Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study

INTRODUCTION

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis characterized by asthma, ear, nose, and throat (ENT) involvement, blood and tissue eosinophilia, and systemic vasculitis manifestations (1, 2). Treatment mainly relies on systemic glucocorticoids and inhaled therapies for respiratory symptoms (3). EGPA usually follows a chronic relapsing course; thus, patients are at risk of permanent tissue or organ damage, which can also be due to glucocorticoid-related toxicity. Therefore, immunosuppressive treatments are often required and are also used as glucocorticoid-sparing agents (3, 4).

Among novel therapeutic options, mepolizumab is a monoclonal antibody targeting interleukin-5 (IL-5), a cytokine involved in eosinophil maturation, differentiation, and survival. Increased serum levels of IL-5 are observed in eosinophilic disorders, including EGPA (5), and a genome-wide association study identified the IL5 region as one of the main EGPA-associated loci (6).

Mepolizumab is approved for the treatment of severe eosinophilic asthma at 100 mg every 4 weeks subcutaneously (7) and for the treatment of hypereosinophilic syndrome (HES) at 300 mg every 4 weeks (8). After encouraging results from previous studies (9, 10), the phase III MIRRA trial proved the efficacy of mepolizumab 300 mg every 4 weeks subcutaneously for relapsing or refractory EGPA (11, 12), leading to its approval by the US Food and Drug Administration (FDA), while in Europe it is currently used off-label.

Recent smaller studies showed the successful use of mepolizumab 100 mg every 4 weeks for the treatment of EGPA, especially for the control of respiratory manifestations (13-15). However, the benefits and side effects of mepolizumab 100 mg every 4 weeks versus 300 mg every 4 weeks for systemic and respiratory EGPA involvement have never been compared. Therefore, its optimal dose is still debated (16). This study aimed to investigate the effectiveness and safety of mepolizumab 100 mg versus 300 mg every 4 weeks in a large European cohort of patients with EGPA.

RESULTS

We included 203 patients, of whom 57.1% were women (Table 1). The median age at the time of mepolizumab initiation was 55.1 years (IQR 46.7–62.5), and the median disease duration was 4.8 years (IQR 4.9–9.2). At the time of EGPA diagnosis, 70 patients (34.5%) were positive for ANCAs, most of whom had either perinuclear ANCAs or myeloperoxidase ANCAs (84.3%). Before mepolizumab treatment was initiated, 150 of 203 patients (73.9%) had received traditional DMARDs, 51 (25.1%) received biologic DMARDs, and 18 (9.0%) received intravenous immunoglobulin. Disease remission, according to clinical judgment, was achieved in 120 patients after induction therapy. At the time of mepolizumab initiation (baseline), 92.1% of the patients had active disease, with a median BVAS score of 4 (IQR 2–8). The most common manifestations were pulmonary (89.7%), ENT (71.4%), constitutional (27.6%), and peripheral neurologic (22.7%). Ten patients had cardiac involvement at baseline, including 1 case of pericarditis, 1 case of myocarditis, and 8 cases of cardiomyopathy with cardiac failure. Of 190 patients with available ANCA test results, 38 (20.0%) were ANCA positive at the time mepolizumab was initiated, most of whom had perinuclear ANCAs or myeloperoxidase-ANCAs (89.5%). At baseline, almost all patients (95.6%) had received stable glucocorticoid treatment in the previous 3 months, at a median prednisone dose of 10 mg/day (IQR 5–20). Additional therapies included conventional DMARDs, mostly methotrexate (18.7%), azathioprine (11.3%), rituximab (11.3%), or intravenous immunoglobulin (5.9%). One hundred ninety-two patients (95%) were receiving inhaled therapy for asthma.

