Tackling Eosinophilic Disorders A Focus on Eosinophilic Granulomatosis with Polyangiitis and Hypereo
Educational Objectives
• Describe the pathophysiologic causes and biopsychosocial burdens of eosinophilic disorders, such as EGPA and HES, including implications for diagnosis and treatment
• Identify patients with EGPA or HES based on symptomatology, red flags, medical history, ancillary testing, and appropriate multidisciplinary collaboration
• Analyze the clinical rationale and trial evidence for biologic therapies for patients with EGPA or HES
• Individualize biologic-based treatment regimens for patients with EGPA or HES to reduce corticosteroid dependence, optimize disease control, and target long-term remission
BURDENS AND PATHOPHYSIOLOGY OF EOSINOPHILIC DISORDERS
Focus on EGPA and HES
The Role of Eos in Health and Disease
Eos in Health
• Eos play multimodal roles in maintaining homeostasis1
• Eos play immunoregulatory and protective roles during parasitic/viral infections1
Eos in Disease
• Pro-inflammatory role: blood eos are increased in type 2 inflammation2
• Can result in tissue/organ damage2
• Elevated blood eos are associated with poor outcomes across multiple disease states3-5
Inflammatory Diseases Associated With Eos
• Multiple diseases are associated with elevated eos, including EGPA and HES6,7
• Unmet needs of patients with eos-driven disease include high CS burden and diagnostic delays8-10
1. Ramirez GA, et al. Biomed Res Int. 2018;2018:9095275; 2. Travers J, Rothenberg ME. Mucosal Immunol. 2015;8(3):464-475; 3. Casciano J et al. J Manag Care Spec Pharm. 2017;23(1):85-91; 4. Curtis C, Ogbogu P. Clin Rev Allergy Immunol. 2016;50(2):240-251; 5. Price DB, et al. Lancet Respir Med. 2015;3(11):849-858; 6. Klion AD, et al. Annu Rev Pathol. 2020;15:179-209; 7. Sastre B, et al. J Investig Allergol Clin Immunol. 2018;28(5):289-304; 8. Zeiger RS et al. J Allergy Clin Immunol Pract. 2017;5(4):1050-1060.e9; 9. Chung KF. Eur Respir J. 2014;43(2):343-373; 10. Pokrzywinski RM, et al. Adv Ther. 2020;37(10):4458-4478.
Overview of EGPA
• Rare autoimmune condition characterized by inflammation in small- and occasionally medium-size blood vessels throughout the body
• Incidence is ~4 cases per million1
• Median age of onset is the fourth or fifth decade of life2
• Characterized by necrotizing granulomatous vasculitis
• ANCA-associated vasculitis
– Distinguished from GPA and MPA by its association with asthma, nasal polyposis, and peripheral eosinophilia
– >90% of patients with EGPA have a prior history of asthma
GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis.
1. Watts RA, et al. Nat Rev Rheumatol. 2022;18(1):22-34; 2. White JPE, Dubey S. Autoimmun Rev. 2023;22(1):103219.
Stages of Disease Progressiona EGPA
Prodromal/Allergic Phase
• Asthma
• Chronic rhinosinusitis
• Fever
• Weight loss
• Malaise
• Myalgia
• Arthralgias
Eosinophilic Phase
Vasculitic Phase
• Peripheral eosinophilia
• Organ involvement: lungs, gastrointestinal, cardiac
• Vasculitis of small to medium vessels
• Constitutional symptoms
• Organ involvement: peripheral nerves, kidneys, skin
aAlthough this disease progression is classically described, in real-world clinical practice, EGPA presentations can be variable. Vega Villanueva KL, Espinoza LR. Curr Rheumatol Rep. 2020;22(1):5.
More than one-third of patients with EGPA report issues with2:
• Diagnostic delays
• Misdiagnosis
1. Merkel P, et al. J Allergy Clin Immunol. 2024;153(2):AB54; 2. Strobel MJ, et al. J Patient Exp. 2022;9:23743735221143953.
Patients with EGPA report difficulty in accessing treatments due to2:
• Lack of diagnosis
• High cost
What Is HES?
