The outcome in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis has considerably improved with the use of potent immunosuppression. In the most severe cases, mortality remains an important risk despite aggressive intervention. However, for most patients who survive, quality of survival is affected by morbidity due to low-grade disease activity, episodes of relapse, damage from the effects of disease and its treatment, development of associated comorbidity, and the social and psychological problems of chronic disease. A rational approach to management of patients with ANCA-associated vasculitis requires careful measurement of these different facets of disease, so that treatment is appropriate. This article reviews the development of assessment tools used to quantify disease in vasculitis, which have been extensively used in clinical trials and are also appropriate for use in individual patient care.
The antineutrophil cytoplasm antibody (ANCA)–associated group of vasculitides encompass Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) but also includes some patients with syndromes that do not neatly fit into these disease categories. The ANCA-associated vasculitides are multisystem diseases that predominantly affect small vessels (including the renal glomeruli and lung capillaries) and, if left untreated, have a uniformly high mortality. Modern therapy has improved outcome, but early death and chronic morbidity (eg, dialysis dependence) remains a feature of these diseases.
With advances in acute therapy for vasculitis, other long-term consequences such as cardiovascular events, thromboembolic events, and malignancy become increasingly important. End-stage organ failure such as kidney failure or respiratory failure can make life difficult for survivors. This morbidity coupled with the effects of drug toxicity can significantly reduce quality of life, which is a crucial end point for patients. In addition, relapse, and low-grade persistent disease manifestations are common and require ongoing immunosuppression that may result in poor long-term outcomes. Clinical trials in the past decade have attempted to determine the optimal therapeutic strategy for induction and maintenance therapy. Outcomes can be judged in terms of life, death, and defined organ failure, but for chronic low-grade morbidity, it is useful to quantify this in a systematic way for clinical trials and for practical use when evaluating the accrual of morbidity in daily practice. To accurately quantify disease morbidity, make appropriate treatment decisions (ie, only use immunosuppression for active disease rather than chronic scarring), and to serve as appropriate outcome measures in clinical trials, several clinical tools have been developed to specifically measure disease activity and disease damage. In addition to reporting the incidence of death and renal failure, these tools can be used to define the main outcome being measured in trials of ANCA-associated vasculitis.
This article provides an overview of the outcomes measured in clinical trials of ANCA-associated vasculitis and describes the main clinical tools that are used to quantify these concepts. Table 1 provides a summary of definitions and outcome measures, some of which are more comprehensively validated than others. The current focus is on disease activity and damage, but future attention will be on patient-reported outcome measures and functional status (eg, ability to work or participate in normal activities).
| Term or Outcome Measure | Definition | How is it Measured or Expressed? | Comment About Use as an Outcome Measure | Recognized Predictors of Outcome | References |
|---|---|---|---|---|---|
| Mortality | Death | Straightforward to measure. Patients who died or survived can be expressed as a proportion of the overall group for a specific timeframe | Mortality depends on the type and severity of ANCA vasculitis and can range from 0% to 27.4% in 1 y. It can be a useful end point for clinical studies of very severe vasculitis, but, in milder forms for which mortality is low, it is not a useful end point. It is an important outcome for long-term studies | Older age Dialysis dependence at baseline Renal involvement Five Factor Score (FFS): >0, increased risk; >1, highest risk Higher Birmingham Vasculitis Activity Score (BVAS) Vasculitis Damage Index (VDI) score ≥1 Albumin ≤30 g/L at baseline Lung involvement Upper respiratory tract involvement reduces risk of mortality | Koldingsnes and Nossent, 2002 Reinhold-Keller et al, 2002 Aasarod et al, 2000 Bligny et al, 2004 Guillevin et al, 1996 and 2008 |
