Low levels of total cholesterol high-density lipoprotein and apolipoprotein a1 in association with anticardiolipin antibodies in patients with systemic lupus erythematosus.
код для вставкиСкачатьARTHRITIS & RHEUMATISM Volume 36 Number 11, November 1993, pp 1566-1574 0 1993, American College of Rheumatology 1566 LOW LEVELS OF TOTAL CHOLESTEROL, HIGH-DENSITY LIPOPROTEIN, AND APOLIPOPROTEIN A1 IN ASSOCIATION WITH ANTICARDIOLIPIN ANTIBODIES IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS R. G. LAHITA, E. RIVKIN, I. CAVANAGH, and P. ROMANO Objective. To determine if there is an association between low levels of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (Apo Al), total cholesterol, and anticardiolipin antibody (aCL) in patients with systemic lupus erythematosus (SLE) who are not taking corticosteroids. Methods. We studied 75 outpatients with documented SLE who were attending our hospital clinics: 57 were aCL positive and 18 were aCL negative. Both IgG and IgM aCL levels were determined by enzyme-linked immunosorbent assay. Lipid fractions (total cholesterol, HDL, low-density lipoprotein, very-low-density lipoprotein, and trigtycerides) were determined by standard enzymatic techniques. Apo A1 and Apo B levels were determined by nephelometry. Results. Patients with SLE who were IgG aCL+ had low levels of serum cholesterol (mean f SD 173.6 f 34.6 mg/dl) and HDL (43.9 2 16.3 mgldl) compared with aCL- SLE patients, normal donors, and patients with other diseases. Apo A1 levels were also low in the aCL+ group (95.5 -+ 50.9 mg/dl) compared with the aCL- group (152.7 f 32.6 mg/dl). There was no Presented in part at the 55th Annual Meeting of the American College of Rheumatology, Boston, MA, November 1991. From the Saint Luke’s Roosevelt Medical Center, Columbia University, New York, New York, and Clinical Diagnostic Laboratories, Englewood, New Jersey. R. G. Lahita, MD, PhD: Saint Luke’s Roosevelt Medical Center, Columbia University; E. Rivkin, PhD: Saint Luke’s Roosevelt Medical Center, Columbia University; I. Cavanagh, MS: Saint Luke’s Roosevelt Medical Center, Columbia University; P. Romano, MD: Clinical Diagnostic Laboratories. Address reprint requests to Robert G. Lahita, MD, PhD, Chief, Division of Rheumatology and Connective Tissue Diseases, Saint Luke’s Roosevelt Hospital Center, 432 West 58th Street, New York, NY 10019. Submitted for publication November 21, 1991; accepted in revised form April 14, 1993. association of total cholesterol level or aCL titer with clinical activity. Conclusion. These data indicate that in SLE patients, there is an association between antibody against the phospholipid cardiolipin and low levels of cholesterol, HDL, and Apo Al. Many mechanisms have been proposed for the actions of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE) (1,2). These include aCL binding to endothelial cells or platelets via membrane phospholipids, with consequent disruption of such functions as prostacyclin release, fibrinolysis, protein C pathways, or platelet aggregation. However, recent evidence indicates that membrane binding of antibody to phospholipid alone is unlikely, because a lipidprotein epitope has been found which may be the principal target of these antibodies in patients with lupus and related diseases. Anticardiolipin antibodies can be found in 3040% of patients with SLE (3) or related illnesses (4), those exposed to certain drugs (5) or infections (6), and patients with a malignancy (7), as well as in approximately 6% of normal individuals (8,9), increasing with age. The incidence of cardiovascular events, such as myocardial infarction and cerebral thrombosis, is reported to be increased in men and women with SLE (lo), and atherosclerosis is known to be accelerated in this patient group (11,12). There is certainly an association of thrombotic events with aCL, but the relationship of this antibody to atherosclerosis is unclear. Apart from the suggested appearance of atherosclerosis in SLE patients as a result of long-term steroid therapy, no explanation