Multidisciplinary approach to eosinophilic disorders: Why and how?

Eosinophilic disorders, such as eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES), often necessitate the use of corticosteroids due to diverse signs and symptoms. However, long-term corticosteroid use is associated with various complications. Patients with poor response to corticosteroids may experience disease recurrence. At an industry-sponsored symposium jointly organized by the Hong Kong Society of Rheumatology and the Hong Kong Thoracic Society, experts shared insights on multidisciplinary team management of eosinophilic disorders and discussed clinical evidence supporting the use of add-on medications, such as mepolizumab, in EGPA and HES.

EGPA and HES: Eosinophilic disorders with distinctive features
“Eosinophilia is prevalent in eosinophilic disorders and other conditions [eg, asthma, haematologic malignancies]. Eosinophilic infiltration can lead to different clinical symptoms, depending on underlying mechanisms and aetiologies,” said Dr Terence Tam, Specialist in Respiratory Medicine in private practice in Hong Kong. [J Allergy Clin Immunol 2012;130:607-612.e9]

“[For example,] EGPA is primarily driven by type 2 T-helper cell response and upregulation of eosinophil-associated cytokines, such as interleukin [IL]-5. Activation leads to high eosinophil counts, which causes endothelial dysfunction and multisystemic manifestations, such as asthma, purpura, neuropathy, and myocardiopathy,” explained Dr Ho SO of the Department of Medicine and Therapeutics, the Chinese University of Hong Kong. “In some cases, vasculitis may be associated with antineutrophil cytoplasmic antibody [ANCA] that induces endothelial injury and vascular inflammation through neutrophil activation.” [Curr Opin Allergy Clin Immunol 2023;23:36-43]

“HES can affect various organs, including the heart, gastrointestinal tract, and central nervous system. Similar to EGPA, many HES patients have lung involvement; however, HES is differentiated from EGPA by the absence of asthma, vasculitis and presence of ANCA,” said Professor Michael Wechsler of the Department of Medicine, National Jewish Health, Colorado, US. “Some myeloproliferative HES patients may carry FIP1L1::PDGFRA fusion protein gene, although most HES patients lack a definitive cause of their disease.” [J Allergy Clin Immunol 2023;151:1415-1428; Clin Rev Allergy Immunol 2016;50:240-251]

Management of EGPA and HES: Current approaches and gaps
EGPA classification criteria of the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) include a list of relevant signs and symptoms, such as obstructive airway disease, nasal polyps, and blood eosinophil count (BEC) ≥1 x 10⁹/L. Patients with small or medium-vessel vasculitis and a cumulative score of ≥6 points are classified as having EGPA. [Ann Rheum Dis 2022;81:309-314]

“Despite good specificity and sensitivity of the diagnosis criteria, EGPA can sometimes go unnoticed in patients with mild symptoms without [significant] vasculitis during the prodrome or earlier disease phases,” Tam commented. “Moreover, in patients with comorbid severe asthma, the use of oral corticosteroids [OCS] may mask eosinophilia and early symptoms critical to EGPA diagnosis.”

“Progression of EGPA can be unpredictable, as classical disease phases may overlap without a specific sequence, resulting in rapid emergence of multiple symptoms,” SO noted. (Figure 1) [Expert Opin Pharmacother 2023;24:1269-1281]

“Notably, long-term disease control in EGPA can be challenging, even for patients initially responsive to standard of care [SoC] involving corticosteroids [with or without an immunosuppressant]. Recurrence and potential damage may occur in later phases,” he continued. (Figure 1)

“One of my patients with a 10-year history of EGPA had steroid-dependent disease. Despite initial treatment with methylprednisolone pulses, followed by six cycles of cyclophosphamide and maintenance therapy with azathioprine, his EGPA remained suboptimally controlled. Over the past decade, he experienced multiple episodes of infections, such as pulmonary tuberculosis, Mycobacterium abscessus pulmonary infection, and Herpes zoster infection. He also developed glucocorticoid-induced osteoporosis, resulting in vertebral collapse. His risk of cardiovascular disease was high,” shared SO. “[For EGPA patients,] a targeted medication with a favourable safety profile is needed.”

