Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis.
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)-alpha 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 TNFalpha 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 antithymocyte 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.
Lee
Richard W
RW
Lupus Research Unit, Rayne Institute, St Thomas' Hospital, London, UK.
D'Cruz
David P
DP
D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019268:Antibodies, Antineutrophil Cytoplasmic; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019317:Evidence-Based Medicine; D014890:Granulomatosis with Polyangiitis / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology
D000890:Anti-Infective Agents; D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha