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Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: From eligibility criteria to real practice. A cross-sectional study
Pulmonary Pharmacology & Therapeutics 60 (2020) 101874
Contents lists available at ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: From eligibility criteria to real practice. A cross-sectional study
T
Francesco Menzellaa,∗, Carla Galeonea, Patrizia Ruggieroa, Diego Bagnascob, Chiara Catellania, Nicola Facciolongoa a b
Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia- IRCCS, 42123, Reggio Emilia, Italy Allergy & Respiratory Diseases, University of Genoa, 16132, Genoa, Italy
A B S T R A C T
The increasing knowledge on immuno-inflammatory pathways allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). It is therefore very important to accurately identify phenotypes and endotypes of patients potentially eligible for innovative treatments. The aim of this study was to describe a cohort of patients affected by SRA referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy. It is an observational cross-sectional study, investigating the proportion of subjects with eligibility criteria for biological treatments (omalizumab, mepolizumab, benralizumab) and nonpharmacological treatment (bronchial thermoplasty, BT). We enrolled 137 patients with SRA referring to the centre from June 1st, 2017 to June 30th, 2019. The results of this study showed that 125 (91%) of patients were eligible for at least one biologic and 94 (69%) were eligible for BT. Only 6 (4%) of patients had no criteria for any available SRA treatments. Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. Considering eligibility criteria for BT, only 6 (4%) patients had inclusion criteria for BT, instead in real life 28% of patients were treated with BT. The major comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of bronchiectasis was much higher in the mepolizumab (45%) and benralizumab (43%) groups than in omalizumab (1%) and BT (7%), p < 0,001; CRSwNP and GERD were equally present and EGPA was only present in the mepolizumab group. Overall, our population was eligible for biologicals in almost all cases, and a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of different therapeutic options and reiterates the need for a correct characterization of patients. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient.
1. Introduction In recent years, the evolution of knowledge allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). For this reason, it is very important to better define the classification of SRA and its subtypes. These are classified into phenotypes, referring to the observable characteristics of the disease in an individual, and in endotypes, the specific biological mechanisms that cause those observed properties of a given phenotype [1,2]. Determining phenotypes and endotypes is a key point, particularly when selecting a targeted biological drug or other immunomodulatory therapies. Hence, there is the need for new biomarkers, especially predictive ones, which will help the clinicians to better select patients and identify options in an increasingly precise way. To this respect, omics provided new exciting evidence on the molecular basis for asthma phenotyping. This may represent a way to develop “precision medicine” approaches. Today, immunologic molecular profile defines two subtypes of SRA. T helper type 2 cell high subtype (T2-high), described by serum ∗
biomarkers as eosinophils and immunoglobulin E (IgE), and the T helper type 2 cell low (T2-low) subtype, characterized by neutrophilic or paucigranulocytic inflammatory patterns. These evidences drove pharmacological research to discover novel biological therapies, which can be added to Bronchial Thermoplasty (BT) for SRA treatment. Omalizumab is the first biological for the treatment of severe allergic asthma. It is a recombinant humanized monoclonal anti-immunoglobulin E (IgE) antibody (mAb) that inhibits binding of IgE to high-affinity receptors expressed on mast cells and basophils [3]. Recently, new targeted treatment options for eosinophilic asthma have been introduced: mepolizumab, which binds to interleuckin 5 (IL-5) reducing peripheral blood and pulmonary eosinophils levels, and benralizumab targeted to IL-5 Receptor (IL-5R), which inhibits eosinophils via antibody-dependent cell-mediated cytotoxicity (ADCC) [4]. Among non-pharmacological options, BT is an endoscopic procedure based on the local delivery of radio frequency at 65 °C to the airways. It acts by changing the airway wall structure, through the reduction of the amount of smooth muscle with a device called Alair™ Catheter (Boston
Corresponding author. E-mail address: [email protected] (F. Menzella).
https://doi.org/10.1016/j.pupt.2019.101874 Received 17 September 2019; Received in revised form 28 November 2019; Accepted 9 December 2019 Available online 16 December 2019 1094-5539/ © 2019 Elsevier Ltd. All rights reserved.
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Scientific, Natick, MA, USA). The aim of this study was to provide a real-life description of SRA population by describing a cohort of patients affected by refractory asthma referring to Pneumology Unit of Azienda USL di Reggio Emilia/ IRCCS, Italy, and enrolled in the SANI registry (Severe Asthma Network Italy) [5]. Patients were selected based on the diagnosis of SRA according to European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines [6] and GINA 2018 classification [7]. It is an observational cross-sectional study, in which we investigated the proportion of patients with eligibility criteria for each biological and nonpharmacological treatment available in our site (omalizumab, mepolizumab, benralizumab and BT).
Table 1 Demographic and clinical characteristics: all patients. Demographic and Clinical Characteristics
2. Materials and methods 2.1. Ethical approval All patients included in this study were enrolled in the Italian asthma network SANI. The protocol for SANI network was approved by the Central Ethics Committee (Comitato Etico Area Vasta Nord-Ovest Toscana; study number: 1245/2016, protocol number: 73714) and the enrolment in our centre started after approval of the local ethics committee (Comitato Etico dell’Area Vasta Emilia Nord – Reggio Emilia 15/ 11/2017). This protocol was performed according to the Good Clinical Practice (ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996; Directive 91/507. EEC, The Rules Governing Medical Products in the European Community) and in accordance with the Italian laws (D.L.vo n.211 del 24 Giugno 2003; D.L.n.200 del 6 Novembre 2007; MD del 21 Dicembre 2007). 