Antiphospholipid Antibody Syndrome: Much Remains to be Learned

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CHICAGO—Antiphospholipid antibody syndrome (APS) mainly affects young women, but can also affect men. APS patients test positive for multiple antibodies, including lupus anticoagulant (LAC), anti-cardiolipin and/or anti-beta2-glycoprotein I. These antibodies are diagnostic of APS, and they place the patient at increased risk for thrombosis and, in women, pregnancy morbidity. Women with LAC or those who are “triple positive” (i.e., have LAC, medium- to high-titer anti-cardiolipin and anti-beta 2-glycoprotien I antibodies) have worse prognoses for pregnancy morbidity.

D. Ware Branch, MD, a maternal-fetal medicine specialist at the University of Utah, Salt Lake City, began the APS session at the 2018 ACR/ARHP Annual Meeting with a discussion of the implications of APS in the field of obstetrics. He noted recurrent early miscarriage (embryonic loss prior to 10 weeks of gestation) is probably the most common clinical criterion for the diagnosis of APS. Women with the diagnosis have been the focus of several treatment trials.

Treatment Trials

Dr. Branch reviewed the data from a half dozen trials representing approximately 500 patients. He and others have been skeptical of conclusions based on these trials because of the variety and number of antiphospholipid antibody tests used, the definition of positive results, the methods used to establish thresholds for positive results, the lack of confirmatory testing and the nature of the study designs. Many experts would argue some of the patients who were low positive for antiphospholipid antibodies should not have been considered to have APS. Moreover, live birth and miscarriage rates in the treatment arms varied considerably.

Analysis of these studies indicated pregnant patients should be given heparin plus low-dose aspirin to prevent pregnancy morbidity. However, “I don’t feel this is a settled matter,” said Dr. Branch. He said treatment with a heparin agent (typically a low molecular weight heparin) for recurrent early miscarriage in a woman with low-titer antiphospholipid antibodies is costly, potentially harmful and may be ineffective.

PROMISSE & IMPACT Studies

Dr. Branch introduced the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) study, which was designed to identify predictors of adverse pregnancy outcomes in patients with APS or mild to moderate and stable systemic lupus erythematosus.¹

Most patients with APS received the conventional treatment of a heparin agent plus low-dose aspirin during the observed pregnancy. Despite this, 19% of patients experienced adverse pregnancy outcomes, such as premature delivery, hypertensive disorders and thrombocytopenia, and 4% experienced fetal death, indicating women with APS are at risk for pregnancy failure, even with the standard conventional treatment. Dr. Branch noted these findings underscore how critical it is to closely monitor both mother and fetus.

The study also found LAC is the most powerful predictor of pregnancy outcome; 44% of pregnancies in women with APS and LAC resulted in adverse pregnancy outcomes despite treatment with heparin and low-dose aspirin.

In recognition that pregnant women with APS have a pronounced unmet medical need, Dr. Branch and colleagues have initiated the Improve Pregnancy in APS with Certolizumab Therapy (IMPACT) study. The investigators want to determine whether tumor necrosis factor-α blockade (certolizumab) during pregnancy, added to a regimen of heparin and low-dose aspirin, reduces the rate of adverse pregnancy outcomes in women with clinical APS and LAC, and alters angiogenic markers of poor placental vascularization. Dr. Branch encouraged the audience to inform their patients about the trial, which is actively recruiting patients from around the country.

Limited Disease Awareness

Doruk Erkan, MD, MPH, attending physician at the Hospital for Special Surgery, New York, and associate professor of medicine at Weill Cornell Medicine, New York, explained one of the biggest problems associated with APS is limited disease awareness. This causes patient frustration, missed diagnosis and overdiagnosis. He said APS is one of the few conditions in which both under and overdiagnosis are problems.

Limited awareness and missed signs and symptoms can lead to misdiagnosis. Over­diagnosis can result from overinterpretation of slightly elevated aPL tests. For example, a young patient with a clot may go to the emergency department and because APS is never under consideration, the antibody levels won’t be checked. A similar patient could enter the emergency department and undergo an antibody test that reveals levels one unit above normal. That patient would inaccurately be diagnosed with APS. Dr. Erkan thus detailed the importance of physician and patient education, and the necessity for an antiphospholipid antibody profile assessment and risk assessment.

He encouraged the audience to download a free book from iTunes that describes APS in detail, Antiphospholipid Syndrome.²

Dr. Erkan also emphasized the importance of collaboration among physicians and/or among organizations. One means of accomplishing this is the APS ACTION group he leads. This collaboration of 57 members from 33 international centers works on multiple projects, including a large registry of approximately 800 patients.

Dr. Erkan is co-primary investigator of a multidisciplinary international project developing rigorous new consensus-based classification criteria to identify patients with a high likelihood of having APS. The project is supported by the ACR and the European League Against Rheumatism (EULAR). The investigators presented its very early results in Chicago.³ The classification criteria can be used for research purposes but should have no impact on reimbursement.

Lastly, Dr. Erkan discussed the most challenging presentations of aPL-positive patients including microthrombotic APS, catastrophic APS and any major bleeding in anti-coagulated APS patients. He stressed the importance of timely multi­disciplinary decisions in these patients, reviewed some immunosuppressive agents for microthrombotic APS and introduced the most recent clinical practice guideline.

Off-Label Treatments

Thomas Lee Ortel, MD, PhD, chief, Division of Hematology, Department of Medicine at Duke University School of Medicine in Durham, North Carolina, explained that most of the treatment options for APS are off label. Research suggests, however, patients should receive three months of anti-coagulant therapy in response to venous thromboembolism provoked by a transient risk factor.⁴ This is because a decrease to one month of therapy is likely to increase recurrent venous thrombo­embolism without achieving a clinically important decrease in bleeding. 

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

References

1. Buyon JP, Kim MY, Guerra MM, et al. Predictors of pregnancy outcome in a prospective, multiethnic cohort of lupus patients. Ann Intern Med. 2015 Aug 4;163(3):153–163.
2. Phialy L, Zuily S, Erkan D. (2016) Antiphospholipid Syndrome. Ed. Université de Lorraine—Faculté de médecine.
3. Barbhaiya M, Zuily S, Ahmadzadeh Y, et al. Development of new international classification criteria for antiphospholipid syndrome: Phase II item reduction survey (abstract 163). 2018 ACR/ARHP Annual Meeting.
4. Kearon C, Ginsberg JS, Anderson DR, et al. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost. 2004 May;2(5):743–749.