PERM STATE MEDICAL

UNIVERSITY

CHURG-STRAUSS
SYNDROME
-JOISY ALOOR
5TH YEAR
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DEFINITION

 Eosinophilic granulomatosis with polyangiitis (EGPA)—or, as it was

traditionally termed, Churg-Strauss syndrome—is a rare systemic necrotizing
vasculitis that affects small-to-medium-sized vessels and is associated with
severe asthma and blood and tissue eosinophilia.
 Like granulomatosis with polyangiitis (Wegener granulomatosis), and the
microscopic form of periarteritis (i.e., microscopic polyangiitis), EGPA is an
antineutrophil cytoplasmic antibody (ANCA)–associated vasculitide.
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 In 1951, Churg and Strauss first described the syndrome in 13 patients who had
asthma, eosinophilia, granulomatous inflammation, necrotizing systemic
vasculitis, and necrotizing glomerulonephritis.
 EGPA is classified as a vasculitis of the small and medium sized arteries,
although the vasculitis is often not apparent in the initial phases of the disease.
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 The most commonly involved organ is the lung, followed by the skin. EGPA,
however, can affect any organ system, including the cardiovascular,
gastrointestinal, renal, and central nervous systems.
 Vasculitis of extra pulmonary organs is largely responsible for the morbidity
and mortality associated with EGPA.
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ETIOLOGY

 Considered an idiopathic condition.

 Exposure to allergens or drugs.
• Propylthiouracil, hydralazine, minocycline, penicillamine.
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EPIDEMIOLOGY

 Rare disease.
 The epidemiology of EGPA remains unclear because of the uncertainties related
to diagnosis. Approximately 10 percent of patients with a major form of vasculitis
are recognized to have EGPA.
 Among the three anti-neutrophil cytoplasmic antibodies (ANCA)-associated
vasculitides (EGPA, granulomatosis with polyangiitis (GPA), and microscopic
polyangiitis), EGPA is least common.
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 Prevalence in Europe ranges from 10.7 to 14/million. In the United States, the
prevalence is approximately 18/million. The highest prevalence reported is from
Australia, at 22.3 cases/million.
 Prevalence:1–2/100,000
 Male: female is 2–3:1.
 Mean age of disease onset is 40 years of age.
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PATHOGENESIS

 Immune Dysregulation.
 Eosinophil infiltration.
• Activated Th2 cells release cytokines IL4, IL13 and IL5
• IL4, IL13 and IL5 promote eotaxin3 release from endothelial and epithelial cells
• Eotaxin3 brings eosinophils from the blood stream into tissue
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• Activated eosinophils secrete granules containing eosinophil basic

protein and eosinophil derived neurotoxin, damaging tissue.
• Activated eosinophils secrete IL25, which activates Th2.
• Dysregulation of the following immune cells are also implicated:
Th1, Th17, IL17A, B cells.
 ANCA induced endothelial damage: ANCA leads to neutrophil
degranulation and tissue damage.
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SITES

 Upper airway tract and lungs

 Kidneys
 Peripheral nervous system
 Gastrointestinal tract
 Heart
 Skin
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SIGNS AND SYMPTOMS

 Eosinophilic granulomatosis with polyangiitis consists of three stages, but not all
patients develop all three stages or progress from one stage to the next in the
same order; whereas some patients may develop severe or life-threatening
complications such as gastrointestinal involvement and heart disease, some
patients are only mildly affected, e.g. with skin lesions and nasal polyps.
 EGPA is consequently considered a highly variable condition in terms of its
presentation and its course.
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CLINICAL FEATURES

 Strongly associated with asthma

 Associated with HLA-DRB4
• 40 - 70% of patients have antimyeloperoxidase ANCA positivity.
• ANCA positivity is associated with renal and peripheral nervous system disease.
• ANCA positivity is less common in eosinophilic granulomatosis with polyangiitis
than in granulomatosis with polyangiitis.
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 Pulmonary and systemic vasculitis, extravascular granulomas, and eosinophilia,

occurring almost exclusively in patients with asthma or a history of allergy.
 Angiitis and extravascular necrotizing granulomas usually with eosinophilic
infiltrates
 Retinal vasculitis → amaurosis fugax or CRAO
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CLINICAL FEATURES/STAGES

 Symptomatology
 Prodromal phase (months to years):
 Asthma, rhinitis arthralgia, fever, malaise, weight loss, nasal polyps, chronic sinusitis
 Eosinophilic phase:
 Peripheral eosinophilia and eosinophilic infiltrative disease involving lung, heart or
gastrointestinal tract
 Vasculitic phase:
 Vasculitis with peripheral neuropathy, renal and skin involvement
 Usually within 3 years of onset of asthma, though may be delayed for decades
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RISK STRATIFICATION