2.2. Study population In this retrospective, cross-sectional, observation study, patients aged > 12 years of age, affected by SRA according to ERS/ATS and GINA 2018 classifications [6,7], referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy from June 1st, 2017 to June 30th, 2019 were included. For each patients we collected: demographic data (age, gender, age of asthma onset, smoking history, presence of allergies, comorbidities); clinical data (lung function, exacerbations, emergency department -EDvisits and hospitalization); patient reported outcomes (asthma quality of life questionnaire - AQLQ, asthma control questionnaire - ACQ); serum biomarkers (blood eosinophils count and total serum IgE); and asthma medications (high-medium daily dose inhaled corticosteroids/ Long-acting β adrenoceptor agonists (ICS/LABA), long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), theophylline, oral corticosteroid (OCS), biological treatments: omalizumab, mepolizumab and benralizumab); and BT (Table 1). Patients who did not meet the diagnosis criteria for SRA following ERS/ATS 2014 and GINA 2018 classification were excluded from the study. The primary endpoint of this study was to describe the proportion of SRA patients complied with one or more anti-IgE or anti-IL5 monoclonal antibodies or BT. The cohort of patients was selected according to the eligibility criteria (Table 2) for each biological treatment. Specifically, omalizumab: age ≥6 ≤ 75 years; total serum IgE levels 76 ≤ IgE ≤1500 IU/L; ≥1 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months; positive result to the skin prick test or serum specific IgE for a perennial allergen; and a Forced Expiratory Volume (FEV1) < 80% pre-bronchodilator (pre-BD). Mepolizumab: age ≥18 years; high peripheral blood eosinophil count (≥150 cells/μl at screening or ≥300 cells/μl within 12 months prior to enrolment); and ≥2 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months. Benralizumab: age ≥18 ≤ 75 years; high peripheral blood eosinophil count (≥300 cells/μl in the previous 12 months before enrolment); and ≥2 asthma exacerbation requiring OCS,
No. of subject
137
Age Female, n(%)
55 ± 13,09 69 (50)
Age onset, mean (SD) Ex smokers, n(%)
34,69 ± 16,42 29 (22)
Atopics, n(%) Patients multi-sensitive
69 (50) 34 (25)
Lung function, pre-bronchodilator Prebronchodilator FEV1-%predicted, mean (SD)
67,26 ± 0,82
Prebronchodilator FVC-%predicted, mean (SD) Prebronchodilator FEV1/FVC, mean (SD) Asthma concomitant medication
84,98 ± 18,30 66,40 ± 12,75
Inhaled corticosteroid-beclometasone or equivalent μg/ day, mean (SD)
1036 ± 547
Oral corticosteroid-prednisone or the equivalent (mg) Patients taking LAMA, n(%) Patients taking LTRA, n(%) Patients taking theophylline, n(%)
6,97 ± 9,27 71 (52) 48 (35) 9 (0,6)
Patient taking oral corticosteroid therapy or more than 6 months per year -no.% Exacerbations/y, mean (SD) ED visits/hospitalizations/y, mean (SD) Patients reported outcome, mean (SD) AQLQ score ACQ score
74 (54)
Blood eosinophils mean (SD), cells/μl ≥150 cells/μl, n(%) ≥300 cells/μl, n(%) ≥400 cells/μl, n(%)
497 ± 551 97 (71) 75 (55) 56 (41)
Total IgE, KU/L, mean (SD)
427,09 ± 1131,76
Comorbidities CRSwNP, n(%)
54 (40)
Bronchiectasis, n(%)
43 (31)
GERD, n(%)
61 (44)
EGPA, n(%)
4 (3)
3,83 ± 2,81 0,66 ± 1,09 2,78 ± 0,90 3,6 ± 1.4
CRSwNP: Chronic rhinosinusitis with nasal polyp GERD: Gastro-Esophageal Reflux Disease EGPA: Eosinophilic Granulomatosis with Polyangiitis
ED or hospitalization in the previous 12 months. BT: age ≥18 years; ≥ 2 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months; and a FEV1 > 60% pre-BD. In addition, we evaluated the treatment overlap in the study population for each biological and non-pharmacological therapies (Fig. 1). Reslizumab and dupilumab were not considered because they were not yet available in Italy at the time of the study. We performed a stratification of all patient in sub-cohorts according to biological treatment and BT considering all the possible treatment switch, which was performed from one treatment to another. 2.3. Statistical analysis Statistical analysis was performed for all demographic and clinical characteristics of patient cohorts with Graph Pad Prism (Version 6). One-way ANOVA with Tukey's multiple comparison test were used to compare the mean scores of continuous data between patient cohorts in 2
Pulmonary Pharmacology & Therapeutics 60 (2020) 101874
3. Results
NA NA > 60
NA
treatment with omalizumab, mepolizumab, benralizumab and BT. Kruskal-Wallis with Dunn's multiple comparison test was performed in case of normality failed. We considered p-values statistically significant when p < 0.05. ≥18 ≥2
Bronchial Thermoplasty
F. Menzella, et al.
≥300 cells/μl in the previous 12 month NA NA NA ≥150 cells/μl at screening or ≥300 cells/μl within 12 months prior to enrollment NA NA NA NA
Overall, 137 patients with SRA according to ERS/ATS 2014 guidelines and GINA 2018 classification, referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy from June 1st, 2019 to June 30th, 2019 were enrolled in this study. Among these, 50% were female and the mean age was 55 years, range 16–79 (Table 1). The mean age of SRA onset was 34 years old, 50% of the study population was atopic, of which 25% was sensitive to more than one aero-allergen, and 54% was eosinophilic. An overlap among atopic and eosinophilic endotypes was present in 23% of patients. Of 137 patients, 29 (21%) were ex-smokers and pre-BD FEV1 was 62.26% of predicted. Regarding asthma concomitant medications, daily mean dose of ICS was 1036 mcg, and 71 (52%) patients took LAMA, 49 (36%) took LTRA and 54% of our study populations received maintenance OCS. 3.2. Eligibility criteria Of the 137 patients screened, 125 (91%) were eligible for at least one biologic and 94 (69%) were eligible for BT according to pulmonary function criteria (FEV1 > 60%). Among these, 6 could only be enrolled on BT (6%), 41 (43%) had eligible criteria both for omalizumab and BT treatment, while 47 (50%) patients were eligible both for mepolizumab, benralizumab and BT. Overlap of omalizumab, mepolizumab, benralizumab and BT was observed in 22 patients (16%). The amount of overlap between omalizumab, mepolizumab and benralizumab was 11 (8%). Only 10 patients were suitable candidates for omalizumab, 26 patients for benralizumab and 27 for mepolizumab. Six patients (4%) out of 137 did not meet any criteria for any SRA treatment. Among these patients, 4 had total IgE ≤30 kU/L and the eosinophils count was ≤150 cells/μl and FEV1 ≤ 60% (mean FEV1% was 41%); whereas 2 patients, although met total IgE criteria (≥30 kU/L), did not have perennial sensitisations and they did not reach lung functional and eosinophils blood criteria (Fig. 1).
≥76 and ≤1500 + < 80
≥18 and ≤75 ≥2 ≥18 ≥2 ≥18 and ≤75 ≥1
3.3. Description of asthma sub-cohorts stratified by biological and nonpharmacological treatment in clinical-practice We described the clinical-practice of our Centre (Fig. 2). Among the different therapies, 53 out of 137 patients (38%) were treated with omalizumab, 38 underwent BT (28%), 22 were enrolled on mepolizumab (16%) and 21 (15%) on benralizumab. Between patients in therapy with anti-IgE, 6 switched to BT, 2 shifted to mepolizumab and 2 to benralizumab. Only one patient switched from BT to benralizumab and 2 from BT to mepolizumab. Two patients double switched: from omalizumab to BT first, then to mepolizumab. When considering clinical-practice, patient baseline demographics were similar between the three biological treatments and BT. Omalizumab group included 43 patients, mepolizumab consists of 22 patients, benralizumab 21 and 38 patients underwent BT. The mean age onset for omalizumab group was 27.79, reflecting the large number of allergic asthma patients with early onset. There was no significant difference in age between other groups (p = 0.98). Female distributions were higher in the BT cohort (23, 60%) in view of only 8 (38%) in the benralizumab group. Exacerbations rates in the different groups were similar except for BT, in which the exacerbation rate was 5.26 ± 3.15 (p = 0.049 between BT versus omalizumab and p = 0.048 between BT and benralizumab). There was a statistically significant difference in
Total serum IgE levels (kU/l) Skin prick test or serum specific IgE for a perennial allergen Pre BD FEV1 (%)
Age (years) Asthma Exacerbation s requiring OCS, ER or hospitalization in the previous 12 months Peripheral blood eosinophil count (cells/μl)
Criteria
Table 2 Eligibility criteria for asthma therapies.
