Eosinophilic Granulomatosis with Polyangiitis

A Review and Update

Dec 7, 2023

Dr. Daniel Ennis, MD FRCPC

Rheumatology and Vasculitis

Disclosures

• Journal Club Support – Abbvie and UCB
• No relevant disclosures to this content.

We would like to acknowledge that we are gathered today on the traditional territories of the Musqueam, Squamish and Tsleil-Waututh peoples.

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Outline

• History
• Definitions and Criteria
• Clinical Manifestations
• Mimics and Workup
• Treatment
• What’s new?

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History

Dr. Churg and Dr. Strauss

“Atypical Periarteritis Nodosa”

• The first recorded case of likely EGPA dates back to 1905.
• First defined as a distinct entity by Drs. Lotte Strauss and Jacob Churg from the Division of Pathology at Mount Sinai Hospital.
• They presented their case series of 13 patients at the 46^th Annual meeting of The American Association of Pathologist and Bacteriologists in Boston in 1949.
• They published their findings in 1951.

Eosinophils ranged from 0-29,000 cells/cm2.

Spleen

• Spleen with subcapsular and parenchymal nodules

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• Diffuse inflammatory infiltration with predominance of eosinophils and scattered granulomata within the exudate

Pulmonary Vessels

• Branch of pulmonary artery showing marked luminal narrowing and a granuloma in the wall.
• Pulmonary vein showing a large subintimal granuloma
• Eosinophilic pneumonia with necrosis of exudate and giant cell.

Renal/Skin

• Focal necrotizing glomerulitis
• Subcutaneous tissue with diffuse inflammatory exudate and conglomerate granulomata

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Histopathology

• Two diagnostically essential lesions:
1. Angiitis
• May be granulomatous or non-granulomatous
• Involves both arteries and veins as well as pulmonary blood vessels
2. Extra-vascular necrotizing granulomas (usually with eosinophilic infiltrates).
• Cutaneous lesions lack diagnostic specificity.

- Lie, A&R, 1990

Classification and Criteria

Lanham Criteria – 1984�Requires all 3 criteria

• Asthma
• Eos >1.5
• Systemic Vasculitis involving 2 or more extrapulmonary organs

1990 ACR Criteria

• This guy is everywhere!

ACR 1990 Criteria – EGPA�at least 4/6 🡪 Sn 85%, Sp 99.7%

• 1. Asthma: History of wheezing or diffusion of high-pitched expiratory rhonchi.
• 2. Eosinophilia greater than 10% on differential white blood cell count.
• 3. Mononeuropathy (including multiplex) or polyneuropathy: Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy (glove/stocking distribution) attributable to systemic vasculitis.

• 4. Non-fixed pulmonary infiltrates: Migratory or transitory pulmonary infiltrates (not including fixed infiltrates) attributable to vasculitis.
• 5. Paranasal sinus abnormality: History of acute or chronic paranasal sinus pain or tenderness or radiographic opacification of the paranasal sinuses.
• 6. Extravascular eosinophils: Biopsy including artery, arteriole, or venule showing accumulations of eosinophils in extravascular areas.

Masi et al. A&R, 1990

Sensitivity/�Specificity

• NOTE: all criteria are compared to other defined vasculitis syndromes

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Some issues with the Criteria

2012 Chapel Hill Definition

• “Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.”

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ACR 2022 Criteria�Total of ≥5 = Sn 88%, Sp 98%

Robson, ACR Abstract, 2018

Clinical Manifestations

And Mimics

The 3 Phases of EGPA

Prodromal

Eosinophilic

Vasculitic/

Systemic

Lanham, Medicine, 1984; Pagnoux, Curr Opin Rheumatol, 2007; Vaglio, Kidney Int, 2009

Phase 1: Prodromal

• Asthma (90%-100%)

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• Sinusitis/Polyposis (42-70%)

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• Rhinitis (17%)

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Prodromal

- Comarmond, A&R, 2013

Phase 2: Eosinophilic

• Eosinophilia >10% or 1.5/mm³ – ~90%
• Mean at diagnosis = 7.5/mm³
• Organ infiltration
• Pulmonary infiltrates: 39-98%
• Cardiomyopathy: 16-22%
• GI: 8-58%

