Characteristics of severe asthma patients on biologics: a real-life European registry study

Stefania Principe, Levi B. Richards, Simone Hashimoto, Johannes Anthon Kroes, Job J.M.H. Van Bragt, Susanne J. Vijverberg, Jacob K. Sont, Nicola Scichilone, Kristina Bieksiene, Anneke Ten Brinke, Zsuzsanna Csoma, Barbro Dahlén, Bilun Gemicioglu, Ineta Grisle, Piotr Kuna, Zorica Lazic, Florin Mihaltan, Sanja Popović-Grle, Sabina Škrgat, Alessandro Marcon, Marco Caminati, Ratko Djukanovic, Celeste Porsbjerg, Anke-Hilse Maitland Van Der Zee on behalf of the SHARP Clinical Research Collaboration
ERJ Open Research 2023 9: 00586-2022; DOI: 10.1183/23120541.00586-2022

Abstract

Background The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs.

Materials and methods We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies.

Results Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids.

Conclusion A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Abstract

The European severe asthma population that starts anti-IL5(R) is broader than represented in RCTs. Centralising clinical real-life registries is an important way to align the management and assessment of the disease. https://bit.ly/3y8optX

Introduction

Asthma is a common chronic disease affecting ∼5–10% of the global population, with an estimated 3–10% of asthma patients suffering from the severe form of the disease [1]. Since the introduction of novel biologics for severe asthma, significant progress has been made in the management of this debilitating condition, starting with the anti-IgE monoclonal antibody omalizumab and more recently, with the anti-interleukin (IL)-5/IL5(R) antibodies (mepolizumab, reslizumab and benralizumab) [2]. The use of biologics is typically restricted to patients who fulfil the definition of severe asthma according to European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines, which are based on evidence of clinical efficacy from randomised controlled trials (RCTs) conducted for regulatory purposes [3].

In clinical practice, however, it has been demonstrated that only 25–35% of severe asthma patients who use biologics meet inclusion criteria from RCTs [4]. While the reasons for this heterogeneity across Europe, and indeed more widely, are unknown, it is plausible that they are due to variability in climate, healthcare systems and expertise. Whether, and to what extent, this influences the decisions about the treatment of severe asthma is also unknown. A study using the Dutch national RAPSODI Registry (Registry of Adult Patients with Severe asthma for Optimal DIsease management) [5] has shown that many patients with severe asthma do not meet the strict ERS/ATS eligibility criteria, but still benefit in a real-life setting from mepolizumab therapy [6]. Moreover, a recent analysis of clinical data from several European national registries, conducted by our Clinical Research Collaboration (CRC) called SHARP (Severe Heterogeneous Asthma Research collaboration, Patient-centred) has shown notable heterogeneity of clinical characteristics amongst severe asthma patients [7]. SHARP Central Registry has been developed with the purpose to collect real-world data on diagnosis and treatment of severe asthma patients.

The criteria for the prescription of biologics for severe asthma set by the European Medicine Agency (EMA) are also very broad. Roughly, the anti-IL-5/IL5(R) biologics are indicated as “add-on therapies for adult patients with severe eosinophilic asthma inadequately controlled despite regular asthma treatment”. Therefore, the prescription criteria of these medications are highly variable in Europe [8]. Hence, it is interesting to investigate whether and to what extent European countries differ in the type of patients to whom anti-IL5 biologics are prescribed in real life, and whether the characteristics of these patients differ from those in the phase III RCTs. This will probably depend largely on differences in local guidelines, in organisation of the healthcare system and in access to expensive medicines.

The overall objective of the current study was to assess to what extent European countries differ in their application of the standard eligibility criteria of RCTs for initiating use of biologics in severe asthma patients. The specific aims of the study were to: 1) characterise patients starting biologic treatment in Europe; 2) compare their characteristics with those from the severe asthma populations participating in RCTs; and 3) evaluate the potential discrepancies between initiation of anti-IL5(R) in real life and in RCTs as judged by different inclusion and exclusion criteria.

We hypothesised that characteristics of patients who are about to start using biologics differ between European countries and do not always match the eligibility criteria specified in clinical trials. If the population prescribed anti-IL5 biologics in real life is broader than the population represented in clinical trials, this could imply that a greater number of patients might benefit from these targeted therapies.

For this study, we used data collected in the SHARP Central Registry, a centralised registry hosted in the Netherlands containing data from 11 European countries, developed for the purpose of providing fully harmonised and longitudinal real-world data from people with severe asthma.

