients with prurigo nodularis. Dupilumab is a biologic that inhibits Th2-mediated inflammation and has been successfully used to treat a variety of dermatologic disorders. Dupilumab has revolutionized the management of PN, with recent clinical trials showing its efficacy in treating both pruritus and prurigo nodules, as well as improving quality of life. It has a favorable safety profile and is well tolerated. Other novel treatments are also currently under investigation for the treatment of PN, with early studies reporting promising results. EXPERT OPINION: Dupilumab is becoming the drug of choice for the treatment of PN and may also be effective in treating patients with systemic underlying causes of their PN, although more studies are needed to assess this. Trials evaluating the long-term efficacy and durability of dupilumab in PN are also of interest.

Prurigo of pregnancy.

A primigravida in her 20s, with 38 weeks period of gestation, came to the emergency ward of obstetrics wing with complaints of extensive itching over the extremities. On local examination, there were multiple, discrete, hyperpigmented papules topped with depigmentation and excoriations on upper and lower extremities. These are of 0.5-1 cm in size and some have central crusts . On clinical findings and exclusion of other pathologies, it was diagnosed as prurigo of pregnancy. The patient had an uneventful follow-up period.

INDIVIDUAL ARTICLE: Prurigo Nodularis: Current Clinicopathologic Overview and Psychodermatological Perspectives.

Prurigo nodularis (PN) is a quintessential neurocutaneous condition characterized by neural sensitization and intractable itch leading to intense scratching. This causes the formation of nodules with epidermal thickening and further release of pro-inflammatory mediators that recruit immune cells and increase dermal nerve proliferation and hypertrophy perpetuating the itch-scratch cycle. Those with PN have a significant quality-of-life (QoL) burden due to itch, anxiety, and sleep disturbance. In addition, PN exhibits psychiatric comorbidities that affect mental wellbeing such as depression, mood disorders, and substance abuse. This paper serves as an overview of the clinicopathologic aspects of PN, the burden of PN on QoL, and the psychodermatological aspects of the disease state.  J Drugs Dermatol. 2023;22:12(Suppl 2):s6-11.

INDIVIDUAL ARTICLE: Patient Journey and the Burden of Systemic Comorbidities and Sequalae in Prurigo Nodularis.

BACKGROUND: Prurigo Nodularis (PN) is a relatively rare chronic inflammatory skin disease characterized by firm pruritic nodules. PN is associated with significantly increased rates of many systemic and non-systemic comorbidities. This results in a higher burden of disease and utilization of specialty care compared to non-PN United States (US) adults. Psychiatric comorbidities associated with PN include depression and anxiety. In this article, we describe the burden of comorbidities. sequelae of disease, inflammatory disease signatures, and the impact of PN in African American and Asian patients. Furthermore, we explore challenges in the recognition and diagnosis of PN and describe methods to increase awareness of PN among dermatologists. J Drugs Dermatol. 2023;22:12(Suppl 2):s12-14.

INDIVIDUAL ARTICLE: Management of Prurigo Nodularis.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease characterized by intense pruritus and nodular lesions associated with reduced quality of life. Until recently, no US Food and Drug Administration (FDA)-approved therapies have been available for the management of PN. Treatment regimens have been highly variable and clinical management guidelines are lacking overall; formal treatment guidelines do not exist within the US. In 2022, dupilumab became the first FDA-approved medication for PN. Multiple novel agents that target the neuroimmune underpinnings of the disease are currently in development and show promise for this challenging disorder. OBJECTIVE: To review current treatments and emerging therapies for effective management of patients with PN. METHODS: We reviewed publications on PN management identified from PubMed, Embase, Web of Science, and the Cochrane Library. We also included publicly available data on clinical trials for PN therapies reported on the US National Library of Medicine ClinicalTrials.gov, the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) Database, and the European Clinical Trials (EudraCT) Database. RESULTS: The recommended management of PN begins with an assessment of disease severity, including disease burden and pruritus intensity, and evaluation of comorbid medical disorders. Treatment goals include resolution of itch, improvement in nodules or cutaneous lesions, and improvement in quality of life. Therapies should be selected based on a patient’s clinical presentation and comorbidities. Treatment should simultaneously address the neural and immunologic components of PN. Combination therapy, particularly with conventional agents, may be beneficial. LIMITATIONS: Data on most conventional PN treatments are limited to anecdotal reports, small clinical trials, or expert consensus recommendations. No head-to-head comparative trials have evaluated the relative efficacy of conventional and/or emerging agents, or combination therapy. CONCLUSION: An effective treatment approach for patients with PN should reduce pruritus, allow nodular lesions to heal, and improve individual quality of life. The treatment landscape for PN is rapidly evolving with one FDA-approved agent and several new promising therapies on the horizon. J Drugs Dermatol. 2023;22:12(Suppl 2):s15-22.

