Safety and Efficacy of Mepolizumab in Patients with Eosinophilic Granulomatosis with Polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis disorder which involves multiple organ systems and is characterized by asthma, pulmonary infiltrates, sinusitis, neuropathy, and peripheral eosinophilia. It also has an effect on the heart, skin, kidneys, and gastrointestinal tract. Interlukin-5 (IL-5) is involved in maturation and activation of eosinophil, the production of which is increased in the EGPA. Treatments of EGPA are limited to systemic corticosteroids and immunomodulators. These drugs are associated with significant side effects. Besides this, the response of patients to these drugs may be disappointing. Frequent relapses, the need for long-term medium-to-high-dose glucocorticoid therapy, and failure to achieve remission are not uncommon findings. There is a need for noble agents that could reduce frequent relapses and the dose of systemic glucocorticoids and maintain a sustained remission without significant side effects. Mepolizumab is IL-5 antagonist and may have value in treating patients with EGPA. Therefore, we did a systematic review to evaluate the efficacy and safety of mepolizumab in patients with EGPA.


Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA), which was previously recognized as Churg-Strauss syndrome (CSS), was first described in 1951 by Churg and Strauss. It is a small-vessel necrotizing vasculitis characterized by multisystemic manifestations like asthma, lung infiltrations, extravascular necrotizing granuloma, and hypereosinophilia [1]. The most commonly involved organ is the lung, followed by the skin. EGPA can virtually affect any organ systems, including cardiovascular, gastrointestinal, renal, and central nervous system [2]. Vasculitis of extrapulmonary organs is largely responsible for the morbidity and mortality in patients with EGPA.
EGPA typically occurs in several phases. The prodromal phase is characterized by asthma and/or allergic rhinitis, which usually begins when the individual is in their second to third decade of life. The eosinophilic infiltration phase is characterized by peripheral eosinophilia and eosinophilic tissue infiltration of different organs. The third phase is the vasculitic phase and it is associated with constitutional signs and symptoms like fever, malaise, fatigue, and weight loss.
Treatments of EGPA are limited to systemic corticosteroids and immunomodulators. These drugs are associated with significant side effects. Despite treatment, the response to disease is limited. Frequent relapses, need for long-term medium-to-high-dose glucocorticoid therapy, and failure to achieve remission are not uncommon findings.
The exact pathogenesis of EGPA is poorly understood. Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60 percent of patients with EGPA and are classified among the ANCA-positive vasculitides [3]. In addition, EGPA is characterized by several other abnormalities of immune function such as heightened Th2 and Th1 immunity (suggested by prominence of allergic features and pulmonary angiocentric granulomatosis, resp.) and altered humoral immunity (suggested by increased serum IgE level) [4,5]. Studies suggest a direct pathogenic effect of eosinophilic  infiltration in the different tissues [4,6,7]. Interlukin-5 (IL-5) mediates proliferation, maturation, differentiation, tissue survival, and activation of eosinophil [8,9]. Levels of IL-5 are increased in patients with EGPA and might correlate with disease activity [5]. Therefore, neutralization of IL-5 offers a rational therapeutic approach for managing a case of EGPA. Mepolizumab is an anti-IL-5 monoclonal antibody that binds to IL-5 and prevents the interaction of IL-5 with its receptor on the surface of eosinophil. Mepolizumab is found to be effective in reducing peripheral eosinophil counts in different hypereosinophilic syndrome [10][11][12]. In this review, we reviewed the current evidence for the efficacy and safety of mepolizumab in patients with EGPA.

Search Strategy.
The PRISMA statement for reporting systematic reviews recommended by the Cochrane Collaboration was followed for conducting this systematic review [ Figure 1]. PubMed, Google Scholar, CENTRAL, and EMBASE were searched for peer-reviewed research published between July 2005 and July 2018. Databases were searched using the search terms under two search themes and combined using the Boolean operator "AND". For the theme "Mepolizumab", we used the following text words: mepolizumab, IL-5 antagonist, and monoclonal antibody. For the theme "Eosinophilic granulomatosis with polyangiitis", we used the following text words: Eosinophilic granulomatosis with polyangiitis, Churg-Strauss Syndrome, EGPA, and CSS [13].

