Mechanisms of histamine release from mast cells beyond the high affinity IgE receptor in severe chronic spontaneous urticaria.

There is growing evidence suggesting that in a subset of patients with severe chronic urticaria [CSU] mast cells are activated via mechanisms that bypass the high affinity IgE receptor. This might explain why some patients do not respond at all to anti-IgE therapy [omalizumab]. The present article reviews the pathogenic mechanisms able to lead to histamine release from mast cells described so far in patients with CSU. These include the activation of the coagulation cascade, the activation of the complement system, the activation of the MRGPRX2 receptor, and the platelet activating factor vicious circle. The article suggests some possible interpretations for the clinical events occurring in this specific subset of patients.

Neutrophilic urticarial dermatosis preceding adult-onset Still's disease.

Neutrophilic urticarial dermatosis is a distinct entity strongly associated with underlying autoinflammatory disease. The pathogenesis of this condition has been considered to center around interleukin-1. We report a young woman with neutrophilic urticarial dermatosis who presented with a recurrent urticarial rash for two years prior to the onset of other systemic features including persistent fevers, sore throat, leukocytosis, elevated ferritin, and splenomegaly. She was ultimately diagnosed with adult-onset Still disease and responded well to treatment with systemic corticosteroids. Although neutrophilic urticarial dermatosis is known to occur in the setting of systemic symptoms and disease, its occurrence preceding the onset of systemic inflammation is less well-described in current literature.

Cutaneous involvement in VEXAS syndrome: clinical and histopathologic findings.

BACKGROUND: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disease with frequent cutaneous manifestations. METHODS: We conducted a retrospective study of all patients with genetically confirmed VEXAS syndrome seen at our institution. Available clinical photographs and skin biopsy slides were reviewed. RESULTS: Cutaneous manifestations developed in 22/25 (88%) patients with VEXAS syndrome. From this group, 10/22 (45%) developed skin involvement before or at the time of other clinical features of VEXAS. Twenty distinct dermatologic presentations of VEXAS from 14 patients were reviewed, and histopathologic patterns were classified as follows: neutrophilic urticarial dermatosis (n = 5, 25%), leukocytoclastic/urticarial vasculitis (n = 4, 20%), urticarial tissue reaction (n = 4, 20%), neutrophilic dermatosis (n = 3, 15%), neutrophilic panniculitis (n = 2, 10%), and nonspecific chronic septal panniculitis (n = 2, 10%). Common systemic findings included macrocytic anemia (96%), fever (88%), thrombocytopenia (76%), weight loss (76%), ocular inflammation (64%), pulmonary infiltrates (56%), deep venous thrombosis or pulmonary embolism (52%), and inflammatory arthritis (52%). CONCLUSIONS: Cutaneous involvement is a common feature of VEXAS syndrome, and histopathologic findings exist on a spectrum of neutrophilic inflammatory dermatoses.

Analysis of clinical features and inflammatory-related molecules with the disease in acute infectious urticaria.

Acute infectious urticaria, a subset of acute urticaria, with severe persistence wheals and systemic symptoms, response well to corticosteroids treatment in combination with antibiotics. The exact pathogenic mechanisms are not fully understood. In this study, we aim to analyze the different clinical features, compare the level of neutrophil activation, and investigate the expression of inflammatory related cytokine in patients with acute urticaria and acute infectious urticaria. Eighteen patients with acute infectious urticaria and eighteen patients with acute urticaria were included in this study. We analyzed the difference between the clinical features and the serum expressions of pro-inflammatory factors in the two groups, then examined the levels of inflammation-associated cytokines before and after treatment of acute infectious urticaria. Hematoxylin & eosin (HE) staining and immunohistochemistry (IHC) were used to further study the relationship between neutrophil and neutrophil-derived Myeloperoxidase (MPO) of lesions in the two groups. The expression levels of C-reactive protein (CRP), D-dimer, interleukin 6 (IL-6), IL-8 and chemokine ligand 8 (CCL8) in serum were significantly higher in acute infectious urticaria than acute urticaria. In acute infectious urticaria, the serum expression levels of CCL8 were significantly decreased after the treatment, a significant correlation observed between CRP levels and IL-6, both CCL8 and CRP were positively correlated with neutrophil granulocytes. Neutrophils infiltration were not observed by HE stains in two groups, but in IHC stains we found a positive expression of MPO in acute infectious urticaria lesions. Elevated neutrophil in the serum, which is associated with the levels of IL-8 & CCL8, and positively expressed MPO in lesions, may be involved in the pathogenic mechanism of acute infectious urticaria.