• HES is a heterogenous group of rare diseases characterized by1,2: – Hypereosinophilia AND – Eosinophil-mediated organ dysfunction and/or damage AND – No other identifiable cause for eosinophil-mediated organ damage
• Wide-ranging clinical manifestations make HES difficult to diagnose2
– Typically associated with cutaneous, pulmonary, neurologic, or gastrointestinal involvement
• Incidence and prevalence is not well characterized, though the SEER database estimates the incidence at 0.4 cases per 1,000,0003 1. Valent P, et al. Allergy. 2023;78(1):47-59; 2. Klion AD, et al. Annu Rev Pathol. 2020;15:179-209; 3. Ruan GJ, et al. m J Hematol. 2020;95(10):E257-E260.
Differentiating HES Subtypes
Myeloproliferative
HES
• Underlying stem cell, myeloid, or eos neoplasm
• End-organ damage attributable to HE
• Eos are neoplastic (clonal)
• Potential for multiple driver genes (eg, PDGFRA)
Lymphocytic HES
• HE considered to be cytokine-driven
• T-cell clones driving IL-3, IL-5, GM-CSF à eosinophilia
• No evidence of reactive or neoplastic condition underlying HE
• End-organ damage attributable to HE
• Familial clustering
• Very rare
• No evidence of reactive or neoplastic condition underlying HE
• End-organ damage attributable to HE
HES Patient Burden
• Patients with HES may face delays of up to 20 years in diagnosis and initiation of effective treatment1,2
• 70% of patients saw >3 clinicians before diagnosis1
• 83% agreed that HES symptoms were burdensome to their family and friends1
• The most common effects on QoL were reduced ability to exercise, impaired work quality, reduced participation in social activities, and anxiety/worry1
Most Common Responses When Asked What They Want Their Doctor to Know About HES1
Role of Eosinophils in EGPA Pathogenesis
Eosinophils participate in both granulomatous and vasculitic features of EGPA and cause damage through innate and antibody-dependent mechanisms.
Eosinophils release mediators, including ECP, EDN, and MBP, that contribute to tissue damage.
APC, antigen-presenting cell; CCR3, chemokine receptors on eosinophils; ECP, eosinophilic cationic protein; EDN, eosinophil -derived neurotoxin; Ig, immunoglobulin; MBP, major basic protein; TSLP, thymic stromal lymphopoietin; Th, T helper.
Adapted from: Vaglio A, et al. Allergy. 2013;68(3):261-273; Khoury P, et al. Nat Rev Rheumatol. 2014;10(8):474-483; Pelaia G, et al. Mediators Inflamm. 2015;2015:879783.
Understanding Pathophysiology of HES
• Pathophysiology is incompletely understood1
– Likely involves dysregulation of IL-3, IL-5, and GM-CSF
• May vary by subtype1,2
Neoplastic/M-HES1,2
• Clonal eosinophilia triggered by certain oncogenic targets
• Vast majority caused by interstitial deletion on chromosome 4 that generates FIP1L1-PDGFRA fusion gene
• Other genetic abnormalities include PDGFRA, PDGFRB, FGFR1, and PCM1-JAK2
L-HES, lymphocytic HES; M-HES, myeloid HES.
L-HES1-3
• Abnormal clonal T cells; release cytokines such as IL-3, IL-5, and GM-CSF, resulting in eosinophilic inflammation
• Cell surface markers on T cells include CD3−
CD4+ (most common); CD3+ CD4- CD8-; CD3+
CD4+ CD7−
• Some potential for malignancy
1. Stella S, et al. Int J Mol Sci. 2021;22(2):486; 2. Valent P, et al. Allergy. 2023;78(1):47-59; 3. Shomali W, et al. Am J Hematol. 2022;97(1):129-148.
Selected Current and Potential Therapeutic Targets in EGPA and HES
IL-5 is necessary for eosinophil development and acts primarily on eosinophils to induce activation, recruitment, and infiltration.
IL-4 and IL-13 also play a role in eosinophil trafficking.
MPO, myeloperoxidase; Siglec-8, sialic acid–binding Ig-like lectin 8. Adapted from: Hua L, Xie M. Ther Adv Respir Dis. 2025;19:17534666251318615; Khoury P, et al. Mayo Clin Proc. 2023;98(7):1054-1070.
1. Sundaresan DD, Sreedharanunni S. Ind J Med Paediatr Oncol. 2023;44:602-610; 2. Valent P, et al. Allergy. 2023;78(1):47-59; 3. Hu Z, et al. Am J Hematol. 2018;93(11):1337-1346.
