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.

Severe asthma and eligibility for biologics in a Brazilian cohort.

OBJECTIVE: This study aims to describe the eligibility for biologic therapies for severe asthma (SA) in a cohort of patients attending the Program for Control of Asthma (ProAR) in Bahia, Brazil. METHODS: Data from SA patients (≥18 years old) attending the ProAR, that were included in a case-control study conducted from 2013 to 2015, were used to reassess patients according to a modified ERS/ATS 2014 SA criteria. Patients were then classified according to the eligibility for SA biological therapy based on current prescription labels. RESULTS: From 544 patients in the cohort, 531 (97.6%) were included and 172 (32.4%) were identified as SA patients according to the ERS/ATS 2014 modified criteria. Of these 172 patients, 69 (40.1%) were ineligible for any of the biologicals approved for asthma (omalizumab, mepolizumab, reslizumab and benralizumab), 60 (34.9%) patients were eligible for one of the biological therapies, and 10 (5.8%) patients were eligible for all biological therapies. CONCLUSIONS: More than half of patients with SA were eligible for biologic therapy in our study, but none of them received this form of treatment. Almost half of them were not eligible to any of the approved biologics, however. The variability and overlap in patients' eligibility highlight the importance of evaluating each patient individually for a more personalized treatment approach. While there is a need to increase access for some of those eligible that may really need a biologic treatment, continuous efforts are required to develop alternatives to those who are not eligible.

Impact of omalizumab in children from a middle-income country with severe therapy-resistant asthma: A real-life study.

BACKGROUND: Severe asthma in children is a global health problem. Severe therapy-resistant asthma (STRA) in children is a major clinical challenge due to persistent symptoms despite high doses of corticosteroids and results in high public health costs. Omalizumab (anti-IgE monoclonal antibody) has been described as an effective add-on therapy in these patients. The characteristics of children with STRA from low- and middle-income countries have scarcely been reported, and no real-life study has been published on the effects of omalizumab in this group of patients. The aim of our study is to report the first clinical real-life experiences with omalizumab in Brazilian children with STRA. METHODS: Children (6-18 years old) from a referral center who were diagnosed with STRA were included in this retrospective study based on our clinical databases. The included children had undergone at least 6 months of omalizumab treatment and fulfilled the following initial criteria: 1) >6 years old; 2) a positive skin-prick test for at least one aeroallergen; and 3) a serum total IgE level between 30 and 1500 IU/mL. Clinical and lung function variables were analyzed before and after treatment. RESULTS: Fourteen children (mean age: 11.9 years; percentage female: 72%) were included in this study. Omalizumab treatment significantly increased control of the disease according to a standardized questionnaire administered at every visit (P < 0.0001), ceased hospitalizations in 70% (P = 0.02) of patients, and allowed 8/9 (89%) patients to be weaned off oral steroids (P = 0.004). CONCLUSIONS: In this retrospective report, the use of omalizumab in Brazilian children with STRA significantly improved disease control, decreased hospitalizations, and allowed suspension of continuous oral corticosteroids.

Pruebas dermatológicas con autosuero en pacientes alérgicos y en pacientes autistas y sus madres / Autoserum skin tests in allergic patients, and in autistic patients and their mothers

Introducción: las alergias se encuentran con frecuencia en pacientes autistas y asimismo el autismo muestra una gran presencia entre los pacientes alérgicos. Objetivo: demostrar que las alergias y el autismo comparten algunos patrones inmunológicos similares. Métodos: la prueba dermatológica con autosuero se utilizó para demostrar la presencia de anti-IgE y/o de anticuerpos de receptores de Ig/E (FcεRIα). Resultados: la prueba ASST confirmó la frecuencia similar de positivos/positivos y de negativos/negativos en pacientes alérgicos y en pacientes autistas. Estas similitudes no existieron cuando se realizó la comparación con el grupo control. Se había hallado una correlación positiva con los resultados obtenidos en pacientes autistas y sus madres. Conclusiones: los pacientes autistas y los pacientes alérgicos comparten ciertas similitudes inmunológicas. Ambos se diferencian del grupo de controles sin estas condiciones. Resulta frecuente encontrar pacientes autistas con síntomas alérgicos y pacientes alérgicos con signos de autismo. Es motivo de análisis si los hallazgos inmunológicos representan un puente clínico entre ambos procesos. Asimismo se mostró una posible correlación genética entre los pacientes con autismo y sus madres(AU)