THERAPIES
Benralizumab Mepolizumab Omalizumab
3.1. Study population: demographic results
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Fig. 1. Overlap of study population stratified on the basis of eligibility criteria for biological and non-pharmacological therapies.
The combination of these data allows to identify a specific inflammatory and clinical phenotype to targeted biological or non-pharmacological therapies [8]. In our cross-section study, we described an SRA population and we reported the characteristics of patients at the time of enrolment until the start of treatments. Other real-life studies identified and analysed asthma patients potentially eligible for biologicals, such as anti-IL5 (mepolizumab, reslizumab), anti-IL5Rα (benralizumab), and anti-IgE (omalizumab) [9,10]. This study adds news insights and, to our knowledge, takes into account BT for the first time. Difficulties in stratification of our study population by eligibility criteria were met, as biological therapies are well established based on serum biomarkers; whereas, no biomarker is yet available in BT. In fact, in the BT cohort, patients were selected based on pulmonary function only (FEV1 > 60%) (Table 1), following AIR1 trial inclusion criteria [11]. Consequently, we identified a large population admissible to BT (70%). In this study, eligibility criteria for BT only included patients with FEV1 > 60%, based on the enrolment criteria of the AIR2 trial. This was applied in order to maintain homogeneity with the indications of the pivotal trial. Recent studies applied other eligibility criteria, such as FEV1 < 50% [12]. These are very recent data on a small population. It should be necessary to evaluate the safety and efficacy of BT on seriously compromised patients through multicentre studies, with longer observation periods. The criteria for biological therapies and for BT led to the identification of 24% patients eligible for all biologic drugs, whereas mepolizumab and benralizumab included almost half of our asthma patients (55%). Only 6 patients had no criteria for any available SRA treatments (4%), in contrast with the IDEAL study findings, where a substantial slice of patients (65–76%) were not eligible for any biological drugs. These relevant differences may be linked to the presence of BT as an additional therapeutic option in our clinical practice.
the rate of ED visits/hospitalizations particularly between benralizumab and BT groups (p = 0.005). In our clinical-practice, serum biomarkers such as IgE levels varied between groups according to eligibility criteria for biological and BT treatment. In detail, the total IgE mean value was 692.53 IU/mL in the omalizumab group compared to 384.68 IU/ml in the mepolizumab group and 706.91 IU/ml in the benralizumab group. Notably, there was a statistically significant difference in total IgE between biological groups and BT, omalizumab and mepolizumab (p = 0.0006), omalizumab and benralizumab (p = 0.0003), and omalizumab versus BT (p < 0.0001). As expected, blood eosinophils count was higher in mepolizumab and benralizumab group as compared to BT (p = 0.0054). There was no statistically significant difference in peripheral eosinophils levels between omalizumab versus mepolizumab and benralizumab (p = 0.08) (Table 3). The most clinically-relevant comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and EGPA. Interestingly, the prevalence of bronchiectasis is much higher in the mepolizumab group (45%) and benralizumab (43%) than in omalizumab (9%) and BT (7%), pvalue < 0,001. Whereas, CRSwNP and GERD were equally present in the different groups and EGPA was only present in the mepolizumab group. The absolute percentage of bronchiectasis in the examined population was 26%.
4. Discussion The availability of different therapeutic approaches implies a new perspective in the management of asthma patients, based not only on clinical evaluation, but also on the identification of specific target inflammatory mediators such as IgE, blood and sputum eosinophils, airway remodelling, fractional exhaled nitric oxide (FeNO) and so on. 4
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Fig. 2. State of art: asthma sub-cohorts stratified by biological and non-pharmacological treatments in real practice. Table 3 Demographic and clinical characteristics: treatment-based sub-cohorts. Omalizumab
Mepolizumab
Benralizumab
Bronchial Thermplasty
Patients, n
43
22
21
38
Age onset, years, mean (SD)
27,79 ± 19,32
37,04 ± 15,86
35,50 ± 16,48
36,55 ± 13,24
Gender, female, n(%) Exacerbations/y, mean ED visit(S)/hospitalizations(S)/y, mean
16(37) 3,14 ± 1,47 0,5 ± 0,7
12(54) 3,63 ± 2,73 0,9 ± 1,39
8(38) 3.28 ± 2.19 0.23 ± 0.53
23(60) 5,26 ± 3,15 1,13 ± 1,47
% predicted FEV1, mean (SD) % predicted FVC,mean (SD) FEV1/FVC, mean (SD)
64,83 ± 13,06 83,41 ± 17,37 65,04 ± 10,71
67,19 ± 16,07 82,76 ± 16,14 66,36 ± 9,72
60,37 ± 19,70 80,58 ± 19,63 64,59 ± 11,24
60,81 ± 19,04 81,70 ± 18,75 65,44 ± 13,67
≥400 Eo/μl, n(%)
13(30)
17(77)
15(71)
9(23)
≥300 Eo/μl, n(%) ≥150 Eo/μl, n(%) Total IgE, kU/L mean (SD)
25 (58) 31(72) 692,53 ± 1088,72
20 (90) 22(100) 384,68 ± 900,67
19 (91) 21(100) 706,81 ± 2199,34
13(34) 20(53) 140,78 ± 160,66
CRSwNP, n(%)
17(39)
12(55)
10(47)
11(29)
Bronchiectasis, n(%) GERD, n(%) EGPA, n(%)
4(9) 15(35) 0(0)
10(45) 11(50) 3(14)
9(43) 8(38) 0(0)
3(7) 20(53) 0(0)
Notably, 6 (4%) patients had inclusion criteria for BT only, whereas, in real-life 38 (28%) patients were actually treated with BT. This discrepancy may be explained by the fact that, when a monoclonal antibody failed or when patients refuse a pharmacological lifetime therapy, BT represented a worthwhile therapeutic choice for the physician. In addition, it has to be taken into consideration that, when our centre started BT treatment, omalizumab was the only available biologic for
Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. We found a proportion of 24% of patients eligible for anti-IL5 and anti-IgE, this was in line with the IDEAL study (27–37%) [9] and in contrast with another reallife study [10], in which 37 patients (29%) were eligible for all the considered biologics.
