Risk calculator of the clinical response to antihistamines in chronic urticaria: Development and internal validation.

Early detection of CSU patients with low probability of a clinical response with antihistamines could undergo prompt initiation of therapeutic alternatives. The aim of the study was to develop and internally validate a model for predicting the clinical response to antihistamines in adult patients with chronic spontaneous urticaria (CSU), who consult allergology and dermatology care centers. A cohort of CSU patients, recruited from four participating centers, were followed up for 12 months. Fifteen candidate variables were selected to be included in the multivariate model and then internal validation was done with bootstrap analysis with 1000 simulations. The outcome variable, clinical response to antihistamines, was evaluated with the UAS (Urticaria Activity Score) scale for seven days: "No response to antihistamines" was defined as UAS7 ≥7 points after at least one month with a maximum dose of antihistamines, while "Response to antiH1" was defined as UAS7 ≤6 points for at least three months with the use of antiH1. A total of 790 patients were included. Among the different models analyzed, the model that included age, angioedema, anxiety/depression, time with the disease, NSAIDs (Non-steroidal anti-inflammatory drugs) intolerance, and UAS7 baseline was considered the one with the best performance (accuracy 0.675, HL 0.87, AUC 0.727). The internal validation analyses demonstrated good consistency of the model. In conclusion, this prediction model identifies the probability of response to antihistamines in patients with chronic spontaneous urticaria. The model could be useful for a personalized therapeutic approach according to individual patient risk.

Biomarkers of Autoimmune Chronic Spontaneous Urticaria.

PURPOSEOF REVIEW: Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers. RECENT FINDINGS: Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.

[Practical update for the diagnosis and treatment of chronic urticaria]. / Actualización práctica de diagnóstico y tratamiento de la urticaria crónica.

Urticaria is a distinctive pattern of inflammatory response of the skin and/or mucous membranes characterized by the sudden appearance of vanishing wheals, angioedema, or both, associated with pruritus. Acute forms are frequent and limited to outbreaks of less than 6 weeks; while the chronic ones have a prevalence of less than 1%, longer duration and can be spontaneous or inducible. The etiopathogenic mechanisms involved in this disease include autoallergy, autoimmunity, and inflammation with cell activation, mainly of the mast cell, leading to its degranulation with the release of vasoactive mediators. Along its approach, diagnostic confirmation, search for indicators of its etiopathogenesis, detection of cofactors that can modulate its activity, recognition of comorbidities, evaluation of possible biomarkers and the assessment of disease activity, impact and control are essential. The pharmacological management aims to control the symptoms, until the urticaria, which is self-resolving, is gone. This is described in a stepwise fashion with increasing complexity.

La urticaria es un patrón distintivo de respuesta inflamatoria de piel y/o mucosas caracterizada por la aparición súbita de ronchas evanescentes, angioedema o ambos, asociados a prurito. Las formas agudas son frecuentes y se limitan a brotes de menos de 6 semanas; mientras que las crónicas tienen una prevalencia menor al 1%, mayor duración y pueden ser espontáneas o inducibles. Los mecanismos etiopatogénicos involucrados en esta enfermedad incluyen la autoalergia, la autoinmunidad y la inflamación con la activación celular, principalmente del mastocito, lo que lleva a su degranulación con liberación de mediadores vasoactivos. En su abordaje son fundamentales la confirmación diagnóstica; la búsqueda de indicadores de su etiopatogenia; la detección de cofactores que pueden modular su actividad; el reconocimiento de comorbilidades; la evaluación de posibles biomarcadores y, el impacto en la calidad de vida, el registro de la actividad y el control de la enfermedad. El manejo farmacológico tiene por objetivo controlar los síntomas, mientras la urticaria resuelve de forma espontánea. Este se describe de forma escalonada con una complejidad creciente.

Impact of COVID-19 pandemic on the course of refractory chronic spontaneous urticaria under omalizumab treatment.

