Comment on Isenberg article (Multiple serologic reactions and their relationship to clinical activity in systemic lupus erythematosus)
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Biomedical subjects
Publications and source records attributed to E N Harris.
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Anticardiolipin antibodies have recently been described in association with arterial and venous thrombosis, and with neurological symptoms, in connective tissue diseases. In a study of 70 patients with Behçet's syndrome 13 patients had these antibodies. Of these 13 patients eight had a history of either retinal vascular pathology, cerebral infarction, or thrombophlebitis. The association of retinal vascular disease and the presence of anticardiolipin antibodies was statistically significant.
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It has been suggested by several authors that so called 'primary' pulmonary hypertension may have an 'autoimmune' basis because of the clinical association of this condition with Raynaud's phenomenon, polyarthritis and its not infrequent association with other conditions affecting connective tissue, such as progressive systemic sclerosis (PSS) and systemic lupus erythematosus (SLE), often in the absence of pulmonary parenchymal disease. In addition, serum protein abnormalities, positive antinuclear factors and the occasional positive rheumatoid flocculation tests or false/positive Wasserman reaction have also been noted. Data are presented on 9 patients with this condition, in whom not only was there a high frequency of antinuclear factor present (ANA) but in addition, a higher than average incidence of antibodies to smooth muscle (SMA). Screening for antibodies to DNA, extractable nuclear antigens, anticentromere antibodies and antibodies to cardiolipin were uniformly negative. The significance of these negative results are briefly discussed.
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A new solid-phase radioimmunoassay for the detection of anticardiolipin antibodies is 200-400 times more sensitive than the precipitation method used in the Venereal Disease Reference Laboratory test. 61% of serum samples from patients with systemic lupus erythematosus (SLE) had high levels of anticardiolipin antibodies of at least one immunoglobulin class. There were strong correlations between raised anticardiolipin levels and the lupus anticoagulant, venous and arterial thrombosis, and thrombocytopenia, but no correlation with anti-DNA antibody levels. Of the 15 patients with the highest anticardiolipin titres, 6 had a history of venous thrombosis, 5 cerebral thrombosis, 5 thrombocytopenia, and 2 each pulmonary hypertension and multiple abortions. This simple immunoassay appears to have predictive value for thrombosis in SLE and related disorders.
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Antiphospholipid antibodies (APAs) may be identified in the laboratory by using either coagulation studies or solid-phase immunologic assays (ELISA; RIA). These methodologies do not necessarily evaluate the same antibody; consequently, it is appropriate to screen a patient's plasma by utilizing both assays. APAs have been associated with a variety of obstetrical complications including recurrent spontaneous abortion, intrauterine fetal death, early onset preeclampsia, deep vein thrombosis, and postpartum serositis syndrome. The Kaolin Clotting Time appears to be the most sensitive coagulation test for identifying the lupus anticoagulant. However, preliminary studies would suggest the presence of anticardiolipin antibodies as detected by solid-phase assays are more sensitive and predictive of the clinical course. Although there are no prospective trials to analyze treatment of patients with APA, preliminary data suggest the use of prednisone in combination with aspirin significantly improves the probability of delivery of a viable infant. In addition, heparin, intravenous gammaglobulin, and exchange plasmaphoresis have all been tried with varying degrees of success in individual patients in small series.
Antiphospholipid antibody, measured by enzyme-linked immunosorbent assay (ELISA) or by radioimmunoassay, and the lupus anticoagulant represent similar but different tests. The ELISA is now well standardized. It is at least partly, and possibly primarily, dependent on the presence of a cofactor, beta 2-glycoprotein I. Tests for both antiphospholipid antibody by ELISA and lupus anticoagulant should be performed in patients suspected of having this syndrome.
Sera positive for autoimmune anti-phospholipid antibodies were studied by a cell surface radioimmunoassay for their cross-reactivity with resting or activated human endothelial cells. The endothelial cell activation by interleukin 1 beta, gamma-interferon, lipopolysaccharide or phorbol-12 myristate-13 acetate did not affect the cross-reactivity. Comparable findings were also found by testing anti-cardiolipin affinity purified preparations. Taken together these data indicate that endothelial cell activation is not sufficient per se to modulate the expression of antigenic determinants recognizable by the anti-phospholipid antibodies. However, anti-cardiolipin affinity purified preparations displayed enhanced cell binding after cell membrane perturbation by paraformaldehyde fixation, suggesting that an alteration in endothelial cell integrity might further trigger the reaction of circulating anti-phospholipid antibodies with vessel walls in vivo.
Anti-phospholipids represent a heterogeneous family of antibodies able to react with the negatively charged phosphodiester groups of phospholipids. It includes the antibodies directed against the cardiolipin moiety of the VDRL antigen, the antibodies reacting with the phospholipids of the prothrombin activator complex and the antibodies able to react with solid phase cardiolipin. Data are reported indicating that reagins share distinct characteristics in comparison to the autoimmune anti-cardiolipin antibodies (ACA). On the contrary anti-phospholipid antibodies responsible for lupus-like anticoagulant activity display a quite similar reactivity with ACA, even if a complete overlapping cannot be demonstrated. The relationships between ACA and anti-DNA antibodies are also reported. The biological and clinical significance of these crossreactivities are discussed.
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We report fifteen patients, thirteen with systemic lupus and two patients with a "lupus-like" illness who developed cerebral infarction. All fifteen patients were shown to have elevated anticardiolipin antibody levels using a newly devised solid phase radioimmunoassay. The lupus anticoagulant was detected in all eleven patients tested. It is proposed that anticardiolipin antibodies and the lupus anticoagulant make up a population of antiphospholipid antibodies capable of causing cerebral vascular injury and thrombosis resulting in cerebral infarction. These antibodies may also play a pathogenic role in autoimmune disorders other than lupus where cerebral thrombotic disease is a prominent feature.
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