Ravi Suppiah

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

To create a prognostic tool to quantify the 5‐year cardiovascular (CV) risk in patients with newly diagnosed Wegeners granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease.

Damage in the anca-associated vasculitides: long-term data from the European Vasculitis Study group (EUVAS) therapeutic trials

OBJECTIVES To describe short-term (up to 12 months) and long-term (up to 7 years) damage in patients with newly diagnosed antineutrophil-cytoplasm antibody-associated vasculitis (AAV). METHODS Data were combined from six European Vasculitis Study group trials (n=735). Long-term follow-up (LTFU) data available for patients from four trials (n=535). Damage accrued was quantified by the Vasculitis Damage Index (VDI). Sixteen damage items were defined a priori as being potentially treatment-related. RESULTS VDI data were available for 629 of 735 patients (85.6%) at baseline, at which time 217/629 (34.5%) had ≥1 item of damage and 32 (5.1%) ≥5 items, reflecting disease manifestations prior to diagnosis and trial enrolment. LTFU data were available for 467/535 (87.3%) at a mean of 7.3 years postdiagnosis. 302/535 patients (56.4%) had VDI data at LTFU, with 104/302 (34.4%) having ≥5 items and only 24 (7.9%) no items of damage. At 6 months and LTFU, the most frequent items were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss and peripheral neuropathy. The frequency of damage, including potentially treatment-related damage, rose over time (p<0.01). At LTFU, the most commonly reported items of treatment-related damage were hypertension (41.5%; 95% CI 35.6 to 47.4%), osteoporosis (14.1%; 9.9 to 18.2%), malignancy (12.6%; 8.6 to 16.6%), and diabetes (10.4%; 6.7 to 14.0%). CONCLUSIONS In AAV, renal, otolaryngological and treatment-related (cardiovascular, disease, diabetes, osteoporosis and malignancy) damage increases over time, with around one-third of patients having ≥5 items of damage at a mean of 7 years postdiagnosis.

ACR/EULAR-endorsed study to develop Diagnostic and Classification Criteria for Vasculitis (DCVAS).

The systemic vasculitides are a group of uncommon diseases characterized by blood vessel inflammation. There are currently no diagnostic criteria for the primary systemic vasculitides and physicians must rely on experience and disease definitions. The absence of validated criteria can result in delays in making the correct diagnosis and starting appropriate therapy. With the increased understanding of the pathophysiology of vasculitis and newer diagnostic tests in widespread clinical use, it is an appropriate time for classification criteria for primary vasculitis to be revised. The Diagnostic and Classification Criteria for Vasculitis (DCVAS) study is a multinational observational study designed to develop and validate diagnostic criteria and to improve and validate classification criteria for primary systemic vasculitis. The analytic approach will be based on the traditional approach of vessel size for classification of vasculitis but will also incorporate detailed clinical data, evaluation of anti-neutrophil cytoplasm antibody diagnostic testing, biopsy and imaging data. The study is following the guidelines for the development of classification criteria established by the American College of Rheumatology and the European League against Rheumatism. The study will incorporate the use of pre-defined cases of each condition to reduce the inherent circularity when developing new classification criteria and will explore alternative approaches to deriving reference standards by creating data-driven classification algorithms. We anticipate recruiting >2,000 patients with primary systemic vasculitis and 1,500 patients with autoimmune diseases and other conditions that mimic vasculitis. As of June 2013, >100 medical centers across 31 countries in Asia, Australasia, Europe, North America, and South America were contributing data to the study. The DCVAS study provides a unique opportunity to increase generalizability and collate a large dataset on the occurrence, presentation, and outcome of vasculitis in different populations.

Development of Outcome Measures for Large-vessel Vasculitis for Use in Clinical Trials: Opportunities, Challenges, and Research Agenda

Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.

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

There has been a marked increase in the past 15 years in the number and quality of clinical trials in the idiopathic inflammatory vasculitides, especially the small-vessel vasculitides known as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis [AAV; granulomatosis, with polyangiitis (Wegener’s)]. These trials have been conducted by multicenter, international groups in Europe and the United States with financial support provided by government agencies and biopharmaceutical companies. This increased clinical trial activity in vasculitis has been accompanied by the development and validation of new outcome measures — a challenging process for these complex, multiorgan system diseases. The international OMERACT Vasculitis Working Group has developed and implemented an iterative research agenda that has utilized accumulated experience and datasets from several multicenter clinical trials and large cohort studies. This work has led to the development, evaluation, validation, and endorsement, through the OMERACT consensus and validation processes, of a “core set” of outcome measurements for use in clinical trials of AAV. The core set includes domains of disease activity, damage assessment, patient-reported outcomes, and mortality; there is at least one validated outcome measurement instrument available for each domain. This report reviews the domains of illness in AAV included in the OMERACT core set, describes the instruments validated to measure these domains, and presents the approved core set.

