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EDITORIAL

ANTICARDIOLIPIN ANTIBODY

MICHAEL D. LOCKSHIN

Studies on antiphospholipid antibodies are be- ing published almost daily. Syndromes associated with antiphospholipid antibodies are defined, and publicly adopted, with various degrees of both fervor and accuracy (1-3). Practicing rheumatologists respond by devising therapies that are perceived to be of benefit. However, because much of current practice is based on 3 unproved assumptions, there is reason for con- cern. These assumptions are: (a) that the associations between antiphospholipid antibodies and stroke, other thrombosis, or fetal death are extremely close associ- ations, (b) that the demonstration of one antiphospho- lipid antibody (such as biologic false-positive test result for syphilis) implies the presence of another (such as anticardiolipin antibody or lupus anticoagul- ant), and (c) that therapy directed at the identified antibody is beneficial.

The paper by Sturfelt and coworkers, which appears elsewhere in this issue of Arthritis and Rheu- matism (4), is a step toward common sense. These Swedish authors present data which were obtained from studying a small group of unselected and (pre- sumably) ethnically homogeneous lupus patients. The data allow the reader to estimate, at a specific point in time, the sensitivities and specificities of anticardi- olipin antibody as predictors of various clinical events. In concluding that no associations exist, the authors are almost certainly guilty of a Type I1 error, since

they calculate probabilities of an association of a common laboratory abnormality (anticardiolipin) with rare events. Neurologic disease was identified in only 14 of their patients (23% of the entire population), and thrombocytopenia in only 6 (10%). They did not study second trimester fetal death. Had the authors asked the questions the other way around (i.e., how likely is it that a patient with a suspect event has anticardiolipin antibody?), or had the affected populations been larger, the conclusions would have been different. Nonetheless, the authors make the points that anticar- diolipin antibody may be present in asymptomatic patients, and that a change in titer does not predict the occurrence of either a clinical event or a remission. The first of the above assumptions, that clinical asso- ciations of anticardiolipin antibody are both strong and explanatory, must therefore be tempered with clinical reality.

Regarding the second assumption, there is am- ple evidence that the results of tests for syphilis, lupus anticoagulant, and anticardiolipin antibody are not equivalent. Phospholipid immunochemistry is com- plex (5-10). The following factors demonstrably affect the outcomes of antiphospholipid antibody assays: whether phospholipid is adherent to a surface or is in particulate suspension; which immunoglobulin class or subclass is analyzed; whether monoclonal or poly- clonal antibodies are analyzed; which phospholipid is used as the antigen; whether there is more than one phospholipid in the reaction mixture; whether a fatty acid chain(s) is saturated; whether fatty acid chains are short or long; whether lysophospholipids are present; the temperature of the reaction mixture; the pH of the

and magnesium. Caution is therefore necessary in the

From the Hospital for Special Surgery, the New York Hospital<ornell University Medical college, New york, New York.

Michael D. Lockshin, MD: Professor of Medicine. Address reprint requests to Michael D. Lockshin, MD,

Hospital for Special Surgery, 535 East 70th Street, New York, NY reaction mixture; and the concentrations Of calcium 10021.

Arthritis and Rheumatism, Vol. 30, No. 4 (April 1987)

472 LOCKSHIN

translation of one assay to another, and in the trans- lation of an in vitro phenomenon to clinical practice.

In direct comparisons, the various antiphospho- lipid antibody assays are not equivalent. In clinical studies, anticardiolipin antibody is more frequently present in patients than is the lupus anticoagulant or a biologic false-positive VDRL. Anticardiolipin anti- body and lupus anticoagulant are discordant in as many as 35% of patients; anticardiolipin antibody and biologic false-positive VDRL are discordant in more than 50% of patients. Anticardiolipin antibody (in contrast to lupus anticoagulant) responds poorly to corticosteroid therapy; it does not reflect the clinical activity of lupus; it does not cross-react with DNA. Although anticardiolipin, biologic false-positive VDRL, and lupus anticoagulant antibodies are related, clinical associations suggested for one of these anti- bodies are not necessarily valid for another.

Regarding the third assumption, that therapy is necessary for patients with anticardiolipin antibody, there are no clinical trials yet available that justify prophylactic use of corticosteroid for any clinical association of either anticardiolipin antibody or for lupus anticoagulant, and there are no studies that justify any treatment at all for a biologic false-positive VDRL alone. Sturfelt anecdotally demonstrates that rising antibody titers do not predict thrombotic events and, thus, by implication, do not justify therapy. Other papers relate successful pregnancies that have fol- lowed corticosteroid treatment of women with prior fetal losses. These papers have given little attention to spontaneous disappearance of antibody or to normal pregnancy without treatment, both of which clearly occur. The papers also ignore successes attributable to modern interventionist obstetrics and perinatology , and they underestimate long-term toxic effects of corticosteroid therapy. No justification has yet been published for the increasingly frequent practice of treating patients prior to conception. Whether anti- coagulation with aspirin or heparin is beneficial to threatened pregnancies is also undocumented.

Information about antiphospholipid antibody

and its clinical associations is increasing rapidly. It is certain that this knowledge will lead to new clinical insights, new forms of therapy, and new clues regard- ing the etiology and pathogenesis of systemic lupus erythematosus. It is also likely that pursuit of this topic will yield basic information about the biology of coagulation, pregnancy, lipid metabolism, and mem- brane physiology. At this time, however, not enough confirmed clinical information is available to justify any but the most tentative therapeutic recommendations.

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Hams EN, Gharavi AE, Hughes GRV: Anti-phospho- lipid antibodies. Clin Rheum Dis 115914509, 1985 Hughes GRV, Harris EN, Gharavi AE: The anti- cardiolipin syndrome. J Rheumatol 13:486489, 1986 Vermylen J, Blockmans D, Spitz B, Deckmyn H: Thrombosis and immune disorders. Clin Haematol 15:393-412, 1986 Sturfelt G, Nived 0, Norberg R, Thorstensson R, Krook K: Anticardiolipin antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 30:382-388, 1987 Eilat D, Zlotnick AY, Fischel R: Evaluation of the cross-reaction between anti-DNA and anti-cardiolipin antibodies in SLE and experimental animals. Clin Exp Immunol65:269-278, 1986 Eilat D: Anti-DNA antibodies: problems in their study and interpretation. Clin Exp Immunol 65:215-222, 1986

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