Efficacy of House Dust Mite Sublingual Immunotherapy in Patients with Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis. OBJECTIVE: To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator's Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained. RESULTS: A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator's Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months. CONCLUSIONS: Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis.

Study of angiopoietin and plasminogen genes in hereditary angioedema.

OBJECTIVE: To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS: Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS: DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION: Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge.

Kisspeptin and its receptor GPR54 have recently been identified as key signaling partners in the neural control of fertility in animal models and humans. The gonadotropin-releasing hormone (GnRH) neurons represent the final output neurons of the neural network controlling fertility and are suspected to be the primary locus of kisspeptin-GPR54 signaling. Using mouse models, the present study addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40-60% of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor alpha and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, approximately 30% of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with 0% in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons. To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54- and Kiss1-null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in approximately 50% of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS. These observations provide the first evidence that kisspeptin-GPR54 signaling is essential for GnRH neuron activation that initiates ovulation. This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation.

Vacinação contra COVID-19 em pacientes portadores de angioedema hereditário: recomendações do Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) / COVID-19 vaccination in patients with hereditary angioedema: recommendations from the Brazilian Group for the Study on Hereditary Angioedema (GEBRAEH)

No curso da pandemia da COVID-19, o desenvolvimento rápido de vacinas seguras e eficazes é a principal estratégia de saúde pública para conter a propagação da doença. Nesse contexto, esclarecimentos em relação à prioridade e segurança da vacinação contra COVID-19 em pacientes portadores de angioedema hereditário (AEH), assim como de outras doenças, são necessários. Todos os pacientes devem receber a vacina seguindo a estratégia do Ministério da Saúde e manter as medidas de higiene, uso de máscaras e distanciamento social até o controle da pandemia.

During the COVID-19 pandemic, the rapid development of safe and effective vaccines is the main public health strategy to avoid the spread of the disease. In this context, clarifications regarding the priority and safety of vaccination against COVID-19 in patients with hereditary angioedema (HAE), as well as other diseases, are needed. All patients should receive the vaccine according to the Brazilian Ministry of Health strategy and adhere to measures such as maintaining general hygienic measures, wearing masks, and keeping social distance until the pandemic is controlled.

Study of angiopoietin and plasminogen genes in hereditary angioedema

SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

RESUMO OBJETIVO Investigar a presença das mutações no gene Angiopoietina (ANGPT1) e gene Plasminogênio (PLG) em pacientes com Angioedema Hereditário (AEH) com inibidor C1 esterase (C1-INH) normal e negativos para mutação do gene F12. MÉTODOS Foram avaliados pacientes com diagnóstico clínico de AEH sem deficiência ou disfunção de C1-INH e negativos para mutação do gene F12. Realizou-se extração, quantificação e diluição do DNA a uma concentração de 100 ng/uL, em seguida amplificação do DNA (PCR) para avaliação molecular do exon 2 do gene ANGPT1 e do exon 9 do gene PLG para identificação das mutações c.807G>T.p.A119S e c.988A>G p.K330E, respectivamente. O produto da PCR foi avaliado em eletroforese em gel de agarose 1%. Foi realizado o sequenciamento pelo método de Sanger. As análises dos eletroferogramas foram realizadas pelo programa FASTA®. RESULTADOS Foram sequenciadas amostras de 15 mulheres, idade entre 10 e 60 anos, com níveis séricos de inibidor de C1 esterase e C4 normais variando de 22 a 39mg/dL e 10 a 40mg/dL, respectivamente. Não foram identificadas mutações nos éxons analisados dos genes ANGPT1 e PLG. Entretanto no gene PLG foram encontrados polimorfismo de nucleotídeo único (SNP), em duas pacientes homozigotas e cinco heterozigotas. CONCLUSÃO Mais estudos sobre SNP são necessários para esclarecer estes achados pois eles podem ser utilizados como marcadores moleculares do AEH e alvo para novos tratamentos.

Alérgenos recombinantes: papel no diagnóstico e na imunoterapia alérgeno-específica / Recombinant allergens: role in diagnosis and in allergen-specific immunotherapy

Nos últimos 30 anos tem havido um avanço notável na identificação, purificação e expressão recombinante de alérgenos relevantes das mais variadas fontes, incluindo ácaros, insetos, mamíferos, polens, alimentos, fungos, látex e outras fontes. Estes avanços resultaram na utilização crescente de alérgenos purificados, naturais ou recombinantes, para melhorar o diagnóstico de alergia pelos métodos que dispomos, incluindo os testes cutâneos de hipersensibilidade imediata, e os métodos in vitro para medida de anticorpos IgE específicos, como ImmunoCAP, ImmunoCAP-ISAC, ELISA e MARIA. Mais recentemente, o uso de alérgenos recombinantes de pólen de bétula (rBet v 1) e de gramas (coquetel de 5 alérgenos) em imunoterapia foi relatado como seguro e eficaz, com resultados comparáveis aos obtidos usando extratos naturais, em pacientes com rinoconjuntivite alérgicos a polens. No presente artigo, apresentamos revisão atualizada do uso de alérgenos recombinantes em diagnóstico de alergia e em imunoterapia alérgeno-específica, incluindo novas estratégias de imunoterapia. Focalizamos na avaliação crítica de estudos que investigaram sensibilidade, especificidade, reatividade cruzada e valor prognóstico de métodos diagnósticos com uso de alérgenos recombinantes versus extratos naturais; nas recomendações atuais para o uso destes novos métodos na prática clínica; e na revisão de estudos clínicos com imunoterapia usando alérgenos recombinantes realizados até o momento.

Over the past 30 years, a great deal of progress has been made in the identification, purification,and recombinant expression of relevant allergens from various sources, including mites, insects,mammals, pollens, foods, fungi, latex, and other sources. These new developments have resultedin an increasing use of purified allergens, either natural or recombinant, to improve the diagnosisof allergy via the methods currently available, including skin tests and in vitro tests for measuringspecific IgE antibodies, e.g., ImmunoCAP, ImmunoCAP-ISAC, ELISA, and MARIA. More recently,the use of recombinant allergens from birch pollen (rBet v 1) and from grass pollen (a cocktailof five allergens) in immunotherapy has been reported to be safe and effective, with resultscomparable to those obtained with natural extracts in patients with rhino-conjunctivitis due topollen allergy. In the present article, we present an up-to-date review on the use of recombinantallergens in the diagnosis of allergy and in allergen-specific immunotherapy, including newstrategies for immunotherapy. We focus on the critical analysis of studies that have investigatedsensitivity, specificity, cross-reactivity, and the prognostic value of diagnostic methods that includerecombinant allergens versus natural extracts; on current recommendations for the use of thesenew methods in clinical practice; and on the review of clinical studies using immunotherapy withrecombinant allergens performed to date.