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BACKGROUND: Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. OBJECTIVES: This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level. METHODS: Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab. RESULTS: This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1+ fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1+ fibroblast and keratinocyte responses toward normal. CONCLUSIONS: This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.

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Resumen: El prurigo crónico nodular (PCN) es una enfermedad dermatológica crónica, caracterizada por la presencia de prurito crónico (PC) y lesiones nodulares pruriginosas cutáneas. El presente trabajo tuvo como objetivo consensuar entre un grupo de expertos, a partir de una revisión bibliográfica no sistemática, un algoritmo para el diagnóstico clínico del PCN. El algoritmo resultante se ha estructurado en tres bloques: 1) identificación precoz del paciente con posible diagnóstico de PCN; 2) diagnóstico y valoración del PCN; y 3) categorización del PCN (identificación de las causas subyacentes o de las comorbilidades asociadas)Consideramos que este algoritmo clínico puede facilitar el diagnóstico correcto de los pacientes con PCN. Además, genera conciencia de la necesidad de un abordaje multidisciplinar y de un tratamiento específico del PCN, pasos indispensables para tomar mejores decisiones terapéuticas. Abstract: Chronic nodular prurigo (CNP) is a chronic dermatological disease characterized by the presence of chronic pruritus and pruritic nodular lesions. The aim of this study was to reach consensus among a group of experts based on a non-systematic literature review and an algorithm for the clinical diagnosis of CNP. The resulting algorithm is structured in 3 blocks: 1) early identification of the patient with a possible diagnosis of CNP; 2) diagnosis and assessment of CNP; and 3) categorization of CNP (identification of the underlying causes or associated comorbidities).We believe that this clinical algorithm can facilitate the correct diagnosis of patients with CNP. Additionally, it raises awareness on the need for a multidisciplinary approach and specific treatment of CNP, steps of paramount importance to make better therapeutic decisions.

Patients with prurigo nodularis (PN) present with pruritus which may lead to sleep disturbances and systemic comorbidities. The objective of our study was to determine the risk of sleep disorders in PN and its association with systemic inflammation and adverse cardiovascular outcomes. We conducted a retrospective population-level cohort using a global health records database to analyze the development of sleep disorders, C-reactive protein (CRP) levels, and risk of cardiovascular disease and mortality in PN compared to controls. PN patients had increased risk of general sleep disorders (RR 1.47, 95%CI 1.42–1.52, obstructive sleep apnea (1.61, 1.54–1.69), insomnia (1.37, 1.29–1.45), hypersomnia (1.47, 1.32–1.64), and restless legs syndrome (1.45, 1.28–1.65). Additionally, PN with sleep disorders had higher CRP levels than PN without sleep disorders (16.2 mg/L vs. 10.6 mg/L). PN patients with sleep disorders were more likely to develop cardiovascular comorbidities, including type 2 diabetes mellitus (RR 2.45, 95%CI 2.25–2.66), metabolic syndrome (4.16, 3.31–5.22), myocardial infarction (2.87, 2.52–3.22), venous thromboembolism (2.93, 2.55–3.39), and greater mortality (HR 1.47, 95%CI 1.34–1.62) compared to PN patients without sleep disorders. Our findings suggest that PN patients are at greater risk of developing various sleep disorders that are associated with adverse cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Prurigo nodularis is a chronic skin condition which has significant negative impacts on the psychosocial function and quality of life of affected patients. It is a heterogeneous disease with complex underlying pathogenic mechanisms, and the clinical efficacy of traditional treatment options is often limited. Recently, great advances have been made in the pathogenesis of prurigo nodularis, which have enabled the development of novel targeted therapies for this disease. Various clinical trials have investigated the therapeutic efficacy of biologics which target the Th2 pathway. Dupilumab, a monoclonal antibody targeting interleukin 4 (IL-4) receptor α, has shown clinical efficacy and obtained United States Food and Drug Administration approval for prurigo nodularis. In addition, nemolizumab (IL-31 receptor A antagonist) and vixarelimab (oncostatin M receptor β antagonist) have shown therapeutic efficacy in clinical trials for prurigo nodularis. Small-molecule inhibitors with clinical promise which are currently under investigation include nalbuphine (opioid receptor modulator), Janus kinase inhibitors, and aprepitant and serlopitant (neurokinin-1 receptor antagonists). The recent development of new biologics and small-molecule inhibitors targeting various immunological and neurological signaling pathways have provided great hope that we are entering a new era of targeted therapies for this challenging clinical condition. In addition, recent advances in RNA sequencing technology may enable the identification of unique signaling pathways and the development of novel treatments for this disease in the future. In this review article, we summarize the current knowledge of the pathogenesis of prurigo nodularis, and discuss recent advances in treatment for this challenging clinical condition.

