Factors Affecting the Ability to Discontinue Oral Corticosteroid Use in Patients with EGPA Treated with Anti-Interleukin-5 Therapy

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by excessive eosinophil accumulation in the peripheral blood and granulomatous vascular organ damage in the affected tissues. Two different inflammatory processes contribute to the development of EGPA: eosinophilic inflammation, which leads to tissue damage caused by eosinophils, and myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-mediated inflammation, which results in necrotizing vasculitis. This leads to the emergence of two EGPA phenotypes based on the presence of MPO-ANCA. MPO-ANCA-positive EGPA is associated with small vessel vasculitis, frequent glomerulonephritis, alveolar hemorrhage, and peripheral nerve neuropathy. On the other hand, MPO-ANCA-negative EGPA is linked to variations in GPA33 and interleukin (IL)-5, and the genetic association is shared with asthma [1]. As EGPA typically develops during the prodromal stage of severe asthma, it can be perceived as a potential complication of severe eosinophilic asthma. Although corticosteroids are the mainstay of EGPA treatment and can significantly improve prognosis, most patients remain dependent on corticosteroid therapy, and relapse is common [2, 3]. Oral corticosteroids (OCSs) are also recommended for treating severe asthma when other treatments fail to control the disease [4].

Despite treatment, the severity of asthma remains unchanged in the months and years following EGPA diagnosis. Cottin et al. [5] reported that more than 80% of patients with EGPA received OCS for several years, with a mean daily dose of >10 mg/day of prednisolone required to control asthma. However, long-term OCS use is associated with complications such as fractures (osteoporosis), susceptibility to infections, obesity, diabetes mellitus, gastrointestinal ulcers, stroke, skin thinning, and cataracts, even at low doses. Dalal et al. [6] reported a significant dose-response relationship between the long-term use of systemic corticosteroids and the risk of developing systemic corticosteroid-related complications in patients with severe asthma. The EGPA Consensus Task Force recommends that the OCS dose be <7.5 mg/day to limit glucocorticoid-induced side effects [7]. Although glucocorticoids are the basis of EGPA treatment, other immunomodulatory agents (e.g., cyclophosphamide, methotrexate, or azathioprine) are also used as adjunct therapies in severe cases to reduce corticosteroid use. However, given the lengthy and high-dose use of immunosuppressive agents that are associated with the risk of complications such as infection and malignancy [8], there is a need for additional, more effective, and safe therapies.

EGPA and asthma have traditionally been considered type 2 inflammation-mediated diseases, mainly because of their prominent eosinophilic components [9]. The Global Initiative for Asthma recommends the use of blood eosinophil counts to identify patients with type 2 inflammation and targets the use of biologics for the management of severe asthma [4, 10]. IL-5 is a key driver of eosinophilia, chemotaxis, differentiation, activation, and eosinophil survival [9]. Preventing the binding of IL-5 to the IL-5R subunit α on the surface of eosinophils is a promising therapeutic strategy. Biological agents that target IL-5 (mepolizumab) have been used to treat severe asthma. Targeting airway eosinophil-related immunological processes can reduce asthma [10]. The MIRRA trial demonstrated that the IL-5-neutralizing antibody, mepolizumab, is a safe and effective steroid-sparing agent in patients with EGPA [11]. In the trial, 18% of patients were able to discontinue oral steroids. However, there is no information on the differences between patients with EGPA treated with mepolizumab who were able to discontinue steroid use and those who were not.

Mepolizumab has been reported to allow patients with EGPA to discontinue steroids, but the factors contributing to this difference are not known. In this study, we will compare the characteristics of patients who responded to steroid reduction with mepolizumab with those who did not and attempt to identify predictors of treatment response. This is expected to contribute to the development of more effective treatment strategies.