Introduction: allergies are frequently found among patients with autism and autism shows an increased frequency among the allergic patients. Objective: to demonstrate that allergies and autism share some similar immunological patterns. Methods: the autoserum skin test (ASST) was used to demonstrate the presence of anti-IgE and/or anti-IgE receptor antibodies (FcεRIα). Results: the ASST demonstrated similar frequency, positives/positives and negatives/negatives, considering allergic and autistic patients. These similarities didn't exist when comparing with the control group. A positive correlation had been found with the results of autistic patients and their mothers. Conclusions: autistic and allergic patients share some immunological similarities. Both differ from normal controls. It is not uncommon autistics with allergic symptoms and allergic patients with autism. If the immunological findings represent a clinical bridge between both processes, it is under discussion. Also it was demonstrated a possible genetic correlation between the patients with autism and their mothers(AU)

Omalizumab for chronic urticaria in Latin America.

BACKGROUND: Chronic urticaria (CU) is defined as the spontaneous appearance of wheals, with or without angioedema, persisting for ≥6 weeks. Chronic Spontaneous Urticaria (CSU) is a type of CU which affects 0.5-1 % of the global population, but it represents a high burden to patients. In recent years, omalizumab is available as treatment of disease. Our aim is to extend previous findings, analyzing effects of omalizumab on symptoms in Latin American patients with CSU. METHODS: Retrospective analysis of patients treated with omalizumab in Cuenca-Ecuador. 150 mg omalizumab was administered every 4 weeks, and its effects were measured by Urticaria Activity Score (UAS) at baseline and each month in follow up. Complete response was defined as a UAS of 0 or 1, and partial response was classified as a UAS of 2 or more. Also, demographic and clinical variables were collected. Descriptive analyses were employed. Response rates were summarized as counts and percentages after 3 and 5 months. Related Samples Wilcoxon signed rank tests were used to compare UAS at baseline and after 3 months. P values <0.05 indicated statistical significance. RESULTS: 26 subjects were enrolled, almost half were female individuals (57.7 %), with mean age 47.8 years (range, 18-81 years). Mean duration of CU after diagnosis was 23.3 months (range, 2-180 months). Mean UAS at baseline was 5.7 points (range, 4-6 points). Nine patients (34.6 %) completed 3 months of treatment (33 % reported a complete response), with a mean difference in UAS of 3.33 (p = 0.01). Four patients completed 5 months of treatment (75.0 % showed a complete response). All patients previously treated with first-generation antihistamines plus corticosteroids showed no responses at neither 3 nor 5 months of treatment. CONCLUSION: Omalizumab is an effective treatment for patients with CU. It is necessary to conduct some future investigations where we can establish if 150 mg could be an option in developing countries.

Real life study of three years omalizumab in patients with difficult-to-control asthma.

