Anti–IL-5 biologic treatment in a patient with asthma and refractory eosinophilic granulomatosis with polyangiitis

History, presentation and initial treatment
A man in his early 60s with >1 year’s history of adult-onset asthma was referred to our rheumatology clinic in 2022. At presentation, he had recurrent asthma exacerbations (two major episodes in 2021 and 2022, one of which required hospitalization) and shortness of breath. However, his asthma responded poorly to steroids, including inhaled corticosteroids. Medium-dose oral prednisolone (15 mg/day) was given during asthma attacks. He had sinusitis for >10 years, while his family history was unremarkable. His body weight was about 70 kg.

Blood test showed elevated blood eosinophil count (BEC; 11 percent) and D-dimer level (>100 mg/L), and myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) test was positive, suggesting eosinophilic granulomatosis with polyangiitis (EGPA). (Table 1) 

High-resolution CT of chest revealed interstitial lung disease (ILD), which was confirmed by lung biopsy and bronchoalveolar lavage. Culture of lung biopsy specimens was negative. Colitis and cardiac asthma were ruled out. These results were consistent with EGPA. (Table 1)

The patient was hospitalized and started on high-dose oral prednisolone (30–40 mg/day) for 6 weeks, followed by tapering of prednisolone (5 mg/day) with addition of concomitant mycophenolate mofetil (MMF; 1,000 mg/day). Although his lung function improved after 3 months of combination therapy, ILD and sinusitis did not resolve. The patient remained MPO-ANCA–positive, and his BEC and D-dimer level were still high. (Table 1)

Treatment with add-on anti–IL-5 biologic and response
Mepolizumab (monthly subcutaneous injection) was added to the patient’s treatment regimen in May 2022. Before mepolizumab initiation, screening showed no evidence of active infections, such as tuberculosis and hepatitis. Regular monitoring was in place at follow-up visits. (Table 1)

The patient responded well to add-on mepolizumab, achieving remission in 2 months. His BEC, D-dimer and inflammatory markers normalized, while his MPO-ANCA status became negative. With markedly improved lung function and control of symptoms, including sinusitis, no asthma exacerbations were reported. The dose of prednisolone was reduced to 1 mg/day. (Table 1)

The patient tolerated mepolizumab well and did not experience injection site reaction or other adverse events (AEs). He reported high satisfaction with mepolizumab treatment. Last seen January 2023, the patient continued to receive mepolizumab and remained in remission. Discontinuation of prednisolone will be considered in the next few months. (Table 1)

Discussion
EGPA, formerly known as Churg-Strauss Syndrome, is a systemic vasculitis associated with asthma and eosinophilia.^1,2 EGPA can be identified with classification criteria of the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR). The criteria include a list of relevant signs and symptoms, such as obstructive airway disease, nasal polyps and high BEC. Among patients with small- or medium-vessel vasculitis, those with a cumulative score of ≥6 points are classified as having EGPA.¹ (Table 2)

EGPA is an underlying cause of asthma that can be managed with appropriate medications.^2,3 However, a lack of awareness can lead to delayed diagnosis of EGPA. In our experience, EGPA may remain undiagnosed for up to 3 years from symptom onset.

Adult-onset asthma is commonly found in patients with EGPA.² In our patient with adult-onset asthma, for example, BEC and D-dimer level were high, and MPO-ANCA was positive. After investigations, EGPA was confirmed approximately 1.5 years from symptom onset. In patients with adult-onset asthma, referral to a rheumatologist can help diagnose EGPA.

Diagnostic workup for EGPA
EGPA shares clinical characteristics with hypereosinophilic syndromes, ANCA-associated vasculitis, as well as infections and allergies, the latter of which may mimic respiratory symptoms of EGPA. Serologic tests, culture and tissue biopsy are useful for confirming EGPA.^4,5 Complete pulmonary assessment with chest imaging and pulmonary function tests is recommended. Pulmonary, renal, cardiac, gastrointestinal and/or peripheral nerve involvement should also be evaluated.⁵ (Table 3)

Our patient underwent diagnostic workup to exclude most differential diagnoses. He had poor lung function without cardiac and gastrointestinal involvement. Despite negative culture results, including Aspergillus spp. In lung biopsy specimens, other infections could not be eliminated. HIV testing was not included because our patient did not have clinical features of HIV infection.