| Remission | The complete absence of disease activity attributable to vasculitis, including other inflammatory features like granulomatous inflammation in WG or tissue eosinophilia in CSS The minimum duration of remission should be stated Proposed that remission should only be defined as occurring if patient is on prednisolone/prednisone ≤7.5 mg/d for a defined period | Usually measured by the BVAS (BVAS1 = 0 and BVAS2≤1) Remission should be qualified by type, duration, and maximum dosage of immunosuppressive therapy | The rates of remission achieved by modern therapy are typically ≥90%. Therefore remission is a realistic primary end point for studies of induction therapy | Type of induction therapy used will determine time to remission Maintenance therapy will determine whether a patient stays in remission Severe disease (defined as BVAS >23) was predictive of higher rate of remission A higher VDI at baseline predicts lower rate of remission | Aasarod et al, 2000 de Groot et al, 2005 and 2009 Koldingsnes and Nossent, 2003 Stegeman et al 1996 Jayne et al, 2003 and 2007 |
| Response | A quantifiable measure of improvement from baseline disease activity | A percentage improvement in a measurable disease activity score. A reduction in the BVAS of ≥50% is the recommended measure | In patients refractory to conventional induction therapy, remission is only achieved in 35%–83% of those given second-line treatment. In this difficult-to-treat group, detecting partial improvement may be clinically important | Each 1-point increase in the VDI increases treatment resistance (odds ratio [OR] 1.53) | Hellmich et al, 2007 Koldingsnes and Nossent, 2003 |
| Relapse | Recurrence or new onset of disease activity attributable to active inflammation | Major relapse is defined as the Recurrence or new onset of potentially organ- or life-threatening disease activity that cannot be treated with increased glucocorticoids alone (ie, requires cyclophosphamide) All other relapses are considered minor | Rate of relapse is used as an end point in studies comparing strategies for maintenance therapy | Predictors of higher rate of relapse include positive ANCA at baseline, fourfold increase in ANCA titer, chronic nasal carriage of Staphylococcus aureus , cardiac involvement at baseline, CrCl>60 mL/min, cumulative cyclophosphamide dose <10 g in 6 mo and prednisone dose ≥20 mg for <2.75 mo Adjunctive cotrimoxazole to normal maintenance therapy reduces rate of relapse | Boomsma et al, 2000 Stegman et al, 1994 and 1996 Koldingsnes and Nossent, 2003 |
| Refractory disease | Patients who fail to achieve remission following induction with standard therapy are termed refractory. (ie, do not achieve remission following cyclophosphamide and glucocorticoids for generalized/severe ANCA-associated vasculitis [AAV]) | Unchanged or increased disease activity in acute AAV after 4 wk of standard therapy or lack of response (≤50% reduction in BVAS) after 6 wk or 1 major or 3 minor items present on BVAS after 12 wk of treatment | Can be used as the entry criteria for studies evaluating new or second-line induction treatments | Each 1 point increase in the VDI increases treatment resistance (OR 1.53) | Hellmich et al, 2007 Koldingsnes and Nossent, 2003 |
| Grumbling (low-grade persistent) disease | Arthralgia, fatigue, or low-grade nasal crusting may continue in patients who are otherwise considered to be in remission | BVAS versions 2 or 3 can be used to score persistent disease This low-grade disease state does not usually require change in immunosuppressive treatment | Not currently used as an outcome measure in clinical trials but may become relevant in long-term follow-up studies | Hellmich et al, 2007 | |
| Damage or organ-specific damage | Irreversible end organ damage as a result of previously active vasculitis | Damage can be recorded globally using an instrument such as the VDI or Combined Damage Assessment (CDA) index or can be focused on a single organ system such as renal failure Reporting of proportion of patients who are dialysis independent is recommended | End-stage renal failure is clinically important for AAV and used as the primary end point in trials involving patients with severe renal presentations Global damage assessment is important in long-term follow-up studies but, to date, this has not been used as the primary end point in therapeutic trials | Higher baseline BVAS and Disease Extent Index (DEI) scores are predictive of higher a VDI score at 6 mo | Seo et al, 2007 Hellmich et al, 2007 Koldingsnes and Nossent, 2002 |
| Adverse events | Adverse change in health status or a side effect that occurs in a person during or after receiving specific therapy. This therapy can be a medication, or procedure (eg, plasma exchange in the context of ANCA vasculitis) | Usually reported as the cumulative frequency of each event. Normally grouped into serious (resulting in death, life-threatening adverse event, or requiring hospital admission) and mild/moderate severity In ANCA vasculitis the common serious adverse events are infection and malignancy | Potential end point for noninferiority studies. This is when a new therapy is assumed to be as effective as conventional therapy and the perceived benefit is a reduction in side effects | Type and intensity of immunosuppressive therapy | de Groot et al, 2005 and 2009 Jayne et al, 2003 and 2007 |