A Systematic Review of Histopathologic Surveys on Mucocutaneous Biopsies in Patients Developed COVID-19 Vaccine-Related Dermatologic Manifestations.

ABSTRACT: Coronavirus 2 is an infectious agent primarily identified as the cause of a pandemic viral pneumonia. With the mass vaccination against this virus, one of the health issues is the safety of currently available vaccines considering their adverse reactions. This systematic review was conducted to assess and summarize all reported data on histopathologic findings associated with mucocutaneous reactions that developed after COVID-19 vaccination for a better pathophysiology interpretation and clinical management of these reactions. A systematic search was performed in PubMed, Web of Science, and Scopus databases as well as Google Scholar engine for relevant English articles published till July 1, 2022. This review includes 131 studies with a total number of 287 cases. Eruptions that underwent a biopsy were mostly described as erythematous maculopapular, papulosquamous, vasculitis-like, lichenoid, or urticarial lesions. Histopathology revealed spongiosis, interstitial, and perivascular lymphohistiocytic infiltration, erythrocyte extravasation, parakeratosis, endothelial inflammation, and the like. Findings were highly consistent with morbilliform erythema, psoriasiform dermatosis, leukocytoclastic vasculitis, and lichenoid or urticarial drug reactions. The majority of these reactions had a mild nature and were primarily observed in patients with underlying health conditions. Microscopic evaluation was also consistent with transient inflammatory changes, and features like neutrophilic infiltrates, subcorneal pustules, and vasculopathy were less frequently reported than what seen in COVID infection. Therefore, dermatologic reactions developing after vaccination in the general population should not hinder a complete vaccination.

Urticaria Multiforme: An Uncommon Hypersensitivity Rash in Children.

The differential diagnosis of rashes in children is challenging. Pediatric rashes indicate a broad spectrum of clinical conditions and include those that are benign and self-limiting to those that may indicate a serious multisystem inflammatory response. It is essential that emergency nurse practitioners have the knowledge and skill set to accurately identify the spectrum of rashes in the pediatric population to arrive at the correct diagnosis for patient management and avoid costly and unnecessary diagnostic testing. The purpose of this article is to describe a case report of a young child with urticaria multiforme, a commonly misdiagnosed clinical condition, including the distinctive clinical features, differential diagnosis, and most current treatment recommendations. Other clinical conditions that present with skin lesions resembling urticaria multiforme conditions have also been discussed.

Diagnostic Pitfall in Atypical Febrile Presentation in a Patient with a Pregnancy-Specific Dermatosis-Case Report and Literature Review.

Pruritic urticarial papules and plaques of pregnancy (PUPPP) usually occurs in the third trimester of pregnancy in primiparous women. It is a self-limiting inflammatory disorder with a still unknown pathogenic mechanism. The abdominal wall overdistension, with a subsequent inflammatory response due to damage to the connective tissue, represents a pathogenesis explanation. Clinical features involve intensely pruritic urticarial rash with edematous, erythematous papules and plaques. The clinical picture and dermal biopsy establish the diagnosis. Topical corticosteroids and oral antihistamines are usually sufficient, but sometimes systemic corticosteroids are necessary. Maternal and fetal prognosis is excellent, and the lesions resolve after birth with no scarring or pigmentary change. We present a case of a 36-year-old patient with a 32-week pregnancy who was admitted with a generalized pruritic rash accompanied by fever. The final diagnosis was decided after multiple pathology exclusions. Treatment consisted of systemic corticoid therapy. The patient gave birth by cesarean section to a healthy newborn without dermatological lesions or other conditions. Adding more PUPPP cases to the literature portfolio will bring more awareness to this under-recognized and under-reported skin disorder. We trust this case will encourage other physicians to publish more cases of pregnancy-specific dermatoses.