Treatment of EGPA
Corticosteroid ± an immunosuppressant is the standard of care for EGPA patients.^3,5 However, some patients, including ours, may respond poorly to combination therapy with high-dose corticosteroids and an immunosuppressant. For these patients, adding a biologic can be considered.^3,6

The ACR recommends mepolizumab and rituximab as add-on biologics for active EGPA.³ Rituximab is an anti–CD 20 monoclonal antibody (mAb) that has demonstrated clinical remission in EGPA and preserved or improved lung function in autoimmune disease–associated ILD.^7-11 However, B-cell depletion may increase the risk of severe COVID-19 in rituximab-treated patients.¹² Our patient had asthma as the predominant manifestation of refractory EGPA during the COVID-19 pandemic. Therefore, add-on mepolizumab was given.

Mepolizumab is a humanized anti–interleukin-5 (IL-5) mAb approved for adult patients with relapsing-remitting or refractory EGPA in Hong Kong. This indication is supported by results from the 52-week, placebo-controlled, phase III MIRRA trial.^6,13

MIRRA included 136 patients with relapsing or refractory EGPA who had a history or presence of asthma and eosinophilia. Results showed a higher rate of protocol-defined remission (ie, Birmingham Vasculitis Activity Score of 0 with a daily dose of oral corticosteroids [OCS] at ≤4.0 mg over weeks) with mepolizumab 300 mg Q4W vs placebo. A significantly greater proportion of patients on mepolizumab vs placebo achieved ≥24 weeks of accrued remission (28 percent vs 3 percent; odds ratio [OR], 5.91; 95 percent confidence interval [CI], 2.68–13.03; p<0.001) as well as remission at both 36 and 48 weeks (32 percent vs 3 percent; OR, 16.74; 95 percent CI, 3.61–77.56; p<0.001). The annualized rate of relapse was significantly reduced with mepolizumab vs placebo (1.14 vs 2.27; rate ratio, 0.50; 95 percent CI, 0.36–0.70; p<0.001).¹³

Notably, more patients on mepolizumab vs placebo received an average daily OCS dose of ≤4.0 mg in weeks 48–52 (44 percent vs 7 percent; OR, 0.20; 95 percent CI, 0.09–0.41; p<0.001), and discontinued OCS at week 52 (18 percent vs 3 percent). These findings indicated that mepolizumab may facilitate OCS tapering.¹³

Use of low-dose OCS at ≤4.0 mg/day over 52 weeks was a remission criterion in MIRRA, while EULAR recommends OCS use at ≤7.5 mg/day for symptom control.^4,13 From the perspective of a rheumatologist, remission criteria should also include absence of asthma exacerbation, sinusitis and other EGPA symptoms (eg, numbness and rash), with normalization of biochemical parameters (eg, BEC, D-dimer, inflammatory markers and MPO-ANCA).

Although the efficacy of mepolizumab may vary in EGPA patients with increased body weight, our patient who weighed about 70 kg responded well to mepolizumab and achieved remission in 2 months after treatment initiation.¹⁴ At the time of writing, he has not experienced asthma exacerbation despite tapering of prednisolone. He may be weaned off prednisolone in the next few months, but concomitant MMF is still required.

Our patient tolerated mepolizumab well and did not experience AEs. Screening before treatment initiation is important to minimize the potential risk of infection.

In MIRRA, the safety profile of mepolizumab was consistent with previous reports, with no new safety signals identified. The most common AEs included headache (32 percent vs 18 percent with placebo) and upper respiratory tract infection (21 percent vs 16 percent). The rate of local injection-site reaction was 15 percent for mepolizumab and 13 percent for placebo.¹³

Summary
Increased awareness is key to early diagnosis of EGPA. This case represents one of the first EGPA patients treated with an add-on biologic (ie, mepolizumab) in Hong Kong. Both our case and clinical trial results support mepolizumab as an appropriate add-on treatment for refractory EGPA patients, including those with recurrent asthma exacerbations and difficulties in OCS tapering.