for the accelerated atherosclerosis has been proposed. LOW LEVELS OF HDL AND APO A1 IN SLE The data we present here suggest that there is an association between anticardiolipin antibody and low levels of total cholesterol, high-density lipoprotein (HDL), and apolipoprotein A1 (Apo Al) in patients with SLE. PATIENTS AND METHODS Patient selection. Patients were selected from the Rheumatology Service of Saint Luke’s Roosevelt Hospital Center of Columbia University. Such patients formed several groups. There were 97 patients with SLE who fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) criteria (13), only 75 of whom were not taking steroids at the time of the study. A series of 54 patients with other rheumatic diseases also were studied. These included 9 patients with rheumatoid arthritis, 10 patients with osteoarthritis, 4 patients with inflammatory muscle disease, and 31 patients with other inflammatory diseases. The patients with the other inflammatory diseases included 5 patients with tendinitis, 1 with fibromyalgia, 5 with mixed connective tissue disease, 4 with Sjogren’s syndrome, 1 with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias), 1 with subacute cutaneous lupus, 1 with vasculitis, 1 with urticaria, 6 with scleroderma, 1 with dermatomyositis, 1 with Still’s disease, 1 with Reiter’s syndrome, 2 with discoid lupus, and 1 with Lyme disease. A total of 72 normal volunteer blood donors also served as a control group. Blood samples were drawn in the early morning in all cases. Although the patients were not necessarily fasting, fasting samples would have favored the results of normal-tolow plasma cholesterol levels. Antibody, lipid, and apolipoprotein analyses were done on the same samples in all cases. Since cholesterol levels are raised by the presence of renal disease and by the ingestion of steroids, such patients were eliminated from analysis. Those with other confounding variables, such as diabetes, liver disease, and ingestion of certain lipid-raising drugs, which might affect apolipoprotein levels were also eliminated from the final study population. Anticardiolipin antibodies. Serum aCL levels were determined by a solid-phase enzyme-linked immunosorbent assay, as described by Loizou et a1 (14) and modified by Gharavi et a1 (15). Sera were diluted 1:lOO and samples were placed in a 96-well flat-bottomed polystyrene 350 IU immunoplate (Beckman, Palo Alto, CA). Reagents used were cardiolipin (Sigma, St. Louis, MO), at a concentration of 50 pg/ml and coated on the plate by evaporation at 4°C for 12 hours, alkaline phosphatase-conjugated monospecific goat anti-human y chain or anti-p chain antibodies (Cappel, Baltimore, MD), p-nitrophenyl phosphate substrate (Sigma #104), phosphate buffered saline (PBS), pH 7.4, 10% fetal calf serum (FCS) in PBS, and glycine buffer. The enzymatic reaction was read at 405 nm on a Titertek multiscan MC 340 (Flow, McLean, VA). Wells used as blanks contained 10% FCS in PBS instead of the target sera. Known positive and negative sera were provided to us by Dr. Nigel Harris (University of 1567 Louisville Medical College, Louisville, KY). Standard normal values used in our laboratory are 0-15 units IgG aCL and 0 4 units IgM aCL. Analysis of lipids. Total cholesterol and HDL levels were measured with a Hitachi 736-30 analyzer (Boehringer Mannheim, Indianapolis, IN). The Hitachi utilizes an enzymatic methodology, which is based on a colorimetric reaction. Samples are read photometrically. The method utilizes the enzymatic reaction of cholesterol with peroxidasei phenol-4-aminophenazone. Microbial esterase produces complete hydrolysis of all cholesterol esters that occur in human sera, thus allowing standardization by primary and secondary standards and direct comparison to the Centers for Disease Control and Prevention (Atlanta, GA) reference procedures (16,17). Serum levels of all lipids were determined within 24 hours after drawing samples of blood. HDL levels were determined by precipitation of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) with phosphotungstic acid and magnesium ions. Subsequent centrifugation left only the HDL fraction in the supernatant, which was then measured photometrically (18). Triglyceride levels were determined by the glycerol phosphate oxidase technique following enzymatic cleavage of fatty acids (Boehringer Mannheim). It was not possible to measure all lipid fractions in all patients. However, cholesterol and HDL were measured in all patients in whom anticardiolipin antibodies were determined. Measurement of apolipoproteins A1 and B. Levels of human Apo A1 and B were determined by nephelometry (Behring Diagnostic Company, Marburg, Germany) of serum samples that had been stored at -40°C. Standard antisera and antigens for apolipoprotein were a gift from Behring Diagnostics. Standard curves revealed that the standard range for Apo A1 was 105-215 mg/dl and that for Apo B was 59-155 mg/dl. Single-point analysis of patient sera indicated that they fell within the confidence limits of 15% of the control sera. Clinical activity. Clinical activity was measured according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), as previously described (19). Statistical analysis. Statistical analysis was performed with the BMDP statistical programs (BMDP, Los Angeles, CA) on a personal computer. These programs were simple data description, comparison of 2 groups with t-tests, and description of groups (strata) with histograms and analysis of variance. * RESULTS T h e sex and age distribution and mean aCL titers of the 75 SLE patients studied are given in Table 1 . The 72 SLE patients who were not taking prednisone had lower cholesterol levels (mean SD 180.9 39.3 mg/dl, range 10CL275) than did the group of 72 normal blood donors (236.5 2 46.2 mg/dl, range 14& 330). This difference was significant, at a level of P = 0.001. * * LAHITA ET AL 1568 In 22 patients with SLE who were taking 5-30 mg/day of prednisone, the overall cholesterol level (186.5 t 55.0 mg/dl, range 115405) was not significantly increased compared with that in the group of SLE patients who were not taking steroids. Cholesterol values were lower in the non-steroid-treated patients regardless of aCL status. Because the cholesterol levels of patients using corticosteroids were elevated, their data were eliminated from analysis and not a part of this study. Cholesterol and HDL values in IgG aCL+ SLE patients were compared with those in IgG aCL- SLE patients, revealing lower cholesterol levels ( P = 0.02) and lower HDL levels ( P = 0.03) in the aCL+ SLE patients (Figure 1). Chi-square analysis of the aCL+ versus the aCL- SLE patients, regardless of sex (Figure 2), showed that more patients with cholesterol values <180 mg/dl were aCL+ (76% and 25%, respectively; P = 0.0005). Comparison of the lipid values in male and female aCL+ patients with those in the group of 72 normal donors showed significantly lower cholesterol and HDL levels in the aCL+ patients (Table 2). We also compared these plasma lipid profiles with those in patients with immunologic diseases other than SLE (Table 2). There was a significantly lower level of total cholesterol compared with this group as well ( P < 0.001). Although differences in the VLDL levels also reached significance ( P = 0.03), the low numbers of subjects in the normal control group and in the group of patients with other immunologic diseases invalidate this comparison; likewise, differences in HDL levels were also invalid. Table 1. Anticardiolipin antibody (aCL) titers and mean ages of the 75 patients with systemic lupus erythematosus (SLE), categorized by sex aCL+ SLE patients No. of patients Age Mean t SD Range IgG aCL titer (mean t SD) aCL- SLE patients No. of patients Age Mean t SD Range IgG aCL titer (mean 2 SD) Males (n = 16) Females (n = 59) 14 43 31.4 5 17.4 10-63 31.5 +- 18.4 39.7 f 14.3 17-72 30.9 f 15.6 2 16 50.1 2 17.7 7*4 38.5 t 14.3 23-56 10.1 f 3.7 250 * ** T T 200 rz ** P= 3 0.02 e 5 loo 50 0 aCLUPlD FRACTIONS aCL+ Figure 1. Comparison of lipid fractions in systemic lupus erythematosus patients with and without anticardiolipin antibodies (aCL). Both the cholesterol (CHOL) and high-density lipoprotein (HDL) fractions were significantly decreased in the aCL+ group; triglycerides (TRIG) were increased. Values are the mean and SD. LDL = low-density lipoprotein: VLDL = very-low-density lipoprotein. P = 0.0005 cn c Y .o 15 Y O n 10 - 5 - 0 L < L 140 140-180 180-225 >225 Cholesterol Figure 2. Cholesterol levels in aCL+ and aCL- systemic lupus erythematosus (SLE) patients, showing that a highly significant number of aCL+ SLE patients had cholesterol levels <180 mg/dl (P = 0.0005 by chi-square analysis). See Figure 1 for abbreviations. LOW LEVELS OF HDL AND APO A1 IN SLE 1569 Table 2. Comparison of plasma lipid profiles of aCL+ SLE patients with those in patients with other immunologic diseases and in normal control subjects* Chol aCL+ SLE patients Mean f SD mg/dl No. of patients Other immunologic disease patients Mean f SD mg/dl No. of patients Normal controls Mean f SD mg/dl No. of subiects HDL LDL 43.9 f 16.3$: 116.7 f 32.7 33 24 173.6 t 34.6t 56 Trig VLDL 121.7 f 83.9 23 23.9 f 7.0 7 17 133.0 f 29.4 11 145.9 ? 127.2 27 37.5 44 236.5 t 46.2 72 58.8 t 23.7 62 161.5 f 40.0 6 185.3 f 153.0 75 50.0 209.9 f 44.9 54.3 f 13.7 f 0.7 2 f 11.3 2 * Patients with other immunologic diseases were as follows: 5 with tendinitis, 1 with fibromyalgia, 5 with mixed connective tissue disease, 4 with Sjogren’s syndrome, 1 with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias), 1 with subacute cutaneous lupus, 1 with vasculitis, 1 with urticaria, 6 with scleroderma, 1 with dermatomyositis, 1 with Still’s disease, 1 with Reiter’s syndrome, 2 with discoid lupus, and 1 with Lyme disease. aCL+ = anticardiolipin antibody positive; SLE = systemic lupus erythematosus; Chol = cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein; Trig = triglycerides; VLDL = very-low-density lipoprotein. t P < 0.001 versus patients with other rheumatic diseases, and P = 0.003 versus normal controls. $: P < 0.001 versus patients with other rheumatic diseases, and P < 0.05 versus normal controls. 72 350 ‘In= 56 43 8 7 27 ! 1 I 1 vl 8 !l -I Y B 0 500- 200 250 150 U loot 50 I I 1 I Normal aCLt aCL- OA RA Other Figure 3. Boxplot analysis of cholesterol levels in aCL+ and aCLsystemic lupus erythematosus (SLE) patients compared with normal blood donors and with patients with other rheumatic diseases. The horizontal line within each box is the 50th percentile; the bar at the bottom is the 25th percentile; open circles at the bottom and top of some plots are the 5th and 95th percentiles, respectively. The 50th percentile €or the aCL+ SLE patients is significantly lower ( P < 0.05) than that in all other groups, except the aCL- SLE patients. Approximately 25% of patients with cholesterol values (150 are in the aCL+ group. OA = osteoarthritis; RA = rheumatoid arthritis; Other = other inflammatory diseases. See Figure 1 for other abbreviations. Boxplot comparisons of cholesterol levels in aCL+ and aCL- SLE patients with those in normal volunteers and patients with other rheumatic diseases showed the lowest median value in aCL+ SLE patients (Figure 3). Approximately 25% of SLE patients with cholesterol levels <150 mg/dl were found in this aCL+ group. Plots of the various lipid fractions in the SLE patients according to IgG aCL positivity showed significantly lower levels of the HDL fraction in the aCL+ patients: 44.3 ? 16 mg/dl in 33 aCL+ patients versus 57.3 ? 18.0 mg/dl in 10 aCL- patients; P < 0.03. However, there was no correlation of IgG aCL titer and HDL level in this group of SLE patients. There were several patients with extremely high aCL titers who did not have either a low total cholesterol or a low HDL level. Triglyceride levels were also significantly elevated in the aCL+ group (139 ? 82 mg/dl, n = 25, versus 77.7 ? 32 mg/dl, n = 10, in the aCL- group). No significant differen between the lipid fractions in any group and IgM antibodies to cardiolipin was found (data not shown). Because the HDL levels in the IgG aCL+ patients were lower, we examined the levels of both Apo A1 and Apo B. Apo A1 is the major apolipoprotein of HDL; Apo B is the major apolipoprotein of LDL. Where possible, we compared these values in LAHITA ET AL 1570 lupus patients who had significantly elevated aCL levels (>I5 units) at the time of study (Table 3). The patients whose aCL titers were > 15 units at the time of study had significantly lower levels of both HDL and Apo A1 and elevated levels of Apo B compared with those whose titers were <I5 units. Serum samples from patients with a history of aCL but without significant titers (>I5 units) at the time of study had lower Apo A1 levels than did those whose aCL titers had never been over 15 units; however, there was no statistically significant decrease in HDL. Apo B levels were not appreciably different between groups. Chi-square comparison of Apo A1 levels in IgG aCL- and aCL+ patients showed a higher percentage of aCL+ patients (15 of 33, 45%) than aCL- patients (1 of 11,9%) with Apo A1 levels < 105 mg/dl (P = 0.03, Figure 4). There was no significant depression or elevation of Apo B levels in any aCL+ patients. The Apo A1:B ratio is of considerable importance in relation to the risk of coronary heart disease (CHD), and some investigators have reported it to be the best single predictor (20). Figure 5 shows the Apo A1:B ratio plotted against the IgG aCL titers of patients with SLE. Ratios of 1.4 for males and 1.6 for 20 = HDL Apo A1 Apo B aCL+ at time of study >15 units Mean r SD 40.1 2 15.17 95.5 f 50.9$ 99.9 t 42.0 Range 25-70 48-207 25-1 88 No. of patients 11 I1 11 <15 units 66.0 2 10.9 152.7 t 32.6 77.9 t 18.3 Mean t SD Range 54-78 108-178 51-90 No. of patients 4 4 4 aCL- at time of study >I5 units Mean t SD 46.6 t 18.8 106.4 k 49.88 90.4 t 31.7 Range 20- 198 45-207 No. of patients 9 33 33 <I5 units Mean t SD 62.3 t 15.4 146.6 f 45.9 105.4 2 23.1 Range 55-198 51-139 No. of patients 4 11 I1 * HDL = high-density lipoprotein; Apo A1 = apolipoprotein A l ; SLE = systemic lupus erythematosus; aCL = anticardiolipin antibody. t P = 0.011 versus those aCL+ at <15 units at the time of study. t P = 0.03 versus those aCL+ at <15 units at the time of study. 0 P = 0.02 versus those aCL- at the time of study and aCL+ at <15 units at some time during the disease course. I 15 3 C .$ 10 2 5 I 0 1 <lo5 -mg/dl >lo5 mg/dl I Apo A1 levels Figure 4. Apolipoprotein A1 (Apo A l ) levels in aCL+ and aCLsystemic lupus erythematosus patients. A significantly greater number of aCL+ patients had Apo A1 levels <I50 mg/dl (lower limit of normal) than is expected by chance (P = 0.03). See Figure 1 for other definitions. Table 3. Levels of HDL, Apo Al, and Apo B in SLE patients positive for aCL at the time of study and in those without significant aCL titers (aCL-) at the time of study but positive at some time during their disease course* IgG aCL titer aCL- 0= aCL+ 100 - 80 - : . : 60 8 c 0 0 ... -20“ 1 -0.5 . 1 I 0.0 0.5 : \ 1.0 1.5 2.0 I I J 2.5 3.0 3.5 R a t i o ADO A1:B Figure 5. Apolipoprotein AI:B (Apo A1:B) ratios plotted against the titer of IgG aCL in systemic lupus erythematosus patients. Ratios of 1.4 (males) and I .6 (females) represent an average risk of developing coronary heart disease (CHD). Ratios 51.0 convey 3 times the average for CHD. The regression line is shown, flanked by the 95% confidence limits. Correlation coefficients are r = -0.23 for the entire group, r = 0.42 for those with aCL values below Apo AI:B ratios of 1.0, and r = -0.20 for those with values above 1.0. See Figure 1 for other definitions. LOW LEVELS OF HDL AND APO A1 IN SLE Clinical activity was measured using the SLEDAI instrument (19). Figures 7A and B show the apparent lack of association between the clinical activity indices and aCL titers, as well as between disease activity and cholesterol values. 