Emerging Therapies in Antiphospholipid Syndrome

Abstract

The antiphospholipid syndrome (APS) is the most common cause of acquired immune-mediated thrombophilia. This syndrome is broadly defined by the presence of arterial or venous thrombosis, or pregnancy morbidity, in the presence of high levels of antiphospholipid antibodies. Despite recognition of this disorder more than 50 years ago, a fundamental unifying pathogenesis has not been determined. Due to this, mechanism-based therapies for APS are not available, and current management following thrombotic events suggests anticoagulation of indeterminate duration, or for obstetric complications, heparin/low molecular weight heparin and aspirin. However, APS is an autoimmune disorder, and several approaches focused on modulating the immune response or its effectors have been employed. Those which have been most extensively studied include hydroxychloroquine, rituximab and eculizumab, an inhibitor of complement C5. In this report, we review in depth, and critique, key clinical studies of these agents. Since all of these studies are small, our conclusions are qualified. However, it appears that hydroxychloroquine may enhance the anticoagulant efficacy of vitamin K antagonists in APS patients, and that rituximab may ameliorate some of the "non-criteria" manifestations of APS. The catastrophic antiphospholipid syndrome (CAPS) is associated with diffuse thrombosis, multi-organ dysfunction, and ∼30% mortality. A high incidence of complement regulatory gene mutations, and compelling data concerning the efficacy of eculizumab in CAPS, suggests an important role for complement in this disorder. However, additional work is needed to clarify the role of complement in non-catastrophic APS, though emerging data suggests that complement inhibition may be effective in preventing thrombosis in these patients as well.

Keywords: Antiphospholipid; Complement; Eculizumab; Lupus; Plasma exchange; Thrombophilia.

Fig. 1.

Potential mechanisms of thrombosis induced by aPL induced by complement, from Chaturvedi, Brodsky and McCrae²⁶.

Fig. 2.

Serum C3a and C4a levels in 17 patients with primary APS, 9 patients with non-systemic SLE connective tissue diseases and 15 healthy volunteers, as reported by Oku et al.³⁶ Low C3/C4 and normal C3/C4 refers to the levels of C3 of C4 in the plasmas being assessed, since some patients with APS were found to have hypocomplementemia.

Fig. 3.

Relation between complement activation and aPL-associated thrombosis, from Devreese and Hoylaerts³⁷.

Fig. 4.

Clinical course and timeline of a case of refractory APS that ultimately responded to eculizumab, as reported by Hussain et al.⁴⁷