Open Respiratory Archives 5 (2023) 100252 Open Respiratory Archives www.elsevier.es/ora Original article Treatment Patterns of Monoclonal Antibodies in Patients With Severe Uncontrolled Asthma Treated by Pulmonologists in Spain Francisco Casas-Maldonado a,∗ , Francisco-Javier Álvarez-Gutiérrez b , Marina Blanco Aparicio c , Christian Domingo Ribas d,e , Carolina Cisneros Serrano f,g , Gregorio Soto Campos h , Berta Román Bernal i , Francisco-Javier González-Barcala j,k,l,m a Servicio de Neumología, Hospital Universitario Clínico San Cecilio, Avenida de la Investigación, s/n, Granada, Spain b Servicio de Neumología, Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, Sevilla, Spain c Servicio de Neumología, Hospital Universitario A Coruña, As Xubias 84, A Coruña, Spain d Servei de Pneumologia, Corporació Sanitària Parc Taulí, Parc Taulí, 1, Sabadell, Barcelona, Spain e Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Bellatera, Cerdanyola del Vallès, Spain f Servicio de Neumología, Hospital Universitario La Princesa, Madrid, Spain g Fundación de Investigación Biomédica La Princesa, Calle de Diego de León, 62, Madrid, Spain h Servicio de Neumología y Alergia, Hospital Universitario de Jerez, Ctra. Trebujena, s/n, Jerez de la Frontera, Cádiz, Spain i Servicio de Neumología, Hospital Dr. José Molina Orosa, Crta. Arrecife-San Bartolomé, Km 1, 3, Arrecife, Las Palmas, Spain j Servicio de Neumología, Hospital Clínico Universitario de Santiago de Compostela, Rúa da Choupana, s/n, Santiago de Compostela, A Coruña, Spain k Departamento de Medicina-Universidad de Santiago de Compostela, Spain l Centro de Investigación Biomédica en Red de Enfermedades Respiratorias – CIBERES, Santiago de Compostela, Spain m Grupo Traslational Research in Airway Diseases-FIDIS, Spain a r t i c l e i n f o a b s t r a c t Article history: Introduction and objectives: The use of monoclonal antibody (mAb)-based therapies is becoming the new Received 8 February 2023 standard of care for severe uncontrolled asthma (SUA). Even though patients may qualify for one or Accepted 24 April 2023 more of these targeted treatments, based on different clinical criteria, a global vision of mAb prescription Available online 8 June 2023 management in a large sample of hospitals is not well characterised in Spain. The objective was to give a global vision of mAb prescription management in a large sample of hospitals Keywords: in Spain. Monoclonal antibodies (mAbs) Materials and methods: We used an aggregate data survey method to interview pulmonology specialists Pneumology Survey in a large sample of Spanish centres (90). The following treatment-related information was obtained on Treatment management patients treated with mAbs: specific mAbs prescribed, treatment interruption, switch and restart and the Severe uncontrolled asthma (SUA) reasons for these treatment changes. Results: mAb prescription was more frequent in females (13.3% females vs 7.4% males; p < 0.001). There were no differences in prevalence by hospital complexity level. In contrast, there were differences by geographical area. Omalizumab was the most prescribed mAb (6.2%), followed by mepolizumab (2.9%). Discontinuation of Omalizumab (due to a lack of effectivity) and switches from this mAb to mepolizumab were more frequent. Very few restarts to the first treatment were observed after a switch from ≥2 mAbs. Conclusions: Omalizumab appeared as the most prescribed mAb in SUA but was also the most with- drawn; a specific and objective characterisation of patients with SUA, along with asthma phenotyping, and together with further evaluation of safety and effectiveness profiles, will lead to future progress in the management of SUA with mAbs. © 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Abbreviations: CI, confidence interval; EMA, European Medicines Agency; FDA, Food and Drug Administration; mAbs, monoclonal antibodies; NHS, National Health System; P25 and P75, percentiles 25 and 75; Q, quartile; SA, severe asthma; SUA, severe uncontrolled asthma. ∗ Corresponding author. E-mail address: franciscocasas@neumosur.net (F. Casas-Maldonado). https://doi.org/10.1016/j.opresp.2023.100252 2659-6636/© 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Patrones