Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers

Abstract

Treatment with the antimalarial drug hydroxychloroquine (HCQ) has been associated with reduced risk of thrombosis in the antiphospholipid (aPL) syndrome (APS) and, in an animal model of APS, with reduction of experimentally induced thrombosis. Recognition of ␤2-glycoprotein I (␤2GPI) by aPL antibodies appears to play a major role in the disease process. We therefore used the techniques of ellipsometry and atomic force microscopy (AFM) to investigate whether HCQ directly affects the formation of aPL IgG-␤2GPI complexes on phospholipid bilayers. HCQ, at concentrations of 1 g/mL and greater, significantly reduced the binding of aPL-␤2GPI complexes to phospholipid surfaces and THP-1 (human acute monocytic leukemia cell line) monocytes. The drug also reduced the binding of the individual proteins to bilayers. This HCQmediated reduction of binding was completely reversed when the HCQ-protein solutions were dialyzed against buffer. HCQ also caused modest, but statistically significant, reductions of clinical antiphospholipid assays. In conclusion, HCQ reduces the formation of aPL-␤2GPI complexes to phospholipid bilayers and cells. This effect appears to be due to reversible interactions between HCQ and the proteins and may contribute to the observed reduction of thrombosis in human and experimental APS. These results support the possibility that HCQ, or analogous molecules, may offer novel nonanticoagulant therapeutic strategies for treating APS. (Blood. 2008;112:1687-1695) IntroductionThe antiphospholipid (aPL) syndrome (APS) is a thrombophilic disorder that is defined by the presence of autoantibodies against phospholipid-binding cofactor proteins in patients with vascular thrombosis and/or pregnancy complications. 1 Of the various phospholipid-binding proteins, aPL antibody recognition of the phospholipid-binding protein, ␤2-glycoprotein I (␤2GPI), appears to particularly correlate with thrombosis 2 and is associated with significantly increased risk of thrombosis. 3 Antiphospholipid antibodies have been demonstrated to play a causal role in the development of thrombosis in animal models (reviewed in Rand 4 ). Long-term anticoagulation with warfarin, a medication that carries a significant risk of bleeding complications, 5 is the standard treatment for APS-associated thrombosis. 6 Hydroxychloroquine (HCQ), an amphiphilic antimalarial compound, has proven to be an effective immunosuppressive treatment of systemic lupus erythematosus (SLE). [7][8][9][10][11] The Hopkins Lupus Cohort reported that the presence of aPL antibodies is an independent predictor of thrombosis in SLE, and that treatment of SLE patients with HCQ was associated with a reduced risk of thrombosis. 12 A cross-sectional study that compared aPL antibody-positive patients with thrombosis to a group of patients having the antibodies but who did not have thrombotic histories indicated that HCQ may be protective against thrombosis. 13 HCQ significantly reduced the extent of thrombosis in an animal model of injuryinduced thrombosis in APS, 14 and, in a si...

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