Materials and methods

Study design and subjects

We conducted a cross-sectional, multicenter, observational registry-based study, which analysed patient clinical characteristics before starting one of the approved anti-IL5 biologics (mepolizumab, benralizumab and reslizumab). Data were collected in the SHARP Central registry, taking into account the characteristics of patients before starting with one of the biologics and were stratified by country. Remedial factors to evaluate asthma such as mistakes in inhaler technique, poor adherence, unmitigated allergen exposure and inadequate management of comorbidities should have been prior considered, to differentiate severe from difficult to treat asthma as stated in the national guidelines [1]. All patients signed an informed consent for their data to be used for research. The study was exempted from approval by ethics committees because it only used data from medical records.

Data source

Data were retrieved from the medical patients’ records from different hospitals in each country on an annual basis and captured in an electronic case report forms platform (CASTOR Electronic Data Capture (EDC); www.castoredc.com/electronic-data-capture-system) in a standardised way. We included clinical, biological and functional information of severe asthma patients before the start of an anti-IL5(R) treatment. Data on number of exacerbations were retrieved for the analysis and exacerbation was defined as: worsening of respiratory symptoms that required an oral corticosteroids (OCS) course of at least 3 days or doubling the normal oral dose in the previous 12 months. The SHARP Central registry database included patients initiating one of the three anti-IL5(R) biologics between 1 January 2016 and 24 September 2021.

Comparison of eligibility criteria for biologic treatment between the SHARP Central registry and RCTs

The characteristics of patients from phase III RCTs of anti-IL5(R) were compared with those of patients starting treatment in SHARP Central. In parallel, a literature review of the phase III RCTs conducted before the approval of anti-IL5 biologics was performed, focusing on the selection of the inclusion/exclusion criteria to assess eligibility and ineligibility [9–18] (supplementary figure S1). According to the study of Richards et al. [6], we defined trial ineligibility as: fulfilling at least one of the exclusion criteria stated in the selected RCTs; or not fulfilling one or more of the inclusion criteria stated in RCTs of the patient prescribed one of the biologics.

Analysis

For the first aim, a descriptive analysis was performed to evaluate the patient clinical characteristics in different countries. Data were stratified per country and summarised using proportions and mean±SD.

For the second aim, data from the SHARP registry were compared with data derived from RCTs using the Welch-modified t-test for continuous and χ2 tests for categorical variables. A false discovery rate (FDR) correction of 10% was applied to reduce the risk of false positives due to the multiple comparisons. FDR-corrected p-values <0.05 were considered as significant differences. If the publications of the selected RCTs and the clinical reports only reported the mean and distribution of the individual treatment arms (mepolizumab, benralizumab or reslizumab), the aggregated means and distribution were calculated.

For the third aim, a selection of trials’ eligibility and ineligibility was made and patients from the registry were evaluated according to the eligibility criteria previously defined. In this way, we distinguished within SHARP Central patients eligible and not eligible for RCTs, according to the fulfilment of the eligibility criteria. This analysis was used to determine the number of eligible patients included in SHARP Central and to evaluate the characteristics of not eligible patients.

Missing data were considered Missed Completely at Random (MCAR) and, when necessary, a complete case analysis was performed to handle missing variables.

Statistical analysis was performed using R version 3.4.4.

Results

We analysed data from SHARP Central Registry of 1231 severe asthma patients that initiated anti-IL5 treatments such as benralizumab, mepolizumab or reslizumab. For the analysis, 11 countries were analysed: Croatia (HR) with 106 asthma patients (n=106), Hungary (HU) n=48, Lithuania (LT) n=60, Latvia (LV) n=15, Netherlands (NL) n=814, Poland (PL) n=17, Romania (RO) n=21, Serbia (RS) n=45, Sweden (SE) n=20, Slovenia (SI) n=43 and Turkey (TR) n=42. Among them were 159 patients with severe asthma who had previously used another biologic for severe asthma (specifically omalizumab, anti-IgE monoclonal antibody), while 1072 patients with severe asthma were first initiators of anti-IL5(R) treatment without prior use of any other biologics.

Characteristics of severe asthma patients in European countries included in SHARP Central Registry

A summary of the characteristics of patients among different countries is presented in table 1, including demographics, clinical characteristics, laboratory tests (blood differential cell counts, total IgE), pulmonary function tests and medication use.

View this table:
TABLE 1

General characteristics of severe asthma patients before the start of anti-interleukin (IL)5(R) stratified per country

In all countries, patients with severe asthma showed similar characteristics. Only Sweden and the Netherlands reported an equal percentage of nonsmokers and ex-smokers (SE: 50% nonsmokers and 50% ex-smokers; NL: 53.6% nonsmokers and 45.6% ex-smokers).

Most countries reported that patients had experienced between two and five exacerbations in the previous year, with the exception of Slovenia and Turkey where a relatively higher percentage of patients had experienced 0 or 1 exacerbation (SI: 67.6% and TR: 83.8%), and in Romania and Sweden, where 50% of patients had experienced between 0 and 1 exacerbation in the previous year. Overall, 277 (22.5%) patients were using OCS. Long-acting muscarinic antagonists (LAMA) and leukotriene receptor antagonists (LTRA) were variably prescribed among countries.

The cohort was further characterised by comorbidities that are known to be associated with asthma. The frequencies of the comorbidities were variable between countries (table 2), the most frequent being: allergic rhinoconjunctivitis (the highest percentage registered in Poland 52.9%) chronic rhinosinusitis (the highest percentage reported in Hungary of 89.6% and in Croatia with 73.6%), nasal polyps (Hungary and Latvia reported the highest percentage of 62.5% and 53.3%, respectively) and gastro-oesophageal reflux disease (GERD) mostly reported in Hungary (56.2%).

View this table:
TABLE 2

Summary of comorbidities in patients with severe asthma included in SHARP Central

Use of anti-IL5(R) biologics by SHARP Central Registry patients

All three biologics were prescribed among the 10 countries, with mepolizumab being the most prescribed, and reslizumab the least (table 3), with the exception of Romania and Serbia where benralizumab was most prescribed (100% and 84.4%, respectively).

View this table:
TABLE 3

Prescription of anti-interleukin (IL)5(R) per country

An overview of the number and the percentage missing data per variable is provided in supplementary table S1. The overall number of missing data at baseline is 27%. The highest amount of missing information is reported for the Asthma Control Questionnaire score, which has been mainly reported by Dutch records. Moreover, the overview of comorbidities provided in table 2 is summarised considering 10 out of 11 countries because of missing data from the Turkish patients included in the SHARP Central Registry.

Comparison of patients from individual RCTs and those from the SHARP Central Registry

10 RCT studies were selected: four for mepolizumab [15–18], three for benralizumab [12–14] and three for reslizumab [9–11]. An overview of trials’ eligibility criteria extracted from the study protocols is provided in supplementary table S2. A summary of the results of the comparison between the trial population and the SHARP Central population anti-IL5(R) starters is provided in supplementary tables S3 to S5. Furthermore, an additional comparison of the characteristics of the eligible patients per biologic with the respective RCTs is presented in supplementary tables S3.1, S4.1 and S5.1. Significant differences were found between baseline characteristics of patients included in the treatment arm of mepolizumab, benralizumab and reslizumab trials and patients with severe asthma of SHARP Central Registry with respect to both demographic (e.g. age and sex) and clinical characteristics (e.g. inhalers usage and OCS consumption). With the selection of only eligible patients those differences were much lower per treatment arm.

Assessment of eligibility of SHARP Central Registry patients for inclusion in pre-registration anti-IL5(R) RCTs

Among SHARP Central Registry patients, 991 (80.5%) did not fulfill the eligibility criteria of RCTs, whereas 240 (19.5%) were considered eligible. 327 (26.56%) patients met the eligibility criteria of at least one of the selected trials (figure 1). After assessing eligibility by biologics, 24 (13.6%) patients were eligible for mepolizumab, 100 (56.8%) for benralizumab and 52 (29.5%) for reslizumab (figure 2). Overall, the major discrepancies characteristics between eligible and not eligible patients according to inclusion and exclusion criteria with respect to the criteria were: high inhaled corticosteroid (ICS) dosage, ACQ score ≥1.5, pack-years ≥10, better lung function and the presence of other respiratory or eosinophilic conditions, as shown in figure 3. The frequencies of reasons for ineligibility in each country are shown in table 4. A description of the distribution of comorbidities in eligible and not eligible patients is provided in supplementary figure S2; RCT-eligible patients in SHARP Central reported to have more frequent comorbidities such as chronic rhinosinusitis, nasal polyps and allergic rhinoconjunctivitis.

FIGURE 1
FIGURE 1

Distribution of the eligibility per trial for severe asthma patients in SHARP following inclusion/exclusion criteria of the selected trials.

FIGURE 2
FIGURE 2

Treatment eligibility stratifying per biologic therapy.

