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Current and emerging treatment options for ANCA-associated vasculitis: potential role of belimumab and other BAFF/APRIL targeting agents.

ABSTRACT: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission induction, and rituximab appeared even more beneficial in patients with relapsing disease. This raised hopes that other B-cell-targeted therapies directed either against CD19, CD20, CD22, or B-cell survival factors, B-cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand could also be beneficial for the management of AAV. BAFF neutralization with the fully humanized monoclonal antibody belimumab has already shown success in human systemic lupus erythematosus and, along with another anti-BAFF reagent blisibimod, is currently undergoing Phase II and III clinical trials in AAV. Local production of BAFF in granulomatous lesions and elevated levels of serum BAFF in AAV provide a rationale for BAFF-targeted therapies not only in AAV but also in other forms of vasculitis such as Behcet's disease, large-vessel vasculitis, or cryoglobulinemic vasculitis secondary to chronic hepatitis C infection. BAFF-targeted therapies have a very solid safety profile, and may have an additional benefit of preferentially targeting newly arising autoreactive B cells over non-self-reactive B cells.

SUBMITTER: Lenert A

PROVIDER: S-EPMC4294650 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Current and emerging treatment options for ANCA-associated vasculitis: potential role of belimumab and other BAFF/APRIL targeting agents.

Lenert Aleksander A Lenert Petar P

Drug design, development and therapy 20150107

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading ...[more]

PMID: 25609919

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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.

Dataset Information

Current and emerging treatment options for ANCA-associated vasculitis: potential role of belimumab and other BAFF/APRIL targeting agents.

Publications

Current and emerging treatment options for ANCA-associated vasculitis: potential role of belimumab and other BAFF/APRIL targeting agents.

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