Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics.

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.

Increased cardiovascular risks and mortality in prurigo nodularis: a global cohort study.

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.

Prurigo nodularis: new insights into pathogenesis and novel therapeutics.

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. Patients with PN suffer from an intractable itch-scratch cycle leading to impaired sleep, psychosocial distress and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines [such as interleukin (IL)-4, -13, -17, -22 and -31] and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to T-helper (Th)17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibres that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of patients with PN and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centred around degrees of type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences, with African Americans having densely fibrotic skin lesions. Dupilumab became the first US Food and Drug Administration-approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31 receptor A inhibitor nemolizumab is in late-stage development with positive phase III data reported. In addition, the oral Janus kinase (JAK) 1 inhibitors, abrocitinib and povorcitinib, are in phase II trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase III studies.

Prurigo nodularis (PN) is a chronic skin condition featuring extremely itchy nodules on the skin of the legs, arms and trunk of the body. PN affects approximately 72 per 100 000 people and the severe itch associated with the condition can negatively impact a person's sleep, work and social life. However, the cause of PN remains unclear. Current understanding of PN is based on imbalances in the immune system leading to widespread inflammation as well as dysregulation of the nerves in the skin. Immune molecules released from T cells [such as interleukin (IL)-4, -13, -31, -17, -22 and -31] increase systemic inflammation and are elevated in people with PN. Activated inflammatory cells (such as mast cells or eosinophils) may also release factors that promote inflammation, itch and neural changes within the skin. Neural dysregulation in PN features a lower density of itch-sensing nerve fibres in the epidermis (upper layer of the skin) and a higher density of itch-sensing nerve fibres in the dermis (lower layer of the skin). Because the pathogenesis of PN is not fully understood, the therapies available for PN have had limited success in reducing itch and nodules. The only drug currently approved for PN in the USA and Europe is dupilumab, an IL-4Rα inhibitor that blocks signalling through IL-4 and IL-13, which is undergoing post-marketing surveillance. Other new drugs are being assessed in various phases of clinical trials, including nemolizumab, vixarelimab, barzolvolimab, ruxolitinib, abrocitinib, povorcitinib and nalbuphine.

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.

Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment.

Chronic nodular prurigo (CNPG) is a recalcitrant chronic itchy disorder that affects the quality of life. It can be triggered by multiple etiologies, such as atopic dermatitis, diabetes, and chronic renal diseases. The mechanisms of CNPG are complicated and involved the interaction of the cutaneous, immune, and nervous systems. Diverse immune cells, including eosinophils, neutrophils, T cells, macrophages, and mast cells infiltrated the lesional skin of CNPG, which initiated the inflammatory cytokines and pruritogens release. In addition, the interaction between the immune cells and activated peripheral sensory nerve fibers by neurotransmitters caused neuroinflammation in the skin and intractable itch. This itch-scratch vicious cycle of CNPG results in disease exacerbation. CNPG is difficult to treat with traditional therapies. Recently, great advances have been made in the pathophysiology of both inflammation and pruritus transmission in CNPG. In this review, we summarize the updated mechanisms and novel therapies for CNPG.

Chronic prurigo.

Chronic prurigo is a distinct disease defined by the presence of chronic pruritus for at least 6 weeks, a history and/or signs of repeated scratching, and multiple localized or generalized pruritic skin lesions (whitish or pinkish papules, nodules and/or plaques). Although chronic prurigo is frequently named prurigo nodularis, the nodular type of chronic prurigo is only the main clinical aspect of chronic prurigo. Chronic prurigo occurs due to neural sensitization to pruritus and the development of a vicious pruritus-scratching cycle. Chronic prurigo can be of allergological, dermatological, systemic, neurological, psychiatric/psychosomatic, mixed or undetermined origin. The prevalence is still debated. The burden is high. Current treatments often remained disappointing. Fortunately, recent research results on the pathophysiology of pruritus evidenced neuroimmune interactions and allow new therapeutic perspectives. Among them, antagonists of T-helper 2 cytokines, κ-opioids and Janus kinase inhibitors may be promising. What is already known about this topic? Chronic prurigo or prurigo nodularis is poorly known by dermatologists and the definition was rather vague until recently. What does this study add? This review provides a summary of the recent developments of nosology and research (from basic research to epidemiology and clinical research), and current and near-future management are then discussed.

