Effectiveness of Mepolizumab in Severe Uncontrolled Asthma Associated or Not with EGPA Based on the Exacto Scale and Separ-Remas Criteria

Introduction

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a systemic disorder characterized by eosinophilic granulomatous inflammation, clinically manifesting as severe asthma often accompanied by eosinophilia, nasal polyposis, or allergic rinitis.¹ Systemic corticosteroids remain the mainstay of treatment; however, chronic relapsing disease can result in irreversible organ damage due to both disease activity and glucocorticoid toxicity. Mepolizumab, an interleukin-5 inhibitor, is approved for type 2 high severe asthma at 100 mg every four weeks and for relapsing or corticosteroid-dependent EGPA at 300 mg every four weeks.^2,3

Assessment of treatment response in EGPA has traditionally relied on the Birmingham Vasculitis Activity Score (BVAS),⁴ which primarily evaluates systemic manifestations rather than asthma control. In contrast, the Exacto scale (from the 2022 Severe Asthma Consensus)⁵ and SEPAR-REMAS criteria (from the 2024 SEPAR-REMAS Consensus)⁶ provide validated metrics for biologic therapy response in severe uncontrolled asthma (SUA). This study aimed to compare baseline clinical and functional characteristics between SUA patients with and without EGPA and evaluate the effectiveness of mepolizumab using the Exacto scale and SEPAR-REMAS criteria.

Materials and Methods

We conducted a retrospective observational cohort study of patients with SUA, defined according to the Spanish Asthma Management Guidelines:⁷ persistent poor symptom control, frequent or severe exacerbations, and airflow limitation despite high-intensity therapy. Patients were followed at the Severe Asthma Unit of our hospital from January 2017 to December 2024. Patients with EGPA were diagnosed according to European College of Rheumatology criteria:⁸ primarily exhibiting asthma, nasal polyposis, and blood eosinophilia >500/µL, with limited systemic involvement (five with mononeuritis multiplex, three with dermatologic manifestations). Given the rarity of EGPA, all available patients were included, resulting in a fixed sample size determined by case availability rather than by a priori calculation. Baseline demographic, clinical, functional, and biomarker data were collected. Historical eosinophilia reflected the highest recorded value, and baseline eosinophils were pre-mepolizumab. All patients received mepolizumab 100 mg every four weeks, with adherence monitored by nursing staff and no patients discontinued treatment during follow-up.

Biologic response was assessed during the first treatment year in each patient using the EXACTO scale for good or complete response and the SEPAR-REMAS criteria for clinical remission. EXACTO quantifies exacerbations, ACT score, FEV₁ variability and adds points for continuous OCS, while SEPAR-REMAS defines remission as no exacerbations or rescue medication, no OCS, well-controlled asthma (ACT ≥20), and normal or near-normal lung function (with negative broncodilatador test) over 12 months. OCS use was defined as daily or alternate-day administration for ≥3 months (≥5 mg/day prednisone) to maintain disease control. Both the proportion of patients on OCS and the mean dose before and after treatment were analyzed. Statistical analyses included parametric and non-parametric tests, chi-square and Fisher exact tests for categorical variables, and effect size calculations where relevant.

Results

We analyzed 142 patients with SUA (mean age 54 ± 17 years; 59.9% female), including 14 patients (9.9%) with EGPA and 128 without EGPA. At baseline, no significant differences were observed between groups with respect to sex, smoking status, or comorbidities such as allergic rhinitis, COPD, bronchiectasis, atopy, anxiety/depression, immunodeficiency, obstructive sleep apnea, or obesity; however, patients with EGPA showed a significantly higher prevalence of nasal polyposis (64.2% vs 29.6%, p<0.01) and more frequent use of OCS (71.43% vs 29.85%, p<0.02). As shown in Table 1, EGPA patients also exhibited higher significant historical eosinophil counts, fewer severe exacerbations and lower baseline daily OCS doses.