Leukocytoclastic vasculitis in association with linear epidermal basement membrane zone immunoglobulin deposition: Linear vasculitis.

Cutaneous leukocytoclastic vasculitis (LCV) has a distinctive clinical and light microscopic presentation; however, the etiologic basis of LCV is varied. Most cases are attributable to immune complex deposition within a vessel wall and represent an Arthus type III immune complex reaction. The prototypic immunoreactant profile is characterized by granular deposits of components of complement activation in concert with immunoglobulin within the cutaneous vasculature. We encountered nine patients with vasculitic and/or vesiculobullous clinical presentations exhibiting an LCV in association with an immunoreactant profile characterized by homogeneous linear deposits of immunoglobulin along the dermal epidermal junction in a fashion resembling an autoimmune vesiculobullous disease. Among the clinical presentations were palpable purpura, urticarial vasculitis, and vesiculobullous eruptions with supervening purpura. Two patients with Crohn disease presented with classic palpable purpura with biopsy-proven LCV, and direct immunofluorescence (DIF) studies demonstrated linear immunoglobulin G (IgG) with floor localization on the salt-split skin assay. Four patients with systemic lupus erythematosus (SLE) showed purpuric vesiculobullous lesions, with evidence of a neutrophilic interface dermatitis and LCV in three of the four. The remaining patient had urticarial nonbullous lesions showing small-vessel vasculitiswith a neutrophilic interface dermatitis. In all of the patients with SLE, DIF studies showed linear immunoglobulin deposits within the basement membrane zone (BMZ). These constellation of findings clinically, light microscopically, and by immunofluorescence were those of a vasculitic presentation of bullous systemic lupus erythematosus. Two patients had linear IgA disease, which was drug induced in one and paraneoplastic in the other, and the dominant morphology on biopsy in both cases was an LCV. One patient microscopically demonstrated drug-associated and eosinophilic enriched LCV with DIF studies showing striking linear deposits of IgG suggestive of bullous pemphigoid, which was consistent with a vasculitic presentation of drug-induced bullous pemphigoid. In all cases, typical granular vascular immunoglobulin and complement deposition compatible with immune complex mediated vasculitis was observed. It is likely that local immune complexes derived from BMZ antigen bound to antibody are pathogenically relevant. We propose the designation of linear vasculitis for this unique scenario of LCV and linear immunoglobulin epidermal BMZ staining, which in some cases represents a vasculitic presentation of conventional autoimmune vesiculobullous disease.

Clinical and histological characterization of transient dermal pain triggered by sweating stimuli.

BACKGROUND: Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated. METHODS: To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments. RESULTS: Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective. CONCLUSIONS: Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine.

Annular urticarial lesions.

Annular urticarial configurations are often associated with acute and chronic urticaria. Such lesions may be short-lived, migratory, transient, pruritic, and resolving with no residual evidence, making the diagnosis of urticaria an obvious one. Annular urticarial lesions can be the presenting signs of various cutaneous and systemic diseases. The differentiation of urticarial lesions may be made by considering the duration of an individual lesion longer than 24 hours, with burning and pain sensation in the lesions or lack of pruritus; skin marks such as postinflammatory pigmentation or purpura after resolution of the lesions; associated scaling or vehiculation in the lesions; systemic symptoms such as arthralgia, fever or fatigue; and several abnormal laboratory findings. The main differential diagnoses of annular urticarial lesions include urticarial vasculitis, autoinflammatory syndromes, hypersensitivity reactions, and connective tissue diseases.

Carbopol emulgel loaded with ebastine for urticaria: development, characterization, in vitro and in vivo evaluation.

Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.

Irritable bowel syndrome is strongly associated with the primary and idiopathic mast cell disorders.

