Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. Characteristic laboratory abnormalities in APS include persistently elevated levels of autoantibodies directed against membrane anionic phospholipids. The 3 main antiphospholipid antibodies (APLAs) include:

• Anticardiolipin antibodies IgG or IgM (ELISA)
• Anti-beta-2-glycoprotein-I (anti-β2GPI) antibodies IgG or IgM (ELISA)
• Lupus anticoagulants (functional clotting assays)

Pathogenesis of APS

In APS, APLAs primarily target β2-glycoprotein I (β2GPI), a plasma protein that binds to phospholipids. The binding of APLAs to β2GPI on the surface of endothelial cells upregulates the expression of prothrombotic cellular adhesion molecules, such as E-selectin and tissue factor (TF). Notably, APLAs against β2GPI disrupt the binding of annexin A5 to phospholipid bilayers, which accelerates coagulation reactions. In addition, APLAs binding to β2GPI suppress the inhibitors of tissue factor pathway, reduce the activity of protein C, and activate complement. Complement activation was also found as a possibly significant role in the pathogenesis of APS. Failure of complement-regulating mechanisms can result in uncontrolled complement activation, leading to direct cellular injury and thrombosis. Evidence from murine models suggests that APLAs mediated complement activation may be a primary event in pregnancy loss.

Fig. 1 Summary of antiphospholipid syndrome pathogenesis

Immunotherapy

Rituximab

Rituximab used in APS therapy is based on the crucial role of B cells in the pathogenesis of the disease. Rituximab may lower APLAs titers. In addition, rituximab may inhibit the expression of inducible co-stimulator (ICOS), which can suppress the activation of T helper cells in the development of APS.

Obinutuzumab

Obinutuzumab can induce potent direct cell death (DCD) by rupturing lysosomes. Due to its ability to avoid rapid internalization like rituximab, this typical type II anti-CD20 antibody may induce more effective antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

Belimumab

Belimumab is a monoclonal antibody targeting the soluble circulating BAFF can lead to B cell depletion. It has been found can reduce APLA titers and ameliorate vascular symptoms.

Eculizumab

Eculizumab can improve outcomes of refractory CAPS described in previous case reports. Thrombocytopenia or kidney injury in CAPS patients with thrombotic microangiopathy (TMA) may respond to eculizumab. In patients with CAPS, eculizumab has resulted in prevention of recurrent APS and rescuing renal allografts after kidney transplantation.

Daratumumab

Daratumumab is a CD38 antibody that can attack plasma cells directly. It has been employed in the management of autoimmune-mediated diseases, including APS, SLE, and rheumatoid arthritis (RA).

Anti-TNF-α therapy

APLAs may increase the expression of TNF-α by stimulating monocytes. In vitro studies have shown that adalimumab, a TNF-α blocker, completely inhibits anti-β2GPI-induced TF expression in monocytes. In mouse models, blocking TNF-α can improve endothelial dysfunction and prevent pregnancy loss.

Bruton tyrosine kinase (BTK) plays a significant role in regulating B cell proliferation, survival, differentiation, and cytokine expression, as well as influencing platelet activation. As such, zanubrutinib, a BTK inhibitor, is being studied in a prospective, single-arm, open-label clinical trial for the treatment of APS with secondary thrombocytopenia (clinicaltrials.gov#: NCT05199909).