11 { 10 DISCUSSION U ' 3 9 0 n O 8 7 a 6 r ii s 2 1571 5 4 3 2 1 0 Relative Risk Figure 6. Numbers of aCL+ and aCL- systemic lupus erythematows patients and their risks for coronary heart disease (CHD), based on apolipoprotein A1:B ratios of 51.0. Note the significant number of aCL+ patients with 3 times the average risk (3x Avg) of developing CHD. See Figure 1 for other definitions. females represent an average risk of developing CHD. Over 50% (n = 15) of these SLE patients had A1:B ratios 5 1.O, and therefore have a 3 times higher risk of developing CHD (Figure 6). There was no significant decrease in Apo A1 or Apo B values in patients who had elevated levels of IgM aCL (data not shown). To determine whether changes in levels of total cholesterol affect the aCL titer, 5 aCL+ SLE patients were evaluated for the effects of corticosteroid therapy (doses up to 60 mg/day). There was an overall increase in plasma cholesterol levels after the corticosteroid therapy. However, there was an appropriate decline in the IgG aCL titers (Table 4). Table 4. Effect of prednisone (60-day course) on cholesterol and anticardiolipin antibody (aCL) levels Before therapy Patient, prednisone dose Cholesterol (mg/dl) PC, 13 mglday JG, 20 mg/day AW, 60 mg/day LH, 30 mg/day SG, 5 mgiday 115 126 157 125 126 IgG aCL (units) 23 >60 39 40 25 After therapy Cholesterol (mg/dl) IgG aCL (units) 164 236 213 171 138 12 7 20 19 11 In this study, we found that SLE patients who were not taking corticosteroids had lower cholesterol levels than expected. Moreover, aCL+ SLE patients had lower total cholesterol, HDL, and Apo A1 levels than did aCL- SLE patients. Patients with a variety of unrelated illnesses and normal volunteer donors had higher values. The HDL values and Apo A1:B ratios were inversely associated with the level of IgG aCL in most SLE patients, and these values did not always correlate with the aCL titers. There was no association of low cholesterol or high IgG aCL values with clinical activity. The evidence supports the notion that SLE patients with IgG aCL have low total cholesterol, HDL, Apo Al , and Apo A1:B ratios. We considered all of the possible reasons for altered lipid metabolism in the design of this study. We excluded hospitalized patients who were critically ill, those who had disturbed liver metabolism and might therefore rapidly clear cholesterol, those who had fat malabsorption, and any patient who appeared to be suffering from starvation. We also eliminated patients who were taking hydroxychloroquine (21). While elimination of these patients would control for lower lipid values, the most common concerns were for hyperlipidemia. Renal disease is a cause of hyperlipidemia and consequent hypertension, and patients with severe renal disease were not included in the study group. Medication histories were of particular importance since an increase in cholesterol levels can be seen with corticosteroid therapy at any dosage (22,23). Concern about drawing the blood samples while the patients were fasting would have been of importance if the features of interest were associated with an increase in plasma cholesterol levels. Risk factors such as smoking and hypertension are also associated with elevated cholesterol levels, which were not of concern in these studies. There are usually no studies of lowered lipid levels in patients with SLE because of attempts to associate elevated levels with atherosclerosis. Antiphospholipid antibodies are present in patients who do not have SLE, as well as in normal subjects. Our principal concern about IgG aCL is the associated thrombotic syndrome. The vasculopathy of the anticardiolipin syndrome in SLE includes both LAHITA ET AL 1572 401- A 0 - arB 35 -a 0 0 t-. 0 0 3 0 0 0 3025- 0 20U 0 34 15- 3 105- 8. 