Eosinophilic

- Comarmond, A&R, 2013

Phase 3: Vasculitic

• Necrotizing vasculitis
• Skin: 40-81%
• Peripheral nerve: 52-92%
• Renal: 20-35%
• CNS: 4-11%
• Cardiac: 10-50%
• GI: 20%

Vasculitic/

Systemic

Ennis et al, Exp Op Biologic Therapy, 2019; Comarmond, A&R, 2013

The 3 Phases of EGPA

Prodromal

Eosinophilic

Vasculitic/

Systemic

Lanham, Medicine, 1984; Pagnoux, Curr Opin Rheumatol, 2007; Vaglio, Kidney Int, 2009

Range: 0-61 years Median: 4-9 years

Differential and Workup

Mimics

Adapted from ACR lecture, Pagnoux, 2017.

Workup for Hypereosinophilia

• CBC, Smear, Cr
• CRP, ESR, TSH, Liver enzymes
• C3/4, ANA, ANCA
• SPEP, Quantitative immunoglobulins, IgE, IgG subclasses (ie. IgG4)
• IgG precipitins to Aspergillus
• IgG and IgE to Aspergillus
• B12, Serum tryptase
• Urinalysis

- Moller, Tan, Carruthers, Dehghan, Chen et al. Eur J Haem. 2020

• Stool O&P
• Strongyloides IgM/IgG and Stool Cx
• Toxocara + HIV
• Trop, BNP, ECG
• Flow cytometry for aberrant T-cells, T-cell receptor clonal rearrangement PCR.
• BMBx: Karyotype, FISH (FIP1L1/PDGFRA, JAK2).
• PFTs, CT Chest, Echo, Bronch

*Groh et al. Task Force Recommendations, 2015

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ANCA in EGPA

• Positive in 6-48%
• Nephrology series show up to 78%

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• 90% of positive ANCAs will be MPO

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Sable-Fourtassou, Ann Int Med. 2005; Sinico, A&R, 2005

Manifestations by ANCA Status

-Sinico, A&R, 2005; Sokolowska, Clin Exp Rheumatol, 2014; Grayson, Rheumatol, 2015

NOTE: These phenotypes are not always dependable

Manifestations by ANCA Status

• ANCA+ = higher relapse risk
• ANCA- = higher mortality risk.

Emmi et al. Nat Rev Rheum. 2023; Sinico, A&R, 2005;

Sokolowska, Clin Exp Rheumatol, 2014; Grayson, Rheumatol, 2015

Treatment

See the CANVASC Guidelines

Mendel A, Ennis D, Go E, et al. J Rheum, Apr 2021.

Treatment

• Treatment is divided into Induction and Maintenance

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• Slight differences in treatment between EGPA and GPA/MPA.

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• 1^st decisions: Is my patient’s disease severe? Is there any life/organ threatening disease
• Use the Five Factor Score to help assess this.

Five Factor Score – prognostic score�EGPA and PAN

• Revised FFS based on 1108 consecutive patients in the French vasculitis cohort
• ENT manifestations are associated with BETTER outcomes. Their absence is scored +1 for EGPA or GPA (but not MPA or PAN)

Guillevin, Medicine. 1996; Guillevin, Pagnoux, Medicine. 2011

CNS

Revised Five Factor Score

• G – GI
• R – Renal
• A - Age
• C – Cardiac
• E - ENT

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Guillevin, Pagnoux, Medicine, 2011

**A score of 1 suggests SEVERE disease

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Some physicians consider eye or neuro involvement to be a score of 1.

Induction

**Despite lack of evidence, adding DMARD to induction often justified if vasculitic manifestations progress.

CANVASC GUIDELINES: Mendel et al. J Rheum, 2021

CanVasc Recommendation - Prednisone

• An initial dose of 1mg/kg/day prednisone equivalent (not exceeding 80mg/day) is recommended for remission induction in patients with severe EGPA

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• Pulse IV MP can be considered in severe, organ- or life-threatening EGPA, but lacks proven efficacy and carries a potential risk of adverse effects.

