Emerging Therapies in Antineutrophil Cytoplasm Antibody-Associated Vasculitis

Shunsuke Furuta; David Jayne

Disclosures

Curr Opin Rheumatol. 2014;26(1):1-6. 

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Other Potential Targets

Bortezomib, the proteasome inhibitor targeting plasmablasts and mature plasma cells, is licensed for multiple myeloma. In an MPO-ANCA mouse model, bortezomib demonstrated similar efficacy for the prevention of necrotizing crescentic glomerulonephritis to glucocorticoid/cyclophosphamide and a stronger effect of reducing MPO-specific plasma cells and MPO-ANCA titers than glucocorticoid/cyclophosphamide.[40] Some plasma cells survive for years, and it might explain the long-term elevation of ANCA occasionally seen after B-cell depletion.

Natalizumab is an antiα4-integrin monoclonal antibody approved for multiple sclerosis and Crohn's disease. It binds to the α4-integrin component of adhesion molecules expressed on lymphocytes, and prevents migration of autoreactive lymphocytes to local sites of inflamed organs. An analogous mechanism explains the immunological effects of a sphingosine 1-phosphate receptor modulator, such as FTY720 (Fingolimod) also approved for multiple sclerosis. Adhesion molecules can be targets for the treatment of AAV.

Spleen tyrosine kinase (Syk) is a nonreceptor cytoplasmic tyrosine kinase, important for transmitting signals from various immunoreceptors including the B-cell receptor. It has been also known that ANCA activates Syk in neutrophil via Fcγ receptor.[41] An English group presented at the 16th international Vasculitis & ANCA workshop in Paris, 2013 that fostamatinib, a small molecule Syk inhibitor, prevented glomerulonephritis and reduced autoantibody production in an autoantibody dependent rat model of crescentic glomerulonephritis.

On the contrary, signaling via type I/II cytokine receptors is transmitted by Janus kinase (Jak). Blocking Jak might be effective for autoimmune diseases with elevated proinflammatory cytokines. Tofacitinib, a small molecule Jak inhibitor, has already been approved for rheumatoid arthritis.

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