IL-5 is a critical cytokine for the growth, maturation, and differentiation of eosinophils, making it an attractive target in EGPA treatment [47]. Mepolizumab, a humanized monoclonal antibody targeting IL-5, was developed in the late 1990s [48], and the results of its first clinical trial for asthma were published in 2000 [49]. MIRRA was the first randomized controlled trial of mepolizumab for treating refractory or relapsing EGPA [25]. Other published studies support the use of mepolizumab for the induction and maintenance of remission in refractory, relapsing, or glucocorticoid-dependent EGPA [25, 50–53]. However, it has not been conclusively determined whether mepolizumab treatment is effective against various vasculitis signs in EGPA or ANCA-positive cases [54].
We administered mepolizumab to EGPA patients for whom conventional therapy failed to induce remission. We showed that there are super-responders and responders with respect to the efficacy of mepolizumab; super-responders were characterized by high peripheral blood eosinophil counts at diagnosis and high serum IgG levels before mepolizumab administration [28]. We also showed mepolizumab to effectively treat vasculitis symptoms in many organs [28].
In the present study, we confirmed that all patients for whom conventional therapy could not induce remission, achieved some clinical benefit after being subsequently treated with mepolizumab; among them were several patients with cardiac symptoms (Table 1). The period required for the effects of clinical improvement with mepolizumab to become apparent varied, with a mean and standard deviation of 3.4 ± 3.0 months, and the percentage of patients who experienced the improvement with mepolizumab within one month was about 34.9%. There were 8/43 (18.6%) cases in which it took more than half a year for the effect to become apparent (Fig. 2). We consider that it is necessary to confirm the effect after at least one year of administration because substantial time may be required for mepolizumab to take effect.
It has been reported that a group with a peripheral blood eosinophil count of 150 or more cells/µL before administration of mepolizumab achieved remissions lasting 24 weeks, compared with a group with a peripheral blood eosinophil count of fewer than 150 cells/µL, and this difference was associated with differences in clinical effects [55]. In this and our previous study [28], the peripheral blood eosinophil count decreased before the administration of mepolizumab and did not increase after the start of mepolizumab treatment. We considered that peripheral blood eosinophil count after the start of treatment was affected by the amounts of steroids and immunosuppressants administered up to that point. Treatment-naïve eosinophil count was a predictor of mepolizumab efficacy [28]. We confirmed the expectation that the mechanism underlying the mepolizumab clinical effects leads to a decrease in eosinophil counts.
This analysis also showed that the high responder group had a higher peripheral blood eosinophil count at the time of diagnosis and a higher serum IgG before mepolizumab compared to the responder group. We reported previously that EGPA patients with repeated relapses have activated CD86+ B cells and a decreased number of CD19+ B cells. As a result, serum IgG levels in these patients decrease and are not correlated with the concurrent prednisolone dose [56]. We have shown in this study that patients can produce IgG even after administration of steroids and other immunosuppressants.
Vasculitis signs, such as arthralgia or myalgia, were higher in the responder group than in the super-responder group (Table 2); we consider that these results reflect the small sample size of the analysis. In both groups, the BVAS at diagnosis was significantly reduced before and after mepolizumab administration (Fig. 5), but the BVAS before and after starting mepolizumab was significantly lower in the super-responder group (Table 2). Most patients in the responder group had immunosuppressants before administration of mepolizumab, and the prednisolone dose at the last visit after treatment with mepolizumab was higher than in the super-responder group.
There are reports that mepolizumab is effective for vascular symptoms in EGPA patients [21, 25, 50–53, 57], but there are no reports regarding its effect on long-term prognosis. In the super-responder group, the relapse rate was significantly lower in the 3rd year and at the last visit (mean and standard deviation of 4.3 ± 1.0 years after the start of mepolizumab) compared with the 1st year after the start of mepolizumab administration (Table 2). These results indicate that mepolizumab administration might reduce the relapse rate in the long term and improve the prognosis.
On the other hand, in the responder group, BVAS decreased after the start of mepolizumab, but the reduction of PSL daily dose was difficult to achieve in the long term, and the relapse rate after mepolizumab administration did not decrease. These results indicated that it was difficult to reduce the daily dose of steroids or other immunosuppressive agents even if mepolizumab had some effect on vascular symptoms in severe and intractable EGPA patients, and mepolizumab could not induce long-term remission.
We reported that the prognosis of EGPA could be improved by intravenous immunoglobulin (IVIG) [15] via an increase of either CD4+CD25+ T cells producing IL-10 [58] or the number of FOXP3+ regulatory T cells [59]. IVIG was administered to 22/25 (88.0%) patients treated with mepolizumab, and it might induce remission by increasing the number of FOXP3 + regulatory T cells [58–60]. IL-33 and ILC2 are involved in the pathogenesis of asthma [61] and EGPA [9, 62]. We previously reported that in EGPA, levels of ILC2 and IL-33 were high during onset and relapse and low levels during remission [9]. In addition, we reported that in the super-responder group, the interval between IVIG treatments after mepolizumab initiation was significantly longer than before mepolizumab [28].
We have also reported that the number of eosinophils in the colonic mucosa significantly correlates with the number of Th17 cells (CD4+ T cells producing IL-17) [45]. Increases in serum IL-17 and IL-22 levels are related to granuloma formation in sarcoidosis [63]. EGPA combines features of both hypereosinophilic disorders (Th2 activity) and ANCA-associated vasculitis (Th1 activity) [8]. In granulomatosis with polyangiitis, Th17 lymphocytes are a possible pathogenetic subset, and Treg cells are possible suppressors of the inflammatory process [64]. Based on these results, we conclude that the synergistic effect of multiple drugs, including IVIG, mepolizumab, steroids, and other immunosuppressants may have durably stabilized immune function and durably decreased the relapse rate in the super-responder group.
Biologics may trigger production of antidrug antibodies against the drug, but there is a report showing that neutralizing antibodies have not been detected [65]. On the other hand, it has been reported that there are cases of patients with asthma in whom the efficacy of mepolizumab is attenuated over time [66].
Long-term administration of biologics in bronchial asthma has been reported only for omalizumab, which has a reported administration period of as long as 10 years [35]. Other biologics such as mepolizumab [35, 36], reslizumab [36, 37], and benralizumab [36, 38] have been reported to be administered for about 2 years. In contrast, for biologics in EGPA, there are no reports of long-term analysis or long-term follow-up, but in this analysis, we administered mepolizumab for at least 3 years. Although omalizumab among biologics has been on the market for the longest time for asthma, the timing of its discontinuation is unclear [67].
There are no reports on the administration duration or discontinuation timing of mepolizumab for EGPA. Our results show that mepolizumab has long-term clinical efficacy and may improve prognosis. A prospective study is considered necessary in the future.