BACKGROUND: The course of chronic spontaneous urticaria (CSU) can be influenced by infections, depression, and stress. OBJECTIVE: Our aim was to investigate the impact of the COVID-19 pandemic on the course of refractory CSU together with patient adherence to omalizumab and treatment adjustments. METHODS: Urticaria Activity Score (UAS7) was used to assess disease activity. Fear of COVID-19 Scale (FC-19s), and Depression Anxiety Stress Scale (DASS-21s) were performed to assess mental health status. All scales were performed during the Quarantine Period (QP) and Return to the Normal Period (RTNP). UAS7 Before Pandemic (BP) was recorded from the patients medical records. RESULTS: The authors evaluated 104 omalizumab-receiving CSU patients. UAS7 scores during QP were significantly higher than those in RTNP and BP (p < 0.01). DASS-21 and FC-19 scores were significantly higher during QP compared to RTNP (p < 0.01). Nineteen (18.2%) patients ceased omalizumab, 9 patients prolonged the intervals between subsequent doses during the pandemic. UAS7 scores in QP were significantly higher in patients who ceased omalizumab than in those who continued (p < 0.001). Among patients who continued omalizumab, 22.4% had an increase in urticaria activity and higher FC-19 scores in comparison with those with stable disease activity (p = 0.008). STUDY LIMITATIONS: The small sample size of patients with prolonged intervals of omalizumab and the lack of mental health evaluation with the same tools prior to the study. CONCLUSION: Fear induced by COVID-19 can determine an increase in disease activity. Therefore, patients on omalizumab should continue their treatment and prolonged interval without omalizumab can be considered in patients with good urticaria control.

[Clinical profile of patients with chronic urticaria in a tertiary care hospital of the social security system in Costa Ricas]. / Perfil clínico de los pacientes con urticaria crónica en un hospital de tercer nivel de atención del sistema de seguridad social de Costa Rica.

OBJECTIVE: To describe the medical and laboratory profile of the patients who have been diagnosed with chronic urticaria in the outpatient clinic of a tertiary care hospital of the social security system in Costa Rica. METHODS: All patients over 13 years of age who had been diagnosed with chronic urticaria between January 1st, 2014, and December 31st, 2018 were included. Variables of medical and laboratory data were statistically analyzed, and the treatment of the patients between their first and last medical consultation was compared. RESULTS: This was about 160 patients who had been diagnosed with chronic urticaria; 129 of them were women, 45.7 % between the ages of 30-49 years; in 17.5 % of them (28 patients), inducible urticaria was associated; 54.8 % (46/84) had positive antithyroperoxidase antibodies; 16.9 % (27 patients) maintained a single dose of second-generation anti-H1 antihistamines in the last consultation; 16.3 % (26 patients) no longer required antihistamine treatment in the last consultation. Cyclosporine was used in 8.8 % (14 patients), and omalizumab was used in 2.5 % (four patients). CONCLUSION: Since this is a real-life study in a geographic region with limited publications on this pathology, we trust that the provided information will contribute to the scientific community in order to improve the quality of life of patients with chronic urticaria through a timely diagnosis and an effective and efficient treatment.

Objetivo: Describir el perfil clínico y de laboratorio de los pacientes diagnosticados con urticaria crónica en la consulta externa de alergología en un hospital de tercer nivel de atención del sistema de seguridad social de Costa Rica. Métodos: Se incluyeron todos los pacientes mayores de 13 años diagnosticados con urticaria crónica entre el 1 de enero de 2014 y el 31 de diciembre de 2018. Se analizaron estadísticamente variables de datos clínicos y de laboratorio y se comparó el tratamiento de los pacientes entre la primera y última consulta. Resultados: Se trató de 160 pacientes con diagnóstico de urticaria crónica: 129 del sexo femenino, 45.7 % con edad entre 30 y 49 años, en 17.5 % (28 pacientes) se asoció urticaria inducible, 54.8 % (46/84) presentó anticuerpo antitiroperoxidasa positivo, 16.9 % (27 pacientes) se mantuvo en la última consulta con una dosis de antihistamínicos anti-H1 de segunda generación; 16.3 % (26 pacientes) ya no requería tratamiento antihistamínico en la última consulta. En 8.8 % de los casos (14 pacientes) se utilizó ciclosporina y en 2.5 % (cuatro pacientes), omalizumab. Conclusión: Al tratase de un estudio de vida real en una región geográfica con limitadas publicaciones sobre esta patología, confiamos que la información provista contribuya a la comunidad científica a mejorar la calidad de vida de los pacientes con urticaria crónica mediante un diagnóstico oportuno y un tratamiento eficaz y efectivo.

