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Rheumatology (Oxford). Jan 2012; 51(1): 100–109.
Published online Oct 28, 2011. doi:  10.1093/rheumatology/ker280
PMCID: PMC3276294

Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis—a meta-analysis

Abstract

Objective. The value of repeated ANCA measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) remains controversial. The aim of this study was to explore whether either of the two distinct patterns of ANCA values during remission, a rise in ANCA or persistently positive ANCA, predicted future relapse.

Methods. MEDLINE and EMBASE searches were performed. Studies with at least 10 subjects with AAV from which both sensitivity and specificity of a rise in ANCA and/or persistent ANCA for future disease relapse could be calculated were included. Likelihood ratios were calculated for each study and pooled to arrive at summary estimates. I2-values were calculated as a measure of heterogeneity and meta-regression was used to explore sources of heterogeneity.

Results. Nine articles on a rise in ANCA and nine articles on persistent ANCA were included. The summary estimates for positive likelihood ratio (LR+) and negative likelihood ratio (LR) of a rise in ANCA during remission on subsequent relapse of disease were 2.84 (95% CI 1.65, 4.90) and 0.49 (95% CI 0.27, 0.87), respectively. The summary estimates for LR+ and LR of persistent ANCA during remission for subsequent disease relapse were 1.97 (95% CI 1.43, 2.70) and 0.73 (95% CI 0.50, 1.06), respectively. There was substantial between-study heterogeneity, which was partially explained by the frequency of ANCA measurements.

Conclusion. Among patients with AAV, a rise in or persistence of ANCA during remission is only modestly predictive of future disease relapse. There is limited use to serial ANCA measurements during disease remission to guide treatment decisions for individual patients with AAV.

Keywords: vasculitis, anti-neutrophil cytoplasmic antibodies, biomarker

Introduction

ANCAs have an undisputed role in establishing the diagnosis of granulomatosis with polyangiitis (Wegener's; GPA) and microscopic polyangiitis (MPA); these diseases, along with Churg–Strauss syndrome (CSS), are often collectively referred to as ANCA-associated vasculitis (AAV) [1–5]. There are data supporting a role for ANCA in the pathogenesis of vasculitis [6] and ANCA has been advocated as a biomarker of disease activity in AAV [7]. Initial reports that serial ANCA measurements were measures of disease activity and valuable predictors of relapses of vasculitis [8, 9] were followed by additional studies that did not support a role for ANCA in patient management [10, 11]. With multiple studies arriving at conflicting conclusions on an important clinical question, a meta-analysis of the published literature could provide estimates for the value of serial ANCA measurements for predicting relapse, while taking into account the heterogeneity between individual studies. Such an analysis could also identify patient subgroups for which serial ANCA testing might be particularly useful and provide possible explanations as to why studies arrive at different conclusions.

Our objective was to specifically examine the usefulness of two distinct properties of ANCA to guide management in AAV: (i) whether a rise in ANCA during remission is predictive for future relapse; and (ii) whether those subjects with persistently positive ANCA during remission are more likely to have relapse of disease compared with those that become ANCA negative after remission is achieved.

Patients and methods

Literature search

We searched MEDLINE and EMBASE without language restrictions from inception through the first week of August 2009 for articles focusing on ANCA measurements for prediction of relapse AAV. Our search was based on various combinations of the following indexed medical subject heading (MeSH) terms: (i) Antibodies, Antineutrophil Cytoplasmic; (ii) Sensitivity and Specificity; (iii) Recurrence; (iv) ROC curves; (v) Vasculitis; and (vi) Longitudinal studies and related non-indexed text words (full search strategy available upon request). In addition, reference lists of retrieved studies and review articles were reviewed, as were abstracts from the recent (2007–09) annual meetings of the American College of Rheumatology, the European League Against Rheumatism and the American Society of Nephrology.

Study selection

One investigator (G.T.) reviewed the study titles and/or abstracts and selected reports for full-text review. Two investigators (G.T. and P.C.G.) reviewed the studies for final determination of inclusion or exclusion, except for two studies in French, which were reviewed by one investigator (A.D.M.), and their content discussed. In the case of a disagreement, a consensus was reached through discussion and any remaining disagreement was adjudicated by a third investigator (P.A.M.). Authors of the primary studies were contacted if clarification or only minimal data elements were needed for a study to meet the criteria for inclusion.

Data from articles were included in the meta-analysis if they met the following criteria: serial ANCA measurements were performed during remission of vasculitis on at least 10 patients and data could be extracted to calculate both sensitivity and specificity for a rise in or persistence of ANCA for future relapse. Articles were excluded from the analysis if the ANCA rise was only concurrent with relapse of disease, if only the number of relapses but not the number of patients with and without relapse during follow-up could be extracted or if ANCA levels were used to define remission or relapse. After a final set of included studies was identified, the papers were reviewed with respect to the possibility of double-counting subjects who might be included in more than one paper.

