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Progress in treatment of ANCA-associated vasculitis.

ABSTRACT: 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. There is, however, a high unmet need in the treatment of AAV. 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.

SUBMITTER: Smith RM

PROVIDER: S-EPMC3446448 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Progress in treatment of ANCA-associated vasculitis.

Smith Rona M RM Jones Rachel B RB Jayne David R W DR

Arthritis research & therapy 20120430 2

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. There is, however, a high unmet need in the treatment of AAV. A proportion of ...[more]

PMID: 22569190

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Project description:Purpose of review With established immunosuppressant treatment regimens for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV), prognosis has significantly improved. The mainstay of treatment still comprises high-dose corticosteroids and cyclophosphamide for severe forms, although rituximab is being increasingly utilised instead of cyclophosphamide as induction therapy. AAV patients experience an excess of infections, malignancies and cardiovascular events as compared to the general population, which is a combination of the systemic inflammatory process associated with vasculitis and the adverse events from treatment. Recent findings Successful therapy should focus on suppressing disease activity and minimising treatment-related toxicity. Infection is the largest contributor to morbidity and mortality in the first year of treatment, and annual pneumococcal and influenza vaccinations, Pneumocystis jiroveci prophylaxis and tuberculosis (TB) and Hepatitis B virus screening are advised. Patients on high-dose corticosteroid treatment should have regular blood sugar monitoring, a FRAX assessment with vitamin D and calcium supplementation, consideration of prophylaxis for gastric ulcers and a cardiovascular risk assessment. Patients who are treated with cyclophosphamide could also receive MESNA to reduce the risk of chemical cystitis. Cyclophosphamide, methotrexate and azathioprine all require blood monitoring schedules due to the risk of bone marrow suppression, liver and renal toxicity. Hypogammaglobulinaemia is a recognised risk of rituximab treatment. Patients of reproductive age need to be counselled on the infertility risks with cyclophosphamide and the teratogenicity associated with it, methotrexate and mycophenolate mofetil. Summary A greater focus on identifying clinical and biological markers that will help identify those patients at greatest risk of relapse, e.g. GPA and PR3-ANCA specificity, from those patients at greatest risk of toxicity, e.g. increasing age and declining GFR, is required to allow treatment to be tailored accordingly.

Project description:Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.

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Progress in treatment of ANCA-associated vasculitis.

Publications

Progress in treatment of ANCA-associated vasculitis.

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