Defining disease activity and damage in patients with small-vessel vasculitis

ASSESSING DISEASE ACTIVITY AND DAMAGE

In the clinical trial setting, GPA and MPA are assessed using the outcomes measures listed in the Table.^2–10

Birmingham Vasculitis Activity Score

Introduced in 1994, the Birmingham Vasculitis Activity Score (BVAS) is a single-page checklist that records weighted data on more than 50 items and nine organ systems; the sum of the individual items provides the final score.² There have been two revisions of the BVAS; one focuses on GPA (BVAS/WG)³ and the other, BVAS version 3 (v.3) is more simplified.⁴ For all of the BVAS tools, remission is defined as a score of 0. Any score greater than 0 defines active disease. Each system is evaluated as being active or not, with items characterized as more severe being weighted more heavily. The use of the BVAS/WG is illustrated in two patients (see “Assessment with the BVAS/WG,” below).

Each of the three BVAS tools has advantages and disadvantages. All of the tools are validated and fairly easy to use; they are inexpensive; they have been employed successfully in clinical trials; and the results are widely accepted by investigators, industry, and both the US Food and Drug Administration (FDA) and the European Medicines Agency. The tools miss some variables, however, including biomarkers and the patient’s own input; it takes training to learn how to use the tools; decisions are subjective, because the investigator must decide whether the disease is active; because the tools lack gradation, a listing of hemorrhage, for example, does not consider the degree of severity of the hemorrhage; weighting is potentially inaccurate and open to interpretation; precision and sensitivity are inadequate; and there are multiple versions, although they have been shown to be well correlated.¹⁰

Every major randomized controlled trial in the past 15 years has used the BVAS or one of its derivatives to define outcomes, but primary outcomes were not defined strictly from the BVAS itself. There were important differences in the trials’ definitions of remission, which is the outcome of interest. For example, some trials allow for minor disease activity concurrent with partial remission, while others require full absence of disease activity to achieve “remission.”

Vasculitis Damage Index

The Vasculitis Damage Index (VDI) is a single-page catalog of damage items separated into 11 groupings. Limitations of the index include lack of attribution (to vasculitis, treatment, or comorbidities), gradation, weighting, and patient input (patient-reported outcomes).⁵ Revisions to the VDI have been made in the ANCA Vasculitis Index of Damage (AVID),⁶ which incorporates an expanded list of damage items, as well as an even more expanded version called the Combined Damage Assessment Index that combines the items from the VDI and AVID.⁷ While these tools provide a means to catalog damage by choosing whether an item is present or not, a more data-driven approach to damage assessment is needed that incorporates weighting into the tool.

Damage assessment may be the most important measure in evaluating the patient with vasculitis. In addition to keeping patients alive, one of the main purposes in treating active disease is to prevent damage, maintaining quality of life for the patient for the long term and improving outcomes.

PATIENT-REPORTED OUTCOMES

Patients have a different perspective on their disease than that provided by assessment tools or physicians. Because physician and patient ratings are often disparate, health-related quality of life (HRQOL) is an increasingly important outcome measure for patients as well as regulatory agencies. In a 2010 study, structured patient-reported assessments of burden of disease were obtained from 264 patients with vasculitis in the United States, Germany, and the United Kingdom. Patients ranked items in terms of most frequent burdens of disease. Across ages and countries, patients most commonly rated fatigue/energy loss, pain, musculoskeletal symptoms, and social manifestations as the most severe ramifications of their disease.¹¹ None of the burdens of disease identified in this study are universally measured in the current assessment tools. Patients with active disease had more of the most commonly listed burden-of-disease items; however, patients still suffered from these burdens when the disease was inactive. These disease burden items are therefore mostly dynamic problems and not simply chronic issues.

Patient ratings differ considerably from physician ratings in terms of importance. For example, patients rate nasal manifestations, weight gain, and some chronic pain and fatigue items higher than renal insufficiency and stroke. There is a clear need to address not only physician-ranked issues, but also patient-ranked issues in assessing and treating vasculitis.¹¹

When measuring HRQOL via the Medical Outcomes Study 36-item short-form health survey (SF-36) in patients with vasculitis, a correlation is noted between QOL and sustained remission. In a study by Tomasson et al, QOL was measured using the SF-36 upon treatment following a flare.¹² In all patients, SF-36 increased dramatically immediately following treatment but then leveled off over time. In patients who achieved sustained remission, SF-36 scores continued to rise from baseline. In patients who did not achieve a sustained remission, the SF-36 scores did not improve. This QOL measure, therefore, captures a value that other assessments do not, further demonstrating its utility as part of the assessment process.

VALIDATED OUTCOME MEASURES

Outcome Measures in Rheumatology (OMERACT) is an international group of clinicians, trialists, epidemiologists, biostatisticians, health economists, industry executives, and FDA and European Medicines Agency officials who meet every 2 years to promote data-based validation of outcome measures for a variety of diseases. OMERACT endorses core sets of validated outcomes when data demonstrate veracity, discrimination, and feasibility.¹³ For each domain in the vasculitis arena, there is an associated validated instrument: for disease activity, the validated instruments are the BVAS, BVAS/WG, and BVAS v.3; for damage assessment, the instrument is the VDI; for patient-reported outcomes, the instrument is the SF-36; and finally, for mortality, the instrument is death.¹³ This core set of measures helps frame how future trials in vasculitis will be standardized and assists in comparing trials, which is particularly important to regulatory agencies.

The tools for disease assessment in vasculitis still need to be refined for activity and damage assessment in order to be more scalable and precise, thereby measuring smaller effects. Patient-reported outcomes and patient perspectives on disease need to be better captured, and reliable biomarkers need to be discovered or further developed. Improved outcome measures must be developed for other types of vasculitis, such as eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), giant cell (temporal) arteritis, and Takayasu arteritis,¹⁴ in order to conduct and report trial results. These outcome measures could also translate into tools that can be used to assess patients and make treatment decisions, thereby helping the clinician at the bedside.