BACKGROUND: Even though there are multiple options for the treatment of asthma, there still exists a fair group of patients with difficult-to-control asthma. We describe for the first time the real-world effects of three-year omalizumab treatment on patients with difficult-to-control asthma, seen in a social security hospital in a Latin American country. METHODS: Difficult-to-control asthmatic patients from the out-patient clinic of a regional hospital were recruited to receive a three-year omalizumab course. Efficacy parameters were asthma control test (ACT) score; FEV1; daily beclomethasone maintenance dose; and unplanned visits for asthma exacerbations (emergency room (ER), hospitalisations, intensive care). RESULTS: 52 patients were recruited, 47 completed the three-year treatment (42 female, 15-67 years, mean age 43.5). Comparing efficacy parameters of the year before omalizumab with the 3rd year of omalizumab: mean ACT improved from 12.4 to 20.5, mean FEV1 from 66.3% (standard deviation (SD) 19.1%) to 88.4% (SD 16.2%) of predicted, while mean beclomethasone dose reduced from 1750 to 766 mcg/day and there was a significant reduction in patients experiencing ER visits (from 95% to 19%, p<0.0001), hospitalisation (38% to 2%, p<0.0001) and intensive care (4% to 0, NS). Five patients discontinued omalizumab, two because of an adverse event (anaphylaxis, severe headache, both resolved without sequelae). CONCLUSION: Omalizumab improved most clinical parameters of Mexican patients with difficult-to-control asthma. Especially the rates of ER visits and hospitalisation were significantly reduced, thus reducing costs. Omalizumab was generally well tolerated.

Eficácia da terapia Anti-IgE no controle da asma / Effectiveness of anti-IgE therapy for asthma control

Avaliar parâmetros de resposta à terapia anti-IgE com omalizumabe em pacientes com asma de difícil controle. Métodos: Foram avaliados 24 pacientes com asma de difícil controle, em uso de omalizumabe há pelo menos 32 semanas e considerados como respondedores à terapia. Avaliou-se a pontuação do teste de controle de asma (TCA), a presença de sintomas de asma, a frequência de uso de ß2-agonista de curta ação, as doses de corticoide inalatório e oral e o percentual previsto do volume expiratório forçado no 1° minuto (VEF1), antes e com 16 e 32 semanas de tratamento. Resultados: Na avaliação da pontuação do TCA foram obtidas as médias 12,4 para o momento inicial, 15,7 e 17,9 para a 16ª semana e 32ª semana respectivamente (p < 0,0001). A dose média de corticoide inalatório diminuiu ao longo das 32 semanas, de 1.416 mcg para 1.250 mcg na 32ª semana (p = 0,0797). O número de idas à emergência e de sintomas noturnos também diminuíram. Observou-se redução da dose de corticoide oral, sendo inicialmente a dose média de 17,4 mg e após 16 e 32 semanas 6,7 mg e 4,4 mg, respectivamente(p < 0,0001). Houve aumento na média do VEF1 (% do previsto), de 37,5% no início do tratamentopara 44,0% na 16ª semana (p = 0,007). Conclusões: O omalizumabe como terapia adjuvante no tratamento de pacientes com asma de difícil controle foi eficaz na melhora de parâmetros clínicose funcionais, contribuindo para o controle da asma e diminuição dos riscos futuros...

To assess parameters of response to anti-IgE therapy with omalizumab in patients with difficult-to-control asthma. Methods: Twenty four patients with difficult-to-control asthma using omalizumab for at least 32 weeks and considered as treatment responders were assessed. The Asthma Control Test (ACT) was used to assess the presence of asthma symptoms, frequency of use of short-acting beta2-agonists, inhaled and oral corticosteroid doses, and percentage of predicted forced expiratory volume in 1 second (FEV1) before treatment and after 16 and 32 weeks of treatment. Results: Mean ACT scores were 12.4 before treatment and 15.7 and 17.9 at 16 and 32 weeks post-treatment, respectively (p < 0.0001). Mean dose of inhaled corticosteroid decreased over the 32 weeks, from 1,416 mcg to 1,250 mcg (p = 0.0797). The number of visits to emergency services and nocturnal symptoms also decreased. There was a reduction in the mean dose of oral corticosteroids, from 17.4 mg at baseline to 6.7 mg and 4.4 mg after 16 and 32 weeks of treatment, respectively (p < 0.0001). Finally, an increase was found in the mean percentage values of predicted FEV1, from 37.5% at baseline to 44.0% at week 16 (p = 0.007). Conclusions: Omalizumab as adjunctive therapy in the treatment of patients with difficult-to-control asthma was effective in improving clinical and functional parameters, contributing to the control of asthma and to the reduction of future risks...