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• A GC tapering protocol should be initiated within 2-4 weeks of induction therapy in EGPA.

CanVasc Recommendations – CYCLO

• We recommend remission induction therapy with a combination of GC and CYC in patients with severe, newly diagnosed EGPA.

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• Patients with non-severe EGPA without major organ involvement or poor prognostic factors may be treated with GC alone for initial induction therapy.

CHUSPAN Studies

• CHUSPAN MP – Cyclo 6 vs. 12 pulses for induction, FFS 1+.
• CHUSPAN SCS BP – Cyclo vs. AZA after failure of Pred monotherapy, FFS 0.
• CHUSPAN 2 – AZA vs. Placebo for induction, FFS 0.

CHUSPAN MP�Cyclophosphamide for induction�6 vs. 12 mths

• 48 new diagnosis EGPA and FFS 1 or higher
• Biopsy confirmed, Eos >1500 or 105, asthma, and systemic manifestations of vasculitis
• Treatment
• 6 vs. 12 Pulses of IV CYCLO (0.6g/m2) every 2 weeks for 1 month then every 4 weeks.

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Cohen, A&R, 2007

CHUSPAN MP

Cohen, A&R, 2007

*With a mean follow-up of 42.5 months, the disease-free survival rate was significantly higher in the 12-pulse group (P 0.015)

Major relapses were no different, but minor relapses were higher in 6 pulse group (P 0.02)

CHUSPAN SCS BP

• 72 new diagnosis EGPA with FFS of 0.
• Treatment:
• All patients treated with Prednisone monotherapy
• Upon relapse/treatment failure 19 patients randomized
• AZA x 6 months or CYC (0.6g/m2) x 6 pulses every 2 weeks for 1 month then every 4 weeks.

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Ribi, A&R, 2008

CHUSPAN SCS BP

• Of the 72 patients, 93% achieved remission with Pred alone.
• 35% relapsed (mainly in the first year)
• Among the 19 randomized patients remission achieved in
• 7/9 AZA
• 5/10 CYC
• Survival of 97% at 5 yr
• 79% required low dose pred for maintenance

Ribi, A&R, 2008

CHUSPAN 2

• 95 patients with newly diagnosed vasculitis (FFS 0)
• (51 EGPA, 25 MPA, 19 PAN)
• All patients received Prednisone taper AND….
• Randomized to AZA (n=46) or Placebo x 12 mths
• Followed for 24 months.

Puechal, A&R, 2017

CHUSPAN 2

• Mean Pred dose (top) and Relapse free survival(bottom) were identical.
• Addition of AZA to Pred for induction of remission of nonsevere EGPA does not improve remission rates, lower relapse risk, spare steroids, or diminish EGPA asthma/rhinosinusitis exacerbation rate.

Puechal, A&R, 2017

• Median follow up of 6.3 years.
• Showed no benefit of 1 year AZA+Pred vs. Pred monotherapy in non-severe EGPA
• Vasculitis relapse: 2 yr-43%, 5 yr-48%
• Asthma/rhinosinusitis relapse: 2 yr-28%, 5 yr-56%

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Puechal, Rheumatology, 2019

Maintenance

Maintenance

PCP prophylaxis

• PCP Prophylaxis:
• For patients receiving combined immune suppression, guidelines suggest:
• TMP/SMX at a dose of 80/400 mg daily or 160/800 mg (DS) 3 times a week.
• Continue for 3 months after CYC
• Continue for 6 months after RITUX

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CANVASC 2020; McGeoch, Can J Kidney Health. Dis. 2015

Biologics in EGPA

Rituximab for induction

• Most major Rituximab trials EXCLUDE EGPA!
• Rituximab is currently under study
• REOVAS – Ritux vs. CYC/Pred monotherapy (conventional induction) in EGPA
• MAINRITSEG – Ritux vs. AZA for remission in EGPA.

