ANAC associated vasculitis is wide and difficult to treat. EGPA is one of them, how to manage

1. Eosinophilic granulomatosis
with polyangiitis (EGPA)
Marwa Abo Elmaaty Besar
Lecturer Of Internal Medicine
(Rheumatology Immunology Unit)
(Pediatric Rheumatology)

2. Eosinophilic granulomatosis with polyangiitis
(EGPA)
• 1951,scientists Jacob Churg and Lotte Strauss, a syndrome characterized by
asthma, fever, eosinophilia, as well as symptoms of heart failure, kidney
damage, and peripheral neuropathy resulting from a vascular compromise in
different organs and systems.
• The histology, tissue eosinophilia, granulomatous, and necrotizing vascular
lesions and extravascular granulomas in most organs.
• 2012, Eosinophilic granulomatosis with polyangiitis (EGPA).

3. Epidemiology
• EGPA is a rare disease.
• annual incidence of 0.5–4.2 cases/1,000,000 inhabitants,
increase to 11–14 cases/1,000,000 inhabitants.
• 40 and 60 years of age, with a mean age onset of 49 years.
• Male= female.
• Familial clustering.

4. Pathogenesis:
• Immunogenetic factors:
The HLA-DRB1 *04 and *07 alleles and the HLADRB4 gene.
ANCA-negative EGPA, IL10.2 of the IL-10 promoter polymorphism.
• Environmental factor:
Silica exposure, infections, vaccines, and medications ( macrolide,
leukotriene receptor antagonists (LRAs)).
Vaglio et al 2013

6. Clinical picture:
• A systemic disease and typically evolves in prodromal phases, the allergic
phase, the eosinophilic phase , and the vasculitis phase.
• These phases partially overlap and do not appear in a defined order.
Sinusitis 2016, 1, 24-43;doi:10.3390/sinusitis1010024

7. Specific organs:
• “limited” forms of EGPA; individual organ, diagnosis by histology.
• Allergic phase:
Upper Airways
• (Allergic rhinitis, chronic rhinosinusitis, and nasal polyps).
• Nasal polyps affect about 50%, recur after surgery if not received
medical treatment.
• Chronic rhinosinusitis 75% , as allergic manifestation or
granulomatous inflammation.
• Advanced stages of the disease; chronic ear drainage, serous otitis
media, sensorineural hearing loss, and facial nerve palsy.

8. Lower airways
• Asthma ;
95%–100%, precede the systemic manifestation.
Arises in adulthood with different levels of severity.
Unlike extrinsic asthma, seasonal exacerbations are not observed.
• The eosinophilic phase: lung, cardiac and GIT.
• Lung affection:
The pulmonary parenchyma, 2/3 patients.
chest X-ray, Migratory peripheral infiltrates.
High-resolution CT, ground-glass opacities, consolidation areas, thickening
of the bronchial wall and small centrilobular nodules.
Alveolar haemorrhage 3%–8% of patients.
Pleuritis and Pleural effusion secondary to eosinophilic.

9. • Cardiac involvement:
Symptomatic cardiac involvement (MRI and histological finding) has poor
prognostic factor.
Peripheral eosinophilia is higher in patient with cardiac involvement who have
initial lesions with eosinophilic infiltration
Complicated by restrictive cardiomyopathy secondary to fibrotic changes.
Endomyocardial infiltration (dominant) > pericarditis, vasculitis, valvular heart
disease.
Increased risk of venous thromboembolic events, DVT and pulmonary embolism.
• Gastrointestinal involvement;
Eosinophilic infiltration of GIT mucosa, the small bowel.
Presented with abdominal pain,GIT bleeding, cholecystitis (rare).

10. The vasculitic phase;
• General symptoms (fever, fatigue, weight loss).
• Paradoxical improvement of asthma.
• Peripheral neuropathy is a cardinal feature
70% of patients.
Affecting the peroneal, tibial, ulnar, and median nerves.
Typical multiplex mononeuritis with asymmetric drop of wrist or foot, but can be symmetric or asymmetric
polyneuropathy.
NCS; axonal damage.
• Skin lesion;
Purpura 25% patients, involve lower limbs.
Nodules, urticaria, livedo and skin ulcer.
• Renal manifestation;
25% of patients.
isolated urinary abnormalities (microscopic hematuria, proteinuria) to rapidly progressive glomerulonephritis.
Histology; pauci-immune focal and segmental necrotizing glomerulonephritis, with or without crescents..

