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Novel Therapies for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

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Abstract

The rapid expansion in the therapeutic modalities available for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (AAV), with clear limitations in existing strategies, prompted us to undertake a review of novel therapies reported in MEDLINE and EMBASE.

Tumour necrosis factor (TNF)-α antagonism with infliximab is described favourably in retrospective series and open-label trials. However, evidence from the WGET (Wegener’s Granulomatosis Etanercept Trial) does not support the clinical use of etanercept, and a significantly higher malignancy rate following TNFα inhibition questions the role of this approach. Uncontrolled evidence alone supports remission induction with rituximab-mediated B-lymphocyte depletion and may be less effective in predominantly granulomatous AAV. Remission following T-lymphocyte depletion can be achieved with alemtuzumab and anti-thymocyte globulin, but it is not yet clear what the clinical role will be for these agents in AAV. In addition, these agents are associated with prolonged lymphopenia and pulmonary complications, respectively. Stem cell transplantation to support immune reconstitution following the use of such agents has been trialled in AAV, but studies included very few patients.

Purine and pyrimidine antimetabolites mycophenolate mofetil and leflunomide are likely to play an important role in the treatment of AAV, but results supporting remission maintenance and induction in the former are limited to uncontrolled trials, such that their use remains experimental at this time. Similarly, 15-deoxyspergualin may provide an alternative to cyclophosphamide but awaits randomized controlled trial evidence. The MEPEX (MEthylprednisolone versus Plasma EXchange) trial supports plasma exchange in renal disease but this may be limited by pulmonary complications. Randomized controlled evidence also exists for intravenous immunoglobulin, although improvement may not be sustained. Antimicrobial therapy may be of use in Wegener’s granulomatosis patients with predominantly upper respiratory tract involvement.

Safety concerns, notably of infection and malignancy, were common and need to be explored in subsequent trials. In addition, concomitant immunosuppressants and non-standardized definitions were major limitations, and future studies of these and newer agents must follow agreed standards of study design and reporting to facilitate clearer interpretation of the circumstances (e.g. disease stage, severity or organ involvement) under which these agents perform optimally. Consequently, use is still limited to centres experienced in such agents and mostly in the context of clinical trials.

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Acknowledgements

We acknowledge the comprehensive advice and assistance from evidence-based and knowledge management librarian Ben Skinner at Brighton and Sussex University Hospitals with regard to the literature search undertaken.

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Lupus Research Unit, Rayne Institute, Lambeth Wing, St Thomas’ Hospital, SE1 7EH, London, UK

    Richard W. Lee &  David P. D’Cruz

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Lee, R.W., D’Cruz, D.P. Novel Therapies for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. Drugs 68, 747–770 (2008). https://doi.org/10.2165/00003495-200868060-00003

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