Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Real-world study in severe eosinophilic asthma patients refractory to anti-IL5 biological agents treated with benralizumab in Spain (ORBE study).

BACKGROUND: Benralizumab, a monoclonal antibody targeting the human interleukin-5 (IL-5) receptor (IL-5R), was used before marketing authorisation in Spain in a real world setting as part of an early-access programme (EAP) to treat patients with severe eosinophilic asthma with prior insufficient response or intolerance to anti-IL5 treatment (mepolizumab or reslizumab). The objective of this study is to describe the patient profile candidate for treatment and to assess benralizumab effectiveness. METHODS: This is an observational, retrospective, multicentre study in severe eosinophilic asthma patients refractory to other biological agents targeting the IL-5 pathway. Baseline characteristics included closest data, from the previous 12 months, to benralizumab treatment onset (index date). Patients were followed until the last treatment dosage while EAP was active (March to December 2018). Effectiveness was evaluated versus baseline, in patients who received at least three doses, with asthma control test (ACT), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), annual severe exacerbation rate, oral corticosteroids treatment (OCS) and asthma-related healthcare resources utilization. RESULTS: Twenty-seven patients treated with benralizumab were included in the analysis. Effectiveness was assessed in 19 patients. Both questionnaires showed clinically meaningful differences, i.e. ACT score ≥ 3 and MiniAQLQ score ≥ 0.5, compared with baseline [mean (SD), 3.3 (6.8) and 1.2 (1.9), respectively]. Patients treated with OCS decreased during follow-up from 88.9% (n = 24/27) at baseline to 78.9% (n = 15/19) and 31.6% (n = 6/19) had an OCS dose reduction ≥ 50%. The difference in annual severe exacerbation rate during follow-up showed a significant reduction vs. baseline (2.12 per patient-year, 95% CI 0.99-3.24, p = 0.002). The differences in annual rate of non-scheduled primary care and specialist visits during follow-up indicated a significant decrease [2.28 per patient-year (95% CI 1.55-3.01; p < 0.001) and 1.47 per patient-year (95% CI 0.65-2.30; p = 0.004), respectively], as well as the difference in annual rate of number of emergency department visits [1.18 per patient-year (95% CI 0.51-1.85; p = 0.007)]. CONCLUSIONS: These results suggest that severe eosinophilic asthma patients receiving benralizumab, presented clinically meaningful improvement in asthma control and asthma-related QoL as well as OCS dose reduction. Results also aim to significant reductions in annual severe exacerbation rates, non-scheduled primary care and specialist visits, and emergency department visits rates.

Real-life retrospective observational study to determine the prevalence and economic burden of severe asthma in Spain.

Objective: We determined the percentage of patients with severe asthma and exacerbations and evaluated the costs of the disease based on blood eosinophil counts.Methods: A retrospective observational study based on the review of medical records in Spain was carried out. Patients ≥18 years of age requiring care during the years 2014-2015; diagnosed with asthma with at least 2 years of continuous records (at least one year prior to the index date defined as the first asthma medication prescription and at least one year after the index date) were included. Study groups: eosinophil counts <300 cells/µl and ≥300 cells/µl. Main variables: comorbidity, clinical parameters, exacerbations and annual asthma total costs.Results: A total of 268 severe asthmatic patients in Spain were included, representing 6.3% of the asthma population, with 58.6% having eosinophil count ≥300 cells/µl and 41.4% eosinophil count <300 cells/µl. The mean age was 56.1 years (63.4% women). Patients with eosinophilic inflammation (≥300 cells/µl) had lower FEV1 values (54.3% vs. 60.7%; p < .001), poorer treatment adherence (65.6% vs. 77.3%; p < .001), and a greater mean number of exacerbations (3.3 vs. 1.9; p < .001). Exacerbations were correlated to FEV1 (ß=‒.606), eosinophils (ß = .255), immunoglobulin E (ß = .152), and age (ß = .128), p < .001. The mean total asthma annual cost (ANCOVA) was 6222 vs. 4152 euros, respectively (p = .016). Health costs were associated with age (ß = .323), FEV1 (ß = .239), eosinophils (ß = .177) and exacerbations (ß = .158), p < .01.Limitations: Those inherent to retrospective studies; the possible inaccuracy of diagnostic coding referring to severe asthma and other comorbidities and the external validity of the results.Conclusions: Health costs of patients with severe asthma were high. Total annual asthma costs and resource use were greater in patients with ≥300 cells/µl. Age, eosinophilia, exacerbations and FEV1 were associated with greater resource utilization and costs for the health system.

Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes.

