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Generalized pustular psoriasis (GPP) is a rare, chronic skin disease, characterized by widespread pustules and erythema, often accompanied with systemic signs and symptoms. GPP flares occur episodically but may be protracted. Left untreated, GPP can be life-threatening. Despite being first reported over 100 years ago, definitions and diagnostic criteria for GPP have been inconsistent and varied due, in part, to its rarity and a limited understanding of its pathogenesis. As such, many patients with GPP face delays in diagnosis and subsequent treatment. This manuscript aims to increase the recognition of GPP and provide foundational considerations to aid in the definition and diagnosis of this disease.

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Skin denervation has been shown to cause remission of psoriatic lesions in patients, which can reappear if reinnervation occurs. This effect can be induced by the activation of dendritic cells through sensory innervation. However, a direct effect of nerves on the proliferation of keratinocytes involved in the formation of psoriatic plaques has not been investigated. We developed, by tissue engineering, a model of psoriatic skin made of patient skin cells that showed increased keratinocyte proliferation and epidermal thickness compared to healthy controls. When this model was treated with CGRP, a neuropeptide released by sensory neurons, an increased keratinocyte proliferation was observed in the psoriatic skin model, but not in the control. When a sensory nerve network was incorporated in the psoriatic model and treated with capsaicin to induce neuropeptide release, an increase of keratinocyte proliferation was confirmed, which was blocked by a CGRP antagonist while no difference was noticed in the innervated healthy control. We showed that sensory neurons can participate directly to keratinocyte hyperproliferation in the formation of psoriatic lesions through the release of CGRP, independently of the immune system. Our unique tissue-engineered innervated psoriatic skin model could be a valuable tool to better understand the mechanism by which nerves may modulate psoriatic lesion formation in humans. STATEMENT OF SIGNIFICANCE: This study shows that keratinocytes extracted from patients' psoriatic skin retain, at least in part, the disease phenotype. Indeed, when combined in a 3D model of tissue-engineered psoriatic skin, keratinocytes exhibited a higher proliferation rate, and produced a thicker epidermis than a healthy skin control. In addition, their hyperproliferation was aggravated by a treatment with CGRP, a neuropeptide released by sensory nerves. In a innervated model of tissue-engineered psoriatic skin, an increase in keratinocyte hyperproliferation was also observed after inducing neurons to release neuropeptides. This effect was prevented by concomitant treatment with an antagonist to CGRP. Thus, this study shows that sensory nerves can directly participate to affect keratinocyte hyperproliferation in psoriasis through CGRP release.

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BACKGROUND: Psoriasis is a major global health burden affecting ~ 60 million people worldwide. Existing studies on psoriasis focused on individual-level health behaviors (e.g. diet, alcohol consumption, smoking, exercise) and characteristics as drivers of psoriasis risk. However, it is increasingly recognized that health behavior arises in the context of larger social, cultural, economic and environmental determinants of health. We aimed to identify the top risk factors that significantly impact the incidence of psoriasis at the neighborhood level using populational data from the province of Quebec (Canada) and advanced tree-based machine learning (ML) techniques. METHODS: Adult psoriasis patients were identified using International Classification of Disease (ICD)-9/10 codes from Quebec (Canada) populational databases for years 1997-2015. Data on environmental and socioeconomic factors 1 year prior to psoriasis onset were obtained from the Canadian Urban Environment Health Consortium (CANUE) and Statistics Canada (StatCan) and were input as predictors into the gradient boosting ML. Model performance was evaluated using the area under the curve (AUC). Parsimonious models and partial dependence plots were determined to assess directionality of the relationship. RESULTS: The incidence of psoriasis varied geographically from 1.6 to 325.6/100,000 person-years in Quebec. The parsimonious model (top 9 predictors) had an AUC of 0.77 to predict high psoriasis incidence. Amongst top predictors, ultraviolet (UV) radiation, maximum daily temperature, proportion of females, soil moisture, urbanization, and distance to expressways had a negative association with psoriasis incidence. Nighttime light brightness had a positive association, whereas social and material deprivation indices suggested a higher psoriasis incidence in the middle socioeconomic class neighborhoods. CONCLUSION: This is the first study to highlight highly variable psoriasis incidence rates on a jurisdictional level and suggests that living environment, notably climate, vegetation, urbanization and neighborhood socioeconomic characteristics may have an association with psoriasis incidence.

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INTRODUCTION: Ocular allergies to brimonidine are frequent in patients treated for glaucoma. There is variability in reporting due to the lack of diagnostic criteria and the absence of cutaneous testing. Many false-negative patch tests (PT) have been described. Alternative methods, such as strip and scratch PT, have been used without a standardized method. OBJECTIVES: The primary objective is to identify the best method of cutaneous testing and brimonidine concentration for patch testing. The secondary objective is to identify clinical signs and symptoms suggestive of ocular allergy. PATIENTS AND METHODS: A retrospective review of patient files suspected of brimonidine ocular allergy was performed. Patch testing method, brimonidine concentration and clinical symptoms were reviewed. RESULTS: Of the 36 patients identified, half tested positive for brimonidine for at least one of the testing methods. The scratch PT demonstrated 17 positive reactions (94% detection rate). Three patients reacted with strip PT. No positive results were found with standard PT. The 5% brimonidine concentration demonstrated the highest sensitivity. The absence of eyelid pruritus was associated with negative testing. CONCLUSION: In the investigation of ocular allergy to brimonidine, scratch PT proved to be an essential tool. Brimonidine 5% pet. appeared as the most sensitive concentration for scratch PT.

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