• Retrospective case series of 41 EGPA patients
• 37% refractory, 51% relapsing, 12% new
• At 6 and 12 months, RTX showed
• Improvement in BVAS: 83% and 88%
• Remission: 34% and 49%
• Partial response: 49% and 39%

**ANCA+ patients more likely to achieve remission: 80% vs. 38%

Mohammad, Ann Rheum Dis, 2016

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• Retrospective study comparing 14 RTX-recipients to 14 CYC-recipients
• Similar remission rates (36% vs 29%) and relapse-free survival rates between groups.

Cambridge Study

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• Retrospective study of 69 EGPA treated with Rituximab in Cambridge
• Majority of patients had a response or partial response to Ritux.

Teixeira, RMD Open, 2019

ANCA Status and Ritux response

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• ANCA positive patients appeared to respond quicker and have longer relapse-free survival time

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• Note: Y-axis is “remission-free probability”

Teixeira, RMD Open, 2019

Major Take-Aways

• At 6 months…
• FFS 0 = no dif between Ritux and GC monotherapy
• FFS > 0 = Ritux similar to CYC
• No difference based on ANCA + or -

CanVasc Recommendation – Ritux

• Consideration of other (off-label) therapies for EGPA should be made in collaboration with centers of expertise.

Mepolizumab

• MIRRA compared Mepo 300 SC monthly to Placebo in 136 patients with refractory, relapsing, or GC-dependent EGPA
• New dx or severe disease excluded
• Remission (BVAS=0) at week 36 and 48: 32% vs. 3% (OR 16.74)
• Relapse rate: 56% vs. 82%
• No clear assessment of specific manifestations

Wechsler, NEJM, 2017

*Long-term access program due in 2022 (NCT03298061)

BUT

• French data suggests that 300 and 100 are essentially as effective.
• We cannot access 300mg in Canada
• Maybe we should push harder to get patients onto this for “Eosinophilic asthma/pneumonia”

CanVasc Recommendation – Mepolizumab

• Mepolizumab 300mg SC monthly can be considered in nonsevere, GC-dependent refractory or relapsing EGPA.

Efficacy and safety of biologics use for EGPA

• 147 patients: Ritux=63, Mepo=51, Omalizumab=33

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Canzian, A&R, Oct 2020

Rituximab Maintenance?

• In an observational study, scheduled rituximab maintenance therapy (500 mg every 6 months) reduced the relapse rate as compared with unscheduled treatment (no relapses in the “scheduled” group).
• In a retrospective study published in 2020, rituximab maintenance also showed efficacy in reducing the median glucocorticoid dose for the control of asthma and systemic manifestations

Emmi et al. Ann Rheum Dis. 2021; Casal Moura et al. Clin Rheumatol. 2020

Benralizumab?

• French Vasculitis Study Group conducted a multicentre retrospective study of 68 patients with EGPA.
• 46% were previously treated with Mepolizumab
• 49% complete response
• 36% partial response
• 15% no response

Cottu, Ann Rheum Dis. 2023

Summary on the use of Biologics

• Evolving evidence for the use of Rituximab
• It does not replace Cyclophosphamide in patients with severe/life-threatening disease
• Good alternative and mounting evidence for maintenance therapy.
• Mepolizumab has shown consistent benefit as a treatment for those without severe/life threatening disease
• It is unclear which manifestations in particular benefit from anti-IL5 therapy
• Benralizumab has a similar mechanism of action to Mepolizumab and appears to be similarly effective in EGPA, even in patients previously exposed to Mepolizumab.

New published French Guideline

• Highlights the evolving evidence for Rituximab and Mepolizumab

Emmi et al. Nat Rev Rheum. 2023

What’s in the pipeline?

Future of Targets in EGPA

• Anti-IL13
• CCL-11
• Siglec-8
• EMR-1
• IL-4
• IL-13
• IL-4/13
• IL-17
• TSLP

Ennis, et al. Exp Op Biol Ther. 2019

Contact Info

• Mary Pack Arthritis Centre
• 895 West 10^th Ave on the first floor
• Phone: 604-875-5460
• Fax: 604-269-3736