The OMERACT Core Set of Outcome Measures for Use in Clinical Trials of ANCA-associated Vasculitis

Currently Used Instruments to Evaluate Disease Activity in Vasculitis

Quantifying disease activity, measuring extent of involvement, and providing prognosis are all features of disease activity assessments. The Birmingham Vasculitis Activity Score (BVAS) and its revisions are by far the most widely accepted measures of disease activity and are able to fulfill all these functions. Alternative options for disease assessment exist but are not used for major clinical trials in vasculitis^13,14,15. BVAS was developed by consensus expert opinion and clinical practice and comprises 59 individual items, in 9 organ systems¹⁶. Most items are based on history and clinical examination, but some require additional investigations. Positive findings are recorded only if attributed to active vasculitis.

The BVAS for Wegener’s granulomatosis (BVAS/WG) is a modification of BVAS specifically designed for use in studies of granulomatosis with polyangiitis (Wegener’s). BVAS/WG was been validated for use and was the primary outcome measurement tool in 2 major multicenter trials of AAV^4,7,17.

The most recent revision of BVAS is BVASv.3; changes were made by consensus expert opinion and included item reduction and simplification of the form. The weighting of items was unchanged. BVASv.3 was initially validated in 313 patients with either primary or secondary forms of vasculitis (excluding giant cell arteritis)¹⁸.

Summary of Validation of Instrument(s) for Domain as per Omeract Filter

Current Status of Instruments in This Domain (Disease Activity)

Both BVAS/WG and BVASv.3 are validated measures recommended for use in clinical trials of AAV. Both tools have been incorporated into large, international multicenter trials. The correlation between the 2 instruments is quite high¹⁴.

Introduction to Domain

Chronic diseases can be described in terms of 2 separate components: disease activity and disease damage. Disease activity represents the reversible aspects of disease while disease damage denotes irreversible aspects of disease. The concept of damage is important to the clinical care of patients with vasculitis because it encourages the clinician to identify which disease manifestations do not merit immunosuppression, thereby helping avoid overtreatment, an important cause of both morbidity (including damage) and mortality. The concept of damage is also important to clinical trials, because it represents the overall, longterm burden of disease borne by the patient as the result of vasculitis. Damage is expected to correlate with other outcomes of interest, such as cumulative disease activity, mortality, and quality of life.

Currently Used Instruments to Evaluate Disease Damage in Vasculitis

The Vasculitis Damage Index (VDI) was developed to standardize the assessment of damage in patients with systemic vasculitis²⁰. The VDI consists of 64 items of damage selected by expert consensus as representative of the forms of damage developed by subjects with systemic vasculitis. Given the diverse expression of damage that can affect patients with systemic vasculitis, perhaps the most valuable contribution of the VDI is that it has provided investigators with a method to ensure that items of damage are uniformly collected across centers.

Endstage renal disease is a particularly notable subset of the domain of disease damage. Renal disease is one of the most common and most serious manifestations of AAV. Among patients with primary systemic vasculitis, renal function is a strong predictor of mortality. Therefore, endstage renal disease (or stage 5 chronic kidney disease, defined by the US National Kidney Foundation as a glomerular filtration rate < 15) or dialysis is another important “hard” endpoint for clinical trials.

Summary of Validation of Instrument(s) for Domain as per OMERACT Filter

Current Status of Instruments in This Domain (Disease Damage)

Assessment of damage using the VDI has become standard in clinical trials of systemic vasculitis, and the VDI is validated for use in clinical trials.

Application of the VDI has raised the possibility that it may not be adequate to measure all forms of damage, particularly those specific to the AAV. Therefore, through consensus of investigators in the USA and EU, the AAV Index of Damage (AVID) was created as a first step towards a new damage-assessment instrument for these diseases. AVID comprises 12 organ-based categories of damage selected to reflect the types of damage incurred by patients with WG and microscopic polyangiitis; items were selected by expert opinion and supplemented by data from clinical trials. AVID was shown to detect more forms of damage among patients with AAV than the VDI²². However, because efforts to develop AVID overlapped with European-based efforts to revise the VDI, the OMERACT group resolved to unite efforts towards the development of a Combined Damage Assessment Index (CDA), which would be particularly suitable to AAV, but also potentially applicable to other small- and medium-vessel vasculitides. Under development, the CDA is not yet ready for routine use. The current draft version, when compared to the VDI in a cross-sectional study, was more sensitive at detecting damage but was more complex and time-consuming to complete²¹. The next-generation damage assessment tool needs to retain the simplicity of the VDI while expanding the scope and precision of damage assessment and aiming for a more scalable score.

Thus, while VDI remains the most validated and widely used damage assessment tool for vasculitis, efforts continue to develop the next-generation of damage assessment tools for vasculitis, with a focus on vasculitis disease-specific instruments.