Mortality in Wegener’s granulomatosis: a bimodal pattern

OBJECTIVE To characterize the long-term mortality in patients with WG compared with matched population-based controls. METHODS We used data from the General Practice Research Database, which contains the computerized records of 6.25 million patients and is representative of the population of the UK. We identified all subjects with a new diagnosis of WG in the period 1989-2004, and for each case, compared mortality with 10 controls matched for age, gender and practice. RESULTS We identified 255 patients with a new diagnosis of WG (mean age 58.1 years, range 9-90 years, 47% females) and 2546 controls (mean age 58.1 years, range 9-89 years, 47% females). Mean follow-up was 6.4 years. The mortality for patients with WG was significantly increased during the first year after diagnosis [HR 9.0 (95% CI 5.8, 13.9)], especially for those ≤ 65 years of age [HR 19.9 (95% CI 8.8, 44.9)]. The excess mortality was less marked after the first year: 1-5 years [HR 1.68 (95% CI 1.08, 2.60)], 5-10 years [HR 2.41 (95% CI 1.43, 4.07)], but started to increase by 10-15 years [HR 4.4 (95% CI 2.0, 9.8)]. The Kaplan-Meier survival curve showed an increase in mortality after 8 years. CONCLUSIONS Despite current therapy, patients with WG have a 9-fold increased risk of death in the first year of disease, attributed to infection, active vasculitis and renal failure. Between 1 and 8 years the risk is at its lowest, although higher than the control population. There is an increased mortality from 8 years onwards that remains unexplained.

A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis

OBJECTIVE Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis. METHODS A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearmans correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physicians global assessment (PGA), the physicians treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity. RESULTS WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρ = 0.82 (95% CI 0.77, 0.85)], PGA [ρ = 0.85 (95% CI 0.81, 0.88)] and the physicians treatment decision [ρ = 0.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρ = 0.18 (95% CI 0.05, 0.30)] or with the VDI [ρ = -0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score. CONCLUSION The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis.

Nomenclature and classification of vasculitis - update on the ACR/EULAR diagnosis and classification of vasculitis study (DCVAS).

Classification of vasculitis remains unsatisfactory. This is largely because the pathogenetic mechanisms of this family of related disorders have not been fully understood. Existing classification criteria are useful but limited. This has become more apparent with the advent of more effective and more specific therapies. A rational basis for classification could significantly improve our approach to treatment. The development of diagnostic criteria in vasculitis is an even greater challenge but may ultimately provide more useful for the non‐specialist clinician. International efforts are underway to provide more effective classification and diagnostic criteria.

Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index

Objectives To compare the Vasculitis Damage Index (VDI) with the Combined Damage Assessment Index (CDA) as measures of damage from vasculitis. Methods A total of 283 patients with vasculitis from 11 European centres were evaluated in a cross-sectional study using the VDI and CDA. Results Wegeners granulomatosis (58.4%) and microscopic polyangiitis (11.0%) were the most common diagnoses. Agreement between VDI and CDA scores (Spearmans correlation) was 0.90 (95% CI 0.87 to 0.92). There was good correlation between individual comparably evaluated organ systems (Spearmans correlation 0.70–0.94). Interobserver reliability (assessed by intraclass correlation coefficient (ICC)) was 0.94 (95% CI 0.89 to 0.98) for VDI and 0.78 (95% CI 0.63 to 0.93) for CDA. Intraobserver reliability was 0.92 (95% CI 0.83 to 1.00) for VDI and 0.87 (95% CI 0.75 to 1.00) for CDA. A total of 13 items were not used in the VDI compared to 23 in the CDA. Observers agreed that the CDA covered the full spectrum of damage attributable to vasculitis but was more time consuming and thus possibly less feasible for clinical and research purposes. Conclusions The VDI and CDA capture reliable data on damage among patients with vasculitis. The CDA captures more detail but is more complex and less practical than the VDI. Further evolution of damage assessment in vasculitis is likely to include key elements from both instruments.

Glucocorticoid treatment and damage in the anti-neutrophil cytoplasm antibody-associated vasculitides: long-term data from the European Vasculitis Study Group trials

OBJECTIVE Granulomatosis with polyangiitis and microscopic polyangiitis are ANCA-associated vasculitides (AAVs). The Vasculitis Damage Index (VDI) quantifies damage. This study aims to determine the factors associated with long-term damage in the AAVs. METHODS Data from 535 patients from four European Vasculitis Study Group trials were studied. A long-term follow-up (LTFU) questionnaire at 7 years post-diagnosis was completed. The associations between baseline (age, creatinine and BVAS score) and cumulative (number of relapses and duration of glucocorticoid use) factors and damage accrued (total VDI scores and individual treatment-related damage items) during follow-up were explored. Multiple regressions identified independent associations between baseline measures, cumulative factors and VDI scores at LTFU. RESULTS Two hundred and ninety-six patients had glucocorticoid use and VDI data available at LTFU, with the mean length of glucocorticoid use being 40.4 months (S.D. 16.7). High levels of damage were independently associated with older age at baseline (P = 0.051), lower glomerular filtration rate (P = 0.041), higher BVAS scores (P = 0.046), increased cumulative glucocorticoid use (P = 0.016) and increasing number of relapses. Patients with longer duration of glucocorticoid treatment were more likely to have a total VDI score ≥5 [odds ratio 1.26 per 12 months of glucocorticoid use (95% CI 1.03, 1.53), P = 0.022]. The main limitation is that approximately half of the patients enrolled had no LTFU data available; these patients were older with more severe initial disease. CONCLUSION Long-term damage in the AAVs may be associated with severity of initial disease, age, number of relapses and duration of glucocorticoid use.