de tratamiento de anticuerpos monoclonales en pacientes con asma grave no controlada atendidos por neumólogos en España r e s u m e n Palabras clave: Introducción y objetivos: El uso de terapias basadas en anticuerpos monoclonales (mAb) se está convir- Anticuerpos monoclonales tiendo en el nuevo estándar de atención para el asma grave no controlada (AGNC). A pesar de que los Neumología pacientes pueden optar a uno o varios de estos tratamientos dirigidos, con base en diferentes criterios Encuesta clínicos, en España no se ha caracterizado bien una visión global de la gestión de la prescripción de mAb Tratamiento Asma grave no controlada en una gran muestra de hospitales. El objetivo fue dar una visión global de la gestión de la prescripción de mAB en una amplia muestra de hospitales en España. Materiales y métodos: Se utilizó un método basado en una encuesta de datos agregados para entrevistar a especialistas en Neumología en una amplia muestra de centros españoles (90). Se obtuvo la siguiente información relacionada con el tratamiento de los casos tratados con mAbs: mAbs específicos prescritos, interrupción del tratamiento, cambio y reinicio, y las razones de estos cambios de tratamiento en consultas de Neumología. Resultados: La prescripción de mAB fue más frecuente en mujeres (13,3% mujeres vs. 7,4% hombres; p < 0,001). No hubo diferencias de prevalencia por nivel hospitalario. En cambio, hubo diferencias por área geográfica. Omalizumab fue el mAb más prescrito (6,2%), seguido de mepolizumab (2,9%). La interrupción y los cambios (debido a la falta de efectividad) también fueron más frecuentes para omalizumab. Conclusiones: Omalizumab fue el mAb más prescrito en el manejo de AGNC, pero también fue el mAB que presentó más retiradas; una caracterización específica y objetiva de los pacientes con AGNC, mediante fenotipificación de asma, junto con una evaluación adicional de los perfiles de seguridad y efectividad, conducirá a nuevos avances en el manejo del AGNC con mABs. © 2023 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Introduction Given the gap in knowledge regarding the mAbs prescription in Spain, in this study we aimed to characterise the management Monoclonal antibody (mAbs) treatments have important ther- pattern of mAbs in a large sample of patients with SUA treated by apeutic applications in different diseases. Currently, a number of Spanish pulmonologists. Complementary to this, we also assessed biological drugs are available that have proven to be quite effective the prevalence of mAbs prescriptions by sex and specialty. and efficient in reducing exacerbations1 and improving quality of life2 in adults and children with moderate to severe asthma (SA).3–5 Methods In this sense, severe uncontrolled asthma (SUA) is as an important challenge not only for health professionals but also for patients who The current study belongs to a broader project where the objec- suffer from it.6 tive is to describe a global map of mAbs prescription for SUA in Different mAbs have emerged to treat different types of SUA. Spain, as well as the characteristics of such prescriptions.20 In the Specifically, there are four biologic mAbs approved for clini- present study, we evaluate the mAbs prescriptions’ patterns, by sex, cal use. These are Omalizumab for allergic asthmatic patients by hospital complexity level, by geographical area, type of mAb, as (anti-IgE)7–9 and three others targeting eosinophilic inflamma- well as treatment interruptions, switches and restarts. tion (mepolizumab,10,11 reslizumab, and benralizumab,12–14,3,15 all which show very positive results. Participants and data collection Among these, Omalizumab was the first mAb approved by the Food and Drug Administration (FDA) in 2003,16 and by the Euro- The study is based on a survey of aggregated data, collected from pean Medicines Agency (EMA) in 2005.17 In the last five years three hospital pharmacy lists of patients with SUA who are currently or new mAbs have emerged for use in eosinophilic SUA. Much of the have been treated with mAbs in the last 5 years. Data were analysed literature cites both the benefits and drawbacks of using these in centres from the