Background: Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective: To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods: In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results: Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P

Jingyao Liang,1,2,* Wei Li,1,2,* Wenyan Liu,1,2 Yihui Yu,1,2 Hui Ye,1,2 Xibao Zhang1,2 1Institute of Dermatology, Guangzhou Medical University, Guangzhou, Guangdong, 510095, People’s Republic of China; 2Department of Dermatology, Guangzhou Dermatology Hospital, Guangzhou, Guangdong, 510095, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xibao Zhang, Department of Dermatology, Guangzhou Dermatology Hospital, 56 Hengfu Road, Guangzhou, Guangdong, 510095, People’s Republic of China, Tel +8620-83593476, Email gzpfbfzs@163.comAbstract: Prurigo nodularis (PN) is a debilitating chronic neuroimmunologic skin condition due to the intense pruritus and difficult to treat. The pruritogenic cytokines, particularly IL-4, IL-13, IL-22, IL-31, and oncostatin M (OSM), play a crucial role in the pathogenesis of PN, potentially involving the JAK1-STAT pathway. An oral JAK1 inhibitor, abrocitinib, is presently undergoing Phase 2 trials for the treatment of PN. We evaluated the efficacy of abrocitinib at a daily dosage of 100 mg in treating two patients with PN affecting both lower limbs: a 50-year-old male with a 16-year disease history and a 38-year-old female with over three years of disease history, both of whom had failed to respond to multiple conventional treatments. Both patients responded rapidly after one week of treatment and exhibited a marked improvement. Following eight weeks of therapy, near-complete resolution of both pruritus and lesions was achieved, and no adverse effects were reported. Additionally, there were no reported side effects during the initial four months of continued treatment. Abrocitinib is an effective targeted therapy for PN, offering a promising new option for refractory patients.Keywords: prurigo nodularis, abrocitinib, pruritus

Atopic dermatitis (AD) and prurigo nodularis (PN) are chronic dermatological conditions marked by severe itching and the presence of eczematous lesions such as papules and nodules. Both diseases can pose significant physical and psychological harm, leading to poor quality of life. Notably, AD and PN were clinically linked in the past, with suggestions by researchers that PN might be a distinct clinical phenotype of AD. However, the extent of their relationship had not been fully quantified until our recent investigations. Through a meticulous systematic review and meta‐analysis adhering to the PRISMA guidelines, we extensively searched databases, including PubMed, EMBASE, Scopus, and the Cochrane Library, up to February 18, 2024. Our random effects meta‐analysis presented a strikingly increased risk of AD in patients suffering from PN as opposed to control groups (pooled unadjusted odds ratio [OR], 16.85; 95% confidence interval [CI], 6.13–46.31; I2 = 100%). Correspondingly, an elevated prevalence of PN was identified in subjects with AD (2.00%; 95% CI, 1.62–2.37%). These findings underscore the close association between AD and PN, suggesting a multifaceted overlap and potential bi‐directionality in developing these skin conditions. However, further comprehensive studies are essential to validate these associations and understand their precise clinical implications, with the ultimate goal of refining patient management strategies. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted‐metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography‐tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long‐chain fatty acids, alpha‐aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up‐regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down‐regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN. [ABSTRACT FROM AUTHOR]

Copyright of Die Dermatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Immune checkpoints are mechanisms that allow cancer cells to evade immune surveillance and avoid destruction by the body's immune system. Tumor cells exploit immune checkpoint proteins to inhibit T cell activation, thus enhancing their resistance to immune attacks. Immune checkpoint inhibitors, like nivolumab, work by reactivating these suppressed T cells to target cancer cells. However, this reactivation can disrupt immune balance and cause immune-related adverse events. This report presents a rare case of prurigo nodularis that developed six months after administering nivolumab for lung adenocarcinoma. While immune-related adverse events are commonly linked to T helper-1- or T helper-17-type inflammations, T helper-2-type inflammatory reactions, as observed in our case, are unusual. The PD-1–PD-L1 pathway is typically associated with T helper-1 and 17 responses, whereas the PD-1–PD-L2 pathway is linked to T helper-2 responses. Inhibition of PD-1 can enhance PD-L1 functions, potentially shifting the immune response towards T helper-1 and 17 types, but it may also influence T helper-2-type inflammation. This study reviews T helper-2-type inflammatory diseases emerging from immune checkpoint inhibitor treatment, highlighting the novelty of our findings. [ABSTRACT FROM AUTHOR]