Anticuerpo monoclonal anti-inmunoglobulina E en el tratamiento de la rinitis alérgica / Anti-immunoblobulin E monoclonal antibody in the treatment of allergic rhinitis

La rinitis alérgica (RA) es una enfermedad con alta incidencia a nivel mundial, sus síntomas están directamente relacionados con la exposición a un alérgeno ambiental que desencadena una cascada inflamatoria mediada por inmunoglobulina E. El tratamiento convencional actual de la RA consta del control ambiental, farmacoterapia e inmunoterapia; la reciente aparición de los anticuerpos monoclonales para el manejo de las enfermedades alérgicas parece ser prometedora. Estudios han demostrado que el Omalizumab, un anticuerpo monoclonal humanizado anti IgE, es capaz de modificar la respuesta inflamatoria dependiente de IgE, constituyéndose en una posible alternativa al manejo de la RA.

Allergic rhinitis (AR) is a disease with global high prevalence, its symptoms are directly related to environmental exposure to an allergen that triggers an inflammatory cascade mediated by Immunoglobulin E. The current standard treatment of AR consists of environmental control, pharmacotherapy and immunotherapy; the recent emergence of Monoclonal Antibodies for the management of allergic diseases appears promising. Studies have shown that Omalizumab, an anti-IgE humanized monoclonal antibody, is capable of modify the inflammatory IgE-dependent response, becoming a possible alternative to the management of AR.

Perfil de ativação de basófilos e evidência de fatores liberadores de histamina na urticária crônica idiopática / Basophils activation profile and evidence of histamine release factor in chronic idiopathic urticaria

INTRODUÇÃO: A Urticária Crônica é caracterizada pelo aparecimento de pápulas eritematosas, pruriginosas recorrentes e transitórias que duram por mais de seis semanas. Na maioria dos pacientes a causa é indeterminada, definida como idiopática (UCI), entretanto, um sub-grupo apresentam autoanticorpos contra a cadeia alfa do receptor de alta afinidade para IgE (FceRI), que são expressos na superfície de mastócitos e basófilos, tornando-os células alvo nesta doença. OBJETIVOS: Avaliar em pacientes com UCI, submetidos ao teste intradérmico de soro autólogo (ASST), o perfil de ativação dos basófilos, pela intensidade de expressão de marcadores de ativação/desgranulação e pela capacidade dos basófilos em responder aos estímulo com a IL-3 e anticorpo anti-IgE. Além disto, a presença de fator liberador de histamina foi avaliado nos soros dos pacientes. METODOLOGIA: Pacientes com UCI (n= 37) foram selecionados no Ambulatório de Urticária do Departamento de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da USP e submetidos ao ASST. O grupo controle foi constituído por indivíduos saudáveis (n=38). A análise da expressão de FceRI, CD63, CD123 e CD203c em basófilos de sangue periférico foi realizada por citometria de fluxo. No ensaio in vitro de estimulação dos basófilos com anti-IgE, as células foram previamente incubadas com IL-3. O ensaio de liberação de histamina mediada por soros de pacientes com UCI foi realizado com três diferentes doadores de leucócitos e a histamina liberada dosada por ELISA de competição. RESULTADOS: Há um baixo número de basófilos no sangue periférico nos pacientes com UCI, coincidente com o baixo nível sérico de histamina. Os escassos basófilos no sangue periférico mostram elevada expressão de FceRI e uma regulação positiva da expressão de CD203c e CD63, independentemente do ASST. A análise funcional dos basófilos, mostra que somente a incubação com IL-3 recombinante já induz aumento significante da expressão de CD203c...

