Eosinophilic Granulomatosis with Polyangiitis (EGPA) (Churg-Strauss Syndrome, Allergic Angiitis and Granulomatosis)

Epidemiology

  • History: first reported in 1951
  • Association with Leukotriene Antagonists: few reported cases associated with asthmatics on zafirlukast (Accolate) during steroid taper
    [Wechsler; JAMA, 1998]

    • Also cases reported with montelukast
    • Believed to be due to unmasking of undiagnosed Churg-Strauss Syndrome by steroid taper (and not due to leukotriene antagonist itself)
    • However, there have been a few cases associated with zafirlukast use (without any steroid use)
      [Green; Lancet, 1999]
    • Incidence: about 1:20,000 treated patients
  • Incidence: 2.4 cases/1 million
  • Age: primarily affects middle-aged men with current or prior asthma (but can affect adults of all ages)
  • Sex: M=F

Physiologic and Pathologic Features

  • Necrotizing Small-Vessel Vasculitis + Eosinophilic Infiltrates + Necrotizing Granulomas:
    • Macroscopic: lung infarcts
    • Microscopic: combination of asthmatic changes + eosinophilic pneumonia + lymphocytic and eosinophilic vasculitis (of small>medium-sized arteries, veins, and capillaries/with fibrinoid necrosis and thrombosis) + necrotizing granulomas (with epithelioid cells and some giant cells)
    • Combination of eosinophilic pneumonia + parenchymal necrosis is also suggestive of Churg-Struass Syndrome

Diagnosis

  • CXR/Chest CT/HRCT: abnormal in 40-75% of cases
  • ESR: elevated
  • Serology
    • p-ANCA (perinuclear pattern, targeted mainly against myeloperoxidase): positive in about 40-70% of patients
  • CBC
    • Moderate Peripheral Eosinophilia: usually >10%
    • Anemia:
    • Leukocytosis:
  • OLB: diagnostic

Clinical Criteria

1990 Am Coll of Rheumatology Criteria

(with confirmation of necrotizing vasculitis on biopsy, sensitivity of criteria is 85% and specificity is 99.7%)

  • Asthma
  • Eosinophilia >10%
  • History of Allergy
  • Mononeuropathy or Polyneuropathy
  • Migratory or Transient Pulmonary Infiltrates
  • Paranasal Sinus Abnormalities

Three Phases of Disease

(although these phases may develop sequentially over years, features may present in other sequences)

  • First Phase: adult-onset asthma + allergic rhinosinusitis
  • Second Phase: eosinophil infiltration of viscera (including GI tract, lungs)
  • Third Phase: necrotizing vasculitis (with mononeuritis multiplex, palpable purpura, cardiomyopathy, pericarditis, focal GLN)

Clinical Manifestations

Cardiovascular Manifestations (15-50% of cases)

(cardiac lesions are the cause of death in about 50% of cases)

  • Cardiomyopathy (see xxxx, [[Congestive Heart Failure]]): systolic and diastolic CHF
  • Conduction Abnormalities
  • Intracavitary Thrombus
  • Pericarditis
  • Coronary Artery Vasculitis (see [[Coronary Artery Disease]])

Dermatologic Manifestations (50-70% of cases)

Gastrointestinal Manifestations (15-60% of cases)

  • General Comments
    • GI manifestations are a major cause of morbidity and mortality*
  • Ulceration
  • Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
  • Ischemia/Infarct (see Acute Mesenteric Ischemia, [[Acute Mesenteric Ischemia]])
  • Perforation
  • Obstruction
  • Weight Loss (see Weight Loss, [[Weight Loss]])

Hematologic Manifestations

  • Splenic Infarct: occurs in 66% of cases

Hepatic Manifestations

  • General Comments: hepatic manifestations occur in 50% of cases
  • Hepatic Infarct

Neurologic Manifestations

  • Mononeuritis Multplex: occurs in 50-75% of cases
  • CNS Disease: occurs in 5-40% of cases
  • Subarachnoid Hemorrhage

