Generation of a healthy heavy smoker patient-derived induced pluripotent stem cell line UHOMi007-A from peripheral blood mononuclear cells.

Human pluripotent stem cells (hiPSC) represent a unique opportunity to model lung development and chronic bronchial diseases. We generated a hiPSC line from a highly characterized healthy heavy smoker male donor free from emphysema or tobacco related disease. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai virus. The cell line had normal karyotype, expressed pluripotency hallmarks, and differentiated into the three primary germ layers. The reported UHOMi007-A iPSC line may be used as a control to model lung development, study human chronic bronchial diseases and drug testing.

Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma.

Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.

Severe asthma care trajectories: the French RAMSES cohort.

Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs). Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients' characteristics were analysed at inclusion and compared between TRCs and SCCs. Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15 years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262 versus 340 mm-3; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26% versus 18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33% versus 24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74% versus 62%; p<0.0001; exhaled nitric oxide fraction: 56% versus 21%; p<0.0001; induced sputum: 6% versus 3%; p=0.0390). Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.

MELTEMI and COLUMBA: 5-Year Comparative Safety Analysis of Benralizumab and Mepolizumab.

BACKGROUND: Benralizumab and mepolizumab are IL-5Rα/IL-5-targeted monoclonal antibodies indicated as add-on treatments for patients with uncontrolled severe eosinophilic asthma (SEA). OBJECTIVE: To evaluate and compare the safety of benralizumab and mepolizumab among patients with SEA treated in MELTEMI and COLUMBA open-label, long-term extension studies, respectively. METHODS: MELTEMI was an extension study of benralizumab Q4W or Q8W for adults (aged 18-75 years) with SEA. MELTEMI participants transitioned from the BORA extension, preceded by participation in 1 of 3 placebo-controlled studies (SIROCCO, CALIMA, or ZONDA). COLUMBA was an extension study of mepolizumab for patients (aged ≥12 years) with SEA who transitioned from the dose-ranging DREAM study. Safety endpoints were presented as drug exposure patient years (MELTEMI, Q4W 784.28, Q8W 797.03; COLUMBA 1,201) for nonserious adverse events (AEs), serious adverse events (SAEs), and infections; malignancies were counted numerically. RESULTS: This analysis included 446 MELTEMI patients (benralizumab Q4W, 220; benralizumab Q8W, 226) and 347 COLUMBA patients (mepolizumab Q4W). Viral upper respiratory tract infection was the most common nonserious AE in both studies (MELTEMI Q8W, 46.5%; Q4W, 47.3%; COLUMBA, 48.7%). Asthma-related events were the most common SAE in both studies: MELTEMI 8.0% (Q8W) and 8.6% (Q4W) and COLUMBA 9.5%. Serious infections included pneumonia (MELTEMI Q8W, 2 [0.9%]; COLUMBA, 6 [1.7%]); cellulitis (MELTEMI Q8W, 1 [0.4%]; COLUMBA, 2 [0.6%]); and respiratory tract infections (COLUMBA, 2 [0.6%]). COLUMBA reported 6 malignancies and MELTEMI reported 4 malignancies in each group. CONCLUSIONS: This analysis demonstrated generally similar safety events between mepolizumab and benralizumab in patients with SEA.

Longitudinal patterns of intermittent oral corticosteroid therapy for asthma in the United Kingdom.

Background: Increasing frequency of intermittent oral corticosteroid (OCS) prescription and cumulative OCS exposure increase the risk of OCS-related adverse outcomes. Objective: We sought to describe the evolution and trajectory of intermittent OCS prescription patterns in patients with asthma and investigate risk factors independently associated with transitioning to a frequent prescription pattern. Methods: This historical cohort study included patients with active asthma managed in UK primary care and included in the Optimum Patient Care Research Database (OPCRD; opcrd.co.uk). Intermittent OCS prescription patterns were categorized as sporadic, infrequent, moderately frequent, or frequent. Prescription pattern sequences were described for those who had a frequent sequence in their final year of prescribing. We examined associations between OCS prescription pattern and the hazard of transitioning into a frequent intermittent OCS prescription pattern using multivariable Cox regression with a 10-year look-back period. Results: Of 105,229 patients with intermittent OCS prescriptions, 57.1% (n = 60,083) had a frequent OCS prescription pattern at some point. Irrespective of baseline pattern, most patients transitioned to frequent prescription during the look back. The strongest risk factors were a more frequent prescription pattern at the start of look-back period, a lower percentage peak expiratory flow rate, and higher Global Initiative for Asthma treatment step. Older age, female sex, obesity, and active smoking were also associated with a higher risk of transitioning. Conclusion: Our findings help identify those most at risk of transitioning to frequent intermittent OCS receipt and encourage earlier intervention with OCS-sparing treatments.

Trends in Systemic Glucocorticoid Utilization in the United Kingdom from 1990 to 2019: A Population-Based, Serial Cross-Sectional Analysis.

Purpose: Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs. Patients and Methods: A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥5 years who were registered for ≥1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year. Results: The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics. Conclusion: Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse.

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma.

BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

Phenotyping of Severe Asthma in the Era of Broad-Acting Anti-Asthma Biologics.

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.

Outcomes and risk assessment in pulmonary veno-occlusive disease.

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. Methods: The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Results: Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. Conclusion: PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Multiple Biologics for Multiple T2 Diseases: A Pharmacoepidemiological Algorithm for Sorting Out Patients by Indication.