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Data availability
SRA [13]. Real practice data of our cohort reflected eligibility criteria per each treatment. Considering the baseline severity of asthma, BT group had higher number of ED visits and exacerbations than other groups. Age onset is lower in omalizumab group than the others, while pulmonary function is similar among each cohort. It is important to note that the total IgE value was higher in patients treated with omalizumab compared to those eligible for mepolizumab, and even higher in the group eligible for benralizumab. This finding can be explained by the presence of atopy in these subjects. In this regard, recent data showed that benralizumab decreased exacerbations and improved lung function regardless of serum IgE concentrations and atopy status [14]. The most prevalent comorbidities were bronchiectasis, CRSwNP, and GERD. Especially with regard to bronchiectasis, the percentage that emerged from our group (26%) is much higher than the SANI data (16%) [5]. SRA associated with bronchiectasis is an emerging phenotype, and bronchiectasis were more frequent in the group of patients undergoing biological therapy for eosinophilic asthma (mepolizumab and benralizumab). This could be explained by a higher number of patients undergoing high-resolution chest CT scan. It also confirms recent data in which real prevalence of this comorbidity in SRA patients may vary in a wide range [15,16]. The exclusive presence of patients with EGPA in the mepolizumab group may be linked to a higher evidence available on this drug, as compared to the benralizumab group. In fact, mepolizumab was introduced as an add-on therapeutic agent in refractory or relapsing EGPA, with promising results on asthma symptoms as well as systemic vasculitis manifestations. It might improve the rate of remission, decreases relapse rate, and allow for reduced glucocorticoid use [17]. Patients who underwent BT (Table 3) had low level of eosinophils and obstructive pulmonary disease, which reflects the T2-low subtype of asthma characterized by neutrophilic or paucigranulocytic airway inflammation [18]. This study has some limitations linked to the retrospective nature of the study and the single centre experience. We performed a retrospective chart review, which is influenced by data availability. In order to reduce biases, we performed a systematic chart abstraction using a standardized data collection form and used stated universally accepted (ERS/ATS) criteria to define our variables. Furthermore, we performed a stratification of the real-life SRA population which is challenging to assimilate to the general population worldwide. This study, in addition to the real-life data present in the literature and in the SRA registers, may allow to better define the epidemiology and the correct selection of patients eligible for biological and BT treatments. The analysis of a large number of homogeneous cases treated in a single Center allows to provide realistic and coherent data that can help clinicians in the choice of treatment, which sometimes is not easy. The study population was eligible for biologicals in almost all cases, and in a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of more therapeutic choices and reiterates the need for a correct characterization of patients, which could be made through the use of biomarkers. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient. In addition, the possibility to carry out a close follow-up thanks to the enrolment in a registry, and to improve the identification of possible comorbidities such as bronchiectasis, allows the clinician to better manage this complex pathology. This may be considered as a “best-practice” example. Furthermore, the advent of a variety of biological therapies added to BT provided to the physician more powerful resources for SRA patients, but increasingly greater knowledge and expertise will be needed for a proper management and to choose the right option for the right patient.
The dataset used to support the findings of this study is available from the corresponding author upon reasoned request. Funding statement The authors received no specific funding for this work. CRediT authorship contribution statement Francesco Menzella: Conceptualization, Methodology, Writing original draft. Carla Galeone: Data curation, Software, Writing - original draft. Patrizia Ruggiero: Data curation, Software. Diego Bagnasco: Writing - review & editing. Chiara Catellani: Software, Writing - review & editing. Nicola Facciolongo: Supervision, Writing review & editing. Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this article. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.pupt.2019.101874. References [1] T.F. Carr, A.A. Zeki, M. Kraft, Eosinophilic and non-eosinophilic asthma, Am. J. Respir. Crit. Care Med. 197 (2018) 22–37. [2] J. Lotvall, C.A. Akdis, L.B. Bacharier, et al., Asthma endotypes: a new approach to classificationof disease entities within the asthma syndrome, J. Allergy Clin. Immunol. 127 (2011) 355–360. [3] J. CorrenNew, Targeted therapies for uncontrolled asthma, J. Allergy Clin. Immunol. Pract. 5 (2019) 1394–1403. [4] D. Bagnasco, M. Caminati, M. Ferrando, T. Aloè, E. Testino, G.W. Canonica, et al., Anti-IL-5 and IL-5Ra: efficacy and safety of new therapeutic strategies in severe uncontrolled asthma, BioMed Res. Int. (2018) 5698212. [5] E. Heffler, F. Blasi, M. Latorre, et al., The severe asthma network in Italy: findings and perspectives, J. Allergy Clin. Immunol. Pract. 7 (2019) 1462-146. [6] K.F. Chung, S.E. Wenzel, J.L. Brozek, et al., International ERS/ATS guidelines on definition, evaluation and the treatment of severe asthma”, Eur. Respir. J. 43 (2014) 343–373. [7] https://ginasthma.org/wp/2018/11/GINA-SA-FINAL-wms.pdf , Accessed date: 16 June 2019. [8] F. Menzella, F. Bertolini, M. Biava M, C. Galeone, C. Scelfo, M. Caminati, Severe refractory asthma: current treatment options and ongoing research, Drugs Context 7 (2018) 212561. [9] F.C. Albers, H. Mullerovà, N.B. Gunsoy NB, et al., Biologic treatment eligibility for real-world patients with seer asthma: the IDEAL study, J. Asthma 55 (2018) 152–160. [10] S. Jeimy, M.W. Tsoulis, J. Hachey, et al., Eligibility of monoclonal antibody-based therapy for patients with severe asthma: a Canadian cross-sectional perspective, Allergy Asthma Clin. Immunol. 14 (2018) 68. [11] M. Castro, A.S. Rubin, M. Laviolette, et al., Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, doubleblind, sham-controlled clinical trial, Am. J. Respir. Crit. Care Med. 181 (2010) 116–124. [12] D. Langton, A. Ing, D. Fielding, et al., Safety and effectiveness of bronchial thermoplasty when FEV1 is less than 50, Chest (2019 Sep 13) pii: S0012-3692(19) 33753-5.. [13] N. Facciolongo N, A. Di Stefano, V. Pietrini, et al., Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma, BMC Pulm. Med. 18 (2018) 29. [14] B.E. Chipps, P. Newbold, I. Hirsch, F. Trudo, M. Goldman, Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma, Ann. Allergy Asthma Immunol. 120 (2018) 504–511. [15] A. Padilla-Galo, C. Olveira, L. Fernández de Rota-Garcia, et al., Factors associated with bronchiectasis in patients with uncontrolled asthma; the NOPES score: a study in 398 patients, Respir. Res. 19 (2018) 43. [16] M. García-Clemente, A.L. Enríquez-Rodríguez, M. Iscar-Urrutia, et al., Severe asthma and bronchiectasis, J. Asthma 1 (2019) 5. [17] D. Ennis, J.K. Lee, C. Pagnoux, Mepolizumab for the treatment of eosinophilic granulomatosis with polyangiitis, Expert Opin. Biol. Ther. 19 (2019) 617–630. [18] L. Swedin, T. Saarne, M. Rehnberg, et al., Patient stratification and unmet need in asthma, Pharmacol. Ther. 169 (2017) 13–34.
