section name header

Info


A. Antineutrophil Cytoplasmic Antibodies (ANCA) [1,3]

  1. Primarily IgG autoantibodies against neutrophil/monocyte primary lysosome granule components
  2. Staining patterns are typically cytoplasmic (c-ANCA) or perinuclear (p-ANCA)
  3. C-ANCA Detects Proteinase 3 (Pr3)
    1. Pr3 is a unique 29K serine protease stored primarily in neutrophil azurophilic granules
    2. Also called p29, azurophilic granule protein 7, myeloblastin
    3. Pr3 is also found in myelperoxidase (MPO) positive granules of monocytes, mast cells
    4. Pr3 degrades a variety of extracellular matrix proteins including fibronectin and elastin
  4. Most p-ANCA staining patterns detect Myeloperoxidase (MPO)
    1. Appearance of the p- (perinuclear) ANCA pattern is dependent on ethanol fixation
    2. In contrast, formaldehyde fixation causes diffuse cytoplasmic appearance of both c-ANCA and anti-MPO p-ANCA
    3. Additional proteins are detected by p-ANCA positive antisera, depending on disease type
  5. Positive ANCA tests should be followed with analysis of Ab specificity (Western Blot)
    1. ELISA Testing and Western Blot Analysis are now available for specific ANCA testing
    2. The ELISA tests can be used to quantitate Ab levels (titer) fairly accurately
    3. Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener's activity [4]
    4. In Wegener's granulomatosis, ANCA levels cannot be used to guide immunosuppression [4]
  6. Prevalence of ANCA in Rheumatoligic Disease [3]
    1. Sometimes found in association with Anti-Glomerular Basement Membrane Abs [2]
    2. Overall low prevalence in patients with non-vasculitic connective tissue diseases
    3. ELISA assays are required to rule out P-ANCA due to cross reaction from ANA tests
    4. Patients with positive ELISA for ANCA nearly always have an ANCA-related vasculitis
  7. Mechanism [12]
    1. The ANCA may be directly involved in endothelial cell damage in some types of vasculitis
    2. Infection or other inflammatory stimuli stimulates production of TNFa and other cytokines
    3. These cytokines stimulate neutrophils and endothelial cells
    4. PR3 and MPO are stimluated to move from neutrophil azurophilic granules to surface
    5. In setting of inflammation, PR3 and MPO become immunogenic, with ANCA forming
    6. ANCA bind to targets on neutrophil surfaces, and Fc region of ANCA stimulate neutrophil
    7. ANCAs induce firm adhesion (not rolling) of neutrophils to endothelial surface
    8. ANCA induce release of reactive oxygen species and proteolytic enzymes from neutrophils
    9. ANCA-activated neutrophils also secrete proinflammatory cytokines
    10. Together, these effects cause neutrophil mediated endothelial damage

B. Sensitivity of ANCA Tests

Disease TypeAnti-Pr3Anti-MPO
Idiopathic Crescentic GMN30%70%
Microscopic Polyarteritis50%50%
Wegener's Granulomatosis80%20%
Churg-Strauss Syndrome10%70%
Polyarteritis Nodosa (PAN)10%20%
Vasculitis Overlap Syndromes40%20%

C. Major ANCA Associated Vasculitides [1]
  1. Relatively uncommon life-threatening conditions [12]
    1. Wegener's Granulomatosis: 10 cases / million
    2. Microscopic Polyangiitis: 3.6 cases / million
    3. Churg-Strauss Syndrome: 2.4 cases per million
  2. Wegener's Granulomatosis
    1. Sinus, nasal, and ear disease with interstitial lung inflammation
    2. Nasal symptoms due to inflammation, may progress to septal erosions
    3. Septal perforation or nasal bridge collapse ("saddle nose deformity") may occur
    4. Both conductive and sensorineural hearing loss can occur
    5. Upper respiratory inflammation in ~90% during course of disease
    6. Subglottic stenosis
    7. Retrobulbar orbital masses, nasolacrimal duct obstruction
    8. Scleritis, episcleritis, uveitis can occur
    9. Lung nodules, pulmonary infiltrates (may be fleeting), alveolar hemorrhage
    10. Segmental necrotizing glomerulonephritis
    11. Arthritis and/or arthralgias are common
    12. Cutaneous nodules also occur
    13. 85% are ANCA+, vast majority of these are PR3+ (c-ANCA)
    14. Necrotizing granulomatous inflammation in skin and lungs
    15. ANCA levels cannot be used to guide immunosuppression [4]
  3. Microscopic Polyangiitis
    1. Leukocytoplastic vasculitis without granulomatous inflammation
    2. Segmental necrotizing glomerulonephritis is most common
    3. Vasculitic neuropathy - mainly mononeuritis multiplex (~55%)
    4. Alveolar hemorrhage can occur
    5. Occasional eye disease
    6. Arthritis and/or arthralgias are common
    7. ~70% ANCA+, mainly MPO (p-ANCA+)
  4. Churg-Strauss Syndrome
    1. Allergic rhinitis is initial symptom in ~65% of cases
    2. Triad of allergies (atopy) with nasal polyps, asthma, eosinophilia
    3. Conductive hearing loss
    4. Occasional eye disease
    5. Vasculitis neuropathy - mainly mononeuritis multiplex (~75%)
    6. Arthritis and/or arthralgias are common
    7. Cutaneous nodules also occur
    8. ~50% p-ANCA+ (MPO Abs)
    9. Eosinophilic tissue infiltrates with vasculitis, granulomas with eosinophilic necrosis
  5. Renal-Limited Vasculitis
    1. ANCA associated glomerulonephritis
    2. Absence of pulmonary disease

