Impact of Initiating Biologics in Patients With Severe Asthma on Long-Term Oral Corticosteroids or Frequent Rescue Steroids (GLITTER): Data From the International Severe Asthma Registry.

BACKGROUND: Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with HOCS alone. OBJECTIVE: To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS. METHODS: This was a propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry. Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCSs for ≥1 year or ≥4 courses of rescue OCSs within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with noninitiators. The impact of biologic initiation on asthma outcomes was assessed using generalized linear models. RESULTS: We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations per year versus noninitiators (0.64 vs 2.06; rate ratio, 0.27 [95% CI, 0.10-0.71]). Biologic initiators were 2.2 times more likely than noninitiators to take a daily long-term OCS dose of less than 5 mg (risk probability, 49.6% vs 22.5%; P = .002) and had a lower risk of asthma-related emergency department visits (relative risk, 0.35 [95% CI, 0.21-0.58]; rate ratio, 0.26 [0.14-0.48]) and hospitalizations (relative risk, 0.31 [95% CI, 0.18-0.52]; rate ratio, 0.25 [0.13-0.48]). CONCLUSIONS: In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and health care resource utilization.

Cluster Analyses From the Real-World NOVELTY Study: Six Clusters Across the Asthma-COPD Spectrum.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are complex diseases, the definitions of which overlap. OBJECTIVE: To investigate clustering of clinical/physiological features and readily available biomarkers in patients with physician-assigned diagnoses of asthma and/or COPD in the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329). METHODS: Two approaches were taken to variable selection using baseline data: approach A was data-driven, hypothesis-free and used the Pearson dissimilarity matrix; approach B used an unsupervised Random Forest guided by clinical input. Cluster analyses were conducted across 100 random resamples using partitioning around medoids, followed by consensus clustering. RESULTS: Approach A included 3796 individuals (mean age, 59.5 years; 54% female); approach B included 2934 patients (mean age, 60.7 years; 53% female). Each identified 6 mathematically stable clusters, which had overlapping characteristics. Overall, 67% to 75% of patients with asthma were in 3 clusters, and approximately 90% of patients with COPD were in 3 clusters. Although traditional features such as allergies and current/ex-smoking (respectively) were higher in these clusters, there were differences between clusters and approaches in features such as sex, ethnicity, breathlessness, frequent productive cough, and blood cell counts. The strongest predictors of the approach A cluster membership were age, weight, childhood onset, prebronchodilator FEV1, duration of dust/fume exposure, and number of daily medications. CONCLUSIONS: Cluster analyses in patients from NOVELTY with asthma and/or COPD yielded identifiable clusters, with several discriminatory features that differed from conventional diagnostic characteristics. The overlap between clusters suggests that they do not reflect discrete underlying mechanisms and points to the need for identification of molecular endotypes and potential treatment targets across asthma and/or COPD.

Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Characterization of Patients in the International Severe Asthma Registry with High Steroid Exposure Who Did or Did Not Initiate Biologic Therapy.

Background: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics. Methods: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson's chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons. Results: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/µL, p=0.003), serious infections (49.0% vs 13.3%, p<0.001), nasal polyps (35.2% vs 23.6%, p<0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147). Conclusion: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.

Patients with Chronic Obstructive Pulmonary Disease and Evidence of Eosinophilic Inflammation Experience Exacerbations Despite Receiving Maximal Inhaled Maintenance Therapy.