Update on Chronic Prurigo. / Prurigo crónico: actualización.

Chronic prurigo is itself a common condition, but it can also occur secondary to a large number of diseases. Management is challenging as historically chronic prurigo has been poorly defined and very few treatments are available. Clinically, it presents as excoriated, hyperkeratotic lesions. When chronic prurigo is suspected, a comprehensive differential diagnosis is essential. New diagnostic criteria have appeared in recent years and new drugs have been developed. Although no truly effective treatment is yet available, patients will benefit from a greater understanding of this condition.

Plasma Steroids and Endocannabinoids Used as Biomarkers to Assess the Pruritus Severity of Patients With Prurigo Nodularis. / [Artículo traducido] Esteroides y endocannabinoides plasmáticos utilizados como biomarcadores para evaluar la gravedad del prurito de los pacientes con prúrigo nodular.

BACKGROUND: Prurigo nodularis (PN) as an extremely pruritic and hyperplastic chronic dermatosis induces psychologically and physiologically stressful responses. PN-induced responses in the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-gonadal axes and endocannabinoid system are abnormal. Extant studies on the PN's pathogenesis mostly focused on the PN's psychological responses. To date, the PN's physiological responses remain not been fully uncovered yet. OBJECTIVES: To investigate the PN-induced physiological responses via the levels of 5steroids and 2endocannabinoids combined with their ratios in plasma and examine the association between the psychological and physiological responses. MATERIALS AND METHODS: Thirty-six patients with PN, 36 age- and gender-matched healthy controls were recruited. The PN's psychological symptoms including pruritus severity, pain and life quality were measured with the visual analogue scale, the prurigo score index, numerical rating scale, verbal rating scale and dermatology life quality index. Their concentrations of steroids and endocannabinoids were determined with liquid chromatography-tandem mass spectrometry. RESULTS: Compared to controls, the PN patients showed lower plasma levels in cortisol, cortisone, N-arachidonoyl-ethanolamine, and the ratio of DHEA to 1-arachydonoyl glycerol (1-AG), which negatively moderately and over correlated with PN's symptoms, especially with the pruritus severity. Additionally, the PN patients exhibited higher levels in the ratios of testosterone and 1-AG to cortisol, which positively moderately and over correlated with pruritus severity. Thus, the 7biomarkers would be sensitive and reliable biomarkers for assessing the pruritus severity of PN because they met the screening criteria that the biomarkers show intergroup differences and showed moderate or over correlation with the pruritus severity of PN. CONCLUSIONS: To the best of our knowledge, this is the first study exploring PN-induced physiological responses. The findigs suggest that alterations in these 3endocrine systems may lead to new insights to psychological mechanisms and responses to PN.

Prurigo pigmentosa following a ketogenic diet: a case report.

A 19-year-old female of South Asian descent presented with a three-day history of pruritic, clustered papules and vesicles on her abdomen, associated with significant pruritus and intermittent pain. She commenced a ketogenic diet four days prior to the emergence of the rash. Histopathological and clinical findings were in keeping with prurigo pigmentosa, an uncommon dermatosis characterised by pruritic, erythematous papules and vesicles presenting reticulated on the back, chest and neck. Prurigo pigmentosa may be distinguished from many other skin lesions by its reticular pattern. Its pathogenesis is unknown, but it has been hypothesised to be induced by a state of ketosis. Clinicians should therefore be aware of its association with the increasingly popular ketogenic diet. This dermatosis responds well to tetracyclines and has an excellent prognosis. In the patient with ketosis-induced prurigo pigmentosa, administration of insulin or an increase in carbohydrates can also resolve symptoms.

Multiple skin ulceration and itch-scratch cycle in a diabetic patient.

Diabetic patients sometimes present generalized pruritus. Severe itching can cause an itch-scratch cycle, resulting in distress and impaired quality of life, but skin ulceration is a rare manifestation.