Data extraction

Data were extracted by two investigators (G.T. and P.C.G.) from the selected studies using a predefined extraction form that included information on type of vasculitis, duration of follow-up, definitions of remission and relapse, frequency of ANCA measurements, laboratory method of ANCA measurements (IF or ELISA), total number of patients who had serial ANCA testing performed during remission, total number of patients who experienced relapse of disease, number of patients who had a rise in or persistence of ANCA before relapse and number of patients who had a rise in or persistence of ANCA not followed by a relapse of disease. Patients described as having renal-limited vasculitis and/or an ANCA-positive necrotizing vasculitis other than GPA or CSS were considered as having MPA.

Statistical analysis

Positive likelihood ratio (LR+) and negative likelihood ratio (LR) were calculated for each study and pooled separately using random-effects models. The standard errors for LRs were calculated as previously described [12] and 0.5 added to all counts for those studies that contained a zero count for true positives, false positives, true negatives or false negatives. Summary estimates for sensitivities and specificities were calculated using a bivariate model accounting for the correlation between sensitivity and specificity [13, 14]. To check for consistency, LRs were also back-calculated from the summary estimates of sensitivity and specificity obtained from the bivariate model [14]. Hierarchical summary receiver operator curves (HSROCs) were generated as previously described [15] to acount for the possible use of different thresholds of rise in and/or persistence of ANCA used by individual studies. All summary estimates are expressed with 95% CIs.

To evaluate for heterogeneity and publication bias, the arcsine transformation [16] of the data was used. This effect size is calculated as the difference in arcsine of the proportion of subjects with a rise in ANCA among those who had relapse and those without relapse. The I2-value was calculated and expressed with 95% CI [17]. To identify sources of heterogeneity, meta-regression was performed with the following independent variables: (i) method of ANCA measurement (IF vs ELISA); (ii) type of antibody (cANCA/anti-PR3 vs pANCA/anti-MPO); a variable was created for each study for the proportion of patients positive for cANCA/anti-PR3; (iii) whether or not ANCA measurements were conducted according to a predefined protocol; (iv) frequency of ANCA measurements; (v) duration of follow-up; and (vi) year of publication. To quantify how individual independent variables in meta-regression affect between-study heterogeneity, we calculated τ2 values from the intercept-only models and the models containing the independent variable of interest [18]. A funnel plot for publication bias was constructed and an Egger test for bias was performed [19]. All statistical analyses were done using SAS version 9.1 (SAS Inc., Cary NC, USA). To generate forest plots, the rmeta package for the R-project statistical software (www.R-project.org) was used.

Results

Literature search and included studies

Our search strategy identified 1429 titles/abstracts and 41 articles were selected for full-text review (Fig. 1; [7–11, 20–55]). Fifteen primary studies on the predictability of ANCA on relapse of disease were included, nine with a total of 503 patients for a rise in ANCA [8, 10, 11, 50–55] and nine with a total of 430 patients on the predictability of persistently positive ANCA [30–33, 36, 39, 50, 51, 55] (Table 1). We found no evidence of overlapping information reported between the included studies.

Fig. 1
Study flow diagram.
Table 1
Characteristics of included studies

Predictability of a rise in ANCA titre on future relapse of disease

The summary LR+ and LR for future relapse were modest, but statistically significant (Fig. 2). A rise in ANCA level was associated with an LR+ of 2.84 (95% CI 1.65, 4.90) of a future relapse and absence of a rise in ANCA was associated with an LR of 0.49 (95% CI 0.27, 0.87). HSROCs were consistent with individual studies using different diagnostic thresholds for defining a rise in ANCA on the underlying receiver operator characteristic (ROC) curve (Fig. 3). Estimated sensitivity and specificity of a rise in ANCA as a predictor of relapse were 0.56 (95% CI 0.33, 0.79) and 0.82 (95% CI 0.75, 0.90), respectively. Back-calculated LR+ and LR from the summary estimates for sensitivity and specificity, were similar to those obtained from the main analysis, with values of 3.16 (95% CI 0.99, 5.33) and 0.53 (95% CI 0.24, 0.83), respectively.

Fig. 2
Forest plots. Forest plots of the LR+ and LR of the nine included studies for the predictability of a rise (A) and of persistence (B) in ANCA on future relapse of disease along with summary estimate (♦) from a random-effects analysis. ...
Fig. 3
Summary receiver operator curves. HSROC for a rise in ANCA (A) and for persistent ANCA (B) as predictor of relapse. Open circles represent individual studies and the size of the circles represents the inverse variance (precision). Closed circles represent ...

