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3.
J Allergy Clin Immunol Pract ; 12(4): 809-823, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38280454

RESUMO

Severe asthma is associated with significant morbidity and mortality despite the maximal use of inhaled corticosteroids and additional controller medications, and has a high economic burden. Biologic therapies are recommended for the management of severe, uncontrolled asthma to help to prevent exacerbations and to improve symptoms and health-related quality of life. The effective management of severe asthma requires consideration of clinical heterogeneity that is driven by varying clinical and inflammatory phenotypes, which are reflective of distinct underlying disease mechanisms. Phenotyping patients using a combination of clinical characteristics such as the age of onset or comorbidities and biomarker profiles, including blood eosinophil counts and levels of fractional exhaled nitric oxide and serum total immunoglobulin E, is important for the differential diagnosis of asthma. In addition, phenotyping is beneficial for risk assessment, selection of treatment, and monitoring of the treatment response in patients with asthma. This review describes the clinical and inflammatory phenotypes of asthma, provides an overview of biomarkers routinely used in clinical practice and those that have recently been explored for phenotyping, and aims to assess the value of phenotyping in severe asthma management in the current era of biologics.


Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Humanos , Antiasmáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Qualidade de Vida , Asma/diagnóstico , Asma/tratamento farmacológico , Eosinófilos , Biomarcadores
4.
Thorax ; 79(2): 186-190, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38071553

RESUMO

Ethnic disparities exist within asthma; however, country of birth is rarely investigated. We described demographic and clinical characteristics by ethnicity and country of birth within the UK Biobank. Lung function and asthma hospitalisations were similar for white, black and North-East Asian participants, however, South-East (SE) Asians more commonly had an FEV1 below the lower limits of normal (LLN; 53.8% vs 32.3%, p<0.001), blood eosinophilia (38.6% vs 23.8%, p<0.001) and asthma hospitalisation (12.5% vs 8.3%, p<0.001) than white participants. First-generation SE Asian immigrants had poorer lung function (57.7% vs 27.7% FEV1 below LLN, p<0.001) than UK/Ireland born participants. These data demonstrate inter-ethnic and intra-ethnic disparities.


Assuntos
Asma , Biobanco do Reino Unido , Humanos , Estudos Transversais , Bancos de Espécimes Biológicos , Etnicidade
5.
Eur Respir J ; 62(6)2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37857423

RESUMO

BACKGROUND: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. METHODS: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. RESULTS: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. CONCLUSIONS: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.


Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Humanos , Feminino , Masculino , Estudos Retrospectivos , Asma/tratamento farmacológico , Biomarcadores , Sistema de Registros , Terapia Biológica , Produtos Biológicos/uso terapêutico , Reino Unido , Antiasmáticos/uso terapêutico
7.
Lancet Rheumatol ; 5(7): e413-e421, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38251552

RESUMO

BACKGROUND: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians. METHODS: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set. FINDINGS: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001). INTERPRETATION: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems. FUNDING: ChemoCentryx.


Assuntos
Asma , Doenças Autoimunes , Ácidos Nipecóticos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Anilina , Vesícula , Glucocorticoides/efeitos adversos , Prednisona/efeitos adversos , Método Duplo-Cego
8.
Am J Respir Crit Care Med ; 206(5): 545-553, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35549845

RESUMO

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).


Assuntos
Antiasmáticos , Asma , Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Biomarcadores , Progressão da Doença , Feminino , Humanos , Masculino , Fenótipo , Fatores de Risco
9.
Semin Arthritis Rheum ; 55: 152010, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35486995

RESUMO

Glucocorticoids (GCs) have been the cornerstone of treating dozens of inflammatory conditions for more than seven decades. GC toxicity is ubiquitous in both clinical trials and clinical practice, and toxicities associated with GC use are central to the experience of most patients being treated for immune-mediated conditions. These conditions span the full range of medical specialties, including rheumatology, nephrology, gastroenterology, neurology, pulmonology, ophthalmology, and others. One of the goals of novel therapies for inflammatory disease must be to diminish the effects of GC toxicity in clinically important ways, thereby differentiating these new treatments from existing approaches. Despite the importance of glucocorticoids in the treatment of inflammatory disease for more than 70 years, no reliable means of calculating the degree to which GC toxicity has worsened or improved over the course of treatment has been available. The Glucocorticoid Toxicity Index (GTI), developed by an international group of subspecialty physician experts as a clinician-facing clinical trials outcome measure, is a standardized, validated measure of the phenomenon known as GC toxicity. The purpose of the instrument is to measure change in GC toxicity between two points in time: for example, between the baseline visit and the time of the primary efficacy outcome assessment. The instrument is designed to quantify both worsening and improvement in GC toxicity. The GTI has been validated in both real-world experiences and clinical trials, including a phase 3, label-enabling trial in ANCA associated vasculitis. This article reviews the history and rationale for the development of the GTI, describes key data from validation studies, considers the minimum clinically important difference, and provides instructions for use of the instrument.