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Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: From eligibility criteria to real practice. A cross-sectional study
T
Francesco Menzellaa,∗, Carla Galeonea, Patrizia Ruggieroa, Diego Bagnascob, Chiara Catellania, Nicola Facciolongoa a b
Department of Medical Specialties, Pneumology Unit, Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia- IRCCS, 42123, Reggio Emilia, Italy Allergy & Respiratory Diseases, University of Genoa, 16132, Genoa, Italy
A B S T R A C T
The increasing knowledge on immuno-inflammatory pathways allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). It is therefore very important to accurately identify phenotypes and endotypes of patients potentially eligible for innovative treatments. The aim of this study was to describe a cohort of patients affected by SRA referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy. It is an observational cross-sectional study, investigating the proportion of subjects with eligibility criteria for biological treatments (omalizumab, mepolizumab, benralizumab) and nonpharmacological treatment (bronchial thermoplasty, BT). We enrolled 137 patients with SRA referring to the centre from June 1st, 2017 to June 30th, 2019. The results of this study showed that 125 (91%) of patients were eligible for at least one biologic and 94 (69%) were eligible for BT. Only 6 (4%) of patients had no criteria for any available SRA treatments. Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. Considering eligibility criteria for BT, only 6 (4%) patients had inclusion criteria for BT, instead in real life 28% of patients were treated with BT. The major comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and eosinophilic granulomatosis with polyangiitis (EGPA). The prevalence of bronchiectasis was much higher in the mepolizumab (45%) and benralizumab (43%) groups than in omalizumab (1%) and BT (7%), p < 0,001; CRSwNP and GERD were equally present and EGPA was only present in the mepolizumab group. Overall, our population was eligible for biologicals in almost all cases, and a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of different therapeutic options and reiterates the need for a correct characterization of patients. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient.
1. Introduction In recent years, the evolution of knowledge allowed the development of new therapeutic options in the field of severe refractory asthma (SRA). For this reason, it is very important to better define the classification of SRA and its subtypes. These are classified into phenotypes, referring to the observable characteristics of the disease in an individual, and in endotypes, the specific biological mechanisms that cause those observed properties of a given phenotype [1,2]. Determining phenotypes and endotypes is a key point, particularly when selecting a targeted biological drug or other immunomodulatory therapies. Hence, there is the need for new biomarkers, especially predictive ones, which will help the clinicians to better select patients and identify options in an increasingly precise way. To this respect, omics provided new exciting evidence on the molecular basis for asthma phenotyping. This may represent a way to develop “precision medicine” approaches. Today, immunologic molecular profile defines two subtypes of SRA. T helper type 2 cell high subtype (T2-high), described by serum ∗
biomarkers as eosinophils and immunoglobulin E (IgE), and the T helper type 2 cell low (T2-low) subtype, characterized by neutrophilic or paucigranulocytic inflammatory patterns. These evidences drove pharmacological research to discover novel biological therapies, which can be added to Bronchial Thermoplasty (BT) for SRA treatment. Omalizumab is the first biological for the treatment of severe allergic asthma. It is a recombinant humanized monoclonal anti-immunoglobulin E (IgE) antibody (mAb) that inhibits binding of IgE to high-affinity receptors expressed on mast cells and basophils [3]. Recently, new targeted treatment options for eosinophilic asthma have been introduced: mepolizumab, which binds to interleuckin 5 (IL-5) reducing peripheral blood and pulmonary eosinophils levels, and benralizumab targeted to IL-5 Receptor (IL-5R), which inhibits eosinophils via antibody-dependent cell-mediated cytotoxicity (ADCC) [4]. Among non-pharmacological options, BT is an endoscopic procedure based on the local delivery of radio frequency at 65 °C to the airways. It acts by changing the airway wall structure, through the reduction of the amount of smooth muscle with a device called Alair™ Catheter (Boston
Corresponding author. E-mail address: [email protected] (F. Menzella).
https://doi.org/10.1016/j.pupt.2019.101874 Received 17 September 2019; Received in revised form 28 November 2019; Accepted 9 December 2019 Available online 16 December 2019 1094-5539/ © 2019 Elsevier Ltd. All rights reserved.
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Scientific, Natick, MA, USA). The aim of this study was to provide a real-life description of SRA population by describing a cohort of patients affected by refractory asthma referring to Pneumology Unit of Azienda USL di Reggio Emilia/ IRCCS, Italy, and enrolled in the SANI registry (Severe Asthma Network Italy) [5]. Patients were selected based on the diagnosis of SRA according to European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines [6] and GINA 2018 classification [7]. It is an observational cross-sectional study, in which we investigated the proportion of patients with eligibility criteria for each biological and nonpharmacological treatment available in our site (omalizumab, mepolizumab, benralizumab and BT).
Table 1 Demographic and clinical characteristics: all patients. Demographic and Clinical Characteristics
2. Materials and methods 2.1. Ethical approval All patients included in this study were enrolled in the Italian asthma network SANI. The protocol for SANI network was approved by the Central Ethics Committee (Comitato Etico Area Vasta Nord-Ovest Toscana; study number: 1245/2016, protocol number: 73714) and the enrolment in our centre started after approval of the local ethics committee (Comitato Etico dell’Area Vasta Emilia Nord – Reggio Emilia 15/ 11/2017). This protocol was performed according to the Good Clinical Practice (ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996; Directive 91/507. EEC, The Rules Governing Medical Products in the European Community) and in accordance with the Italian laws (D.L.vo n.211 del 24 Giugno 2003; D.L.n.200 del 6 Novembre 2007; MD del 21 Dicembre 2007). 