0 -10 - 0 10 20 30 40 50 60 01 100 0 . I 150 I 200 I 250 I 300 CARDlOLlPlN TITER CHOLESTEROL Figure 7. A, IgG anticardiolipin antibody levels and B, cholesterol levels plotted against SLE clinical activity, as assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The regression line is shown, flanked by the 95% confidence limits. venous and arterial thromboses (24). Ischemic heart disease, transient ischemic attacks, and “stroke” occur frequently in patients with the antiphospholipid syndrome and are said to be the result of “thromboses”; however, very few of these patients have undergone angiography (cerebrakoronary) (25) to prove this as a cause of the acute events. Anticardiolipin antibodies in SLE have also been associated with deep vein thrombosis, cerebrovascular accidents, early myocardial infarction, recurrent abortions, thrombocytopenia, pulmonary hypertension, and more recently, valvular heart disease (2632). Less commonly, Addison’s disease, peripheral arterial occlusions, bowel infarcts, avascular necrosis of bone, and a variety of neurologic conditions have been reported in association with these antibodies (33,34). Recent studies of the antigen for the aCL assay indicate that phospholipid is associated with a cofactor which is an apolipoprotein. Apolipoprotein H (&glycoprotein I) is part of the major antigen for these antibodies (35,36). Apolipoprotein H is involved in the coagulation process as a natural antagonist of plasminogen inhibitor (37) and as a direct inhibitor of platelet prothrombinase activity (38). Apolipoproteins such as Apo A1 are also closely associated with phospholipids, but have not been shown to be cofactors with phospholipids in the in vitro antiphospholipid assay. Apo A1 is a protein that has been found to have immunogenicity in at least one patient with SLE (39), as shown by data from our laboratory in which a gene homologous to Apo A1 was cloned using serum from an SLE patient with cerebrovascularatherosclerosis (39). Evidence in support of a greater role of apolipoproteins as antigens comes from the present study and from previous studies of SLE patients not ingesting steroids (40). Levels of HDL and Apo A1 were found to be decreased; however, aCL levels were not measured (40). Antibody binding to epitopes on phospholipid, apolipoprotein, or both might account for a variety of pathologic effects found in certain diseases like SLE, and the type of apolipoprotein bound might determine the pathologic effect. The data presented herein indicate that the SLE patients were at risk of developing atherosclerosis and CHD even if their aCL status was unknown. Any relationship between the apolipoproteins and antiphospholipid antibody and atherosclerosis in SLE would be of considerable interest. The incidence of atherosclerosis is noticeably higher in patients with SLE than in the normal population as well as in patients with other rheumatic diseases. Many cases of myocardial infarction have been described in patients with SLE (11,41-44), and accelerated atherosclerosis has always been a curious aspect of SLE. One study LOW LEVELS OF HDL AND APO A1 IN SLE (12) showed that 5% of female SLE patients were affected, and in another study of 507 lupus patients, 45 had angina or early myocardial infarctions (45). The incidence of atherosclerosis seems to be astonishingly high by some reports, coronary atherosclerosis being found in 40% of lupus patients versus 2% of agematched controls (46,47), and the mortality rate for myocardial infarction in SLE patients is 10 times higher than in age-matched controls. This accelerated atherosclerosis seems to occur predominantly in young premenopausal women, an age group in which the prevalence should be low (48,49). Many reasons for this accelerated atherosclerosis have been proposed, such as steroid therapy for the SLE (22,50,51) and dyslipoproteinemia (21,40,47,52). As mentioned above, several studies report abnormalities of HDL and Apo A1 in patients not ingesting prednisone (40,52). Although thrombosis is frequently mentioned and associated with aCL, particularly in patients with myocardial infarction (24,25,53-55), atherosclerosis is rarely mentioned, despite the clinical observation that myocardial infarctions are frequent in patients with SLE (25,53,5&58). The fate of immune complexes that form and involve Apo A1 would be of considerable interest to those studying the origins of atherosclerosis. These antibodies might occur in diseases unrelated to lupus, and a role in atherosclerosis in other