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.

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.

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.

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.

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.

Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus.

BACKGROUND: Prurigo nodularis (PN) is a chronic disease characterized by intensely pruritic, raised, nodular lesions. Because there are currently no United States Food and Drug Administration-approved therapies specifically for PN, management is highly variable, and no consensus exists on treatment regimens. OBJECTIVE: To provide practical guidance to help United States dermatologists diagnose and effectively treat patients with PN. METHODS: We participated in a roundtable discussion to develop consensus recommendations on diagnosis and treatment of PN from a United States perspective. RESULTS: The core findings in PN are the presence of firm, nodular lesions; pruritus lasting at least 6 weeks; and a history or signs, or both, of repeated scratching, picking, or rubbing. The diagnostic workup involves a complete review of systems, considering potential systemic diseases, and assessment of disease severity, including disease burden and pruritus intensity. Treatment should be selected based on a patient's clinical presentation, comorbidities, and response to prior treatments and should address both neural and immunologic components of pruritus. LIMITATIONS: Data on PN are from anecdotal or small clinical trials, and all treatments are currently used off-label. CONCLUSION: An effective treatment approach for patients with PN should be based on clinical judgment and tailored to the individual needs of the patient.

Prurigo pigmentosa in a patient with newly diagnosed type one diabetes with diabetic ketoacidosis.

Prurigo pigmentosa is a rare inflammatory cutaneous disorder associated with ketosis that resolves with reticulate hyperpigmentation. A 19-year-old man was admitted to the hospital with diabetic ketoacidosis. He also had developed reticulate papules coalescing into plaques over the posterior neck, back, and abdomen. Histopathological findings consistent with the clinical findings suggested the diagnosis of prurigo pigmentosa. After treatment with topical triamcinolone and oral doxycycline along with resolution of his ketosis after insulin administration, the patient's rash healed with reticulate hyperpigmentation.

Prurigo nodularis: Pathogenesis and management.

Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.

A unique case of prurigo pigmentosa related to ketogenic diet.

Prurigo pigmentosa is a rare inflammatory dermatosis that primarily affects Japanese patients. Various triggers have been identified, including the ketogenic diet. Given the current popularity of the ketogenic diet, the incidence of prurigo pigmentosa may be on the rise. Herein, to the best of our knowledge, we present the first case of prurigo pigmentosa reported in a Hispanic patient in the United States.

Colchicine may be of therapeutic benefit in prurigo pigmentosa.

Prurigo pigmentosa (PP) is a rare inflammatory skin disease. Neutrophil-mediated inflammation is considered to be responsible for the etiopathogenesis of PP. We consider that colchicine may be an effective agent in the treatment of PP since it exerts an antiinflammatory effect by inhibiting neutrophil chemotaxis. Further studies are required to verify whether colchicine is an effective treatment option for PP.

Folliculitis in prurigo pigmentosa: a proposed pathogenesis based on clinical and pathological observation.

BACKGROUND: Prurigo pigmentosa is a rare inflammatory dermatosis whose exact etiology is not understood yet. The purpose of this study was to provide evidence of hair follicle involvement in the pathogenesis by analyzing its clinicopathologic features. METHODS: Patients who fulfilled both the clinical and histological diagnostic criteria of prurigo pigmentosa were recruited. Their histopathologic findings, clinical features and medical histories were analyzed. RESULTS: A total of 32 confirmed patients were enrolled from 2002 to 2013. Their ages ranged from 11 to 79 years with a female predominance. Patient lesions were primarily reddish-brown and located on the back. A total of 25 patients (78%) had pathological involvement of hair follicles, either bacterial colonies in the hair follicles (21/32, 66%), folliculitis (8/32, 25%) or perifolliculitis (15/32, 47%). There was a significantly higher proportion of patients with hair follicle involvement compared with control groups with either noninflammatory (5/43, 12%, p < 0.001) or inflammatory skin diseases (12/32, 38%, p = 0.002) on the back. Minocycline was an effective antibiotic treatment either singly or in combination with steroids. CONCLUSIONS: The frequent presence of bacterial colonies along with sequelae of inflammatory changes on biopsy provides new evidence to support the theory that prurigo pigmentosa is a reactive inflammation associated with bacterial folliculitis.

Acquired Reactive Perforating Dermatosis is a Variant of Prurigo Nodularis.

Patients with chronic pruritus may develop scratch-induced lesions with elevated borders and central necrosis. This so-called umbilicated type of prurigo (UP) is rare and is assumed to develop preferentially in the context of metabolic diseases. The aim of this study was to characterize UP in its clinical and histological dimension. Demographic and clinical data were collected from 23 patients with UP. Intensive light microscopical analysis of biopsied lesions was performed. Statistical comparison with previous results for prurigo nodularis (PN) showed that UP is clearly a subtype of PN. In addition, clinical and microscopic features of epidermal perforation identical to those in acquired reactive perforating dermatosis (ARDP) were observed. Hence, we suggest that ARDP is identical to UP and is therefore a subtype of PN. We assume that reduced wound healing capacities due to underlying systemic disorders, particularly diabetes mellitus and uraemia, underlie the pathomechanism of development of umbilicated skin lesions with a perforating aspect.

[Prurigo pigmentosa after fat-reduced diet, treated with doxycycline]. / Prurigo pigmentosa nach fettreduzierter Diät, therapiert mit Doxycyclin.

Prurigo pigmentosa is a rare inflammatory skin disease of unknown origin, mostly described in the ethnic Japanese population. Etiology and pathogenesis are not completely known. Tetracyclines or dapsone are the therapy of choice. A 17-year-old Swiss patient with Turkish parents presented with pruritic rash on the neck and trunk, which started after a diet. Under therapy with doxycycline over 5 weeks, complete healing with slight reticular hyperpigmentation was observed.

[Dyspnea, itching and depression in palliative medicine]. / Luftnot, Jucken und Depression in der Palliativmedizin.

Palliative medicine focuses on relieving burdening symptoms to improve quality of life. The most common symptoms are physical weakness, pain, loss of appetite, nausea as well as dyspnea, itching and depression. Frequently, good symptom control can be achieved using the most effective drug combination therapy or non-medicinal interventions. This article specifically addresses the physical symptoms dyspnea, itching and the psychological symptom depression.