Antinuclear Cytoplasmic Antibody-Associated Vasculitis

Antinuclear cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). All 3 diseases cause life-threatening small-vessel vasculitis with a wide range of systemic manifestations, which can involve the lungs, kidneys, skin, and heart. Diagnosis is suspected by clinical presentation and a positive cytoplasmic (c)- or perinuclear (p)-ANCA test. Biopsy of involved tissue confirms the diagnosis. Glucocorticoids and immunosuppressive therapy are the mainstays of treatment.

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Overview

Definition

Antinuclear cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing small vessel vasculitis and a positive ANCA test without significant immune complex deposition.

Classification

AAV includes the following diseases:

  • Granulomatosis with polyangiitis (GPA)
  • Microscopic polyangiitis (MPA)
  • Eosinophilic granulomatosis with polyangiitis (EGPA) (also known as Churg-Strauss syndrome)

Epidemiology

  • Often presents in the 6th and 7th decades of life
  • Affects women and men equally
  • More common in White individuals

Pathophysiology

  • Multifactorial
  • Initiating inflammatory event (e.g., infection, drugs) → ANCA-induced activation of neutrophils → destructive vascular necrosis:
    • Neutrophils play a central role:
      • Neutrophils have ANCA autoantigens sequestered in cytoplasmic granules.
      • Release of ANCA antigens on the surface of neutrophils → ANCA binds to ANCA antigens and activates neutrophils
      • ANCA-activated neutrophils release factors activating the alternative complement pathway.
      • Activated neutrophils adhere to and penetrate vessel walls → release toxic oxygen radicals and destructive enzymes causing apoptosis and necrosis
    • A highly specific immune response and formation of antibodies against neutrophil granules creates an ANCA cytoplasmic (c) or perinuclear (p) positive test: 
      • In 85% of GPAs:
        • 80% of cases are c-ANCA+.
        • 10% of cases are p-ANCA+.
      • In 70% of MPAs: The majority of cases are p-ANCA+.

Clinical Presentation

Presentation may be acute, weeks, months, or recurrent with different localizations.

Constitutional symptoms

Constitutional symptoms may be present weeks or months before specific clinical features develop: 

  • Arthralgias
  • Fevers, night sweats
  • Fatigue, lethargy
  • Loss of appetite
  • Weight loss

Upper respiratory tract involvement

  • More common in GPA (95%) than in MPA (35%)
  • Manifestations include: 
    • Sinusitis
    • Otitis media
    • Purulent/bloody nasal discharge
    • Mucosal ulcers
    • Polychondritis
    • Bone/cartilage destruction:
      • Loss of teeth
      • Conductive hearing loss or saddle nose deformity (typical for GPA) 
Example of a collapsed nasal bridge

Example of the collapsed nasal bridge (saddle nose deformity) seen in granulomatosis with polyangiitis (GPA):
The individual also shows orbital involvement with proptosis (protrusion of the eyeball), eyelid edema, and limited ocular movements. Orbital involvement typically does not occur until years after disease onset.

Image: “Anterior and lateral appearance of the patient” by Aletaha M, Tavakoli M, Kanavi MR, Hashemlou A, Roghaei S. License: CC BY 2.5

Lower respiratory tract involvement

  • Airways:
    • Hoarseness
    • Stridor
    • Cough
    • Dyspnea
    • Rhonchi
    • Wheezing
    • Hemoptysis 
  • Parenchyma:
    • Rales
    • Diffuse alveolar hemorrhage
    • Signs of consolidation and/or pleural effusion, including dullness to percussion
  • History of asthma suggests EGPA over GPA/MPA.
Progression to diffuse alveolar hemorrhage in a patient with granulomatosis with polyangiitis (GPA)

Progression to diffuse alveolar hemorrhage in an individual with granulomatosis with polyangiitis (GPA):
A) frontal chest X-ray on admission
B) frontal chest X-ray in the same individual after 4 days

Image: “Posterior-anterior chest X-ray 4 days prior to admission” by Cardenas-Garcia J, Farmakiotis D, Baldovino BP, Kim P. License: CC BY 2.0

Kidney involvement

  • Glomerulonephritis is seen in 20% of individuals at the time of diagnosis and 80% of individuals after 2 years.
  • Manifestations include:
    • Hematuria
    • Cellular casts
    • Hypertension
    • ↑ Creatinine
  • Rapidly progressive glomerulonephritis (RPGN): rapidly ↓ renal function over days-to-weeks and glomerular crescent formation on histology

Cutaneous manifestations

  • Affects 50% of individuals
  • Includes:
    • Purpura
    • Ulcerations
    • Urticaria
    • Livedo reticularis
    • Nodules
Multiple ulcerations in a patient with microscopic polyangiitis (MPA)