| Patient-reported outcomes | Outcomes that patients regard as important. These outcomes usually encompass the ability to function at home and work, and quality of life | There are currently no vasculitis-specific patient-reported outcome measures. Generic tools such as the Short Form 36 (SF-36) questionnaire, Health Assessment Questionnaire (HAQ), and the Hospital Anxiety and Depression Score (HADS) are currently used | Vasculitis-specific patient-reported outcome measures are needed | We are not sure what factors will ultimately predict patient-reported outcomes but we suspect that they will be different from physician-based assessments | McHorney et al, 1992 Fries et al, 1982 Zigmond and Snaith, 1983 |
Mortality
Death is an important and valid outcome measure when assessing the balance of efficacy and safety of treatment regimens. Most early deaths in ANCA vasculitis are attributable to infection or active vasculitis, whereas late deaths may relate to increased cardiovascular disease and malignancy. Severity and distribution of organ involvement are currently the best predictors of short- and medium-term survival. Predictors of mortality in ANCA-associated vasculitis are shown in Table 1 . As a result of routine treatment with immunosuppressive therapy, mortalities have fallen dramatically for patients with ANCA-associated vasculitis ( Table 2 ). Mortality is now too insensitive to use as a primary end point in clinical trials, which, as a consequence, has driven the development and adoption of clinical tools that can better differentiate between treatments in terms of disease activity and organ damage.
| Diagnosis | Five-Year Survival (%) |
|---|---|
| WG | 75 |
| MPA | 45–75 |
| CSS | 68–100 |
Disease activity
Disease activity is a well-recognized concept for most chronic inflammatory diseases, and there has been a move away from subjective physician assessments to objective measures of activity. In the context of vasculitis, determining disease activity is complex because of the heterogeneous and multisystem nature of disease. There is no single clinical, serologic, or radiological marker that informs us about disease activity. Inflammatory markers such as serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) provide some information about disease activity but are not specific because they can be high, due to infection or other disease processes, or low as a result of recent glucocorticoid therapy. In addition, CRP and ESR do not correlate well with our current best clinical measures of disease activity. An increase in ANCA titers using new capture and anchor enzyme-linked immunosorbent assay techniques has been proposed as a potential method of predicting an imminent relapse (ie, an increase in disease activity), but currently this assay is not able to adequately perform this role. Therefore, in the absence of any single measure, a comprehensive clinical tool that incorporates the multiorgan nature of vasculitis has been required to adequately measure disease activity.
ANCA Titers to Measure Disease Activity and Relapse
From the first descriptions of ANCA directed against proteinase-3 (PR3) and myeloperoxidase (MPO) in the small-vessel vasculitides, measurement of ANCA has been proposed as a tool to measure disease activity. The measurement of increasing MPO- and PR3-ANCA titers has been shown to predict clinical relapse in patients with WG, CSS, and MPA. A meta-analysis of 8 studies evaluating the increase of ANCA titers showed a positive likelihood ratio of 3.39 (95% confidence interval [CI]: 1.69–6.82) for a future flare with the absence of an increase in ANCA having a negative likelihood ratio of 0.45 (95% CI: 0.23–0.87). In addition, patients in clinical remission but with rising titers of ANCA who are then randomized to increased immunosuppression have a lower rate of clinical relapse than those with positive titers who are randomized to no increase in immunosuppression. However, there is controversy about the use of ANCA as a sole marker of disease activity because discordance between ANCA levels and relapse has also been shown. In clinical practice, rising ANCA titers must be used in conjunction with evidence of other clinical disease activity when determining the presence of relapse, especially before an increase in immunosuppression is considered!
Early Clinical Tools
Early measures of disease activity include the Groningen Index for WG. This tool used a combination of clinical features and laboratory results but required biopsy evidence of active vasculitis for each time disease activity was measured. Biopsy findings are appropriate at diagnosis, but are not practical for follow-up of patients. An alternative called the Vasculitis Activity Index (VAI) was developed by the Baltimore group. The VAI consists of 9 organ systems that are graded 0 to 4 depending on the impressions of the physician regarding overall activity in that organ system. The main problem with this scale is observer bias; hence, it is not widely used.