 The French Vasculitis Study Group has developed a five-point system ("five-factor score") that predicts the
risk of death in Churg–Strauss syndrome using clinical presentations. These factors are:
1. Reduced renal function (creatinine >1.58 mg/dl or 140 µmol/l)
2. Proteinuria (>1 g/24h)
3. Gastrointestinal hemorrhage, infarction, or pancreatitis
4. Involvement of the central nervous system
5. Cardiomyopathy
 The lack of any of these factors indicates milder case, with a five-year mortality rate of 11.9%. The presence
of one factor indicates severe disease, with a five-year mortality rate of 26%, and two or more indicate very
severe disease: 46% five-year mortality rate.
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DIAGNOSIS

 Clinical diagnosis
 Biopsy of an affected organ with microscopic confirmation: characteristic
pathological changes are helpful but not essential to make the diagnosis
 In 1984, new clinical diagnostic criteria were proposed:
 3 diagnostic criteria, all must be present
1. Asthma
2. Blood eosinophilia exceeding 1,500/mm3 or > 10%
3. Evidence of vasculitis involving 2 or more organs
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UPDATED DIAGNOSTC CRITERIA

 Diagnostic markers include eosinophil granulocytes and granulomas in affected tissue, and antineutrophil
cytoplasmic antibodies (ANCA) against neutrophil granulocytes. The American College of Rheumatology
1990 criteria for diagnosis of Churg–Strauss syndrome lists these criteria:
• Asthma
• Eosinophilia, i.e. eosinophil blood count greater than 500/microliter, or hyper eosinophilia, i.e. eosinophil
blood count greater than 1,500/microliter
• Presence of mononeuropathy or polyneuropathy
• Unfixed pulmonary infiltrates
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 Presence of paranasal sinus abnormalities

 Histological evidence of extravascular eosinophils
 For classification purposes, a patient shall be said to have EGPA if at least four of these
six criteria are positive.
 The presence of any four or more of the six criteria yields a sensitivity of 85% and a
specificity of 99.7%.
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LABORATORY MARKERS

 Peripheral eosinophilia (usually > 1,500 cells/μl or > 10%) is present in active
disease
 Perinuclear / antimyeloperoxidase ANCA
 Renal involvement: hematuria, proteinuria, elevated serum creatinine
 Emerging biomarkers: eotaxin3 (at cutoff level of 80 pg/ml, the sensitivity and
specificity of eotaxin3 for the diagnosis was 87.5% and 98.6%, respectively)
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TREATMENT

 Immunosuppressants (e.g. cyclophosphamide, glucocorticoids, azathioprine)

 B cell depleting agent rituximab: (375 mg/m2/week × 4) to cure renal disease.
 Anti-IL5 antibody mepolizumab
 High dose of corticosteroids (1–2 mg prednisolone/kg of body weight). Taper after 3-4 weeks. In
most cases, monotherapy with corticosteroids is efficient, and maintenance treatment is not
longer necessary as 1 year
 Cyclophosphamide dose from 100 mg to 150 mg/day.
 Azathioprine for patients with steroid-resistant
 In case of active vasculitis and neuropathy pulsed doses of 500–1,000 mg/m2 of
cyclophosphamide intravenously could be given
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 The FAUCI-Schema (cyclophosphamide 1–2 mg/kg bw daily) is indicated if

cardiac or CNS involvement is present
 A single dose of 500 mg/m2 of cyclophosphamide for life-threatening condition
 IVIG
 Interferon-α for therapy-resistant patients
 The chimeric anti-CD20 monoclonal antibody rituximab (RTX) (for 4 weeks,
375 mg/m2/week)
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 Traditionally, cyclophosphamide has been given for a year or more in patients with
Churg-Strauss syndrome.
 In a research study, Churg-Strauss syndrome patients did equally well if treated with
cyclophosphamide for 6 or for 12 months.
 Oral administration of cyclophosphamide (2 mg/kg/day) was previously reported.
However recently, monthly intravenous pulse cyclophosphamide (400―800
mg/body/day) has been used for the treatment of CSS and has been found to be better
tolerated.
 The most effective route of cyclophosphamide administration has not been confirmed.
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 A systematic review conducted in 2007 indicated all patients should be treated with
high-dose steroids, but in patients with a five-factor score of one or higher,
cyclophosphamide pulse therapy should be commenced, with 12 pulses leading to fewer
relapses than six. Remission can be maintained with a less toxic drug, such as
azathioprine or methotrexate.
 On December 12, 2017, the FDA approved mepolizumab, the first drug therapy
specifically indicated for the treatment of eosinophilic granulomatosis with polyangiitis.
 Patients taking mepolizumab experienced a "significant improvement" in their
symptoms.
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 The optimal duration of maintenance therapy remains unknown; 18–24 months

following remission induction could be recommended.
 A recent study established that ANCA-positivity, cutaneous manifestations and a
low eosinophil count at the time of EGPA diagnosis were predictive of relapse.
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PROGNOSIS

 Overall 5 year survival rate is 97%

 The following criteria are associated with a higher 5 year mortality
1. Age > 65
2. Cardiac symptoms
3. Gastrointestinal involvement
4. Renal insufficiency (serum creatinine > 150 μmol/l)
5. Lack of ear, nose and throat manifestations
 The 1-year survival rate is 90 %
 The mortality correlates primarily with the severity of cardiac involvement, followed by CNS and
renal manifestations
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