FIGURE 3
FIGURE 3

Overall distribution of the severe asthma SHARP patients according to trials’ eligibility. Trial ineligibility was defined as: fulfilling at least one of the exclusion criteria stated in the selected randomised controlled trials (RCTs); or not fulfilling one or more of the inclusion criteria stated in RCTs of the patient prescribed one of the biologics. OCS: oral corticosteroids; ICS: inhaled corticosteroids; FEV1: forced expiratory volume in 1 s; preBD: prebronchodilator; eos.: eosinophils; FENO: exhaled nitric oxide fraction; ACQ: Asthma Control Questionnaire; resp.: respiratory.

View this table:
TABLE 4

Characteristics of patients with severe asthma included in SHARP Central, ineligible for Phase III randomised controlled trials

Comparison of countries across Europe showed significant differences between countries in concordance in inclusion/exclusion criteria between the patients for treatment in clinics and those enrolled in RCTs, with overall discordance being lowest in the Netherlands (58.7%) and highest in Romania (100%). A smoking history of ≥10 pack-years was the most common characteristic that would have made patients started on an anti-IL5 biologic ineligible by RCT criteria. All ineligible patients in all the countries reported at least one respiratory disease other than with severe asthma, with the highest overall number of patients registered in Romania (79.6%). The reported other respiratory diseases were: bronchiectasis (the highest number of patients registered in Romania (61.9%)) and eosinophilic granulomatosis with polyangiitis (EGPA) mainly reported in Croatia (17.7%) as well as eosinophilic pneumonia with 13.5% and 17.1% of the patients reporting allergic bronchopulmonary aspergillosis, mostly in Sweden (6.2%). Five countries reported RCT-ineligible severe asthma patients according to Asthma Control score ≤1.5: Croatia mean±sd 1.12±1.15, Hungary 1.12±0.66, Poland 1.45±0.82, Sweden 1(NA) and Turkey 1.33(NA). In all countries the RCT-ineligible patients received a lower dose of ICS compared to trials, with the lowest dose registered in Latvia (mean±sd 314.5±230.8 µg·day−1).

Discussion

This study shows that characteristics of patients who received biological treatment for severe asthma in real life differed from country to country in terms of smoking history, clinical characteristics (ACQ-5 score, number of exacerbations in the previous year, comorbidities) and medication use (OCS, LAMA, LTRA). The characteristics of severe asthma patients included in the SHARP Central Registry differed from the characteristics of patients enrolled in phase III RCTs of anti-IL5(R) therapies. The main discrepancies between patients treated in the real world and those in RCTs were the higher number of pack-years smoked, concomitant non-asthma-related respiratory or eosinophilic diseases, lower maintenance dose of ICS and lower ACQ score in the real-world patients. Thus, a large proportion of patients in the SHARP Central Registry would not have been eligible for anti-IL5(R) treatment if the inclusion and exclusion criteria of the RCTs had been followed.

The present study confirms and extends the results from a recent study by Richards et al. [6], who showed that 119 patients from the Dutch severe asthma registry received treatment with mepolizumab, although they would normally have been excluded from clinical trials because of heavy smoking in the past, severe comorbidities, hypereosinophilic syndromes (HES) or fixed airway obstruction.

Trial eligibility in a real-life severe asthma cohort was also assessed by Brown et al. [19] who selected data from the Wessex Severe Asthma Cohort and compared these with 37 RCTs evaluating 20 biological therapies. They found that only 9.8% (range 3.5% to 17.5%) of patients would have been eligible for inclusion in trials investigating anti-IL5 treatment. In line with our results, 26% of severely asthmatic patients in their study were current smokers or ex-smokers with a smoking history of ≥10 pack-years and were considered ineligible for RCTs even if they reported high blood or sputum eosinophil counts.

Another study [20] identified the most frequent causes for exclusion from RCTs in asthma patients. These included comorbidities such as anxiety and depression (3.3%), arrhythmias (2.3%), coronary artery disease (1.2%), active smoking (34.3% of the population) and lung diseases other than asthma (5%). Notably, our analyses show that in real life these patients are not excluded for anti-IL5(Rα) therapy as shown in table 2.

Several studies have already shown that anti-IL5(R) biologics can be efficacious in patients with severe asthma who do not fulfil the strict criteria of the Phase III RCTs. In particular, have these treatments been proven to be effective in severe asthma patients with other respiratory diseases, or patients with a concomitant hypereosinophilic disease. A recent single-centre study [21] showed that mepolizumab improved symptom control (Asthma Control Test score from a mean±sd of 13±4.8 to 20.7±4.6) and reduced asthma exacerbation and OCS use in patients with coexistent severe asthma and bronchiectasis after 6 months of treatment.