Morphologic Evaluations1-3
• Bone marrow aspirate and biopsy with immunohistochemistry
• Tissue evaluation to confirm HE (including organ-restricted disease)
• Blood to assess eosinophil morphology, dysgranulopoiesis
HES Severity and Risk Factors
• Eos counts are the most common biomarker used to monitor disease activity1
• Patient-reported outcomes guide severity assessment and treatment decisions1
• Age >60 years, hemoglobin <10 g/dL, cardiac involvement, and hepatosplenomegaly are associated with decreased overall survival2
5-Year Survival Rate in HES, Stratified by Risk Factors2
1. Khoury P, et al. Front Med (Lausanne). 2017;4:240; 2. Pardanani A, et al. Leukemia. 2016;30(9):1924-1926.
Common Clinical Presentation EGPA
>90% of patients with EGPA have asthma that arises in adulthood, rarely shows seasonal exacerbations, and worsens over time.
ENT symptoms, such as CRSwNP, are common and polyps commonly recur after surgical excision.
The diagnosis of EGPA should be considered in patients with asthma, CRSwNP, and eosinophilia.
CRSwNP, chronic rhinosinusitis with nasal polyps; ENT, ears, nose and throat. Emmi G, et al. Nat Rev Rheumatol. 2023;19(6):378-393.
Determining Risk
of Eosinophilic vs Vasculitic Manifestations
Cardiomyopathy
Pericarditis
In patients with ANCA-negative EGPA, eosinophilic infiltration is the predominant pathology, with a higher prevalence of myocarditis and pulmonary involvement.
Watanabe R, Hashimoto M. J Clin Med. 2023;12(8):5996.
In patients with ANCA-positive EGPA, vasculitis is the main pathology, with a higher prevalence of rapidly progressive glomerulonephritis and peripheral
2022 ACR/EULAR Classification Criteria
• Used to classify a patient as having EGPA when a diagnosis of small- or medium-vessel vasculitis has been made
• Alternative diagnoses mimicking vasculitis should already be excluded
EGPA
Prognosis
and Disease Severity Revised Five-Factor Score (FFS)
Criteria1
GI involvement 5. Absence of ENT manifestations (presence is associated with a better prognosis)
• Predicts the risk of mortality in patients with an established diagnosis of EGPA (along with other vasculitides)1 1. Guillevin L, et al. Medicine. 2011;90(1):19-27; 2. Karadag O, et al. Ann Rheum Dis. 2015;74:523. 1. Age >65 years 2. Cardiac insufficiency 3. Renal insufficiency (creatinine ≥150 µmol/L)
Is It EGPA or HES?
& lymphoproliferative subtypes
JPE, Dubey S. Autoimmun Rev. 2023;22(1):103219.
Differentiating Between EGPA and HES
• Similarities1,2
– Persistent eosinophilia
– Systemic manifestations
• Differences pointing to EGPA1:
– Frequent asthma and nasal polyps
– Vasculitic complications
– ANCA positivity (~40%)
• Differences pointing to HES2: – FIP1L1-PDGFRA fusion
– CD3− CD4+
– Hematologic abnormalities
– Dermatologic symptoms (for L-HES)
1. Groh M, et al. Eur J Intern Med. 2015;26(7):545-553; 2. Khoury P, et al. Mayo Clin Proc. 2023;98(7):1054-1070.
EVOLVING MANAGEMENT RECOMMENDATIONS FOR EGPA
2022 EULAR Treatment Algorithm EGPA
Remission-Induction
aRecommendation states mepolizumab but was published before benralizumab was FDA and EMA approved for the treatment of EGPA; bConsider RTX over CYC in patients of childbearing potential or previous exposure to CYC at an individual cumulative dosage considered to be associated with increased risk of complications. CYC, cyclophosphamide; RTX, rituximab. Hellmich B, et al. Ann Rheum Dis. 2024;83(1):30-47.
2022 EULAR Treatment Algorithma Maintenance of EGPA Remission
Switch to or continueb AZA, MTX, anti–IL-5/5R agent,c or RTX, and continue CS taper Induction of remission Relapse
Achieved Remission
Assess individual relapse risk, comorbidities, and patient preferences
Continue or stop maintenance treatment YES
aRecommendation was published before benralizumab was FDA approved for the treatment of EGPA; bIndividualized duration of maintenance treatment; cIn patients with relapsing or refractory EGPA without organ-threatening manifestations at the time of relapse, MEP is preferred for maintenance of remission, and AZA, MTX, or RTX can be used as alternatives if MEP is not tolerated or is ineffective. MTX, methotrexate.
