Effectiveness of mepolizumab therapy on symptoms, asthma exacerbations, steroid dependence, and small airways in patients with severe eosinophilic asthma

Background/aim The efficacy of mepolizumab has been largely demonstrated in clinical trials in patients with severe eosinophilic asthma (SEA). However, reports on experience with mepolizumab in a real-life cohort are limited. Moreover, data about the effectiveness of mepolizumab on small airways is scarce. This study evaluated the effectiveness of mepolizumab therapy on symptoms, asthma exacerbations, blood eosinophils, steroid dependence, and small airways in a real-life cohort of patients with SEA. Materials and methods We retrospectively analyzed patients with SEA who were receiving fixed-dose mepolizumab. The effects of mepolizumab on clinical, laboratory, functional parameters were evaluated at 12th, 24th, and 52nd weeks. Small airways were assessed with the FEF 25-75. Results A total of 41 patients were enrolled in the study. Mepolizumab significantly reduced asthma exacerbation rates, reduced mOCS dose, and improved asthma control test (ACT) scores at 12th, 24th, and 52nd weeks. However, we found no significant changes in FEV1 and FEF25-75 values at baseline, 12th, 24th, and 52nd weeks (78.9 ± 23.3%, 82.9 ± 23.4%, 81.9 ± 23.9%, and 78.9 ± 23.5% for FEV1; 45.1 ± 23.1%, 48.8 ± 23.5%, 48.7 ± 23.1%, and 41.0 ± 20.1% for FEF25-75, respectively) Conclusion In this study, mepolizumab significantly improved all outcomes (symptom scores, asthma exacerbations, OCS sparing, and blood eosinophils) except functional parameters. Still, despite the dose reduction in mOCS dosage, no significant deterioration was observed in FEV1 and FEF25-75 values.


Introduction
Eosinophilic asthma generally refers to the clinical inflammatory phenotype of asthma wherein a significant number of sputum, airway, and/or blood eosinophils are present [1]. Eosinophils are key effector cells in bronchial inflammation and represent one of the main targets for biological agents. Interleukin-5 (IL-5) is the pivotal cytokine responsible for the maturation, activation, proliferation and survival of eosinophils [2,3]. Therefore, IL-5 represents a suitable specific target for biological treatments of severe eosinophilic asthma (SEA). Mepolizumab is a humanized IgG1/k monoclonal antibody which targets human IL-5 and thus prevents its interaction with the α chain of the IL-5 receptor [4,5].
Previous effectiveness studies of mepolizumab have clearly demonstrated that mepolizumab caused a meaningful lowering effect on blood eosinophils, was able to reduce asthma exacerbation rates, had a significant glucocorticoid-sparing effect and improved symptom control in asthma [6][7][8][9]. On the contrary, data regarding post-marketing studies that have evaluated the effects of mepolizumab in real-life settings are limited. Furthermore, the data about the effectiveness of mepolizumab therapy on small airways is quite limited in patients with SEA. Therefore, we evaluated effectiveness of mepolizumab on symptoms, asthma exacerbations, blood eosinophils, steroid dependence, and small airways in the real-life settings.

Materials and methods
This retrospective study included 41 severe asthmatics who had been treated with mepolizumab between 2018 and 2020. All patients were treated with high-dose inhaled glucocorticoids (ICS) (extrafine hydrofluoroalkanebeclomethasone dipropionate), and a long-acting β 2agonist, along with a second controller montelukast at least 6 months and most of patients were receiving mOCS therapy before the mepolizumab treatment. Indications to be treated with mepolizumab were approved on the basis of the Turkey Social Security Institution Health Application Communique, according to which, mepolizumab can be administered to patients with SEA having: a) blood eosinophil count ≥300 cells/µL (≥150 cells/µL: If the patient is under long-term regular OCS therapy); b) controlled or uncontrolled asthma treated with regular systemic steroids for at least 6 months and/or uncontrolled asthma (relatively two attacks per year requiring systemic corticosteroids for at least 3 days) despite use of a high combination dosage of ICS (> 800 mcg/day budesonide or equivalent) and inhaler long-acting β 2 agonist for at least one year [10]. 1 Throughout the study period, parameters including mOCS (presented as methyl-prednisone equivalent in milligrams), asthma control test (ACT) score, blood eosinophil count, forced expiratory volume in 1 s (FEV 1 ) and FEF25-75 were measured at baseline, at week 12, at week 24, and at week 52 after the first injection of mepolizumab. In addition, the numbers of asthma exacerbations were also recorded at baseline, week 24, and week 52 ( Figure 1).
All patients were under follow-up at our asthma outpatient clinic provided written informed consent. Ethical approval was obtained from the Erciyes University Ethics Committee.