2.2. Study population In this retrospective, cross-sectional, observation study, patients aged > 12 years of age, affected by SRA according to ERS/ATS and GINA 2018 classifications [6,7], referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy from June 1st, 2017 to June 30th, 2019 were included. For each patients we collected: demographic data (age, gender, age of asthma onset, smoking history, presence of allergies, comorbidities); clinical data (lung function, exacerbations, emergency department -EDvisits and hospitalization); patient reported outcomes (asthma quality of life questionnaire - AQLQ, asthma control questionnaire - ACQ); serum biomarkers (blood eosinophils count and total serum IgE); and asthma medications (high-medium daily dose inhaled corticosteroids/ Long-acting β adrenoceptor agonists (ICS/LABA), long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), theophylline, oral corticosteroid (OCS), biological treatments: omalizumab, mepolizumab and benralizumab); and BT (Table 1). Patients who did not meet the diagnosis criteria for SRA following ERS/ATS 2014 and GINA 2018 classification were excluded from the study. The primary endpoint of this study was to describe the proportion of SRA patients complied with one or more anti-IgE or anti-IL5 monoclonal antibodies or BT. The cohort of patients was selected according to the eligibility criteria (Table 2) for each biological treatment. Specifically, omalizumab: age ≥6 ≤ 75 years; total serum IgE levels 76 ≤ IgE ≤1500 IU/L; ≥1 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months; positive result to the skin prick test or serum specific IgE for a perennial allergen; and a Forced Expiratory Volume (FEV1) < 80% pre-bronchodilator (pre-BD). Mepolizumab: age ≥18 years; high peripheral blood eosinophil count (≥150 cells/μl at screening or ≥300 cells/μl within 12 months prior to enrolment); and ≥2 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months. Benralizumab: age ≥18 ≤ 75 years; high peripheral blood eosinophil count (≥300 cells/μl in the previous 12 months before enrolment); and ≥2 asthma exacerbation requiring OCS,
No. of subject
137
Age Female, n(%)
55 ± 13,09 69 (50)
Age onset, mean (SD) Ex smokers, n(%)
34,69 ± 16,42 29 (22)
Atopics, n(%) Patients multi-sensitive
69 (50) 34 (25)
Lung function, pre-bronchodilator Prebronchodilator FEV1-%predicted, mean (SD)
67,26 ± 0,82
Prebronchodilator FVC-%predicted, mean (SD) Prebronchodilator FEV1/FVC, mean (SD) Asthma concomitant medication
84,98 ± 18,30 66,40 ± 12,75
Inhaled corticosteroid-beclometasone or equivalent μg/ day, mean (SD)
1036 ± 547
Oral corticosteroid-prednisone or the equivalent (mg) Patients taking LAMA, n(%) Patients taking LTRA, n(%) Patients taking theophylline, n(%)
6,97 ± 9,27 71 (52) 48 (35) 9 (0,6)
Patient taking oral corticosteroid therapy or more than 6 months per year -no.% Exacerbations/y, mean (SD) ED visits/hospitalizations/y, mean (SD) Patients reported outcome, mean (SD) AQLQ score ACQ score
74 (54)
Blood eosinophils mean (SD), cells/μl ≥150 cells/μl, n(%) ≥300 cells/μl, n(%) ≥400 cells/μl, n(%)
497 ± 551 97 (71) 75 (55) 56 (41)
Total IgE, KU/L, mean (SD)
427,09 ± 1131,76
Comorbidities CRSwNP, n(%)
54 (40)
Bronchiectasis, n(%)
43 (31)
GERD, n(%)
61 (44)
EGPA, n(%)
4 (3)
3,83 ± 2,81 0,66 ± 1,09 2,78 ± 0,90 3,6 ± 1.4
CRSwNP: Chronic rhinosinusitis with nasal polyp GERD: Gastro-Esophageal Reflux Disease EGPA: Eosinophilic Granulomatosis with Polyangiitis
ED or hospitalization in the previous 12 months. BT: age ≥18 years; ≥ 2 asthma exacerbation requiring OCS, ED or hospitalization in the previous 12 months; and a FEV1 > 60% pre-BD. In addition, we evaluated the treatment overlap in the study population for each biological and non-pharmacological therapies (Fig. 1). Reslizumab and dupilumab were not considered because they were not yet available in Italy at the time of the study. We performed a stratification of all patient in sub-cohorts according to biological treatment and BT considering all the possible treatment switch, which was performed from one treatment to another. 2.3. Statistical analysis Statistical analysis was performed for all demographic and clinical characteristics of patient cohorts with Graph Pad Prism (Version 6). One-way ANOVA with Tukey's multiple comparison test were used to compare the mean scores of continuous data between patient cohorts in 2
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3. Results
NA NA > 60
NA
treatment with omalizumab, mepolizumab, benralizumab and BT. Kruskal-Wallis with Dunn's multiple comparison test was performed in case of normality failed. We considered p-values statistically significant when p < 0.05. ≥18 ≥2
Bronchial Thermoplasty
F. Menzella, et al.
≥300 cells/μl in the previous 12 month NA NA NA ≥150 cells/μl at screening or ≥300 cells/μl within 12 months prior to enrollment NA NA NA NA
Overall, 137 patients with SRA according to ERS/ATS 2014 guidelines and GINA 2018 classification, referring to the Pneumology Unit of Azienda USL di Reggio Emilia/IRCCS in Reggio Emilia, Italy from June 1st, 2019 to June 30th, 2019 were enrolled in this study. Among these, 50% were female and the mean age was 55 years, range 16–79 (Table 1). The mean age of SRA onset was 34 years old, 50% of the study population was atopic, of which 25% was sensitive to more than one aero-allergen, and 54% was eosinophilic. An overlap among atopic and eosinophilic endotypes was present in 23% of patients. Of 137 patients, 29 (21%) were ex-smokers and pre-BD FEV1 was 62.26% of predicted. Regarding asthma concomitant medications, daily mean dose of ICS was 1036 mcg, and 71 (52%) patients took LAMA, 49 (36%) took LTRA and 54% of our study populations received maintenance OCS. 3.2. Eligibility criteria Of the 137 patients screened, 125 (91%) were eligible for at least one biologic and 94 (69%) were eligible for BT according to pulmonary function criteria (FEV1 > 60%). Among these, 6 could only be enrolled on BT (6%), 41 (43%) had eligible criteria both for omalizumab and BT treatment, while 47 (50%) patients were eligible both for mepolizumab, benralizumab and BT. Overlap of omalizumab, mepolizumab, benralizumab and BT was observed in 22 patients (16%). The amount of overlap between omalizumab, mepolizumab and benralizumab was 11 (8%). Only 10 patients were suitable candidates for omalizumab, 26 patients for benralizumab and 27 for mepolizumab. Six patients (4%) out of 137 did not meet any criteria for any SRA treatment. Among these patients, 4 had total IgE ≤30 kU/L and the eosinophils count was ≤150 cells/μl and FEV1 ≤ 60% (mean FEV1% was 41%); whereas 2 patients, although met total IgE criteria (≥30 kU/L), did not have perennial sensitisations and they did not reach lung functional and eosinophils blood criteria (Fig. 1).
≥76 and ≤1500 + < 80
≥18 and ≤75 ≥2 ≥18 ≥2 ≥18 and ≤75 ≥1
3.3. Description of asthma sub-cohorts stratified by biological and nonpharmacological treatment in clinical-practice We described the clinical-practice of our Centre (Fig. 2). Among the different therapies, 53 out of 137 patients (38%) were treated with omalizumab, 38 underwent BT (28%), 22 were enrolled on mepolizumab (16%) and 21 (15%) on benralizumab. Between patients in therapy with anti-IgE, 6 switched to BT, 2 shifted to mepolizumab and 2 to benralizumab. Only one patient switched from BT to benralizumab and 2 from BT to mepolizumab. Two patients double switched: from omalizumab to BT first, then to mepolizumab. When considering clinical-practice, patient baseline demographics were similar between the three biological treatments and BT. Omalizumab group included 43 patients, mepolizumab consists of 22 patients, benralizumab 21 and 38 patients underwent BT. The mean age onset for omalizumab group was 27.79, reflecting the large number of allergic asthma patients with early onset. There was no significant difference in age between other groups (p = 0.98). Female distributions were higher in the BT cohort (23, 60%) in view of only 8 (38%) in the benralizumab group. Exacerbations rates in the different groups were similar except for BT, in which the exacerbation rate was 5.26 ± 3.15 (p = 0.049 between BT versus omalizumab and p = 0.048 between BT and benralizumab). There was a statistically significant difference in
Total serum IgE levels (kU/l) Skin prick test or serum specific IgE for a perennial allergen Pre BD FEV1 (%)
Age (years) Asthma Exacerbation s requiring OCS, ER or hospitalization in the previous 12 months Peripheral blood eosinophil count (cells/μl)
Criteria
Table 2 Eligibility criteria for asthma therapies.
