Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype.

Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95-19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27-547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22-438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91-0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01-9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45-79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12-117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52-519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14-142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94-89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77-804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88-0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31-100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01-9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

Association between Single Nucleotide Polymorphisms Related to Vitamin D Metabolism and the Risk of Developing Asthma.

Asthma is a chronic non-communicable disease that affects all age groups. The main challenge this condition poses is its heterogeneity. The role of vitamin D in asthma has aroused great interest, correlating low vitamin D levels and polymorphisms in the genes involved in its metabolic pathway with the risk of asthma. The aim of this study was to evaluate the influence of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolism on the susceptibility to asthma. An observational case-control study was performed, including 221 patients with asthma and 442 controls of Caucasian origin from southern Spain. The SNPs CYP24A1 (rs6068816, rs4809957), CYP27B1 (rs10877012, rs4646536, rs703842, rs3782130), GC (rs7041), CYP2R1 (rs10741657) and VDR (ApaI, BsmI, FokI, Cdx2, TaqI) were analyzed by real-time PCR, using TaqMan probes. The logistic regression model adjusted for body mass index revealed that in the genotype model, carriers of the Cdx2 rs11568820-AA genotype were associated with a higher risk of developing asthma (p = 0.005; OR = 2.73; 95% CI = 1.36-5.67; AA vs. GG). This association was maintained in the recessive model (p = 0.004). The haplotype analysis revealed an association between the ACTATGG haplotype and higher risk of asthma for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130 and rs10877012 genetic polymorphisms (p = 0.039). The other SNPs showed no effect on risk of developing asthma. The Cdx2 polymorphism was significantly associated with the susceptibility of asthma and could substantially act as a predictive biomarker of the disease.

Impact of Omalizumab in Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Most patients with asthma can control their symptoms with a basic standard of medical care and with maintenance and rescue medication. However, between 5% and 10% of asthmatics worldwide do not achieve control of their symptoms and have recurrent exacerbations and respiratory difficulties. The objective of the study was the real-life evaluation of the clinical improvement of patients with severe eosinophilic asthma treated with omalizumab, together with the search for biomarkers associated with the response. An observational retrospective cohort study was conducted that included patients with severe uncontrolled allergic asthma being treated with omalizumab. Three types of response were evaluated: lower use of oral corticosteroids, improvement in lung function, and reduction in exacerbations. A total of 110 patients under treatment with omalizumab were included, with a mean age of 48 ± 16 years. After 12 months had elapsed, significant reductions were found in the number of exacerbations, use of oral cortico-steroids and doses of inhaled corticosteroids (p < 0.001). Lung function and asthma control improved significantly (p < 0.001; p = 0.004) and eosinophil levels were significantly reduced (p = 0.004). Low scores in the Asthma Control Test were associated with the oral corticosteroid-saving effect; lower previous FEV1 levels and absence of chronic obstructive pulmonary disease (COPD) were related to improvement in lung function, and prior FEV1 values higher than 80% and absence of gastroesophageal reflux disease (GERD) with a reduction in exacerbations. The results of this study confirm the clinical benefit obtained after the introduction of omalizumab and the possible predictive biomarkers of response to the treatment.

Impact of Anti-IL5 Therapies on Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Severe Uncontrolled Asthma (SUA) counts for more than 25% of cases of severe asthma. The main factors that impair the quality of life of these patients are high doses of oral corticosteroids, the presence of exacerbations, and reduced lung function. The objective of this study was to evaluate, in real life, the clinical improvement of patients with SUA treated with anti-interleukin 5 (IL5) therapies: mepolizumab and benralizumab, together with the search for biomarkers associated with the response. We conducted a retrospective observational cohort study that included patients with severe uncontrolled eosinophilic asthma in a tertiary hospital receiving biological therapies. Three types of response were evaluated: improvement in lung function, reduction in exacerbations, and decrease in the use of oral corticosteroids. After 12 months of treatment, significant reductions were found in the number of exacerbations, the use of oral corticosteroids, and blood eosinophil levels for both biological therapies (p < 0.001). Lung function improved, achieving a significant improvement in %FEV1 (p < 0.001), as well as asthma control, with a significant increase in asthma control test (ACT) scores in both therapies. The markers associated with the corticosteroid-saving effect were the low doses of oral corticosteroids and absence of exacerbations for mepolizumab, and higher blood eosinophilia, absence of chronic obstructive pulmonary disease (COPD), and reduction in oral corticosteroid cycles for benralizumab. The greatest improvement in lung function in both therapies was linked to lower previous FEV1 levels and absence of other respiratory diseases. The reduction in exacerbations was associated with absence of exacerbations the previous year for mepolizumab and never smokers for benralizumab. The results of this real-life study confirm the clinical benefit obtained after the introduction of an anti-IL5 biological therapy and the possible predictive biomarkers of response to treatment.

Is asthma in the elderly different? Functional and clinical characteristics of asthma in individuals aged 65 years and older.