[Urticaria associated with COVID-19 in allergic patients. A case series]. / Urticaria asociada a COVID-19 en pacientes alérgicos. Serie de casos.

INTRODUCTION: In December 2019, a new coronavirus was identified as the causal agent of the 2019 coronavirus disease (COVID-19) with a wide clinical spectrum that goes from asymptomatic cases to critical and fatal cases. Its usual manifestations are fever, cough, and fatigue; although some cases present skin lesions. CASES REPORT: The first case was a 30-year-old woman with a history of controlled solar urticaria who presented erythematous and pruritic wheals in malar and cervical regions and extremities; associated with general malaise, headaches, and nausea, in whom the presence of COVID-19 was confirmed; her condition improved with a quadruple dose of antihistamines. The second case was a 47-year-old woman with a history of wasp sting anaphylaxis, without mastocytosis, who presented nasal congestion, headaches, and hypogeusia associated with generalized, erythematous, and pruritic wheals, with confirmation of COVID-19; her condition improved with quadruple doses of antihistamines. CONCLUSIONS: Cutaneous manifestations associated with COVID-19 are frequent and can be classified as inflammatory and vascular. Among them, urticarial lesions occupy the fourth place, and although there could be some predominance of these in patients with a history of allergies, more studies are required to define an association.

Introducción: En diciembre de 2019 fue identificado un nuevo coronavirus como agente causal de la enfermedad por coronavirus del 2019 con un amplio espectro clínico, desde casos asintomáticos hasta críticos y fatales. Generalmente se manifiesta con fiebre, tos y fatiga, aunque algunos casos se presentan con lesiones cutáneas. Reporte de casos: El primer caso es una mujer de 30 años con antecedente de urticaria solar controlada quien presentó habones eritematosos y pruriginosos en región malar, cervical y extremidades, asociado a malestar general, cefalea y náuseas, en quien se confirmó la presencia de COVID-19, y mejoró con antihistamínicos a dosis cuádruple. El segundo caso es una mujer de 47 años con antecedente de anafilaxia por picadura de avispa, sin mastocitosis, quien presentó congestión nasal, cefalea e hipogeusia asociado a habones generalizados, eritematosos y pruriginosos, con confirmación de COVID-19, y mejoría con dosis cuadruple de antihistamínicos. Conclusiones: Las manifestaciones cutáneas asociadas a COVID-19 son frecuentes y se pueden clasificar en inflamatorias y vasculares. Dentro de ellas, las lesiones urticariales ocupan el cuarto lugar, y aunque podría existir algún predominio de estas en pacientes con antecedentes de alergias, se necesitan más estudios para definir una asociación.

[Cutaneous manifestations in patients with COVID-19 with significant attention to urticaria]. / Manifestaciones cutáneas en los pacientes con COVID-19 con especial atención en la urticaria.

