Changes in disease burden and treatment reality in patients with severe asthma.

BACKGROUND: Biologics are clinically available for patients with severe asthma, but changes in asthma control over time are unknown. We examined changes in disease burden and treatment in severe asthma patients. METHODS: This retrospective study used a Japanese health insurance database (Cross Fact) and included patients aged ≥16 years treated continuously with an inhaled corticosteroid (ICS) for a diagnosis of asthma in each calendar year from 2015 to 2019. Severe asthma was defined as annual use of high-dose ICS plus one or more asthma controller medications four or more times, oral corticosteroids for ≥183 days, or biologics for ≥16 weeks. Changes in asthma exacerbations, prescriptions, and laboratory testing were examined. RESULTS: Demographic characteristics were similar throughout the study. The number and proportion of patients with severe asthma among those with asthma increased (2724; 15.3% in 2015 vs 4485; 19.0% in 2019). The proportion of severe asthma patients with two or more asthma exacerbations decreased from 24.4% to 21.5%. Odds ratios (95% confidence interval) of ≥2 asthma exacerbations in each year compared with 2015 were 0.96 (0.85-1.08) in 2016 and 0.86 (0.76-0.97) in 2017, with significant reductions observed in subsequent years. Short-acting beta agonists and oral corticosteroid prescriptions for asthma exacerbations decreased and long-acting muscarinic antagonist and biologic prescriptions for maintenance treatment increased. CONCLUSIONS: This study showed improvements in disease burden and treatment in severe asthma patients. There remains an unmet medical need for patients with severe asthma, given the proportion who continue to have asthma exacerbations.

Relationship between serum IgA levels and low percentage forced expiratory volume in the first second in asthma.

Objective: Immunoglobulin A (IgA) is suggested to have pathogenic effects in respiratory inflammatory diseases, including asthma. We aimed to analyze the relationship between serum IgA, and clinical indicators and biomarkers of asthma.Methods: This study was a post hoc analysis of the NHOM Asthma Study. In this study, serum IgA was measured using serum samples stored. We determined an association between the serum IgA level and clinical variables and biomarkers using multivariate linear regression and analyzed the differences in clinical indices between IgA high- and IgA low-asthma.Results: In this study, 572 patients with asthma were included in the final analysis. Lower percentage forced expiratory volume in the first second (%FEV1), higher serum eotaxin levels, lower serum ST2 levels, and higher serum MIP-1ß levels, were independently and significantly associated with higher serum IgA levels among asthma patients by multivariate linear regression analysis (%FEV1, 95% confidence interval [CI], -8.18- -0.613, p < 0.05; eotaxin, 95% CI, 8.95-46.69, p < 0.001; ST2, 95% CI, -73.71- -7.37, p < 0.05; and MIP-1ß, 95% CI, 1.47-18.71, p < 0.05). Furthermore, IgA high-asthma (serum IgA ≥ 238 mg/dL, n = 270) and IgA low-asthma (serum IgA < 238 mg/dL, n = 302) were compared separately. %FEV1 was significantly lower, the percentage of atopy was higher, and serum MIP-1ß level was higher in IgA high-asthma.Conclusions: This study suggests that serum IgA may be involved in the worsening of asthma outcomes, as assessed by %FEV1 and enhanced inflammation via elevated serum MIP-1ß.

A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T.

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Relationship Between Asthma Control Status and Health-Related Quality of Life in Japan: A Cross-Sectional Mixed-Methods Study.