Table 1. Characteristics of the patients with EGPA at the time of mepolizumab initiation Overall Mepolizumab 100 mg/4 weeks Mepolizumab 300 mg/4 weeks P (n = 203) (n = 158) (n = 33) Female 116 (57.1) 88 (55.7) 22 (66.7) 0.333 Smoking status Former 44 (21.7) 36 (22.8) 5 (15.2) 0.640 Current 3 (1.5) 3 (1.9) 0 Age at diagnosis, median (IQR) years 49.1 (37.7–57.1) 48.7 (37.9–57.5) 49.2 (39.8–53.4) 0.380 Age at mepolizumab initiation, median (IQR) years 55.1 (46.7–62.5) 55.1 (46.7–62.8) 53.0 (47.3–59.3) 0.426 Disease duration at mepolizumab initiation, median (IQR) years 4.8 (4.9–9.2) 4.9 (1.6–8.9) 3.9 (1.1–14.1) 0.921 Active organ involvement at mepolizumab initiation Constitutional 56 (27.6) 50 (31.7) 3 (9.1) 0.009 Purpura 15 (7.4) 11 (7.0) 2 (6.1) 1.000 ENT 145 (71.4) 121 (76.6) 17 (51.5) 0.005 Pulmonary 182 (89.7) 141 (89.2) 29 (87.9) 0.765 Cardiac 10 (4.9) 8 (5.1) 1 (3.0) 1.000 Gastrointestinal 9 (4.4) 8 (5.1) 1 (3.0) 1.000 Renal 5 (2.5) 5 (3.2) 0 NA Peripheral neurologic 46 (22.7) 36 (22.8) 6 (18.2) 0.650 Active disease at mepolizumab initiation (BVAS >0) 187 (92.1) 144 (91.1) 31 (93.9) 0.792 BVAS score at mepolizumab initiation, median (IQR) 4 (2–8) 4 (2–8) 4 (2–7) 0.163 Laboratory parameters at mepolizumab initiation ANCA positive 38 (20.0) 28 (18.9) 9 (27.3) 0.339 Perinuclear ANCA 34 (17.9) 26 (17.6) 8 (24.2) Cytoplasmic ANCA 4 (2.1) 2 (1.4) 1 (3.0) MPO ANCA 34 (17.9) 27 (18.2) 8 (24.2) PR3 ANCA 4 (2.1) 2 (1.4) 1 (3.0) Eosinophil count, median (IQR) 610 (200–1,040) 700 (200–1,080) 440 (200–910) 0.328 Pharmacologic therapies administered before mepolizumab initiation Oral glucocorticoids 201 (99.0) 156 (98.7) 33 (100.0) NA Azathioprine 91 (44.8) 69 (43.7) 17 (51.5) 0.446 Methotrexate 78 (38.4) 56 (35.4) 18 (54.6) 0.050 Cyclophosphamide 57 (28.1) 44 (27.9) 11 (33.3) 0.531 Mycophenolate 39 (19.2) 29 (18.4) 6 (18.2) 1.000 Cyclosporine 21 (10.3) 18 (11.4) 1 (3.0) 0.206 Rituximab 39 (19.2) 36 (22.8) 3 (9.1) 0.097 IV immunoglobulin 18 (8.9) 17 (10.8) 1 (3.0) 0.321 Omalizumab 17 (8.4) 13 (8.2) 2 (6.1) 1.000 Other immunosuppressants 16 (7.9) 13 (8.2) 1 (3.0) 0.471 Pharmacologic therapies at mepolizumab initiation Prednisone equivalent daily dose in the previous 3 months, median (IQR)§ 10 (5–20) 10 (IQR 5-20) 10 (IQR 5-22.5) 0.854 Oral glucocorticoids 194 (95.6) 149 (94.3) 33 (100.0) NA Prednisone equivalent daily dose, median (IQR) 10 (5–20) 10 (5–20) 10 (5–25) 0.511 Methotrexate 38 (18.7) 29 (18.4) 9 (27.3) 0.240 Azathioprine 23 (11.3) 19 (12.0) 3 (9.1) 0.772 Mycophenolate 18 (8.9) 12 (7.6) 4 (12.1) 0.486 Cyclosporine 2 (1.0) 1 (0.6) 0 NA Rituximab 23 (11.3) 20 (12.7) 3 (9.1) 0.771 IV immunoglobulin 12 (5.9) 11 (7.0) 1 (3.0) 0.695 Other immunosuppressants 5 (2.5) 3 (1.9) 1 (3.0) 0.535 Inhaled therapy for asthma 192 (95.0) 150 (94.9) 30 (90.9) 0.407