Birmingham Vasculitis Activity Score
The current standard, and the tool recommended by the European League Against Rheumatism (EULAR) for assessing disease activity in clinical trials is the Birmingham Vasculitis Activity Score (BVAS). The original version of the BVAS was developed and validated in 1994. It was constructed by a consensus group of physicians interested in vasculitis and comprised 59 individual items, organized into 9 organ systems (systemic; cutaneous; mucous membranes/eyes; ear, nose, and throat [ENT]; chest; cardiovascular; abdominal; renal; and neurologic). Most of the symptoms and signs were easily ascertainable by history and clinical examination but a few items, such as hematuria and serum creatinine, required additional investigations. Positive findings were only recorded if directly attributed to active vasculitis and other potential causes had been excluded; this distinction was made because several features in this tool, such as fever or hematuria, could easily relate to infection, malignancy, drug toxicity, or some other cause. The symptoms and signs were recorded if present at time of assessment or during the preceding 4 weeks. The individual items were given a weight (between 1 and 9) based on the relative importance placed on them by the consensus group (objective items, and items involving the renal, gastrointestinal (GI), and neurologic systems were rated the highest), with a maximum score applied to each organ system. The overall range of possible scores for the BVAS is 0 to 63, with the higher the score the more active the disease. The original BVAS was validated in a sample of 213 patients with mixed primary and secondary vasculitis, and evaluated against a physician global assessment, VAI, Groningen Index and assessed for feasibility, sensitivity to change, and inter observer reliability. In addition, the expert observers agreed that BVAS made biologic sense (construct validity).
The BVAS was adopted by the European Vasculitis Study Group (EUVAS) for its clinical trials in ANCA-associated vasculitis, and as a result underwent further refinement. Adjustments were made to the items, including the addition of smoldering disease; that is, not new or worse activity but grumbling (low-grade persistent disease) activity was recorded in a separate column that could have a maximum score of 36. Four of the original items that were believed to occur very rarely were removed and 7 new items, including features available after subspecialist opinion, were added (total of 64 items); however, the overall range of scores for the BVAS remained the same. This tool is now called BVAS version 2, but is scored as 2 separate components; BVAS1 (new/worse disease) and BVAS2 (persistent disease). For the EUVAS trials, the BVAS scores were used to determine remission when assessing induction therapy, and to define relapse when assessing maintenance therapy. Remission was defined as the absence of new or worse clinical disease activity (BVAS1 = 0), but allowed persistent activity (BVAS2) in 1 item scoring less than 2 points. Major relapse was defined by the recurrence or first appearance of at least 1 item on the BVAS1 involving a vital organ (kidney, lung, brain, eye, motor nerve, or gut), and minor relapse by the recurrence or first appearance of at least 3 other items on the BVAS1. In the last decade, the BVAS has been used in numerous clinical trials in ANCA-associated vasculitis, with some trials incorporating the BVAS score as part of the primary end point (see Table 1 ).
The latest iteration of the BVAS is version 3, which was published and validated in 2009 ( Table 3 ). The changes were made by consensus expert opinion and include reduction in the total number of items to 56 by omission or merging, and the persistent boxes for each variable were replaced by a single persistent box for the whole form that is only checked if all the items are considered persistent disease. The weighting of items was unchanged. The new version was validated in 313 patients with primary and secondary vasculitis (although most had ANCA-associated vasculitis) for convergent validity against the previous BVAS versions, treatment decisions, physician global assessment, CRP, and VAI, and was shown to be reliable, reproducible, and sensitive to change.
| Original BVAS (Luqmani et al, 1994 ) N = 213 | BVAS v3 (Suppiah et al, 2010) N = 285 | |
|---|---|---|
| CSS | Not available | 0–24 |
| MPA | Not available | 0–25 |
| Wegener’s granulomatosis | 11–25 | 0–37 |
| Nonrenal Wegener’s | 1–19 | 0–25 |
| Behcet disease | 4–19 | 0–19 |
| Giant cell arteritis | 1–9 | Not available |
| Polyarteritis nodosa | 10–29 | 0–6 |
| Rheumatoid vasculitis | 1–16 | 0–12 |
| Takayasu arteritis | 7–14 | 0–5 |
A modified version of the BVAS called the BVAS/WG has been adapted by North American investigators for trials involving patients with WG. Features unlikely to occur in WG (such as loss of pulses) were omitted and new items specific for WG, such as endobronchial lesions, were introduced. The weighting of the BVAS was changed, assigning 1 point to any item judged to be of minor importance, and 3 points to major items (which typically require aggressive therapy with cyclophosphamide). A physician global assessment (as a 10-cm visual analog scale) is incorporated into the BVAS/WG and allows for the assignment of remission, minor flare, or major flare. The BVAS/WG has only been validated in patients with WG, but has been shown to correlate with the BVAS (old and new) in cases of WG and MPA in the literature. However, it has not been validated in current patients with MPA, other ANCA vasculitis, or any other types of vasculitis; caution is therefore advised if considering the use of BVAS/WG for assessment in diseases other than WG.