Background: Some patients with chronic obstructive pulmonary disease (COPD) experience frequent exacerbations despite maximal inhaled therapy ("triple therapy"), possibly leading to high health care resource utilization (HCRU). Aim: Describe characteristics, future HCRU, and mortality of patients with COPD who experience frequent exacerbations despite triple therapy; characterize individuals who may be candidates for biologic therapies. Methods: This descriptive observational study used primary care data of patients aged ≥40 years in the United Kingdom receiving maintenance therapy for COPD who had ≥1 year of data prior to index date and ≥1 year of follow-up data. We described these patients' clinical and demographic characteristics, including blood eosinophil counts (BEC), pattern of exacerbations, hospitalizations, and corticosteroid exposure, as well as future exacerbations, hospitalizations, and death. Results: Of 43,753 patients with maintenance-treated COPD, 6480 experienced exacerbations despite ≥3 months of triple therapy. Of these, 5669 had available BEC: 1287 (22.7%) had BEC ≥250 cells/µL and ≥3 exacerbations in the year prior to the index date; 471 (36.6%) received ≥4 acute courses of oral corticosteroids. Patients with a pattern of high disease burden continued to have high disease burden: 51.1% experienced ≥3 exacerbations and 2.6% experienced ≥3 hospitalizations. Patients who experienced exacerbations despite triple therapy had a significantly higher risk of COPD-related death than other maintenance-treated patients (5.8% vs 2.1%). Conclusion: Nearly one-quarter of patients receiving triple therapy for COPD who experienced frequent exacerbations had elevated BEC and ≥3 exacerbations, suggesting a potential mechanism of persistent eosinophilic inflammation that could be a target for eosinophil-depleting biologic therapy.

Real World Biologic Use and Switch Patterns in Severe Asthma: Data from the International Severe Asthma Registry and the US CHRONICLE Study.

INTRODUCTION: International registries provide opportunities to describe use of biologics for treating severe asthma in current clinical practice. Our aims were to describe real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma, elucidate reasons underlying these patterns, and examine associated patient-level factors. METHODS: This was a historical cohort study including adults with severe asthma enrolled into the International Severe Asthma Registry (ISAR; http://isaregistries.org, 2015-2020) or the CHRONICLE Study (2018-2020) and treated with a biologic. Eleven countries were included (Bulgaria, Canada, Denmark, Greece, Italy, Japan, Kuwait, South Korea, Spain, UK, and USA). Biologic utilization patterns were defined: 1) continuing initial biologic; 2) stopping biologic treatment; or 3) switching to another biologic. Reasons for discontinuation/switching were recorded and comparisons drawn between groups. RESULTS: A total of 3531 patients were included. Omalizumab was the most common initial biologic in 2015 (88.2%) and benralizumab in 2019 (29.6%). Most patients (79%; 2791/3531) continued their first biologic; 10.2% (356/3531) stopped; 10.8% (384/3531) switched. The most frequent first switch was from omalizumab to an anti-IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti-IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater health care resource utilization. CONCLUSION: The description of real-life patterns of continuing, stopping, or switching biologics enhances our understanding of global biologic use. Prospective studies involving structured switching criteria could ascertain optimal strategies to identify patients who may benefit from switching.

Global Variability in Administrative Approval Prescription Criteria for Biologic Therapy in Severe Asthma.

BACKGROUND: Regulatory bodies have approved five biologics for severe asthma. However, regional differences in accessibility may limit the global potential for personalized medicine. OBJECTIVE: To compare global differences in ease of access to biologics. METHODS: In April 2021, national prescription criteria for omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab were reviewed by severe asthma experts collaborating in the International Severe Asthma Registry. Outcomes (per country, per biologic) were (1) country-specific prescription criteria and (2) development of the Biologic Accessibility Score (BACS). The BACS composite score incorporates 10 prescription criteria, each with a maximum score of 10 points. Referenced to European Medicines Agency marketing authorization specifications, a higher score reflects easier access. RESULTS: Biologic prescription criteria differed substantially across 28 countries from five continents. Blood eosinophil count thresholds (usually ≥300 cells/µL) and exacerbations were key requirements for anti-IgE/anti-IL-5/5R prescriptions in around 80% of licensed countries. Most countries (40% for dupilumab to 54% for mepolizumab) require two or more moderate or severe exacerbations, whereas numbers ranged from none to four. Moreover, 0% (for reslizumab) to 21% (for omalizumab) of countries required long-term oral corticosteroid use. The BACS highlighted marked between-country differences in ease of access. For omalizumab, mepolizumab, benralizumab, and dupilumab, only two, one, four, and seven countries, respectively, scored equal or higher than the European Medicines Agency reference BACS. For reslizumab, all countries scored lower. CONCLUSIONS: Although some differences were expected in country-specific biologic prescription criteria and ease of access, the substantial differences found in the current study present a challenge to implementing precision medicine across the world.