BACKGROUND: The prevalence of chronic diseases in the elderly (> 65 years), including asthma, is growing, yet information available on asthma in this population is scarce.Our objective is to determine the differential clinical and functional characteristics of the population > 65 years old with asthma included in the Integrated Research Programs of Asthma Databank of the Spanish Society of Pneumology and Thoracic Surgery (www.bancodatosasma.com). METHODS: Retrospective comparative descriptive study of demographic, clinical and functional variables for 1713 patients with asthma categorized into 3 age groups as follows: adults aged < 65 years (A), younger elderly aged 65-74 years (B) and older elderly aged ≥75 years (C). RESULTS: Predominant features of elderly patients with asthma (N = 471) were the female sex, fewer smokers, greater obesity, poorer lung function, and lower values of nitric oxide in exhaled air (p < 0.01). The most frequently associated comorbidity was gastroesophageal reflux. The highest doses of inhaled corticosteroids were by group A (60.8%). For the sample overall, 23.2% (N = 398) were being treated with omalizumab and 8.2% (N = 140) were corticosteroid-dependent (10.6% in group B). The highest percentage of patients receiving antileukotriene agents was in group B (42.9%). CONCLUSIONS: Asthma in adults aged> 65 is more severe and associated with greater comorbidity, which would indicate the need for a more integrated and multidimensional approach to asthma treatment for these patients.

Modelo predictivo de ansiedad y depresión en pacientes españoles con enfermedad pulmonar obstructiva crónica estable / Predictive Model for Anxiety and Depression in Spanish Patients with Stable Chronic Obstructive Pulmonary Disease

Introducción: La asociación entre la enfermedad pulmonar obstructiva crónica (EPOC) y la ansiedad o la depresión no se conoce adecuadamente, y puede haber diferencias entre distintos países. Investigamos un modelo predictivo para esta asociación en una población española. Pacientes y método: Estudio prospectivo descriptivo transversal incluyendo 204 pacientes con EPOC estable. Se diagnostica la presencia de ansiedad o depresión mediante valoración psiquiátrica, aplicando los criterios diagnósticos de la 10.ª revisión del International Statistical Classification of Diseases and Related Health Problems (ICD-10). Se analizan variables sociodemográficas, clínicas y de función pulmonar. Resultados: Un 36% de pacientes con EPOC estable tienen comorbilidad psiquiátrica, pero en el 76% de los casos se desconocía dicho diagnóstico. Presentan un trastorno de ansiedad pura el 19%, depresión aislada el 9,8% y un trastorno mixto de ansiedad y depresión el 7,3% de los pacientes. En el análisis multivariante las variables predictoras son: edad más joven, mayor nivel de estudios, falta de apoyo domiciliario, mayor índice de BODE y mayor número de agudizaciones. La curva ROC del modelo muestra un AUC de 0,765 (p<0,001). Conclusiones: En la EPOC, una mayoría de pacientes con comorbilidad psiquiátrica no son identificados. Los trastornos de ansiedad son más frecuentes que la depresión, en base a un diagnóstico mediante entrevista estructurada. Los pacientes más jóvenes y con mayor nivel de estudios tienen más riesgo de de padecer ansiedad o depresión. Otros factores predictivos son: un mayor índice BODE, más agudizaciones y la falta de apoyo domiciliario

Introduction: The association between chronic obstructive pulmonary disease (COPD) and anxiety and depression is not yet completely characterized, and differences between countries may exist. We used a predictive model to assess this association in a Spanish population. Patients and method: Prospective transversal descriptive study of 204 patients with stable COPD. Concomitant anxiety or depression were diagnosed by psychiatric assessment, using the diagnostic criteria of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Sociodemographic, clinical and lung function parameters were analyzed. Results: In total, 36% of stable COPD patients had psychiatric comorbidities, but 76% were unaware of their diagnosis. Nineteen percent had a pure anxiety disorder, 9.8% had isolated depression, and 7.3% had a mixed anxiety-depression disorder. Predictive variables in the multivariate analysis were younger age, higher educational level, lack of home support, higher BODE index, and greater number of exacerbations. The ROC curve of the model had an AUC of 0.765 (P<0.001). Conclusions: In COPD, concomitant psychiatric disorders are significantly associated with sociodemographic factors. Anxiety disorders are more common than depression. Patients with more severe COPD, according to BODE, younger patients and those with a higher educational level have a greater risk of being diagnosed with anxiety or depression in a structured psychiatric interview. In our population, most patients with psychiatric comorbidities remain unidentified

Predictive Model for Anxiety and Depression in Spanish Patients with Stable Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The association between chronic obstructive pulmonary disease (COPD) and anxiety and depression is not yet completely characterized, and differences between countries may exist. We used a predictive model to assess this association in a Spanish population. PATIENTS AND METHOD: Prospective transversal descriptive study of 204 patients with stable COPD. Concomitant anxiety or depression were diagnosed by psychiatric assessment, using the diagnostic criteria of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Sociodemographic, clinical and lung function parameters were analyzed. RESULTS: In total, 36% of stable COPD patients had psychiatric comorbidities, but 76% were unaware of their diagnosis. Nineteen percent had a pure anxiety disorder, 9.8% had isolated depression, and 7.3% had a mixed anxiety-depression disorder. Predictive variables in the multivariate analysis were younger age, higher educational level, lack of home support, higher BODE index, and greater number of exacerbations. The ROC curve of the model had an AUC of 0.765 (P<0.001). CONCLUSIONS: In COPD, concomitant psychiatric disorders are significantly associated with sociodemographic factors. Anxiety disorders are more common than depression. Patients with more severe COPD, according to BODE, younger patients and those with a higher educational level have a greater risk of being diagnosed with anxiety or depression in a structured psychiatric interview. In our population, most patients with psychiatric comorbidities remain unidentified.