Sessa A, Meroni M, Gattini G (eds): Systemic Lupus erythematosus: Renal Vasculitis. Contrib Nephrol. Basel, Karger, 1992, vol 99, pp 123-125
Clinical Implication of Antiphospholipid Antibodies in Systemic Lupus erythematosus P. Stratta, C. Canavese, A. Thea, G. Tognarelli, M. Dogliani, M.C. Porcu, G. Garis, A. Borchiellini, P.C. Schinco, A. Vercellone
Antiphospholipid antibodies (APA) are one of the now well-recognised classes of antibodies detected in SLΕ and other autoimmune diseases [ 1]. They have been, however, described even outside of the autoimmune orthodox clinical disease (`primary' antiphospholipid syndrome) [2], and in all cases a strong association with multiple thrombosis and recurrent abortion has been universally recognised [3-5]. APA are a group of antibodies directed against negatively charged phospholipid antigens, which are widespread in nature, for example, in endothelial cell membranes, platelets, and brain tissue [6]. The traditional tests for these antibodies were: (a) the Wassermann reaction or Venereal Disease Research Laboratory (detecting anticardiolipin), and (b) the lupus anticoagulant test able to detect a functional factor interfering with the clotting assay. Recently, more sensitive immunoassays have been developed: solidphase radioimmunoassays for anticardiolipin (up to 400 times more sensitive than the VDRL test) and ELISA systems for IgG, IgM, IgA with specificity for different phospholipid antigens. Reciprocal correlations between these different tests and the true significance of such a kind of autoantibody in terms of clinical implication and pathogenesis of disease are still a matter of study. The aim of this work was to evaluate the incidence, the mutual relationship, and the clinical implications of these antibodies in our patients with SLΕ.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:29:05 AM
Departments of Nephrology, Medicine and Experimental Oncology (Hematology Section), University of Turin, Italy
Stratta et al.
124
Patients and Methods 124 patients satisfying the criteria of the American Rheumatism Association for the diagnosis of SLΕ were followed in our Renal Unit since 1970. The following parameters were recorded for this study: Wassermann or VDRL tests, lupus-like anticoagulant (LLAC) test, using the activated partial thromboplastin time assay (APTT) and kaolin clotting time which is not corrected by the in vitro addition of normal plasma; antiphospholipid antibodies (using solid-phase enzyme-linked immunosorbent in microtiter plates coated with a mixture of cardiolipm, phosphatidic acid, phosphatidylserine, phosphatidylethanolamine) (Asserachron, Stago). Clinicopathologic associations with extrarenal complications (thrombosis, neurological involvement, thrombocytopenia, antiplatelet antibodies) were also investigated.
Results In the first 10 years (1970-1980) only the Wassermann and VDRL tests together with AP'AT were available, while the LLAC test was performed in the next years and ΑPΑ were employed only in the last year. In the pre-LLAC years, prolonged APTT was recorded in 23.8% of patients, all suffering from thrombosis and or C'S involvement [7]. In the following year, LLAC resulted positive in 17/54 (31.4%) patients. Α comparison between LLAC-positive (n = 17) and LLAC-negative (n = 37) patients shows that in the former group RW-positive test (57 vs. 33%), prolonged APTT (75 vs. 5%) and thrombocytopenia (56 vs. 20%) are significantly more frequent, while antiplatelet antibodies do not (34 vs. 47%). As to clinical correlations, both thrombosis (64.5 vs. 11%) and C'S involvement (70.5 vs. 2.7%) are consistently more frequent in LLAC-positive patients. As to the renal histological picture, the presence of thrombi was not differently represented in both groups (20 vs. 25%); it is interesting that in the LLAC-positive patients a peculiar pattern of atherosclerotic damage without any other significant changes was shown in 50% of the cases. ΑPΑ was detectable in 45% of the LLAC-positive patients, and they always belonged to the IgG class.
In agreement with previous reports, a LLAC-positive test was, in our experience, strongly associated with prolonged APTT, thrombocytopenia, thrombosis and C'S involvement. Again as previously reported, RW or VDRL were frequently positive in LLAC-positive patients. When present, ΑPΑ were of the IgG class as in other studies. However, though in a small sample, ΑPΑ were more frequently negative than expected in LLAC-positive
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:29:05 AM
Discussion
Clinical Implιcation of Antiphospholipid Antibodies in SLE
125
patients. The lack of correlation can be explained by the difference in test sensitivity, in antibody specificity, and/or in the different conformational state of the phospholipid employed. In other words, though a mixture of phospholipid is used in the ELISA, it could be that this mixture cannot cover the range of antibodies responsible for the functional result in LLAC test. Thus, we conclude that, as screening for evaluating the risk of thrombosis or C'S involvement in lupus patients, a rationale algorithm cannot avoid a LLAC assay as the first step. The potential usefulness of APA is greater than that of LLAC in that they allow a better possibility for a quantitative parameter (susceptible to correlation) and for more specific recognition of specific antibodies against specific antigens, able to increase the knowledge into the pathogenesis. However, the mixture available up to now seems less sensitive than LLAC, as confirmed in a recent larger study [ 10], in predicting thrombosis or C'S involvement in lupus nephritis.