As with any biologic tool, the BVAS will benefit from continual review and improvement, ideally through a data-driven process. We anticipate that this process will be facilitated in the future through the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) initiative. The main target for future improvements should be to rationalize the weighting system (which is currently based on expert opinion) to one that is based on hard outcomes from prospective studies.
Other Disease Assessment Tools
The Disease Extent Index (DEI) measures the number of organ systems (out of a possible 10) involved, each given a score of 2, and the presence of constitutional symptoms are given a score of 1 (maximum score = 21). The DEI can be calculated from the individual components of the BVAS, and therefore also correlates with the BVAS score. The DEI can complement the BVAS by showing whether a high BVAS score is due to multiorgan involvement or severe involvement of 1 organ.
The French Vasculitis Study Group (FVSG) developed a prognostic tool called the Five Factor Score (FFS). The original version was created from a cohort of patients with polyarteritis nodosa (PAN) and CSS. Renal failure, proteinuria, cardiomyopathy, GI tract involvement, and central nervous system (CNS) signs are scored as being present or absent, with a higher total score being predictive of higher 5-year mortality ( Table 4 ). This score has been revised to include patients with WG and MPA, and incorporates ENT involvement, which is associated with a reduced risk of death (see Table 4 ).
| Original FFS (Guillevin et al, 1996 ) Includes PAN, MPA, CSS | Revised FFS (Guillevin et al, 2008 ) Includes PAN, MPA, CSS, WG | |
|---|---|---|
| Criteria and how to score |
|
|
| 5-y mortality risk (%) | FFS of 0 = 11.9 FFS of 1 = 26 FFS of ≥2 = 46 | FFS of 0 = 7.5 FFS of 1 = 20 FFS of ≥2 = 47 |
Disease activity
Disease activity is a well-recognized concept for most chronic inflammatory diseases, and there has been a move away from subjective physician assessments to objective measures of activity. In the context of vasculitis, determining disease activity is complex because of the heterogeneous and multisystem nature of disease. There is no single clinical, serologic, or radiological marker that informs us about disease activity. Inflammatory markers such as serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) provide some information about disease activity but are not specific because they can be high, due to infection or other disease processes, or low as a result of recent glucocorticoid therapy. In addition, CRP and ESR do not correlate well with our current best clinical measures of disease activity. An increase in ANCA titers using new capture and anchor enzyme-linked immunosorbent assay techniques has been proposed as a potential method of predicting an imminent relapse (ie, an increase in disease activity), but currently this assay is not able to adequately perform this role. Therefore, in the absence of any single measure, a comprehensive clinical tool that incorporates the multiorgan nature of vasculitis has been required to adequately measure disease activity.
ANCA Titers to Measure Disease Activity and Relapse
From the first descriptions of ANCA directed against proteinase-3 (PR3) and myeloperoxidase (MPO) in the small-vessel vasculitides, measurement of ANCA has been proposed as a tool to measure disease activity. The measurement of increasing MPO- and PR3-ANCA titers has been shown to predict clinical relapse in patients with WG, CSS, and MPA. A meta-analysis of 8 studies evaluating the increase of ANCA titers showed a positive likelihood ratio of 3.39 (95% confidence interval [CI]: 1.69–6.82) for a future flare with the absence of an increase in ANCA having a negative likelihood ratio of 0.45 (95% CI: 0.23–0.87). In addition, patients in clinical remission but with rising titers of ANCA who are then randomized to increased immunosuppression have a lower rate of clinical relapse than those with positive titers who are randomized to no increase in immunosuppression. However, there is controversy about the use of ANCA as a sole marker of disease activity because discordance between ANCA levels and relapse has also been shown. In clinical practice, rising ANCA titers must be used in conjunction with evidence of other clinical disease activity when determining the presence of relapse, especially before an increase in immunosuppression is considered!