Hellmich B, et al. Ann Rheum Dis. 2024;83(1):30-47.
Evolution of EGPA Therapies Over Time Advancing Toward Targeted Care
Conventional Immunosuppressants
Initial Immunosuppressant
aBiologic therapy used off-label for EGPA. MMF, mycophenolate mofetil. Emmi G, et al. Nat Rev Rheumatol. 2023;19(6):378-393; Hua L, Xie M. Ther Adv Respir Dis. 2025;19:17534666251318615.
Importance of Reducing Systemic CS Use Numerous Body Systems Affected1-4
T2D, type 2 diabetes; VTE, venous thromboembolism.
Patients with EGPA had significantly longer periods of systemic CS use at doses ≥7 mg/day compared with patients with asthma.5
1. Sweeney J, et al. Thorax. 2016;71(4):339-346; 2. Sullivan PW, et al. J Allergy Clin Immunol. 2018;141(1):110-116.e7; 3. Price DB, et al. J Asthma Allergy. 2018;11:193-204; 4. Dalal AA, et al. J Manag Care Spec Pharm. 2016;22(7):833-847; 5. Bell CF, et al. J Manag Care Spec Pharm. 2021;27(9):1249-1259.
Targeting IL-5 Pathways in EGPA
FDA-Approved Biologics for the Treatment of EGPA
• Targets IL-5
• Indicated for:
– Adult patients with EGPA
– Patients aged ≥12 years with HES for ≥6 months without an identifiable nonhematologic secondary cause
– Add-on maintenance treatment of patients with severe asthma aged ≥6 years and with an eosinophilic phenotype
– Add-on maintenance treatment of adults with CRSwNP
– Add-on maintenance treatment of adults with inadequately controlled COPD and an eosinophilic phenotype
• Targets IL-5Rα
– Eos depletion through antibody-dependent cellmediated cytotoxicity
• Indicated for:
– Adult patients with EGPA
– Add-on maintenance treatment of patients with severe asthma aged ≥6 years and with an eosinophilic phenotype
aBenralizumab is being investigated in pediatric patients with eosinophilic diseases, including EGPA, in the phase 3 CLIPS stu dy (NCT06512883).
Efficacy of Mepolizumab in Patients With Relapsing or Refractory EGPA Phase 3 MIRRA Study
In patients with relapsing or refractory EGPA, treatment with mepolizumab resulted in significantly more weeks in remission and a higher proportion of patients in remission compared with placebo, allowing reduced CS
aP<0.001.
Multicenter, double-blind, parallel-group, phase 3 trial that randomly assigned (1:1) participants with relapsing or refractory EGPA who
were taking a stable
SQ, subcutaneous.
Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
Comparable Efficacy of Benralizumab and Mepolizumab in EGPA Phase 3 MANDARA Study
Multicenter, double-blind, phase 3, randomized, active-controlled, noninferiority trial that evaluated the efficacy and safety of benralizumab compared with mepolizumab. Adults with relapsing or refractory EGPA who
Wechsler ME, et al. N Engl J Med. 2024;390(10):911-921.
2-Year Efficacy of Anti–IL-5/5R Therapy for Patients With EGPA Phase
3 MANDARA Study
Remission Complete Withdrawal of OCS
for
Mepolizumab as a Steroid-Sparing Option
Phase 3 MIRRA Study
End of treatment period
Patients with relapsing or refractory EGPA who received mepolizumab had lower average doses of prednisolone or prednisone during weeks 48 through 52 than patients who received placebo.
aP<0.001.
Multicenter, double-blind, parallel-group, phase 3 trial that randomly assigned (1:1) participants with relapsing or refractory EGPA who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab (n=68) or placebo (n=68), administered SQ every 4 weeks, plus standard care, for 52 weeks. BL, baseline.
Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
Benralizumab and Mepolizumab as SteroidSparing Options in Patients With EGPA Phase 3 MANDARA Study
During Weeks 48-52
41% achieved complete CS withdrawal with benralizumab vs 26% with mepolizumab.
Wechsler ME, et al. N Engl J Med. 2024;390(10):911-921.