Background: Several biologics (Bx) and targeted synthetic drugs (TSD) exist to treat T2 diseases, including chronic spontaneous urticaria (CSU), severe asthma (SA), chronic rhinosinusitis with nasal polyposis (CRSwNP) or atopic dermatitis (AD). Objective: To identify patients treated with Bx/TSD from a dynamic dispensing database using an algorithm-based methodology. Methods: We used the LRx database (Lifelink Treatment dynamics, IQVIA) which covers nearly 45% of the French retail pharmacies. Patients who had at least one Bx/TSD dispensing from April 2021 to March 2022 were included. An algorithm was designed to determine the indication of the Bx/TSD prescription analyzing all previous drug dispensation since March 2012 following a 3-steps procedure. Results: A total of 21,677 patients received at least one Bx/TSD between March 2021 and April 2022. The algorithm identified 91.7% (n = 19,884) patients with a T2 disease (AD = 18.4%, CRSwNP = 1.5%, SA = 59.5%, and CSU = 12.4%), the rest having either an association of diseases (1%) or an undetermined one (7.3%). SA was the main reason for Bx/TSD initiation (52%), followed by AD (29%), CSU (14%) and CRSwNP (5%). For SA patients already under biologic at entry, omalizumab was the most frequently prescribed (48%) followed by benralizumab, mepolizumab (22% each) and dupilumab (8%). Dupilumab was mostly prescribed for AD patients (89% for patient-initiated vs 96% for patient-renewed) followed by baricitinib. Conclusion: The algorithm was able to identify patients with T2 diseases under Bx/TSD treatments. This tool may help to follow the evolution of prescription patterns in the future.

Improvement in severe asthma patients receiving biologics and factors associated with persistent insufficient control: a real-life national study.

BACKGROUND: Biological therapies have revolutionized the treatment of severe asthma with type 2 inflammation. Although such treatments are very effective in reducing exacerbation and the dose of oral steroids, little is known about the persistence of symptoms in severe asthma patients treated with biologics. PURPOSE: We aim to describe asthma control and healthcare consumption of severe asthma patients treated with biologics. DESIGN: The Second Souffle study is a real-life prospective observational study endorsed by the Clinical Research Initiative in Severe Asthma: a Lever for Innovation & Science Network. METHODS: Adults with a confirmed diagnosis of severe asthma for at least 12 months' duration were enrolled in the study. A self-administered questionnaire including the Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ) and a compliance evaluation test was given to the patients. Healthcare consumption within 12 months prior to enrolment was documented. In patients receiving biologics, doctors indicated whether the patients were biologic responders or non-responders. RESULTS: The characteristics of 431 patients with severe asthma were analysed. Among them, 409 patients (94.9%) presented asthma with type 2 inflammation (T2 high) profile, and 297 (72.6%) patients with a T2 high phenotype were treated with a biologic. Physicians estimated that 88.2% of patients receiving biologics were responders. However, asthma control was only achieved in 25.3% of those patients (ACQ > 0.75). A high proportion of patients (77.8%) identified as responders to biologics were not controlled according to the ACQ score. About 50% of patients continue to use oral corticosteroids either daily (25.2%) or more than three times a year for at least three consecutive days (25.6%). Gastro-oesophageal Reflux Disease (GERD) and Obstructive Sleep Apnoea syndrome (OSA) were identified as independent factors associated with uncontrolled asthma. CONCLUSION: Although a high proportion of severe asthma patients respond to biologics, only 25.3% have controlled asthma. GERD and OSA are independent factors of uncontrolled asthma.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Arterial Sleeve Lobectomy: Does Pulmonary Artery Reconstruction Type Impact Lung Function?

BACKGROUND: The aim of this single-center retrospective cohort study was to assess the impact of arterial reconstruction technique on lung perfusion. The second objective was to ascertain the functional validity of arterial sleeve lobectomy. METHOD: Between January 2001 and December 2020, a total of 81 patients underwent lobectomy with pulmonary artery (PA) reconstruction for lung cancer at the University Hospital of Montpellier. After excluding patients with an incomplete postoperative pulmonary function test, we conducted a comparative analysis of the preoperative and postoperative functional outcomes (FEV1) of 48 patients, as well as the preoperative and postoperative Technetium99m scintigraphic pulmonary perfusion results of 28 patients. Then, we analyzed postoperative perfusion results according to the pulmonary artery reconstruction techniques use. RESULTS: PA reconstruction types were as follows: 9 direct angioplasties (19%), 14 patch angioplasties (29%), 7 end-to-end anastomoses (15%), 6 prosthetic bypasses (12%), 11 arterial allograft bypasses (23%), and 1 custom-made xenopericardial conduit bypass. Regardless of the type of vascular reconstruction performed, the comparative analysis of lung perfusion revealed no significant difference between the preoperative and postoperative perfusion ratio of the remaining parenchyma (median = 29.5% versus 32.5%, respectively; p = 0.47). Regarding the pulmonary functional test, postoperative predicted FEV1 significantly underestimated the actual postoperative measured FEV1 by about 260 mL (11.4%) of the preoperative value. The patency rate was 96% and the 5-year overall survival was 49% for a mean follow up period of 34 months. CONCLUSION: Lobectomy with PA reconstruction is a valid parenchymal-sparing technique in terms of perfusion and respiratory function.