National Health System (NHS) hospital cata- drugs in SUA. However, given the complexity of asthma and its logue, in Spain, available on the website of the Ministry of Health management, the presence of SUA, and specifically, to what extent for 2018.21 these mAbs are or are not prescribed and why is not fully under- The inclusion criteria of the selected centres included: belonging stood. to the NHS in any region, having a pulmonology department and Different health professionals have been involved in controlling a hospital pharmacy, as well as data on the prescription of mAbs the disease depending on where the patients seek help, i.e. general in patients with SUA from the last 5 years. All private and public practitioners or specialists. However, in some cases there is not hospitals without these characteristics were excluded. always an accurate diagnosis of asthma, thus leading to the inade- Pulmonology specialists who agreed to participate in the study quate management of SA.18 Due to this, the mAbs prescription that completed an electronic survey from 1 July to 4 November 2019. comes from the different health consultations is not well charac- A proportional randomised sampling of centres was carried out, terised. That is, in the field of pulmonology, due to the complex and stratifying by five geographical areas of Spain (north, south, east, very heterogeneous inflammatory nature of respiratory processes, Canary Islands and central zone)20 and four hospital complexity the use of these treatments has been delayed despite a high preva- levels (according to the number of beds: level 1, ≤250; level 2, lence of SUA cases in this specialty. Furthermore, given that sex has 251–500; level 3, 501–800; level 4, >800 beds), based on a finite been reported to play a key role in asthma,19 assessing how these population of 189 hospitals that fulfilled the inclusion criteria, mAbs treatment patterns may differ between males and females is which was adopted as a sampling basis. of particular interest. 2 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Using this sample and considering the finite population sam- Table 1 Population treated by sex, hospital level and geographical area. pling correction factor, to estimate an unknown proportion (assuming a case weighting of 50%) with a 95% confidence inter- Population treated with p value val and with an estimation error of ±5%, data from 112 hospitals mAb in pulmonology, median (P25, P75) were needed. To prevent a 20% loss of information, 140 hospi- tals had to be recruited. Investigators from 140 hospitals of the Sex pulmonology departments were contacted and 100 principal inves- Men 11.0 (6.25,18.8) <0.001 Women 23.0 (12.0,37.8) tigators agreed to participate. Centres that provided the necessary information to assess the total number of patients currently treated Hospital level Level 1 12.0 (7.50,23.2) <0.001 with mAbs and the size of the centre’s reference population were Level 2 29.5 (15.5,37.0) considered valid. Level 3 50.0 (34.5,80.5) Level 4 57.0 (42.0,78.0) Variables collected Geographical area Canary Islands 52.0 (51.0,63.0) 0.391 Variables related to the stratified study design, the demographic Central area 30.5 (21.8,45.5) characteristics of patients with mAbs, and the mAb prescription East area 31.0 (21.5,47.5) were collected, which included hospital complexity levels (see North area 29.5 (13.2,48.0) South area 37.0 (19.2,93.5) above), sex of patients, prevalence and number of cases treated with mAbs, type of mAb prescribed (omalizumab, mepolizumab, mAb: monoclonal antibodies; P25, P75, percentile 25 and 75. reslizumab, benralizumab), and time (current and since the introduction of the use of mAbs). It also included treatment inter- ruption, switch and restart and reasons for treatment changes. nificant difference in the prevalence of current mAb treatment by The prescription of mAbs was stratified according to sex and sex (p < 0.001) (Fig. 1a) with females showing a higher prevalence: time. 13.3% (11.1–15.5%) in females and 7.4% (6.3–8.6%) in males. The dis- tribution by sex of the total number of patients treated with mAbs Statistical analysis since their use was established in each centre and it