New Consensus for ANCA Testing
Systemic necrotizing vasculitides are inflammatory diseases of blood vessels, which are difficult to distinguish from infectious, connective tissue, and degenerative diseases. Biopsies often reveal only nonspecific acute or chronic inflammation. Standard laboratory tests such as hemoglobin, WBC, ESR, ANA, and urinalysis have poor predictive value for vasculitis, because none of them are specific for vasculitis.
In patients with clinical features of vasculitis, the presence of antineutrophil cytoplasmic antibody (ANCA) with specificity for myeloperoxidase (MPO) or proteinase 3 (PR3) has a high positive predictive value for a diagnosis of one of the ANCA-associated vasculitides, which include granulomatosis with polyangiitis (GPA, Wegener), microscopic polyangiitis (MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis (EGPA).
The international consensus of ANCA testing, which was published in 1999 recommended using indirect fluorescence to screen for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) pattern and then testing positive specimens with an immunoassay for PR3 and MPO autoantibodies.
Since publication of the 1999 consensus, immunoassays for MPO and PR3 have been developed, which are more sensitive and specific than immunofluorescence testing for diagnosis of ANCA associated vasculitis. A revised international consensus on ANCA testing, published in 2017, recommended that primary screening for ANCA should now be performed using high quality antigen specific assays for PR3 and MPO autoantibodies.
A positive test for MPO or PR3 autoantibody has high sensitivity and specificity for a diagnosis of ANCA associated vasculitis and is a major determinant of the clinical presentation of ANCA associated vasculitis. MPO positive vasculitis is usually associated with kidney-limited disease, severe renal fibrosis, and worse renal prognosis. Some patients develop pulmonary fibrosis. Patients with PR3 positive vasculitis have granulomatous inflammation, respiratory tract involvement, more extensive extra-renal manifestations and poor renal prognosis.
Immunofluorescent ANCA testing adds little additional benefit in the diagnosis of ANCA associated vasculitis when the pretest probability for disease is high. Since no immunoassay has a sensitivity of 100%, immunofluorescent testing might be warranted when the clinical suspicion is high and antigen tests are negative.
References
Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int 1998; 53:743.
Bossuyt X et al. Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nature Reviews, Rheumatology, 2017;13:683-92.
Csernok, E et al. Anti-neutrophil cytoplasm antibodies (ANCA): Recent methodological advances-Lead to new consensus recommendations for ANCA detection. J Immunol Meth 2018;456:1-6.
