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Dr Harris's results1 showed that indirect immunofluorescence is a more sensitive technique than antigen specific enzyme linked immunosorbent assay (ELISA) for the diagnosis of systemic necrotising vasculitis (70% v 50%) but that ELISAs have a higher positive predictive value (87% v 76%). It was the greater sensitivity of indirect immunofluorescence that prompted the “International consensus statement on testing and reporting antineutrophil cytoplasmic antibodies (ANCA)”2 to require all laboratories to screen for ANCA by indirect immunofluorescence, but to confirm the specificity of fluorescent sera by ELISA. In our hands, adherence to the minimum requirements of the consensus statement results in a higher positive predictive value than either indirect immunofluorescence or ELISA alone (62% compared with 44% and 50%, respectively). Screening by indirect immunofluorescence has the additional advantages of being a quicker and cheaper technique than using the two commercial antigen specific ELISAs that are usually required and, furthermore, indirect immunofluorescence might demonstrate coincidental but unsuspected autoantibodies such as antinuclear antibodies. We believe that the use of ELISAs alone to diagnose a systemic necrotising vasculitis is analogous to testing for systemic lupus erythematosis with anti-double stranded DNA antibodies rather than initially screening for antinuclear antibodies by indirect immunofluorescence.
The authors reply
Our study was carried out following the preliminary observation that in our laboratory a positive immunofluorescence antineutrophil cytoplasmic antibody (ANCA) result was less frequently associated with a diagnosis of systemic necrotising vasculitis than a positive enzyme linked immunosorbent assay result (PR3 or myeloperoxidase). Our clinicians frequently did not alter management based on the immunofluorescence ANCA result. In fact, our renal physicians invariably proceeded with renal biopsy, regardless of immunofluorescence results, to confirm or refute the diagnosis of systemic necrotising vasculitis. The ELISA result frequently came back too late to alter clinical management, the ELISA test being done when immunofluorescence was positive. Our study has shown that for active systemic necrotising vasculitis, ELISA has a superior positive predictive value and specificity, and comparable sensitivity to the immunofluorescence technique.
Savige et al quoted our sensitivity results with respect to “all cases” of systemic necrotising vasculitis, active and inactive combined, which are largely irrelevant parameters in clinical practice because the need is to identify active cases. The principal result of the study was the finding that in active, biopsy confirmed cases of systemic necrotising vasculitis, ELISA ANCA is just as sensitive (85% v 88%; p = 0.056) yet has a significantly better specificity (97% v 90%; p = 0.0006) and positive predictive value (73% v 50%; p = 0.0013) compared with immunofluorescence ANCA.
The fact that the sensitivity of ELISA ANCA falls as inactive cases are added to active cases implies that ELISA more quickly becomes negative as active disease settles, whereas immunofluorescence remains positive. This observation suggests that ELISA is also a better test in following disease activity after diagnosis and initiation of treatment.
Savige et al reported their finding of a higher positive predictive value if results of ELISA and immunofluorescence ANCA are combined. This was not found in our study. In fact, combining immunofluorescence and ELISA ANCA resulted in a lower positive predictive value than ELISA ANCA alone. It would be of interest to review the data Savige et al have used.
Based on our results, we conclude that ELISA ANCA is the principal serological test for the diagnosis of systemic necrotising vasculitis. Immunofluorescence ANCA should be avoided because its inferior specificity and poor positive predictive value open the way to incorrect or delayed diagnosis and treatment. We would like to restate the importance of recognising the different clinical syndromes caused by systemic necrotising vasculitis and of appropriate histological testing even with a positive or negative ELISA ANCA result.
We have not investigated the value of ANCA with respect to the diagnosis of other conditions, such as inflammatory bowel disease, and so we do not recommend which tests should be used in a particular laboratory. We have only compared ELISA and immunofluorescence ANCA in a particular disease (systemic necrotising vasculitis) and found ELISA to be superior by all criteria. Our results indicate that the “International consensus statement on the testing and reporting of ANCA”1 should be revisited.