Anca Vasculitis Review Article Text

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Note: this article is based on research that utilizes the sources cited here as well as the collective experience of the lab tests online editorial review board. This article is periodically reviewed by the editorial board and may be updated as a result of the review. Any new sources cited will be added to the list and distinguished from the original sources used. Available online at bronfenbrener, r october 12, 2012 antineutrophil cytoplasmic autoantibody, cytoplasmic c anca.

Antigen specific anca elisas have different sensitivities for active and treated vasculitis and for nonvasculitic disease. Available online at © 1995–2010 unit code 83012: antineutrophil cytoplasmic antibodies vasculitis panel, serum. Harrison's principles of internal medicine, 16th edition, mcgraw hill, pp 2002 2003. Autoantibodies to neutrophil cytoplasmic antigen associated vasculitis aav is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed aav from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity.

A proportion of patients are refractory to current therapies 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte targeted and cytokine targeted agents have been evaluated for the treatment of aav and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.

Classification of systemic vasculitis euvas disease categorisation of and randomised controlled trials in aav according to disease severity prior to effective treatment, aav had a mortality of 93% within 2 years, primarily due to renal and respiratory failure 7 . The introduction of glucocorticoids in 1948 and cyclophosphamide in the 1960s, together with adjunctive therapies such as antihypertensive drugs and renal replacement therapy, has transformed survival with 5 year survival rates now approaching 80% 6 . This therapeutic revolution has converted vasculitis into a chronic relapsing disorder with progressive organ damage and disability, eventually affecting over 95% of patients. The cumulative exposure to glucocorticoids and immunosuppressive drugs contributes to organ damage, and there has been particular concern caused by cyclophosphamide related toxicities of myelosuppression, infections, urothelial malignancy and infertility 8 ,9 . Rates of cardiovascular disease and malignancy are increased and it is unclear to what extent these reflect the underlying disease process or its treatment 10 .

Early treatment related leucopaenia and infection, and later cardiovascular disease, are now the predominant causes of death, rather than uncontrolled vasculitis 11 . Treatment related toxicity, together with the 10 to 30% of patients who do not respond to traditional immunosuppressive agents and pursue a refractory course and the 50% of patients who relapse within 5 years despite continued immunosuppression, has shifted the focus of treatment for aav 12 . From learning how to best use traditional agents to minimise toxicity without losing efficacy, to the advent of new targeted biological agents, a second revolution in the treatment of aav is on the horizon. Both genetic susceptibility and environmental exposures contribute to the aetiology of aav. Anca have been demonstrated pathogenic in animal models but their contribution to human disease remains unclear. Transfer of murine myeloperoxidase anca igg to mice without functioning b cells or t cells results in a pauci immune, necrotising crescentic glomerulonephritis, similar to that seen in aav in humans 3 .

Human anti pr3 antibodies from individuals with aav were recently demonstrated to cause comparable renal and pulmonary lesions in mice with a humanised immune system 13 . Two lines of investigation have linked infections to anca formation through molecular mimicry 14 ,15 . Fimbriated bacteria can induce novel anca, antibodies to human lysosome membrane protein 2, which can induce a crescentic glomerulonephritis in animal models 15 . Microbial superantigens are responsible for t cell dysregulation in kawasaki disease 16 , and infection with staphylococcus aureus is associated with relapse of gpa 17 ,18 . In sensitive assays, the pr3 anca binding level is predictive of outcome and rises in anca precede relapse. The clinical correlation with anca is closest for alveolar and glomerular capillaritis, both lesions capable of being induced by anca in experimental models. Patients who are consistently anca negative, however, may fit the clinical phenotype of aav, and the efficacy of b cell depletion with rituximab is not associated with anca status.

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Despite the pauci immune nature of the histology in anca vasculitis, there is evidence of a role for immune complexes and complement activation in renal vasculitis. There is activation of circulating t lymphocytes and b lymphocytes and infiltration of plasmoblasts into affected tissues 19 . Autoreactive b cells are necessary for the development of autoantibody producing cells, but may play a more important role in supporting autoreactive t cell activity through antigen presentation, co stimulation and the direct production of proinflammatory cytokines, such as il 6 and tnf x003b1. In view of their role as precursors of anca secreting plasma cells, b cells are a therapeutic target in aav. The autoantibodies are class switched that is, mainly igg , which means the autoreactive b cell has received cognate t cell help. Also, in biopsy specimens t cells are seen to infiltrate tissues, causing damage via direct cytotoxicity and by the recruitment and activation of macrophages 21 . A cd8 t cell gene expression signature has been associated with relapse frequency in aav 22 , and t cell targeted therapies including cyclosporin 23 and alemtuzumab have been effective 24 .