Safety of Mepolizumab and Benralizumab in Patients With EGPA Phase 3 MANDARA Study
aThe 5 most common adverse events are listed. Wechsler ME, et al. N Engl J Med. 2024;390(10):911-921.
EVOLVING MANAGEMENT RECOMMENDATIONS FOR PDGFRANEGATIVE HES
Defining HES Remission and Flares
• Flare1
– Worsening HES–related symptoms
– Eos count increase requiring escalation in therapy (including CS)
Conventional Therapies for PDGFRANegative Patients With HES
Therapy Considerations
CS1,2
Hydroxyurea1,2
IFN-α1,2
Cyclosporine2
• Considered first-line therapy for FIP1L1-PDGFRA–negative patients, particularly in the acute setting for severe manifestations of HES
• Associated with multiple adverse events with long-term use
• Second-line therapy with some efficacy for I-HES, though often discontinued due to adverse events or lack of efficacy
• Second-line therapy with some efficacy in I-HES and L-HES, though often discontinued due to substantial toxicity
• Second-line agent for L-HES, but renal toxicity is a significant concern
Conventional treatment is likely insufficient for disease management and patients may require biologics.
I-HES, idiopathic HES.
Khoury P, et al. Mayo Clin Proc. 2023;98(7):1054-1070; 2. Klion AD, et al. Hematology Am Soc Hematol Educ Program. 2022;2022(1):47-54.
Durable Disease Control With Mepolizumab in HES
Mepolizumab Reduced the Risk of HES Flares1
Number of flares or withdrawals from the study
Probability of flare by week 32
aP<0.005.
Durable Disease Control With Benralizumab in HES
Phase 3 NATRON Study
Benralizumab Reduced the Risk of HES Flare1
• Benralizumab significantly reduced1,2:
– Proportion of patients with flares
– Annualized flare rate
– Risk of hematologic relapse
– Rate of oral CS dose increases
• Significant improvements in fatigue scores and eos levels1,2
Orphan Drug Designation in 2019 reflects the unmet need and emerging role of benralizumab in HES.3
N=133 patients who were aged ≥12 years, FIP1L1-PDGFRA negative, with HES flare signs/symptoms at screening or ≥2 flares within the past year, and corticosteroid responsive were randomly assigned 1:1 to placebo or benralizumab, plus background therapy, every 4 weeks for 24 weeks.
Biologics As Steroid-Sparing Regimens in HES
Mepolizumab Benralizumab
• 26% of patients receiving mepolizumab experienced a flare, which was often treated with OCS, vs 52% receiving placebo1
• Slight trend toward increased mepolizumab benefit in flare reduction with increasing baseline OCS doses1
• In a phase 2 study, 4 of 5 patients who responded to benralizumab at week 48 who were taking OCS at baseline reduced their dosage or eliminated OCS2
• In the phase 3 NATRON study, 25.4% of patients receiving benralizumab and 48.5% receiving placebo required an increase in OCS dose3
1. Roufosse F, et al. J Allergy Clin Immunol. 2020;146(6):1397-1405; 2. Kuang FL, et al. N Engl J Med. 2019;380(14):1336-1346; 3. Ogbogu P, et al. Blood. 2025;148(suppl 1):79.
Treatment Algorithm by HES Subtype in PDGFRA-Negative Disease
No FIP1L1-PDGFRA fusion detected
Abnormal T-cell immunophenotype and clonal T-cell receptor gene rearrangement
No Yes
End-organ damage present
Yes
L-HES
• CS
• Mepolizumab
• IFN-α
I-HES
• CS
HSCT, hematopoietic stem cell transplantation. Shomali W, Gotlib J. Am J Hematol. 2024;99(5):946-968.
• Mepolizumab
• Hydroxyurea
• IFN-α
• Imatinib
• HSCT
• Clinical trial
• Hydroxyurea
• Clinical trial
Key Takeaways
• Patients with EGPA and HES experience a tremendous disease burden and in severe cases, a higher risk of mortality compared with that of the general population
• EGPA and HES are both difficult to diagnose due to the heterogeneity of symptoms, requiring numerous laboratory tests, imaging, and potential biopsies
• Treatment for HES should be tailored to the patient’s HES subtype
• Biologic therapy has demonstrated efficacy and safety in the treatment of EGPA and HES and may allow for lower doses or discontinuation of systemic CS
