Anti-IL-5 and anti-IL-5 receptor therapy significantly improves quality of life and FEV1 values in patients with severe asthma

doi:10.21203/rs.3.rs-6543940/v1

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Anti-IL-5 and anti-IL-5 receptor therapy significantly improves quality of life and FEV1 values in patients with severe asthma

https://doi.org/10.21203/rs.3.rs-6543940/v1

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published 13 Aug, 2025

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Asthma is a chronic inflammatory disease of the airways triggered by exogenous antigens. Among its variants, it is crucial to differentiate between severe asthma and asthma, which is difficult to control. Severe asthma is characterized by a lack of response to high doses of inhaled corticosteroids and long-acting beta-2 agonists, whereas difficult-to-control asthma is associated with poor adherence to treatment, inappropriate use of inhalers, or the presence of uncontrolled comorbidities. In recent years, the use of monoclonal antibodies directed against interleukin-5 (anti-IL-5) and its receptor alpha (anti-IL-5R) has proven to be an effective therapeutic option for patients with severe asthma by reducing the number of eosinophils, which may promote disease remission. This study aimed to evaluate clinical improvement and remission in patients with severe asthma treated with anti-IL-5 and anti-IL-5R antibodies over a period of 12 months. A cohort study was conducted with 49 patients who were diagnosed with severe eosinophilic asthma and who did not respond to conventional treatment. During follow-up, medical control was carried out every 3 months via spirometry, eosinophil counts, quality of life scales and disease control. The results revealed an improvement in FEV1 from 3 months of treatment, with statistical significance at 12 months in patients treated with anti-IL-5 and at 9 months in those treated with anti-IL-5R. In addition, better perceptions of asthma control and quality of life were observed, with significant differences at 6 and 12 months. The correlations between spirometry and the ACT, ACQ and AQLQ reflect a progressive recovery of well-being and function. Finally, the remission rate was 41.1% with anti-IL-5 therapy and 47.3% with anti-IL-5R therapy after one year of follow-up. These findings support the efficacy of treatment with anti-IL-5 and anti-IL-5R in improving severe asthma control and patients' quality of life, suggesting their key role in disease remission.

Asthma

Anti-IL-5

Anti-IL5R

ACQ5

Asthma is a heterogeneous disease characterized by chronic inflammation of the airways caused by exogenous antigens. Different immunological mechanisms are altered in this illness, such as the balance between Th1 and Th2 lymphocytes, leading to an inadequate response to infections and IgE-mediated inflammation of the airways (1). During the early phase of inflammation, antigen-presenting cells present antigens to Th2 lymphocytes, which produce interleukins, including IL-4, IL-5, and IL-13 (1). B lymphocytes secrete IgE, which binds to the receptors of mast cells, eosinophils and basophils, sensitizing patients toallergens. Finally, the allergen binds to the IgE present in effector cells, releasing mediators such as histamine, prostaglandins, leukotrienes, etc., contributing to inflammation and classic asthma symptomatology (1). Many clinical phenotypes of asthma have been identified, some of which are as follows: (I) allergic asthma, (II) nonallergic asthma, (III) cough-variant asthma, cough-predominant asthma, (IV) adult-onset asthma, (V) asthma with persistent airflow limitation, and (VI) asthma with obesity (1).

Severe asthma is defined as asthma that remains uncontrolled despite optimized treatment with high doses of inhaled corticosteroids and long-acting beta-2 agonists (ICS-LABAs); asthma is a common disorder affecting approximately 7.8% of the U.S. population or 23 million Americans (2). Approximately 10% of adults and 2.5% of children with asthma develop severe asthma, which negatively impacts their quality of life and increases the risk of airflow limitation, exacerbation, hospitalization, and even death (3). Additionally, this pathology encompasses various clinical phenotypes varying by age of onset, presence of allergies, and coexisting conditions (2, 3). These phenotypes include type 2 (T2) and non-T2 asthma, with significant differences in treatment response, particularly to inhaled corticosteroids (ICSs) (1). T2 asthma primarily features eosinophilic airway inflammation in 50% of cases associated with increased blood eosinophil counts or elevated fractions of exhaled nitric oxide (FeNO), whereas non-T2 asthma includes neutrophilic and pancigranulocytic asthma (3–7).

