Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies.

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. RESEARCH QUESTION: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? STUDY DESIGN AND METHODS: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment. RESULTS: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with 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.

YKL-40 and genetic status of CHI3L1 in a large group of asthmatics.

BACKGROUND: Studies have shown a relationship between asthma, serum YKL-40, and the single nucleotide polymorphism (SNP) (-131 C/G, rs4950928) in the CHI3L1 gene that codes for YKL-40. However, the findings differ. We studied the relationship between clinical asthma phenotypes, serum YKL-40, and SNP (-131 C/G, rs4950928). METHODS: In this study, 1,137 patients with asthma, 415 with rhinitis only, and 275 non-asthmatic controls were included. Assessment included a clinical interview concerning the diagnosis of asthma, severity of asthma, and asthma treatment as well as clinical tests to assess asthma and rhinitis. Serum YKL-40 was measured, and genotyping for the SNP (-131 C/G) was conducted. RESULTS: No significant difference in the serum concentration of YKL-40 was found between patients with asthma, patients with rhinitis, and non-asthmatic controls; however, YKL-40 was increased in patients with severe asthma. No association was found between the SNP (-131 C/G rs4950982) and the risk of having asthma (odds ratio = 0.90, p=0.4). Higher levels of serum YKL-40 were found in all subjects when comparing CC genotype to CG and GG genotypes (45 µg/L vs. 32 µg/L and 19 µg/L, p<0.0001). CONCLUSION: There was no association between polymorphisms of SNP (-131 C/G) and asthma. The highest serum YKL-40 concentrations were seen in severe asthmatics. Individuals with less severe asthma showed a smaller difference against controls, limiting its clinical usefulness. More research is needed to clarify the relationship between different asthma phenotypes, YKL-40, and CHI3L1.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Internet-based monitoring of asthma: a long-term, randomized clinical study of 300 asthmatic subjects.

BACKGROUND: Experience from other fields of internal medicine shows that Internet-based technology can be used to monitor various diseases. The new technology handles complex calculation programs easily, and it is a unique way of communicating. These advantages might be used in optimizing the treatment for asthmatic subjects because undertreatment is a common problem found in European asthmatic subjects. OBJECTIVE: We sought to investigate the outcome of monitoring and treatment using a physician-managed online interactive asthma monitoring tool and to assess whether the outcome differs from that of monitoring and treatment in an outpatient respiratory clinic or in primary care. METHODS: Three hundred asthmatic subjects were randomized to 3 parallel groups in a 6-month prospective study: (1) Internet-based monitoring (n = 100); (2) specialist monitoring (n = 100); and (3) general practitioner (GP) monitoring (n = 100). All the patients were examined on entry into the study and after 6 months of treatment. RESULTS: The treatment and monitoring with the Internet-based management tool lead to significantly better improvement in the Internet group than in the other 2 groups regarding asthma symptoms (Internet vs specialist: odds ratio of 2.64, P = .002; Internet vs GP: odds ratio of 3.26; P < .001), quality of life (Internet vs specialist: odds ratio of 2.21, P = .03; Internet vs GP: odds ratio of 2.10, P = .04), lung function (Internet vs specialist: odds ratio of 3.26, P = .002; Internet vs GP: odds ratio of 4.86, P < .001), and airway responsiveness (Internet vs GP: odds ratio of 3.06, P = .02). CONCLUSION: When physicians and patients used an interactive Internet-based asthma monitoring tool, better asthma control was achieved.