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Antiphospholipid: to test, or not to test, that is the question

What applies to the UK-NHS may not apply elsewhere. The authors worry about underdiagnosis, but overdiagnosis is also a concern. False and low positive tests (for which no action is required) are common. The authors recommend treatment for persons in which a true positive test is found, but treatment may be ineffective; the dangers of overtreatment for persons falsely diagnosed are greater than the authors concede. The authors do not discuss the inaccuracy of antiphospholipid antibody (aPL) tests. Yet since the first identification of a simple test for anticardiolipin antibodies by Dr Hughes’s group in 1983, regularly scheduled workshops and international APS meetings have acknowledged difficulties with testing (2–4). These workshops have not had great success in improving the quality of commercial testing. Similarly, despite consortia dedicated to standardise lupus anticoagulant (LAC) testing (5), commercial and hospital laboratories do not routinely adhere to published recommendations (6–8). Concern about accurate testing has context. In an analysis of patients referred for APS with at least one positive aPL result, 47% had no aPL [negative aPL enzyme-linked immunosorbent assay (ELISA) and LAC test], based on the final diagnostic assessment, and only 18% fulfilled criteria for APS (9,10). In a different study of aPL-associated pregnancies, using our highly experienced core laboratories as a gold standard, 147 (53%) of the 279 patients referred as having aPL (based on commercial screening) were false positive; another 10 of 239 patients (4%) referred with negative tests had positive tests in our core laboratories – results that do not speak well for commercial laboratory testing in the United States (11). In an earlier study, we compared several commercial and research laboratories and concluded, ‘On same day specimens, the consistency of anticardiolipin (aCL) results among suppliers ranged from 64% to 88% and the correlation ranged from 0.5 to 0.8. Agreement was moderate for aCL immunologlobulin G (IgG) and aCL immunologlobulin M (IgM); however, for aCL immunologlobulin A (IgA) agreement was marginal’ (12). It is not better with LAC (6–8). In our pregnancy study cited above, 64 patients had LAC. We had used three screening tests to determine LAC. Of these, the dilute prothrombin time identified 54 (84%), the dilute Russell’s viper venom time 24 (38%), and the activated partial thromboplastin time 36 (56%). Thus, a panel of tests is necessary to exclude LAC but, the United States, insurers and hospital laboratories do not offer clinicians a menu of tests to perform. One reason is that a full aPL panel (IgG, IgM, and IgA aCL, IgG, IgM, and IgA antibody to b2-glycoprotein I, and LAC) currently costs $1085 at our hospital (Hospital for Special Surgery Laboratories, personal communication, 19 December 2011). Then there is the issue of an evidence base for recommended treatment. If an aPL test is positive, is treatment necessary? Current clinical research emphasises that risk and trigger factors are highly important initiators of thrombosis events (13), so would one advise a patient screened positive to avoid these trigger events, or would one treat prophylactically? The risk of new events in asymptomatic bearers of aPL is low, less than 2% per year for all persons with positive tests for any aPL (14), and about 5% per year in persons with ‘triple positivity’ (15); the overall risk clearly increases with non-aPL thrombosis risk factors and systemic autoimmune diseases. The risk for adverse pregnancy outcome seems to be limited to persons with LAC; women with high titre aCL without LAC, in our study, had no increased attributable risk. Although most authorities agree that anticoagulation, probably lifelong, is appropriate treatment for persons who have already suffered thrombosis, there is no definitive evidence that supports the lifelong part of the recommendation. Evidence is either In the previous issue, Graham Hughes and Yehuda Shoenfeld, world leaders in the field of antiphospholipid syndrome (APS), put forth the argument that testing for APS is not done often enough, leading to delay in diagnosis and, eventually, increase in personal, fiscal and societal costs (1). The evidence they provide is a survey of tests offered by United Kingdom-National Health Service (UK-NHS) sites, coupled with their own experiences. PERSPECT IVE