OBJECTIVES: To describe the most frequent dermatological conditions observed in COVID-19 patients and to determine whether their presence could be used to establish an early diagnosis or to predict the progression of the infection. METHODS: There was a review in PubMed/MEDLINE and EMBASE of all the articles that had been published between January 1st and November 1st, 2020, with the search terms focused on "SARS-CoV-2", "COVID-19" and "Skin diseases". RESULTS: Eighty three studies met the inclusion criteria. Skin lesions have been reported in 0.2 % of the patients. The most frequently reported dermatoses were: maculopapular/ morbilliform rashes, urticaria and angioedema, chilblain-like acral pattern, and vesicular lesions. Among researchers, there are differences of opinion about a possible diagnostic or prognostic value of the skin diseases that are associated to the infection. CONCLUSIONS: It is advisable to consider the diagnosis of SARS-CoV-2 infection in patients who call the doctor for skin lesions, urticaria, or angioedema, with or without other symptoms of the infection, especially if there is a previous history of recent exposure to other infected subjects.

Objetivos: Describir las afecciones dermatológicas más frecuentes en los pacientes con la COVID-19 y precisar si su presencia puede ser utilizada para establecer un diagnóstico temprano o para predecir la evolución de la infección. Métodos: Se realizó una revisión en PubMed/MEDLINE y EMBASE de todos los artículos publicados entre enero 1 y noviembre 1 de 2020, con los términos de la búsqueda centrados en "SARS-CoV-2", "COVID-19" y "Enfermedades cutáneas". Resultados: Cumplieron los criterios de inclusión 83 estudios. Lesiones de la piel han sido reportadas en 0.2 % de los pacientes. Las erupciones maculopapulares/morbiliformes, la urticaria y el angioedema, el patrón acral parecido a sabañones y las lesiones vesiculares fueron las dermatosis más frecuentemente informadas. Existen diferencias de opinión entre los investigadores, acerca de un posible valor diagnóstico o pronóstico de las afecciones cutáneas asociadas con la infección. Conclusiones: Es recomendable considerar el diagnóstico de la infección por SARS-CoV-2 en pacientes que consultan por presentar lesiones cutáneas, urticaria o angioedema con o sin otros síntomas de la infección y en especial si existe algún antecedente de exposición reciente a otros sujetos infectados.

[Recommendations for the diagnosis and treatment of urticaria in children]. / Recomendaciones para el diagnóstico y tratamiento de la urticaria en pediatría.

Urticaria is one of the most common skin disorders in children. We define acute urticaria when it persists for less than 6 weeks, and chronic urticaria (CU), when it persists longer. Urticaria affects 25 % of the population; in most cases, it is acute urticaria. CU represents 0.1 %, with higher prevalence in women (60 %). CU is subclassified in chronic inducible urticaria when there is a specific external trigger and chronic spontaneous urticaria if it is not present. Although the pathophysiology is complex, mast cell degranulation is recognized as a key event. Second-generation H1 antihistamines are the first line of treatment in both, acute urticaria and CU. In unresponsive patients, other therapies will be considered. We will emphasize in CU due to the difficulty in its diagnosis, the increase in its prevalence and the severe impairment it causes in children´s quality of life.

La urticaria es una de las afecciones cutáneas más comunes en niños. Se define urticaria aguda cuando persiste hasta 6 semanas, y crónica, cuando la duración es mayor. Afecta al 25 % de la población. La forma aguda es la más frecuente. La crónica representa el 0,1 %, con mayor predominio en mujeres (el 60 %). Se subdivide en urticaria crónica inducible cuando hay un desencadenante externo específico y urticaria crónica espontánea si este no está presente. Aunque la fisiopatología es compleja, la degranulación del mastocito se considera un evento clave. Los antihistamínicos anti-H1 de segunda generación son la primera línea de tratamiento tanto en la urticaria aguda como en la crónica. En pacientes no respondedores, se considerarán otras terapias. Se hará énfasis en urticaria crónica dada la dificultad en su diagnóstico, el aumento de su prevalencia y la gran afectación que produce en la calidad de vida de los niños.

What the physicians should know about mast cells, dendritic cells, urticaria, and omalizumab during COVID-19 or asymptomatic infections due to SARS-CoV-2?