One hundred sixty-eight patients initially received mepolizumab at 100 mg every 4 weeks, and 35 at 300 mg every 4 weeks. During follow-up, 10 patients switched from 100 mg to 300 mg every 4 weeks due to inefficacy. Another 2 patients switched from 300 mg to 100 mg every 4 weeks due to personal reasons (Supplementary Figure 1, available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41943). Conversely, in 158 patients (77.8%) and 33 patients (16.3%), stable treatment with mepolizumab of 100 mg every 4 weeks and 300 mg every 4 weeks, respectively, was maintained over the entire follow-up period.

Baseline demographic and clinical characteristics were comparable between these 2 groups, with the exception of constitutional and ENT manifestations, which were more frequent among patients receiving mepolizumab 100 mg every 4 weeks than those receiving 300 mg every 4 weeks (31.7% versus 9.1% [P = 0.009] and 76.6% versus 51.5% [P = 0.005], respectively) (Table 1).

Effectiveness of mepolizumab on systemic disease activity

At 3 months, complete response to treatment had already been achieved in 25 of 203 patients (12.3%), whereas partial response to treatment had been achieved in 64 patients (31.5%) (Supplementary Table 1, available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41943). Complete response rates increased to 23.6% at 6 months, 30.4% at 12 months, and 35.7% at 24 months. Response rates were similar between patients receiving mepolizumab 100 mg every 4 weeks and those receiving 300 mg every 4 weeks (Figure 1). In particular, complete response to treatment had been achieved in 12.0% and 18.2% of patients receiving 100 mg every 4 weeks and 300 mg every 4 weeks, respectively, at 3 months, whereas partial response to treatment had been achieved in 32.9% and 36.4% of patients receiving 100 mg every 4 weeks and 300 mg every 4 weeks, respectively, at 3 months (P = 0.474). Complete response rates further increased during follow-up for both treatment groups (P = 0.204 and P = 0.809 for mepolizumab 100 mg versus 300 mg every 4 weeks at 6 months and 12 months, respectively). At 24 months, only 39 patients receiving mepolizumab 100 mg every 4 weeks and 12 patients receiving 300 mg every 4 weeks had available follow-up data. A greater proportion of patients receiving mepolizumab 300 mg every 4 weeks had complete response to treatment (58.3% versus 33.3%) or partial response to treatment (33.3% versus 30.8%), but these differences were not statistically significant (P = 0.168). Notably, the small number of patients at the different follow-up time points, particularly those receiving mepolizumab 300 mg every 4 weeks, did not allow sufficient power to detect significant differences in the proportion of complete responses between the 2 doses at the different time points (Supplementary Table 2, available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41943).

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Complete and partial response rates in patients with eosinophilic granulomatosis with polyangiitis who received stable treatment with mepolizumab 100 mg every 4 weeks (A) and 300 mg every 4 weeks (B). Complete response was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and daily prednisone dose ≤4 mg/day. Partial response was defined as no disease activity (BVAS = 0) and daily prednisone dose >4 mg/day. No response was defined as active disease (BVAS >0).

Of 71 patients in whom complete response to treatment had been achieved, 22 (31.0%) experienced a relapse after a median time of 6 months (IQR 6–9). At all time points, relapse rates were comparable between both treatment groups (P = 1.000 at 6 months and 12 months; P = 0.642 at 24 months), the overall relapse rates being 32.1% (17 of 53) and 25.0% (4 of 16) for mepolizumab 100 versus 300 mg every 4 weeks, respectively. The median time to relapse was 6 months (IQR 3–9) and 10 months (IQR 9–12) in the mepolizumab 100 mg every 4 weeks group compared to the 300 mg every 4 weeks group, respectively (P = 0.081). Response rates were higher among ANCA-negative patients, especially at 24 months, but the differences were not statistically significant (Supplementary Table 3, available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41943).

