Management of Non-Severe Eosinophilic Granulomatosis with Polyangiitis without Immunosuppressants Using Mepolizumab: Clinical Implications

Management of Non-Severe Eosinophilic Granulomatosis with Polyangiitis without Immunosuppressants Using Mepolizumab: Clinical Implications | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Management of Non-Severe Eosinophilic Granulomatosis with Polyangiitis without Immunosuppressants Using Mepolizumab: Clinical Implications Nami Masumoto, Yuga Yamashita, Takuya Nakashima, Yuka Kodama, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8125801/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: To investigate whether long-term remission can be maintained with corticosteroids plus mepolizumab, without the addition of conventional immunosuppressants, following initial remission induction in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Methods: We retrospectively recruited 72 EGPA patients treated at the National Hospital Organization Yokohama Medical Center (April 2022 to March 2025). Patients were categorized into an IS-combination group (immunosuppressant + corticosteroid + mepolizumab) and a non-IS group (corticosteroid + mepolizumab) on the basis of immunosuppressant use at mepolizumab initiation. Peripheral blood eosinophil counts, Birmingham Vasculitis Activity Score (BVAS), systemic corticosteroid dosage, remission induction rates, and duration of relapse-free period following the introduction of mepolizumab were compared. Results: Compared with the IS-combination group, the non-IS group was older at EGPA onset ( P = 0.02), had a shorter interval from diagnosis to study entry ( P = 0.004), had less myocardial involvement ( P = 0.01), and had lower BVAS before treatment with mepolizumab ( P < 0.001). Immunosuppressant Use during initial treatment was 100% in the IS-combination group and 75% in the non-IS group ( P = 0.001). The non-IS group achieved remission faster ( P = 0.03), had a higher cumulative remission rate ( P = 0.01), and had a higher relapse-free rate ( P = 0.02). Conclusion: In non-severe EGPA, treatment with corticosteroids plus mepolizumab without concomitant immunosuppression should achieve earlier remission and maintain long-term disease control. anti–IL-5 antibody Churg–Strauss syndrome eosinophilic granulomatosis with polyangiitis immunoglobulin immunosuppressant mepolizumab Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare small-vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs). It differs from other ANCA-associated vasculitides, such as microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), by its frequent association with asthma, eosinophilia, and peripheral nerve involvement (1, 2). Although corticosteroids are effective for inducing remission in ANCA-associated vasculitides, EGPA relapses more frequently than MPA or GPA, even in patients without poor-prognosis factors (3). In EGPA patients with a Five-Factor Score (FFS) (4) of 0, glucocorticoid monotherapy has historically been considered sufficient, yet relapse occurs in approximately 35% (5). Peripheral neuropathy is a strong predictor of relapse, highlighting the limitations of FFS alone as a guide to initial therapy (6). Although an FFS of 0 may indicate that there will be no adverse effect on overall survival, relapse contributes to irreversible damage, as reflected by higher Vasculitis Damage Index scores (7). These findings support the early introduction of immunosuppressive therapy, even in patients without poor-prognosis factors. Cyclophosphamide (CYC) remains a key agent for remission induction in severe EGPA, and its efficacy is dose dependent. In a prospective multicenter trial, 12 pulses of intravenous cyclophosphamide (IVCY) reduced relapse significantly more than 6 pulses, highlighting the importance of adequate dosing for long-term disease control (8). Although toxicity concerns often limit CYC use in elderly patients, low-dose IVCY regimens (500 mg/body × 6 courses) have shown efficacy comparable to that of conventional protocols (600 mg/m²), with fewer adverse effects (9). These findings indicate that immunosuppressive therapy should not be withheld solely because of age and suggest the importance of proactive immunosuppressive strategies in EGPA, regardless of initial FFS, to reduce relapse risk and minimize long-term organ damage. Combination therapy with systemic corticosteroids plus IVCY is often recommended for EGPA with life-threatening or major organ involvement. However, both corticosteroids and cytotoxic immunosuppressants carry substantial risks, including infection, malignancy, and long-term organ toxicity (10, 11). Mepolizumab, an anti–IL-5 monoclonal antibody, reduces blood eosinophil counts and has proven effective in severe asthma (12, 13). In EGPA, a 2010 pilot study demonstrated that intravenous mepolizumab (750 mg every 4 weeks) safely reduced peripheral eosinophils (14). The 2017 MIRRA trial—the first randomized, double-blind, placebo-controlled study of subcutaneous mepolizumab (300 mg monthly) in relapsing or refractory EGPA—showed significantly longer remission, with 53% of patients achieving remission versus 19% with placebo (15). However, current guidelines leave the role of mepolizumab in the treatment of EGPA incompletely defined. European Alliance of Associations for Rheumatology (EULAR) recommendsations adding mepolizumab to corticosteroids for relapsing or refractory disease without organ- or life-threatening manifestations—specifically glomerulonephritis, alveolar hemorrhage, meningeal or central nervous system involvement, retinal vasculitis, mesenteric ischemia, or multiple mononeuritis—while prioritizing CYC or rituximab (RTX) for patients presenting with organ- or life-threatening features (16). The timing of mepolizumab initiation is not addressed. The guidelines also suggest switching from CYC to maintenance agents (azathioprine [AZA], methotrexate [MTX], RTX, or mepolizumab) after remission induction, but they do not specify a preferred sequence. Other proposed treatment algorithms vary. Raffray and Guillevin (17) recommend corticosteroids as initial therapy for patients with an FFS of 0, with mepolizumab added if induction of remission fails or asthma persists; for patients with FFS ≥ 1, CYC is used for induction, and following remission, maintenance therapy with AZA, MTX, or RTX is initiated, with mepolizumab added if needed. This algorithm implies that mepolizumab should be considered in nearly all patients except those achieving remission with corticosteroids alone. However, the criteria for selecting mepolizumab over other agents remain undefined. Emmi et al. (18) recommend combining mepolizumab with maintenance therapy after induction in newly diagnosed EGPA, regardless of severity. In relapsing disease, they suggest corticosteroids alone or with mepolizumab for non-severe cases, whereas severe relapses require high-dose corticosteroids in combination with CYC or RTX. Mepolizumab is not mentioned in the context of severe relapses. Notably, neither approach defines how mepolizumab compares with conventional immunosuppressants in severe disease, leaving its optimal timing and integration uncertain. We previously investigated mepolizumab in EGPA, assessing remission induction, corticosteroid-sparing effects, and its effectiveness across a broad spectrum of vasculitic manifestations. In one study, we also confirmed potential synergy between mepolizumab and intravenous immunoglobulin (IVIG) (19). In another, we found that long-term administration of mepolizumab (> 3 years on average) significantly suppressed relapse rates, particularly in patients classified as super-responders (20). Across those studies, serious adverse events typically associated with conventional immunosuppressants—such as bone marrow suppression, infection, hepatotoxicity, nephrotoxicity, or increased risk of malignancy—were observed during treatment with mepolizumab. However, it remains unclear whether long-term remission can be sustained with corticosteroids plus mepolizumab alone, without AZA or MTX, following initial remission induction. In Japan, mepolizumab has been approved for clinical use since 2018. Patients diagnosed before its approval were typically treated with corticosteroids plus conventional immunosuppressants before subsequent addition of mepolizumab. In contrast, in patients diagnosed after 2018—particularly those without cardiac involvement—mepolizumab is often initiated following corticosteroid therapy, without the addition of immunosuppressants. In this retrospective study, we compared patients who were and were not receiving immunosuppressants at the time of mepolizumab initiation, and we assessed peripheral blood eosinophil counts, Birmingham Vasculitis Activity Score (BVAS) (21), systemic corticosteroid dosage, relapse rates, remission induction rates, and remission maintenance duration following the introduction of mepolizumab. Methods Patients We retrospectively enrolled 72 patients with EGPA who were treated at the Department of Respirology, National Hospital Organization Yokohama Medical Center, Kanagawa, Japan between April 2022 and March 2025. EGPA was diagnosed according to the criteria for allergic granulomatosis angiitis (known as Churg–Strauss syndrome) (22) and classified by using both the 1990 (23) and 2022 (24) American College of Rheumatology criteria. Inclusion required at least four of the following six features: asthma, eosinophilia, polyneuropathy, pulmonary infiltrate, paranasal sinus abnormality, and extravascular eosinophils. All patient data were collected retrospectively from medical records. The study was approved by the Ethics Committee of the National Hospital Organization Yokohama Medical Center (approval no. 2022-06), and written informed consent was obtained from all patients or their legal representatives. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Study Design Of 72 patients with EGPA, 60 who did not achieve remission with conventional therapy (e.g., corticosteroids, CYC, AZA, or MTX) received mepolizumab. As mepolizumab was approved in Japan in June 2018, these 60 patients were categorized into two cohorts according to the year of diagnosis (Fig. 1 ). One cohort comprised 35 patients diagnosed before 2018. Of these, 30 had already been receiving corticosteroids plus immunosuppressants at mepolizumab initiation and were assigned to the IS-combination group (CS + IS + mepolizumab). Five patients could not receive immunosuppressants owing to adverse effects and were assigned to the non-IS group (CS + mepolizumab). The other cohort comprised 25 patients diagnosed in or after 2018. Mepolizumab was initiated without concurrent immunosuppressants in 15 cases (non-IS group [CS + mepolizumab]), including 12 without cardiac involvement, 1 with cardiac involvement that had improved with conventional therapy, and 2 elderly patients who developed EGPA at the ages of 77 and 83 years. In these cases, any immunosuppressants used during initial treatment were discontinued before mepolizumab initiation. The remaining 10 patients in this cohort who failed to achieve remission with conventional therapy were treated with mepolizumab in combination with corticosteroids plus immunosuppressants (IS-combination group [CS + IS + mepolizumab]). Definitions A state of remission was defined as the absence of clinical signs or symptoms of active vasculitis after initial treatment. A state of relapse was defined as the recurrence, after remission, of vasculitis symptoms and signs that required the resumption of immunosuppressive therapy or an increased dose of immunosuppressants or additional intravenous immunoglobulin (IVIG). Exacerbation of asthma or sinusitis (with or without an increase in the proportion of eosinophils among white blood cells) was excluded from our definition of relapse. Although a large increase in tissue eosinophilia might have been correlated with an increase in the severity of vasculitis signs and symptoms, this criterion was not considered in our definition of relapse. Frequent relapse was defined as ≥ 1 relapse every 2 years after a period of initial remission; infrequent relapse was defined as < 1 relapse every 2 years (25). Assessment of organ involvement Multiple mononeuritis, a measure of motor nerve dysfunction, was evaluated by using manual muscle testing (0 to 5, on the Medical Research Council scale), as well as by electromyographic examination. Sensory nerve dysfunction was evaluated subjectively on the basis of symptoms and physical examination. Lung involvement was considered in cases with ground glass opacity, nodules within the ground glass opacity, interlobular septal thickening (26, 27), bronchial wall thickening, lymphadenopathy (28, 29), pleural effusion (identified by high-resolution computed tomography) (26, 30), or infiltration by eosinophils (identified by lung biopsy). Cardiac involvement was defined as cardiac symptoms—specifically chest pain, chest discomfort, back pain, and palpitations; abnormal signs on cardiac echocardiography, Holter electrocardiogram, and myocardial imaging using 123 I-metaiodobenzylguanidine; or abnormal plasma B-type natriuretic peptide levels (31). Gastrointestinal involvement was defined as symptoms of epigastralgia, abdominal pain, diarrhea, constipation, positive endoscopy signs, and gastrointestinal eosinophil infiltration or colonic submucosal edematous change detected by biopsy (32). Skin involvement was defined as the presence of purpura, erythema, livedo, ulceration, acrocyanosis, nodule formation, or eosinophilic infiltration as detected by biopsy. Central nervous system involvement was defined as the presence of headache, visual disturbance, abnormal visual sensation, cerebral infarction or bleeding, or cranial nerve dysfunction. Renal involvement was defined by any one of the following: presence of eosinophiluria, glomerulonephritis, nephrosis (proteinuria > 3.5 g/day), renal dysfunction (i.e., elevation of creatinine level to > 20% of baseline), or proteinuria (> 0.5 g/day or 50 mg/dL). Otitis media was diagnosed by an otorhinolaryngologist. In all patients with EGPA, disease severity was scored by using FFS 1996 (4) or FFS 2009 (33). When the total number of organs involved was counted, those that were compromised by asthma or sinusitis were not included. We evaluated the disease activity at onset and at first relapse by using the BVAS, which examines symptoms and signs within nine categories (systemic; cutaneous; mucous membranes and eyes; ear, nose, and throat; chest; heart and vessels; gastrointestinal tract; renal system; and nervous system) (21). The maximum number of points is 7 in each category, with a maximum total score of 63. Data collection We investigated white blood cell count, eosinophil count, MPO-ANCA (myeloperoxidase-antineutrophil cytoplasmic autoantibody), PR3-ANCA (proteinase 3-ANCA), and immune complex levels in the serum at EGPA onset. Treatments were extracted from the patients’ medical records, including methylprednisolone (mPSL) pulse therapy (1000 mg/day for 3 consecutive days), initial doses of prednisolone (PSL), immunosuppressants (CYC, AZA, MTX, cyclosporine, and RTX) during induction or maintenance, and IVIG (400 mg/kg daily for 5 days; Venilon, Teijin, Tokyo, Japan). Endpoints The primary endpoint was the last examination performed during the study period. We evaluated eosinophil count in the peripheral blood, daily dose of PSL, and BVAS, and we recorded survival status, cause of death, remission or relapse status, and ongoing treatment at last examination. Statistical analysis Continuous variables are expressed as means ± SD and medians (range), unless otherwise specified. Differences between groups were assessed by using repeated-measures two-way ANOVA, followed by Newman–Keuls post hoc tests. The two mean values obtained by this process were compared by using the Wilcoxon matched-pairs t- test. Correlations were evaluated with Spearman’s rank correlation coefficient. Survival analyses were performed by using Kaplan–Meier analysis with log-rank test and Wilcoxon tests. Statistical significance was defined as P < 0.05. Statistical analyses was performed by using SPSS for Windows, version 29 (SPSS, Inc., Chicago, IL, USA). Results Comparison of baseline characteristics at diagnosis between the IS-combination group and the non-IS group Characteristics of the 60 EGPA patients treated with mepolizumab are summarized in Table 1. There were no significant differences in baseline characteristics such as age at study admission, sex, peripheral blood eosinophil count, positivity rates for MPO-ANCA, PR3-ANCA, immune complexes (IC), rheumatoid factor (RF)RF, B-type natriuretic peptide (BNP), or serum total IgE and IgG levels between the IS-combination group and the non-IS group. In contrast, age at asthma onset ( P = 0.02) and EGPA onset ( P = 0.02) was higher in the non-IS group, and the interval from EGPA diagnosis to study admission was shorter ( P = 0.004). Most clinical manifestations at diagnosis and BVAS at diagnosis did not differ between the two groups, except for myocardial involvement, which was significantly more prevalent in the IS-combination group ( P = 0.01). BVAS before treatment with mepolizumab was also higher in the IS-combination group ( P < 0.001). Scores on ACR 1990 ACR 2022, FFS 1998, and FFS 2009 did not differ between the two groups (data not shown). There was no significant difference between the two groups in the proportion of patients who received mPSL pulse therapy or in the initial dose of PSL. As expected, all patients in the IS-combination group received immunosuppressants during initial treatment, compared with 75% in the non-IS group ( P = 0.001). Conversely, CYC was used more frequently as part of the initial treatment in the non-IS group (80%). Maintenance doses of PSL, both before initiation of mepolizumab and at the final examination, did not differ significantly. However, at the final examination, 10 out of 40 patients (25%) in the IS-combination group were able to discontinue immunosuppressants. No patient discontinued PSL by the time of the final examination. The interval from EGPA diagnosis to mepolizumab initiation was significantly longer in the IS-combination group ( P = 0.03). The duration of mepolizumab treatment also tended to be longer in the IS-combination group, but the difference was not statistically significant ( P = 0.06). In contrast, the time to remission was significantly longer in the IS-combination group ( P = 0.03). Changes in eosinophil count, PSL dose, BVAS, and relapse rate In both the IS-combination group and the non-IS group, peripheral blood eosinophil counts had already decreased significantly before the initiation of mepolizumab ( P < 0.01). A further significant reduction was observed 1 month after mepolizumab initiation, and counts remained low through to the final follow-up visit (Fig. 2 − 1). The daily dose of PSL decreased in both groups following conventional therapy. A further significant reduction was observed at 1 year after mepolizumab initiation and at the final visit ( P < 0.01). There was no significant difference in the degree of reduction between groups (Fig. 2 – 2 , Table 1). At diagnosis, BVAS did not differ significantly between the two groups. However, BVAS was higher in the IS-combination group both before the initiation of mepolizumab ( P < 0.001) and at the final visit ( P = 0.03) (Fig. 2 – 3 ) . Relapse rates (times/year) increased in both groups before the initiation of mepolizumab ( P < 0.01). In the non-IS group, relapse rates decreased after 1 year of mepolizumab ( P < 0.01) and remained low until the final visit ( P < 0.01). In contrast, the IS-combination group did not show a significant decrease in relapse rate at 1 year after mepolizumab initiation; however, a significant reduction was observed by the time of the final visit ( P < 0.01) (Fig. 2 – 4 ) . Cumulative remission rate and relapse-free rate Cumulative remission after mepolizumab initiation was analyzed by using the Kaplan–Meier method (Fig. 3 ). The non-IS group had a shorter interval from diagnosis to mepolizumab initiation than the IS-combination group (Table 1). Furthermore, the cumulative remission rate was significantly higher in the non-IS group (log-rank P = 0.03; Wilcoxon P = 0.01). Moreover, remission was achieved in a significantly shorter period following mepolizumab initiation in the non-IS group than in the IS-combination group (6.8 ± 9.8 months vs. 11.9 ± 5.1 months; P = 0.03; data not shown). Relapse-free survival after the initiation of mepolizumab was also analyzed by using the Kaplan–Meier method (Fig. 4 ). The non-IS group had a significantly higher relapse-free rate than the IS-combination group (log-rank P = 0.02; Wilcoxon P = 0.03). Approximately half of the patients in the non-IS group maintained long-term remission throughout the follow-up period. Discussion In this study, we demonstrated the clinical impact of mepolizumab in patients with EGPA, focusing on differences between those who received concomitant immunosuppressive therapy (IS-combination group) at the time of initiation and those who did not (non-IS group). To our knowledge, this is among the few studies to directly compare outcomes—including peripheral eosinophil counts, BVAS, corticosteroid dose, relapse rates, remission