“The SoC of HES is glucocorticoids. Studies showed variable efficacy of glucocorticoids in HES patients, [including those with FIP1L1::PGFRA–negative HES],” said Wechsler. “Imatinib is only for HES patients with FIP1L1::PGFRA mutations.” [J Allergy Clin Immunol Pract 2018;6:190-195; Am J Hematol 2019;94:1149-1166]

Multidisciplinary approach to eosinophilic disorders
“EGPA should be considered in all asthma patients, especially if the condition remains or becomes difficult to control despite standard asthma treatment strategies,” advised Tam. “While ANCA positivity is not a diagnostic criterion for EGPA, ANCA assessment may help pulmonologists identify patients with undiagnosed EGPA. Regularly inquiring about vasculitis-associated symptoms is also essential.”

“As a pulmonologist, the initial step in diagnosing [EGPA] involves comprehensive assessment of medical history, including evaluation of respiratory symptoms and extrapulmonary manifestations, such as numbness, fever, myalgia, and weight loss,” Wechsler suggested. “Similarly, for patients with suspected HES, thorough investigations and differential diagnosis should be considered.”

“A collaborative, multidisciplinary team of pulmonologists, rheumatologists and other specialists is important for management of eosinophilic disorders,” Wechsler continued.

“[At our centre], we may conduct multidisciplinary rounds with rheumatologists, dermatologists, haematologists, neurologists, and pathologists in management of complex [hypereosinophilic disorders],” shared SO.

Mepolizumab for eosinophilic disorders
Mepolizumab is a humanized anti–IL-5 monoclonal antibody approved for adult patients with relapsing-remitting or refractory EGPA, as well as those with inadequately controlled HES without an identifiable non-haematologic secondary cause. [Nucala Hong Kong Prescribing Information]

MIRRA trial: EGPA
In the 52-week, placebo-controlled, phase III MIRRA trial, 136 patients with relapsing or refractory EGPA and a stable dose of prednisolone or prednisone (7.5–50 mg/day, with or without immunosuppressive therapy) were randomized 1:1 to receive mepolizumab 300 mg Q4W or placebo. [N Engl J Med 2017;376:1921-1932]

Results showed a higher rate of protocol-defined remission (ie, Birmingham Vasculitis Activity Score of 0 with a daily OCS dose of ≤4.0 mg over 52 weeks) with mepolizumab 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).

During the study period, a lower proportion of patients in the mepolizumab vs placebo group experienced first relapse (56 percent vs 82 percent; hazard ratio [HR], 0.32; 95 percent CI, 0.21–0.50; p<0.001). (Figure 2) 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).

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).

The safety profile of mepolizumab was consistent with previous reports, with no new safety signals identified. The most common adverse events (AEs) included headache (32 percent vs 18 percent with placebo) and upper respiratory tract infection (21 percent vs 16 percent). Local injection-site reactions occurred in 15 percent vs 13 percent of patients in the mepolizumab vs placebo group.

200622 trial: FIP1L1::PDGFRA–negative HES
“Mepolizumab is the first treatment proven to reduce disease flares in patients with FIP1L1::PDGFRA–negative HES,” Wechsler noted. [J Allergy Clin Immunol 2020;146:1397-1405]

In the 32-week, randomized, placebo-controlled, phase III 200622 trial, the efficacy and safety of add-on mepolizumab 300 mg Q4W was investigated in 108 patients with FIP1L1::PDGFRA–negative HES who experienced ≥2 flares (ie, worsening of HES-related symptoms or BEC requiring therapeutic escalation) in the past 12 months and had BEC ≥1,000 cells/μL at baseline.

Results showed a 50 percent lower rate of ≥1 flare (ie, worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue OCS) or withdrawing from the study in the mepolizumab vs placebo group (28 percent vs 56 percent; p=0.002). Logistic regression analysis was consistent with the primary analysis (OR, 0.28; 95 percent CI, 0.12–0.64; p=0.003). In addition, there was a 66 percent reduction in risk of first flare during treatment with mepolizumab vs placebo (HR, 0.34; 95 percent CI, 0.18–0.67; p=0.002). (Figure 3)

Treatment-related AEs of any grade occurred in 22 percent of patients on mepolizumab (n=12) vs 13 percent of patients on placebo (n=7). Local injection-site reactions were reported in 7 percent (n=4) vs 4 percent (n=2) of patients. No new safety signals were identified.

Key takeaway
EGPA and HES are eosinophilic disorders with heterogeneous signs and symptoms that require multidisciplinary management. The MIRRA and 200622 trials demonstrated the efficacy and tolerability of mepolizumab as an add-on treatment for relapsing or refractory EGPA and idiopathic HES.