We conducted a systematic retrospective study of patients with EGPA, whose data were entered into our hospital’s database. The diagnosis of EGPA was based on the diagnostic criteria of the Japanese Ministry of Health, Labor and Welfare [12]. Patients with EGPA and severe eosinophilic asthma requiring long-term continuous OCS to maintain disease control, for whom prior OCS dose-weaning efforts had failed, were administered subcutaneous mepolizumab therapy at a dose of 300 mg for 4 weeks. Since a trial period of at least 4−6 months is generally recommended to determine the efficacy of biologics used for asthma, the evaluation of asthma efficacy in EGPA followed this recommendation [13].

Mepolizumab was administered to 20 patients with OCS-dependent EGPA and eosinophilic asthma. They were predominantly middle-aged (mean ± standard deviation 60.60 ± 9.52 years), 85% were female, with a mean body mass index of 23.67 ± 2.60 kg/m², and all had adult-onset asthma. Given the ongoing OCS therapy, asthma symptom scores were suggestive of optimally controlled disease (asthma control test [ACT], 22.58 ± 3.24). The institutional Ethics Committee approved the study design, and written informed consent was obtained from all patients.

Comparisons of variables before and after mepolizumab treatment were performed using the Mann-Whitney U test [14]. Results are presented as the mean ± standard deviation. Linear regression analysis was performed to investigate the biological relationships. Data were analyzed using the GraphPad Prism 9 software. A p value <0.05 was considered significant.

Approximately 25% were MPO-ANCA-positive, and 65% had histological confirmation of EGPA. Additionally, 80% of the patients had rhinosinusitis, 70% had neurological symptoms of EGPA, 55% had skin eruption, and 15% had cardiac involvement. All patients had been receiving moderate- to high-dose OCS (mean daily prednisolone dose 8.88 ± 4.99 mg/day; 85% received ≥5 mg/day). Exactly 55.0% received doses below the 7.5 mg/day prednisolone threshold suggested by the European League Against Rheumatism (EULAR), consistent with remission [7]. Some patients were treated with at least one other immunomodulatory agent (cyclophosphamide, 10%; azathioprine 5%; methotrexate, 5%; or intravenous immunoglobulin, 30%). Following treatment (166.8 ± 84.26 weeks, range 28.0∼322.0 weeks), the dose of OCS was reduced in 95% of patients with no major safety concerns (Table 1). There was a significant reduction in the maintenance mean OCS dose, from a prednisolone equivalent of 8.88 ± 4.99 mg/day to 3.18 ± 3.47 mg/day (p < 0.0001) (shown in Table 1). Most patients (80.0%) had a ≥50% maintenance OCS dose reduction, 90.0% had their doses ≤7.5 mg/day prednisolone, and 40% of patients could stop OCS completely (shown in Table 1). This occurred alongside a nonsignificant change in the ACT score from 22.58 ± 3.24 to 23.47 ± 2.20 (p = 0.4844). No significant changes were observed in the percentage predicted forced expiratory volume in 1 s (%FEV1), from 76.30 ± 17.79% to 77.37 ± 28.4% (p = 0.2166). Despite the reduction in OCS exposure, peripheral blood eosinophil counts remained suppressed from 547.6 ± 518.2/μL to 82.63 ± 186.8/μL (p < 0.0001), no significant change in fractional exhaled nitric oxide (FeNO) occurred from 71.0 ± 57.78 ppb to 62.19 ± 49.37 ppb (p = 0.7869), and no increase in exacerbation frequency or hospitalization was observed.

