IL-31 Inhibition as a Therapeutic Approach for the Management of Chronic Pruritic Dermatoses.

Chronic pruritus is a debilitating symptom with limited treatment options. Identifying molecular targets underlying chronic pruritic dermatoses is essential for the development of novel, targeted therapies. IL-31 is an important mediator of itch by integrating dermatologic, neural, and immune systems. IL-31 helps induce and maintain chronic pruritus via both indirect stimulation of inflammatory cells and through direct neural sensitization. IL-31 is overexpressed in various chronic pruritic skin conditions, and exogenous IL-31 induces itch and scratching behavior. Studies have demonstrated that IL-31R and IL-31 antagonism significantly reduces itch in patients with atopic dermatitis and prurigo nodularis, two extremely pruritic skin conditions. Emerging evidence, including recent phase II clinical trials of IL-31R antagonists, demonstrates that IL-31 plays an important role in itch signaling. Additional studies are ongoing to evaluate IL-31R and IL-31 antagonism as treatments of chronic pruritus.

Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis.

Introduction: Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intensely pruritic, hyperkeratotic nodules distributed on the trunk and extensor surfaces of the extremities. PN has a profoundly negative impact on sleep and quality of life in patients with PN. There are currently no U.S. Food and Drug Administration-approved agents and patients are often recalcitrant to current therapies, highlighting the importance of further research into this severely debilitating condition. Areas covered: A PubMed search was conducted to find available literature on the pathophysiology and clinical management of PN. In this review article, we discuss the current understanding of the pathophysiology, recommended diagnostic approach, and treatment options available for PN. Expert opinion/commentary: PN is an extremely difficult condition to treat, because there is a lack of effective therapies available due to our limited understanding of its pathophysiology. Currently, available treatment options are often multimodal due to the intersection of neuroimmune etiologic factors in the pathogenesis of PN. Fortunately, as our knowledge of PN expands, novel treatments targeting specific molecular biomarkers of PN are emerging, providing hope to this long-suffering patient population.

Effectiveness of Dupilumab for the Treatment of Generalized Prurigo Nodularis Phenotype of Adult Atopic Dermatitis.

BACKGROUND: Generalized prurigo nodularis (GPN) is a debilitating, inflammatory skin disease characterized by chronic pruritus, signs of prolonged scratching, and multiple pruriginous papules and nodules. Recent studies identified several forms of GPN as a clinical phenotype of adult atopic dermatitis (AD). OBJECTIVE: The aim of the study was to evaluate the effectiveness of dupilumab (D) in adults affected by persistent AD showing a clinical feature of GPN. METHODS: A retrospective study was performed on adult patients affected with GPN clinical variant of AD, treated with D from July 2018 to March 2019. Atopic dermatitis severity was evaluated using the Eczema Area and Severity Index, visual analog scales ranging from 0 to 10 for pruritus, and Dermatology Life Quality Index. RESULTS: Ninety AD patients (52 males [57.7%]; mean age = 44.6 years; range = 18-66 years) were treated with D. In 9 (10.0%) of 90 cases, GPN pattern was observed. A significant improvement in Eczema Area and Severity Index, Dermatology Life Quality Index, and pruritus visual analog scale score was observed after treatment with D. CONCLUSIONS: Generalized prurigo nodularis is currently considered to be a rather common clinical pattern of adult AD. Dupilumab can be an efficacious treatment of this condition, especially in cases where history of atopy is recorded and conventional treatments are ineffective.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

Idiopathic Papular Dermatitis in the Spectrum of Chronic Papular Eruptions (Subacute Prurigo): Reappraisal and Diagnostic Algorithm.

BACKGROUND: The clinical diagnosis of papular eruptions is common but poorly characterized in the literature and the etiology is often unknown. OBJECTIVE: To characterize the entity of idiopathic papular dermatitis in the spectrum of chronic papular eruptions. METHODS: The cohort consisted of patients who presented at a tertiary medical center in 2005-2014 with a papular eruption of at least 4 months' duration. Findings on histological analysis and thorough clinical investigation, performed in all cases, were collected. The patients completed a questionnaire on disease course and outcome. RESULTS: Sixty-five patients were included. Sixteen patients showed morphological changes over time and were excluded. Investigations in the remaining 49 patients with a consistent papular morphology yielded a well-defined diagnosis in 23 (46%). Twenty-six patients (54%; 14 male) were diagnosed with idiopathic papular dermatitis. Their mean age at onset was 61.6 ± 14.4 years and the mean duration of disease 3.11 ± 2.726 years. In 60%, the rash resolved with conservative treatment during follow-up (mean 4.35 ± 2.53 years). CONCLUSIONS: Chronic papular eruptions encompass a wide range of skin diseases. In more than half of the cases, the etiopathogenesis remains unclear. On the basis of our results, we propose a diagnostic algorithm for idiopathic papular dermatitis.

