The antiphospholipid syndrome (APS) is a common disorder affecting patients with and without autoimmune disease. Despite wider recognition of APS among physicians as well as the expanding research collaborations, many clinical questions are still encountered in clinical practice, which require further evidence-based studies.
In this “Across the Table” edition, Drs. Cush and Erkan discuss some of these APS-related questions. Our guest expert, Dr. Doruk Erkan offers up his approach to diagnosis and management of APS. Dr. Doruk Erkan is an Associate Physician-Scientist at the Barbara Volcker Center for Women and Rheumatic Diseases, Associate Attending Rheumatologist and Clinical Researcher at Hospital for Special Surgery, and Associate Professor of Medicine at Weill Cornell Medicine. Dr Erkan is also the Executive Committee Co-chair of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) (www.apsaction.org); he was the Organization Committee Chair of the 15th International Congress on Antiphospholipid Antibodies (aPL) (www.apsistanbul2016.org), which takes place every three years.
Dr. Cush: What are the pitfalls in testing for antiphospholipid syndrome?
Dr. Erkan: The major pitfall in testing antiphospholipid antibody (aPL) is the interpretation of the results. As you know, the most commonly used tests to detect aPL are the lupus anticoagulant [LA] coagulation assay, anticardiolipin antibody (aCL) enzyme-linked immunosorbent assay [ELISA], and anti-β2-glycoprotein-I antibody (aβ2GPI) ELISA. Given that not every positive aPL test is clinically significant, it is critical to determine whether patients have ‘clinically significant’ (rather than positive or negative) aPL profiles. The following points may help:
Transient aPL positivity is common during infections. Thus documentation of persistent (at least 12 weeks apart) autoimmune aPL test is important.
A positive LA test is a better predictor of aPL-related clinical events compared with other aPL tests. However, it is important to note that false-negative/positive results may occur in warfarin-, heparin-, or direct oral anticoagulant (DOAC) - receiving patients. Thus, the test should not be ordered in anticoagulated patients.
Moderate to high titer aCL/aβ2GPI (≥40 U) correlates better with clinical events than do lower titers; IgG isotypes are more predictive than IgM isotype; and triple clinically significant aPL positivity (LA, aCL, and aβ2GPI) is more meaningful than single or double aPL.
Clinical judgment is required when interpreting the significance of aPL tests if aCL or aβ2GPI IgG/IgM titers are in the lower range (20-40 U); only one aPL determination is available; and/or aCL or aβ2GPI IgA is the only positive ELISA test.
Dr. Cush: How extensive should antiphospholipid antibody (aPL) testing be? Should we order all possible aPL tests?
Dr. Erkan: We should order all the tests discussed above; moderate-to-high titer isolated IgA aCL or aβ2GPI positive patients with a negative LA test is extremely rare but possible. Recently, several additional aPL tests have been developed; their prognostic and clinical significance are still to be determined with additional clinical studies, and most of them are not commercially available. Among them, based on the conclusions of the 14th International Congress on aPL Laboratory Diagnostics Task Force, antiphosphatidylserine/prothrombin (aPS/PT) antibodies are the most promising, which may contribute to APS diagnosis and to risk stratification in aPL-positive patients. Thus, when APS is highly suspected in LA, aCL, and aβ2GPI negative patients, aPS/PT can be considered if available.
Dr. Cush: Of those diagnosed (clinically and serologically) with the antiphospholipid syndrome - who needs to be on lifelong anticoagulation?
Dr. Erkan: Antiphospholipid Syndrome patients with vascular events generally receive life-long anticoagulation, despite the lack of high-quality data on the risk of recurrence and optimal duration of anticoagulation. Given that at least 50% of thrombotic events in aPL-positive patients have recognizable triggers, the possibility of discontinuing anticoagulation in highly selected patients exists, especially when the triggers are eliminated. However, discontinuation of anticoagulation is a critical decision that requires careful assessment of co-morbidities, triggers, and residual thrombosis as well as patient education. The 13th International Congress on aPL Treatment Task Force recommended that “in cases of first venous event, low-risk aPL profile, and a known transient precipitating factor, anticoagulation could be limited to 3–6 months.” Given the importance of this question, i.e., anticoagulation withdrawal in APS, the development of a multicenter clinical trial protocol to determine whether indefinite anticoagulation is appropriate for all APS patients, is in progress.
Dr. Cush: Is there a role of rivaroxaban or similar drugs in antiphospholipid syndrome?
Dr. Erkan: No, until further evidence is available, direct oral anticoagulants (DOACs), i.e., rivaroxaban, apixaban, edoxaban, or dabigatran are not recommended in APS patients requiring long-term anticoagulation. Firstly DOACs are not indicated in general population patients with arterial thrombosis and/or recurrent thrombosis on therapeutic anticoagulation. Secondly, a recent randomized controlled trial of warfarin vs rivaroxaban (RAPS Trial) demonstrated that rivaroxaban was inferior to warfarin (in this study, the primary outcome measure was percentage change in endogenous thrombin potential, not a clinical thrombotic event). The APS Treatment Trends Task Force of the 15th International Congress on aPL concluded that “insufficient evidence exists to make recommendations at this time regarding DOAC use in APS; the RAPS trial suggests that rivaroxaban might be useful in selected APS patients with single venous thromboembolism requiring standard-intensity anticoagulation; however, this needs to be confirmed with additional studies using clinical outcome measures”. Randomized controlled trials designed to determine the role of DOACs in the management of thrombotic APS patients are in progress.
Dr. Cush: Should hydroxychloroquine be used in all antiphospholipid antibody-positive patients?
Dr. Erkan: No, hydcroxychloroquine (HCQ) should not be used in all aPL-positive patients. Antithrombotic properties of HCQ have been established in experimental models; there are studies both in the general population and in aPL-positive/negative systemic lupus erythematosus patients suggesting that HCQ decreases the risk of thrombosis. However, well-designed controlled studies assessing the prophylactic role of HCQ against thrombosis in persistently aPL-positive patients without other systemic autoimmune diseases are still lacking. Thus, HCQ should be considered only in aPL-positive patients with lupus or lupus-like disease (primarily for non-aPL purposes), and in those with aPL-manifestations not responsive to the standard treatment.
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