Multiple ulcerations in an individual with microscopic polyangiitis (MPA)

Image: “Ulcérations cutanées aux membres inférieurs” by Khammassi N, Chakroun A. License: CC BY 2.0

Ophthalmic manifestations

  • Pain
  • Blurred vision/diplopia
  • Conjunctivitis
  • Episcleritis/scleritis
  • Corneal ulceration, uveitis, retinitis
  • Optic neuropathy
Eyelid edema, scleritis, chemosis, and subconjunctival hemorrhage in a patient with granulomatosis with polyangiitis (GPA)

Eyelid edema, scleritis, chemosis, and subconjunctival hemorrhage in an individual with granulomatosis with polyangiitis (GPA)

Image: “The eye involvement of Wegener’s granulomatosis and signs of an acute epistaxis” by Bîrluţiu V, Rezi EC, Bîrluţiu RM, Zaharie IS. License: CC BY 4.0

Neurologic manifestations

  • Mononeuritis multiplex (multifocal peripheral neuropathy)
  • Sensory deficits
  • Cranial nerve abnormalities
  • Sensorineural hearing loss
  • Meningismus

Heart disease

  • Pericarditis
  • Myocarditis
  • Conduction abnormalities

Other organs (rare)

  • GI involvement
  • Arthritis
  • Thyroid or parathyroid disease

Diagnosis

Diagnostic approach

Suspected diagnosis:

  • Suggestive clinical features
  • Screening tool for EGPA:
    • American College of Rheumatology diagnostic criteria for EGPA includes 4 of the 6 criteria with a specificity of almost 100%:
      • Asthma
      • > 10% eosinophils on CBC with differential
      • Mononeuropathy (e.g., foot drop) or polyneuropathy 
      • Fleeting pulmonary infiltrates
      • Paranasal sinus abnormality
      • Extravascular accumulation of eosinophils on biopsy 
    • Inflammatory markers:
      • Erythrocyte sedimentation rate (ESR)
      • Leukocytosis
      • Thrombocytosis
  • Positive test for ANCA:
    • Proteinase 3 (PR3)-ANCA (c-ANCA): more commonly associated with GPA
    • Myeloperoxidase (MPO)-ANCA (p-ANCA): more commonly associated with MPA, EGPA

Confirmation of diagnosis includes biopsy of affected organs:

  • Suspected diagnosis can be confirmed with a biopsy of lung, skin, or peripheral nerve (may show granulomas).
  • Biopsy sites and findings:
    • GPA: Tissue biopsy from a site of the active disease shows segmental, crescentic-necrotizing glomerulonephritis with little/no immunoglobulin or complement deposition (pauci-immune); renal and lung biopsies are the most specific.
    • MPA: Lung biopsy and/or renal biopsy (crescentic glomerulonephritis) shows necrotizing arteritis (histologically identical to polyarteritis nodosa).
    • EGPA: Lung biopsy shows small, necrotizing granulomas with necrotizing vasculitis involving small arteries and venules.

Other laboratories:

  • ↑ ESR, normocytic normochromic anemia, leukocytosis, and thrombocytosis
  • ↑ Creatinine
  • Proteinuria
  • Cytopenias
  • Eosinophilia

Imaging: chest X-ray and CT:

  • Consolidation
  • Nodules
  • Pleural effusion
  • Fleeting infiltrates
  • Hilar adenopathy

Other diagnoses positive for ANCA

  • Goodpasture syndrome
  • Drug-induced vasculitis
  • Polyarteritis nodosa
  • Primary sclerosing cholangitis
  • Ulcerative colitis

Management

All individuals with a confirmed diagnosis of AAV require immunosuppressive therapy. Therapy can be initiated early based on a presumptive diagnosis of the following criteria:

  • Suggestive clinical features
  • + ANCA test
  • ↓ Probability of other etiologies 

Induction of remission

  • MPA and GPA:
    • Cyclophosphamide + glucocorticoids are the criterion standard for induction of remission.
    • Rituximab is a less toxic alternative to cyclophosphamide for induction of remission in GPA or MPA and is the 1st treatment approved by the FDA.
  • EGPA: 
    • Glucocorticoids alone are usually adequate for the treatment of EGPA.
    • Cytotoxic drugs (cyclophosphamide) are necessary in < 20% of individuals.
  • Plasma exchange may be required with disease (e.g., RPGN or pulmonary hemorrhage).