Also patients with EGPA and HES have been shown to benefit from anti-IL5 treatments. Two studies reported relevant steroid-sparing effect of reslizumab and benralizumab for severe asthma patients with EGPA [22, 23], and a double-blind phase III RCT of 136 participants reported in addition an improvement in the disease remission with mepolizumab at the dosage of 300 mg [24]. In fact, the EMA have already approved mepolizumab as an add-on treatment for patients with EGPA. In patients with HES, mepolizumab significantly reduced the occurrence of flares in a phase III RCT, and is now the first and only biologic Food and Drug Administration (FDA)-approved treatment for this rare group of serious eosinophilic diseases. In addition, according to robust real-word evidence, “asthma tailored” mepolizumab 100 mg is able to maintain EGPA remission and to exert at the same time a significant steroid-sparing effect in patients with persisting severe eosinophilic asthma after systemic disease resolution [25–27]. Since not all eosinophilic diseases are sensitive to anti-IL5(R) biologics, further research is needed in order to identify new potential phenotypes and endotypes [28] for better classification of patients with eosinophilic airway disease. This will allow us to assess whether a patient with eosinophilic airway disease will benefit from treatment with an anti-IL5(R) biologic or not.

A common difference between patients who receive specific treatment in real life and those who participate in RCTs is age. Previous studies [4, 6] in patients with severe asthma have shown that the mean age of patients enrolled in clinical trials is lower than the age of patients represented in clinical registries. This might be explained by the fact that elderly patients with severe asthma are excluded from phase III RCTs because their airways may have undergone age-related structural, functional and immunological changes [29], which could potentially reduce the response to biologic therapies. However, in our study, we did not observe any age differences between countries, nor did it appear to be a relevant characteristic of non-eligibility. This is in line with the results of a meta-analysis of anti-IL5(Rα) RCTs, showing that age does not negatively affect the efficacy of these monoclonal antibodies. Thus, the use of these biologics could also be extended to a frail population [30, 31]. The same findings were recently confirmed by a real-life analysis focusing on clinical response of mepolizumab and omalizumab in different sexes and age ranges [32].

Our study has several clinical and research implications. First, it shows once again the importance of collecting real-world data and comparing it with data from phase III RCTs. Our findings show that the real-life severe asthma population appears to be different from the populations in clinical trials and suggests that a broader population than the one represented in clinical trials could profit from anti-IL5 treatment. Not only patients with multiple comorbidities, whether or not related to asthma, but also the elderly, heavy smokers and patients with airway remodelling appear to benefit from this treatment. Second, our study emphasises the importance of a long-term registration of data from patients with chronic conditions such as severe asthma who are receiving new treatments. Without such data collection and privacy-proof storage it would not be possible to get an impression of the real-life efficacy of this biological therapy. Third, our study highlights the importance of harmonising data and unifying national registries in order to reduce differences in management practice in different countries and extend the knowledge of severe asthma across Europe.

Apart from SHARP Central, several other active projects are collecting real-life data from severe asthma patients on a large scale, such as the International Severe Asthma Registry (ISAR) project and the ongoing 3TR pan-European consortium [33, 34]. Like SHARP Central, these multinational programmes will hopefully contribute to a better characterisation and understanding of the complexities of severe asthma. The discrepancies between RCTs and real-life registries observed in our study may already provide an important source of inspiration for identifying novel mechanisms and treatment targets, not only for patients with severe asthma but also for patients with a variety of type 2 inflammatory diseases.

Our study has several strengths and a few limitations. First, to our knowledge, our study is the first to have used data from clinical care facilities from 11 different European countries to characterise patients with severe asthma who were prescribed anti-IL5(Rα) biologics in real life, and to investigate differences in prescription practices between countries. Second, it is unique that for this study 11 different countries used disease registries with an identical data model and treating physicians entered patient data via an e-CRF translated into 11 different languages. As a result, there was no bias due to incorrect data harmonisation. Potential limitations of this study include first that our results represent a snapshot, which may change over time, since collection of data in the SHARP Central Registry is still ongoing. Yet, we were able to select >1000 patients from 11 different European countries, so we believe the population to be quite representative of the actual real-life clinical care setting. Second, we lacked reliable data in the SHARP Central Registry about the exact frequency of exacerbations, which was an inclusion criterion in many RCTs. However, we believe that the use of frequency categories (0–1, 2–5, >5) did not influence the interpretation of our results. Third, there were quite a few missing data, which is unavoidable in clinical registries that are not closely monitored. Fourth, there were differences between countries in patient numbers. Small numbers or multiple missing data may have led to overestimation of differences in quantitative data like age or body mass index, but not in qualitative data like smoking history or comorbidities. Lastly, we could not include the same information per trial when we compared baseline characteristics of SHARP Central Registry patients and RCTs. This is due to the fact that we do not have access to the original raw data of previously published RCTs. Furthermore, each variable in SHARP Central Registry might have been retrieved in a different way to that in RCTs (e.g. exacerbations previously explained). Therefore, we could only present comparison of data that we were sure could have been retrieved in the same way to that in the SHARP central registry. Even though this information might be considered incomplete, it is an important “first-step” to understand the discrepancies in real-life populations with RCTs.