Prurigo nodularis is a chronic skin condition which has significant negative impacts on the psychosocial function and quality of life of affected patients. It is a heterogeneous disease with complex underlying pathogenic mechanisms, and the clinical efficacy of traditional treatment options is often limited. Recently, great advances have been made in the pathogenesis of prurigo nodularis, which have enabled the development of novel targeted therapies for this disease. Various clinical trials have investigated the therapeutic efficacy of biologics which target the Th2 pathway. Dupilumab, a monoclonal antibody targeting interleukin 4 (IL-4) receptor α, has shown clinical efficacy and obtained United States Food and Drug Administration approval for prurigo nodularis. In addition, nemolizumab (IL-31 receptor A antagonist) and vixarelimab (oncostatin M receptor β antagonist) have shown therapeutic efficacy in clinical trials for prurigo nodularis. Small-molecule inhibitors with clinical promise which are currently under investigation include nalbuphine (opioid receptor modulator), Janus kinase inhibitors, and aprepitant and serlopitant (neurokinin-1 receptor antagonists). The recent development of new biologics and small-molecule inhibitors targeting various immunological and neurological signaling pathways have provided great hope that we are entering a new era of targeted therapies for this challenging clinical condition. In addition, recent advances in RNA sequencing technology may enable the identification of unique signaling pathways and the development of novel treatments for this disease in the future. In this review article, we summarize the current knowledge of the pathogenesis of prurigo nodularis, and discuss recent advances in treatment for this challenging clinical condition. [ABSTRACT FROM AUTHOR]

Purpose: Prurigo nodularis (PN) is a skin disease characterized by intensely itchy skin nodules and is associated with a significant healthcare resource utilization (HCRU). This study aimed to estimate the HCRU of patients in England with PN overall and moderate-to-severe PN (MSPN) in particular.Methods: This retrospective cohort study used data from the Clinical Practice Research Datalink and Hospital Episode Statistics in England. Patients with Mild PN (MiPN) were matched to patients with MSPN by age and gender for the primary analysis. Patients were enrolled in the study between 1st April 2007 and 1st March 2019. All-cause HCRU was calculated, including primary and secondary care contacts and costs (cost-year 2022).Results: Of 23,522 identified patients, 8,933 met the inclusion criteria, with a primary matched cohort of 2,479 PN patients. During follow up, the matched cohort’s primary care visits were 21.27 per patient year (PPY) for MSPN group and 11.35 PPY for MiPN group. Any outpatient visits were 10.72 PPY and 4.87 PPY in MSPN and MiPN groups, respectively. Outpatient dermatology visits were 1.96 PPY and 1.14 PPY in MSPN and MiPN groups, respectively.Conclusion: PN, especially MSPN, has a high HCRU burden in England, highlighting the need for new and improved disease management treatments.

Chronic nodular prurigo (CNP) is a chronic dermatological disease characterized by the presence of chronic pruritus and pruritic nodular lesions. The aim of this study was to reach consensus among a group of experts based on a non-systematic literature review and an algorithm for the clinical diagnosis of CNP. The resulting algorithm is structured in 3 blocks: 1) early identification of the patient with a possible diagnosis of CNP; 2) diagnosis and assessment of CNP; and 3) categorization of CNP (identification of the underlying causes or associated comorbidities).We believe that this clinical algorithm can facilitate the correct diagnosis of patients with CNP. Additionally, it raises awareness on the need for a multidisciplinary approach and specific treatment of CNP, steps of paramount importance to make better therapeutic decisions. Resumen: El prurigo crónico nodular (PCN) es una enfermedad dermatológica crónica, caracterizada por la presencia de prurito crónico (PC) y lesiones nodulares pruriginosas cutáneas. El presente trabajo tuvo como objetivo consensuar entre un grupo de expertos, a partir de una revisión bibliográfica no sistemática, un algoritmo para el diagnóstico clínico del PCN. El algoritmo resultante se ha estructurado en tres bloques: 1) identificación precoz del paciente con posible diagnóstico de PCN; 2) diagnóstico y valoración del PCN; y 3) categorización del PCN (identificación de las causas subyacentes o de las comorbilidades asociadas)Consideramos que este algoritmo clínico puede facilitar el diagnóstico correcto de los pacientes con PCN. Además, genera conciencia de la necesidad de un abordaje multidisciplinar y de un tratamiento específico del PCN, pasos indispensables para tomar mejores decisiones terapéuticas.