INTRODUCTION: There is limited information regarding multidimensional relationships between asthma control and health-related quality of life (HRQoL), work productivity, and asthma symptom burden in Japan. Furthermore, systematic qualitative investigations about asthma burden have not been performed. METHODS: This cross-sectional, mixed-methods study included Japanese patients (≥ 20 years) with asthma adherent to inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA). The primary endpoint was impact of asthma on HRQoL, measured using the Asthma Health Questionnaire-33 (AHQ-33). Secondary endpoints were cough burden (Japanese-adapted Leicester Cough Questionnaire [J-LCQ]) and impact of asthma on work/activities (asthma-specific Work Productivity and Activity Impairment Questionnaire [WPAI:Asthma]). Quantitative data were assessed for the overall population and for well-controlled (WC) and not well-controlled (NWC) asthma subgroups. Qualitative verbal interviews further assessed the impact of NWC asthma on patients' HRQoL; emergent themes were extracted using thematic analyses. RESULTS: Of 454 patients, 45.2% (n = 205) had NWC asthma. Patients with NWC asthma had significantly worse asthma- and cough-related HRQoL across all AHQ-33 and J-LCQ domains and significantly greater work and activity impairment versus patients with WC asthma, across all assessed WPAI:Asthma domains. AHQ-33 total score was highly correlated with J-LCQ total and domain scores (r = - 0.8132 to r = - 0.7407). Nine themes emerged from qualitative interviews and confirmed that patients with NWC asthma had considerable HRQoL impairment due to asthma symptoms. CONCLUSIONS: Patients with NWC asthma had higher symptom burden and worse HRQoL than patients with WC asthma, despite ICS/LABA adherence. Cough burden correlated with HRQoL, suggesting cough may be one of the key markers to inform treatment strategy for patients with asthma.

Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: Analysis of the REDES study.

Introduction: Clinical remission as a multicomponent treatment goal in severe asthma is being explored in clinical practice. This post hoc analysis used data from the REDES study to assess the proportion of patients with severe eosinophilic asthma achieving our multicomponent definitions of clinical remission after 1 year of mepolizumab treatment. Methods: The real-world, retrospective observational REDES study enrolled patients with severe eosinophilic asthma who were newly prescribed mepolizumab and with ≥12 months of medical records pre-enrolment. Multicomponent clinical remission was defined as: oral corticosteroid (OCS)-free; exacerbation-free; asthma control test (ACT) score ≥20; and with or without post-bronchodilator forced expiratory volume in 1 second ≥80%. Baseline characteristics were also assessed in those who did/did not achieve clinical remission. Results: 37% and 30% of patients with severe eosinophilic asthma met our proposed three- and four-component on-treatment clinical remission definitions; an increase from 2% and 3% at baseline. Most frequently achieved individual components of clinical remission were: OCS-free; ACT score ≥20. For patients fulfilling the multicomponent clinical remission definitions, at baseline we observed higher blood eosinophil counts, better ACT scores and lung function, lower maintenance OCS use, and a slightly lower rate of prior exacerbations versus those who did not. Discussion: Clinical remission is a realistic target in clinical practice for a subset of patients with severe eosinophilic asthma receiving mepolizumab. Further studies are required to elucidate whether features linked to the underlying endotype can help predict treatment outcomes, increase rates of clinical remission, and potentially modify disease progression.

Questionnaire for diagnosing asthma-COPD overlap in COPD: Development of ACO screening questionnaire (ACO-Q).

BACKGROUND: The considerable prevalence and worse outcomes of asthma-COPD overlap (ACO) in COPD have been reported, and optimal introduction of ICS is essential for ACO. However, diagnostic criteria for ACO consist of multiple laboratory tests, which is challenging during this COVID-19 era. The purpose of this study was to create a simple questionnaire to diagnose ACO in patients with COPD. METHODS: Among 100 COPD patients, 53 were diagnosed with ACO based on the Japanese Respiratory Society Guidelines for ACO. Firstly, 10 candidate questionnaire items were generated and further selected by a logistic regression model. An integer-based scoring system was generated based on the scaled estimates of items. RESULTS: Five items, namely a history of asthma, wheezing, dyspnea at rest, nocturnal awakening, and weather- or season-dependent symptoms, contributed significantly to the diagnosis of ACO in COPD. History of asthma was related to FeNO >35 ppb. Two points were assigned to history of asthma and 1 point to other items in the ACO screening questionnaire (ACO-Q), and the area under the receiver operating characteristic curve was 0.883 (95% CI: 0.806-0.933). The best cutoff point was 1 point, and the positive predictive value was 100% at a cutoff of 3 points or higher. The result was reproducible in the validation cohort of 53 patients with COPD. CONCLUSIONS: A simple questionnaire, ACO-Q, was developed. Patients with scores ≥3 could be reasonably recommended to be treated as ACO, and additional laboratory testing would be recommended for patients with 1 and 2 points.