Maintenance of remission

Once remission is achieved, individuals switch to less toxic agents:

  • Azathioprine
  • Rituximab
  • Mycophenolate mofetil
  • Methotrexate

General measures

  • Antibiotic prophylaxis while on immunosuppressive therapy
  • Trimethoprim-sulfamethoxazole to prevent pneumocystis pneumonia (PCP)

Comparison Table

Table showing suggestive laboratory and clinical features of the 3 main types of AAV:

Table: Suggestive laboratory and clinical features of the 3 main types of AAV
AAV diseaseANCAGranuloma on biopsyTypical case
GPA
  • In 85%
  • c-ANCA
+Adult with:
  • Nasal/sinus bleeding or ulcers (90%)
  • Pulmonary infiltrates/hemorrhage
  • Glomerulonephritis (↑ creatinine, hematuria)
MPA
  • In 70%
  • p-ANCA
Similar to GPA, but without serious nasal/sinus disease (only in 30%)
EGPA
  • In 50%
  • p-ANCA
+Young adult with:
  • Peripheral neuropathy (foot drop) (75%)
  • Cutaneous involvement with a history of asthma/allergic rhinitis + eosinophilia
GPA: granulomatosis with polyangiitis
MPA: microscopic polyangiitis
EGPA: eosinophilic granulomatosis with polyangiitis

Differential Diagnosis

  • Drug-induced ANCA vasculitis: ANCA positive vasculitis from medication exposures are linked to the development of vasculitis (propylthiouracil, methimazole, carbimazole, hydralazine, and minocycline), causing constitutional symptoms such as arthralgias, fatigue, and skin rash. However, the full range of clinical features (including rapidly progressive renal failure and alveolar hemorrhage) can also occur.
  • Goodpasture syndrome: a rare autoimmune disease where antibodies attack the basement membrane in the lungs and kidneys, which leads to bleeding from the lungs and kidney failure. Goodpasture syndrome results in permanent lung and kidney damage and often leads to death. Treatment includes immune system suppressing medications (e.g., corticosteroids and cyclophosphamide) and plasmapheresis.
  • Polyarteritis nodosa: a systemic vasculitis of small and medium vessels. Polyarteritis nodosa involves the skin, peripheral nerves, muscles, joints, gastrointestinal tract, and kidneys. Individuals present with nonspecific symptoms, hypertension, risk of myocardial infarction, and polyneuropathy. Angiography shows a beading appearance of alternating aneurysms and vessel stenosis. Management is immunosuppressive regimens.
  • Giant cell arteritis: a vasculitis of medium and large arteries (particularly the carotid arteries and aorta). Individuals present with new-onset headache, tender/hardened temporal artery, jaw claudication, and amaurosis fugax. Laboratory studies show elevated ESR and CRP. Biopsy shows mononuclear infiltration of vessel walls and the formation of giant cells. Treatment involves prompt administration of glucocorticoids.
  • Henoch-Schönlein purpura: an autoimmune small vessel vasculitis. The condition typically presents as a triad of abdominal pain, hematuria, and purpuric rash. The pathophysiology involves IgA immune complex deposition in multiple vessels following a trigger. Symptoms depend on the tissues supplied by the vessels. The disease has a clinical diagnosis and is managed symptomatically. 
  • Rheumatoid arthritis: an inflammatory polyarthritis presenting with pain in symmetric joints. The pain is worse in the morning but improves during the day, The proximal interphalangeal and metacarpophalangeal joints are included, but the distal interphalangeal joints are spared. Management is with NSAIDs, methotrexate, sulfasalazine, hydroxychloroquine, and TNF-α inhibitors.
  • Systemic lupus erythematosus: a chronic inflammatory condition with involvement of the skin, joints, kidneys, blood cells, and CNS. The condition is an autoimmune disorder associated with the formation of autoantibodies such as ANA, anti-Smith, and anti-double-stranded DNA (dsDNA). Features include malar rash, joint pain, fever, proteinuria, hypertension, anemia, lymphopenia, seizures, and/or psychosis.

References

  1. King, T.E. Jr. (2020). Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). UpToDate. Retrieved May 17, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss
  2. Lowe, S. (2020). Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome) Workup. Emedicine. Retrieved August 17, 2021, from https://emedicine.medscape.com/article/333492-workup#c4 
  3. Tracy, C. (2019). Granulomatosis with Polyangiitis (GPA, formerly Wegener Granulomatosis) Workup. Emedicine. Retrieved August 17, 2021, from https://emedicine.medscape.com/article/332622-workup#c10
  4. Farid-Moayer, M. (2020). Microscopic Polyangiitis Differential Diagnoses. Emedicine. Retrieved August 17, 2021, from https://emedicine.medscape.com/article/334024-differential 
  5. Falk, R. (2020). Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis. UpToDate. Retrieved August 17, 2021, from https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis 

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