Otolaryngologic Manifestations

  • Sinusitis: occurs in 20-70% of cases -> generally not destructive
  • Allergic Rhinitis

Pulmonary Manifestations (50% of cases)

(pulmonary symptoms occur in almost all patients and may precede the development of other manifestations by years)

  • Asthma (mean age of onset: 35 y/o): essentially universal
    • CXR/Chest CT: bronchial wall thickening, hyperinflation
  • Pneumonia-Like Presentation (see [[Pneumonia]]): eosinophilic infiltrates occur in 30-50% of cases
    • CXR/Chest CT
      • Fleeting patchy alveolar or nodular infiltrates:
      • Hilar adenopathy: may occur
      • Bronchial wall thickening (on HRCT): distinguishes Churg-Strauss from other causes of pulmonary infiltrates with eosinophilia
  • Pleural Effusion (see [[Pleural Effusion-Exudate]]): occurs in 30% of cases
    • Pleural Fluid: low pH, low glucose exudate with associated eosinophilia and markedly elevated LDH
      (same pattern is also seen in Paragonimiasis)
  • Diffuse Alveolar Hemorrhage (see [[Diffuse Alveolar Hemorrhage]]): 0-20% of cases
    • Must less common than in Wegener’s Granulomatosis

Renal Manifestations (25-60% of cases)

  • Glomerulonephritis: much less common than in Wegener’s Granulomatosis

Rheumatologic Manifestations

  • Arthralgias/Mylagias: occur in 50% of cases
  • Vasculitis (mean age of onset: 38 y/o): usually difficult to control
    • Palpable purpura

Prostate/Lower Urinary Tract Manifestations

Ocular Manifestations

  • General Comments
    • Occur in <5% of cases

Vascular Manifestations

Constitutional Manifestations (common)

  • Fever (see xxxx, [[xxxx]])
  • Malaise

Treatment

  • Discontinue leukotriene antagonists: in cases where diseaes is associated with one of these medications: although this is believed to be due to unmasking of undiagnosed Churg-Strauss Syndrome by steroid taper (and not due to leukotriene antagonist itself)

European Vasculitis Study Group Recommendations for Induction Therapy

(induction therapy is typically given until remission has been achieved or for the first 1 year)

  • Limited Disease: localized upper airway disease
    • Constitutional Symptoms: no
    • Renal Function: Cr <1.4 mg/dL
    • Threatened Organ Function: no
    • Treatment
      • Corticosteroids or Methotrexate or Azathioprine
      • Alternatively: Bactrim alone has been recommended for this group , but efficacy is unproven
  • Early Generalized Disease
    • Constitutional Symptoms: yes
    • Renal Function: Cr <1.4 mg/dL
    • Threatened Organ Function: no
    • Treatment Options
      • Corticosteroids + Cyclophosphamide
      • Corticosteroids + Methotrexate: NORAM Trial demonstrated that methrorexate is as efficacious as cyclophosphamide for the induction of remission in ealr generalized disease
  • Active Generalized Disease
    • Constitutional Symptoms: yes
    • Renal Function: Cr <5.7 mg/dL
    • Threatened Organ Function: yes
    • Treatment
      • Corticosteroids + Cyclophosphamide: pulsed IV cyclophosphamide is as effective as PO cyclophosphamide (1 mg/kg/day) with fewer side effects
  • Severe Disease
    • Constitutional Symptoms: yes
    • Renal Function: Cr >5.7 mg/dL
    • Threatened Organ Function: yes (diffuse alveolar hemorrhage, etc)
    • Treatment
      • Corticosteroids + Cyclophosphamide + Plasma Exchange
        • Addition of plasma exchangeis superior to pulsed high-dose teroids in restoring renal function in cases with severe renal impairment
        • This strategy may also be beneficial in the treatment of Diffuse alveolar hemorrhage
        • Other agents described in case reports that may have benefit in diffuse alveolar hemorrhage: activated human factor 7, extra-corporeal membrane oxygenation (ECMO) (used mainly to support patient until other therapies can take effect)
  • Refractory Disease
    • Constitutional Symptoms: yes
    • Renal Function: any
    • Threatened Organ Function: yes
    • Treatment
      • Rituximab (see [[Anti-CD20 Therapy]]): has been demonstrated to be equivalent to cyclophosphamide in inducing remission and may be superior in terms of treating relapsed disease
        [N Engl J Med 2010; 363:221-232]
      • IVIG (see [[Intravenous Immunoglobulin]])
        • May be useful to treat residual or persistent disease after other therapy
        • Response to IVIG is transient
        • Side effects (such as renal insufficinecy) are frequent
      • Anti-Thymocyte Globulin (see [[Anti-Thymocyte Globulin]])

