Page 181 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Detection Techniques and Clinical Relevance of ANCA Testing … 157

regional center in the year prior to and following the consensus guidelines [4] to ensure
appropriate usage by auditing clinical outcomes in patients in whom ANCA testing was
declined and documenting the absence of either GPA or MPA in all so studied.

Their findings demonstrated that adherence to gating policy for ANCA testing coupled
with close liaison between clinician and laboratory does not result in either a missed or
delayed diagnosis of a small-vessel vasculitis belonging to the GPA-MPA spectrum.

ANCA Levels and Disease Activity

The clinical usefulness of measuring ANCA levels in relation to disease activity and in
guiding therapy is still controversial. Although ANCA titers are typically high at presentation
and predictably relate to disease activity [13], there are potential confounders of the
relationship between ANCA levels and disease activity including, publication bias against
negative results, definition of relapse, intensity of clinical screening for disease activity,
intervals of followup visit, and variable methods and intervals employed in sequential ANCA
detection. A rise in serial ANCA measurements in patients with AAV presumably in
remission status can be a clue to the prediction of disease relapse.

However ANCA levels should not be used alone to guide treatment. Notwithstanding, a
significant increase in ANCA levels or the reappearance of ANCA in the proper clinical and
histopathological context, may suggest the need for more attentive management.

PR3- and MPO-ANCA-Subtypes

Of all the possible known ANCA target antigens, only two, PR3 and MPO are closely
associated with small-vessel vasculitis. Extrarenal manifestations, granuloma formation and
relapse were more frequent in patients with PR3-ANCA than in those with MPO-ANCA [14,
15]. Among 173 patients screened at the time of diagnosis with renal biopsy tissue, both
active and chronic renal lesions were more common in MPO-ANCA-positive than PR3-
ANCA-positive [16].

Despite substantial overlap there were clinical and pathologic differences between
patients with PR3-ANCA and MPO-ANCA that may reflect different pathogenic interactions
between ANCA, their target antigens, and organ involvement at the molecular level. A
genome-wide association study [17] confirmed a genetic component in the pathogenesis of
AAV revealing distinctions between GPA and MPA that were associated with ANCA
specificity, suggesting that the response against PR3-ANCA was a central pathogenic feature
of PR3-ANCA associated vasculitis.

Moreover, the strongest genetic associations were with antigenic specificity of ANCA,
not the clinical syndrome. HLA-DP and the genes encoding a1-antityrpsin (SERPINA1),
proteinase 3 (PRTN3) were associated with PR3-ANCA specificity, whereas MPO-ANCA
was associated with HLA-DQ.

About 10% of patients with GPA do not have demonstrable ANCA by IFT or antigen
specific assays and are likely to have localized disease.

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