Prurigo Nodularis and Its Management.

Prurigo nodularis occurs with chronic pruritus and the presence of single to multiple symmetrically distributed, hyperkeratotic, and intensively itching nodules. Diverse dermatologic, systemic, neurologic, or psychiatric conditions can lead to prurigo nodularis. Structural analysis demonstrated a reduced intraepidermal nerve fiber density and increased dermal levels of nerve growth factor and neuropeptides such as substance P and calcitonin gene-related peptide. Novel therapy concepts such as inhibitors at neurokinin-1, opioid receptors, and interleukin-31 receptors have been developed. The mainstays of prurigo nodularis therapy comprise topical steroids, capsaicin, calcineurin inhibitors, phototherapy, and the systemic application of anticonvulsants, µ-opioid receptor antagonists, or immunosuppressants.

Chronic Prurigo of Nodular Type: A Review.

Prurigo nodularis (PN) is a subtype of chronic prurigo presenting single to multiple symmetrically distributed, hyperkeratotic and intensively itching papules and nodules. PN evolves along with chronic pruritus in the context of diverse dermatological, systemic, neurological or psychiatric conditions. Permanent scratching is possibly a major trigger of PN, although its exact pathophysiology remains unclear. Current state-of-the-art therapy for PN consists of topical steroids, capsaicin, calcineurin inhibitors, ultraviolet (UV) therapy, systemic administration of gabapentinoids, µ-opioid receptor antagonists, antidepressants or immunosuppressants. Novel treatment concepts, such as inhibitors of neurokinin-1, opioid and interleukin-31 receptors, have been developed and are currently being clinically tested.

Increased angiogenesis and VEGF expression correlates with disease severity in prurigo patients.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) is known as the major skin angiogenesis factor and can be produced by various resident skin cells including keratinocytes. OBJECTIVES: To identify and characterize the role of VEGF-A in the pathogenesis of prurigo. METHODS: Expression of VEGF, VEGFR2, CD-31, and D2-40 was analyzed in the skin of eleven prurigo patients and seven healthy controls by immunohistochemistry. RESULTS: VEGF immunoreactivity (IR) was markedly increased in the epidermis, dermis and subcutis of prurigo patients, whereas expression of the main receptor for VEGF-A in the skin, VEGFR2, was comparable to that of healthy controls. The increased VEGF expression in the skin was associated with a marked increase in the number (12.8 ± 2.1 vs 5.6 ± 0.5, P < 0.05) but not in the size of blood vessels, as assessed by staining of the endothelial cell marker CD31. This increase in small blood vessels correlated closely with increases in the epidermal thickness in prurigo lesions. The number of lymphatic vessels as assessed by D2-40 staining was found to be similar in prurigo patients and healthy controls. CONCLUSIONS: Based on these findings, we speculate that the observed profound vascular remodelling in prurigo might contribute to the pathogenesis of prurigo and the corresponding clinical symptoms and that targeting of VEGF may present a novel therapeutic strategy in the treatment of prurigo patients.

[Prurigo]. / Les prurigos.

Prurigo is a medical term which includes several clinical, pathological and etiologic entities. Diagnostic and therapeutic management is different depending on if we face acute prurigo or chronic prurigo. Acute prurigo is almost always linked to parasites or insects. Chronic prurigo can be linked to dermatologic diseases or may reveal internal pathologies. Complementary exams we should ask for are focused on these diseases. Idiopathic chronic prurigo, without underlying disease, is the most frequent one. It needs regular survey, as it can reveal cutaneous or internal diseases after months or even years. Treatment of prurigo is treatment of the underlying disease. Symptomatic treatment against pruritus, topic or systemic, must be added.

Less well-defined dermatoses of pregnancy.

Over the past several decades, many specific and nonspecific dermatoses of pregnancy have been described. The lack of a well-defined clinical and histological features as well as reproducibility in some of these entities has led to confusing reports in the literature. In this review article, an account of these nonspecific dermatoses of pregnancy will be presented in an attempt to shed light on their nosology and to better categorize them in view of the recent literature findings.

Prurigo pigmentoso / Prurigo pigmentosa

El prurigo pigmentoso es una dermatosis inflamatoria infrecuente de etiología desconocida caracterizada por episodios recurrentes de pápulas eritematosas y pruriginosas que evolucionan hacia una intensa pigmentación reticulada. Se ha referido más frecuentemente en mujeres adultas jóvenes en Japón. Sólo se han descrito fuera de Japón unos 30 casos. Describimos una paciente española de 32 años que desarrolló una dermatosis pruriginosa con las características clínicas y hallazgos histopatológicos del prurigo pigmentoso. Se revisan las características epidemiológicas, clínicas e histopatológicas de esta peculiar enfermedad cutánea

Prurigo pigmentosa is an infrequent inflammatory dermatosis of unknown etiology, characterized by recurrent episodes of pruritic erythematous papules which develop into intense reticulated pigmentation. It has been referenced most frequently in young women in Japan. Only thirty cases have been described outside of Japan. We describe a 32-year-old Spanish female who developed a pruritic dermatosis with the clinical characteristics and histopathological findings of prurigo pigmentosa. We review the epidemiological, clinical and histopathological characteristics of this peculiar skin disease

Active "itch fibers" in chronic pruritus.

An itch-specific neuronal pathway was recently discovered in healthy humans and animals. Here the authors report that activity in this specific pathway coincides with itch under pathophysiologic conditions in a patient with chronic pruritus. Microneurographic recordings from the symptomatic area revealed spontaneous activity in six single C-fiber afferents that had the characteristic features of "itch fibers." Itch may be caused by activity in a specific subpopulation of C-fiber afferents.

Prurigo solar en la niñez: manifestaciones cutáneas, oculares y labiales / Actinic prurigo in childhood: cutaneous, ocular and labial manifestations

Introducción. El prurigo solar o actínico es una de las enfermedades de la piel más frecuentes en la niñez, particularmente en la población indígena o mestiza de México y de otros países de América Latina. En su patogénesis participan diversos factores como el HDL-DR4, ambientales como la luz solar; la altitud y la nutrición (deficiente aporte proteico). Material y métodos. Se llevó a cabo un estudio de las características clínicas e histológicas de 50 niños con diagnóstico de prurigo solar durante el lapso de 1990-1995. El diagnóstico se basó en niños con diagnóstico de prurigo solar durante el lapso de 1990-1995. El diagnóstico se basó en criterios clínicos y se sustentó en la biopsia de piel. Se puso particular énfasis en los cambios labiales y conjuntivales. Analizándose antecedentes familiares, lugar de residencia, edad, sexo y características sociogeográficas, entre otros. Resultados. Todos los pacientes fueron residentes de la Ciudad de México (altitud de 2450 m sobre el nivel del mar); provenientes de bajo nivel sociocultural y con pobre aporte proteico en su dieta. Con edades de 2 a 14 años, e igual distribución por sexo. En 15 pacientes se demostró queilitis y en 26 conjuntivitis. La evolución de la enfermedad fue de 6 a 18 meses antes del diagnóstico. Conclusión. El prurigo solar es una enfermedad frecuente en nuestro medio debido a la influencia solar (altura), mala nutrición y factores sociogeográficos, de inicio en la niñez, con manifestaciones clínicas e histológicas suficientemente características. Las pápulas pruriginosas con distribución hacia las zonas expuesta son la característica sine qua non, e interesantemente las mucosas conjuntival y labial se ven afectadas hasta en 50 por ciento de los pacientes. La afección conjuntival parece ser característica de esta enfermedad y los cambios en la mucosa labial se correlacionan con lo descrito en la literatura

What is actinic prurigo in Britain?

Actinic prurigo (AP) belongs to the group of idiopathic photodermatoses sharing a predilection for occurring more commonly in females, and there is much controversy as to whether it is only a more severe form of polymorphous light eruption (PMLE) or whether it is a distinct entity in its own right. The condition is characterised by intensely itchy papules, plaques and nodules, along with excoriations and scars usually starting before puberty, and predominantly involves the sun-exposed areas although it may also affect covered sites. Seasonal exacerbations at the beginning of spring with improvement in the fall are typical, although the lesions frequently do not clear completely in the winter. The disorder may run a chronic course and persist into adulthood, but often spontaneous resolution occurs in late adolescence. Diagnosis is predominantly based on the clinical features, cutaneous irradiation tests and histology often being normal or non-specific. HLA typing has also been performed in both PMLE and AP patients, showing a strong association between HLA-DR4, in particular with the DRB1*0407 subtype, and AP; no HLA association has been found in PMLE. This HLA association is likely to be of pathogenic significance and strongly suggests a critical role for MHC-restricted antigen presentation in the development of photosensitivity AP.

Eosinophils in atopic dermatitis.

The eosinophilic granulocyte is commonly associated with allergic inflammation. Although blood eosinophilia frequently accompanies atopic dermatitis, accumulation of tissue eosinophils is not prominent. Recent studies have elucidated the structure, content, and activities of the eosinophil. In addition, immunofluorescence localization of eosinophil granulate proteins has shown that eosinophils disrupt in tissue depositing toxic granule proteins in several diseases. Here, evidence for eosinophil degranulation in atopic dermatitis is presented and mechanisms whereby eosinophil degranulation may mediate pathophysiologic effects in atopic dermatitis and related conditions are discussed.