The predictability of persistently positive ANCA titres for relapse of disease

The summary LR+ and LR for future relapse were small and of borderline statistical significance (Fig. 2). Persistent ANCA during follow-up was associated with an LR+ of 1.93 (95% CI 1.41, 2.66) of a future relapse and absence of persistently positive ANCA was associated with an LR of 0.74 (95% CI 0.51, 1.08). Estimated sensitivity and specificity of persistent ANCA as a predictor of relapse were 0.38 (95% CI 0.23, 0.52) and 0.78 (95% CI 0.71, 0.85), respectively (Fig. 3). The back-calculated LRs from the summary estimates for sensitivity and specificity were 1.73 (95% CI 0.81, 2.65) and 0.80 (95% CI 0.59, 1.00) for LR+ and LR, respectively.

Subgroup analysis, heterogeneity and publication bias

Among the studies on a rise in ANCA there was high level of heterogeneity, which was statistically significant with an I2-value of 0.90 (95% CI 0.83, 0.94). Heterogeneity among the studies on persistence of ANCA was moderate and statistically significant with an I2-value of 0.68 (95% CI 0.35, 0.84). For a rise in ANCA, frequency of serial ANCA measurements during remission explained a moderate proportion of the between-study heterogeneity and is consistent with more frequent measurements during remission, resulting in better predictability for future relapse, with LR+ of 4.34 for measurements every month and 1.44 for measurements every 3 months (P = 0.12) and LR of 0.19 and 1.11 for measurements every 1 and 3 months, respectively (P = 0.03) (Table 2, supplementary figure 1, available as supplementary data at Rheumatology Online). With respect to the type of ANCA, a rise in pANCA/MPO was estimated to predict the future relapse of disease better with LR+ of 10.0 vs 1.4 for cANCA/PR3 (P = 0.01) and LR of 0.42 vs 0.52 (P = 0.81) for pANCA/MPO and cANCA/PR3, respectively. This finding was driven mainly by one study and did not explain between-study heterogeneity. Similar findings were not observed for studies on persistent ANCA and other study-level variables neither identified other potential subgroups where ANCA measurements might be of more value, nor explained the between-study heterogeneity.

Table 2
Subgroups and heterogeneity

For studies on a rise in ANCA, asymmetry in the funnel plot was present by visual inspection (supplementary figure 2, available as supplementary data at Rheumatology Online), consistent with the presence of publication bias; however, the Egger test did not reject the null hypothesis of no publication bias (P = 0.36). For studies on persistently positive ANCA, the funnel plot was symmetric by visual inspection, with no suggestion of publication bias, and the Egger test results were null (P = 0.96).

Discussion

The utility of serial ANCA measurements among patients with an established diagnosis of AAV to assess disease activity or predict disease relapse has received considerable attention, but remains highly controversial. The published data on serial ANCA testing is heterogeneous with multiple study-level variables possibly affecting the interpretation of results, including types of ANCA testing assays used, time intervals between measurements, definitions of rises in ANCA titres and inclusion of subgroups of patients with different disease manifestations.

In this analysis, we chose to address two specific aspects of serial ANCA testing on future disease relapse: (i) the predictability of a rise in ANCA titres, and (ii) the persistence of ANCA. We have carefully accounted for as many confounding variables as possible given the available data. We found that both a rise in and persistence of ANCA during remission of vasculitis only modestly predict subsequent relapse of disease and that routine ANCA testing does not alter clinical risk estimates enough to substantially affect clinical practice. For example, given that a rise in ANCA has a summary LR+ of 2.84 and a summary LR of 0.46, if the pre-test risk of relapse is estimated at 40%, then the post-test risk for subsequent relapse is 69% if there is a rise in ANCA, and 23% if there is no rise in ANCA (additional examples shown in supplementary Table 1, available as supplementary data at Rheumatology Online). Furthermore, the summary risk estimates for a rise in ANCA should not be interpreted as being associated with immediate relapse since studies were included where a rise in ANCA sometimes preceded relapse by more than 1 year.

There are several strengths to our approach to this meta-analysis. Multiple studies have reported on the association between ANCA values and disease activity in AAV, including elevation in ANCA at the time of relapse [7, 20, 24, 26, 54]. The present analysis focused on serial ANCA measurements to predict future relapse of disease and thus has direct implications to current clinical practice. We also provide data on a pattern in serial ANCA testing that has not been a primary focus of many previous publications, i.e. persistently positive ANCA. Most original studies included for this latter analysis had another primary aim. In this situation, when the meta-analysis outcome is tangential to the main finding of the included studies, it is less likely that summary estimates are affected by biases in primary studies rising from low methodological quality. Our approach thus provides insight into the controversial topic of the value of ANCA to guide therapy in AAV, with results from meta-regression offering some explanation of why individual studies might differ. The identification of subtypes and frequency of ANCA measurements where testing might be of more value provides guidance for future research on the value of serial ANCA testing.