Table 1 Comparison Analysis of Clinical, Functional and Inflammatory Parameters at Baseline Visit in the Group of Patients with Severe Uncontrolled Asthma with Our without EGPA

After one year of treatment (Figure 1), rates of good or complete response and clinical remission were higher in patients with EGPA than in patients without EGPA, although the differences were not statistically significant (p = 0.30). The proportion of patients receiving oral corticosteroids (OCS) was significantly higher in the EGPA group compared with the non-EGPA group (p < 0.001). Compared with baseline, the reduction in the proportion of patients using OCS was smaller in the EGPA group, with no statistically significant difference between groups (p = 0.55). Mean daily OCS dose increased in EGPA patients from 9.8 (7.4) to 15.3 (11) mg, whereas it decreased in non-EGPA patients from 18.4 (12.3) to 10.3 (12.8) mg.

Figure 1 Evaluation of treatment effectiveness during the first year of mepolizumab in patients with severe uncontrolled asthma (SUA) with or without EGPA a, b. a Statistical analysis employed (p < 0.05, with IC 95%): the chi-square test.b After one year of treatment (Figure 1), rates of good or complete response and clinical remission were higher in patients with EGPA than in patients without EGPA, although the differences were not statistically significant (p = 0.30). The proportion of patients receiving OCS was significantly higher in the EGPA group compared with the non-EGPA group (p < 0.001). Compared with baseline, the reduction in the proportion of patients using OCS was smaller in the EGPA group, with no statistically significant difference between groups (p = 0.55).

Discussion

In our cohort, patients with EGPA showed higher rates of good or complete response and clinical remission—according to the EXACTO scale and SEPAR-REMAS criteria—although these differences were not statistically significant. In addition, EGPA patients exhibited a smaller reduction in oral corticosteroid (OCS) use compared with non-EGPA patients, along with an increase in mean daily OCS dose. These findings align with other studies evaluating biologic response in EGPA, although the response definitions differ. Portacci et al defined response based on improvements in ACT (>6 points), FEV1 (>500 mL), absence of exacerbations and OCS use, categorizing 78.1% of patients as “super-responders” if at least two criteria were met.⁹

Two complementary hypotheses may explain these observations. First, the pathophysiology of EGPA—marked by higher eosinophilic inflammation, nasal polyposis prevalence, and OCS dependence—may confer enhanced sensitivity to IL-5 blockade. Second, EGPA is a systemic disease that is usually diagnosed by internal medicine specialists and subsequently managed through a shared care model involving both internal medicine and pulmonology. Because internal medicine teams often retain primary responsibility for systemic disease control, they may be more likely to maintain or escalate OCS doses to prevent systemic relapse, particularly in patients with long-term OCS exposure. This multidisciplinary management approach may help explain why, despite relative reductions, patients with EGPA remained more OCS-dependent overall.

An additional strength of our study is that clinically meaningful improvements were achieved despite the use of a lower mepolizumab dose (100 mg), which the formulation was initially prescribed for the treatment of SUA in our cohort. Although dose escalation to 300 mg is possible when clinically indicated, but it was not required in our patients. This finding is consistent with previous studies in which the 300 mg dose was frequently used without demonstrating significant differences in efficacy compared with the 100 mg dose.^2,3

Additionally, using the EXACTO and SEPAR-REMAS criteria allowed a more precise assessment of biologic response in asthma than systemic EGPA-focused scores such as BVAS, which is particularly appropriate given the limited systemic involvement in our cohort. Finally, the main limitation of our study, and likely the reason why the results did not reach statistical significance regarding biologic response, is the small sample size of the EGPA group, as this is a rare disease (14 patients out of 142 in total). Future studies with larger multicenter cohorts are warranted to confirm these findings and optimize dosing strategies.

Conclusion

In our cohort, patients with SUA and EGPA treated with mepolizumab 100 mg showed higher biologic response rates than patients with SUA alone, although these differences were not statistically significant. These findings suggest that asthma-focused assessment tools, such as the EXACTO scale and SEPAR-REMAS criteria, may be useful for evaluating treatment response in EGPA patients with predominantly asthmatic manifestations and limited systemic involvement.