Selection Criteria.
Studies published in the English language were included in the review if they aimed to assess efficacy and safety of mepolizumab in patients with EGPA. Studies that aimed to assess efficacy and safety of mepolizumab in disease conditions other than EGPA, like asthma, hypereosinophilic syndrome, and eosinophilic esophagitis, were excluded. In addition, case reports, case series, editorials, and correspondences were also excluded [13]. Diagram detailing the study identification and selection process is given in Figure 1.

Data Abstraction.
The authors (RRP and GN) independently screened the articles based on the inclusion and exclusion criteria. Full texts were obtained for articles that met inclusion criteria. The authors developed a data abstraction spreadsheet using Microsoft Excel version 2013 (Microsoft Corp., Redmond, WA, USA) and included the following information: author, year of publication, journal, country where the study was done, study design, sample size, baseline characteristics of the patients, dose, frequency, and the route of administration of the drug, efficacy in the terms of period of remission, relapse, and reduced dose of steroid, and the safety of the drug. Any discrepancies were solved by consultation with a third author (SM) [13].

Study Characteristics.
The study characteristics are represented in Table 1. All the three articles included in this review were of good quality, considering the presence of  , and local injection-site reactions (similar in the two groups). One patient in mepolizumab group died from cardiac arrest during this study; however, this participant had a prior history of coronary artery disease [14]. In the study performed by Kim et al., there was significantly lower exacerbation rate during the treatment period (0.14 events per week, two events during a 14-week period) compared to the nontreatment period (0.69 events per week, 18 events over a 26-week period). In this study, they found that mepolizumab effectively served as a corticosteroid-sparing therapy. The mean dose at baseline was 12.9 milligrams (mg) per day, which was reduced to 4.6 mg per day after 12 weeks of therapy (study week 16), that is, 64% reduction in corticosteroid dose (p=0.0001) after 4 doses of mepolizumab. As per this study, mepolizumab was safe to use, and there were no severe adverse events noted during the study period. The common adverse events were mild transient headache (n= 3), mild pruritus (n=1), and loose stool (n=1). In the same study, participants experienced wheeze or cough (n=4), sore throat (n=4), nausea or abdominal discomfort (n=3), sinusitis (n=6), and arthritis (n=1) during the trial. However, these adverse events were not due to mepolizumab; rather they were presumably related to corticosteroid tapering, signs of EGPA activity, or both [16].
In a similar study conducted by Moosig et al., out of 10 patients, eight reached remission, one had BVAS of zero but did not achieve glucocorticoid dose less than 7.5 mg/day, and one reached remission but was excluded because of nonadherence. There was no relapse noted with mepolizumab therapy. The daily dose of glucocorticoid was reduced significantly at week 32 (median, 19 mg at baseline to 4 mg at week 32; p=0.006). Mepolizumab was well tolerated and the most common adverse events associated with mepolizumab therapy were eczema, edema, swelling of left hand, urinary tract infection, dentalgia, abdominal pain, wound infection, otitis media, bronchitis, herpes zoster, and herpes simplex. Severe adverse events like anaphylaxis (n=1), Pulmonary Medicine 5 norovirus infection (n=1), cerebral micro embolism (n=1), and de Quervain thyroiditis (n=1) were noted. However, these serious adverse events were probably unrelated to mepolizumab therapy [15].
The present work is, to the best of our knowledge, the first systematic review of the latest three trials, allowing the direct comparison of efficacy and safety of mepolizumab in patients with EGPA.

