/ EDITORIAL

Lupus and Antiphospholipid Either, Neither, or Both

Antibody Syndrome:

MICHAEL D. LOCK-SHIN, M.D., F.A.c.P., Bethesda, Maryland

A pproximately a decade ago, rheumatologists began to codify what they knew in their hearts

to be true: that many persons said to have systemic lupus erythematosus (SLE) do not fit the “classic” or “textbook” descriptions of the disease. Physi- cians then seriously began to use, for publication purposes, a revised SLE scoring system (American Rheumatism Association [ARA, now American Col- lege of Rheumatology] Criteria for the Classifica- tion of SLE) [l]. These criteria classify patients into discrete groups: SLE or not SLE.

Also a decade ago, Harris and colleagues [2] intro- duced a simple and reproducible test for antibody to cardiolipin. The intent of this test was to simplify and standardize [3,4] a serum assay for the plasma- based, relatively unstandardized test for lupus anti- coagulant [5], but it instead identified a class of autoantibodies now generically called antiphospho- lipid antibodies (aPL) [6,7]. Many lupus clinics then broadly applied the aPL test and described the clinical events now associated with aPL: thrombotic episodes, fetal losses, and thrombocytopenia.

The early clinical events attributed to aPL were muddled because the patients came from lupus clinics and had initial diagnoses of SLE or SLE-like disease. A second wave of reports in the late 1980s rigorously applied the ARA criteria for SLE to aPL patients regardless of their initial diagnoses. To no one’s surprise, many of these patients had fewer than the four criteria needed to label a patient as having SLE. Thus, in 1989, was born the concept of the primary antiphospholipid antibody syndrome (primary APS), i.e., clinical aPL-associated events without diagnosable SLE [8-lo].

Identification of a new disease, primary APS, left

From the Extramural Program, National Institute of Arthritis and Mus- culoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

Requests for reprints should be addressed to Michael D. Lockshin, M.D., F.A.C.P., Extramural Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 31, Room 4C-32, Bethesda, Maryland 20892.

Manuscript submitted February 15, 1993, and accepted March 8, 1993.

unanswered several important questions: do the clinical events associated with aPL result from pre- sent or subclinical SLE, from antibody alone, or from both together? Will patients with primary APS later develop SLE? Inherent in these ques- tions is a more basic question: is aPL directly patho- genic or is it merely a footprint of a past event and irrelevant to the event’s causation?

In this issue of the Journal, Vianna et al [ll] begin to sort out these questions. Using an interna- tional, multicenter cooperation now well organized between London and Barcelona, the authors have gathered together a sizable number of patients who have aPL and who clinically cleanly fit into either the primary APS or the SLE (secondary APS) com- partment. The authors then compared the primary APS and the secondary APS groups side by side.

Their conclusions are not startling but are very useful for future thinking. Compared with primary APS patients, secondary APS patients experience more neutropenia, autoimmune hemolytic anemia, endocardial vegetations, and low C4 levels. Anti- DNA and anti-ENA antibodies were exclusion cri- teria for primary APS patients, but the primary APS and the secondary APS patients are otherwise serologically and clinically similar. The authors do not discuss lupus glomerulonephritis, but other in- vestigators have commented that, in SLE, an in- verse relationship exists between aPL and inflam- matory renal disease [12]. Although the follow-up in the present study is short, patients with primary APS do not appear to develop SLE. Sadly, however, under standard care, both they and secondary APS patients do develop further clotting events.

Vianna et al [ll] have provided information that will allow doctors cleanly to sort which pathology is due to SLE and which to aPL. In doing so, they clarify our thinking about both SLE and primary APS. By demonstrating similar aPL-associated symptoms in both patient groups, and an absence of SLE-associated symptoms in the primary APS group, Vianna’s clinical data support the concept that aPL are directly responsible for the symptoms associated with their presence. These data also vali- date the animal models of primary APS now being developed [13-X], and the animal models, in turn, provide the standardized experimental situations

January 1994 The American Journal of Medicine Volume 96 1

LUPUS AND aPL SYNDROME / LOCKSHIN

in which more effective treatment interventions can be tried.

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2. Harris EN, Gharavi AE, Boey ML, et a/. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythe- matosus. Lancet 1983; 2: 1211-4.

3. Harris EN, Gharavi AE, Pate1 SP, Hughes GRV. Evaluation of the anticardiolipin

antibody test: report of an international workshop held on 4April, 1986. Clin Exp lmmunol 1987; 69: 215-22.

4. Harris EN. The Second International Anticardiolipin Antibody Standardization Workshop/the Kingston Antiphospholipid Antibody Study (KAPS) Group. Am J Clin Pathol 1990; 94: 476-84.

5. Triplett DA. Coagulation assays for the lupus anticoagulant: review and cri- tique of current methodology. Stroke 1992; 23 Suppl 2: 11-4.

6. McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv lmmunol 1991; 49: 193-280.

7. Sammaritano LR, Gharavi AE, Lockshin MD. Antiphospholipid antibody syn- drome: immunologic and clinical aspects. Semin Arthritis Rheum 1990; 20:

81-96.

6. Asherson RA, Khamashta MA, Ordi-Ros J, et al. The ‘primary’ antiphospholi- pid antibody syndrome: major clinical and serologic features. Medicine (Balti- more) 1989; 68: 366-74. 9. Alarcon-Segovia D, Sanchez-Guerrero J. Primary antiphospholipid syndrome. J Rheumatol 1989; 16: 482-8.

10. Mackworth-Young C, Loizou S, Walport M. Primary antiphospholipid syn-

drome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis 1989; 4.81 362-7.

11. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome. A European multicenter study of 114 patients. Am J Med 1994; 96: 3-9.

12. lshii Y, Nagasawa K, Mayumi T, Niho Y. Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. Ann Rheum Dis

1990; 49: 387-90.

13. Gharavi AE, Sammaritano LR, Wen J, Elkon K. Induction of antiphospholipid autoantibodies by immunization with beta-2 glycoprotein 1 (apolipoprotein H). J Clin Invest 1992; 90: 1105-g.

14. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonai anticardiolipin antibodies. Proc Natl Acad Sci U S A 1991; 88: 3069-73.

15. SumidaT, Yoshida S, Matsuura E, lkehara S. KoikeT. Anticardiolipin antibod- ies in NZW X BXSB Fl mice. A model of antiphospholipid antibody syndrome. J

lmmunol 1992; 149: 1063-8.

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