The article explores racial and geographic disparities in global clinical trials for prurigo nodularis (PN), a chronic skin condition. Studies indicate that PN is more prevalent among skin of color (SOC) and atopic dermatitis (AD) patients, with Black patients in the United States being disproportionately affected. The analysis of phase II/III PN clinical trials reveals a lack of diversity in participant representation, with the majority being White. The study emphasizes the need to diversify clinical trials to better reflect the affected patient population and improve outcomes for those disproportionately affected by PN. [Extracted from the article]

BackgroundPrurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis.MethodsThis double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891.FindingsOf 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, -50.6% versus -29.4% (LS-mean difference [95% CI], -21.2% [-40.82, -1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, -54.4% versus -32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), -56.3% versus -30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]).InterpretationVixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis.FundingKiniksa Pharmaceuticals, Ltd.

Prurigo nodularis (PN) is a chronic inflammatory skin condition that presents with intensely pruritic, hyperkeratotic nodules. The pathophysiology underlying PN is not entirely clear, making treatment challenging. Patients often require a multimodal approach, although many of the available therapies have low efficacy or adverse effects. In this review, we discuss the use of nemolizumab for the treatment of PN in adults. Nemolizumab is a biological therapy that reduces type 2 cytokines and the neuroimmune response implicated in the pathophysiology of PN. It also helps maintain skin barrier integrity, which may be damaged during the vicious itch-scratch cycle. Nemolizumab has demonstrated great efficacy in improving itch and clearing lesions in recent clinical trials with respectable tolerance. Nemolizumab is a promising drug for PN that seems comparable to the recently approved dupilumab in terms of its therapeutic effect and excellent safety profile, although nemolizumab may work more rapidly on itch. JAK inhibitors are also emerging as competitors of biologics for PN, however, their safety profile in this population may differ. Trials evaluating these drugs are needed to assess which is preferable. Additional data on the durability and longevity of nemolizumab for PN treatment is highly anticipated. [ABSTRACT FROM AUTHOR]

Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell–neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to the release of inflammatory cytokines and itch-inducing substances. Activated sensory nerve fibers aggravate pruritus by releasing neurotransmitters, perpetuating a vicious cycle of itching and scratching. Traditional treatments often fail, but recent advancements in understanding the inflammatory and itch transmission mechanisms of PN have paved the way for innovative therapeutic approaches, which are explored in this review. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated a new imaging technique called ex vivo confocal microscopy to examine rare skin conditions. By analyzing tissue samples from different skin disorders, we found that this technique could accurately identify unique microscopic features of both common and rare skin diseases. Importantly, examiners with more experience in interpreting these images achieved higher accuracy in diagnosis. This suggests that ex vivo confocal microscopy has the potential to be a valuable tool alongside traditional methods for diagnosing rare skin conditions early and accurately, leading to better treatment outcomes for patients. While ex vivo confocal laser scanning microscopy has previously demonstrated its utility in most common skin diseases, its use in the assessment of dermatological entities with lower incidence remains unexplored in most cases. We therefore aimed to evaluate the diagnostic efficacy of some rare skin tumors as well as a few inflammatory skin diseases, that have not yet been studied in ex vivo confocal laser scanning microscopy. A total of 50 tissue samples comprising 10 healthy controls, 10 basal cell carcinoma, 10 squamous cell carcinoma, and 20 rare skin conditions were imaged using the newest generation ex vivo confocal microscopy (Vivascope 2500 M-G4, Vivascope GmbH, Munich, Germany). Three blinded investigators were asked to identify characteristic features of rare skin disorders and distinguish them from more common skin diseases in the ex vivo confocal microscopy images. Our findings present the capability of ex vivo confocal microscopy to display distinctive morphologic patterns in common and rare skin diseases. As might be expected, we found a strong correlation between imaging experience and diagnostic accuracy. While the imaging inexperienced dermatohistopathologist reached 60% concordance, the imaging-trained dermatologist obtained 88% agreement with dermatohistopathology. The imaging-trained dermatohistopathologist achieved concordance up to 92% with gold-standard dermatohistopathology. This study highlights the potential of ex vivo confocal laser scanning microscopy as a promising adjunct to conventional dermatohistopathology for the early and precise identification of rare dermatological disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Abstract Background Prurigo nodularis (PN) is a chronic, debilitating dermatologic disease characterised by the presence of highly pruritic nodular lesions. PN highly impacts on patients' quality of life as there are no specific treatments available in Spain. Objectives Determine the main value drivers in the treatment of PN in Spain and its main unmet needs using Multi‐Criteria Decision Analysis (MCDA). Methods Literature review to synthesise relevant evidence in an evidence matrix based on the MCDA EVIDEM framework adapted to Spain. A multidisciplinary panel composed of dermatologists, hospital pharmacists and a patient weighted (5‐point scale; 0 minimum importance, 5 maximum importance) and scored each criterion included in the framework (from −5 to 5 or 0 to 5 depending on the criterion). Results were discussed in a reflective group session. Results PN was considered a severe (3.3 ± 0.7) and infrequent (2.0 ± 0.7) disease, with high unmet needs (4.2 ± 0.7) mainly due to the lack of available treatments with specific indication for PN. Current off‐label treatments were perceived to have limited efficacy/effectiveness (1.8 ± 1.1), an unfavourable long‐term safety profile (2.1 ± 0.9) and low therapeutic impact (1.7 ± 1.1). The measure of patient‐reported outcomes (2.7 ± 0.9) was perceived as important, but available tools are not specific. Although the cost of available treatments was not considered high (2.4 ± 1.5), experts agreed that PN is associated with moderately high other medical costs (3.6 ± 1.1) and indirect costs (3.1 ± 0.9). Experts considered that current guidelines and consensus (2.6 ± 0.7) are not clear on severity criteria and treatment algorithm. The quality of evidence (1.4 ± 0.5) of currently used off‐label treatments was perceived as low due to a lack of published clinical trials. Conclusions PN was considered a severe disease associated with relevant unmet needs, including the lack of specific and effective treatments for PN, the lack of consensus on the disease definition, defined severity criteria, prevalence estimations and awareness of PN in Spain.

Introduction: Prurigo nodularis is a chronic and debilitating condition of not fully elucidated etiopathogenesis. There are scarce data in the literature on the presence of microorganisms in the lesional skin of prurigo nodularis. Objective: To explore the microbiome composition in patients with prurigo nodularis using amplicon-based next-generation sequencing. Material and methods: Adult patients with prurigo nodularis were recruited for the study. Controls were healthy volunteers who presented for a routine nevi check-up. Skin swabs for microbiome analysis were collected, without prior cleaning, from active nodules in patients with prurigo nodularis and corresponding skin areas in healthy volunteers. The V3-V4 region of the 16S rRNA gene was amplified from the extracted DNA. Illumina platform on the MiSeq instrument was used for sequencing. The Silva v.138 database was utilized for identification of taxa. Results: In total, the microbiome profile of 60 active nodules from 24 patients with prurigo nodularis and corresponding skin areas (n = 14) from 9 healthy volunteers was analyzed. Skin microbiome of prurigo nodularis lesions showed decreased alpha and beta diversity when compared with healthy volunteers. Staphylococcus aureus was significantly more abundant in samples from prurigo nodularis patients than in the control samples, while Pseudomonas stutzeri had a greater share in the microbiome from healthy volunteers than from prurigo nodularis patients. Conclusions: Our results highlight several alterations in the diversity and composition of cutaneous microbiome in prurigo nodularis. However, further research on the role of microorganisms in this debilitating condition is necessary. [ABSTRACT FROM AUTHOR]