Conclusion of Included Studies.
Based on the studies analyzed, we found that mepolizumab allows substantial corticosteroid tapering at the cost of maintaining clinical stability. In all the studies, there was a significant decrease in mean corticosteroid dose few weeks after start of therapy with mepolizumab. We also found a significantly higher proportion of remission and a lower rate of relapse with mepolizumab therapy. Mepolizumab does not only control the asthma symptoms but also has an effect on systemic vasculitis manifestations as suggested by decreased BVAS in all the three studies. The safety of mepolizumab is well established from the three studies, except for few minor side effects. The serious adverse events also occurred during the trials; however, those events were probably unrelated to mepolizumab therapy. In all the three studies, the pattern of exacerbation, clinical symptoms, and dose of corticosteroid improved while patients were under mepolizumab therapy but worsened after it was withdrawn. Given the substantial adverse effects of long-term systemic corticosteroid, such as weight gain, impaired blood sugar, iatrogenic Cushing syndrome, thinning of skin, osteoporosis, adrenal suppression, and increased risk of infection, mepolizumab could establish itself as a noble agent in treating patients with EGPA.

Comparison with Other Studies.
A meta-analysis of randomized placebo-controlled trials of mepolizumab in patients with eosinophilic asthma found significantly decreased exacerbation risk compared to placebo (OR, 0.30; 95%CI, 0.13 to 0.67; p=0.004) and a significant improvement in the scores on the Asthma Quality of Life Questionnaire (AQLQ) (mean difference, 0.26; 95% CI, 0.03 to 0.49; p=0.03). The same study found that mepolizumab was well tolerated. Some serious adverse events reported such as cerebrovascular disorder, asthma exacerbation, and gastrointestinal disturbance were not considered by the investigators to be related to study medication. The common adverse events were headache, chest pain, facial flushing, erectile or ejaculatory dysfunction, rash, conjunctivitis, fatigue, upper respiratory tract infection, rhinitis, bronchitis, sinusitis, viral infection, injury, nausea, and pharyngitis [17].
A study conducted by Nair et al. in patients with prednisone-dependent asthma with sputum eosinophilia found that the rate of exacerbation was significantly lower in mepolizumab group compared to placebo group. Patients who received mepolizumab were able to reduce their prednisone dose by a mean (±SD) of 83.8±33.4% of their maximum possible dose, as compared with 47.7±40.5% in the placebo group (p=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. There were no serious adverse events [18].
A randomized controlled trial done by Rothenberg et al. in patients with negative FIP1L1-PDGFRA fusion gene hypereosinophilic syndrome with mepolizumab discovered that mepolizumab treatment enabled clinically significant reductions in corticosteroid dose and often corticosteroid discontinuation [19].
Studies have shown that mepolizumab is associated with marked decreases in peripheral blood and esophageal eosinophilia in patients with eosinophilic esophagitis and improved clinical outcomes [20,21].
3.8. Justification of Use. Treatment of EGPA remains a challenge for physicians because the current available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapses. The long-term use of high-dose corticosteroid is associated with potential adverse effects like impaired blood sugar, increased risk of infection, Cushing syndrome, glaucoma, weight gain, and adrenal suppression. So it is necessary to find an alternative to corticosteroids and immunomodulators. Mepolizumab is a potential alternative that binds to IL-5 and prevents its interaction with its receptor on the eosinophil surface. Besides EGPA, mepolizumab is also found to be effective in other hypereosinophilic syndromes. The safety of mepolizumab is well established from different studies.

3.9.
Limitations of the Review. The result of our systematic review should be considered with caution, owing to limited number of available studies and subjects. The sample size was small to reach a convincing conclusion. Secondly, the drug dose and treatment duration differing in the trials involved in our review made it difficult to determine the optimal dose of mepolizumab which would be mostly appropriate for patients with EGPA.

Conclusions
To conclude, this review has found that mepolizumab is efficacious and safer to use in patients with EGPA. It has an effect on asthma symptoms as well as systemic vasculitis manifestations. It might improve the rate of remission, decreases relapse rate, and allow for reduced glucocorticoid use, at cost of any serious adverse drug effects.