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1.
J Allergy Clin Immunol ; 151(5): 1351-1356, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36343773

RESUMEN

BACKGROUND: Chronic spontaneous urticaria (CSU) is a dermatologic condition characterized by spontaneous, pruritic hives and/or angioedema that persists for 6 weeks or longer with no identifiable trigger. Antihistamines and second-line therapies such as omalizumab are effective for some CSU patients, but others remain symptomatic, with significant impact on quality of life. This variable response to treatment and autoantibody levels across patients highlight clinically heterogeneous subgroups. OBJECTIVE: We aimed to highlight pathways involved in CSU by investigating the genetics of CSU risk and subgroups. METHODS: We performed a genome-wide association study (GWAS) of 679 CSU patients and 4446 controls and a GWAS of chronic urticaria (CU)-index, which measures IgG autoantibodies levels, by comparing 447 CU index-low to 183 CU index-high patients. We also tested whether polygenic scores for autoimmune-related disorders were associated with CSU risk and CU index. RESULTS: We identified 2 loci significantly associated with disease risk. The strongest association mapped to position 56 of HLA-DQA1 (P = 1.69 × 10-9), where the arginine residue was associated with increased risk (odds ratio = 1.64). The second association signal colocalized with expression-quantitative trait loci for ITPKB in whole blood (Pcolocalization = .997). The arginine residue at position 56 of HLA-DQA1 was also associated with increased risk of CU index-high (P = 6.15 × 10-5, odds ratio = 1.86), while the ITKPB association was not (P = .64). Polygenic scores for 3 autoimmune-related disorders (hypothyroidism, type 1 diabetes, and vitiligo) were associated with CSU risk and CU index (P < 2.34 × 10-3, odds ratio > 1.72). CONCLUSION: A GWAS of CSU identified 2 genome-wide significant loci, highlighting the shared genetics between CU index and autoimmune disorders.


Asunto(s)
Urticaria Crónica , Urticaria , Humanos , Estudio de Asociación del Genoma Completo , Calidad de Vida , Enfermedad Crónica , Urticaria Crónica/genética , Urticaria/genética , Urticaria/inducido químicamente , Omalizumab/efectos adversos
2.
Am J Respir Crit Care Med ; 206(5): 545-553, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35549845

RESUMEN

Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).


Asunto(s)
Antiasmáticos , Asma , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Biomarcadores , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Fenotipo , Factores de Riesgo
3.
Eur Respir J ; 59(4)2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34561291

RESUMEN

BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.


Asunto(s)
Asma , Etnicidad , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Humanos , Grupos Minoritarios , Método Simple Ciego
4.
Ann Allergy Asthma Immunol ; 128(5): 553-560, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35101644

RESUMEN

BACKGROUND: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI). OBJECTIVE: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category. METHODS: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m2 [normal or underweight], n = 397; 25 to <30 kg/m2 [overweight], n = 330; ≥ 30 kg/m2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance. RESULTS: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39]). CONCLUSION: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI. TRIAL REGISTRATION: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available.


Asunto(s)
Antiasmáticos , Asma , Adulto , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Beclometasona/farmacología , Beclometasona/uso terapéutico , Índice de Masa Corporal , Método Doble Ciego , Volumen Espiratorio Forzado , Humanos , Obesidad/tratamiento farmacológico , Omalizumab/farmacología , Omalizumab/uso terapéutico , Sobrepeso , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Delgadez/tratamiento farmacológico , Resultado del Tratamiento
5.
Am J Respir Crit Care Med ; 203(1): 37-53, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32667261

RESUMEN

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).


Asunto(s)
Asma/metabolismo , Biomarcadores/orina , Inflamación/metabolismo , Leucotrieno E4/metabolismo , Leucotrieno E4/orina , Prostaglandinas/metabolismo , Prostaglandinas/orina , Adulto , Asma/fisiopatología , Femenino , Humanos , Inflamación/fisiopatología , Masculino , Persona de Mediana Edad
6.
BMC Pulm Med ; 22(1): 418, 2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36376851

RESUMEN

BACKGROUND: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy. METHODS: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts. RESULTS: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment. CONCLUSIONS: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma.


