Antiphospholipid Syndrome: Management & Future Directions

ACR CONVERGENCE 2020—Maria Laura Bertolaccini, PhD, postdoctoral research associate, King’s College London, started off the session on antiphospholipid syndrome (APS) talking about novel and non-criteria antibodies for APS and their potential to predict thrombotic episodes. Currently, three antibody tests are required for the diagnosis and classification of APS: lupus anticoagulant, anti-cardiolipin and anti-β₂ glycoprotein I (anti-β₂GPI). These three, although widely available, are not sufficient to identify all patients with APS. In searching for new diagnostic antibodies, researchers have found that IgG antibodies that recognize epitope Gly40-Arg43 in domain I of β₂-gycoprotein I not only cause lupus anticoagulant, but their presence correlates strongly with thrombosis. This area of domain I is likely also covered by a carbohydrate chain in solution, making the epitope cryptic.

Dr. Bertolaccini

Antibodies for APS
A 2006 study found that pathogenic anti-β₂-glycoprotein antibodies recognize domain I of β₂ glycoprotein only after a conformational change.¹ The anti-β₂-GPI antibodies thus bind an epitope that is only exposed on β₂-GPI when bound to a negatively charged surface. These antibodies to domain I of β₂ glycoprotein (anti-DI) have been shown to increase the hazard ratio for APS and to be associated with thrombosis and pregnancy morbidity. Additional studies in animal models suggest these anti-DI antibodies are pathogenic. Nevertheless, because they are more specific but less sensitive than anti-β2GPI, their presence does not increase the diagnostic yield and their routine clinical use is still debated.

Data on antibodies to other domains of β2GPI were also presented.

Dr. Bertolaccini discussed antibodies to domain IV/V of β2GPI and explained that available data show these antibodies fail to induce thrombosis in a rat model. That said, preliminary evidence suggests that the anti-DI to anti-D IV/V ratio may be a useful new biomarker for APS that is helpful for identifying pathogenic anti-β₂GPI.

A lot of interest has been directed to antiphosphatidylserine/prothrombin antibodies (aPS/PT). Animal models have revealed aPS/PT antibodies to be pathogenic and an independent risk factor for thrombosis. The antibodies are independent of the presence of lupus anticoagulant and their risk is additive to other routine antiphospholipid antibodies. Dr. Bertolaccini explained that, along with lupus anticoagulant and anti-β₂ glycoprotein I, aPS/PT offer the best diagnostic accuracy for APS and they may be useful in identifying additional patients with APS.

Treatment of Thrombotic APS
Thomas Ortel, MD, PhD, chief of the Division of Hematology in the Department of Medicine at Duke University Medical Center, Durham, N.C., then presented his current recommendations for the treatment of thrombotic APS, as well as evidence against the use of direct oral anticoagulants. He highlighted three key references that addressed the treatment of thrombotic APS.

Dr. Ortel began with the recent European League Against Rheumatism (EULAR) recommendations for the management of APS in adults.² EULAR emphasizes that high-quality evidence is limited in APS. Nevertheless, the EULAR recommendations state that anticoagulant therapy is the treatment of choice for APS patients with new venous thromboembolism (VTE). Treatment should be initiated with either unfractionated heparin or low molecular weight heparin. When treating a first VTE, EULAR suggests that direct oral anticoagulants be considered in patients not able to achieve a target international normalized ratio (INR) despite good adherence to vitamin K antagonist or those with contraindications to vitamin K antagonist, such as allergy.

TRAPS Study
The Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) study, a randomized, controlled trial that compared the ability of rivaroxaban and warfarin to prevent recurrent thrombosis in patients with APS and a prior thrombotic event, enrolled high-risk patients who were triple positive for lupus anticoagulant, anti-cardiolipin and anti-β₂GPI, and these patients were randomized to receive either rivaroxaban 20 mg/day or warfarin, with a target INR of two to three.³ The study closed after 120 patients were enrolled because it showed an increased rate of events with rivaroxaban compared to warfarin. A second prospective, randomized clinical trial comparing rivaroxaban to warfarin obtained similar results.⁴

A recent Cochrane Review addressed antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with APS.⁵ The authors identified eight studies including 811 participants that compared different antiplatelet or anticoagulant agents. They concluded that non-vitamin K antagonist oral anticoagulants, such as rivaroxaban, compared with standard-dose non-vitamin K antagonists, such as warfarin, may increase the risk of stroke and do not appear to alter the risk of other outcomes, such as any thromboembolic events and major bleeding.

Dr. Ortel concluded with his personal recommendations for the treatment of APS with VTE, which he emphasized must be individualized to the patient. He explained that he treats VTE with anticoagulant therapy, but he avoids direct oral anticoagulants in triple positive APS patients with VTE. He does consider, however, direct oral anticoagulants to be an option for selected APS patients who are not triple positive. He also reminded the audience that selected APS patients with provoked VTE may not need indefinite anticoagulant therapy.

Dr. Ortel then summarized his approach to treating patients with APS with arterial thrombosis, which he believes also must be individualized to the patient. He treats definite APS patients with an initial arterial thrombosis with anticoagulant therapy, although antiplatelet therapy may be an effective alternative for selected patients with an initial arterial event and antiphospholipid antibodies. He avoids direct oral anticoagulants in most APS patients with arterial thrombosis, preferring warfarin over a direct oral anticoagulant in all definite APS patients with arterial thrombosis. He also treats patients for any other risk factors for arterial thrombosis.

Jason S. Knight, MD, PhD, foresees the field becoming more personalized, with rheumatologists treating APS proactively rather than reactively.

Dr. Knight

The Next Decade
Jason S. Knight, MD, PhD, the Marvin and Betty Danto Research Professor of Connective Tissue Research and associate professor of internal medicine at the University of Michigan, Ann Arbor, concluded the session with an overview of what to expect in the new decade for APS. He foresees the field becoming more personalized with rheumatologists treating APS proactively rather than reactively. Advances in immunomodulation should also make it possible to treat APS at its source. Finally, he called for more investigators to become interested in APS to generate a better understanding of B cell repertoire, metabolomics, epigenetics and the influence of the microbiome.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

References

1. De Laat B, Derkson RHWM, van Lummel M, et al. Pathogenic anti-β₂-glycoprotein I antibodies recognize domain I of β₂-glycoprotein I only after a conformational change. Blood. 2006 Mar 1;107(5):1916–1924.
2. Tektonidou MG, Andreoli L, Limper M, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019 Oct;78(10):1296–1304.
3. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365–1371.
4. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized noninferiority trial. Ann Intern Med. 2019 Nov 19;171(10):685–694.
5. Bala MM, Celinska-Lowenhoff M, Szot W, et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome (Review). Cochrane Database Syst Rev. 2020 Oct 12;10:CD012169.