THERAPIES
Benralizumab Mepolizumab Omalizumab
3.1. Study population: demographic results
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Fig. 1. Overlap of study population stratified on the basis of eligibility criteria for biological and non-pharmacological therapies.
The combination of these data allows to identify a specific inflammatory and clinical phenotype to targeted biological or non-pharmacological therapies [8]. In our cross-section study, we described an SRA population and we reported the characteristics of patients at the time of enrolment until the start of treatments. Other real-life studies identified and analysed asthma patients potentially eligible for biologicals, such as anti-IL5 (mepolizumab, reslizumab), anti-IL5Rα (benralizumab), and anti-IgE (omalizumab) [9,10]. This study adds news insights and, to our knowledge, takes into account BT for the first time. Difficulties in stratification of our study population by eligibility criteria were met, as biological therapies are well established based on serum biomarkers; whereas, no biomarker is yet available in BT. In fact, in the BT cohort, patients were selected based on pulmonary function only (FEV1 > 60%) (Table 1), following AIR1 trial inclusion criteria [11]. Consequently, we identified a large population admissible to BT (70%). In this study, eligibility criteria for BT only included patients with FEV1 > 60%, based on the enrolment criteria of the AIR2 trial. This was applied in order to maintain homogeneity with the indications of the pivotal trial. Recent studies applied other eligibility criteria, such as FEV1 < 50% [12]. These are very recent data on a small population. It should be necessary to evaluate the safety and efficacy of BT on seriously compromised patients through multicentre studies, with longer observation periods. The criteria for biological therapies and for BT led to the identification of 24% patients eligible for all biologic drugs, whereas mepolizumab and benralizumab included almost half of our asthma patients (55%). Only 6 patients had no criteria for any available SRA treatments (4%), in contrast with the IDEAL study findings, where a substantial slice of patients (65–76%) were not eligible for any biological drugs. These relevant differences may be linked to the presence of BT as an additional therapeutic option in our clinical practice.
the rate of ED visits/hospitalizations particularly between benralizumab and BT groups (p = 0.005). In our clinical-practice, serum biomarkers such as IgE levels varied between groups according to eligibility criteria for biological and BT treatment. In detail, the total IgE mean value was 692.53 IU/mL in the omalizumab group compared to 384.68 IU/ml in the mepolizumab group and 706.91 IU/ml in the benralizumab group. Notably, there was a statistically significant difference in total IgE between biological groups and BT, omalizumab and mepolizumab (p = 0.0006), omalizumab and benralizumab (p = 0.0003), and omalizumab versus BT (p < 0.0001). As expected, blood eosinophils count was higher in mepolizumab and benralizumab group as compared to BT (p = 0.0054). There was no statistically significant difference in peripheral eosinophils levels between omalizumab versus mepolizumab and benralizumab (p = 0.08) (Table 3). The most clinically-relevant comorbidities were: bronchiectasis, chronic rhinosinusitis with nasal polyps (CRSwNP), gastro-esophageal reflux disease (GERD), and EGPA. Interestingly, the prevalence of bronchiectasis is much higher in the mepolizumab group (45%) and benralizumab (43%) than in omalizumab (9%) and BT (7%), pvalue < 0,001. Whereas, CRSwNP and GERD were equally present in the different groups and EGPA was only present in the mepolizumab group. The absolute percentage of bronchiectasis in the examined population was 26%.
4. Discussion The availability of different therapeutic approaches implies a new perspective in the management of asthma patients, based not only on clinical evaluation, but also on the identification of specific target inflammatory mediators such as IgE, blood and sputum eosinophils, airway remodelling, fractional exhaled nitric oxide (FeNO) and so on. 4
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Fig. 2. State of art: asthma sub-cohorts stratified by biological and non-pharmacological treatments in real practice. Table 3 Demographic and clinical characteristics: treatment-based sub-cohorts. Omalizumab
Mepolizumab
Benralizumab
Bronchial Thermplasty
Patients, n
43
22
21
38
Age onset, years, mean (SD)
27,79 ± 19,32
37,04 ± 15,86
35,50 ± 16,48
36,55 ± 13,24
Gender, female, n(%) Exacerbations/y, mean ED visit(S)/hospitalizations(S)/y, mean
16(37) 3,14 ± 1,47 0,5 ± 0,7
12(54) 3,63 ± 2,73 0,9 ± 1,39
8(38) 3.28 ± 2.19 0.23 ± 0.53
23(60) 5,26 ± 3,15 1,13 ± 1,47
% predicted FEV1, mean (SD) % predicted FVC,mean (SD) FEV1/FVC, mean (SD)
64,83 ± 13,06 83,41 ± 17,37 65,04 ± 10,71
67,19 ± 16,07 82,76 ± 16,14 66,36 ± 9,72
60,37 ± 19,70 80,58 ± 19,63 64,59 ± 11,24
60,81 ± 19,04 81,70 ± 18,75 65,44 ± 13,67
≥400 Eo/μl, n(%)
13(30)
17(77)
15(71)
9(23)
≥300 Eo/μl, n(%) ≥150 Eo/μl, n(%) Total IgE, kU/L mean (SD)
25 (58) 31(72) 692,53 ± 1088,72
20 (90) 22(100) 384,68 ± 900,67
19 (91) 21(100) 706,81 ± 2199,34
13(34) 20(53) 140,78 ± 160,66
CRSwNP, n(%)
17(39)
12(55)
10(47)
11(29)
Bronchiectasis, n(%) GERD, n(%) EGPA, n(%)
4(9) 15(35) 0(0)
10(45) 11(50) 3(14)
9(43) 8(38) 0(0)
3(7) 20(53) 0(0)
Notably, 6 (4%) patients had inclusion criteria for BT only, whereas, in real-life 38 (28%) patients were actually treated with BT. This discrepancy may be explained by the fact that, when a monoclonal antibody failed or when patients refuse a pharmacological lifetime therapy, BT represented a worthwhile therapeutic choice for the physician. In addition, it has to be taken into consideration that, when our centre started BT treatment, omalizumab was the only available biologic for
Among biologics, there were only 11 (8%) patients resulting in overlap between omalizumab, mepolizumab and benralizumab, and 22 (16%) overlap of patients when BT was included. We found a proportion of 24% of patients eligible for anti-IL5 and anti-IgE, this was in line with the IDEAL study (27–37%) [9] and in contrast with another reallife study [10], in which 37 patients (29%) were eligible for all the considered biologics.