showed the same trend (p < 0.001): median (Q1, Q3) in females 23 (12, 37.8); The SUA prevalence was calculated by multiplying the reference and in males 11 (6.2, 18.8) (Fig. 1b). population of each site by the percentage of adults in the Span- ish population (84.2%),22 the estimated prevalence of asthma in an Prevalence of mAb treatments by hospital complexity level adult population (5%),23 and the proportion of asthma patients with SUA (3.9%).1 The prevalence of treatment with mAbs in patients By hospital complexity level, the prevalence was 8.8% with SUA was calculated by dividing the number of patients cur- (6.9–10.6%) in level 1, 11.7% (7.1–16.3%) in level 2, 11.7% rently treated with any mAbs by the estimated number of patients (9.6–13.8%) in level 3 and 9.4% (8.3–10.5%) in level 4; no statistically with SUA. significant differences were observed (p = 0.597) (Fig. 2). Medians and quartiles (Q1, Q3), and absolute and relative frequencies were used to describe quantitative and categorical Prevalence of mAb treatments by geographical area variables, respectively. Comparisons of population treated with mAb by groups (sex, hospital complexity level, geographical area) By geographical area, the prevalence was 13.3% (13.3–13.3%) were performed by means of the Mann–Whitney U test or the in the Canary Islands, 5.8% (4.4–7.3%) in the central area, 8.9% Kruskal–Wallis test. (7.0–10.8%) in the eastern area, 9.1% (7.6–10.6%) in the northern Prevalence estimates of current treatment with mAb and com- area, and 15.9% (10.1–21.7%) in the southern area; statistically sig- parisons by sex, hospital complexity level and geographical area nificant differences were observed (p = 0.01) (Fig. 3). were performed taking into account the survey design using the Table 1 shows the descriptive results of the population treated survey package24 of the R statistical software version 4.2.0, 2022. by sex, hospital complexity level, and geographic area. Ethics Prescription of mAb This work has been carried out in accordance with the Helsinki For each of the four mAbs, the prevalence of treatment Declaration of 1975, revised in 1983 and all the pulmonologists by pulmonology services was: omalizumab, 6.2% (4.8–7.5%); were informed about the study and signed an informed consent. mepolizumab, 2.9% (2.6–3.2%); reslizumab, 0.4% (0.2–0.5%); and benralizumab, 1.0% (0.8–1.2%) (Fig. 4). eTable1 shows the results of Results the prevalence of treatment by sex, hospital complexity level, and geographic area. The descriptive results of the population treated A total of 91 centres were initially included. One of them was with each of the mAbs by sex, hospital complexity level and geo- discarded because there was missing information regarding the graphic area shown in eTable 2 of eSupplement Material. objective of the study. The classification of the 90 final partici- pant centres by the capacity of the hospital was: level 1 n = 20 mAb prescribed: treatment interruption, switches and restarts (22.2%), level 2 n = 30 (33.4%), level 3 n = 19 (21.1%) and level 4 n = 21 (23.3%). 100% of pulmonology specialists prescribed mAb for eTable3 shows the total number of treatment interruptions of SUA. mAbs, along with the reasons for all centres. Discontinuations were higher for omalizumab, followed by mepolizumab. The main reason Prevalence of mAb treatments by sex for discontinuation was a lack of effectivity (Fig. 5a). Table 2 shows the distribution of the total number of patients Global current mean prevalence (95% confidence interval [CI]) who have had their prescribed mAbs switched, with omal- of cases treated with mAbs was 10.4% (8.8–12.1%). There was a sig- izumab showing the highest number of switches, especially to 3 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Fig. 1. Prevalence and number of patients with mAb prescription by sex. (a) Prevalence of patients with mAb prescription by sex. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients with mAb prescription by sex. Numerical data indicate mean (standard deviation). Fig. 2. Prevalence and number of patients treated with mAb by hospital level. (a) Prevalence of patients treated with mAb by hospital level. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients treated with mAb by hospital level. Numerical data indicate mean (standard deviation). mepolizumab. Again, the main reason for switching was a lack of Discussion effectiveness of treatment. The second mAb showing more switches was mepolizumab to benralizumab (Fig. 6). When this study was first constructed and designed, it was the eTable4 shows the distribution of the total number of patients first study to describe the pattern and type of mAb prescription where the first prescribed mAb was restarted after a switch from in SUA. It was implemented in a large sample of public health ≥2 mAbs. There were a few restarts to the first treatment that, centres with a pulmonology service, taking into account sex, hos- in most cases, was omalizumab, followed by benralizumab and pital complexity level and geographical area. In January 2022, an mepolizumab. The lack of effectiveness appeared as the main rea- international registry that describes real-life global patterns of bio- son for restarting the first mAb treatment (Fig. 5b). logic use (continuation, switches, and discontinuations) for severe 4 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Fig. 3. (a) Prevalence and number of patients treated with mAb by geographical area. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients treated with mAb by geographical area. Numerical data indicate mean (standard deviation). Fig. 4. Prevalence of treatment. Numerical data indicate the mean (95% confidence interval [CI]). Patients’ distribution attending different mAb prescriptions (a) since mAb prescription was established in each centre and (b) patients who discontinued the mAb treatment and do not continue with other mAb. Numerical data indicate mean (standard deviation). asthma was published.25 In our study, notably, a sex difference main switches were from omalizumab to mepolizumab, and from was found, with females showing a higher prevalence of mAbs mepolizumab to benralizumab. These results are similar to those being prescribed. As in the international registry,25 Omalizumab published in the international registry.25 There were few restarts was the most prescribed mAb, as it has been available for a longer to the first treatment (after a change of ≥2 mAbs) which in most period of time, followed by mepolizumab. However Omalizumab cases was omalizumab. Lack of effectivity was the main reason for also showed the highest levels of treatment discontinuation. The treatment discontinuation and switches. 5 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Fig. 5. (a) Number of treatment interruptions of mAbs treatments. (b) Number of patients where the first prescribed mAb was restarted after a switch from ≥2 mAbs. Table 2 mAbs switches and reasons. Switch Total Adverse effects Lack of effectivity Other reasons Unknown Omalizumab to mepolizumab 424 32 368 13 11 Omalizumab to reslizumab 45 5 37 1 2 Omalizumab to benralizumab 82 3 71 6 2 Mepolizumab to benralizumab 102 14 82 1 5 Mepolizumab to omalizumab 7 0 6 1 0 Mepolizumab to reslizumab 28 2 25 0 1 Reslizumab to benralizumab 3 1 2 0 0 Reslizumab to mepolizumab 3 1 1 1 0 Reslizumab to omalizumab 0 0 0 0 0 Benralizumab to mepolizumab 5 3 2 0 0 Benralizumab to omalizumab 1 0 1 0 0 Benralizumab to reslizumab 2 0 2 0 0 mAb: monoclonal antibodies. Patients with SUA are eligible for mAb treatments, depending females.29 In this regard, future studies on mAb prescription should on different clinical and medical criteria. However, there is a lack of take into account the type of SA. Therefore, there is a need to bet- characterisation of mAb prescription mapping, especially in some ter characterise and phenotype patients with SA before requesting European countries. Routine options for treating asthma remain mAb treatment, also taking into account the phases (stable or exac- limited and there are very few studies on the proportion of patients erbations) in which patients seek healthcare help.30 Studies on the eligible for mAb. We found that 10.4% of patients with SUA were impact of sex on treatment effectiveness are unclear, with some treated with mAbs. In a population with SA from a Canadian aller- studies indicating that sex does not