On the other hand, difficult-to-treat asthma is defined as uncontrolled asthma despite adequate treatment. A number of factors, such as poor adherence to treatment or the misuse of inhalers, may lead to treatment failure and to an uncontrolled patient (1). It is important to distinguish between severe asthma and difficult-to-control asthma, which is caused by modifiable factors such as poor inhalation technique, poor treatment adherence, or the presence of comorbidities such as chronic rhinosinusitis or obesity (3). To differentiate between uncontrolled and controlled asthma, tools such as the Asthma Control Questionnaire (ACQ5) and Asthma Control Test (ACT) are used in adolescents and adults to assess asthma control and classify patients into different levels on the basis of the reported symptoms (41).

There are different treatments for severe asthma patients. Recently, monoclonal antibodies such as anti-interleukin-5 (Anti-IL-5) and anti-interleukin-5 receptor alpha (Anti-IL5R) have been used to control patients with severe asthma (3). However, few studies have focused on patients treated with these therapies in real-life settings, especially regarding clinical remission and complete remission, which may involve discontinuation of the therapy. Notably, both antibodies reduce the number of eosinophils, while the anti-IL-5R antibody also depletes basophils (3).

This study aims to compare current epidemiological and follow-up data on biomarkers, respiratory function tests, quality of life scales, and annual remission in patients with severe eosinophilic asthma treated with anti-IL-5 or anti-IL-5R.

This cohort study was conducted at ISSSTE Aguascalientes General Hospital, Valentín Gómez Farías Zapopan Hospital, and the Mexican Institute of Social Security Tepic Hospital between February 2021 and February 2023. The study included patients aged 18 to 99 years with confirmed severe eosinophilic asthma type 2, regardless of sex, who did not respond to conventional treatment with high-dose corticosteroids. Those who did not meet the definition of severe asthma, experienced an exacerbation at baseline, were pregnant, or had conditions that could mask asthma control symptoms, such as ischemic heart disease, neurodegenerative diseases, or concomitant cardiorespiratory conditions, were excluded. The study was approved by the ethics committee (Approval No. 2024-RCEI-9), and all participants provided informed consent.

Patients who met the definition of severe eosinophilic asthma characterized by uncontrolled asthma despite adequate adherence to inhaled therapy, high-dose ICS/LABA, and controlled modifiable risk factors were included (1). In addition, patients received at least one year of treatment with anti-IL-5 or anti-IL-5R monoclonal antibodies (benralizumab 30 mg every 4 weeks and then every 8 weeks or mepolizumab 100 mg every 4 weeks) at their respective hospitals. This therapy has been extensively evaluated in controlled clinical trials, establishing that the greatest therapeutic effect is observed with those doses (4–26).

During the follow-up period, every three months, medical control, including spirometry tests and eosinophil counts, was performed for each patient. Quality of life (Table 1) and asthma control scales (Table 2) were applied at each visit to determine the patients’ quality of life, treatment adherence, and biological treatment. (Figs. 1–3)

Table 1

Quality-of-life tools used in this study
Test/tool	Characteristics	Scores/Interpretation
Asthma Quality of Life Questionnaire (AQLQ)	It is an instrument to assess the quality of life in disease through physical and emotional impact¨. It has 32 items corresponding to 4 dimensions of health: limitations of habitual activities (11 items), symptoms (12 items), emotional function (5 items), and environmental stimuli (4 items)²⁷	0 = good health-related quality of life 10 = poor health-related quality of life
Mini Asthma Quality of Life Questionnaire (mini AQLQ)	It consists of 15 questions, grouped into 4 dimensions: symptoms (5 items), activity limitation (4 items), emotional function (3 items) and environmental stimuli (3 items) ²⁸	1 = Lower degree of disability 7 = greater degree of autonomy
Saint George's Respiratory Questionnaire (SGRQ- 1)	It has 73 items and 3 domains: symptoms, activity, and impact of the disease on daily life. ³⁰	0 = better health status 100 = worse health status
The University of California, San Diego Shortness of Breath Questionnaire (UCSD)	It is a self-administered questionnaire for dyspnea associated with activities of daily living (ADLs) featuring 24 items. Respondents are asked to rate themselves from 0 ("Not at all") to 5 ("Maximum or unable to do so due to shortness of breath") in two areas: 1. How short of breath they feel when performing various activities (21 items). 2. To what extent shortness of breath, fear of hurting oneself due to overexertion, and fear of shortness of breath limits them in their daily lives (3 items)	Scores range from 0 to 120, with higher scores indicating greater dyspnea.
The King’s Brief Interstitial Lung Disease (K-BILD)	It is a questionnaire on health-related quality of life (HRQoL), a specific measure of interstitial lung disease (ILD), which comprises 15 items. It has three domains: psychological (KBILD-P), dyspnea and activities (KBILD-B), and chest symptoms (KBILD-C)) combined into a total score (KBILD-T)²⁷	Score ranges from 0 to 100; 100 represents the best state of health.
Modified Dyspnea Scale from British Medical Research Council (mMRC)	It is used to establish a baseline in respiratory impairment due to dyspnea. It has 5 items (0: absence of dyspnea, 1: dyspnea when walking fast on the flat, 2: dyspnea that limits the pace of other people, 3: dyspnea that causes resting when walking approximately 100 meters, 4: dyspnea that prevents leaving the house) ³¹	With grades from 0 to 4, where the highest score expresses a greater functional limitation.
Hospital Anxiety and Depression Scale (HADS)	Instrument for the detection of depressive and anxiety disorders in the framework of hospital or psychiatric services. It is made up of 14 items grouped into two subscales, each with 7 items. Anxiety subscale (psychic manifestations) and depression subscale (focused on anhedonia)³²	In each subscale, the score obtained is interpreted according to the following criteria: * 0–7 normal * 8–10 probable case * 11–21 case of anxiety or depression

