Systemic vasculitis--is it time to reclassify?

The way forward in approaching a diagnosis of vasculitis Vasculitides are a group of related disorders characterized by inflammation of blood vessels leading to tissue or end-organ injury. However, the classification of vasculitis has been controversial for many years. In 1990, the ACR proposed the criteria for classification of some vasculitides based on an analysis comparing the clinical features of patients with seven types of established vasculitis: GCA, Takayasu’s arteritis (TA), WG, Churg–Strauss syndrome (CSS), PAN, HScP and hypersensitivity vasculitis (HSV). The sensitivities of these criteria ranged from 71.0 to 95.3% and the specificities ranged from 78.7 to 99.7% [1]. The ACR criteria have been widely accepted and used, and helped advance the field of vasculitis research; however, over the past 20 years, some important limitations have been recognized that affect the application of the criteria to both clinical research and practice. Patients do not always fall neatly into one of the seven categories or overlap between two or more classifications. For example, a patient who presents with weight loss, myalgias, polyneuropathy, urinary sediment, respiratory symptoms, pulmonary infiltrates on chest radiograph and paranasal sinus abnormalities could potentially fit the ACR classification criteria for PAN, CSS or WG. The criteria present specific problems relating to the ANCA-associated vasculitides (AAV). The criteria were developed before the widespread introduction of ANCA testing, which now plays a key role in establishing a diagnosis of WG, microscopic polyangiitis (MPA) and CSS and in excluding a diagnosis of PAN. In some circumstances, positive tests for ANCA may replace tissue biopsy. The criteria also do not include MPA, which was a term not in common use during the 1980s (although its initial description was in 1948) [2]. Moreover, since the ACR criteria do not address many other types of idiopathic vasculitis, the field now has a patchwork of criteria that are overlapping, inconsistent, and thus neither comprehensive nor practical for routine use. Furthermore, while the ACR criteria were not originally intended to be diagnostic tools, they have nonetheless been widely adopted as such; however, the criteria do not work well for diagnostic purposes [3], leading to problems in conducting clinical trials. In 1994, the Chapel Hill Consensus conference (CHCC) produced definitions for vasculitis [4], including one for MPA, but these criteria were not intended for either classification or diagnostic purposes. The definitions take into consideration that relevant histological data will not always be available and the concept of surrogate markers of vasculitis was introduced; however, a list of such markers was not provided and neither ANCA nor other surrogate markers were prominent in the definitions. Although the ACR criteria and CHCC definitions have been used in parallel, this approach results in an unacceptable degree of overlap, especially between MPA and PAN [5]. To address this problem, an algorithm to classify AAV for epidemiological studies was developed that includes MPA and incorporates ANCA [5]. The algorithm was subsequently validated but remains untested in a clinical trial setting [6]. The shortcomings of the present systems for classification, diagnosis and definitions for the vasculitides affect both practising clinicians and researchers. These issues were the focus of a working group of individuals from Europe, the USA, Mexico and Japan, and included representatives from all major relevant medical disciplines. Through a series of meetings, key questions and issues were identified related to the current definitions, classification and diagnostic criteria in vasculitis. There was unanimous support to develop a revised classification system (details published in the group’s initial report [7]). A working draft of a revised classification scheme was developed on the basis of: (i) the traditional approach of classifying vasculitis by size of predominant vessel involved; (ii) diagnostic autoantibodies (ANCA); and (iii) current understanding of pathogenesis (Fig. 1). Revised draft classification scheme for the primary vasculitides. Modified with permission from Suppiah et al. [8]. Vasculitis will likely continue to be divided into primary and secondary forms. Additional factors that will be incorporated into a new classification system include aetiopathogenesis or the major salient features of condition, specific tissue biopsy data, ANCA testing, new biomarkers as they become available, new forms of diagnostic imaging and levels of certainty. Additionally, eponyms would be gradually replaced as new classifications are developed. We must be open to the idea that a system incorporating new diagnostic approaches, updated knowledge of pathophysiology and patient-level data will result in novel groupings and a substantially revised set of classification and diagnostic criteria. Thus, while this draft schema is useful for highlighting issues under consideration, a properly validated revised classification system will require a major international effort that is data based and not solely reliant on expert opinion. Such an effort is now underway to use sophisticated, data-driven methods to develop both a revised single classification system for the vasculitides and a validated set of diagnostic criteria for the vasculitides in accordance with standards established by the ACR and the EULAR [9]. The method used in generating the current ACR criteria depended on the submitting physicians’ diagnosis as the gold standard. The new initiative will avoid this inherent circularity by using real and hypothetical clinical vignettes, classified by consensus of an expert panel, to establish relevant cut-off points and identify specific clustering of features to define the important components of each disease. Pathophysiologically based approaches will be made (e.g. using the presence of ANCA or immune complexes) to distinguish one form of vasculitis from another. As a consequence of this process, new categories of vasculitis may emerge. We will test the validity of these criteria in development and validation cohorts that will include patients with vasculitis and patients without vasculitis who present with clinical features similar to those with vasculitis. This ambitious project, which aims to produce criteria useful in advancing both research and clinical care for vasculitis, has the support of the international vasculitis research community, Vasculitis Foundation, ACR and EULAR. Disclosure statement: The authors have declared no conflicts of interest.