OBJECTIVE(S): Folic acid, a micronutrient supporting the natural defense system, may elevate antidepressant responses, although the lymphocyte serotonergic system has not been explored in folate-supplemented depressed patients. METHODS: Twenty-seven patients were randomly assigned to groups receiving fluoxetine (20 mg) and folic acid (10 mg/day) or fluoxetine and placebo for 6 weeks. Clinical outcome was assessed according to the Hamilton Depression Rating Scale (HDRS) at the beginning, during and at the end of treatment. Blood samples were taken, plasma was separated, and lymphocytes were obtained by density gradient centrifugation with Ficoll/Hypaque and differential adhesion to plastic dishes. Fifteen healthy subjects served as controls. Plasma folate, homocysteine and vitamin B12, and serotonin concentration in lymphocytes were determined by HPLC. The HDRS score was significantly lower in patients receiving fluoxetine and folic acid compared with those receiving fluoxetine and placebo after 6 weeks of treatment (7.43 +/- 1.65 vs. 11.43 +/- 1.31, respectively; p = 0.04). Plasma homocysteine statistically significant decreased after folic acid (p = 0.02), but no significant changes were observed in vitamin B12. RESULTS: Serotonin was significantly reduced after fluoxetine either with folate (p = 0.03) or placebo (p = 0.01) probably by the effect of transporter blockade. 5-Hydroxyindoleacetic acid was lower in lymphocytes of patients receiving folate (p = 0.04), indicating a reduced turnover rate, thus accumulating serotonin in the cells. A significant negative correlation was noted between homocysteine and folate. No significant correlations were present among biochemical parameters and depression severity. CONCLUSION: Modifications due to treatment with fluoxetine and folic acid may alter lymphocyte function in depression probably indirectly by reducing homocysteine levels and directly on lymphocytes by modifying the serotonergic system.

[Validation of the PRIME-MD for the detection of generalized anxiety disorder]. / Validación del PRIME-MD para la detección del trastorno de ansiedad generalizada.

The objectives of this study were first, to validate the Primary Care Evaluation of Mental Disorders (PRIME-MD) as an instrument that identifies the generalized anxiety disorder (GAD) in psychiatric consultations and second, to determine the frequency of GAD in two types of psychiatric consultation settings. To begin with, 1000 medical records of outpatients from the Psychiatry Department of the Hospital Vargas de Caracas were checked to determine the frequency of GAD diagnosis. Then, the PRIME-MD was validated with 100 outpatients from the Hospital Vargas de Caracas and 200 outpatients from private hospitals. The frequency of GAD diagnosis was 2.8% in the medical records checked. The prevalence of GAD in the 300 patients evaluated was 3.7%. The PRIME-MD showed 90.9% of sensitivity and 88.9% of specificity for the diagnosis of GAD. The global comorbidity of GAD was 36.6%. GAD was more frequent in patients between 40 and 49 years old, with a female/male rate of 2:1. Overall, the GAD frequency was lower than in other studies. The PRIME-MD proved to be a valid instrument to diagnose GAD in psychiatric outpatients.

Validación del PRIME-MD para la detección del trastorno de ansiedad generalizada / Validation of the PRIME-MD for the detection of generalized anxiety disorder

Los objetivos del presente estudio fueron validar la entrevista Evaluación de los Trastornos Mentales en la Atención Primaria (PRIME-MD) como prueba para la detección del trastorno de ansiedad generalizada (TAG) en consultas psiquiátricas y determinar la frecuencia del TAG en 2 tipos de consultas psiquiátricas. Se revisaron 1000 historias de la consulta externa del Servicio de Psiquiatría del Hospital Vargas de Caracas a fin de determinar la frecuencia del diagnóstico de TAG. Se validó el PRIME-MD con 100 pacientes del Hospital Vargas y con 200 de la consulta privada. En las 1000 historias examinadas se diagnosticó 2,8 por ciento de casos de TAG. La prevalencia del TAG en los 300 pacientes evaluados mediante la Entrevista Clínica Estructurada para el DSM-IV fue de 3,7 por ciento. La sensibilidad del PRIME-MD fue de 90,9 por ciento y la especificidad de 88,9 por ciento. La comorbilidad global del TAG fue de 36,6 por ciento. El TAG fue más frecuente en pacientes entre 40 y 49 años, con una relación entre mujeres y hombres de 2:1. Se encontró que la frecuencia del TAG resultó ser inferior a la reportada en otros estudios. El PRIME-MD probó ser un instrumento válido para detectar el TAG en consultas psiquiátricas en Venezuela.