induction, and remission maintenance—between these two therapeutic strategies. We used frequent relapse was defined as ≥ 1 relapse every 2 years or infrequent relapse was defined as < 1 relapse every 2 years (25). Patients with frequent relapses exhibit upregulated expression of CD80 and CD86 on B cells, which has been found to induce Apo-1, leading to a reduction in B cell numbers and suggesting a functional abnormality that may contribute to the mechanism underlying frequent relapses (25). We found that patients in the non-IS group, many of whom had non-severe disease, achieved earlier remission induction and significant reductions in relapse rates as early as 1 year after treatment initiation. In contrast, patients in the IS-combination group, who presented with more refractory disease, required longer treatment duration to achieve comparable control. The non-IS group was characterized by an older age at diagnosis, lower frequency of cardiac involvement, and a significant reduction in BVAS following conventional treatment before mepolizumab. Notably, 75% of patients in this group (15/20) had previously received immunosuppress as part of their initial therapy, with 80% of them treated with CYC. Nearly half (45%) had an FFS 1998 score of 0; nevertheless, the early administration of adequate immunosuppressive therapy may have contributed to the successful induction and long-term maintenance of remission in this cohort. Among the 35 patients diagnosed before 2018 who subsequently received mepolizumab, five could not receive concomitant immunosuppressive therapy owing to adverse effects, despite requiring it for vasculitis. In contrast, of the 25 patients diagnosed from 2018 onwards, 15 were able to discontinue immunosuppressants before mepolizumab initiation: 12 had non-severe disease without cardiac involvement, one had mild cardiac involvement that improved by mepolizumab initiation, and two were elderly patients in whom immunosuppressants were avoided for safety reasons. This indicates a higher proportion of non-severe cases in the 2018-onwards cohort, making direct comparison between the pre-2018 and 2018-onwards groups inherently limited. Additionally, patients in the IS-combination group had lower BVAS scores both before mepolizumab initiation and at final follow-up compared with the non-IS group, suggesting a more treatment-refractory disease course. Although While the IS-combination group did not show reduced relapse rates within the first year of mepolizumab therapy, a decrease was observed at the final follow-up, implying that prolonged treatment may be necessary in this subgroup. In contrast, the non-IS group demonstrated a significant reduction in relapse rates as early as 1 year after mepolizumab initiation, suggesting a more favorable and rapid therapeutic response (Fig. 2 – 4 ). These findings suggest that, in non-severe EGPA, early remission induction (Fig. 3 ) and sustained remission (Fig. 4 ) may be achievable through mepolizumab, potentially reflecting improved long-term prognosis. Our results are consistent with prior data. In a previous report (20), we demonstrated that, in the super-responder group, relapse rates were significantly lower in the third year of mepolizumab and at the last visit (mean ± SD, 4.3 ± 1.0 years after initiation) than in the first year, suggesting that long-term administration promotes sustained remission. Similarly, in the present IS-combination group, immunosuppressants were successfully discontinued in 10 patients (25%), highlighting the potential of mepolizumab to reduce long-term reliance on conventional immunosuppressive therapy. The adverse effects of CYC—including bone marrow suppression, infertility, hemorrhagic cystitis, ovarian failure, sperm abnormalities, and increased malignancy risk—are well documented (34). Other immunosuppressants such as AZA and MTX also have substantial toxicities. AZA may cause leukopenia, hepatotoxicity, and hypersensitivity reactions, whereas MTX carries risks of hepatotoxicity, pulmonary toxicity, and bone marrow suppression (11). In a retrospective study of 57 patients with EGPA, both AZA and MTX were effective for induction and maintenance of remission. MTX was associated with earlier remission and greater steroid-sparing effects in some clinical settings, but it also resulted in a higher incidence of adverse events. The most common MTX toxicities were gastrointestinal disturbance (37%) and elevated transaminase levels (26%) (35). These adverse effects are especially relevant in older patients and during long-term administration, necessitating careful monitoring and individualized risk–benefit assessment. Safer alternatives such as mepolizumab, with more favorable side-effect profiles, are increasingly important for long-term disease control, particularly in older patients or those at high risk of treatment-related complications. Long-term extension of the MIRRA trial confirmed sustained disease control and a favorable safety profile with prolonged mepolizumab use, highlighting its role in remission maintenance and glucocorticoid tapering (36). Adding to this body of evidence, a recent meta-analysis of eight retrospective studies confirmed the overall efficacy and safety of mepolizumab 300 mg in EGPA, including in patients with varied severity and treatment histories. The pooled data demonstrated consistent reductions in disease activity, relapse rates, and corticosteroid use, further supporting this drug’s incorporation into EGPA treatment algorithms (37, 38). Alternative biologics are also emerging. Benralizumab, an anti–IL-5Rα monoclonal antibody, was introduced in 2024, and it demonstrated non-inferiority to mepolizumab in the head-to-head MANDARA trial (39). A Japanese study suggested differential response patterns between mepolizumab and benralizumab, possibly reflecting mechanistic differences that may guide therapeutic choice by disease phenotype or immunological profile (40). A large European real-world study reported comparable efficacy between the two agents, although further prospective head-to-head comparisons are needed (41). In addition to anti–IL-5 agents, other biologics, including omalizumab (anti-IgE) (42) and dupilumab (anti–IL-4/IL-13) (43, 44), have also been investigated in EGPA, particularly in patients with overlapping eosinophilic or atopic features. Potential biomarkers may further guide therapy. In a previous study, we found that super responders to mepolizumab were characterized by elevated peripheral eosinophil counts at diagnosis (before corticosteroid exposure) and marked reduction in BVAS in response to conventional treatment (19). We also reported that, in EGPA, levels of ILC2 and IL-33 levels were high during disease onset and relapse and low during remission (45). These findings suggest that eosinophil counts and immunologic signatures may help identify patients most likely to benefit from anti–IL-5 therapy. Several limitations should be acknowledged. This was a retrospective study, subject to inherent bias and confounding. Disease severity differed between patients diagnosed before 2018 and from 2018 onwards, limiting direct comparability. Subgroup sizes were small, reducing statistical power, and the findings may not be generalizable outside our setting. Conclusion In summary, our study provides real-world evidence that mepolizumab is effective in both non-severe and refractory EGPA. Patients in the non-IS group—many with non-severe disease and high eosinophil counts at diagnosis—achieved early remission induction and reduced relapse rates within one year. These patients also demonstrated favorable responses to conventional therapy, and their high eosinophil counts in the steroid-naïve state may serve as a predictive biomarker for robust response to mepolizumab. Patients in the IS-combination group, who had more refractory disease, required longer treatment to achieve similar control, but one-quarter were able to discontinue immunosuppressants. Taken together, these findings underscore the importance of early and individualized treatment strategies. Mepolizumab remains a key therapeutic option, not only for relapsing or refractory disease but also for eosinophil-driven, non-severe phenotypes. Prospective studies are warranted to validate biomarkers of treatment response and to optimize the integration of biologics into personalized EGPA management. Abbreviations ANCA antineutrophil cytoplasmic autoantibody BVAS Birmingham Vasculitis Activity Score EGPA eosinophilic granulomatosis with polyangiitis FFS Five-Factor Score GPA granulomatosis with polyangiitis IVIG intravenous immunoglobulin MIRRA Mepolizumab in Relapsing or Refractory EGPA MPA microscopic polyangiitis MPO myeloperoxidase PR3 proteinase 3 PSL prednisolone EULAR European Alliance of Associations for Rheumatology Declarations Ethics approval and consent to participate My ethics approval number is no. 2022-06 in the Ethics Committee of the National Hospital Organization Yokohama Medical Center Consent for publication We had written informed consent was obtained from all patients or their legal representatives. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests N. Masumoto, Y. Yamashita, T. Nakashima, Y. Kodama, K. Terada, H. Masumitsu, A. Miyasaka, T. Muraoka, T. Kaneko have no conflicts of interest to disclose regarding this study. N. Tsurikisawa has received lecture fees from GlaxoSmithKline Co., Ltd. and Teijin Healthcare Co., Ltd. The work was not funded by any grant or other external source of financial support. Funding None Authors' contributions N.M: examination of patients, analysis of data, construction of figures and tables, and writing of main document Y.Y: examination of patients, analysis of data, and contributions to the discussion T.N, Y.K, K.T, H.M, A.M, and T.M: examination of patients, and contributions to the discussion T.K: contributions to the discussion N.T: examination of patients, analysis of data, construction of figures and tables, discussion and summary of paper All authors have read and approved the final manuscript. Acknowledgments Not applicable References Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol. 1951;27:277–301. Jennette JC. 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Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 2024; 390: 911-921. Shiomi M, Watanabe R, Ishihara R, Tanaka S, Nakazawa T, Hashimoto M. Comparative Insights on IL-5 Targeting with Mepolizumab and Benralizumab: Enhancing EGPA Treatment Strategies. Biomolecules. 