CONQUEST Quality Standards: For the Collaboration on Quality Improvement Initiative for Achieving Excellence in Standards of COPD Care.

Background: Chronic obstructive pulmonary disease (COPD) are managed predominantly in primary care. However, key opportunities to optimize treatment are often not realized due to unrecognized disease and delayed implementation of appropriate interventions for both diagnosed and undiagnosed individuals. The COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST) is the first-of-its-kind, collaborative, interventional COPD registry. It comprises an integrated quality improvement program focusing on patients (diagnosed and undiagnosed) at a modifiable and higher risk of COPD exacerbations. The first step in CONQUEST was the development of quality standards (QS). The QS will be imbedded in routine primary and secondary care, and are designed to drive patient-centered, targeted, risk-based assessment and management optimization. Our aim is to provide an overview of the CONQUEST QS, including how they were developed, as well as the rationale for, and evidence to support, their inclusion in healthcare systems. Methods: The QS were developed (between November 2019 and December 2020) by the CONQUEST Global Steering Committee, including 11 internationally recognized experts with a specialty and research focus in COPD. The process included an extensive literature review, generation of QS draft wording, three iterative rounds of review, and consensus. Results: Four QS were developed: 1) identification of COPD target population, 2) assessment of disease and quantification of future risk, 3) non-pharmacological and pharmacological intervention, and 4) appropriate follow-up. Each QS is followed by a rationale statement and a summary of current guidelines and research evidence relating to the standard and its components. Conclusion: The CONQUEST QS represent an important step in our aim to improve care for patients with COPD in primary and secondary care. They will help to transform the patient journey, by encouraging early intervention to identify, assess, optimally manage and followup COPD patients with modifiable high risk of future exacerbations.

Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort.

BACKGROUND: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. RESEARCH QUESTION: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? STUDY DESIGN AND METHODS: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). RESULTS: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. INTERPRETATION: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort.

BACKGROUND: Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort. METHODS: Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis. RESULTS: Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses. CONCLUSION: This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications.

Validation of a diagnosis-agnostic symptom questionnaire for asthma and/or COPD.

Background: The Respiratory Symptoms Questionnaire (RSQ) is a novel, four-item patient-reported diagnosis-agnostic tool designed to assess the frequency of respiratory symptoms and their impact on activity, without specifying a particular diagnosis. Our objective was to examine its validity in patients with asthma and/or chronic obstructive pulmonary disease (COPD). Methods: Baseline data were randomly sampled from patients who completed the RSQ in the NOVELTY study (ClinicalTrials.gov: NCT02760329). The total sample (n=1530) comprised three randomly selected samples (n=510 each) from each physician-assigned diagnostic group (asthma, asthma+COPD and COPD). The internal consistency and structural validity of the RSQ were evaluated using exploratory and confirmatory factor analyses; psychometric performance was observed using Classical Test Theory and Item Response Theory analyses. Results: For the total sample, the mean±sd RSQ score was 5.6±4.3 (range 0-16). Irrespective of diagnosis, the internal consistency of items was uniformly adequate (Cronbach's α=0.76-0.80). All items had high factor loadings and structural characteristics of the measure were invariant across groups. Using the total sample, RSQ items informatively covered the θ score range of -2.0 to 2.8, with discrimination coefficients for individual items being high to very high (1.7-2.6). Strong convergent correlations were observed between the RSQ and the St George's Respiratory Questionnaire (0.77, p<0.001). Conclusions: The RSQ is a valid, brief, patient-reported tool for assessing respiratory symptoms in patients across the whole spectrum of asthma and/or COPD, rather than using different questionnaires for each diagnosis. It can be used for monitoring respiratory symptoms in clinical practice, clinical trials and real-world studies.

International severe asthma registry (ISAR): protocol for a global registry.

BACKGROUND: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. METHODS: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. CONCLUSIONS: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Blood eosinophil count predicts treatment failure and hospital readmission for COPD.