11. Sinusitis 2016, 1, 24-43;doi:10.3390/sinusitis1010024
At least 4 of 6 criteria.
Sensitivity 85%, Specificity 99.7%

12. Diagnosis
I-Blood Cells and Biomarkers:
• CBC; eosinophilia (>1500 cells/μL or > 10%).
Eosinophilia correlates with disease activity and relapses.
• Acute phase reactant; C-reactive protein (CRP, ESR); higher in the active phase.
• Serum total IgE level; elevated in most patient, non specific.
• Serum IgG4 levels; high in 75% of patients, active EGPA.
• ANCA appear several years before the onset of vasculitis , (p-ANCA) in 74%–90%.
• New biomarker; eotaxin-3, a chemokine, induces eosinophil chemo-attraction.
Serum levels were significantly higher in active EGPA than other DD.
Sensitivity and specificity; 87.5% and 98.6%.

13. ? ANCA has role in development of vasculitis in EGPA.
? prognostic role of ANCA
? whether ANCA has role in follow up

14. Diagnosis
II-Histopathology;
• More accessible affected tissue; nasal polyps, skin, lung, kidney, or nerves.
• Eosinophilic tissue infiltration and/or necrotizing vasculitis and/or extravascular eosinophilic
granulomas.
III-Imaging;
• Chest Radiography and CT Scan;
Lobar or segmental opacity, diffuse interstitial or mi liar patterns, migratory infiltrates
of the lower lobe or subpleural.
Hilar, or mediastinal lymphadenopathy.
Pleural effusion, and pulmonary haemorrhage, ground glass opacity and hyperinflation
• Sino nasal CT Scan; imaging of choice, pneumatic bone, solid bone, and soft
tissue.
• Sin nasal Plain X-rays; non specific but low cost.

16. Diagnosis:
IV-Lung Function;
• An obstructive or restrictive pattern according to airway or parenchyma
involvement.
V-Bronchoscopy;
• Eosinophilic infiltration.

17. Differential Diagnosis:
• Eosinophilic Lung Diseases
Acute and chronic eosinophilic pneumonia
Allergic bronchopulmonary aspergillosis
Broncho centric granulomatosis
Loffler’s syndrome
Idiopathic hyper eosinophilic syndrome
• Small and MediumVesselVasculitis
Granulomatosis with polyangiitis
Polyarteritis nodosa
Microscopic polyangiitis

18. Therapeutic Options:
• “Five Factors Score” (FFS) as prognostic index for EGPA;
1. Cardiomyopathy
2. Gastrointestinal involvement
3. Central nervous system involvement
4. Proteinuria (>1 g/24 h)
5. Serum creatinine (>150 mmol/L)
• (FFS = 0) = Glucocorticoids alone, relapse high, azathioprine or cyclophosphamide as
adjuvant therapy.
• One or more risk factors (FFS ≥ 1) , a worse prognosis = glucocorticoids and
immunosuppressants.
• Moosig et al 2013. chose the medication according to the activity and extent of the
disease.
Guillevin, L etal2011

19. • Corticosteroids reduce eosinophil burden in blood and tissues and inhibit the
prolongation of eosinophil survival in extravascular tissues, 93% remission.
• Cyclophosphamide used for induction of remission, based on the FFS.
six or 12 pulses of cyclophosphamide were equally effective for inducing remission, but
relapse high in the six-pulse group.
• Methotrexate used for induction, 73% remission.
• High doses of intravenous immunoglobulin is effective in in neuropathy or
cardiomyopathy refractory to conventional therapy.
• Plasma exchange is effective rapidly progressive glomerulonephritis or alveolar
haemorrhage.
• Interferon-alpha, failed to achieve remission with high adverse effect.
Therapeutic Options:

20. BiologicalTherapies
(Monoclonal Antibodies)
Mepolizumab
• Anti-IL-5 antibodies.
• >50% complete remission, > 75% reduction of glucocorticoids (<7.5mg/day).
• Safety and tolerance good but relapse is high after stoppage.
Rituximab
• B-cell depletion, a chimeric anti-CD20 monoclonal antibody.
• Effectively induces remission in AAV.
• Induce clinical remission and eosinophil count normalization and IL-5 reduction.
Omalizumab
• Recombinant humanized monoclonal anti-IV Ig E antibody, in refractory EGPA.