Introduction to Domain

When first described, the systemic form of granulomatosis with polyangiitis (Wegener’s) was a uniformly fatal disease, with mortality approaching 90% in the first year after diagnosis. The advent of modern immunosuppressive regimens, including cytotoxic agents, has largely transformed AAV into chronic conditions, characterized by cycles of relapse and remission. Despite these advances, recent clinical trials of the primary systemic vasculitides continue to experience substantial mortality, ranging from 2% to 9%, depending on the patient population recruited. It is important to note that patients recruited to clinical trials continue to experience increased mortality that persists well beyond the end of the trial. For example, in a longterm followup study of participants in the Wegener’s Granulomatosis Etanercept Trial, the median age of death was 57.2 years, 19 years less than the average life expectancy in the US²³. A recent study using the UK General Practice Research Database showed that the risk of death was 9-fold higher in the first year after a diagnosis of granulomatosis with polyangiitis (Wegener’s) compared with an age, sex, and location-matched control group²⁴. Analysis of longterm followup of 4 European trials in AAV demonstrated a 2.6-times higher rate of death compared with a matched control population²⁵.

Current Status of Mortality as an Outcome Measure in Vasculitis

Introduction to Domain

Physician-reported disease-specific measures are the most widely used instruments for determining efficacy of treatment in AAV. However, physicians and patients rate differently the importance of individual disease manifestations of AAV^26,27. Currently used outcome measures in AAV that are based only on physician assessments might overlook potential benefits of a treatment that are important to patients. Incorporation of health-related quality of life (HRQOL) measured by a generic instrument such as the Medical Outcomes Study Short-Form 36 (SF-36) therefore will likely add to the content validity of the core set of outcome measures for AAV. This is also likely to improve the discriminatory power properties of the core set; a composite measure identifying different, but somewhat overlapping, domains of disease is likely to differentiate better between active treatment and placebo than its individual components²⁸. Incorporating patients’ concerns and values into trial outcomes is both appropriate and increasingly mandated by regulatory bodies. The OMERACT community encouraged the OMERACT Vasculitis Working Group to gather data on HRQOL assessment in vasculitis, and these new data have helped inform the process of approving the core set.

Currently Used Instruments to Evaluate Patient-Reported Outcomes—HRQOL in Vasculitis

The SF-36 is a widely used measure of HRQOL, one aspect of quality of life that is affected by health status^29,30. Inclusion of the SF-36 has become standard practice for almost all clinical trials and observational studies for most rheumatic diseases, including vasculitis^21,23. Until recently, the performance of the SF-36 had not been formally evaluated as an outcome measure in AAV. Both clinical practice and trial data consistently demonstrate that HRQOL is impaired among patients with AAV^{24,25,31,32,33,34}.

Summary of Validation of Instrument(s) for Domain as per OMERACT Filter

Current Status of Instruments in This Domain (HRQOL:PRO)

Inclusion of the SF-36 has become standard practice for all clinical trials in vasculitis and is validated for this use. Its addition to the disease-specific instruments in AAV could improve statistical properties of the core set measures and identify domains of disease important to patients. Future research includes (1) validation of its properties in other cohorts of patients with small-vessel vasculitis; (2) determination of its sensitivity to change in longitudinal studies; (3) determination of its additive contribution beyond other core set items; (4) its ability to differentiate between truly effective treatment and placebo; and (5) its predictability for hard outcomes in AAV such as disability and mortality.

Development of a Patient-reported, Disease-specific Assessment Tool

Beyond the data on “generic” HRQOL, little is known or published about patients’ perspectives of their burden of disease in systemic vasculitis. While the SF-36 is now included in nearly all clinical trials of vasculitis (see above), and is the main PRO instrument for use in vasculitis, no vasculitis-specific PRO tool has been validated. Because patients’ subjective experiences are important, particularly in making treatment decisions, such patient-reported burden of disease should be included in the outcome measurement process. The OMERACT Vasculitis Working Group has been advancing the development of a vasculitis-specific PRO tool. A draft of an instrument was developed for patients to identify and rank vasculitis-related burdens²⁶. Patients were asked to rank 40 vasculitis-related items and to list the 5 most important aspects of the disease in open-text spaces. Data were gathered from 265 patients at 3 meetings (one each in the USA, UK, and Germany). Among the many findings were that fatigue, reduced energy level, pain, and musculoskeletal symptoms were considered the most important disease burdens in vasculitis; manifestations associated with severe organ damage were rated lower. Patients’ perspectives of the effects of vasculitis differed substantially from previous physicians’ ratings.

The preliminary questionnaire captures face, content, and construct validity and therefore seems to measure what it intends to measure²⁶. Discrimination between patients in remission and those in active disease was also demonstrated²⁶. The first version of the instrument is easy to use, was accepted by the patients with almost no missing data, and appears feasible in terms of interpretability, completion time and cost²⁶.

The initial work on a vasculitis-specific PRO tool has been promising. However, much remains to be done to arrive at a final version of a vasculitis-specific PRO instrument and to validate the instrument per the OMERACT filter. Plans for this project include conducting focus groups with patients to help ensure more complete data elements and/or new subdomains are included, with subsequent form revision and validation.