We examined associations between blood eosinophil counts (BEC) and risk of treatment failure or hospital readmission following acute oral corticosteroid (OCS)-treated COPD exacerbations. We conducted studies from the Optimum Patient Care Research Database (OPCRD) (www.optimumpatientcare.org/opcrd) and Clinical Practice Research Datalink (CPRD) (www.cprd.com/home/), validated databases for medical research, with linked Hospital Episode Statistics (HES) data for ∼20 000 COPD patients aged ≥40 years. For patients with OCS-treated COPD exacerbations treated in primary care, with BECs recorded on first day of OCS treatment (Cohort 1), we assessed treatment failure (COPD-related hospitalisations and OCS prescriptions beyond index OCS course). For patients hospitalised for COPD exacerbations, with BEC measured over an exacerbation-free period during the year prior to admission (Cohort 2), we assessed readmission rate. Cox proportional hazards regression analysis was adjusted for confounders to estimate the association between BEC and treatment outcomes. Of patients treated with OCS for COPD exacerbations in primary care (Cohort 1), 44% experienced treatment failure following single OCS courses, and 10% (255/2482) were hospitalised for ≤6 weeks. Greater BEC was associated with reduced hospital-admission risk (hazard ratio [HR]=0.26; 95% CI: 0.12-0.56, per 100 cells·µL-1 increase). BEC increases of ≥200 cells·µL-1 from exacerbation-free periods to exacerbations were associated with least hospitalisation risk (HR=0.32; 95% CI: 0.15-0.71) versus no BEC change. For patients hospitalised for COPD exacerbations (Cohort 2), 4-week hospital readmission was 12% (1189/10 245). BEC increases during an exacerbation-free period within the past year were associated with reduced risk of short-term readmission (HR=0.78; 95% CI: 0.63-0.96). Greater BEC predicted better outcomes for patients with OCS-treated COPD exacerbations, whether community or hospital managed. Eosinopenia predicted worse outcomes.

Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management.

Systemic corticosteroid use to manage uncontrolled asthma and its associated healthcare burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE and Embase databases to identify English-language articles published in 2010-2017, using search terms for asthma with keywords for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use in children (>5 yr old), adolescents (12-17 yr old), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroids were commonly used for asthma management and were more frequently used in patients with severe asthma than in those with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with an increased risk of acute and chronic adverse events, even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and healthcare resource use. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated adverse events for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and the risks of acute and chronic complications increase with the cumulative oral corticosteroid dosage.

Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma.

BACKGROUND: Fixed airflow obstruction (FAO) is associated with severe eosinophilic asthma. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: We evaluated FAO influence on benralizumab treatment response. METHODS: We performed a post hoc analysis of pooled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) data for patients with severe, uncontrolled asthma with baseline blood eosinophil counts of 300 or more cells/µL who received benralizumab 30 mg every 8 weeks or placebo. Demographics, baseline clinical characteristics, and treatment responses were evaluated by FAO status. FAO+ and FAO- were defined as ratios of postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity of less than 70% and 70% or more, respectively, at baseline. RESULTS: FAO+ prevalence was 63% (935/1493). With benralizumab, similar annual asthma exacerbation rate (AER) reductions vs placebo were achieved for FAO+ and FAO- patients (rate ratio [95% confidence interval (CI)] = 0.56 [0.44-0.71] and 0.58 [0.41-0.83], respectively), whereas annual AER reductions associated with emergency department visits or hospitalizations were greater for FAO+ vs FAO- patients (rate ratio [95% CI] = 0.55 [0.33-0.91] and 0.70 [0.33-1.48], respectively). Prebronchodilator FEV1 (95% CI) increase from baseline to end of treatment was greater for FAO+ vs FAO- patients receiving benralizumab compared with placebo (0.159 L [0.082-0.236] vs 0.103 L [-0.008 to 0.215]). Other lung function measures, patient-reported outcomes, and symptom improvements were also numerically greater for FAO+ vs FAO- patients. CONCLUSION: Benralizumab improved asthma control across several measures for patients with severe, uncontrolled eosinophilic asthma and FAO. TRIAL REGISTRATION: SIROCCO trial: NCT01928771 (URL: https://clinicaltrials.gov/ct2/show/NCT01928771) CALIMA trial: NCT01914757 (URL: https://clinicaltrials.gov/ct2/show/NCT01914757).