Background: Prurigo nodularis (PN) is a complex chronic skin disease characterized by severe pruritic nodules. PN is often associated with mental health disorders and chronic medical comorbidities. Until recently, PN treatment has been challenging and difficult. Objectives: This study aims to describe the demographic, clinical characteristics, and comorbidities associated with PN. Also, we aim to describe the effectiveness of systemic therapies, including methotrexate, cyclosporine, and narrow band ultraviolet (NB-UVB) in adult patients with PN. Methods: This is a retrospective chart review of adult patients diagnosed with PN at Hamilton Health Science Center and/or McMaster University in Hamilton, Ontario, between 2015 and 2023. Results: The study included 81 patients (57% female). The mean age was 52.8 years, and the mean age of PN diagnosis was 50 years. Reported symptoms included: itching (100%), dry skin (53%), pain (17%), and burning sensation (5%). Lower and upper extremities were the most common areas involved in 93% and 69%, respectively. Mental health disorders were present in 79% of patients, with depression (58%) and anxiety (52%) being the most common. Atopic dermatitis was the most common skin comorbidity noted. Treatments used included cyclosporine, and NB-UVB, and MTX, which resulted in significant improvement of pruritus in 38%, 35%, and 31% of patients, respectively, at week 16. Conclusions: PN is associated with increased risk of mental health disorders and other medical comorbidities. Cyclosporine, methotrexate, and NB-UVB therapy may be effective treatment options, however clinicians must consider the potential short- and long-term adverse effects of these treatments. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a skin disease characterized by firm, itchy, erythematous lesions. Treatment consists of systemic and non-systemic modes of therapy. Non-systemic forms of treatment are first-line and include topical corticosteroids, topical steroid-sparing agents, and phototherapy. The objective was to review the efficacy of non-systemic treatment used to treat PN. A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42023412012). The search consisted of keywords and Medical Subject Heading (MeSH) terms and translated to Ovid MEDLINE, Embase, and Scopus. Google Scholar was also searched for the first 200 articles. Article quality of evidence was scored using GRADE criteria. The search yielded 1151 results; 37 met criteria for inclusion. There were 14 studies on phototherapy, and 11 studies on topical corticosteroids, most of which were also combined with topical antihistamines, antipruritics, and/or phototherapy. There were 2 studies each on topical antipruritics used in isolation, vitamin D analogues, and intralesional triamcinolone acetonide. There was 1 study each on topical pimecrolimus, tacrolimus, 2% dinitrochlorobenzene, cryotherapy, acupuncture, and the Paul Gerson Unna boot. Most were case reports and case series, although 2 randomized controlled trials on phototherapy and topical pimecrolimus were included. Corticosteroids had varying levels of positive response in patients and appeared more effective when used in combination or under occlusive dressing. Phototherapy is likely effective, but the risk of relapse is high. Cryotherapy may also be a lesion-directed agent to circumvent challenges to adherence and avoidance of systemic medication. [ABSTRACT FROM AUTHOR]

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. 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. 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. [ABSTRACT FROM AUTHOR]

(1) Background: Prurigo nodularis (PN) is a persistent and inflammatory dermatological condition characterized by chronic itching and the formation of hardened nodules, significantly impacting the affected individuals' quality of life and psychological well-being. The management of PN poses challenges due to the limited efficacy and undesirable side effects associated with current interventions. (2) Methods: This article examines sixteen patients affected by PN treated with dupilumab, a fully human monoclonal antibody targeting interleukin IL-4 and IL-13 signaling. This involves a retrospective descriptive statistical analysis. (3) Results and (4) Conclusions: In all patients, dupilumab proves to be an effective drug in achieving disease clearance, as indicated by all the parameters considered as assessed by both physicians and patients at each evaluation point (Week 6, Week 16, Week 32, Week 52, Week 68, and Week 84), in comparison to the initial baseline. [ABSTRACT FROM AUTHOR]

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin–liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN. [ABSTRACT FROM AUTHOR]

Background: Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N‐terminal 20 (PAMP) activates mast cell degranulation via Mas‐related G protein‐coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear. Objective: To determine the role of PAMP‐induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN. Methods: The expression of PAMP and the number of MRGPRX2‐expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9‐20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT‐PCR, ELISA, flow cytometry, and siRNA techniques. Results: PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9‐20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and β‐hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF‐α, and GM‐CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE‐FcεRI activation. Conclusions: The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a chronic inflammatory skin disorder with a high disease burden. In this cross‐sectional, web‐based survey, Global Questions (GQ), the Numerical Rating Scales (NRS) for pruritus, burning sensation and sleep disturbance, the Short‐Form‐8 (SF‐8) Health Survey, Dermatology Life Quality Index (DLQI), Patient Health Questionnaire 9 (PHQ‐9), Work Productivity and Activity Impairment (WPAI), and Treatment Satisfaction Questionnaire for Medication–9 (TSQM‐9) scores were used to assess the current disease burden and treatment satisfaction among patients with PN in Japan. In total, 97 patients were included (55.7% male, median age 51 years, median duration of PN 36 months). Based on GQ scores, 35.1% of patients had mild disease, 50.5% moderate, and 14.4% severe disease. Disease burden increased as the severity of PN increased, as indicated by worsening of pruritus NRS scores and quality of life (DLQI, PHQ‐9, WPAI presenteeism, work productivity loss, and activity impairment scores). Patients with comorbid atopic dermatitis (AD) also had more intense pruritus than those without AD. Mean ± standard deviation TSQM‐9 scores for effectiveness, convenience, and global satisfaction were 54.7 ± 18.1%, 62.4 ± 15.2%, and 57.4 ± 15.9%, respectively. TSQM‐9 scores were lowest in patients receiving the most intensive guideline‐directed treatment (i.e., topical corticosteroids + systemic oral corticosteroids or cyclosporine), highlighting an unmet need for more effective treatment options for patients with PN. In summary, Japanese patients with PN reported increased disease burden and reduced treatment satisfaction with increased disease severity, despite the use of guideline‐recommended therapies. [ABSTRACT FROM AUTHOR]

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Summary: Background: Prurigo nodularis (PN) presents with intensely itchy hard nodules. Despite being limited to the skin, PN was noted to be associated with systemic diseases including diabetes and chronic renal failure. In previous smaller retrospective studies, several cardiac and vascular diseases were found more frequently in patients with PN. However, small cohort sizes, partially discrepant outcomes, missing data, and incomplete risk assessment limit these findings. Methods: Electronic health records (EHR)s of 64,801 patients (59.44% females) with PN and an equal sized propensity-matched control group were retrieved. In these cohorts, the risks to develop cardiac and vascular diseases and mortality following the diagnosis of PN were determined. Sub-analyses included stratification for sex, ethnicity, and treatments. Findings: PN was associated with a higher risk for a broad range of acute cardiac events including heart failure and myocardial infarction. For example, the hazard ratio of myocardial infarction was 1.11 (95%-CI: 1.041–1.184, p = 0.0015) following PN diagnosis. Also, all-cause mortality was higher in patients with PN. Further, chronic vascular as well as structural heart diseases, e.g., peripheral arterial disease, chronic ischaemic heart disease and valval disorders were found more frequently following a PN diagnosis. Risks were more pronounced in white and female patients. Having established an increased risk for death and cardiovascular disease, we next addressed if dupilumab that has been recently licenced for use in this indication can modulate these risks. The risk of death but not of any cardiovascular disease was slightly reduced in patients with PN treated with dupilumab as opposed to those treated with systemic therapies other than dupilumab. The study is limited by retrospective data collection and reliance on ICD10-disease classification. Interpretation: PN is associated with higher mortality and an increased risk for the development of a wide range of cardiac and vascular diseases. Health care professionals should take this into account when managing patients with PN. Funding: This work was supported by the University of Lübeck, the Deutsche Forschungsgemeinschaft and the State of Schleswig-Holstein.

Background: Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with several systemic comorbidities. However, there is lack of evidence supporting specific laboratory testing in the diagnostic workup of PN patients. Objective: To characterize the frequency and severity of clinical laboratory abnormalities in PN patients compared to controls. Methods: Cross-sectional study of adult patients between October, 2015 and August, 2021 using TriNetX, a global health records database encompassing over 74 million patients. Results: A total of 12,157 PN patients were matched to 12,157 controls. Significantly, greater proportions of PN patients had moderate-to-severely decreased hemoglobin, elevated transaminases, decreased albumin, increased bilirubin, increased serum creatinine, decreased estimated glomerular filtration rate, higher hemoglobin A1c levels, and alterations in thyroid stimulating hormone. Limitations: Our data identifies associated laboratory abnormalities in PN patients but is unable to support a causal relationship. Conclusion: PN patients are more likely to have laboratory abnormalities on renal, hepatic, hematologic, endocrine, and metabolic laboratory testing, demonstrating a role for systemic testing in the diagnostic workup of PN patients.