Table 2

Asthma control tools used in this study.
Test/tool	Characteristics	Scores/Interpretation
Asthma Control Test (ACT)	It assesses frequency of respiratory distress and general asthma symptoms, use of rescue medications, effect of asthma on daily functioning, and overall self-assessment of asthma control.	Scores range from 5 (asthma control) to 25 (complete asthma control). An ACT score > 19 indicates well-controlled asthma.
Asthma Control Questionnaire (ACQ)	A questionnaire that helps measuring the adequacy of asthma control that occurs spontaneously or because of treatment. The questionnaire consists of 5 questions. ³⁴	Each question is scored from 0 to 6. The points are added up and divided by 5. According to the result: * Less than or equal to 0.75: Adequate asthma control. 0.75 to 1.50: Partially controlled asthma. Over 1.50: Inadequate asthma control
Inhaler adherence test (TAI)	Questionnaire aimed at patients with asthma and COPD that allows us to identify patients with low adherence, establish the intensity of adherence (good, intermediate or poor), and provide guidance on the patient's time or pattern of noncompliance. It is made up of 10 questions. ³⁵	The score ranges from 1 (low compliance) to 5 (best compliance) The score provides a total ranging from 10 (minimum) to 50 (maximum)

Clinical remission was considered in patients with a sustained absence of asthma symptoms (ACQ < 1 or ACT > 20), no exacerbations in the past year, and optimized lung function with postbronchodilator FEV1 > 80%. Owing to study limitations, complete pathological remission was not evaluated.

Statistical analysis. The data obtained in this study were analyzed, and the results were plotted via GraphPad Prism 8.0 software. Descriptive statistics were used to analyze demographic data and remission percentages obtained from patients. Clinical data from the spirometry-FEV1 (percentage as well as the Z-point score), ACT, and ACQ instruments were analyzed via paired RM one-way ANOVA. Quality of life was analyzed via the AQLQ, mini-AQLQ, SGRQ-1, UCSD, K-BILD, and HADSR tests and compared with the paired Friedman test and Dunn’s multiple comparisons. The difference between population data and p values was obtained and plotted in each figure.

After completing the 12-month timeline defined in this study, which included and compared data from patients who passed through all the diagnostic tests, we established a population of 49 patients (100%) in this study. In total, 76% of the patients were females, and 24% were males; in terms of age, our population had a mean age of 55.78 years (range 21–60. SD: 14.88). An average body mass index of 29.73 was determined (range 20–53). SD 6.1), nasal polyps were found in 20% of the patients, and tobacco was consumed in 29% of the patients. In this study, 17 patients were treated with anti-IL-5 antibodies (35%), and 35 individuals were treated with anti-IL-5 receptor antibodies (65%). The quantification of basal eosinophils before starting the treatment in the anti-IL-5 group revealed a mean of 573.1/1x105 cells/µl (range 180–1,100/1x10⁵ cells/µl). SD: 265.2), and for the anti-IL-5R group, the mean number of cells was 839.3/1x105 cells/µl (range: 180–2,668/1x10⁵ cells/µl). SD: 547.7). In this study, the following results belong to the two previously mentioned groups.