2025 Apr 8;15(4):544. Mattioli I, Urban ML, Padoan R, Mohammad AJ, Salvarani C, Baldini C, et al. Mepolizumab versus benralizumab for eosinophilic granulomatosis with polyangiitis (EGPA): A European real-life retrospective comparative study. J Autoimmun 2025 May:153:103398. Basta F, Mazzuca C, Nucera E, Schiavino D, Afeltra A, Antonelli Incalzi R Omalizumab in eosinophilic granulomatosis with polyangiitis: friend or foe? A systematic literature review. Clin Exp Rheumatol 2020; 38 Suppl 124(2): 214–20. Molina B, Padoan R, Urban ML, Novikov P, Caminati M, Taillé C, et al. Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study. Ann Rheum Dis 2023 Dec; 82(12): 1587–93. Adachi S, Oshikata C, Kaneko T, Tsurikisawa N . Rituximab and dupilumab improve eosinophilic granulomatosis with polyangiitis with multiple pulmonary thrombi. Allergy Asthma Clin Immunol. 2022;18:18 Tsurikisawa N, Oshikata C, Watanabe M, Tsuburai T, Kaneko T, Saito H. Innate immune response reflects disease activity in eosinophilic granulomatosis with polyangiitis. Clin Exp Allergy. 2018;48:1305–16. Table Table 1 is available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table1.xls Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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13:58:39","extension":"html","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":130330,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/b84ffd91a305b84c81a6a845.html"},{"id":97260605,"identity":"d1dee1ff-6f73-4d7a-9b32-43bd7c1ed9c8","added_by":"auto","created_at":"2025-12-02 13:58:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":297075,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy protocol.\u003c/strong\u003e Of 72 patients with EGPA seen at the National Hospital Organization Yokohama Medical Center (April 2022 to March 2025), 60 who did not achieve remission with conventional therapy received mepolizumab. Because mepolizumab was approved in Japan in 2018, patients were grouped by year of diagnosis (35 before 2018, 25 diagnosed in or after 2018). Use of immunosuppressants in combination with systemic corticosteroids at mepolizumab initiation was retrospectively assessed.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/15b714047895dd71a6932b52.png"},{"id":97366750,"identity":"c9149200-a911-4a71-a367-4c6c73c2d885","added_by":"auto","created_at":"2025-12-03 16:06:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1083766,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e2-1. Changes in peripheral blood eosinophil counts.\u003c/strong\u003e Eosinophil counts are shown throughout the course of treatment in EGPA patients in (\u003cstrong\u003ea\u003c/strong\u003e) the IS-combination group and (\u003cstrong\u003eb\u003c/strong\u003e) the non-IS group. The short horizontal line represents the mean count at each measurement point (value above each set of measurements is mean ± SD). Mean values were compared by using the Wilcoxon matched-pairs \u003cem\u003et\u003c/em\u003e-test. * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05; † \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01; NS, not significant. Upper brackets above each set of measurements indicate the significance of differences between time at diagnosis and subsequent time points (before mepolizumab, 1 month after initiation, and last examination). Medium and lower brackets indicate differences between before mepolizumab and later time points (1 month and last examination)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2-2. Changes in daily prednisolone dose.\u003c/strong\u003e Prednisolone dose is shown from diagnosis to before mepolizumab, after mepolizumab initiation, and last examination in patients with EGPA in (\u003cstrong\u003ea\u003c/strong\u003e) the IS-combination group and (\u003cstrong\u003eb\u003c/strong\u003e) the non-IS group. The short horizontal line represents the mean dose of prednisolone (value above each set of measurements is mean ± SD). Mean values were compared by using the Wilcoxon matched-pairs \u003cem\u003et\u003c/em\u003e-test. † \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01; NS, not significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2-3. Changes in Birmingham Vasculitis Activity Scores (BVAS).\u003c/strong\u003e BVAS is shown (\u003cstrong\u003ea\u003c/strong\u003e) at diagnosis, (\u003cstrong\u003eb\u003c/strong\u003e) before mepolizumab, and (\u003cstrong\u003ec\u003c/strong\u003e) at last examination in EGPA patients in the IS-combination group and the non-IS group. Mean values were compared by using the Mann–Whitney U test. \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2-4. Changes in relapse frequency.\u003c/strong\u003e Relapse rates (times/year) are shown for the periods from diagnosis to 1 year before mepolizumab treatment, the year before mepolizumab, the year after mepolizumab, and the final year of follow-up in EGPA patients in (\u003cstrong\u003ea\u003c/strong\u003e) the IS-combination group and (\u003cstrong\u003eb\u003c/strong\u003e) the non-IS group. Mean values for each patient group were compared by using the Wilcoxon matched-pairs \u003cem\u003et\u003c/em\u003e-test. \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered statistically significant. † \u0026lt; 0.01; NS, not\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/fcc8955aa908cd4be9e99012.png"},{"id":97260606,"identity":"2b8c8be0-207e-4c91-b004-1dd75059148b","added_by":"auto","created_at":"2025-12-02 13:58:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141993,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative remission rate after mepolizumab initiation. \u003c/strong\u003eKaplan–Meier curves show cumulative remission in EGPA patients in the non-IS group (solid line) and the IS-combination group (dotted line). Data were censored after a maximum of 66 months of follow-up. \u003cem\u003eP\u003c/em\u003e-values were determined by log-rank test and Wilcoxon test. \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/6eb0281c4e56cdb9f5ca1b09.png"},{"id":97260610,"identity":"74454433-b38b-4b17-b813-2888b410b021","added_by":"auto","created_at":"2025-12-02 13:58:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":143290,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelapse-free rate after mepolizumab initiation\u003c/strong\u003e. Kaplan–Meier curves show relapse-free survival in EGPA patients in the non-IS group (solid line) and the IS-combination group (dotted line). Data were censored after a maximum of 60 months of follow-up. \u003cem\u003eP\u003c/em\u003e-value were determined by log-rank test and Wilcoxon test. \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/a815e72329285023f67f4774.png"},{"id":98429760,"identity":"7fd9b679-ee3e-452a-b0f1-bd0b578cabd1","added_by":"auto","created_at":"2025-12-17 16:44:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2454801,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/fe89dac6-842c-4dcf-bf69-30c9f51d6cb2.pdf"},{"id":97366834,"identity":"d9ce6d3a-b949-4eee-a496-ea13bc234379","added_by":"auto","created_at":"2025-12-03 16:08:41","extension":"xls","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46080,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xls","url":"https://assets-eu.researchsquare.com/files/rs-8125801/v1/c1d3687c0eed62bf1cae4161.xls"}],"financialInterests":"No competing interests reported.","formattedTitle":"Management of Non-Severe Eosinophilic Granulomatosis with Polyangiitis without Immunosuppressants Using Mepolizumab: Clinical Implications","fulltext":[{"header":"Background","content":"\u003cp\u003eEosinophilic granulomatosis with polyangiitis (EGPA) is a rare small-vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs). It differs from other ANCA-associated vasculitides, such as microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), by its frequent association with asthma, eosinophilia, and peripheral nerve involvement (1, 2). Although corticosteroids are effective for inducing remission in ANCA-associated vasculitides, EGPA relapses more frequently than MPA or GPA, even in patients without poor-prognosis factors (3). In EGPA patients with a Five-Factor Score (FFS) (4) of 0, glucocorticoid monotherapy has historically been considered sufficient, yet relapse occurs in approximately 35% (5). Peripheral neuropathy is a strong predictor of relapse, highlighting the limitations of FFS alone as a guide to initial therapy (6). Although an FFS of 0 may indicate that there will be no adverse effect on overall survival, relapse contributes to irreversible damage, as reflected by higher Vasculitis Damage Index scores (7). These findings support the early introduction of immunosuppressive therapy, even in patients without poor-prognosis factors.\u003c/p\u003e\u003cp\u003eCyclophosphamide (CYC) remains a key agent for remission induction in severe EGPA, and its efficacy is dose dependent. In a prospective multicenter trial, 12 pulses of intravenous cyclophosphamide (IVCY) reduced relapse significantly more than 6 pulses, highlighting the importance of adequate dosing for long-term disease control (8). Although toxicity concerns often limit CYC use in elderly patients, low-dose IVCY regimens (500 mg/body \u0026times; 6 courses) have shown efficacy comparable to that of conventional protocols (600 mg/m\u0026sup2;), with fewer adverse effects (9). These findings indicate that immunosuppressive therapy should not be withheld solely because of age and suggest the importance of proactive immunosuppressive strategies in EGPA, regardless of initial FFS, to reduce relapse risk and minimize long-term organ damage.\u003c/p\u003e\u003cp\u003eCombination therapy with systemic corticosteroids plus IVCY is often recommended for EGPA with life-threatening or major organ involvement. However, both corticosteroids and cytotoxic immunosuppressants carry substantial risks, including infection, malignancy, and long-term organ toxicity (10, 11).\u003c/p\u003e\u003cp\u003eMepolizumab, an anti\u0026ndash;IL-5 monoclonal antibody, reduces blood eosinophil counts and has proven effective in severe asthma (12, 13). In EGPA, a 2010 pilot study demonstrated that intravenous mepolizumab (750 mg every 4 weeks) safely reduced peripheral eosinophils (14). The 2017 MIRRA trial\u0026mdash;the first randomized, double-blind, placebo-controlled study of subcutaneous mepolizumab (300 mg monthly) in relapsing or refractory EGPA\u0026mdash;showed significantly longer remission, with 53% of patients achieving remission versus 19% with placebo (15).