References
Dr. Piero Stratta, Department of Nephrology, S. Giovanni-Molinette Hospital, Corso Bramante 88, I-10126 Torino (Italy)
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1 Mackworth-Young CG, Loizou S, Walport MJ: Antiphospholipid antibodies and disease. Q J Med 1989;269:767-777. 2 Hughes GRV, Asherson RA, Khamashta MA: The antiphospholipid syndrome — from theory to discovery. Postgrad Med J 1989;65:691-704. 3 Editorial: Lupus anticoagulant. Lancet 1984;i:1157-1158. 4 Perico N, Pusineri F, Remuzzi G: The lupus anticoagulant. Proc Soc Exp Biol Med 1984;176:337-341. 5 Hughes RV, Kamashta MA: Anticardiolipin antibody. Br Med J 1989;299:1414-1415. 6 Hughes GRV: Autoantibodies in lupus and its variants: Experience in 1,000 patients. Br Med J 1984;289:339-342. 7 Stratta P, Canavese C, Valmaggia P, Rotunno M, Levi E, Bulla A, Vercellone A: Coagulation and fibrinolysis study in systemic lupus erythematosus: Haematological, urinary and tissue parameters. Thromb Haemost 1981;46:575-580. 8 Galli M, Comfurius P, Maassen C, Hemker HC, De Baets ΜΗ, Van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM: Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet l990;í:1544-1547. 9 MacNeil HP, Simpson RJ, Chesterman CN, Krilis SA: Antiphospholipid antibodies are directed against a complex antigen that include a lipid-binding inhibitor of coagulation: Beta-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120-4124. 10 Frampton G, Hiks J, Cameron JS: Significance of anti-phospholipid antibodies in patients with lupus nephritis. Kidney Int 1991;39:1225-1231.
Clinical Implication of Antiphospholipid Antibodies in Systemic Lupus erythematosus P. Stratta, C. Canavese, A. Thea, G. Tognarelli, M. Dogliani, M.C. Porcu, G. Garis, A. Borchiellini, P.C. Schinco, A. Vercellone
Antiphospholipid antibodies (APA) are one of the now well-recognised classes of antibodies detected in SLΕ and other autoimmune diseases [ 1]. They have been, however, described even outside of the autoimmune orthodox clinical disease (`primary' antiphospholipid syndrome) [2], and in all cases a strong association with multiple thrombosis and recurrent abortion has been universally recognised [3-5]. APA are a group of antibodies directed against negatively charged phospholipid antigens, which are widespread in nature, for example, in endothelial cell membranes, platelets, and brain tissue [6]. The traditional tests for these antibodies were: (a) the Wassermann reaction or Venereal Disease Research Laboratory (detecting anticardiolipin), and (b) the lupus anticoagulant test able to detect a functional factor interfering with the clotting assay. Recently, more sensitive immunoassays have been developed: solidphase radioimmunoassays for anticardiolipin (up to 400 times more sensitive than the VDRL test) and ELISA systems for IgG, IgM, IgA with specificity for different phospholipid antigens. Reciprocal correlations between these different tests and the true significance of such a kind of autoantibody in terms of clinical implication and pathogenesis of disease are still a matter of study. The aim of this work was to evaluate the incidence, the mutual relationship, and the clinical implications of these antibodies in our patients with SLΕ.
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:29:05 AM
Departments of Nephrology, Medicine and Experimental Oncology (Hematology Section), University of Turin, Italy
Stratta et al.
124
Patients and Methods 124 patients satisfying the criteria of the American Rheumatism Association for the diagnosis of SLΕ were followed in our Renal Unit since 1970. The following parameters were recorded for this study: Wassermann or VDRL tests, lupus-like anticoagulant (LLAC) test, using the activated partial thromboplastin time assay (APTT) and kaolin clotting time which is not corrected by the in vitro addition of normal plasma; antiphospholipid antibodies (using solid-phase enzyme-linked immunosorbent in microtiter plates coated with a mixture of cardiolipm, phosphatidic acid, phosphatidylserine, phosphatidylethanolamine) (Asserachron, Stago). Clinicopathologic associations with extrarenal complications (thrombosis, neurological involvement, thrombocytopenia, antiplatelet antibodies) were also investigated.