To determine the correlation between spirometry results and the perceived improvement of patients participating in this asthma protocol, we used the asthma control test (ACT) as well as the asthma control questionnaire (ACQ). The ACT results from the anti-IL-5 group showed a similar pattern to those of the spirometry group, demonstrating a significant time-dependent improvement at the end of 12 months in comparison to the first data point at 3 months (Fig. 5A). Asthma control perception was also enhanced over time in the anti-IL5R group (Fig. 5B). Furthermore, the ACQ results revealed a reduction in the scores for both groups (Fig. 5C and D), indicating significant differences only at 12 months.

Next, to continue the evaluation of qualityoflife, repercussions after treatment with anti-IL-5 and anti-IL5R antibodies were similar to previously reported data. This study compiled the results of both groups for the six different questionnaires and compared them within the time points set every three months against the baseline data. First, the results from the asthma quality of life questionnaire (AQLQ) (Fig. 6A) revealed a significant difference at 6 months of treatment. Additionally, these results correlated with the results of the mini-AQLQ instrument used in this work (Fig. 6B). Afterward, the St. George’s Respiratory Questionnaire (SGRQ) was used to measure the overall wellness perceptions of the patients (Fig. 6C); interestingly, the patients mentioned an improvement in quality of life with treatment after 3 months. Similar results were observed for the UCSD, K-BILD, and HADSR questionnaires (Fig. 6D, E, and F), demonstrating a general improvement in different conditions that were reflected in the patients’ perceptions, as well as in their incorporation into normal life.

Severe asthma encompasses various clinical phenotypes that differ on the basis of age of onset, presence of allergies, and other coexisting conditions. These phenotypes include T2 and non-T2 asthma, with significant differences in treatment response, particularly to inhaled corticosteroids (ICSs). T2 asthma is characterized primarily by eosinophilic airway inflammation in 50% of cases and is associated with increased blood eosinophil counts or elevated levels of fractional exhaled nitric oxide (FeNO) (3). On the other hand, non-T2 asthma includes neutrophilic asthma and paucigranulocytic asthma. It is estimated that up to 83.8% of patients present an eosinophilic phenotype; a Latin American registry reported that 44% of patients had blood eosinophil counts of > 300 cells/mm³ (37). In this study, 49 patients were evaluated, 76% of whom were women with ages similar to the average age reported previously (55.7 years). Nasal polyposis was observed as a comorbidity in 22% of the patients, which is consistent with previously reported rates (9.8%-35%). However, in our population, active smoking was reported in 29% of cases, which is a higher rate than that reported in previous studies (XALOC 4%, ARABIA 9%, SIROCCO 1%) (7, 17, 18, 38). This could impact lung function or even exacerbate the condition.

In addition, this study reported that 65% of patients used anti-IL-5R therapies, differing from previous real-world studies in which most patients were treated with IL-5 inhibitors. This may explain the higher initial blood eosinophil counts in our study, which reached 2,668 cells/mm³. Previous studies have not demonstrated statistically significant improvements in FEV1. In our study, a significant improvement in FEV1 was observed at 12 months for patients treated with anti-IL-5 and at 9 months for those treated with anti-IL-5R. These findings suggest that respiratory functional effects may occur over the long term. Further studies with longer follow-up periods are necessary to evaluate the effectiveness of pulmonary function, particularly for patients receiving anti-IL-5 therapies.

