Definitions of non-response and response to biological therapy for severe asthma: a systematic review.

Background: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. Methods: We searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. Results: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated "very low" to "low" for quality of measurement properties and none met all quality standards. Conclusions: This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.

Identifying and appraising outcome measures for severe asthma: a systematic review.

BACKGROUND: Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing end-points for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties. METHODS: A literature search was performed to identify "candidate" outcome measures published between 2018 and 2020. A modified Delphi exercise was conducted to select "key" outcome measures within healthcare professional, patient, pharmaceutical and regulatory stakeholder groups. Initial validation studies for "key" measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify "priority" outcome measures. Subsequently, four bibliographic databases were searched from inception to 20 July 2020 to identify development and validation studies for these end-points. Two reviewers screened records, extracted data, assessed their methodological quality and graded the evidence according to COSMIN. RESULTS: 96 outcome measures were identified as "candidates", 55 as "key" and 24 as "priority" for severe asthma, including clinical, healthcare utilisation, quality of life, asthma control and composite. 32 studies reported measurement properties of 17 "priority" end-points from the latter three domains. Only the Severe Asthma Questionnaire and Childhood Asthma Control Test were developed with input from severe asthma patients. The certainty of evidence was "low" to "very low" for most "priority" end-points across all measurement properties and none fulfilled all quality standards. CONCLUSIONS: Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Narrative review to capture patients' perceptions and opinions about non-response and response to biological therapy for severe asthma.

BACKGROUND: There are now many biological therapies to treat severe asthma. To assess which work best for which patient, we need to develop definitions of response. This narrative review aims to capture severe asthma patients' perceptions about non-response and response to biological therapy. METHODS: Four bibliographic databases were searched from inception to September 2021. Grey literature was searched with the involvement of patient representatives. A thematic approach was used for synthesis. No qualitative studies specifically explore patients' perspectives on response to biological therapy for severe asthma. Three papers and one published asthma patient interview were included. Relevant grey literature was included from online discussion forums, blogs and social media websites. RESULTS: Adult patients framed positive response to biological therapy in terms of reduced burden of disease and treatment. Both were multifaceted. Some patients experienced reduced benefit from biological therapy over time. There was a group of patients who described a limited response or non-response to biological therapy. This was framed within the context of continuing hospitalisation and oral corticosteroid treatment. The speed of onset of benefit was felt to be important by some. CONCLUSIONS: Definitions of non-response and response need to be patient-centred, yet there is a complete lack of qualitative research focused on this topic. By combining relevant published and grey literature we have provided a description of adult patients' perceptions of response to biological therapy in severe asthma. We now need to understand the views of children and adolescents with severe asthma and their carers, and diverse patient experiences in real-world settings.

Real-world efficacy of treatment with benralizumab, dupilumab, mepolizumab and reslizumab for severe asthma: A systematic review and meta-analysis.

BACKGROUND: Severe asthma is a major cause of morbidity. Some patients may benefit from biological therapies. Most evaluations of these treatments are derived from randomized controlled trials (RCTs), but few patients are eligible for these trials. Studies involving more diverse groups of participants exist, but there is a lack of precise pooled estimates. OBJECTIVE: This systematic review aims to evaluate the real-world efficacy of recently and nearly licensed biological therapies for severe asthma to assess the generalizability of the RCT data. METHODS: Clinical outcomes including exacerbation rate, oral corticosteroid usage, forced expiratory volume in 1 second (FEV1 ) and fractional exhaled nitric oxide (FeNO) were examined. Studies were assessed for risk of bias using the Critical Appraisal Skills Programme checklist tool. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: A total of 21 studies examining biologicals in real-world settings were identified; they mostly focused on benralizumab and mepolizumab. The introduction of biologicals reduced the annualzsed exacerbation rate significantly by -3.79 (95% confidence interval [CI] -4.53, -3.04), -3.17 (95% CI -3.74, -2.59) and -6.72 (95% CI -8.47, -4.97) with benralizumab, mepolizumab and reslizumab, respectively. Likewise, improvements were observed in FEV1 (0.17 L 95% CI 0.11, 0.24) and FeNO (-14.23 ppb 95% CI -19.71, -8.75) following the treatment with mepolizumab. After treatment with benralizumab, there was an increase in FEV1 (0.21 L 95% CI 0.08, 0.34). CONCLUSIONS: These data demonstrate that anti-IL5 biologicals may improve the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs. The data were mainly retrospective and unadjusted, so estimated effect sizes may not be reliable. More data are needed to acquire accurate effect estimates in different subpopulations of patients.

Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1-mediated epithelial-mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-ß-induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial-mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1-tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-ß-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor-like repeats. Together, these data identify that aberrant bidirectional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.