In conclusion, we have demonstrated that patients receiving asthma biologics in routine clinical asthma care, across a wide European spectrum, differ from patients who participate in phase III RCTs. The population benefiting from these drugs in real life is much more diverse and broader than the population enrolled in RCTs. Future research should focus on gathering more patient-level data in a longitudinal long-term setting, to evaluate whether the population considered ineligible in randomised trials might derive genuine benefits from anti-IL5 treatment comparable to those already reported in clinical trials. This study demonstrates the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material 00586-2022.SUPPLEMENT

Acknowledgement

The SHARP CRC would like to acknowledge the support and expertise of the following individuals and groups without whom the study would not have been possible: Emmanuelle Berret (European Respiratory Society, Lausanne, Switzerland), Elisabeth Bel (University of Amsterdam, Amsterdam, the Netherlands) and Aruna Bansal (Acclarogen Ltd, St John's Innovation Centre, Cambridge, UK) from the SHARP team that helped in the writing assistance of the manuscript.

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Conflict of interest: S. Principe is an employee of the University of Palermo with co-EU research funds EU-REACT FESR o FSE, PON Ricerca e Innovazione 2014–2020 - DM 1062/2021.

  • Conflict of interest: A. Ten Brinke reports grants from AstraZeneca, GSK and TEVA, fees for advisory boards and lectures from AstraZeneca, GSK, Novartis, TEVA and Sanofi Genzyme.

  • Conflict of interest: I. Grisle declares honoraria for lectures from AZ, Novartis, GSK, Berlin Chemie, Boehringer Ingelheim and Norameda.

  • Conflict of interest: P. Kuna declares honoraria for lectures/presentations from AstraZeneca, GSK, Boehringer Ingelheim, Berlin Chemie, Menarini, FAES, Adamed, Polpharma, Glenmark, Novartis and Teva, and support for attending meetings from AstraZeneca, Berlin Chemie and Menarini.

  • Conflict of interest: S. Popović-Grle declares consulting fees from AZ, GSK, Novartis, Pliva Teva, Sanofi and ALK, and honoraria for lectures from AZ, GSK, Novartis, Pliva TEVA, Sanofi and ALK.

  • Conflict of interest: S. Škgrat declares, in the past 36 months, honoraria for lectures and educational events from AstraZeneca (AZ), Pliva Teva, Berlin Chemie, Chiesi and Medis, and participation on advisory boards for AZ and Berlin Chemie.

  • Conflict of interest: C. Porsbjerg declares, in the past 36 months, grants from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, consulting fees from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, honoraria for lectures from AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK, participation for advisory boards AZ, GSK, Novartis, TEVA, Sanofi, Chiesi and ALK.

  • Conflict of interest: All the other authors declare that they have no conflicts of interest.

  • Support statement: The SHARP CRC has been supported by financial and other contributions from the following consortium partners: European Respiratory Society, GlaxoSmithKline Research and Development Limited, Chiesi Farmaceutici SPA, Novartis Pharma AG, Sanofi-Genzyme Corporation and Teva Branded Pharmaceutical Products R&D, Inc.

  • Received November 2, 2022.
  • Accepted February 21, 2023.
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