Early Clinical Tools
Early measures of disease activity include the Groningen Index for WG. This tool used a combination of clinical features and laboratory results but required biopsy evidence of active vasculitis for each time disease activity was measured. Biopsy findings are appropriate at diagnosis, but are not practical for follow-up of patients. An alternative called the Vasculitis Activity Index (VAI) was developed by the Baltimore group. The VAI consists of 9 organ systems that are graded 0 to 4 depending on the impressions of the physician regarding overall activity in that organ system. The main problem with this scale is observer bias; hence, it is not widely used.
Birmingham Vasculitis Activity Score
The current standard, and the tool recommended by the European League Against Rheumatism (EULAR) for assessing disease activity in clinical trials is the Birmingham Vasculitis Activity Score (BVAS). The original version of the BVAS was developed and validated in 1994. It was constructed by a consensus group of physicians interested in vasculitis and comprised 59 individual items, organized into 9 organ systems (systemic; cutaneous; mucous membranes/eyes; ear, nose, and throat [ENT]; chest; cardiovascular; abdominal; renal; and neurologic). Most of the symptoms and signs were easily ascertainable by history and clinical examination but a few items, such as hematuria and serum creatinine, required additional investigations. Positive findings were only recorded if directly attributed to active vasculitis and other potential causes had been excluded; this distinction was made because several features in this tool, such as fever or hematuria, could easily relate to infection, malignancy, drug toxicity, or some other cause. The symptoms and signs were recorded if present at time of assessment or during the preceding 4 weeks. The individual items were given a weight (between 1 and 9) based on the relative importance placed on them by the consensus group (objective items, and items involving the renal, gastrointestinal (GI), and neurologic systems were rated the highest), with a maximum score applied to each organ system. The overall range of possible scores for the BVAS is 0 to 63, with the higher the score the more active the disease. The original BVAS was validated in a sample of 213 patients with mixed primary and secondary vasculitis, and evaluated against a physician global assessment, VAI, Groningen Index and assessed for feasibility, sensitivity to change, and inter observer reliability. In addition, the expert observers agreed that BVAS made biologic sense (construct validity).
The BVAS was adopted by the European Vasculitis Study Group (EUVAS) for its clinical trials in ANCA-associated vasculitis, and as a result underwent further refinement. Adjustments were made to the items, including the addition of smoldering disease; that is, not new or worse activity but grumbling (low-grade persistent disease) activity was recorded in a separate column that could have a maximum score of 36. Four of the original items that were believed to occur very rarely were removed and 7 new items, including features available after subspecialist opinion, were added (total of 64 items); however, the overall range of scores for the BVAS remained the same. This tool is now called BVAS version 2, but is scored as 2 separate components; BVAS1 (new/worse disease) and BVAS2 (persistent disease). For the EUVAS trials, the BVAS scores were used to determine remission when assessing induction therapy, and to define relapse when assessing maintenance therapy. Remission was defined as the absence of new or worse clinical disease activity (BVAS1 = 0), but allowed persistent activity (BVAS2) in 1 item scoring less than 2 points. Major relapse was defined by the recurrence or first appearance of at least 1 item on the BVAS1 involving a vital organ (kidney, lung, brain, eye, motor nerve, or gut), and minor relapse by the recurrence or first appearance of at least 3 other items on the BVAS1. In the last decade, the BVAS has been used in numerous clinical trials in ANCA-associated vasculitis, with some trials incorporating the BVAS score as part of the primary end point (see Table 1 ).
The latest iteration of the BVAS is version 3, which was published and validated in 2009 ( Table 3 ). The changes were made by consensus expert opinion and include reduction in the total number of items to 56 by omission or merging, and the persistent boxes for each variable were replaced by a single persistent box for the whole form that is only checked if all the items are considered persistent disease. The weighting of items was unchanged. The new version was validated in 313 patients with primary and secondary vasculitis (although most had ANCA-associated vasculitis) for convergent validity against the previous BVAS versions, treatment decisions, physician global assessment, CRP, and VAI, and was shown to be reliable, reproducible, and sensitive to change.
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