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Data availability
SRA [13]. Real practice data of our cohort reflected eligibility criteria per each treatment. Considering the baseline severity of asthma, BT group had higher number of ED visits and exacerbations than other groups. Age onset is lower in omalizumab group than the others, while pulmonary function is similar among each cohort. It is important to note that the total IgE value was higher in patients treated with omalizumab compared to those eligible for mepolizumab, and even higher in the group eligible for benralizumab. This finding can be explained by the presence of atopy in these subjects. In this regard, recent data showed that benralizumab decreased exacerbations and improved lung function regardless of serum IgE concentrations and atopy status [14]. The most prevalent comorbidities were bronchiectasis, CRSwNP, and GERD. Especially with regard to bronchiectasis, the percentage that emerged from our group (26%) is much higher than the SANI data (16%) [5]. SRA associated with bronchiectasis is an emerging phenotype, and bronchiectasis were more frequent in the group of patients undergoing biological therapy for eosinophilic asthma (mepolizumab and benralizumab). This could be explained by a higher number of patients undergoing high-resolution chest CT scan. It also confirms recent data in which real prevalence of this comorbidity in SRA patients may vary in a wide range [15,16]. The exclusive presence of patients with EGPA in the mepolizumab group may be linked to a higher evidence available on this drug, as compared to the benralizumab group. In fact, mepolizumab was introduced as an add-on therapeutic agent in refractory or relapsing EGPA, with promising results on asthma symptoms as well as systemic vasculitis manifestations. It might improve the rate of remission, decreases relapse rate, and allow for reduced glucocorticoid use [17]. Patients who underwent BT (Table 3) had low level of eosinophils and obstructive pulmonary disease, which reflects the T2-low subtype of asthma characterized by neutrophilic or paucigranulocytic airway inflammation [18]. This study has some limitations linked to the retrospective nature of the study and the single centre experience. We performed a retrospective chart review, which is influenced by data availability. In order to reduce biases, we performed a systematic chart abstraction using a standardized data collection form and used stated universally accepted (ERS/ATS) criteria to define our variables. Furthermore, we performed a stratification of the real-life SRA population which is challenging to assimilate to the general population worldwide. This study, in addition to the real-life data present in the literature and in the SRA registers, may allow to better define the epidemiology and the correct selection of patients eligible for biological and BT treatments. The analysis of a large number of homogeneous cases treated in a single Center allows to provide realistic and coherent data that can help clinicians in the choice of treatment, which sometimes is not easy. The study population was eligible for biologicals in almost all cases, and in a significant percentage of patients showed the presence of an overlap of allergic and eosinophilic endotypes. This implies the possibility of more therapeutic choices and reiterates the need for a correct characterization of patients, which could be made through the use of biomarkers. This study confirmed how the identification of inflammatory endotypes and phenotypes represent a key role in the selection of the right therapy for the right patient. In addition, the possibility to carry out a close follow-up thanks to the enrolment in a registry, and to improve the identification of possible comorbidities such as bronchiectasis, allows the clinician to better manage this complex pathology. This may be considered as a “best-practice” example. Furthermore, the advent of a variety of biological therapies added to BT provided to the physician more powerful resources for SRA patients, but increasingly greater knowledge and expertise will be needed for a proper management and to choose the right option for the right patient.
The dataset used to support the findings of this study is available from the corresponding author upon reasoned request. Funding statement The authors received no specific funding for this work. CRediT authorship contribution statement Francesco Menzella: Conceptualization, Methodology, Writing original draft. Carla Galeone: Data curation, Software, Writing - original draft. Patrizia Ruggiero: Data curation, Software. Diego Bagnasco: Writing - review & editing. Chiara Catellani: Software, Writing - review & editing. Nicola Facciolongo: Supervision, Writing review & editing. Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this article. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.pupt.2019.101874. References [1] T.F. Carr, A.A. Zeki, M. Kraft, Eosinophilic and non-eosinophilic asthma, Am. J. Respir. Crit. Care Med. 197 (2018) 22–37. [2] J. Lotvall, C.A. Akdis, L.B. Bacharier, et al., Asthma endotypes: a new approach to classificationof disease entities within the asthma syndrome, J. Allergy Clin. Immunol. 127 (2011) 355–360. [3] J. CorrenNew, Targeted therapies for uncontrolled asthma, J. Allergy Clin. Immunol. Pract. 5 (2019) 1394–1403. [4] D. Bagnasco, M. Caminati, M. Ferrando, T. Aloè, E. Testino, G.W. Canonica, et al., Anti-IL-5 and IL-5Ra: efficacy and safety of new therapeutic strategies in severe uncontrolled asthma, BioMed Res. Int. (2018) 5698212. [5] E. Heffler, F. Blasi, M. Latorre, et al., The severe asthma network in Italy: findings and perspectives, J. Allergy Clin. Immunol. Pract. 7 (2019) 1462-146. [6] K.F. Chung, S.E. Wenzel, J.L. Brozek, et al., International ERS/ATS guidelines on definition, evaluation and the treatment of severe asthma”, Eur. Respir. J. 43 (2014) 343–373. [7] https://ginasthma.org/wp/2018/11/GINA-SA-FINAL-wms.pdf , Accessed date: 16 June 2019. [8] F. Menzella, F. Bertolini, M. Biava M, C. Galeone, C. Scelfo, M. Caminati, Severe refractory asthma: current treatment options and ongoing research, Drugs Context 7 (2018) 212561. [9] F.C. Albers, H. Mullerovà, N.B. Gunsoy NB, et al., Biologic treatment eligibility for real-world patients with seer asthma: the IDEAL study, J. Asthma 55 (2018) 152–160. [10] S. Jeimy, M.W. Tsoulis, J. Hachey, et al., Eligibility of monoclonal antibody-based therapy for patients with severe asthma: a Canadian cross-sectional perspective, Allergy Asthma Clin. Immunol. 14 (2018) 68. [11] M. Castro, A.S. Rubin, M. Laviolette, et al., Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, doubleblind, sham-controlled clinical trial, Am. J. Respir. Crit. Care Med. 181 (2010) 116–124. [12] D. Langton, A. Ing, D. Fielding, et al., Safety and effectiveness of bronchial thermoplasty when FEV1 is less than 50, Chest (2019 Sep 13) pii: S0012-3692(19) 33753-5.. [13] N. Facciolongo N, A. Di Stefano, V. Pietrini, et al., Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma, BMC Pulm. Med. 18 (2018) 29. [14] B.E. Chipps, P. Newbold, I. Hirsch, F. Trudo, M. Goldman, Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma, Ann. Allergy Asthma Immunol. 120 (2018) 504–511. [15] A. Padilla-Galo, C. Olveira, L. Fernández de Rota-Garcia, et al., Factors associated with bronchiectasis in patients with uncontrolled asthma; the NOPES score: a study in 398 patients, Respir. Res. 19 (2018) 43. [16] M. García-Clemente, A.L. Enríquez-Rodríguez, M. Iscar-Urrutia, et al., Severe asthma and bronchiectasis, J. Asthma 1 (2019) 5. [17] D. Ennis, J.K. Lee, C. Pagnoux, Mepolizumab for the treatment of eosinophilic granulomatosis with polyangiitis, Expert Opin. Biol. Ther. 19 (2019) 617–630. [18] L. Swedin, T. Saarne, M. Rehnberg, et al., Patient stratification and unmet need in asthma, Pharmacol. Ther. 169 (2017) 13–34.
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