predict response to mAbs.31,32 gist’s practice, between 41% and 78% of patients (depending on the Omalizumab was the most prescribed mAb, followed by mAb) were eligible for at least one mAb.26 Our data are fall below mepolizumab. Omalizumab was the first mAb approved for allergic these eligibility percentages. A study conducted in Spain on a sam- SA.33 There is variability in the published data on the percentage of ple of 303 patients with SA (67% women) shows that mAb are not patients with allergic and eosinophilic asthma. Allergic asthma is usually prescribed during the severe exacerbation phases, but only demonstrable in a variable proportion of patients (11–60% of cases) during the stable phase in 39% of cases.27 while the eosinophilic phenotype accounts for about 25–58% of the Consistent with previous studies,27,28 mAb treatments were cases,34,35 the idiosyncrasies of patients in the centres evaluated prescribed significantly more in females. Sex plays an impor- may contribute to these results. tant role in asthma, from males having the highest prevalence Interestingly, since patients with SA may present with an over- in childhood to females in adulthood.19 A new hypothesis lap of eosinophilic and allergic phenotypes, both omalizumab and related to SA pathophysiology phenotypes involves asthma with mepolizumab, primarily, are commonly discussed as the best treat- non-eosinophilic inflammation, obesity and occurrence only in ment for these cases.36 In this regard, both mAbs have shown 6 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 Fig. 6. Number of patients who have had their prescribed mAbs switched. similar efficacy in patients with SUA.37 Previous literature shows switches stand? It seems difficult to find an alternative in severe that the high heterogeneity of cases and the different selection cri- cases that maximises disease control. teria for the use of the two mAbs probably do not allow for a specific This study is not without limitations. The nature of the survey and concrete criterion for using one or the other mAb, also taking method has several inherent advantages, but also weaknesses. For into account that they have similar efficacy patterns.37 example, there were centres that were difficult to access, as we The prevalence of treatment discontinuation was also more could not survey the initially calculated sample size. The reliabil- reported for these two mAbs. Omalizumab withdrawal rates ity of the survey also depends on different factors, such as errors have been shown to vary considerably depending on the type of in the data due to non-response, or differences in the number of study, ranging from 2% to 19% in double-blind and open-label respondents (in this case, centres) who chose to participate from studies.38 those who chose not to, which creates bias. In SUA cases, switching between mAbs can occur.39 Most In conclusion, we found differences in overall mAb prescribing switches were observed from omalizumab (about 78%, 551 out according to sex, specialty and hospital complexity level. Omal- of 702) to mepolizumab (60%), and from mepolizumab to benral- izumab appeared as the most prescribed mAb, but also with higher izumab (14%). There is a clear effect of sample size treated with rates of treatment discontinuation, mainly due to lack of effective- omalizumab that makes treatment discontinuation more evident ness. Proper knowledge and management of the disease as well as for this mAb. This could be because it was the monoclonal available its associated comorbidities are essential for the successful man- for most of the study period. It could also be possible that more agement of the disease in the future, as there are still high drop-out failures could have been seen with other mAbs if the study had rates. lasted longer. In addition, despite omalizumab being considered the gold standard treatment in severe allergic asthma, it is possible Funding that incorrect asthma phenotype selection has occurred, leading to a negative clinical outcome.40 Some studies suggest that switching Funding obtained from the Asthma Area of the Spanish Society from omalizumab to mepolizumab in patients with uncontrolled of Pneumology and Thoracic