BACKGROUND: Mounting evidence supports a mechanistic association between irritable bowel syndrome (IBS) symptoms and mast cell hyperactivity. Yet, association between IBS and mast cell disorders (MCDs) has not been studied. We examined this association using two large databases and verified with manual chart review. METHODS: The IBM Watson Health Explorys database (Somers, NY), an aggregate of electronic health record (EHR) data from over two dozen US healthcare systems, and Epic's SlicerDicer tool, a self-service tool containing de-identified data from the Epic EHR, were used to identify patients with IBS and MCDs. Patients with organic gastrointestinal disease or diseases associated with secondary mast cell hyperproliferation were excluded. Results were verified with manual chart review from two academic centers. KEY RESULTS: Up to 4% of IBS patients had a comorbid MCD. IBS was strongly associated with all MCDs. The strongest association was between IBS and mast cell activation syndrome (OR 16.3; 95% CI 13.1-20.3). Odds ratios for IBS+urticaria, IBS+idiopathic urticaria, IBS+non-malignant mastocytosis, and IBS+mast cell malignancy ranged from 4.5 to 9.9. Patients from each of these overlap cohorts were predominantly female, and the overlap occurred with all IBS subtypes. Thorough endoscopic evaluation and comorbid mood disorders and migraines are more common in the overlap cohorts than in IBS alone. CONCLUSIONS/INFERENCES: In a large US database encompassing >53 million patients over >20 years, patients with IBS are at least 4 times more likely to have a MCD than the general population. Further study of mast cell involvement in the pathogenesis of IBS is warranted.

Identification, Mechanism, and Treatment of Skin Lesions in COVID-19: A Review.

Coronavirus disease 2019 (COVID-19) is a multisystem disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that primarily causes respiratory symptoms. However, an increasing number of cutaneous manifestations associated with this disease have been reported. The aim of this study is to analyze the scientific literature on cutaneous manifestations associated with SARS-CoV-2 by means of a narrative literature review until June 2021. The search was conducted in the following electronic databases: Medline (PubMed), SciELO, and Cochrane Library Plus. The most common cutaneous manifestations in patients with COVID-19 are vesicular eruptions, petechial/purpuric rashes, acral lesions, liveoid lesions, urticarial rash, and maculopapular-erythematous rash. These manifestations may be the first presenting symptoms of SARS-CoV-2 infection, as is the case with acral lesions, vesicular eruptions, and urticaria. In relation to severity, the presence of liveoid lesions may be associated with a more severe course of the disease. Treatment used for dermatological lesions includes therapy with anticoagulants, corticosteroids, and antihistamines. Knowledge of the dermatologic manifestations associated with SARS-CoV-2 contributes to the diagnosis of COVID-19 in patients with skin lesions associated with respiratory symptoms or in asymptomatic patients. In addition, understanding the dermatologic lesions associated with COVID-19 could be useful to establish a personalized care plan.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

The Role of Interleukin 10 and 18 in Chronic Spontaneous Urticaria Pathogenesis in the Context of Angioedema Coexistence.

Chronic spontaneous urticaria (CSU) is defined using clinical symptoms as spontaneous occurrence of itchy wheals and/or angioedema for at least 6 weeks. Angioedema is underdiagnosed in CSU patients, and its presence has significant negative impact on health-related quality of life, daily activities, health care resource utilization, and work. Various cytokines have been found to be involved in pathogenesis of CSU. To study levels of interleukin (IL)-10 and IL-18 in CSU patients and to look for the differences in CSU subgroups divided with regard to angioedema reoccurrence, we included consecutive CSU patients into the study. To assess disease activity, urticaria activity score was used. In addition, we calculated disease duration time. In all groups, Il-10 and Il-18 serum concentrations were measured. The study involved 52 patients with CSU and 47 healthy volunteers. The IL-10 level was statistically significantly higher in patients with CSU compared to the control group. There were no significant differences in level of IL-18 between those groups. Comparison of patients with CSU and angioedema with those without angioedema showed no significant differences in level of IL-10 and IL-18. We see the need for further studies of serum levels of IL-10 and IL-18 to better understand the pathogenesis of the disease and to find markers useful in predicting the symptom type in the course of CSU.