\u003c/p\u003e\u003cp\u003e However, current guidelines leave the role of mepolizumab in the treatment of EGPA incompletely defined. European Alliance of Associations for Rheumatology (EULAR) recommendsations adding mepolizumab to corticosteroids for relapsing or refractory disease without organ- or life-threatening manifestations\u0026mdash;specifically glomerulonephritis, alveolar hemorrhage, meningeal or central nervous system involvement, retinal vasculitis, mesenteric ischemia, or multiple mononeuritis\u0026mdash;while prioritizing CYC or rituximab (RTX) for patients presenting with organ- or life-threatening features (16). The timing of mepolizumab initiation is not addressed. The guidelines also suggest switching from CYC to maintenance agents (azathioprine [AZA], methotrexate [MTX], RTX, or mepolizumab) after remission induction, but they do not specify a preferred sequence.\u003c/p\u003e\u003cp\u003eOther proposed treatment algorithms vary. Raffray and Guillevin (17) recommend corticosteroids as initial therapy for patients with an FFS of 0, with mepolizumab added if induction of remission fails or asthma persists; for patients with FFS\u0026thinsp;\u0026ge;\u0026thinsp;1, CYC is used for induction, and following remission, maintenance therapy with AZA, MTX, or RTX is initiated, with mepolizumab added if needed. This algorithm implies that mepolizumab should be considered in nearly all patients except those achieving remission with corticosteroids alone. However, the criteria for selecting mepolizumab over other agents remain undefined. Emmi et al. (18) recommend combining mepolizumab with maintenance therapy after induction in newly diagnosed EGPA, regardless of severity. In relapsing disease, they suggest corticosteroids alone or with mepolizumab for non-severe cases, whereas severe relapses require high-dose corticosteroids in combination with CYC or RTX. Mepolizumab is not mentioned in the context of severe relapses. Notably, neither approach defines how mepolizumab compares with conventional immunosuppressants in severe disease, leaving its optimal timing and integration uncertain.\u003c/p\u003e\u003cp\u003eWe previously investigated mepolizumab in EGPA, assessing remission induction, corticosteroid-sparing effects, and its effectiveness across a broad spectrum of vasculitic manifestations. In one study, we also confirmed potential synergy between mepolizumab and intravenous immunoglobulin (IVIG) (19). In another, we found that long-term administration of mepolizumab (\u0026gt;\u0026thinsp;3 years on average) significantly suppressed relapse rates, particularly in patients classified as super-responders (20). Across those studies, serious adverse events typically associated with conventional immunosuppressants\u0026mdash;such as bone marrow suppression, infection, hepatotoxicity, nephrotoxicity, or increased risk of malignancy\u0026mdash;were observed during treatment with mepolizumab. However, it remains unclear whether long-term remission can be sustained with corticosteroids plus mepolizumab alone, without AZA or MTX, following initial remission induction.\u003c/p\u003e\u003cp\u003e In Japan, mepolizumab has been approved for clinical use since 2018. Patients diagnosed before its approval were typically treated with corticosteroids plus conventional immunosuppressants before subsequent addition of mepolizumab. In contrast, in patients diagnosed after 2018\u0026mdash;particularly those without cardiac involvement\u0026mdash;mepolizumab is often initiated following corticosteroid therapy, without the addition of immunosuppressants.\u003c/p\u003e\u003cp\u003eIn this retrospective study, we compared patients who were and were not receiving immunosuppressants at the time of mepolizumab initiation, and we assessed peripheral blood eosinophil counts, Birmingham Vasculitis Activity Score (BVAS) (21), systemic corticosteroid dosage, relapse rates, remission induction rates, and remission maintenance duration following the introduction of mepolizumab.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eWe retrospectively enrolled 72 patients with EGPA who were treated at the Department of Respirology, National Hospital Organization Yokohama Medical Center, Kanagawa, Japan between April 2022 and March 2025. EGPA was diagnosed according to the criteria for allergic granulomatosis angiitis (known as Churg\u0026ndash;Strauss syndrome) (22) and classified by using both the 1990 (23) and 2022 (24) American College of Rheumatology criteria. Inclusion required at least four of the following six features: asthma, eosinophilia, polyneuropathy, pulmonary infiltrate, paranasal sinus abnormality, and extravascular eosinophils.\u003c/p\u003e\u003cp\u003eAll patient data were collected retrospectively from medical records. The study was approved by the Ethics Committee of the National Hospital Organization Yokohama Medical Center (approval no. 2022-06), and written informed consent was obtained from all patients or their legal representatives.\u003c/p\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eOf 72 patients with EGPA, 60 who did not achieve remission with conventional therapy (e.g., corticosteroids, CYC, AZA, or MTX) received mepolizumab. As mepolizumab was approved in Japan in June 2018, these 60 patients were categorized into two cohorts according to the year of diagnosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOne cohort comprised 35 patients diagnosed before 2018. Of these, 30 had already been receiving corticosteroids plus immunosuppressants at mepolizumab initiation and were assigned to the IS-combination group (CS\u0026thinsp;+\u0026thinsp;IS\u0026thinsp;+\u0026thinsp;mepolizumab). Five patients could not receive immunosuppressants owing to adverse effects and were assigned to the non-IS group (CS\u0026thinsp;+\u0026thinsp;mepolizumab).\u003c/p\u003e\u003cp\u003eThe other cohort comprised 25 patients diagnosed in or after 2018. Mepolizumab was initiated without concurrent immunosuppressants in 15 cases (non-IS group [CS\u0026thinsp;+\u0026thinsp;mepolizumab]), including 12 without cardiac involvement, 1 with cardiac involvement that had improved with conventional therapy, and 2 elderly patients who developed EGPA at the ages of 77 and 83 years. In these cases, any immunosuppressants used during initial treatment were discontinued before mepolizumab initiation. The remaining 10 patients in this cohort who failed to achieve remission with conventional therapy were treated with mepolizumab in combination with corticosteroids plus immunosuppressants (IS-combination group [CS\u0026thinsp;+\u0026thinsp;IS\u0026thinsp;+\u0026thinsp;mepolizumab]).\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003eA state of remission was defined as the absence of clinical signs or symptoms of active vasculitis after initial treatment.\u003c/p\u003e\u003cp\u003eA state of relapse was defined as the recurrence, after remission, of vasculitis symptoms and signs that required the resumption of immunosuppressive therapy or an increased dose of immunosuppressants or additional intravenous immunoglobulin (IVIG). Exacerbation of asthma or sinusitis (with or without an increase in the proportion of eosinophils among white blood cells) was excluded from our definition of relapse. Although a large increase in tissue eosinophilia might have been correlated with an increase in the severity of vasculitis signs and symptoms, this criterion was not considered in our definition of relapse.\u003c/p\u003e\u003cp\u003eFrequent relapse was defined as \u0026ge;\u0026thinsp;1 relapse every 2 years after a period of initial remission; infrequent relapse was defined as \u0026lt;\u0026thinsp;1 relapse every 2 years (25).\u003c/p\u003e\n\u003ch3\u003eAssessment of organ involvement\u003c/h3\u003e\n\u003cp\u003eMultiple mononeuritis, a measure of motor nerve dysfunction, was evaluated by using manual muscle testing (0 to 5, on the Medical Research Council scale), as well as by electromyographic examination. Sensory nerve dysfunction was evaluated subjectively on the basis of symptoms and physical examination.\u003c/p\u003e\u003cp\u003eLung involvement was considered in cases with ground glass opacity, nodules within the ground glass opacity, interlobular septal thickening (26, 27), bronchial wall thickening, lymphadenopathy (28, 29), pleural effusion (identified by high-resolution computed tomography) (26, 30), or infiltration by eosinophils (identified by lung biopsy).\u003c/p\u003e\u003cp\u003eCardiac involvement was defined as cardiac symptoms\u0026mdash;specifically chest pain, chest discomfort, back pain, and palpitations; abnormal signs on cardiac echocardiography, Holter electrocardiogram, and myocardial imaging using \u003csup\u003e123\u003c/sup\u003eI-metaiodobenzylguanidine; or abnormal plasma B-type natriuretic peptide levels (31).\u003c/p\u003e\u003cp\u003eGastrointestinal involvement was defined as symptoms of epigastralgia, abdominal pain, diarrhea, constipation, positive endoscopy signs, and gastrointestinal eosinophil infiltration or colonic submucosal edematous change detected by biopsy (32).\u003c/p\u003e\u003cp\u003eSkin involvement was defined as the presence of purpura, erythema, livedo, ulceration, acrocyanosis, nodule formation, or eosinophilic infiltration as detected by biopsy.\u003c/p\u003e\u003cp\u003eCentral nervous system involvement was defined as the presence of headache, visual disturbance, abnormal visual sensation, cerebral infarction or bleeding, or cranial nerve dysfunction.\u003c/p\u003e\u003cp\u003eRenal involvement was defined by any one of the following: presence of eosinophiluria, glomerulonephritis, nephrosis (proteinuria\u0026thinsp;\u0026gt;\u0026thinsp;3.5 g/day), renal dysfunction (i.e., elevation of creatinine level to \u0026gt;\u0026thinsp;20% of baseline), or proteinuria (\u0026gt;\u0026thinsp;0.5 g/day or 50 mg/dL).\u003c/p\u003e\u003cp\u003eOtitis media was diagnosed by an otorhinolaryngologist.\u003c/p\u003e\u003cp\u003eIn all patients with EGPA, disease severity was scored by using FFS 1996 (4) or FFS 2009 (33). When the total number of organs involved was counted, those that were compromised by asthma or sinusitis were not included. We evaluated the disease activity at onset and at first relapse by using the BVAS, which examines symptoms and signs within nine categories (systemic; cutaneous; mucous membranes and eyes; ear, nose, and throat; chest; heart and vessels; gastrointestinal tract; renal system; and nervous system) (21). The maximum number of points is 7 in each category, with a maximum total score of 63.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eWe investigated white blood cell count, eosinophil count, MPO-ANCA (myeloperoxidase-antineutrophil cytoplasmic autoantibody), PR3-ANCA (proteinase 3-ANCA), and immune complex levels in the serum at EGPA onset. Treatments were extracted from the patients\u0026rsquo; medical records, including methylprednisolone (mPSL) pulse therapy (1000 mg/day for 3 consecutive days), initial doses of prednisolone (PSL), immunosuppressants (CYC, AZA, MTX, cyclosporine, and RTX) during induction or maintenance, and IVIG (400 mg/kg daily for 5 days; Venilon, Teijin, Tokyo, Japan).