Coronavirus disease (COVID-19) pandemic presents several dermatological manifestations described in the present indexed literature, with around 700 cases reported until May 2020, some described as urticaria or urticarial rashes. Urticaria is constituted by evanescent erythematous-edematous lesions (wheals and flare), which does not persist in the same site for more than 24 to 48 hours and appears in other topographic localization, resolving without residual hyper pigmentation. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, some cytokines are synthesized, including Interferon (IFN) type I, TNF-α, and chemokines which may induce mast cells (MCs) and basophils degranulation by mechanisms similar to the autoinflammatory monogenic or polygenic diseases. In this article, we discuss the spectrum of the urticaria and urticarial-like lesions in the COVID-19's era, besides other aspects related to innate and adaptative immune response to viral infections, interactions between dermal dendritic cells and MCs, and degranulation of MCs by different stimuli. Plasmacytoid dendritic cells share, in allergic patients, expression of the high-affinity IgE receptors on cell membranes and demonstrated a low pattern of type I IFN secretion in viral infections. We discuss the previous descriptions of the effects of omalizumab, a monoclonal antibody directed to IgE and high-affinity IgE receptors, to improve the IFN responses and enhance their antiviral effects.

[Cold urticaria with risk of anaphylaxis treated with omalizumab. A case report]. / Urticaria por frío y riesgo de anafilaxia tratada con omalizumab. a propósito de un caso.

BACKGROUND: Omalizumab, which is a monoclonal anti-IgE antibody, has recently been used as an option in the treatment of inducible urticaria. CASE REPORT: We describe the case of a 46-year-old woman who was referred to the Department of Allergy and Immunology of "Hospital Civil de Guadalajara, Dr. Juan I. Menchaca" due to a history of hives, body itching, changes in the color of the skin after exposure to water, and chest tightness after the intake of cold beverages; therefore, she used to limit her outdoor activities and personal hygiene. We conducted challenge tests with heat, soaked towels, treadmill walks, and dermographism; which were negative. The ice cube test was positive. To establish the speed of wheal formation, we established intervals of exposure to cold of one, three, five, and ten minutes; a positive result was obtained from the third minute. Due to the poor response to the drug treatment and to measures to avoid the cold, as well as to the poor quality of life, the high risk of anaphylaxis, and the advent of winter season, omalizumab was administered at monthly doses of 150 mg during the winter season. After the first dose, there were no reports of episodes of hives in areas exposed to cold; the ice cube test was negative before the second dose and in the following months, and the patient was able to ingest cold beverages and cold food. There were no adverse reactions that could be attributable to the use of omalizumab. Three years after the first dose, the patient was still asymptomatic. CONCLUSION: The described case is one of the first cases of cold urticaria with risk of anaphylaxis with a positive response to omalizumab, which was reflected in symptom control and the improvement in the quality of life.

Antecedentes: Omalizumab, un anticuerpo monoclonal anti-IgE, recientemente es utilizado como una opción en el tratamiento de la urticaria inducible. Caso clínico: Describimos el caso de una mujer de 46 años referida al Servicio de Alergia e Inmunología del Hospital Civil de Guadalajara Dr. Juan I. Menchaca, por historia de urticaria, picazón en el cuerpo, cambios en el color de la piel tras la exposición al agua y opresión en el pecho posterior el consumo de bebidas frías; en consecuencia, ella limitaba sus actividades al aire libre y de higiene personal. Se realizaron pruebas de desafío con calor, toalla húmeda, caminata en banda sinfín y dermografismo, las cuales fueron negativas; la prueba del cubo de hielo fue positiva. Para establecer la velocidad de la formación de la roncha establecimos intervalos de exposición al frío durante uno, tres, cinco y 10 minutos; se obtuvo un resultado positivo desde el tercer minuto. Debido a la mala respuesta al tratamiento farmacológicos y a las medidas para evitar el frío, así como por la mala calidad de vida, el alto riesgo de anafilaxis y el advenimiento de la temporada de invierno, se administraron 150 mg/mes de omalizumab durante la temporada de invierno. Después de la primera dosis no se notificaron episodios de urticaria en zonas expuestas al frío; la prueba del cubo de hielo antes de la segunda dosis y en los meses siguientes fue negativa y la paciente pudo ingerir bebidas y alimentos fríos. No se produjeron reacciones adversas atribuibles al uso de omalizumab. Tres años después de la primera dosis, la paciente permanecía asintomática. Conclusión: El caso descrito constituye uno de los primeros de urticaria inducida por el frío con riesgo de anafilaxia con respuesta positiva a omalizumab, lo que se reflejó en el control de los síntomas y la mejoría en la calidad de vida.