References

  1. ↵
    Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2022. Available from: https://ginasthma.org/
  2. ↵
    1. Israel E,
    2. Reddel HK
    . Severe and difficult-to-treat asthma in adults. N Engl J Med 2017; 377: 965–976. doi:10.1056/NEJMra1608969
    OpenUrlCrossRefPubMed
  3. ↵
    1. Chung KF,
    2. Wenzel SE,
    3. Brozek JL, et al.
    International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014, 43: 343–373. doi:10.1183/09031936.00202013
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Comberiati P,
    2. McCormack K,
    3. Malka-Rais J, et al.
    Proportion of severe asthma patients eligible for mepolizumab therapy by age and age of onset of asthma. J Allergy Clin Immunol Pract 2019; 7: 2689–2696.e2. doi:10.1016/j.jaip.2019.05.053
    OpenUrl
  5. ↵
    1. He
    1. t Rapsodi register
    Rapsodi. Het Rapsodi register [Rapsodi register]. www.rapsodiregister.nl/ Date last updated: 6 July 2022.
  6. ↵
    1. Richards LB,
    2. van Bragt JJMH,
    3. Aarab R, et al.
    Treatment eligibility of real-life mepolizumab-treated severe asthma patients. J Allergy Clin Immunol Pract 2020; 8: 2999–3008.e1. doi:10.1016/j.jaip.2020.04.029
    OpenUrl
  7. ↵
    1. van Bragt JJMH,
    2. Adcock IM,
    3. Bel EHD, et al.
    Characteristics and treatment regimens across ERS SHARP severe asthma registries. Eur Respir J 2020; 55: 1901163. doi:10.1183/13993003.01163-2019
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Frix A-N,
    2. Heaney LG,
    3. Dahlén B, et al.
    Heterogeneity in the use of biologics for severe asthma in Europe: a SHARP ERS study. ERJ Open Res 2022; 8: 00273-2022. doi:10.1183/23120541.00273-2022
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Bjermer L,
    2. Lemiere C,
    3. Maspero J et al.
    Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest 2016; 150: 789–798. doi:10.1016/j.chest.2016.03.032
    OpenUrlCrossRefPubMed
    1. Corren J,
    2. Weinstein S,
    3. Janka L, et al.
    Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest 2016; 150: 799–810. doi:10.1016/j.chest.2016.03.018
    OpenUrlCrossRefPubMed
  11. ↵
    1. Castro M,
    2. Zangrilli J,
    3. Wechsler ME, et al.
    Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3: 355–366. doi:10.1016/S2213-2600(15)00042-9
    OpenUrl
  12. ↵
    1. Nair P,
    2. Wenzel S,
    3. Rabe KF, et al.
    Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med 2017; 376: 2448–2458. doi:10.1056/NEJMoa1703501
    OpenUrlPubMed
    1. FitzGerald JM,
    2. Bleecker ER,
    3. Nair P, et al.
    Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 388: 2128–2141. doi:10.1016/S0140-6736(16)31322-8
    OpenUrlCrossRefPubMed
  14. ↵
    1. Bleecker ER,
    2. FitzGerald JM,
    3. Chanez P, et al.
    Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; 388: 2115–2127. doi:10.1016/S0140-6736(16)31324-1
    OpenUrlCrossRefPubMed
  15. ↵
    1. Chupp GL,
    2. Bradford ES,
    3. Albers FC, et al.
    Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med 2017; 5: 390–400. doi:10.1016/S2213-2600(17)30125-X
    OpenUrl
    1. Pavord ID,
    2. Korn S,
    3. Howarth P, et al.
    Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–659. doi:10.1016/S0140-6736(12)60988-X
    OpenUrlCrossRefPubMed
    1. Bel EH,
    2. Wenzel SE,
    3. Thompson PJ, et al.
    Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: 1189–1197. doi:10.1056/NEJMoa1403291
    OpenUrlCrossRefPubMed
  18. ↵
    1. Ortega HG,
    2. Liu MDC,
    3. Pavord ID, et al
    . Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 13: 1198–1207. doi:10.1056/NEJMoa1403290
    OpenUrl
  19. ↵
    1. Brown T,
    2. Jones T,
    3. Gove K, et al.
    Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur Respir J 2018; 52: 1801444. doi:10.1183/13993003.01444-2018
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Battaglia S,
    2. Basile M,
    3. Spatafora M, et al.
    Are asthmatics enrolled in randomized trials representative of real-life outpatients? Respiration 2015; 89: 383–389. doi:10.1159/000375314
    OpenUrlPubMed
  21. ↵
    1. Crimi C,
    2. Campisi R,
    3. Nolasco S, et al.