Figure 1 shows the reasons steroids could not be discontinued after mepolizumab administration. The most common reason for failure to discontinue steroids after mepolizumab administration was worsening asthma control (50%, n = 6) followed by an exacerbation of eosinophil-related diseases (33.3%; chronic sinusitis and chronic otitis media, n = 1 and peripheral blood eosinophilia, n = 3); exacerbation of vasculitis was less common (8.3%, n = 1). Table 2 shows the background of the groups that were able to discontinue steroids after receiving mepolizumab and those that were not. There were no significant differences in baseline demographics, medical history, comorbidities, pulmonary function, laboratory data, or clinical background of corticosteroid therapy between the two groups. There was no association between MPO-ANCA positivity and OCS discontinuation. We analyzed changes in the data at 4 months (6 months for some patients) after the initiation of mepolizumab. %FEV1 increased significantly 4 months after mepolizumab treatment in the successful OCS discontinuation group. In contrast, in the failed OCS discontinuation group, the %FEV1 did not increase 4 months after treatment with mepolizumab (shown in Fig. 2). The change in peripheral blood eosinophil count from pre-mepolizumab initiation to 4 months post-mepolizumab initiation in patients with EGPA was significant in both the successful OCS discontinuation group (from 404.0 ± 299.1 to 31.4 ± 28.5%, p = 0.015) and the failed OCS discontinuation group (from 654.6 ± 694.1 to 43.33 ± 42.4, p = 0.039).

A positive correlation was observed between the %FEV1 and eosinophil count in the group that discontinued steroids after mepolizumab treatment (shown in Fig. 3b). Despite adequate disease control, treatment-limiting adverse effects were observed in 1 patient who reported a local reaction four times after subcutaneous mepolizumab infusion.

IL-5 is a potent eosinophil-selective activator of various cellular functions. Eosinophils release cationic proteins such as eosinophil cationic proteins, eosinophil peroxidases, eosinophil-derived neurotoxins, and eosinophil granule major basic proteins, which are directly involved in mediating tissue damage [9]. Mepolizumab is increasingly being used for diseases in which eosinophils are key immune effectors, such as eosinophilic asthma and EGPA. Although the clinical effects of mepolizumab in severe asthma have been extensively investigated and reviewed [15, 16], its effectiveness in EGPA remains to be seen in real-life studies. Our findings revealed that mepolizumab treatment reduced OCS and that asthma control is an important factor in steroid reduction in EGPA.

EGPA is now considered a chronic and frequently relapsing disease requiring long-term immunosuppression and is unfortunately associated with non-negligible sequelae [17]. Chronic high-dose OCS use is associated with severe and sometimes irreversible adverse effects, including increased risk of infection, osteoporosis, and secondary adrenal insufficiency [18, 19]. An OCS dose >10 mg/day was significantly associated with infectious complications (bacterial pneumonia, herpes zoster, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia) [19]. Therefore, the EGPA Consensus Task Force recommends a maintenance corticosteroid dose of <7.5 mg/day to limit corticosteroid-induced side effects [7].

EGPA encompasses a broad heterogeneity of endotypes that benefit from different treatments [7]. Immunosuppressants other than corticosteroids (e.g., cyclophosphamide, methotrexate, and azathioprine) are also recommended for remission induction and maintenance therapies in EGPA but are associated with significant treatment-related toxicity, opportunistic infections, and malignancy [2, 7]. Immunosuppressants other than glucocorticoids control systemic EGPA features but not ear/nose/throat (ENT) manifestations and/or asthma. According to the EGPA task force, remission excludes ENT manifestations and/or asthma. Only a minority of EGPA patients can be weaned-off glucocorticoids [3], and most require >7.5 mg/day of prednisolone administration (e.g., the EULAR threshold for vasculitis remission), mainly to control their asthma and/or ENT symptoms [20, 21]. Steroids were administered to all patients, regardless of whether they were used for asthma or EGPA.

Patients would benefit from maintenance therapy to avoid relapse and allow glucocorticoid tapering. Several studies have demonstrated that mepolizumab can be a glucocorticoid-sparing treatment in patients with EGPA and also in those with severe asthma, with an excellent safety profile [11, 15]. In the MIRRA trial, mepolizumab was administered at a dose of 300 mg every 4 weeks, higher than the approved asthma dose of 100 mg/4 weeks. The MIRRA study was the first randomized controlled trial conducted on EGPA and one of the largest clinical trials involving patients with EGPA. Compared with placebo, mepolizumab resulted in at least a twofold increase in the percentage of patients who achieved remission (from 19% to 53%) and reduced OCS use by 50% or more (from 21% to 57%), resulting in relapse-free follow-up (from 18% to 44%) for over 52 weeks. Mepolizumab is also associated with a twofold reduction in the number of relapses, including vasculitis, ENT symptoms, and asthma [11].