Maintenance Therapy

  • Timing of Transition to Maintenance Therapy: controversial, some argue that patient should be converted to maintenance after remission has been achieved and others argue patient should be converted to maintenance after the first year of induction therapy
    • CYCAZA-REM Trial: patients with active generalized disease can be transitioned to PO cyclophosphamide maintenance to azathioprine once clinical remission has been achieved (using clinical criteria, generally within 3-6 months) -> no increase in relapse rates, disease activity scores, or change in renal function
  • Regimens
    • Low-Dose Corticosteroids + Methotrexate
    • Low-Dose Corticosteroids + Azathioprine (2 mg/kg/day)
    • Cellcept
    • Leflunomide
    • Cyclosporine A
  • Duration of Maintenance Therapy: most experts recommend at least 2 years of maintenance therapy
  • Bactrim: decreases frequency of relapse, related to a reduction in nasal Staph aureus carriage
    • Whatever the case, Bactrim should be used for PCP prophylaxis (if not sulfa allergic) in patients on immumosuppressive regimens
  • European Vasculitis Study Group Placebo-Controlled Trial of Nasal Mupirocin for the Prevention of Relapse (MUPIBAC Trial): in progress

Side Effects of Therapy

  • Infection
    • 10% of cyclophosphamide-treated patients develop clinically important infection (even in the absence of cyclophosphamide-induced leukopenia)
    • Combined steroids + cyclophosphamide increase the risk over cyclophosphamide alone
  • Cyclophosphamide-Specific Side Effects:
    • 12% of cyclophosphamide-treated patients develop cystitis
    • 8% of cyclophosphamide-treated patients develop myelodysplastic syndrome
    • 5% of cyclophosphamide-treated patients develop a solid malignancy

Relapse

  • Prevalance of Relapse
    • 50% of all ANCA-associated vasculitis patients have at least one relapse, despite active treatment
    • Relapse occurs in 15-25% of Churg-Strauss cases (in contrast, relapse occurs in 25-33% of Microscopic Polyangiitis cases and 40-65% of Wegener’s Granulomatosis cases)
  • Site of Relapse: may be in an initially affected organ or in a new organ
  • Treatment of Relapse: repeat induction

Prognosis

  • 5-Year Survival: 68-100%
  • Prognostic Score: score of at least 2 predicts increased mortality -> 1 point each for:
    • Proteinuria >1g/24 hrs
    • Cr >1.58 mg/dL
    • Clinically significant GI disease
    • Clinically significant cardiac disease
    • Clinically sgnificant CNS disease

References

Diagnosis

  • xxxx

Clinical

  • The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. Aug 1990;33(8):1094-100
  • A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res Ther. 2014 Sep 25;16(5):435. doi: 10.1186/s13075-014-0435-y [MEDLINE]
  • Venous thromboembolic events in systemic vasculitis. Ann Rheum Dis. 2015 Mar;74(3):e27. doi: 10.1136/annrheumdis-2014-206849. Epub 2014 Nov 7 [MEDLINE]

Treatment

  • xxxx