21. Chronic Rhinosinusitis with Nasal Polyps
• Aim;
Eradicate polyps.
Reduce sino nasal inflammation.
Eliminate symptoms.
Prevent recurrences.
• Treatment:
Corticosteroids is the first line, most effective.
Saline nasal irrigation and antihistamines.
Anti-leukotrienes, aspirin desensitization.
Biological products such as anti-ige and anti-il-5,
 immunosuppressants.
Endoscopic surgery after with nasal and oral corticosteroid

23. Pearls :
• Churg-Strauss syndrome or eosinophilic granulomatosis with polyangiitis is
thus a pleiotropic systemic vasculitis with a dual face of manifestations- based
on eosinophilic damage orANCA associated small and medium vessel injury.
• The dichotomy has made it challenging to identify a gold standard for
diagnosis and has also made prognosis somewhat variable.
• Treatment with immunomodulators with the use of plasma exchange or
IVIG is reserved for more refractory cases.
• It responds well to treatment and characterized by a high remission rate.
• Characterized by a lingering persistence of difficult to control asthma and
systemic manifestations affecting the quality of life

24. Prognosis:
• EGPA has a favourable prognosis with a 5-year survival of 90%.
• Risk factors for relapse :
The sudden rise in eosinophil count
Persistent ANCA positivity
Gastrointestinal tract (GI) involvement
The rise in ANCA titres.
• (Guillevin et al.2007): 5 factor associated with high mortality;
1. Proteinuria (greater than 1 gm per day)
2. Renal insufficiency (Cr greater than 1.58 mg/dl)
3. Cardiomyopathy
4. GI tract involvement
5. CNS involvement

25. Reference:
• Guillevin, L.; Pagnoux, C.; Seror, R.; Mahr, A.; Mouthon, L.; leToumelin, P.The five-factor score revisited: Assessment of prognoses
of systemic necrotizing vasculitides based on the FrenchVasculitis Study Group (FVSG) cohort. Medicine 2011, 90, 19–27.
• Moosig, F.; Bremer, J.P.; Hellmich, B.; Holle, J.U.; Holl-Ulrich, K.; Laudien, M.; Matthis, C.; Metzler, C.; Nölle, B.; Richardt, G.; et al. A
vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-
Strauss, EGPA): Monocentric experiences in 150 patients. Ann. Rheum. Dis. 2013, 72, 1011–1017.
• Ribi C, Cohen P, Pagnoux C, Mahr A, Arène JP, Lauque D, Puéchal X, Letellier P, Delaval P, Cordier JF, Guillevin L., FrenchVasculitis
Study Group.Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized,
open-label study of seventy-two patients. Arthritis Rheum. 2008 Feb;58(2):586-94
• Cohen P, Pagnoux C, Mahr A, Arène JP, Mouthon L, Le GuernV, André MH, Gayraud M, Jayne D, Blöckmans D, Cordier JF, Guillevin
L., FrenchVasculitis Study Group. Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing
glucocorticoids and six or twelve cyclophosphamide pulses in forty-eight patients. Arthritis Rheum. 2007 May 15;57(4):686-93.
• Ruppert AM, Averous G, Stanciu D, Deroide N, Riehm S, PoindronV, Pauli G, Debry C, de Blay F. Development of Churg-Strauss
syndrome with controlled asthma during omalizumab treatment. J Allergy Clin Immunol. 2008 Jan;121(1):253-4.
• Mahr A, Moosig F, NeumannT, SzczeklikW,Taillé C,Vaglio A, Zwerina J. Eosinophilic granulomatosis with polyangiitis (Churg-
Strauss): evolutions in classification, etiopathogenesis, assessment and management. Curr Opin Rheumatol. 2014 Jan;26(1):16-23