Controversies in ANCA testing
ABSTRACTAntineutrophil cytoplasmic antibody (ANCA) detection is a well-known tool for diagnosing small-vessel vasculitis. Its diagnostic utility, however, depends on the methodologic accuracy of the test and the appropriate ordering of testing in the right clinical setting. While ANCA testing is of proven value, the utility of serial ANCA testing is not entirely clear. Correlation of ANCA levels with disease activity and predicted relapse remains unconfirmed. The best gauge of the predictive value of serial testing is to perform long-term serial testing for some individual patients in order to establish a relationship between ANCA level and clinical disease manifestation over time. ANCA-antigen specificity can be used to assess prognosis in patients with ANCA-associated vasculitis. Proteinase 3-ANCA is associated with higher mortality, higher relapse rate, and faster renal deterioration compared with myeloperoxidase-ANCA. Overall, ANCA is an important diagnostic and prognostic marker for small-vessel vasculitis and warrants further investigation.
WHAT IS THE PROGNOSTIC VALUE OF SERIAL ANCA TESTING?
Persistent changes in ANCA levels in relapsing disease may have some value in predicting outcome. The issues to consider include the methodology used to determine serial ANCA levels, correlations between ANCA and disease activity, and the use of ANCA changes to guide treatment.
Does methodology matter when determining serial ANCA levels?
Methodology in serial ANCA testing is probably unimportant as long as the same method is used serially. Analysis of large groups of ANCA-positive patients show a statistically highly significant correlation among results obtained with different detection methods, including immunofluorescence, direct ELISA, or capture ELISA. However, at the individual patient level there is some variability.
Do ANCA levels correlate with disease activity?
In a prospective study, serial ANCA samples obtained during the Wegener’s Granulomatosis Etanercept Trial (WGET)11 were processed in the same manner (collected every 3 months, mean follow-up of 22 months, uniform handling of samples). All samples were analyzed by capture ELISA, and disease activity was measured by the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG). The results indicated that an increase in PR3-ANCA levels was not a significant predictor of relapse. The frequency of a relapse within 1 year of an increase in PR3-ANCA levels was found to be approximately 50%,11 a result similar to that reported in several smaller studies of different design and methodology.
Should ANCA changes guide treatment?
The available data regarding serial ANCA testing are limited mostly to PR3-ANCA. Serial ANCA testing has limited value as a guide to treatment and, in general, changes in ANCA levels alone should not be used to guide treatment decisions. In new patients without documented serial ANCA level associations, an increase in PR3-ANCA levels has no reliable predictive value. The existing literature suggests that this lack of association is not dependent on the method used for ANCA detection. For individual patients in whom long-term serial ANCA testing has been performed and a relationship between PR3-ANCA levels and disease activity has been established, serial ANCA testing can have some predictive value and can be used to guide treatment. For example, when remission is achieved by depleting B cells in patients with chronically relapsing GPA, ANCA levels usually go down. After B-cell reconstitution, the ANCA level rises in most patients, and this rise is usually associated with a flare shortly thereafter. A flare can be preempted when this pattern is determined in a specific patient, and preemptive treatment is applied accordingly.12
WHAT IS THE IMPLICATION OF ANCA TYPE?
Available reports consistently suggest that PR3-ANCA is associated with a higher mortality than MPO-ANCA (relative risk [RR], 3.78),13 and a higher relapse rate.14,15 A more rapid loss of renal function among patients with glomerulonephritis and PR3-ANCA than those with MPO-ANCA has also been reported.16 Using remission as the starting point, the number of days from complete remission to first disease flare was plotted for patients with MPO- versus PR3-ANCA in an analysis of long-term data from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial.17 The resulting curve demonstrated a divergence in the probability of remaining in remission, confirming that remission maintenance is clearly greater in patients with MPO-ANCA than in patients with PR3-ANCA.
The primary end point of the RAVE trial was remission of disease without the use of prednisone at 6 months. There was little difference in end point achieved based on comparison of diagnosis (microscopic polyangiitis or granulomatosis) or treatment arms (rituximab versus cyclophosphamide); however, an analysis of end point data separating the patients by ANCA type showed that the treatment response to rituximab was superior to that of cyclophosphamide among patients with PR3-ANCA, whereas in patients with MPO-ANCA, there was little difference in response associated with either treatment. Regarding the likelihood of attaining an ANCA-negative status after 6 months, again MPO-ANCA patients showed no difference in frequency on either treatment. Among PR3-ANCA–positive patients, 50% in the rituximab arm attained ANCA-negative status compared with only 17% in the cyclophosphamide arm.17
SUMMARY
Diagnostic utility of ANCA testing depends on the methodology and clinical setting. Only cANCA/PR3-ANCA and pANCA/MPO-ANCA pairings have positive predictive value for diagnosis of small-vessel vasculitis. Mismatches in results, findings of human neutrophil elastase–ANCA, or identification of multiple positive antigens should be considered in cases of cocaine or drug use.
The clinical utility of serial ANCA testing is unconfirmed. Good data currently exist only for PR3-ANCA, and different drugs may affect ANCA levels in different ways. ANCA type is significant in that PR3-ANCA portends a higher relapse rate and poorer patient outcomes compared with MPO-ANCA.