Background: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by severely itchy and often painful bumps on the arms, legs, and trunk. It is unknown whether patients with PN have increased risk of developing sleep disorders. Objective: To evaluate the association of PN with sleep disorders. Methods: This retrospective, population-level, matched-cohort study was conducted using The Health Improvement Network. The study included 4193 patients with newly diagnosed PN and 4193 age, sex, and race/ethnicity-matched controls. A Cox regression model was used to assess the development of sleep disorders, including insomnia, sleep apnea, and restless legs syndrome, in patients with PN compared with control patients. Results: Compared with controls, PN was associated with insomnia (adjusted hazard ratio [aHR] = 1.77; 95% CI = 1.48-2.12) and overall sleep disorder (aHR = 1.72; 95% CI = 1.46-2.02), but not with sleep apnea (aHR = 1.51; 95% CI = 0.93-2.44) or restless legs syndrome (aHR = 1.54; 95% CI = 0.92-2.57). Limitations: As a retrospective cohort study, our analysis is subject to potential confounders not already included. Conclusions: PN was associated with subsequent development of insomnia. Thus, clinicians should consider insomnia among patients with PN and develop strategies for treatment and prevention.

Immune checkpoints are mechanisms that allow cancer cells to evade immune surveillance and avoid destruction by the body’s immune system. Tumor cells exploit immune checkpoint proteins to inhibit T cell activation, thus enhancing their resistance to immune attacks. Immune checkpoint inhibitors, like nivolumab, work by reactivating these suppressed T cells to target cancer cells. However, this reactivation can disrupt immune balance and cause immune-related adverse events. This report presents a rare case of prurigo nodularis that developed six months after administering nivolumab for lung adenocarcinoma. While immune-related adverse events are commonly linked to T helper-1- or T helper-17-type inflammations, T helper-2-type inflammatory reactions, as observed in our case, are unusual. The PD-1–PD-L1 pathway is typically associated with T helper-1 and 17 responses, whereas the PD-1–PD-L2 pathway is linked to T helper-2 responses. Inhibition of PD-1 can enhance PD-L1 functions, potentially shifting the immune response towards T helper-1 and 17 types, but it may also influence T helper-2-type inflammation. This study reviews T helper-2-type inflammatory diseases emerging from immune checkpoint inhibitor treatment, highlighting the novelty of our findings.

Abstract Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized by the presence of pruritic nodules. We report a 57‐year‐old woman in whom PN might have been induced by COVID‐19 vaccination. PN lesions started 2 days after she received the second dose of COVID‐19 vaccine. She had a poor response to a variety of treatments but achieved satisfactory efficacy after Dupilumab therapy, an interleukin‐4 receptor inhibitor.

Abstract Background Secukinumab has been approved by the U.S. FDA and the European Medicines Agency for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis with the documented adverse effects. Here we reported in one case that a new symptom, Prurigo Nodularis (PN), developed during the programmed dosing of secukinumab. Case introduction A 22-years-old male with a 6-month history of severe plaque psoriasis vulgaris was presented to the dermatology clinic two weeks after the fifth serial weekly doses of secukinumab, for the reason of the outbreaks of multiple erythematous papules and pruritus nodules on the trunk and extremities. Physical examination showed that psoriatic rash were under effective control with the previous targeted therapy of secukinumab for plaque psoriasis vulgaris, but new dermatologic condition was spotted with multiple edematous red firm papules on the trunk and extremities, in the form of soy or hemispherical nodules, red in color, firm to touch, with some ulcerated crusts visible at tops, but negative Auspitz sign. Pathological examination confirmed these papules as PN. Conclusion This case report is shared to inform clinicians about an unannounced adverse effect of the secukinumab in the treatment of psoriasis, and it is recommended that patients be carefully informed of the possible risk of PN before starting treatment.

Key Clinical Message Prurigo nodularis is frequently difficult to manage with conventional therapy. Given the pathogenesis and refractory nature, we demonstrate a case in which inhibition of JAK–STAT signaling may significantly improve prurigo nodularis. Based on the results, we would like to draw a conclusion that abrocitinib as an inhibitor of Jak is a promising choice for the treatment of prurigo nodularis.

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