The improvements in disease control, as measured by the ACT and ACQ-6, were similar in both groups (anti-IL-5R and anti-IL-5), which is consistent with the findings of previous studies, which revealed significant improvements at 12 months of treatment compared with early time points (7, 8, 9 & 14). However, the quality of life scales (AQLQ and mini-AQLQ) showed statistically significant improvements as early as 6 months after treatment initiation. he SGRQ-1 questionnaire score decreased during the first 3 months, indicating clinically significant improvements in respiratory symptoms and overall perception of lung function. This positive effect persisted throughout follow-up, although no additional significant differences were observed after the initial months, suggesting that benefits are achieved mainly during the early stages of treatment. This finding is consistent with other studies in which significant correlations were found between changes in SGRQ scores and comparison measures, which is a valid measure of impaired health in diseases of chronic airflow limitation that is repeatable and sensitive (43). The UCSD questionnaire showed a similar trend, with significant improvements in scores from baseline to 3 and 6 months. While the scores continued to improve, they did not reach statistical significance, possibly indicating a stabilization in the impact of the intervention on daily functioning after the first few months. There is evidence of the use of this scale in interstitial lung disease, where there is evidence of excellent agreement and a moderate positive correlation with the scores of the MRC scale; (44) however, there is not enough evidence in patients with severe asthma. The K-BILD results revealed statistically significant and sustained improvements across all follow-up points, highlighting the continuous benefits of the intervention on patients’ general well-being and reinforcing its importance in comprehensive condition management. For the HADSR questionnaire, improvements were more modest than those for the other questionnaires. While significant score reductions were observed at 3 and 6 months, these differences were not maintained at 12 months. This suggests that although the intervention initially contributes to improving mental health symptoms, additional strategies may be needed to sustain these effects.

Early improvements in quality of life, despite delayed disease control, may be attributed to patients being initially highly symptomatic or being diagnosed late with severe asthma. Therefore, even minimal improvements in disease control could have an early and meaningful impact on quality of life.

In our study, clinical remission was achieved in 41.10% of patients treated with anti-IL-5 and in 47.3% of patients treated with anti-IL-5R. This percentage is higher than that reported in previous studies, where the maximum percentage of remission was 43.2% (REMI-M) (40). Another multicenter observational study reported that 30.12% of patients treated with Anti-IL5 and 40% with Anti-IL5R achieved complete remission after 12 months of treatment (42). In particular, there was a trend toward higher remission rates with anti-IL-5R, as previously reported (7, 17, 18, 38), although the difference was not statistically significant. The high remission rate in our study may be due to improved lung function at baseline, fewer exacerbations, and a perception of uncontrolled disease at baseline.

Improvements in quality of life occurred before disease control occurred in both groups, and earlier improvements were observed in the anti-IL-5R group. Long-term comparative studies are needed to establish statistically significant differences between the two groups.

This real-world cohort study demonstrated that biological therapy with anti-IL-5 and anti-IL-5R monoclonal antibodies is effective in improving clinical asthma control, quality of life, and lung function in patients with severe eosinophilic asthma who do not respond to conventional treatment. Both therapies showed significant improvements in ACT, ACQ, and AQLQ scores, with over 40% clinical remission after 12 months of follow-up. Benefits were observed from the early stages of treatment—earlier with anti-IL-5R—and were sustained over time. These findings support the use of targeted therapies as a key tool to modify the clinical course of severe asthma, particularly in settings where optimizing outcomes and resources is essential. Further studies are needed to evaluate the long-term sustainability of these effects and their impact on complete disease remission.

The following abbreviations are used in this manuscript:

Anti-IL-5

Anti-IL-5R

FEV1

ACT

TAI

ACQ

AQLQ

mini-AQLQ

SGRQ

UCSD

K-BILD

HADS

mMRC

IL-4

IgE

ICS

LABA

FeNO

ANOVA

REMI-M

Anti-interleukin-5

Anti-interleukin-5 receptor alpha

Forced expiratory volume

Asthma Control Test

Inhaler adherence test

Asthma Control Questionnaire

Asthma Quality of Life Questionnaire

Mini Asthma Quality of Life Questionnaire

Saint George's Respiratory Questionnaire

The University of California, San Diego Shortness of Breath Questionnaire

The King’s Brief Interstitial Lung Disease

Hospital Anxiety and Depression Scale

Modified Dyspnea Scale from British Medical Research Council

Interleukin-4

Immunoglobulin E

Inhaled corticosteroids

Long-acting beta-2 agonists

Fraction of exhaled nitric oxide

Analysis of variance

Standard deviation

Maximum percentage of remission

Author Contribution

Conceptualization, E.H.; methodology, J.D.; software, J.D.; validation, J.A., D.G., S.P.; formal analysis, H.G., E.,H; research, H.G.; data curation, J.A.; drafting: preparation of the original draft, A.V.; writing: revision and editing, A.V., S.P.; visualization, J.P., A.LL., J.P.,; supervision, S.P.; project management, S.P. All authors have read and agree with the published version of the manuscript.

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Anti-IL-5 and anti-IL-5 receptor therapy significantly improves quality of life and FEV1 values in patients with severe asthma

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