Of evidence and uncertainties

Abstract

New British Society for Rheumatology guideline for the treatment of ANCA vasculitis This article refers to BSR and BHPR guideline for the management of adults with ANCA associated vasculitis, by E. Ntatsaki et al., doi:10.1093/rheumatology/ket445, on pages 2306–09. In this issue of the journal an expert panel from the British Society for Rheumatology (BSR) presents an update of the 2007 BSR guideline for the treatment of ANCA-associated vasculitides (AAVs) [1]. It is remarkable that in recent years enough new evidence has accumulated to call for a revision of these recommendations, in particular because it is still challenging to conduct well-designed trials in these rare conditions. Many of the authors of the guideline have contributed significantly to the field. The British vasculitis scene belongs to the most active and productive groups worldwide and is a key part of the European Vasculitis Society (EUVAS). The guideline reflects the rapidly increasing evidence from controlled trials available in the past years and now includes biologicals [namely rituximab (RTX)] as a mainstay of treatment. The Rituximab versus Cyclophosphamide in ANCA-associated Vasculitis (RITUXVAS) EUVAS trial initiated by British vasculitis experts was one of the landmark studies in this context [2]. A milestone in 2013 was the approval of RTX for the treatment of AAV. This represents the first formal drug approval for AAV by the European Medicines Agency (EMA) in more than 40 years. Accordingly, questions concerning the appropriate use of RTX are among the most prominently discussed issues in this well-structured and straightforward guideline. Despite of the significant accrual of knowledge in recent years, the guideline also reflects that we still have to face a lot of uncertainty in the treatment of AAV patients. The guideline [1] refers to patients with disease consistent with the 2012 Chapel Hill Consensus Conference definitions [3] and thereby formally excludes a significant proportion of AAV patients. This underlines the urgent need for real diagnostic, not just classification, criteria. The ongoing EUVAS/ACR study for the development of diagnostic and classification criteria for primary vasculitis will probably establish such standards. Other definitions need international harmonization in order to increase the comparability of reported data. The present guideline defines remission as BVAS ≤1 and a daily prednisolone dose of ≤10 mg for at least 6 months. The 2007 European League Against Rheumatism (EULAR) recommendations on clinical trials in AAV suggest a BVAS of zero and a prednisolone dose of ≤7.5 mg/day [4]. Several other definitions have been used in different trials and observational studies. Furthermore, the 6 month criterion for remission in the new BSR guideline [1] is problematic. The guideline recommends switching to maintenance therapy after successful induction of remission, after treatment with CYC for example. Strict compliance with the above-mentioned definition could lead to a therapeutic gap of several months or prolonged use of CYC, which clearly is not the intention of the authors. This illustrates the difficulty in defining clinically and scientifically meaningful endpoints. Other uncertainties pertain to drug treatment regimens per se. Although it is generally accepted that high-dose glucocorticoids are the mainstay of treatment, there is still a notable lack of proven information on dosing, tapering or duration of therapy. The availability of RTX for induction of remission in AAV represents a major progression. Drug approval in this case was granted on the basis of randomized controlled trials—the RAVE trial [5] and the RITUXVAS trial [2]. These studies helped to establish an alternative treatment to CYC, yet a lot of important questions remain unanswered, such as who is the ideal patient for treatment with RTX and who should still be treated with CYC? There is a consensus that when considering first-line treatment, RTX may be the better choice for younger patients in order to preserve fertility, an advantage of RTX. While this is mechanistically logical, it still lacks formal proof. The guideline also states that RTX may be preferred in patients at high risk of infections [1]. When looking at the data from RAVE [5, 6] and RITUXVAS [2], no clear superior treatment for patients at high risk of infection could be determined during the relatively short observational periods. Considering the treatment of CYC-refractory patients, the overwhelming consensus among experts that RTX should be the drug of first choice is contrasted by a prominent lack of sufficient data. Another ongoing controversy outlined in the guideline [1] is the use of RTX for maintenance of remission. According to some uncontrolled retrospective data (e.g. [7]) and the as yet unpublished results from the French MAINRITSAN trial, addressing repetitive RTX administration for maintenance, moderate repeated doses of RTX (0.5–1 g) given at relatively long intervals (4–6 months) seem to be a promising future option. Apart from proving that RTX represents an option for maintenance there is hope that it may even be superior to conventional standard maintenance treatment such as AZA. Finding the optimal dose in order to maintain maximum remission rates and to reduce potential side effects is another major issue for future research. The ongoing RITAZAREM study assessing RTX administered as a 1 g dose every 4 months vs standard AZA will help to answer these questions. When looking at distinct clinical situations in AAV, in many cases the evidence level is still that of case series. This is especially true for the rarest of the rare AVV entities, e.g. eosinophilic granulomatosis with polyangiitis (EGPA). The guideline, capturing the available data, mainly refers to GPA and microscopic polyangiitis, but not EGPA. When considering the sparse data on many of the relevant topics, this guideline [1] will be a most valuable aid for clinical decisions in daily work. The generation of further evidence from clinical trials will hopefully lead to an update of the EUVAS/EULAR 2009 [8] recommendations, making standardization of the diagnostic and classification standards a worthwhile future task of the EULAR/EUVAS. Disclosure statement: The authors have declared no conflicts of interest.