Definitions 2.1.1 Treatment response to mepolizumab
Mepolizumab was continued if there was a clinical response at week 12. Responder: ACT variations were higher than the accepted minimal clinically important differences of three points in real life [10]. Eligibility of patients to continue treatment was based on an increased in ACT score of ≥3 from the baseline or clinically significant reduced dose of mOCS without deterioration in ACT or reduction of exacerbation rate by at least 50%.

Asthma exacerbations
An exacerbation was defined as worsening of asthma symptoms, requiring OCS at least three days a week or an increase in the mOCS dose.

Chronic rhinosinusitis with nasal polyposis (CRSwNP)
CRSwNP is characterized by the occurrence for more than 12 weeks of symptoms as nasal discharge, stuffiness, facial pressure or pain, dysfunction or loss of the sense of smell, and cough from post-nasal drip. The polypoid inflammation filling the nasal airway in the paranasal sinus computerized tomography (PNCT) [11,12].

Glucocorticoid reduction phase scheme
The dose of methylprednisone was reduced every four weeks according to a predefined schedule (Table 1), if the patient did not have an exacerbation with a decrease in ACT score. In patients who were receiving a daily dose of 8 mg or more of methylprednisone at baseline, the dose of the drug was not reduced to 0 without consulting to endocrinology due to concern regarding withdrawal effects.

Pulmonary function assessments
Pulmonary function tests were performed at the Erciyes University Medical Faculty Chest Diseases outpatient clinic by trained and experienced respiratory function test technicians of at least 5 years using a Vmax 20c spirometre device while the patients were at a sitting position. Following at least 3 acceptable maneuvers of the pulmonary function test, the best test was recorded. FEV 1 (Forced expiratory volume in 1 s), FVC (forced vital capacity), FEV 1 /FVC, FEF25-75 values were measured and presented as the percentage of the expected value, according to the patient's age and height.

Statistical analysis
Data were entered into Statistical Package for Social Sciences software v: 17.0 (SPSS Inc; Chicago, IL, USA), and analyses were made using the same software program. The distribution of continuous variables was tested with the one-sample Kolmogorov-Smirnov test, and the data are shown as mean ± standard deviation or median and minimum-maximum intervals. For all parametric variables, between group comparisons were made by using repeated measures Anova. For all nonparametric variables, between group comparisons were made by Friedman test, and Dunnett's multiple comparison test was made within groups when the difference was statistically significant. A p value of < 0.05 was considered to be significant in all analyses.
A total of 31/34 (91%) patients continued the mepolizumab treatment after 24 weeks. Three patients were not included in the 24 weeks' assessment for mepolizumab efficacy [two were nonresponders (6%), one stopped due to adverse drug reaction in the "possible category" (heart failure) before the 24th week] ( Figure  2). Of the responders, 31/33 (94%) were still responders at the 24th weeks' assessment. After the 24th week under mepolizumab treatment, the decrease in blood eosinophil     When compared to baseline, at week 24, a significant decrease in the exacerbation rates within the last 24 weeks was observed (1 (0-8) vs. 0 (0-0); p < 0.001). A total of 21/31 (68%) patients continued mepolizumab treatment after 52 weeks. Ten patients were not included in the 52 weeks' assessment for mepolizumab efficacy (9 were awaiting 52 weeks assessment, one was nonresponder before 52nd weeks) ( Figure 2). Of the responders, 21/22 (95%) were still responders at the 52 weeks' assessment. After 52 week under mepolizumab treatment, the decrease in blood eosinophil counts (baseline eosinophil count: 6.2 ± 6.1%; 52nd week eosinophil count: 1.2 ± 0.8%; p < 0.001) and improvement in ACT scores (baseline ACT: 17 (7-25); 52nd week ACT: 24 (17-25); p < 0.001) continued. mOCS dose was additionally reduced in five patients when comparing to 24th week results. In total, the OCS dose of 18/21 (85.7%) patients could be reduced at the end of 52 weeks. mOCS treatment was withdrawn in four additional patients at week 52. In total, 11/21 (52%) patients were able to discontinue mOCS at the end of 52 weeks. At this time point a significant decrease in the exacerbation rates within the last 52 weeks was observed when compared to baseline (1 (0-8) vs. 0 (0-3); p < 0.001). Comparison of mOCS dose, number of asthma exacerbations, ACT scores, and peripheral blood eosinophils at the beginning of mepolizumab and at 12th, 24th, and 52th weeks after treatment was shown table Table 3.