The efficacy outcomes in the 10 patients who switched from mepolizumab 100 mg every 4 weeks to 300 mg every 4 weeks are summarized in Supplementary Figure 2 (http://onlinelibrary.wiley.com/doi/10.1002/art.41943). Follow-up data suggested no clear benefit in terms of EGPA control following the increase in monthly mepolizumab dose.

The impact of mepolizumab on the different disease manifestations is summarized in Table 2 and in Supplementary Table 4 (available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41943). A significant reduction in all active manifestations was already observed at 3 months in patients receiving stable mepolizumab 100 mg every 4 weeks. Control of constitutional, pulmonary, ENT, and peripheral neurologic manifestations was maintained during follow-up. With mepolizumab 300 mg every 4 weeks, a significant reduction in the proportion of patients with pulmonary and ENT manifestations was observed at all time points, whereas no clear effect was observed on nonrespiratory manifestations.

Table 2. Organ involvement among the patients with EGPA receiving stable treatment with mepolizumab 100 mg or 300 mg every 4 weeks Mepolizumab initiation (baseline) 3 months P, 3 months 6 months P, 6 months vs. baseline 12 months P, 12 months vs. baseline 24 months P, 24 months vs. baseline (n = 158/33) (n = 158/33) vs. baseline (n = 151/32) (n = 122/29) (n = 39/12) Constitutional symptoms 100 mg/4 weeks 50 (31.7) 25 (15.8) <0.001 23 (15.2) <0.001 15 (12.3) <0.001 6 (15.4) 0.035 300 mg/4 weeks 3 (9.1) 0 NA 2 (6.3) 0.564 2 (6.9) 1.564 0 NA Purpura 100 mg/4 weeks 11 (7.0) 6 (3.8) 0.025 4 (2.7) 0.014 3 (2.5) 0.008 0 NA 300 mg/4 weeks 2 (6.1) 1 (3.0) 0.317 1 (3.1) 0.317 2 (6.9) 1.000 0 NA ENT 100 mg/4 weeks 121 (76.6) 64 (40.5) <0.001 55 (36.4) <0.001 34 (27.9) <0.001 8 (20.5) <0.001 300 mg/4 weeks 17 (51.5) 12 (36.4) 0.025 7 (21.9) 0.003 8 (27.6) 0.034 0 NA Pulmonary 100 mg/4 weeks 141 (89.2) 61 (38.6) <0.001 46 (30.5) <0.001 37 (30.3) <0.001 7 (18.0) <0.001 300 mg/4 weeks 29 (87.9) 10 (30.3) <0.001 5 (15.6) <0.001 9 (31.0) <0.001 1 (8.3) 0.005 Cardiac 100 mg/4 weeks 8 (5.1) 4 (2.5) 0.046 4 (2.7) 0.046 3 (2.5) 0.046 1 (2.6) 0.317 300 mg/4 weeks 1 (3.0) 0 NA 0 NA 0 NA 0 NA Gastrointestinal 100 mg/4 weeks 8 (5.1) 0 0.005 5 (3.3) 0.257 4 (3.3) 0.257 0 0.083 300 mg/4 weeks 1 (3.0) 1 (3.0) NA 0 NA 0 NA 0 NA Renal 100 mg/4 weeks 5 (3.2) 1 (0.6) 0.046 0 NA 1 (0.8) 0.180 0 0.317 300 mg/4 weeks 0 2 (6.1) 0.157 0 NA 1 (3.5) 0.317 0 NA Peripheral neurologic 100 mg/4 weeks 36 (22.8) 23 (14.6) 0.005 21 (13.9) 0.001 15 (12.3) 0.001 2 (5.1) 0.005 300 mg/4 weeks 6 (18.2) 6 (18.2) NA 3 (9.4) 0.157 2 (6.9) 0.157 0

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