Surgery. severe allergic and eosinophilic asthma may lead to clinically sig- nificant improvements in asthma control.40,41 The literature is not Authors’ contributions sufficiently clear on which mAb (mepolizumab or benralizumab) is the best for treating eosinophil SA. On one hand, studies high- All the authors of this document made substantial contributions light similar efficacy42 ; however on the other hand, some studies to conception and design. FC contributed to draft it and all authors attribute unique characteristics to benralizumab in inhibiting the revised it critically for important intellectual content; gave final mechanism of eosinophil depletion and maturation in the bone approval of the version to be published; and agreed to be account- marrow, thus inducing cell-mediated, antibody-dependent cyto- able for all aspects of the work. toxicity in both circulating and tissue-resident eosinophils43–45 that have not been attributed to other mAbs (i.e. mepolizumab). Benralizumab is therefore postulated as an alternative to other Conflicts of interest agents targeting the IL-5 pathway in the treatment of eosinophilic asthma.44 Francisco Casas-Maldonado declares that he has received fees There were few restarts of the first treatment after a switch from in the last three years for acting as a speaker from AstraZeneca, ≥2 mAbs, and, in the few cases, it was to omalizumab. We found Bial, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, that the rates of withdrawal or switches from omalizumab, as well Grifols, Laboratorios Esteve, Laboratorios Ferrer, Menarini, Novar- as the other mAbs, have been associated with a lack of efficacy, in tis, Rovi, TEVA, VERTEX, and Zambon; he has also received grants agreement with previous studies.46,47 The question here is: where for conference attendance from Boehringer Ingelheim, Grifols, do these severe cases that do not respond to even two treatment Menarini, and Novartis; finally, he has received consulting fees 7 F. Casas-Maldonado, F.-J. Álvarez-Gutiérrez, M. Blanco Aparicio et al. Open Respiratory Archives 5 (2023) 100252 from AstraZeneca, Chiesi, GlaxoSmithKline, CSL Behring, and Gri- 8. Kupryś-Lipińska I, Molińska K, Kuna P. The effect of omalizumab on eosinophilic fols. Marina Blanco Aparicio declares that in the last three years inflammation of the respiratory tract in patients with allergic asthma. Pneu- monologia i alergologia polska. 2016;84:232–43. she has received fees for participating as a speaker at meet- 9. Samitas K, Delimpoura V, Zervas E, Gaga M. Anti-IgE treatment, airway inflam- ings sponsored by Astrazeneca, Novartis, TEVA, and GSK and mation and remodelling in severe allergic asthma: current knowledge and future as a consultant for AstraZeneca, GSK, Chiesi, Novartis, and Bial. perspectives. Eur Respir Rev. 2015;24:594–601. 10. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. She also received financial aid to attend congresses. Francisco- Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl Javier González-Barcala declares that in the last three years he J Med. 2014;371:1198–207. has received grants for attending congresses, lectures or research 11. Menzies-Gow A, Flood-Page P, Sehmi R, Burman J, Hamid Q, Robinson DS, et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil matura- grants from ALK, Astra-Zeneca, Bial, Boehringer Ingelheim, Chiesi, tional arrest and decreases eosinophil progenitors in the bronchial mucosa of Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Menarini, atopic asthmatics. J Allergy Clin Immunol. 2003;111:714–9. Mundipharma, Novartis, Rovi, Roxall, Stallergenes-Greer, and Teva. 12. Pelaia C, Calabrese C, Vatrella A, Busceti MT, Garofalo E, Lombardo N, et al. Benralizumab: from the basic mechanism of action to the potential use in the Christian Domingo Ribas declares having received in the last three biological therapy of severe eosinophilic asthma. BioMed Res Int. 2018;2018: years collaborations for travel and participation in congresses, 4839230. conferences or scientific meetings from Novartis, Sanofi, GSK, 13. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. TEVA, Boehringer-Ingelheim, Esteve, Almirall, Astra-Zeneca, Chiesi, Efficacy and safety of benralizumab for patients with severe asthma uncon- trolled with high-dosage inhaled corticosteroids and long-acting ␤(2)-agonists Menarini, Takeda, Pfizer, Ferrer, Stallergenes, ALK-Abelló, Allergy (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. therapeutics, Hall Allergy, Inmunotek, and Roxall. Carolina Cis- 2016;388:2115–27. neros Serrano declares having received fees in the last three years 14. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Ben- ralizumab, an anti-interleukin-5 receptor ␣ monoclonal antibody, as add-on for acting as a speaker from Astrazeneca, GSK, TEVA, Menarini, treatment for patients with severe, uncontrolled, eosinophilic asthma (CAL- Mundipharma, and Novartis; she received grants for attending IMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. congresses from Chiesi, TEVA, Menarini, and Mundipharma; and 2016;388:2128–41. 15. Long AA. Monoclonal antibodies and other biologic agents in the treatment of she has also received fees for acting as a consultant from ALK, asthma. mAbs. 2009;1:237–46. Astrazeneca, MundiPharma, TEVA, GSK, and Novartis. Gregorio 16. Drugs@FDA: FDA-Approved Drugs. Available from: https://www.accessdata.fda. Soto Campos reported having received fees in the last three years gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. 17. Xolair. European Medicines Agency. Available from: https://www.ema.europa. for acting as a speaker for Astrazeneca, Boehringer and Novartis eu/en/medicines/human/EPAR/xolair [published 17.9.18.]. and as a consultant for AstraZeneca, GSK, Chiesi, Novartis, and 18. Gillis RME, van Litsenburg W, van Balkom RH, Muris JW, Smeenk FW. The con- Bial. He also received financial aid for attending congresses from tribution of an asthma diagnostic consultation service in obtaining an accurate asthma diagnosis for primary care patients: results of a real-life study. NPJ Pri- Boehringer, Menarini, and Novartis and received grants for research mary Care Respir Med. 2017;27:35. projects from Novartis, GSK and Boehringer. Berta Román Bernal 19. Yung JA, Fuseini H, Newcomb DC. Hormones, sex, and asthma. Ann Allergy in the last three years reports having received honoraria for par- Asthma Immunol. 2018;120:488–94. ticipating as a speaker from Astrazeneca, Teva, Novartis, and GSK. 20. Casas-Maldonado F, Álvarez-Gutiérrez FJ, Blanco-Aparicio M, Domingo-Ribas C, Cisneros-Serrano C, Soto-Campos G, et al. Monoclonal antibody treat- She has also received grants for attending congresses and courses ment for severe uncontrolled asthma in Spain: analytical map. J Asthma. from Astrazeneca, Teva, Novartis, Menarini, and GSK. Francisco- 2022;59:1997–2007. Javier González-Barcala declares that in the last three years he 21. Ministerio de Sanidad – Ciudadanos – Sistema Nacional de Salud – Hos- pitales. Available from: https://www.sanidad.gob.es/ciudadanos/prestaciones/ has received grants for attending congresses, lectures or research centrosServiciosSNS/hospitales/ [accessed 2.4.22]. grants from ALK, Astra-Zeneca, Bial, Boehringer Ingelheim, Chiesi, 22. Abellán García A, Aceituno Nieto P, Pérez Díaz J, Ramiro Fariñas D, Ayala Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Menarini, García A, Pujol Rodríguez R. Un perfil de las personas mayores en España, 2019. Indicadores estadísticos básicos. Madrid 2019. Available from: http:// Mundipharma, Novartis, Rovi, Roxall, Stallergenes-Greer, and Teva. envejecimiento.csic.es/documentos/documentos/enred-indicadoresbasicos 2019.pdf [accessed 16.3.21]. Acknowledgements 23. Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et al. Uniform definition of asthma severity, control, and exacerbations: doc- ument presented for the World Health Organization Consultation on Severe We would like to thank all the researchers from the different Asthma. J Allergy Clin Immunol. 2010;126:926–38. hospitals that have participated in this study for their efforts in 24. Lumley T. Survey analysis of complex survey samples. J Stat Softw. 2004;9:1–19. 25. Menzies-Gow AN, McBrien C, Unni B, Porsbjerg CM, Al-Ahmad M, Ambrose CS, collecting the data, and all those responsible for the hospital phar- et al. 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