Results In the first 10 years (1970-1980) only the Wassermann and VDRL tests together with AP'AT were available, while the LLAC test was performed in the next years and ΑPΑ were employed only in the last year. In the pre-LLAC years, prolonged APTT was recorded in 23.8% of patients, all suffering from thrombosis and or C'S involvement [7]. In the following year, LLAC resulted positive in 17/54 (31.4%) patients. Α comparison between LLAC-positive (n = 17) and LLAC-negative (n = 37) patients shows that in the former group RW-positive test (57 vs. 33%), prolonged APTT (75 vs. 5%) and thrombocytopenia (56 vs. 20%) are significantly more frequent, while antiplatelet antibodies do not (34 vs. 47%). As to clinical correlations, both thrombosis (64.5 vs. 11%) and C'S involvement (70.5 vs. 2.7%) are consistently more frequent in LLAC-positive patients. As to the renal histological picture, the presence of thrombi was not differently represented in both groups (20 vs. 25%); it is interesting that in the LLAC-positive patients a peculiar pattern of atherosclerotic damage without any other significant changes was shown in 50% of the cases. ΑPΑ was detectable in 45% of the LLAC-positive patients, and they always belonged to the IgG class.
In agreement with previous reports, a LLAC-positive test was, in our experience, strongly associated with prolonged APTT, thrombocytopenia, thrombosis and C'S involvement. Again as previously reported, RW or VDRL were frequently positive in LLAC-positive patients. When present, ΑPΑ were of the IgG class as in other studies. However, though in a small sample, ΑPΑ were more frequently negative than expected in LLAC-positive
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:29:05 AM
Discussion
Clinical Implιcation of Antiphospholipid Antibodies in SLE
125
patients. The lack of correlation can be explained by the difference in test sensitivity, in antibody specificity, and/or in the different conformational state of the phospholipid employed. In other words, though a mixture of phospholipid is used in the ELISA, it could be that this mixture cannot cover the range of antibodies responsible for the functional result in LLAC test. Thus, we conclude that, as screening for evaluating the risk of thrombosis or C'S involvement in lupus patients, a rationale algorithm cannot avoid a LLAC assay as the first step. The potential usefulness of APA is greater than that of LLAC in that they allow a better possibility for a quantitative parameter (susceptible to correlation) and for more specific recognition of specific antibodies against specific antigens, able to increase the knowledge into the pathogenesis. However, the mixture available up to now seems less sensitive than LLAC, as confirmed in a recent larger study [ 10], in predicting thrombosis or C'S involvement in lupus nephritis.
References
Dr. Piero Stratta, Department of Nephrology, S. Giovanni-Molinette Hospital, Corso Bramante 88, I-10126 Torino (Italy)
Downloaded by: National Univ. of Singapore 137.132.123.69 - 3/27/2017 5:29:05 AM
1 Mackworth-Young CG, Loizou S, Walport MJ: Antiphospholipid antibodies and disease. Q J Med 1989;269:767-777. 2 Hughes GRV, Asherson RA, Khamashta MA: The antiphospholipid syndrome — from theory to discovery. Postgrad Med J 1989;65:691-704. 3 Editorial: Lupus anticoagulant. Lancet 1984;i:1157-1158. 4 Perico N, Pusineri F, Remuzzi G: The lupus anticoagulant. Proc Soc Exp Biol Med 1984;176:337-341. 5 Hughes RV, Kamashta MA: Anticardiolipin antibody. Br Med J 1989;299:1414-1415. 6 Hughes GRV: Autoantibodies in lupus and its variants: Experience in 1,000 patients. Br Med J 1984;289:339-342. 7 Stratta P, Canavese C, Valmaggia P, Rotunno M, Levi E, Bulla A, Vercellone A: Coagulation and fibrinolysis study in systemic lupus erythematosus: Haematological, urinary and tissue parameters. Thromb Haemost 1981;46:575-580. 8 Galli M, Comfurius P, Maassen C, Hemker HC, De Baets ΜΗ, Van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM: Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet l990;í:1544-1547. 9 MacNeil HP, Simpson RJ, Chesterman CN, Krilis SA: Antiphospholipid antibodies are directed against a complex antigen that include a lipid-binding inhibitor of coagulation: Beta-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120-4124. 10 Frampton G, Hiks J, Cameron JS: Significance of anti-phospholipid antibodies in patients with lupus nephritis. Kidney Int 1991;39:1225-1231.