Assuntos
Glucocorticoides , Glucocorticoides/toxicidade , Humanos , Neurologia , Avaliação de Resultados em Cuidados de Saúde , Reumatologia
10.
Eur Respir J ; 59(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210787

RESUMO

BACKGROUND: Reduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity. OBJECTIVES: To use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12 months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient-reported outcome measures (PROMs). METHODS: A longitudinal, real-world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a specialist UK regional severe asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12 months treatment (V2). RESULTS: There was significant reduction in oral glucocorticoid exposure (V1 median 4280 mg prednisolone per year (interquartile range 3083-5475 mg) versus V2 2450 mg prednisolone per year (1243-3360 mg), p<0.001). Substantial improvements in individual toxicities were observed, but did not correlate with oral glucocorticoid reduction. Mean±sd GTI aggregate improvement score (AIS) was -35.7±57.8 with a wide range in toxicity change at individual patient level (AIS range -165 to +130); 70% (71 out of 101) had a reduction in toxicity (AIS <0); 3% (three out of 101) had no change (AIS=0); and 27% (27 out of 101) an increase in overall toxicity. 62% (62 out of 101) of patients met the AIS minimally clinically important difference of ≤-10, but AIS did not correlate with glucocorticoid reduction or change in PROMs. CONCLUSION: Mepolizumab resulted in substantial oral glucocorticoid reduction, but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab.


Assuntos
Antiasmáticos , Glucocorticoides , Anticorpos Monoclonais Humanizados , Humanos , Estudos Prospectivos
11.
Lancet Respir Med ; 9(10): 1174-1184, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971168

RESUMO

BACKGROUND: Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab. METHODS: This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230. FINDINGS: Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SEHIGH) with exacerbations with a low sputum eosinophil count (<2%; SELOW), the SEHIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per µL [20 to 70]; p=0·0009). By contrast, SELOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related. INTERPRETATION: Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab. FUNDING: UK Medical Research council.


Assuntos
Antiasmáticos , Asma , Eosinofilia Pulmonar , Anticorpos Monoclonais Humanizados , Asma/induzido quimicamente , Asma/tratamento farmacológico , Eosinófilos , Humanos , Estudos Prospectivos , Eosinofilia Pulmonar/tratamento farmacológico
12.
J Allergy Clin Immunol Pract ; 9(1): 365-372.e5, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882446

RESUMO

BACKGROUND: Glucocorticoid (GC)-associated morbidity in severe asthma (SA) is well recognized but varies in individual patients; systematic measurement of GC toxicity is important to measure improvement with steroid-sparing monoclonal antibodies. OBJECTIVE: To describe for the first time individual patient GC toxicity in steroid-dependent SA using the Glucocorticoid Toxicity Index (GTI). METHODS: An observational consecutive patient cohort study was performed at a UK Regional SA Specialist clinic for systematic assessment of GC-associated morbidity using the GTI in routine clinical care. GTI was correlated with commonly used patient-reported outcome measures. An approach to GTI scoring, calculation of minimal clinically important difference (MCID), and development of digital GTI application in routine clinical care are described. RESULTS: All patients had significant oral GC exposure (cumulative prednisolone/prior year, 4280 [3083, 5475] mg) with wide distribution of toxicity in individual patients (mean GTI score, 177.5 [73.7]). GTI score had only modest correlation with recent prednisolone exposure: maintenance prednisolone dose (rho = 0.26, P = .01), cumulative exposure/prior year (rho = 0.38, P < .001), and GC boosts/prior year (rho = 0.25, P = .01). GTI toxicity demonstrated stronger associations with asthma-related quality of life (mini-Asthma Quality of Life Questionnaire [mini-AQLQ] r = -0.50, P < .001 and St. George's Respiratory Questionnaire r = 0.42, P < .001). GTI MCID was calculated as 10 points. Multiple linear regression demonstrated that age and mini-AQLQ were strongest predictors of GC toxicity. CONCLUSIONS: The GTI is a useful tool to systematically capture and quantify GC toxicity at the individual patient level. GC toxicity varies widely between individual patients with SA and correlated only modestly with GC exposure over the preceding year. Age and mini-AQLQ are better predictors of GC toxicity. The GTI and MCID will facilitate assessment of individual SA response to steroid-sparing agents in clinical trials and routine care.


Assuntos
Asma , Glucocorticoides , Asma/tratamento farmacológico , Asma/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Morbidade , Qualidade de Vida , Inquéritos e Questionários
13.
Allergy ; 75(2): 302-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267562

RESUMO

The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type-2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type-2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non-type-2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Asma/imunologia , Fenótipo , Células Th2/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Asma/diagnóstico , Biomarcadores , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Eosinófilos/imunologia , Humanos , Inflamação/imunologia , Terapia de Alvo Molecular/métodos , Escarro/imunologia , Resultado do Tratamento
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