Our approach has some limitations to consider. With only a few studies in each meta-analysis, we had limited opportunity to explore heterogeneity. Additionally, it is possible that in the original studies the ANCA values were spuriously associated with future relapse due to closer surveillance of patients with ANCA rises or persistently positive ANCA, or led to decreased risk of relapse if any treatment was given based on the ANCA results. Approximately half of the included studies measured ANCA at fixed intervals during follow-up in a protocolized fashion; those studies are likely less susceptible to bias, but we did not find that their results differed compared with the studies in which measurement of ANCA during follow-up was not protocolized. Furthermore, we did not formally address the quality of individual studies. Although methods for quality assessment of studies on diagnostic tests have been proposed [56], we felt these criteria would not have allowed us to rank the included studies. We pooled LR+ and LR in our main analyses, a common practice in diagnostic test meta-analysis [57], which has been recently warned against, as values within the CIs for LRs can correspond to impossible values of sensitivity and specificity (e.g. below 0 or above 1) [58]. This is why we also back-calculated LRs from the pooled sensitivity and specificity and found that the two methods gave consistent results.

The between-study heterogeneity merits further consideration. For both study questions, most of the overall variability rose from between-study heterogeneity with I2-values close to 1. However, the random-effects analysis incorporated the heterogeneity by making wider CIs; therefore, pooling of results to arrive at summary estimates is justifiable. We had low power to detect the effects of subgroups of patients and assays or to explore this heterogeneity; nonetheless, we did find that frequent ANCA measurements better predicted disease relapse than less frequent ANCA measurements. However, even the LRs estimated for monthly measurements of ANCA were not so different from 1.0 to provide strong evidence for or against future disease relapse. The frequency of ANCA measurements during remission was the only study-level factor that explained a moderately large proportion of the between-study heterogeneity. Our findings that pANCA/MPO might predict the future relapse of disease better than a rise in cANCA/PR3 should be interpreted with caution. Although this difference was statistically significant and of potential clinical importance for the LR+, this finding was largely determined by one study on MPO antibody levels as a predictor of future flares of vasculitis [55] and did not explain between-study heterogeneity. Current ELISA tests rely on distinct sources of antigens, coating materials and conjugates, and substantial variability exists among different ELISA assays [59, 60]. The between-study heterogeneity limits the generalizability of the studies and underscores the need for adopting international standards for ANCA testing. Other study-level factors tested (assay type, duration of follow-up, protocolized vs non-protocolized ANCA measurements and publication year) did not explain the observed heterogeneity or suggest that predictability of ANCA varied across subgroups. In addition, the effect of several other study-level factors, such as severity of flare and organs involved (renal vs non-renal), could not be tested, as this information was lacking from the primary reports. Different definitions for remission and relapse by the individual studies are likely to contribute to the between-study heterogeneity. We could not identify subgroups among the included studies with similar definitions of these disease states or account for this heterogeneity in other ways. The contribution to heterogeneity of the use of different definitions of a rise in ANCA by the individual studies was not assessed since different thresholds for ANCA rise were accounted for by the methods used to calculate summary estimates.

In conclusion, although drawn from a heterogeneous literature, we believe the summary estimates presented here provide the best estimate for the true value of serial ANCA testing for prediction of relapses in AAV. We found that both a rise in ANCA and persistently positive ANCA are significantly associated with disease relapse—although the performance of serial ANCA testing does not appear to be sufficient to rely on isolation for management decisions. It is possible that serial ANCA testing could contribute to a prediction rule that takes into account clinical features and future biomarkers. Our analyses are informative in several additional areas, and the better performances for predicting relapses of ANCA testing among pANCA/MPO-positive patients or more frequent (monthly) ANCA titre measurements are promising and should be the focus of future studies. Conversely, newer methods of ANCA measurements do not appear to perform better with respect to prediction of future relapse compared with older methods relying on IF.

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Supplementary data

Supplementary data are available at Rheumatology Online.

Supplementary Data:

Acknowledgements

We are grateful to Jan Damoiseaux, Laboratory of Clinical Immunology, Maastricht University Medical Center, for providing explanations and additional data elements regarding one of the included primary studies in this meta-analysis.

Funding: Supported in part by The National Institute of Arthritis and Musculoskeletal and Skin Diseases Multidisciplinary Clinical Research Center grant P60 AR047785.

Disclosure statement: The authors have declared no conflicts of interest.

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