oa Editorial [Hot Topic: Clinical Trials in ANCA Associated Vasculitis (Guest Editor: Chetan Mukhtyar)]

Wegener's granulomatosis (WG) was described in 1936 [1], Churg-Strauss syndrome (CSS) in 1951 [2], and microscopic polyangiitis (MPA) was formally recognized in 1994 [3]. These three conditions have been linked under the umbrella term of ANCA associated vasculitis (AAV) due to their association with antibodies directed against antigens in the neutrophil cytoplasm (ANCA). All three conditions produce necrotising vasculitis of medium and small vessels with differing predilections to various organs. Although these conditions have been recognized since the 1930's, the first clinical trial was not published till 1983. Fauci et al. shared their experience of using open label, uncontrolled oral cyclophosphamide and glucocorticoid combination therapy in patients with WG [4]. That paper described 85 patients recruited in one centre over 21 years. 27 years later, two randomised clinical trials were published in the same week [5-6]. Between the two, the papers described 245 patients with WG or MPA recruited over 4 years and followed up for predefined durations in 17 centres across the world. Compared to the first 60 years of WG, our understanding and thus our methodology of investigating potential therapies for these conditions has changed dramatically. In the last decade there have been 12 randomised controlled trials in patients with AAV (Table 1). It has taken a huge amount of co-ordinated effort to overcome the challenges of studying these relatively rare conditions. Till the Chapel Hill Consensus conference (CHCC), MPA had not been formally defined, although its existence distinct from polyarteritis nodosa (PAN) had been recognised [3]. Prior to the CHCC definitions it was common to club together MPA and even CSS under the umbrella of ‘PAN’. Although these definitions are not diagnostic, they have been of value in identifying homogenous populations for clinical trials. This in turn led to the recognition that the different AAV may have different clinical outcomes [7]. The first clinical trials in AAV were single centre studies. This often meant that the studies were either underpowered, took a long time to recruit adequate numbers of patients, or mixed the differing vasculitis syndromes. All of these problems often made the data difficult to interpret. This problem brought together vasculitis researchers to form research groups. The French Vasculitis Group (FVSG), the European Vasculitis Study Group (EUVAS) and the American Vasculitis Clinical Research Consortium (VCRC) were born out of efforts to conduct meaningful vasculitis research. Of the 12 RCT’s conducted in the last decade (Table 1), 10 have been from these three groups. After the discovery of ANCA, there was hope that this could perhaps serve as a biomarker for activity in patients with AAV. Initial studies suggested that treating patients according to ANCA levels prevented relapse [8], but the present general consensus does not support treatment changes based on serial ANCA monitoring alone [9]. In the absence of valid biomarkers, the invention of structured clinical examination and monitoring has become the accepted surrogate for disease activity. Various clinical tools have been used to measure disease activity, but the one that has been accepted as consensus has been the Birmingham Vasculitis Activity Score (BVAS) [10]. Of the 12 RCT's in the past decade, 9 have used different versions of the BVAS as the outcome measure, and the other 3 applied the BVAS retrospectively as they had started recruiting patients prior to the validation of the first version of BVAS. The use of a single validated clinical tool to measure disease activity in all the clinical trials has made it possible to compare outcomes from different clinical trials. Clinical trials in AAV can be divided into those for inducing remission and those for preventing a relapse. However, the definitions of remission and relapse have been widely different across the clinical trials. This has been discussed in detail elsewhere [11], but in brief, the definition of remission has varied from “When the patient's general condition improved, no new manifestations of WG appeared, and the ESR returned to normal” [12] to being as strict as “Absence of clinical, serologic”, and radiologic (including MRI) evidence of disease activity. These conditions had to be sustained for at least 6 months after the discontinuation of pulse CYC treatment, without further immunosuppressive therapy, including withdrawal of prednisolone” [13]. Of the 12 clinical RCT's in Table 1, 8 were designed to trial therapies for remission induction. Of the 8, 5 had remission (as defined by BVAS = 0) as the primary outcome. Similarly relapse has also been defined by the reappearance of clinical manifestations which could be scored on the BVAS. From the examples of the definitions of remission, it can be seen that a specified disease state can mean different things in different clinical trials. The European League Against Rheumatism (EULAR) has attempted to standardize these definitions and indeed the entire conduct of clinical trials in AAV [14]. However, the exact nature of definitions still varies and cannot be compared across clinical trials without looking at the raw data again. For example, remission was defined as BVAS (v.3) = 0 for 6 months in Jones et al. [6], and BVAS/WG = 0 off prednisolone in Stone et al. [5].....