Incapacitating solar urticaria: successful treatment with omalizumab.

Solar urticaria is a rare form of physical urticaria mediated by immunoglobulin E. The lesions appear immediately after the sun exposure, interfering with the patient's normal daily life. Omalizumab, a monoclonal anti-IgE antibody, has been recently approved for the treatment of chronic spontaneous urticaria, and the latest reports support its role also in the treatment of solar urticaria. Hereby, we report a case of solar urticaria refractory to conventional treatment strategies, with an excellent response to treatment with omalizumab and phototesting normalization.

Consensus on the diagnostic and therapeutic management of chronic spontaneous urticaria in adults - Brazilian Society of Dermatology.

BACKGROUND: Urticarias are frequent diseases, with 15% to 20% of the population presenting at least one acute episode in their lifetime. Urticaria are classified in acute ( ≤ 6 weeks) or chronic (> 6 weeks). They may be induced or spontaneous. OBJECTIVES: To verify the diagnostic and therapeutic recommendations in chronic spontaneous urticaria (CSU), according to the experience of Brazilian experts, regarding the available guidelines (international and US). METHODS: A questionnaire was sent to Brazilian experts, with questions concerning diagnostic and therapeutic recommendations for CSU in adults. RESULTS: Sixteen Brazilian experts answered the questionnaire related to diagnosis and therapy of CSU in adults and data were analyzed. Final text was written, considering the available guidelines (International and US), adapted to the medical practices in Brazil. Diagnostic work up in CSU is rarely necessary. Biopsy of skin lesion and histopathology may be indicated to rule out other diseases, such as, urticarial vasculitis. Other laboratory tests, such as complete blood count, CRP, ESR and thyroid screening. Treatment of CSU includes second-generation anti-histamines (sgAH) at licensed doses, sgAH two, three to fourfold doses (non-licensed) and omalizumab. Other drugs, such as, cyclosporine, immunomodulatory drugs and immunosuppressants may be indicated (non-licensed and with limited scientific evidence). CONCLUSIONS: Most of the Brazilian experts in this study partially agreed with the diagnostic and therapeutic recommendations of the International and US guidelines. They agreed with the use of sgAH at licensed doses. Increase in the dose to fourfold of sgAH may be suggested with restrictions, due to its non-licensed dose. Sedating anti-histamines, as suggested by the US guideline, are indicated by some of the Brazilian experts, due to its availability. Adaptations are mandatory in the treatment of CSU, due to scarce or lack of other therapeutic resources in the public health system in Brazil, such as omalizumab or cyclosporine.

Incapacitating solar urticaria: successful treatment with omalizumab

Abstract: Solar urticaria is a rare form of physical urticaria mediated by immunoglobulin E. The lesions appear immediately after the sun exposure, interfering with the patient's normal daily life. Omalizumab, a monoclonal anti-IgE antibody, has been recently approved for the treatment of chronic spontaneous urticaria, and the latest reports support its role also in the treatment of solar urticaria. Hereby, we report a case of solar urticaria refractory to conventional treatment strategies, with an excellent response to treatment with omalizumab and phototesting normalization.