Characterization of Severe Asthma Worldwide: Data From the International Severe Asthma Registry.

BACKGROUND: Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region. METHODS: The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017. RESULTS: We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles. CONCLUSIONS: Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study.

Pharmaco-utilisation and related costs of drugs used to treat schizophrenia and bipolar disorder in Italy: the IBIS study.

BACKGROUND: Schizophrenia and bipolar disorder (BD) are psychiatric diseases that are commonly managed with antipsychotics. Treatment pathways are highly variable and no universal treatment guidelines are available. The primary objective of the Italian Burden of Illness in Schizophrenia and BD (IBIS) study was to describe pharmaco-utilisation of antipsychotic treatments and characteristics of patients affected by schizophrenia or BD. A secondary objective was to describe costs of illness for patients with schizophrenia or BD. METHODS: IBIS was a multicentre, real-world, retrospective, observational cohort study based on data obtained from administrative databases of 16 Local Health Units in Italy (~7.5 million individuals). Patients with schizophrenia or BD ≥18 years of age treated with antipsychotics between 1 January 2008 and 31 December 2009 were included in the primary analysis. Pharmaco-utilisation data were gathered over a follow-up period of 12 months. RESULTS: Patients with schizophrenia and BD received a wide variety of antipsychotic medications. The proportion of patients on antipsychotic monotherapy was 68% in patients with schizophrenia and 70% in patients with BD. In patients with schizophrenia, ~1/3 of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants (34.7%) compared with over half of those on antipsychotic polytherapy (52.2%). In patients with BD, use of mood stabilisers and/or antidepressants was even higher; 76.9% of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants compared with 85.5% of patients on antipsychotic polytherapy. Switch therapy was more frequent in patients with BD than in patients with schizophrenia, whereas add-on therapy was more frequent in patients with schizophrenia than in patients with BD. The mean total disease-related cost per patient per annum was higher in patients with schizophrenia (€4,157) than in patients with BD (€3,301). The number and cost of hospitalisations was higher in patients with BD, whereas the number and cost of nursing home stays was higher in patients with schizophrenia. CONCLUSION: Use of administrative databases has permitted retrieval of comprehensive information about therapeutic pathways, diagnostic history and costs in patients affected by schizophrenia or BD. A need for personalised treatment pathways has been described. TRIAL REGISTRATION: clinicaltrials.gov: NCT01392482 ; first received June 29, 2011.

A nationwide prospective study on prescribing pattern of antidepressant drugs in Italian primary care.

PURPOSE: Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care. METHODS: Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients' characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation. RESULTS: SSRIs were the most frequently prescribed ADs (N = 1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N = 378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N = 242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation. CONCLUSIONS: In Italy, ADs-especially SSRIs-are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate.

A national survey of the management of atrial fibrillation with antithrombotic drugs in Italian primary care.

The aims of this study were to investigate trends in the incidence of diagnosed atrial fibrillation (AF), and to identify factors associated with the prescription of antithrombotics (ATs) and to identify the persistence of patients with oral anticoagulant (OAC) treatment in primary care. Data were obtained from 400 Italian primary care physicians providing information to the Health Search/Thales Database from 2001 to 2004. The age-standardised incidence of AF was: 3.9-3.0 cases, and 3.6-3.0 cases per 1,000 person-years in males and females, respectively. During the study period, 2,016 (37.2%) patients had no prescription, 1,663 (30.7%) were prescribed an antiplatelet (AP) agent, 1,440 (26.6%) were prescribed an OAC and 301 (5.5%) had both prescriptions. The date of diagnosis (p = 0.0001) affected the likelihood of receiving an OAC. AP, but not OAC, use significantly increased with a worsening stroke risk profile using the CHADS2 risk score. Older age increased the probability (p < 0.0001) of receiving an AP, but not an OAC. Approximately 42% and 24% of patients persisted with OAC treatment at one and two years, respectively, the remainder interrupted or discontinued their treatment. Underuse and discontinuation of OAC treatment is common in incident AF patients. Risk stratification only partially influences AT management.