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eEndpoints\u003c/h2\u003e\u003cp\u003eThe primary endpoint was the last examination performed during the study period. We evaluated eosinophil count in the peripheral blood, daily dose of PSL, and BVAS, and we recorded survival status, cause of death, remission or relapse status, and ongoing treatment at last examination.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables are expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and medians (range), unless otherwise specified. Differences between groups were assessed by using repeated-measures two-way ANOVA, followed by Newman\u0026ndash;Keuls \u003cem\u003epost hoc\u003c/em\u003e tests. The two mean values obtained by this process were compared by using the Wilcoxon matched-pairs \u003cem\u003et-\u003c/em\u003etest. Correlations were evaluated with Spearman\u0026rsquo;s rank correlation coefficient. Survival analyses were performed by using Kaplan\u0026ndash;Meier analysis with log-rank test and Wilcoxon tests. Statistical significance was defined as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Statistical analyses was performed by using SPSS for Windows, version 29 (SPSS, Inc., Chicago, IL, USA).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eComparison of baseline characteristics at diagnosis between the IS-combination group and the non-IS group\u003c/h2\u003e\u003cp\u003eCharacteristics of the 60 EGPA patients treated with mepolizumab are summarized in Table\u0026nbsp;1. There were no significant differences in baseline characteristics such as age at study admission, sex, peripheral blood eosinophil count, positivity rates for MPO-ANCA, PR3-ANCA, immune complexes (IC), rheumatoid factor (RF)RF, B-type natriuretic peptide (BNP), or serum total IgE and IgG levels between the IS-combination group and the non-IS group. In contrast, age at asthma onset (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) and EGPA onset (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) was higher in the non-IS group, and the interval from EGPA diagnosis to study admission was shorter (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003cp\u003eMost clinical manifestations at diagnosis and BVAS at diagnosis did not differ between the two groups, except for myocardial involvement, which was significantly more prevalent in the IS-combination group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). BVAS before treatment with mepolizumab was also higher in the IS-combination group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Scores on ACR 1990 ACR 2022, FFS 1998, and FFS 2009 did not differ between the two groups (data not shown).\u003c/p\u003e\u003cp\u003eThere was no significant difference between the two groups in the proportion of patients who received mPSL pulse therapy or in the initial dose of PSL. As expected, all patients in the IS-combination group received immunosuppressants during initial treatment, compared with 75% in the non-IS group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Conversely, CYC was used more frequently as part of the initial treatment in the non-IS group (80%).\u003c/p\u003e\u003cp\u003eMaintenance doses of PSL, both before initiation of mepolizumab and at the final examination, did not differ significantly. However, at the final examination, 10 out of 40 patients (25%) in the IS-combination group were able to discontinue immunosuppressants. No patient discontinued PSL by the time of the final examination.\u003c/p\u003e\u003cp\u003eThe interval from EGPA diagnosis to mepolizumab initiation was significantly longer in the IS-combination group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). The duration of mepolizumab treatment also tended to be longer in the IS-combination group, but the difference was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). In contrast, the time to remission was significantly longer in the IS-combination group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eChanges in eosinophil count, PSL dose, BVAS, and relapse rate\u003c/h2\u003e\u003cp\u003eIn both the IS-combination group and the non-IS group, peripheral blood eosinophil counts had already decreased significantly before the initiation of mepolizumab (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). A further significant reduction was observed 1 month after mepolizumab initiation, and counts remained low through to the final follow-up visit (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe daily dose of PSL decreased in both groups following conventional therapy. A further significant reduction was observed at 1 year after mepolizumab initiation and at the final visit (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). There was no significant difference in the degree of reduction between groups (Fig.\u0026nbsp;\u0026lt;link rid=\"fig2\"\u0026gt;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u0026lt;/link\u0026gt;\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eAt diagnosis, BVAS did not differ significantly between the two groups. However, BVAS was higher in the IS-combination group both before the initiation of mepolizumab (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and at the final visit (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRelapse rates (times/year) increased in both groups before the initiation of mepolizumab (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In the non-IS group, relapse rates decreased after 1 year of mepolizumab (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and remained low until the final visit (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In contrast, the IS-combination group did not show a significant decrease in relapse rate at 1 year after mepolizumab initiation; however, a significant reduction was observed by the time of the final visit (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eCumulative remission rate and relapse-free rate\u003c/h2\u003e\u003cp\u003eCumulative remission after mepolizumab initiation was analyzed by using the Kaplan\u0026ndash;Meier method (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The non-IS group had a shorter interval from diagnosis to mepolizumab initiation than the IS-combination group (Table\u0026nbsp;1). Furthermore, the cumulative remission rate was significantly higher in the non-IS group (log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03; Wilcoxon \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). Moreover, remission was achieved in a significantly shorter period following mepolizumab initiation in the non-IS group than in the IS-combination group (6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 months vs. 11.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1 months; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03; data not shown).\u003c/p\u003e\u003cp\u003eRelapse-free survival after the initiation of mepolizumab was also analyzed by using the Kaplan\u0026ndash;Meier method (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The non-IS group had a significantly higher relapse-free rate than the IS-combination group (log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02; Wilcoxon \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). Approximately half of the patients in the non-IS group maintained long-term remission throughout the follow-up period.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we demonstrated the clinical impact of mepolizumab in patients with EGPA, focusing on differences between those who received concomitant immunosuppressive therapy (IS-combination group) at the time of initiation and those who did not (non-IS group). To our knowledge, this is among the few studies to directly compare outcomes\u0026mdash;including peripheral eosinophil counts, BVAS, corticosteroid dose, relapse rates, remission induction, and remission maintenance\u0026mdash;between these two therapeutic strategies.\u003c/p\u003e\u003cp\u003eWe used frequent relapse was defined as \u0026ge;\u0026thinsp;1 relapse every 2 years or infrequent relapse was defined as \u0026lt;\u0026thinsp;1 relapse every 2 years (25). Patients with frequent relapses exhibit upregulated expression of CD80 and CD86 on B cells, which has been found to induce Apo-1, leading to a reduction in B cell numbers and suggesting a functional abnormality that may contribute to the mechanism underlying frequent relapses (25).\u003c/p\u003e\u003cp\u003eWe found that patients in the non-IS group, many of whom had non-severe disease, achieved earlier remission induction and significant reductions in relapse rates as early as 1 year after treatment initiation. In contrast, patients in the IS-combination group, who presented with more refractory disease, required longer treatment duration to achieve comparable control.\u003c/p\u003e\u003cp\u003eThe non-IS group was characterized by an older age at diagnosis, lower frequency of cardiac involvement, and a significant reduction in BVAS following conventional treatment before mepolizumab. Notably, 75% of patients in this group (15/20) had previously received immunosuppress as part of their initial therapy, with 80% of them treated with CYC. Nearly half (45%) had an FFS 1998 score of 0; nevertheless, the early administration of adequate immunosuppressive therapy may have contributed to the successful induction and long-term maintenance of remission in this cohort.\u003c/p\u003e\u003cp\u003eAmong the 35 patients diagnosed before 2018 who subsequently received mepolizumab, five could not receive concomitant immunosuppressive therapy owing to adverse effects, despite requiring it for vasculitis. In contrast, of the 25 patients diagnosed from 2018 onwards, 15 were able to discontinue immunosuppressants before mepolizumab initiation: 12 had non-severe disease without cardiac involvement, one had mild cardiac involvement that improved by mepolizumab initiation, and two were elderly patients in whom immunosuppressants were avoided for safety reasons. This indicates a higher proportion of non-severe cases in the 2018-onwards cohort, making direct comparison between the pre-2018 and 2018-onwards groups inherently limited.