Discussion
Our study showed that mepolizumab therapy reduced the rate of asthma exacerbations, decreased mOCS dose, improved ACT scores, and decreased peripheral blood eosinophil counts in patients with SEA. On the contrary, we found no marked changes in FEV 1 and FEF25-75 values with 52-week mepolizumab add-on treatment.
We suggested that SC fixed-dose mepolizumab administration significantly decreased blood eosinophil levels, asthma exacerbations, mOCS doses and improved ACT scores in patients with SEA in agreement with the placebo-controlled studies and real life studies [6][7][8][9][13][14][15]. There were no significant change in FEV 1 values after 12, 24, and 52 weeks of mepolizumab treatment, compared to baseline in agreement with some studies [7,[15][16][17][18]]. Yet, the important point here is that there was no deterioration in pretreatment FEV 1 values, and improved ACT scores despite dose reduction or discontinuation of OCS.
The small airway impairment, as assessed with FEF25-75 and might contribute to long-term persistent asthma  and the subsequent risk for poor asthma outcomes, independently of large airway status [19]. Therefore, we evaluated mepolizumab effectiveness on small airways with mid expiratory flow rates. Despite no unanimous consensus on the algorithm to assess small airway function and structure, several noninvasive techniques can detect small airway dysfunction. FEF25-75 is generally thought to be more reflective of small airways obstruction than is FEV 1 [20,21]. Contrary to our expectation, we didn't find any significant improvement in FEF25%-75% with mepolizumab effect on small airways. However, there was no deterioration in pretreatment FEF25-75 values despite dose reduction or discontinuation of OCS. To the best of our knowledge, there are only two studies evaluating the effect of mepolizumab on small airways in the literature. In the first study conducted by Farah et al, mepolizumab could significantly improve small airways in SEA measured with multiple breath nitrogen washout [22]. The improvement in small airway function was associated with asthma control in the study [22]. Unlike this study, the absence of changes in small airways in our study may result from small airway assessment method differences. The nitrogen washout method may be more sensitive than the FEF25-75 measurement in detecting the change in small airways   in patients receiving mepolizumab treatment [23,24]. On the other hand, our study cohort differed from this study cohort. At baseline, our patient population were younger and most of the patients was using mOCS, had nasal polyposis and higher FEV 1 values. In the second study, Sposato et al. showed that FEF25-75 improved after mepolizumab therapy in patients with SEA on the contrary to our results [25]. Although both studies had similar patient cohorts, different results were obtained. As an explanation of this different results might be due to the low number of patients in our study. Another explanation is that the mOCS doses could be reduced rapidly within 3 months in majority of our cases because there was a significant increase in the symptom scores of the patients and the absence of asthma exacerbation. This decreasing continued until the end of the 52nd week. Therefore, while the dose of OCS can be reduced, we also reduce the improving effect of OCS on small airways. The limitation of the present study was its retrospective design. Another limitation is that the lack of validity of the FEF25-75 measurement to reflect small airway functions and inflammation [26,27]. However, The FEF25-75 is the spirometric variable most commonly cited as an indicator of small airway obstruction in literature [28]. The small airways were evaluated retrospectively with FEF25-75 values in our study. If it was a prospective study and our primary aim was to evaluate small airways, we could make a comparison using one of the other methods to evaluate small airways. In this way, we could more clearly evaluate the effect of mepolizumab on small airways.
In conclusion, mepolizumab has been shown to be effective in reducing exacerbations and daily doses of mOCS in this real-life cohort of patients with SEA. Although we found no improving effect of mepolizumab therapy on small airways assessed with mid expiratory flow rates there was no significant deterioration compared to pretreatment FEF25-75 values, and there were improved ACT scores despite dose reduction or discontinuation of mOCS. Further studies comparing the effectiveness of mepolizumab treatment on the small airways with different techniques are needed.