D. Other ANCA+ Diseases [1]

  1. Other Vasculitides with ANCA+
    1. Behcet's Syndrome
    2. Relapsing Polychondritis
    3. Rheumatoid Arthritis with Secondary Vasculitis
    4. These are almost uniformly p-ANCA (Anti-MPO) type
  2. Occurrence of p-ANCA in Other Diseases
    1. Ulcerative Colitis ~60%
    2. Crohn's Disease ~15%
    3. Autoimmune Hepatitis ~60% (check ANA and anti-smooth muscle antibody also)
    4. Primary Biliary Cirrhosis ~30% (check ANA and anti-mitochondrial antibody also)
    5. Sclerosing Cholangitis ~60% (may be associated with Inflammatory Bowel Disease)
    6. Felty's Syndrome >90%
  3. Drug-Associated ANCA+ Disease [5]
    1. Minocycline-induced autoimmune disease [6]
    2. Propylthiouracil (PTU) reaction - associated with very high p-ANCA levels
    3. Hydralazine
    4. Cocaine abuse (chronic) can be associated with c-ANCA [7]
  4. Malignant Pyoderma [8]
    1. Usually found on face, ears, neck
    2. Most strongly associated with Wegener's granulomatosis and positive c-ANCA
  5. Circulating Endothelial Cells [9]
    1. Normal or large vessel vasculitis <20 endothelial cells/mL
    2. Elevated levels (median 136 cells/mL, 20-5700 cells/mL) in small vessel ANCA+ vasculitis

D. Therapeutic Overview [10,12]

  1. Induction Therapy
    1. Glucocorticoids with cyclophosphamide induction therapy in most cases
    2. Oral cyclophosphamide is usually used except with very severe renal insufficiency
    3. Cotrimoxazole (TMP/SMX) + glucocorticoids can be used in isolated upper respiratory tract involvement, usually only in mild to moderate Wegener's
    4. Methotrexate + glucocorticoids can be sued in place of cyclophosphamide for generalized, non-organ threatening disease
    5. Plasma exchange is added to induction agents in patients with renal progression
    6. Plasma exchange leads to a higher rate of renal recovery than intravenous methylprednisolone in severe vasculitis patients [13]
    7. Glucocorticoids alone for Churg-Struass Syndrome unless renal disease
  2. Maintenance
    1. Increasing use of methotrexate, but risk of relapse is high and monitoring required
    2. Cyclophosphamide oral chronically is generally avoided due to side effects
    3. Azathioprine + daily prednisone maintenance therapy after 3 months of cyclophosphamide
    4. Glucocorticoids alone for Churg-Strauss Syndrome
    5. Maintenance therapy should only be instituted only when patient is in clinical remission
  3. Female, black patients, severe kidney disease associated with resistance to initial treatment [11]

References

  1. Seo P and Stone JH. 2004. Am J Med. 117(1):39 abstract
  2. Bosch X, Guilabert A, Fant J. 2006. Lancet. 368(9533):404 abstract
  3. Merkel PA, Polisson RP, Chang Y, et al. 1997. Ann Intern Med. 126(11):866 abstract
  4. Finkelman JD, Merkel PA, Schroeder D, et al. 2007. Ann Intern Med. 147(9):611 abstract
  5. Helfgott SM and Smith RN. 2002. NEJM. 347(2):122 (Case Record) abstract
  6. Elkayam O, Levartovsky D, Brautbar C, et al. 1998. Am J Med. 105(6):484 abstract
  7. Rowshani AT, Schot LJ, ten Berge IJM. 2004. Lancet. 363(9411):782 (Case Report) abstract
  8. Gibson LE, Daoud MS, Muller SA, Perry HO. 1997. Mayo Clin Proc. 72(8):734 abstract
  9. Woywodt A, Streiber F, de Groot K, et al. 2003. Lancet. 361(9353):206 abstract
  10. Jayne D, Rasmussen N, Andrassy K, et al. 2003. NEJM. 349(1):36 abstract
  11. Hogan SL, Falk RJ, Chin H, et al. 2005. Ann Intern Med. 143(9):621 abstract
  12. Bosch X, Guilabert A, Espinosa G, Mirapeix E. 2007. JAMA. 298(6):655 abstract
  13. Jayne DR, Gaskin G, Rasmussen N, et al. 2007. J Am Soc Nephrol. 18(7):2180 abstract