Síntesis de serotonina y presencia de hidroxilasa de triptófano en linfocitos de pacientes con depresión mayor tratados con fluoxetina y ácido fólico / Synthesis of serotonin and tryptophan hydroxylase in lymphocytes from patients with major depression treated with fluoxetine and folic acid

El ácido fólico ha sido utilizado como coadyuvante antidepresivo, y se han reportado bajos niveles séricos en deprimidos. Debido al papel del ácido fólico y a la relevancia del sistema serotonérgico linfocitario en la depresión, el objetivo de este estudio es determinar la capacidad de producción de serotonina y la presencia de la hidroxilasa del triptófano en linfocitos de pacientes deprimidos tratados con fluoxetina y ácido fólico. Los pacientes fueron diagnosticados con los criterios del Manual Diagnóstico y Estadístico de la Asociación Psiquiátrica Americana, la intensidad del episodio depresivo se determinó mediante la Escala de Hamilton para Depresión. Veintisiete pacientes (21-58 años) fueron seleccionados, no presentaban otra patología ni riesgo suicida. Se distribuyeron en forma aleatoria en dos grupos experimentales, unos (14) recibieron fluoxetina, 20 mg/d, más ácido fólico, 10 mg/d y otros (13) fluoxetina más placebo. El grupo control fue constituido por 15 sujetos aparentemente sanos (26-49 años). Se tomaron muestras de sangre al principio y después de seis semanas. Diez pacientes de cada grupo experimental culminaron el estudio. La homocisteína plasmática disminuyó con la administración de ácido fólico. Los linfocitos fueron aislados por gradientes de densidades con Ficoll/Hypaque y adhesión diferencial al plástico. Las concentraciones de serotonina en linfocitos se determinaron por cromatografía líquida de alta resolución con detector electroquímico y no difirieron entre los dos grupos ni en relación al control, pero fueron bajas en los que recibieron el tratamiento. La síntesis de serotonina a partir de triptófano fue menor en los pacientes en relación a controles, y disminuyó después de los dos tratamientos. El número de linfocitos con la enzima fue menor en los pacientes y decreció después del ácido fólico.

Validación del cuestionario de preocupaciones de la Universidad Estatal de Pensilvania (PSWQ) / To validate the Penn State Worry questionaire for the detection (PSWQ)

Validar el Cuestionario de Preocupaciones de la Universidad Estatal de Pensilvania para detectar el trastorno de ansiedad generalizada. Se evaluaron 100 pacientes del Servicio de Psiquiatría del Hospital Vargas de Caracas. Inmediatamente después de que contestaron el Cuestionario de Preocupaciones de la Universidad Estatal de Pensilvania, todos fueron examinados mediante la Entrevista Clínica Estructurada para los Trastornos del Eje I del DSM-IV (SCID). En el análisis estadístico se utilizó la prueba de la probabilidad exacta de Fisher (dos colas) con un criterio de significancia estadística del 5 por ciento. Los valores de sensibilidad y de especificidad del Cuestionario de Preocupaciones de la Universidad Estatal de Pensilvania fueron de 76,9 por ciento y 66,6 por ciento respectivamente. La prevalencia del trastorno de ansiedad generalizada según la SCID fue de 13 por ciento. Casi la mitad presentó comorbilidad, principalmente con depresión mayor. El trastorno de ansiedad generalizada fue más frecuente en mujeres mayores de 30 años. El Cuestionario de Preocupaciones de la Universidad Estatal de Pensilvania con un punto de corte > 60 es un instrumento válido para detectar el trastorno de ansiedad generalizada, sin embargo, los pacientes tuvieron dificultades para responderlo.

To validate the Penn State Worry Questionnaire for the detection of Generalized Anxiety Disorder. 100 outpatients from the Psychiatry Department of the Hospital Vargas de Caracas were evaluated. After completing the Penn State Worry Questionnaire, they were assessed with the Structured Clinical Interview for DSM-IV for Axis I Disorders (SCID-I). The Fisher Exact Test (two-tailed) was used for statistical analysis with a P > 0.05. The Penn State Worry Questionnaire showed 76.9 percent of sensitivity and 66.6 percent of specificity for the diagnosis of Generalized Anxiety Disorder. The Generalized Anxiety Disorder prevalence according to the SCID was 13 percent. Almost half of the patients presented comorbidity, especially with Major Depression. Generalized Anxiety Disorder was more frequent in women over 30 years old. The Penn State Worry Questionnaire is a valid questionnaire to diagnose Generalized Anxiety Disorder in psychiatric outpatients, however, patients had difficulties to answer it.