In our study, the proportion of patients who were able to discontinue oral steroids was much higher than that in the MIRRA trial [11] (40% vs. 18%). The most common reason for failure to discontinue steroids in patients on mepolizumab was poor asthma control. Therefore, it is important to optimize asthma treatment in patients with EGPA. We encountered several specific and difficult-to-manage clinical situations in EGPA management. Persistent asthma is a major burden for patients with EGPA, and asthma exacerbations can occur repeatedly throughout the disease course, especially when the prednisone dose is <10 mg/day and/or the eosinophil count exceeds 500/mm³ [3]. Emmi et al. [1] reported that the severity and pulmonary function test results of asthma remained unchanged during long-term follow-up regardless of ICS or OCS therapy for EGPA. In patients who were able to eliminate steroid administration after receiving mepolizumab, a correlation was observed between %FEV1 and peripheral blood eosinophil count at 4 months. This correlation suggests that airway inflammation is not effectively managed by mepolizumab.

Based on the presence or absence of MPO-ANCA positivity, EGPA has two phenotypes: eosinophilic inflammation causing eosinophilic tissue damage and ANCA-mediated inflammation causing necrotizing vasculitis. Clinically, MPO-ANCA-positive EGPA is associated with small vessel vasculitis, frequent glomerulonephritis, pulmonary hemorrhage, and peripheral neuropathy, and responds well to rituximab, but the effect of mepolizumab in patients with MPO-ANCA-positive EGPA remains poorly understood. However, although there were fewer patients with MPO-ANCA-positive EGPA in this study, we found no difference in steroid discontinuation between patients with and without MPO-ANCA positivity.

This study had some limitations. The study population was small, and all subjects were treated at a single center. Further, due to the single-arm retrospective nature of the study, it was not a clinical trial and was therefore open to bias. The absence of a control group means we cannot discount the possibility of a placebo effect or regression of the mean reduction in the OCS dose and maintenance of asthma control. However, our observations are consistent with previous reports on mepolizumab in EGPA [11]. Despite these limitations, the results successfully demonstrated real-life practices and outcomes associated with using mepolizumab.

In summary, we expect that mepolizumab will mainly be used as a steroid-sparing agent in patients with EGPA where the OCS dose cannot be tapered in real-life practice while maintaining asthma control. This study highlights that asthma control inhibits steroid reduction with mepolizumab. In our study, 40% of patients with EGPA were able to successfully discontinue steroid use, with subsequent improved respiratory function. Based on these findings, it may be feasible to discontinue steroids if FEV1 increases after mepolizumab treatment. However, further studies with larger patient cohorts and longer follow-up periods are necessary to comprehensively assess the effectiveness of mepolizumab in the treatment of EGPA.

We thank Kyoko Uekawa and Shoko Tachibana for their assistance in the preparation of this manuscript.

In accordance with the guidelines for human studies and the World Medical Association Declaration of Helsinki, we obtained written informed consent from all participants to participate in the study. The study protocol was reviewed and approved by the Osaka Habikino Medical Center Ethics Committee, approval number [1037]. This committee has confirmed that our study adheres to ethical standards and patient rights.

Written informed consent was obtained from the patient to publish the details of their medical case and any accompanying images. The patient was made aware of the potential risks and benefits of publication, and their privacy was protected in accordance with relevant regulations.

The presented data are part of our clinical work, and the authors declare no conflicts of interest. O.M. has received speaker fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi.

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Osamu Matsuno was involved in data generation, analysis, and drafting of the manuscript.

Edited by: H.-U. Simon, Bern.

Data are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author.