Molecular mechanisms of pruritus in prurigo nodularis.

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.

Patient Perspectives on Living With Severe Prurigo Nodularis.

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

Clinical and Pathological Spectrum of Prurigo Pigmentosa in Central European Individuals.

Importance: Based on early studies, prurigo pigmentosa (PP) was considered a rare inflammatory dermatosis affecting primarily Asian individuals. However, several case reports subsequently showed that the disease is not restricted to those of Asian origin. Large studies on PP in central European individuals, on the other hand, are missing. Objective: To increase awareness of PP by describing the clinical, histopathological, and immunohistochemical features in central European individuals. Design, Setting, and Participants: This observational, retrospective case series analyzed clinicopathological features of 20 central European patients diagnosed with PP. Data collection was performed by means of archive material, including physician's letters, clinical photographs, and histopathological records, at the Department of Dermatology at the Medical University of Graz in Austria from January 1998 to January 2022. Main Outcomes and Measures: Demographic, clinical, histopathological, and immunohistochemical characteristics for patients diagnosed with PP were recorded. Results: Of the 20 patients included, 15 (75%) were female, and the mean (range) age was 24.1 (15-51) years. The study cohort consisted entirely of European patients. The most common site of involvement of PP was the breast, followed by the neck and back. Other involved clinical sites were the abdomen, shoulders, face, head, axillae, arms, and genital region and groin. Clinically, lesions were characterized by a symmetric pattern in 90% (n = 18) of all cases. Marked hyperpigmentation was observed only in 25% (n = 5) of patients. In some cases, triggers such as malnutrition, long-term pressure, and friction were noted. Histologic findings revealed presence of neutrophils in all cases and necrotic keratinocytes in 67% (n = 16) of cases. Immunohistochemistry results showed predominance of CD8+ lymphocytes in the epidermis, as well as the presence of plasmacytoid dendritic cells and myeloid cell nuclear differentiation antigen-positive neutrophil precursors. Conclusions and Relevance: This case series found that most clinical features observed in Asian patients were also observed in central European patients, but hyperpigmentation was primarily mild to moderate. Histopathological features were similar to those reported in the literature with the additional presence of myeloid cell nuclear differentiation antigen-positive precursor neutrophils. These results expand previous knowledge about PP in central European individuals.

Case Report: Prurigo nodularis-like linear IgA/IgG bullous dermatosis: a case report and literature review.

Linear IgA/IgG bullous dermatosis (LAGBD) is a rare autoimmune subepidermal bullous disorder characterized by linear deposition of concurrent IgA and IgG autoantibodies along the basement membrane zone (BMZ). The clinical features of LAGBD can be diverse, including tense blisters, erosions, erythema, crusting and mucosa involvement, while papules or nodules are generally absent. In this study, we present a unique case of LAGBD, which showed prurigo nodularis-like clinical appearance on physical examination, linear deposition of IgG and C3 along the basement membrane zone (BMZ) in direct immunofluorescence (DIF), IgA autoantibodies against the 97-kDa and 120-kDa of BP180 and IgG autoantibodies against the 97-kDa of BP180 by immunoblotting (IB), while BP180 NC16a domain, BP230, and laminin 332 were negative by enzyme-linked immunosorbent assay (ELISA). After administration of minocycline, the skin lesions improved. We performed a literature review of LAGBD cases with heterogeneous autoantibodies and found clinical presentations of most cases resemble bullous pemphigoid (BP) and linear IgA bullous disease (LABD), which is consistent with previous reported findings. We aim to increase our understanding of this disorder and to enhance the importance of applying immunoblot analyses and other serological detection tools in clinic for precise diagnosis as well as accurate treatment strategy of various autoimmune bullous dermatoses.

A review of the current management and burden of prurigo nodularis in the United States.

Prurigo nodularis (PN) is a chronic neural- and immune-mediated disease that is characterized by intense itch, history of skin scratching, and development of papulonodular lesions. These lesions can develop consequent to a cycle of itching and scratching associated with inflammation and changes in skin cells and nerve fibers (eg, pathogenic skin fibrosis, tissue remodeling, and chronic neuronal sensitization). Diagnosis of PN involves individual evaluation of clinical characteristics to identify disease and symptom severity. In the United States, adult patients with PN (estimated, < 90,000) are more likely to be older (age, 50-60 years); in addition, this disease is detected at higher rates in women and Black individuals relative to other demographic subgroups. Still, the small population of patients with PN exhibits considerably high use of health care resources and experiences considerable symptom burden and negatively impacted quality of life. Further, PN is associated with increased rates of a range of comorbid diseases compared with other inflammatory dermatoses (eg, atopic dermatitis, psoriasis). Adequate treatment must address both the neural and immunological component of the disease; there remains a great unmet need for safe and effective therapies that can reduce the burden of disease.