Asunto(s)
Asma , COVID-19 , Hipersensibilidad , Humanos , COVID-19/epidemiología , Prueba de COVID-19 , Estudios Retrospectivos , Asma/complicaciones , Asma/epidemiología , Asma/diagnóstico , Hipersensibilidad/complicaciones , Hipersensibilidad/epidemiología , Tratamiento Farmacológico de COVID-19
7.
J Allergy Clin Immunol ; 148(5): 1324-1331.e12, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34536416

RESUMEN

BACKGROUND: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. OBJECTIVE: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. METHODS: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. RESULTS: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans. CONCLUSIONS: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/epidemiología , Productos Biológicos/uso terapéutico , Etnicidad , Grupos Minoritarios , Grupos Raciales , Adolescente , Asma/terapia , Estudios de Casos y Controles , Niño , Determinación de la Elegibilidad , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Fenotipo , Estados Unidos/epidemiología , Adulto Joven
8.
Clin Exp Allergy ; 51(4): 546-555, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33217063

RESUMEN

BACKGROUND: Current biologic therapies target allergic, eosinophilic or type 2 inflammation phenotypic asthma. However, frequency and degree of overlap among these subtypes is unclear. OBJECTIVE: To characterize overlap among allergic, eosinophilic and type 2 asthma phenotypes. METHODS: Post hoc analyses of baseline data were performed in two adult populations: (a) not selected for any asthma subtype (N = 935) and (b) selected for allergic asthma (N = 1049). Degree of overlap was examined using commonly accepted phenotypic definitions to guide treatment for allergic asthma (skin prick-positive and/or positive serum-specific immunoglobulin E > 0.35 kU/L) and eosinophilic asthma (blood eosinophil high count ≥ 300 cells/µL; low cut-off ≥ 150 cells/µL). Consistent with previous studies, fractional exhaled nitric oxide high level of ≥ 35 ppb and low cut-off of ≥ 25 ppb were selected as local markers of type 2 inflammation and to prevent overlap with the systemic eosinophilic asthma definition. RESULTS: In the non-subtype-selected population, 78.0% had allergic asthma; of these, 39.5% had eosinophilic asthma and 29.5% had type 2 asthma. Within patients with eosinophilic asthma (40.6% of total), 75.8% had allergic asthma and 41.3% had type 2 asthma. Within patients with type 2 asthma (28.3% of total), 81.1% had allergic asthma and 59.2% had eosinophilic asthma. In the allergic asthma-selected population, 38.3% had eosinophilic asthma and 29.2% had type 2 asthma. Within patients with eosinophilic asthma, 46.3% had type 2 asthma. Within patients with type 2 asthma, 60.8% had eosinophilic asthma. Overlaps among subtypes increased at low cut-off values. CONCLUSIONS AND CLINICAL RELEVANCE: In this post hoc analysis in adults with moderate-to-severe asthma, allergic asthma was the most prevalent phenotype, followed by eosinophilic and type 2 asthma. Despite observed overlaps, a considerable proportion of patients had only a predominantly allergic subtype. Understanding the degree of overlap across phenotypes will help patient management and guide treatment options.


Asunto(s)
Asma/inmunología , Eosinofilia/inmunología , Inflamación/inmunología , Adulto , Asma/clasificación , Asma/metabolismo , Asma/fisiopatología , Femenino , Prueba de Óxido Nítrico Exhalado Fraccionado , Humanos , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Hipersensibilidad Respiratoria/inmunología , Índice de Severidad de la Enfermedad
9.
Ann Allergy Asthma Immunol ; 127(2): 223-231, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33838339

RESUMEN

BACKGROUND: The anti-immunoglobulin E therapy, omalizumab, improves asthma control and reduces exacerbations in patients with moderate-to-severe allergic asthma. However, it has been suggested that omalizumab should be reserved for highly allergic patients with multiple allergen sensitivities or perennial-only sensitivities. OBJECTIVE: To examine impact of allergy burden, including number and type of allergen sensitivities, on omalizumab response in a real-world setting. METHODS: This post hoc analysis evaluated a subset of omalizumab-treated patients from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (NCT01922037) who had completed 13 allergen assessments (N=478). Patients were classified by allergen burden (nonsensitized, 1, 2-4, or ≥5 allergen sensitivities) and type of allergen (nonsensitized, seasonal, perennial, or both). Outcome measures included exacerbation rate vs previous year and improvements in lung function and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: Comparable adjusted exacerbation rates were observed after omalizumab initiation, regardless of number or type of allergen sensitizations (0.56-0.85/y). Improvements in forced expiratory volume in 1 second from baseline at months 6 (0.03-0.09 L) and 12 (-0.08 to 0.08 L) were also similar across subgroups. Least squares mean change in AQLQ from baseline at months 6 (1.0-1.2) and 12 (1.1-1.4) was comparable across patient subgroups, and similar percentages of patients achieved AQLQ minimal clinically important difference of at least a 0.5-point improvement at month 6 (71%-75%), which was maintained or improved to month 12 (71%-89%). In all analyses, 95% confidence intervals overlapped. CONCLUSION: Overall findings suggest that patients with allergic asthma achieved comparable improvements across distinct outcome measures after omalizumab therapy in a real-world setting, regardless of number and type of allergen sensitizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922037.


Asunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Asma/tratamiento farmacológico , Omalizumab/uso terapéutico , Adulto , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Inmunoglobulina E/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida
10.
Ann Allergy Asthma Immunol ; 126(6): 666-673, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33465457

RESUMEN

BACKGROUND: Comorbidities are common in asthma and may complicate treatment response. OBJECTIVE: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities. METHODS: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis. RESULTS: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances. CONCLUSION: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden. TRIAL REGISTRATION: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037).


Asunto(s)
Antialérgicos/uso terapéutico , Antiasmáticos/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Omalizumab/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Comorbilidad , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/epidemiología , Reflujo Gastroesofágico/fisiopatología , Humanos , Hipersensibilidad/epidemiología , Hipersensibilidad/fisiopatología , Masculino , Persona de Mediana Edad , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/epidemiología , Pólipos Nasales/fisiopatología , Sinusitis/tratamiento farmacológico , Sinusitis/epidemiología , Sinusitis/fisiopatología , Resultado del Tratamiento , Adulto Joven
11.
Clin Exp Allergy ; 50(12): 1342-1351, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32909660

RESUMEN

BACKGROUND: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. OBJECTIVE: To report safety and efficacy results from enrolled participants with available data from CLAVIER. METHODS: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling. RESULTS: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. CONCLUSIONS & CLINICAL RELEVANCE: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling. CLINICAL TRIAL REGISTRATION: NCT02099656.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/efectos de los fármacos , Interleucina-13/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Adolescente , Adulto , Anciano , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Asma/inmunología , Asma/fisiopatología , Método Doble Ciego , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Humanos , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Transducción de Señal , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
12.
Thorax ; 74(1): 95-98, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30021810

RESUMEN

We investigated the time course of change of type-2 asthma biomarkers after a severe asthma exacerbation. Blood eosinophils were lowest immediately after treatment was initiated (0.07 vs 0.33×109/L, p<0.001) while serum IgE levels were at their highest (339 vs 249 U/L, p<0.001). Fractional exhaled Nitric Oxide levels were lowest 2 weeks after treatment (23 vs 33 ppb, p=0.06) and serum periostin levels were lowest 1 week after treatment (45·9 vs 50·9 ng/mL, p<0.001). A delay of 4-8 weeks following a severe exacerbation is required if these biomarkers are used to guide the ongoing management of patients with asthma. TRIAL REGISTRATION NUMBER: Post-results; The Australia New Zealand Trial Registry, >ACTRN12614000443695.


Asunto(s)
Asma/sangre , Moléculas de Adhesión Celular/sangre , Eosinófilos , Inmunoglobulina E/sangre , Brote de los Síntomas , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Pruebas Respiratorias , Humanos , Recuento de Leucocitos , Persona de Mediana Edad , Óxido Nítrico/análisis , Factores de Tiempo , Adulto Joven
13.
Thorax ; 74(8): 806-809, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30940770

RESUMEN

Type-2 biomarkers and related cytokines (IL-5, IL-13), lung function and asthma symptoms were measured in 44 poorly-controlled severe oral corticosteroid (OCS)-dependent asthmatics for up to 88 days after a 7-day prednisolone boost (0.5 mg/kg). High-dose OCS reduced median blood eosinophils (-60 cells/µl; 95% CI -140 to 10), periostin (-8.4 ng/mL; -11.6 to -2.8), FeNO (-19.0 ppb; -28.5 to -4.0), IL-5 (-0.17 pg/mL; -0.28 to -0.08) and IL-13 (-0.15 pg/mL; -0.27 to -0.03). There were small improvements in mean FEV1 (0.16 L; 0.05 to 0.27) and (Asthma Control Questionnaire) ACQ-7 score (0.3; 0.0 to 0.7). Study measures returned to baseline 1-month postintervention. Following rescue OCS, 1 month is sufficient before using type-2 biomarkers to guide long-term treatment. TRIAL REGISTRATION NUMBER: NCT01948401.


Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Eosinófilos , Interleucina-13/sangre , Interleucina-5/sangre , Prednisolona/uso terapéutico , Administración Oral , Adulto , Antiinflamatorios/administración & dosificación , Asma/sangre , Biomarcadores/sangre , Pruebas Respiratorias , Moléculas de Adhesión Celular/sangre , Femenino , Volumen Espiratorio Forzado , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Óxido Nítrico/análisis , Prednisolona/administración & dosificación , Capacidad Vital
15.
J Allergy Clin Immunol ; 139(3): 790-796, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27484037

RESUMEN

BACKGROUND: Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking. OBJECTIVE: Little is known about biomarkers of type 2 inflammation in early life in relation to asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children. METHODS: Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed. RESULTS: Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio [OR], 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/µL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (≥2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0). CONCLUSIONS: Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development.


Asunto(s)
Asma/sangre , Factores de Edad , Contaminantes Atmosféricos/inmunología , Alérgenos/inmunología , Asma/epidemiología , Biomarcadores/sangre , Moléculas de Adhesión Celular/sangre , Niño , Preescolar , Eosinófilos , Femenino , Humanos , Inmunoglobulina E/sangre , Exposición por Inhalación , Recuento de Leucocitos , Masculino , Oportunidad Relativa
16.
J Lipid Res ; 58(8): 1713-1721, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28655726

RESUMEN

Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.


Asunto(s)
Asma/sangre , Lipoproteínas HDL/sangre , Adulto , Asma/inmunología , Biomarcadores/sangre , Estudios de Casos y Controles , Moléculas de Adhesión Celular/sangre , Eosinófilos/metabolismo , Femenino , Humanos , Inflamación/sangre , Masculino
17.
Pulm Pharmacol Ther ; 46: 88-98, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28843617

RESUMEN

Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV1], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day-1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients.


Asunto(s)
Antiasmáticos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Asma/tratamiento farmacológico , Modelos Biológicos , Antiasmáticos/farmacocinética , Antiasmáticos/farmacología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Asma/fisiopatología , Disponibilidad Biológica , Biomarcadores/metabolismo , Volumen Espiratorio Forzado , Semivida , Humanos , Óxido Nítrico/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad
18.
Am J Respir Crit Care Med ; 193(9): 949-56, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-26756066

RESUMEN

Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression.


Asunto(s)
Moléculas de Adhesión Celular/genética , Trastornos Respiratorios/genética , Humanos
19.
BMC Pulm Med ; 16(1): 67, 2016 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-27130294

RESUMEN

BACKGROUND: Periostin levels are associated with airway eosinophilia and are suppressed by corticosteroid treatment in asthma. This study sought to determine the relationship between serum and sputum periostin, airway inflammatory phenotype and asthma control. METHODS: Adults with poorly-controlled asthma (n = 83) underwent a clinical assessment, sputum induction and blood sampling. Dispersed sputum was used for a differential cell count and periostin assessment (ELISA). Serum periostin was determined by the Elecsys® immunoassay. RESULTS: Periostin levels were significantly higher in serum (median (IQR) of 51.6 (41.8, 62.6) ng/mL) than in sputum (1.1 (0.5, 2.0) ng/mL) (p < 0.001). Serum and sputum periostin were significantly higher in patients with eosinophilic asthma (n = 37) compared with non-eosinophilic asthma. Both serum and sputum periostin levels were significantly associated with proportion of sputum eosinophils (r = 0.422, p < 0.001 and r = 0.364, p = 0.005 respectively) but were not associated with asthma control. In receiver operator characteristic curve analysis, the area under the curve (AUC) for serum periostin (n = 83) was 0.679, p = 0.007. Peripheral blood eosinophils assessed in 67 matched samples, had a numerically greater AUC of 0.820 compared with serum periostin, p = 0.086 for the detection of eosinophilic asthma. CONCLUSION: In poorly-controlled asthma, sputum and serum periostin levels are significantly related to sputum eosinophil proportions while their ability to predict the presence of eosinophilic asthma is modest.


Asunto(s)
Asma/complicaciones , Moléculas de Adhesión Celular/metabolismo , Eosinófilos/patología , Glucocorticoides/uso terapéutico , Eosinofilia Pulmonar/metabolismo , Esputo/química , Adulto , Anciano , Anciano de 80 o más Años , Asma/tratamiento farmacológico , Asma/metabolismo , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Humanos , Inmunoensayo , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/etiología , Curva ROC , Esputo/citología , Adulto Joven
20.
Thorax ; 70(8): 748-56, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26001563

RESUMEN

INTRODUCTION: In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. METHODS: LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. RESULTS: The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. CONCLUSIONS: These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. TRIAL REGISTRATION NUMBERS: The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Asma/tratamiento farmacológico , Pulmón/fisiopatología , Adolescente , Adulto , Anciano , Asma/diagnóstico , Asma/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
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