INTRODUCTION: Chronic Urticaria is characterized by recurrent, transitory, pruritic and erythematous wheals present for at least six weeks. In most patients the cause is unknown, defined as idiopathic (CIU), however, a sub-group has autoantibodies against the alfa chain of the high affinity IgE receptor (FceRIa) expressed on mast cells and basophils surface making it the target cells in this disease. OBJECTIVES: To evaluate in CIU patients, undergone autologous serum skin test (ASST), the activation profile of the basophils assessed by the expression of activation/degranulation markers and by the ability to release histamine in response to IL-3 priming and cross-linking with anti-IgE antibodies. Furthermore, the presence of histamine releasing factor in sera of patients was evaluated. METHODS: CIU patients (n = 37) were selected from the Dermatological Outpatient Clinic of the Hospital das Clínicas de São Paulo (HC-FMUSP) and submitted to the ASST. The control group consisted of healthy subjects (n=38). The analysis of the expression of FceRI, CD63, CD123 and CD203c on basophils from peripheral blood was assessed by flow cytometry. For the in vitro stimulation with anti-IgE antibodies, the cells were previously primed with human recombinant IL-3. The histamine release assay mediated by sera from patients with CIU was performed with three different donors of leukocytes and released histamine measured by competition ELISA. RESULTS: There is a low number of basophils in peripheral blood of patients with CIU, reflecting a low serum levels of histamine. The scarce basophils in peripheral blood show high expression of FceRI and an up-regulation of CD203c and CD63 marker expression, independently of the ASST. The functional analysis of basophils, revealed that recombinant IL-3 per se induces a significant increase in CD203c expression and the histamine release from basophils of patients with CIU, which are enhanced followed for 15 and 40 minutes...

Papel de los anticuerpos en la urticaria autoinmune / Antibodies role in autoimmune urticaria

Autoimmune urticaria occurs in patients in whom there are functional autoantibodies directed against FcepsilonR1 and IgE. The antibodies concerned are of subtypes IgG1 and IgG3. It is generally more severe and treatment-resistant. The significance of diagnosing autoimmune urticaria is that patients can be offered an explanation for an otherwise unremitting and puzzling condition. It also opens up the prospect of effective treatment by immunomodulatory treatment in selected patients with autoimmune urticaria. The utologous serum skin test is used as a screening test for autoimmune urticaria. The sensitivity and specificity are about 80% respectively. The diagnosis can be confirmed by demonstrating release of histamine from target basophils or dermal mast cells. Treatment of autoimmune urticaria involves the use of low sedation H1 antihistamines in licensed dosages. Off-label dosages are used if the condition is still poorly controlled. Prednisolone can be used in acute and severe flare-ups. Immunomodulatory treatment with cyclosporin can be considered in recalcitrant cases.

La urticaria autoinmune aparece en pacientes que generan autoanticuerpos funcionales contra el FcepsilonR1 y la IgE. Los anticuerpos involucrados pertenecen al subtipo IgG1 e IgG3. Generalmente es una forma de urticaria más grave y resistente al tratamiento. La importancia de diagnosticar urticaria autoinmune radica en que al hacerlo los enfermos pueden recibir una explicación acerca de una enfermedad desconcertante y que habitualmente no remite. En casos seleccionados de urticaria autoinmune también se abre un espectro de tratamientos eficaces que incluyen terapias inmunomuduladoras. La prueba de suero autólogo se utiliza como estudio de rastreo para esta patología. La sensibilidad y especificidad son cercanas al 80%. El diagnóstico puede confirmarse mediante la demostración de liberación de histamina de basófilos o células cebadas de dermis. El tratamiento de la urticaria autoinmune consiste en la utilización de antihistamínicos H1 con escaso efecto sedante en las dosis recomendadas. Las dosis superiores a las habituales se utilizan en pacientes en quienes la enfermedad se controla escasamente. En casos agudos y durante las exacerbaciones puede administrarse prednisolona. El tratamiento inmunomodulador con ciclosporina puede considerarse en casos refractarios.