Biologics for severe asthma: The real-world evidence, effectiveness of switching, and prediction factors for the efficacy.

Biologics have been a key component of severe asthma treatment, and there are currently biologics available that target IgE, IL-5, IL-4/IL-13, and TSLP. Randomized controlled trials have established clinical evidence, but a significant portion of patients with severe asthma in real-life settings would have been excluded from those trials. Therefore, real-world research is necessary, and there is a growing body of information about the long-term efficacy and safety of biologics. Multiple clinical phenotypes of severe asthma exist, and it is crucial to choose patients based on their phenotypes. Blood eosinophil count is an important biomarker for anti-IL-5 therapies, and FeNO and eosinophil counts serve as prediction markers for dupilumab. Reliable markers for predicting response, however, have not yet been fully established for omalizumab. Identification of clinical or biological prediction factors is crucial for the path toward clinical remission because the current treatment goal includes clinical remission, which is defined as a realistic goal for remission off treatment. Additionally, since there are now multiple biologic options and overlaps in eligibility for biologics in clinical practice, the evidence regarding the effectiveness of switching the biologics is crucial. Investigations into the clinical trajectory following the cessation of biologics are another important issue. Recent research on omalizumab, mepolizumab, benralizumab and dupilumab's real-world effectiveness, the prediction factor for the efficacy, and the impact of switching or discontinuation will be reviewed and discussed in this review.

Nationwide survey of refractory asthma with bronchiectasis by inflammatory subtypes.

RATIONALE: Bronchiectasis and bronchiolitis are differential diagnoses of asthma; moreover, they are factors associated with worse asthma control. OBJECTIVE: We determined clinical courses of bronchiectasis/bronchiolitis-complicated asthma by inflammatory subtypes as well as factors affecting them. METHODS: We conducted a survey of refractory asthma with non-cystic fibrosis bronchiectasis/bronchiolitis in Japan. Cases were classified into three groups, based on the latest fractional exhaled NO (FeNO) level (32 ppb for the threshold) and blood eosinophil counts (320/µL for the threshold): high (type 2-high) or low (type 2-low) FeNO and eosinophil and high FeNO or eosinophil (type 2-intermediate). Clinical courses in groups and factors affecting them were analysed. RESULTS: In total, 216 cases from 81 facilities were reported, and 142 were stratified: 34, 40 and 68 into the type 2-high, -intermediate and -low groups, respectively. The frequency of bronchopneumonia and exacerbations requiring antibiotics and gram-negative bacteria detection rates were highest in the type 2-low group. Eighty-seven cases had paired latest and oldest available data of FeNO and eosinophil counts; they were analysed for inflammatory transition patterns. Among former type 2-high and -intermediate groups, 32% had recently transitioned to the -low group, to which relatively low FeNO in the past and oral corticosteroid use contributed. Lastly, in cases treated with moderate to high doses of inhaled corticosteroids, the frequencies of exacerbations requiring antibiotics were found to be higher in cases with more severe airway lesions and lower FeNO. CONCLUSIONS: Bronchiectasis/bronchiolitis-complicated refractory asthma is heterogeneous. In patients with sputum symptoms and low FeNO, airway colonisation of pathogenic bacteria and infectious episodes are common; thus, corticosteroids should be carefully used.

Diversities of allergic pathologies and their modifiers: Report from the second DGAKI-JSA meeting.

In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host-pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.

Findings of in vitro Analyses of Basophil Functions May Help Us Better Understand Drug Desensitization.