\u003c/p\u003e\u003cp\u003eAdditionally, patients in the IS-combination group had lower BVAS scores both before mepolizumab initiation and at final follow-up compared with the non-IS group, suggesting a more treatment-refractory disease course. Although While the IS-combination group did not show reduced relapse rates within the first year of mepolizumab therapy, a decrease was observed at the final follow-up, implying that prolonged treatment may be necessary in this subgroup. In contrast, the non-IS group demonstrated a significant reduction in relapse rates as early as 1 year after mepolizumab initiation, suggesting a more favorable and rapid therapeutic response (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These findings suggest that, in non-severe EGPA, early remission induction (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and sustained remission (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) may be achievable through mepolizumab, potentially reflecting improved long-term prognosis.\u003c/p\u003e\u003cp\u003eOur results are consistent with prior data. In a previous report (20), we demonstrated that, in the super-responder group, relapse rates were significantly lower in the third year of mepolizumab and at the last visit (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 years after initiation) than in the first year, suggesting that long-term administration promotes sustained remission. Similarly, in the present IS-combination group, immunosuppressants were successfully discontinued in 10 patients (25%), highlighting the potential of mepolizumab to reduce long-term reliance on conventional immunosuppressive therapy.\u003c/p\u003e\u003cp\u003eThe adverse effects of CYC\u0026mdash;including bone marrow suppression, infertility, hemorrhagic cystitis, ovarian failure, sperm abnormalities, and increased malignancy risk\u0026mdash;are well documented (34). Other immunosuppressants such as AZA and MTX also have substantial toxicities. AZA may cause leukopenia, hepatotoxicity, and hypersensitivity reactions, whereas MTX carries risks of hepatotoxicity, pulmonary toxicity, and bone marrow suppression (11). In a retrospective study of 57 patients with EGPA, both AZA and MTX were effective for induction and maintenance of remission. MTX was associated with earlier remission and greater steroid-sparing effects in some clinical settings, but it also resulted in a higher incidence of adverse events. The most common MTX toxicities were gastrointestinal disturbance (37%) and elevated transaminase levels (26%) (35).\u003c/p\u003e\u003cp\u003eThese adverse effects are especially relevant in older patients and during long-term administration, necessitating careful monitoring and individualized risk\u0026ndash;benefit assessment. Safer alternatives such as mepolizumab, with more favorable side-effect profiles, are increasingly important for long-term disease control, particularly in older patients or those at high risk of treatment-related complications.\u003c/p\u003e\u003cp\u003eLong-term extension of the MIRRA trial confirmed sustained disease control and a favorable safety profile with prolonged mepolizumab use, highlighting its role in remission maintenance and glucocorticoid tapering (36). Adding to this body of evidence, a recent meta-analysis of eight retrospective studies confirmed the overall efficacy and safety of mepolizumab 300 mg in EGPA, including in patients with varied severity and treatment histories. The pooled data demonstrated consistent reductions in disease activity, relapse rates, and corticosteroid use, further supporting this drug\u0026rsquo;s incorporation into EGPA treatment algorithms (37, 38).\u003c/p\u003e\u003cp\u003eAlternative biologics are also emerging. Benralizumab, an anti\u0026ndash;IL-5Rα monoclonal antibody, was introduced in 2024, and it demonstrated non-inferiority to mepolizumab in the head-to-head MANDARA trial (39). A Japanese study suggested differential response patterns between mepolizumab and benralizumab, possibly reflecting mechanistic differences that may guide therapeutic choice by disease phenotype or immunological profile (40). A large European real-world study reported comparable efficacy between the two agents, although further prospective head-to-head comparisons are needed (41). In addition to anti\u0026ndash;IL-5 agents, other biologics, including omalizumab (anti-IgE) (42) and dupilumab (anti\u0026ndash;IL-4/IL-13) (43, 44), have also been investigated in EGPA, particularly in patients with overlapping eosinophilic or atopic features.\u003c/p\u003e\u003cp\u003ePotential biomarkers may further guide therapy. In a previous study, we found that super responders to mepolizumab were characterized by elevated peripheral eosinophil counts at diagnosis (before corticosteroid exposure) and marked reduction in BVAS in response to conventional treatment (19). We also reported that, in EGPA, levels of ILC2 and IL-33 levels were high during disease onset and relapse and low during remission (45). These findings suggest that eosinophil counts and immunologic signatures may help identify patients most likely to benefit from anti\u0026ndash;IL-5 therapy.\u003c/p\u003e\u003cp\u003eSeveral limitations should be acknowledged. This was a retrospective study, subject to inherent bias and confounding. Disease severity differed between patients diagnosed before 2018 and from 2018 onwards, limiting direct comparability. Subgroup sizes were small, reducing statistical power, and the findings may not be generalizable outside our setting.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study provides real-world evidence that mepolizumab is effective in both non-severe and refractory EGPA. Patients in the non-IS group\u0026mdash;many with non-severe disease and high eosinophil counts at diagnosis\u0026mdash;achieved early remission induction and reduced relapse rates within one year.\u003c/p\u003e\u003cp\u003eThese patients also demonstrated favorable responses to conventional therapy, and their high eosinophil counts in the steroid-na\u0026iuml;ve state may serve as a predictive biomarker for robust response to mepolizumab. Patients in the IS-combination group, who had more refractory disease, required longer treatment to achieve similar control, but one-quarter were able to discontinue immunosuppressants. Taken together, these findings underscore the importance of early and individualized treatment strategies. Mepolizumab remains a key therapeutic option, not only for relapsing or refractory disease but also for eosinophil-driven, non-severe phenotypes. Prospective studies are warranted to validate biomarkers of treatment response and to optimize the integration of biologics into personalized EGPA management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eANCA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eantineutrophil cytoplasmic autoantibody\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBVAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBirmingham Vasculitis Activity Score\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEGPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eeosinophilic granulomatosis with polyangiitis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFive-Factor Score\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egranulomatosis with polyangiitis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIVIG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eintravenous immunoglobulin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMIRRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMepolizumab in Relapsing or Refractory EGPA\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emicroscopic polyangiitis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMPO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emyeloperoxidase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePR3\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eproteinase 3\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePSL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprednisolone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEULAR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEuropean Alliance of Associations for Rheumatology\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMy ethics approval number is no. 2022-06 in the Ethics Committee of the National Hospital Organization Yokohama Medical Center\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe had written informed consent was obtained from all patients or their legal representatives.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eN. Masumoto, Y. Yamashita, T. Nakashima, Y. Kodama, K. Terada, H. Masumitsu, A. Miyasaka, T. Muraoka, T. Kaneko have no conflicts of interest to disclose regarding this study.\u0026nbsp;N. Tsurikisawa\u0026nbsp;has received lecture fees from GlaxoSmithKline Co., Ltd. and Teijin Healthcare Co., Ltd.\u003c/p\u003e\n\u003cp\u003eThe work was not funded by any grant or other external source of financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN.M: examination of patients, analysis of data, construction of figures and tables, and writing of main document\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eY.Y: examination of patients, analysis of data, and contributions to the discussion\u003c/p\u003e\n\u003cp\u003eT.N, Y.K, K.T, H.M, A.M, and T.M: examination of patients, and contributions to the discussion\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eT.K: contributions to the discussion\u003c/p\u003e\n\u003cp\u003eN.T: examination of patients, analysis of data, construction of figures and tables, discussion and summary of paper\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChurg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol. 1951;27:277\u0026ndash;301.\u003c/li\u003e\n\u003cli\u003eJennette JC. Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol. 2013;17:603-6.\u003c/li\u003e\n\u003cli\u003ePavone L, Grasselli C, Chierici E, Maggiore U, Garini G, Ronda N, et al. Outcome and prognostic factors during the course of primary small-vessel vasculitides. J Rheumatol. 2006;33:1299-306.\u003c/li\u003e\n\u003cli\u003eGuillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome: a prospective study in 342 patients. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e 1996; 75: 17\u0026ndash;28.\u003c/li\u003e\n\u003cli\u003eRibi C, Cohen P, Pagnoux C, Mahr A, Ar\u0026egrave;ne JP, Lauque D, et al. Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum. 2008;58:586-94.\u003c/li\u003e\n\u003cli\u003eSamson M, Pu\u0026eacute;chal X, Devilliers H, Ribi C, Cohen P, Bienvenu B, et al. Mononeuritis multiplex predicts the need for immunosuppressive or immunomodulatory drugs for EGPA, PAN and MPA patients without poor-prognosis factors. Autoimmun Rev. 2014;13:945-53.\u003c/li\u003e\n\u003cli\u003eExley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers DM, Moots R. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI). Br J Rheumatol. 1998;37:57-63. \u003c/li\u003e\n\u003cli\u003eCohen P, Pagnoux C, Mahr A, Ar\u0026egrave;ne JP, Mouthon L, Le Guern V, et al. Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum. 2007;57:686-93\u003c/li\u003e\n\u003cli\u003ePagnoux C, Qu\u0026eacute;m\u0026eacute;neur T, Ninet J, Diot E, Kyndt X, de Wazi\u0026egrave;res B, et al. Treatment of systemic necrotizing vasculitides in patients aged sixty-five years or older: results of a multicenter, open-label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy. Arthritis Rheumatol. 2015;67:1117-27.\u003c/li\u003e\n\u003cli\u003eBosch X, Guilabert A, Espinosa G, Mirapeix E. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA. 2007;298:655-69.\u003c/li\u003e\n\u003cli\u003eCatherine K, Lorraine H, Mark L. The complications of vasculitis and its treatment. Best Pract Res Clin Rheumatol 2018;32:125-136.\u003c/li\u003e\n\u003cli\u003ePavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multi centre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842): 651\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eOrtega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198\u0026ndash;207\u003c/li\u003e\n\u003cli\u003eKim S, Marigowda G, Oren E, Israel E, Wechsler ME. Mepolizumab as a steroid sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010;125:1336\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003eWechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eHellmich B, Sanchez-Alamo B, Schirmer JH, Berti A, Blockmans D, Cid MC, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024; 83: 30\u0026ndash;47.\u003c/li\u003e\n\u003cli\u003eRaffray L, Guillevin L. Updates for the treatment of EGPA. Presse Med. 2020;49:104036.\u003c/li\u003e\n\u003cli\u003eEmmi G, Bettiol A, Gelain E, Bajema IM, Berti A, Burns S, et al. Evidence-based guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nat Rev Rheumatol. 2023;19:378-393.\u003c/li\u003e\n\u003cli\u003eTsurikisawa N, Oshikata C, Watanabe M, Fukuda N, Yamaguchi T, Kiyohara H, Kaneko T. Clinical Features of Patients with Active Eosinophilic Granulomatosis with Polyangiitis Successfully Treated with Mepolizumab. Int Arch Allergy Immunol. 2021;182:744-56.\u003c/li\u003e\n\u003cli\u003eMasumoto N, Oshikata C, Nakadegawa R, Motobayashi Y, Osada R, Manabe S, et al. Long-term mepolizumab treatment reduces relapse rates in super-responders with eosinophilic granulomatosis with polyangiitis. \u003cem\u003eAllergy Asthma Clin Immunol\u003c/em\u003e 2023; 19: 40.\u003c/li\u003e\n\u003cli\u003eLuqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. \u003cem\u003eQ J Med\u003c/em\u003e 1994; 87: 671\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eOzaki S. ANCA-associated Vasculitis: Diagnostic Therapeutic Strategy. \u003cem\u003eAllergol Int\u003c/em\u003e. 2007; 56(2): 87\u0026ndash;96.\u003c/li\u003e\n\u003cli\u003eMasi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). \u003cem\u003eArthritis Rheum\u003c/em\u003e 1990; 33: 1094\u0026ndash;100.\u003c/li\u003e\n\u003cli\u003eGrayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis. \u003cem\u003eArthritis Rheumatol \u003c/em\u003e2022; 74: 386\u0026ndash;392.\u003c/li\u003e\n\u003cli\u003eTsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K. Decreases in the Numbers of Peripheral Blood Regulatory T Cells, and Increases in the Levels of Memory and Activated B Cells, in Patients with Active Eosinophilic Granulomatosis and Polyangiitis. \u003cem\u003eJ Clin Immunol\u003c/em\u003e 2013; 33(5): 965\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eSilva CI, M\u0026uuml;ller NL, Fujimoto K, Johkoh T, Ajzen SA, Churg A. 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Churg-Strauss syndrome: the spectrum of pulmonary CT findings in 17 patients. \u003cem\u003eAm J Roentgenol\u003c/em\u003e 1998; 170: 297\u0026ndash;300.\u003c/li\u003e\n\u003cli\u003eHoriguchi Y, Morita Y, Tsurikisawa N, Akiyama K. \u003csup\u003e123\u003c/sup\u003eI-MIBG imaging detects cardiac involvement and predicts cardiac events in Churg-Strauss syndrome. \u003cem\u003eEur J Nucl Med Mol Imaging\u003c/em\u003e 2011; 38: 211\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eTsurikisawa N, Oshikata C, Tsuburai T, Sugano S, Nakamura Y, Shimoda T, et al. Th17 cells reflect colon submucosal pathologic changes in active eosinophilic granulomatosis with polyangiitis. \u003cem\u003eBMC Immunol\u003c/em\u003e 2015; 16: 75\u0026ndash;86\u003c/li\u003e\n\u003cli\u003eGuillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Toumelin P. The five-factor score revisited. Assessment of prognosis of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) Cohort. Medicine 2011;90:19\u0026ndash;27.\u003c/li\u003e\n\u003cli\u003ede Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150: 670\u0026ndash;680.\u003c/li\u003e\n\u003cli\u003eMilanesi A, Delvino P, QuagliniS, Montecucco C, MontiS. Azathioprine vs methotrexate in eosinophilic granulomatosis with polyangiitis: a monocentric retrospective study. Rheumatology (Oxford). 2024 Apr 2;63(4):945-952\u003c/li\u003e\n\u003cli\u003eWechsler ME, Silver J, Wolff G, Price RG, Verghis R, Weller PF, et al. Long-term safety and efficacy of mepolizumab in eosinophilic granulomatosis with polyangiitis. Arthritis Rheumatol. 2025 2025 Aug;77(8):1052-62. doi: 10.1002/art.43146.\u003c/li\u003e\n\u003cli\u003eSpataro F, Cacciapaglia F, Carlucci P, Solimando AG, Desantis V, Girolamo AD, et al. Efficacy and Safety of Mepolizumab 300 mg in Eosinophilic Granulomatosis With Polyangiitis: A Meta-Analysis of Eight Retrospective Studies. Allergy 2025 16:1587158\u003c/li\u003e\n\u003cli\u003eLazzeronil M, Longoni V, SchiavoP, Bizzi E, Brucato A, Gramellini G. Anti-IL5/IL-5 receptor therapies for eosinophilic granulomatosis with polyangiitis: an updated Systematic Review. Front Immunol 2025:16:1587158\u003c/li\u003e\n\u003cli\u003eWechsler ME, Nair P, Terrier B, Walz B, Bourdin A, Jayne DRW, et al. Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. \u003cem\u003eN Engl J Med\u003c/em\u003e 2024; 390: 911-921.\u003c/li\u003e\n\u003cli\u003eShiomi M, Watanabe R, Ishihara R, Tanaka S, Nakazawa T, Hashimoto M. Comparative Insights on IL-5 Targeting with Mepolizumab and Benralizumab: Enhancing EGPA Treatment Strategies. Biomolecules. 2025 Apr 8;15(4):544.\u003c/li\u003e\n\u003cli\u003eMattioli I, Urban ML, Padoan R, Mohammad AJ, Salvarani C, Baldini C, et al. Mepolizumab versus benralizumab for eosinophilic granulomatosis with polyangiitis (EGPA): A European real-life retrospective comparative study. J Autoimmun 2025 May:153:103398. \u003c/li\u003e\n\u003cli\u003eBasta F, Mazzuca C, Nucera E, Schiavino D, Afeltra A, Antonelli Incalzi R Omalizumab in eosinophilic granulomatosis with polyangiitis: friend or foe? A systematic literature review. \u003cem\u003eClin Exp Rheumatol\u003c/em\u003e 2020; 38 Suppl 124(2): 214\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eMolina B, Padoan R, Urban ML, Novikov P, Caminati M, Taill\u0026eacute; C, et al. Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study. \u003cem\u003eAnn Rheum Dis\u003c/em\u003e 2023 Dec; 82(12): 1587\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eAdachi S, Oshikata C, Kaneko T, Tsurikisawa N\u003cstrong\u003e. \u003c/strong\u003eRituximab and dupilumab improve eosinophilic granulomatosis with polyangiitis with multiple pulmonary thrombi. Allergy Asthma Clin Immunol. 2022;18:18\u003c/li\u003e\n\u003cli\u003eTsurikisawa N, Oshikata C, Watanabe M, Tsuburai T, Kaneko T, Saito H. Innate immune response reflects disease activity in eosinophilic granulomatosis with polyangiitis. Clin Exp Allergy. 2018;48:1305\u0026ndash;16.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"anti–IL-5 antibody, Churg–Strauss syndrome, eosinophilic granulomatosis with polyangiitis, immunoglobulin, immunosuppressant, mepolizumab","lastPublishedDoi":"10.21203/rs.3.rs-8125801/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8125801/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e To investigate whether long-term remission can be maintained with corticosteroids plus mepolizumab, without the addition of conventional immunosuppressants, following initial remission induction in patients with eosinophilic granulomatosis with polyangiitis (EGPA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We retrospectively recruited 72 EGPA patients treated at the National Hospital Organization Yokohama Medical Center (April 2022 to March 2025). Patients were categorized into an IS-combination group (immunosuppressant + corticosteroid + mepolizumab) and a non-IS group (corticosteroid + mepolizumab) on the basis of immunosuppressant use at mepolizumab initiation. Peripheral blood eosinophil counts, Birmingham Vasculitis Activity Score (BVAS), systemic corticosteroid dosage, remission induction rates, and duration of relapse-free period following the introduction of mepolizumab were compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Compared with the IS-combination group, the non-IS group was older at EGPA onset (\u003cem\u003eP\u003c/em\u003e = 0.02), had a shorter interval from diagnosis to study entry (\u003cem\u003eP\u003c/em\u003e = 0.004), had less myocardial involvement (\u003cem\u003eP\u003c/em\u003e = 0.01), and had lower BVAS before treatment with mepolizumab (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). Immunosuppressant Use during initial treatment was 100% in the IS-combination group and 75% in the non-IS group (\u003cem\u003eP\u003c/em\u003e = 0.001). The non-IS group achieved remission faster (\u003cem\u003eP\u003c/em\u003e = 0.03), had a higher cumulative remission rate (\u003cem\u003eP\u003c/em\u003e = 0.01), and had a higher relapse-free rate (\u003cem\u003eP\u003c/em\u003e = 0.02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In non-severe EGPA, treatment with corticosteroids plus mepolizumab without concomitant immunosuppression should achieve earlier remission and maintain long-term disease control.\u003c/p\u003e","manuscriptTitle":"Management of Non-Severe Eosinophilic Granulomatosis with Polyangiitis without Immunosuppressants Using Mepolizumab: Clinical Implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 13:58:33","doi":"10.21203/rs.3.rs-8125801/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"01aecbf4-daec-457d-b13e-cd8c72488ef0","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-12T14:24:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 13:58:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8125801","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8125801","identity":"rs-8125801","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}