    Mepolizumab effectiveness in patients with severe eosinophilic asthma and co-presence of bronchiectasis: a real-world retrospective pilot study. Respir Med 2021; 185: 106491. doi:10.1016/j.rmed.2021.106491
    OpenUrl
  22. ↵
    1. Manka LA,
    2. Guntur VP,
    3. Denson JL, et al.
    Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis. Ann Allergy Asthma Immunol 2021; 126: 696–701.e1. doi:10.1016/j.anai.2021.01.035
    OpenUrlPubMed
  23. ↵
    1. Padoan R,
    2. Chieco Bianchi F,
    3. Marchi MR, et al.
    Benralizumab as a glucocorticoid-sparing treatment option for severe asthma in eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract 2020; 8: 3225–3227.e2. doi:10.1016/j.jaip.2020.05.033
    OpenUrl
  24. ↵
    1. Michael EW,
    2. Praveen A,
    3. David J, et al.
    Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017; 376: 1921–1932. doi:10.1056/NEJMoa1702079
    OpenUrlCrossRefPubMed
  25. ↵
    1. Bettiol A,
    2. Urban ML,
    3. Dagna L, et al.
    Mepolizumab for eosinophilic granulomatosis with polyangiitis: a European multicenter observational study. Arthritis Rheumatol 2022; 74: 295–306. doi:10.1002/art.41943
    OpenUrl
    1. Caminati M,
    2. Crisafulli E,
    3. Lunardi C, et al.
    Mepolizumab 100 mg in severe asthmatic patients with EGPA in remission phase. J Allergy Clin Immunol Pract 2021; 9: 1386–1388. doi:10.1016/j.jaip.2020.09.025
    OpenUrlPubMed
  27. ↵
    1. Bettiol A,
    2. Urban ML,
    3. Bello F, et al.
    Sequential rituximab and mepolizumab in eosinophilic granulomatosis with polyangiitis (EGPA): a European multicentre observational study. Ann Rheum Dis 2022; 81: 1769–1772. doi:10.1136/annrheumdis-2022-eular.4320
    OpenUrlFREE Full Text
  28. ↵
    1. Carpagnano GE,
    2. Scioscia G,
    3. Lacedonia D, et al.
    Severe uncontrolled asthma with bronchiectasis: a pilot study of an emerging phenotype that responds to mepolizumab. J Asthma Allergy 2019; 12: 83–90. doi:10.2147/JAA.S196200
    OpenUrlCrossRef
  29. ↵
    1. Baptist AP,
    2. Busse PJ
    . Asthma over the age of 65: All's well that ends well. J Allergy Clin Immunol Pract 2018; 6: 764–773. doi:10.1016/j.jaip.2018.02.007
    OpenUrl
  30. ↵
    1. Isoyama S,
    2. Ishikawa N,
    3. Hamai K, et al.
    Efficacy of mepolizumab in elderly patients with severe asthma and overlapping COPD in real-world settings: a retrospective observational study. Respir Investig 2021; 59: 478–486. doi:10.1016/j.resinv.2021.02.009
    OpenUrl
  31. ↵
    1. Principe S,
    2. Benfante A,
    3. Calzetta L, et al.
    Age does not affect the efficacy of anti-IL-5/IL-5R in severe asthmatics. World Allergy Organ J 2019; 12: 100081. doi:10.1016/j.waojou.2019.100081
    OpenUrl
  32. ↵
    1. Benoni R,
    2. Panunzi S,
    3. Batani V, et al.
    Clinical response to biologicals for severe asthma: any relevance for sex in different age ranges? ERJ Open Res 2022; 8: 00670-2021. doi:10.1183/23120541.00670-2021
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Porsbjerg C,
    2. Maitland-Van der Zee AH,
    3. Brusselle G, et al.
    3TR: a pan-European cross-disease research consortium aimed at improving personalised biological treatment of asthma and COPD. Eur Respir J 2021; 58: 2102168. doi:10.1183/13993003.02168-2021
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Fitzgerald JM,
    2. Tran TN,
    3. Alacqua M, et al.
    International severe asthma registry (ISAR): Protocol for a global registry. BMC Med Res Methodol 2020; 20: 212. doi:10.1186/s12874-020-01065-0
    OpenUrl
Back to top
Email
Print
Citation Tools
Characteristics of severe asthma patients on biologics: a real-life European registry study
Stefania Principe, Levi B. Richards, Simone Hashimoto, Johannes Anthon Kroes, Job J.M.H. Van Bragt, Susanne J. Vijverberg, Jacob K. Sont, Nicola Scichilone, Kristina Bieksiene, Anneke Ten Brinke, Zsuzsanna Csoma, Barbro Dahlén, Bilun Gemicioglu, Ineta Grisle, Piotr Kuna, Zorica Lazic, Florin Mihaltan, Sanja Popović-Grle, Sabina Škrgat, Alessandro Marcon, Marco Caminati, Ratko Djukanovic, Celeste Porsbjerg, Anke-Hilse Maitland Van Der Zee
ERJ Open Research May 2023, 9 (3) 00586-2022; DOI: 10.1183/23120541.00586-2022
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

Subjects