Drug hypersensitivity can be an important problem during pharmacological management of various diseases. Patients diagnosed as having a drug allergy usually need to avoid the offending drug, either temporarily or for life. Another way of overcoming a drug allergy is to establish desensitization using the allergen drug itself. We previously investigated in vitro desensitization of human basophils using a subthreshold dose of an IgE-crosslinking reagent. We found that basophil desensitization occurred in a dose-dependent manner over a period of one to several hours. We think that inducible basophil desensitization occurring without histamine release may explain, at least in part, the clinical features of drug desensitization in type 1 drug allergy.

Reduction in asthma exacerbation rate after mepolizumab treatment initiation in patients with severe asthma: A real-world database study in Japan.

OBJECTIVE: To investigate the changes in asthma exacerbation, as well as in oral corticosteroid (OCS) use, exacerbation-related healthcare resource utilization (HRU), and healthcare costs before and after mepolizumab treatment initiation in patients with severe asthma who started treatment with mepolizumab in a real-world clinical setting in Japan. METHODS: A retrospective, observational, self-controlled study was conducted in Japan using a hospital-based administrative claims database. Patients who were diagnosed with asthma and who were new users of mepolizumab were included in the study. The primary outcome was the incidence rate of any asthma exacerbation/patient-year during the 12-month period before (baseline period) and after (follow-up period) the first mepolizumab prescription. Secondary outcome measures included the proportion of patients with ≥1 any asthma exacerbation, patients with exacerbation requiring hospitalization, the incidence rate of exacerbations requiring hospitalization/patient-year, the median daily OCS dose (OCS sparing effect), exacerbation-related HRU (hospitalization length, the proportion of patients with emergency visits, and the number of emergency/outpatient visits), and associated costs. RESULTS: Of the 377 patients included, 56.2% were ≥65 years of age. Following the first mepolizumab prescription, incidence rates for any asthma exacerbation were reduced by 40.6% (4.00/patient-year to 2.38/patient-year; the incidence rate ratio [95% confidence interval]: 0.60 [0.53-0.67]; p < 0.0001) from the baseline to follow-up periods. The incidence rate of exacerbations requiring hospitalization was reduced by 55.8% (0.37/patient-year to 0.16/patient-year) from the baseline to follow-up periods. The proportion of patients experiencing any exacerbation decreased from 84.4% to 57.8% and those requiring hospitalization decreased from 23.9% to 10.3% both from the baseline to follow-up periods. The median daily OCS dose decreased by 44.6% (median [interquartile range]: 6.7 [4.7-9.9] mg/day to 3.3 [0.9-5.6] mg/day) from the last baseline quarter to the 4th quarter of the follow-up period. All exacerbation-related HRUs decreased from the baseline to follow-up periods. Inpatient cost reduced by >50% (123,279 Japanese Yen [JPY]/patient-year vs. 57,283 JPY/patient-year), reducing the total cost by 80,716 JPY from the baseline to follow-up periods. CONCLUSION: Mepolizumab was effective in treating patients with severe asthma by reducing the incidence rates of exacerbations and exacerbation requiring hospitalization, OCS dose, exacerbation-related HRU, and cost in routine clinical practice in Japan.

[THE OVERLAPPING ELIGIBILITY FOR BIOLOGICS IN PATIENTS WITH SEVERE ASTHMA AND PHENOTYPES].

BACKGROUND: Biologics are an important treatment option for patients with severe asthma. Four biologics are available in Japan, and an overlapping eligibility has been observed. The eligibility and availability of drugs depend on the local regulations of different countries. However, there is no precise information about the eligibility for biologics, including dupilumab, in Japan. The aim of the study was to investigate the overlapping eligibility and to analyze the phenotypes of patients with multiple eligibility. METHODS: In this observational study, a retrospective chart review of patients was performed. The eligibility criteria for omalizumab were IgE 30-1500IU/mL and positive IgE for perennial aeroallergen. The eligibility criteria for IL-5-targeted biologics (mepolizumab and benralizumab) were eosinophil counts (Eos) > 150µL, while those for dupilumab were Eos > 150µL or fraction of exhaled nitric oxide (FeNO) > 150ppb or IgE > 167IU/mL. Severe asthma was defined by the severity criteria under treatment based on Japanese guidelines for adult asthma. RESULTS: One hundred patients with severe asthma were identified. The eligibility for omalizumab, IL-5-targeted therapies, and dupilumab was 43%, 69%, and 82%, respectively. Thirty percent of the patients were eligible for all the four biologics and showed the lowest FEV1, frequent exacerbation history, and the highest levels of Eos, FeNO, and serum periostin. Only 11% of the patients were not indicated for any biologics. CONCLUSION: A considerable portion of patients was eligible for all the biologics. Asthma control was poor, and type 2 inflammation was prominent in such patients.

Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients' DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2'-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2'OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

Mepolizumab decreased the levels of serum galectin-10 and eosinophil cationic protein in asthma.

BACKGROUND: Mepolizumab, a humanized antibody targeting interleukin-5, decreases the number of blood eosinophils and the frequency of exacerbation of severe asthma. Galectin-10 is a protein within the cytoplasm of eosinophils and constitutes Charcot-Leyden crystals, which promotes key features of asthma. However, the relationship between time kinetics and clinical response of eosinophil-derived molecules such as galectin-10 or eosinophil cationic protein (ECP) has not been precisely investigated. OBJECTIVE: This study aimed to clarify the precise time course of the levels of serum galectin-10 and ECP after mepolizumab treatment and to analyze the relationship between the levels of eosinophil-derived molecules and the clinical background or response to mepolizumab treatment. METHODS: This multicenter, prospective open-label study recruited 20 patients with severe eosinophilic asthma. Mepolizumab was administered every 4 weeks for 32 weeks and the levels of various biomarkers were serially analyzed. RESULTS: The serum galectin-10 and ECP significantly and rapidly decreased 4 weeks after initial administration of mepolizumab. In contrast, basophil count, fractional exhaled nitric oxide, and the serum total IgE level were unchanged during treatment. Asthma Control Questionnaire-5, Asthma Health Questionnaire-33, and Lund-Mackay scores significantly improved after mepolizumab treatment. Both high ECP and eosinophil count related to better response in forced expiratory volume in 1 second (FEV1) and measurable ECP level at 4 weeks after administration of mepolizumab related to the further improvement in FEV1 toward week 32. No significant difference in improvement in FEV1 was observed in galectin-10 high group. The level of ECP at baseline was significantly related to the higher prevalence of nasal polyp and Lund-Mackay score. CONCLUSION: This study was the first to show that the levels of serum galectin-10 decreases after initial administration of mepolizumab. The significant relationship between serum ECP and better response in FEV1 suggested the potential role of serum ECP as a predictive biomarker for the efficacy of mepolizumab (UMIN000030466).

The impact of the COVID-19 pandemic on asthma treatment in Japan: Perspectives based on doctors' views.

The coronavirus disease 2019 (COVID-19) pandemic has had a great influence on medical practice in Japan. In this study, an online questionnaire-based survey was conducted among doctors routinely involved in the treatment of asthma. The questions included in the survey pertained to their thoughts on asthma treatment amidst COVID-19, changes in their clinical approach toward patients with asthma, and the behavioral changes in patients in the pandemic era. The results revealed a significant impact of the pandemic on asthma treatment. Regardless of whether or not they were directly involved in the treatment of patients with COVID-19, the doctors had avoided using nebulizers in outpatient wards/clinics and routine pulmonary function testing. An increase in canceled appointments and inappropriate/non-adherence to treatment among their patients were noticeable. Furthermore, the survey revealed an extensive impact of the pandemic on the doctors engaged in asthma treatment irrespective of the differences in their medical backgrounds.