conditions might be possible. There are data, for example, which present an immune etiology for atherosclerosis (59-61), and antigen-driven processes associated with infections have also been linked to atherosclerosis (62-64). Patients with infections as well as other conditions have had aCL, and we believe aCL titers should be measured in patients with accelerated atherosclerosis. ACKNOWLEDGMENTS T h e authors thank Drs. R. A. Asherson, S. Hashim, and S. Majewski for their helpful comments. REFERENCES 1. Knight PJ, Peter JB: Occurrence of antibodies to cardiolipin in systemic lupus erythematosus (abstract). Arthritis Rheum 29 (suppl 1):S27, 1986 2. Sturfelt G, Nived 0, Norberg R, Thorstensson R, Krook K: Anticardiolipin antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 30:382-388, 1987 3. Hams EN, Gharavi AE, Boey ML: Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet II:1211-1214, 1991 4. Fort JG, Cowchock FS, Abruzzo JL, Smith JB: Anticardiolipin 1573 antibodies in patients with rheumatic diseases. Arthritis Rheum 301752-760, 1987 5 . Levy RA, Qamar T, Lockshin MD: Nonspecific binding of IgM anticardiolipin antibodies: idiopathic and chlorpromazine induced (abstract). Clin Exp Rheumatol6:206A, 1988 6. Vaarala 0, Palosuo T, Kleemola M, Aho K: Anticardiolipin response in acute infections. Clin Immunol Immunopathol 41: 8-15, 1986 7. Bellotti V, Gamba G, Merlini G, Montani N: Study of three patients with monoclonal gammopathies and 'lupus-like' anticoagulants. Br J Hematol73:221-227, 1989 8. Fields RA, Toubbeh H, Searles RP, Bankhurst AD: The prevalence of anticardiolipin antibodies in a healthy elderly population and its association with antinuclear antibodies. J Rheumatol 16:623425, 1989 9. Manoussakis MN, Tzioufas AG, Silk MP: High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol69:557-565, 1987 10. Klippel JH: Survival in SLE (abstract), Second International Conference on Systemic Lupus Erythematosus. Singapore, 1989 11. Tsakraklidesm VG, Blieden IC, Edwards JE: Coronary atherosclerosis and myocardial infarction associated with systemic lupus erythematosus. Am Heart J 87:637-641, 1974 12. Hejtmancik MR, Wright JC, Quint R, Jennings FL: The cardiovascular manifestations of systemic lupus erythematosus. Am Heart J 68:119-130, 1964 13. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield N, Schaller JG, Tala1 N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 251271-1277, 1982 14. Loizou S, Mackworth-Young CG, Cofiner C, Walport MJ: Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis. Clin Exp Rheumatol 80:171-176, 1990 15. Gharavi AE, Hams EN, Asherson RA, Hughes GRV: Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 46: 1-6, 1987 16. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC: Enzymatic determination of total serum cholesterol. Clin Chem 20:470475, 1974 17. Roeschlau P, Bernt E, Gruber W: Enzymatic determination of total cholesterol in serum. Z Klin Chem Klin Biochem 12:226, 1974 18. Assmann G, Funke H: HDL metabolism and atherosclerosis. J Cardiovasc Pharmacol 16 (suppl9):S15-S20, 1990 19. Liang MH, Socher SA, Larson MG, Schur PH: Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 32: 1107-11 18, 1989 20. Naito HK: Serum apolipoprotein measurements: an improved discriminator for assessing coronary heart disease risk. Comprehensive Ther 13:43-52, 1987 21. Wallace DJ, Metzger AL, Stechler VJ, Turnbull BA, Kern PA: Cholesterol lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 89:322-326, 1990 22. Ettinger WH, Goldberg AP, Applebaum-Bowden D, Hazzard WR: Dyslipoproteinemia in systemic lupus erythematosus: effect of corticosteroids. Am J Med 83503-508, 1987 23. Pauciullo P, de Simone B, Rubba P, Mancini M: A case of association between type I hyperlipoproteinemia and systemic lupus erythematosus (SLE): effects of steroid treatment. J Endocrinol Invest 9517-520, 1986 24. Asherson RA, McKay KR, Hams EN: Myocardial infarction in a young male with systemic lupus erythematosus, deep vein 1574 thrombosis and antibodies to phospholipid. Br Heart J 56: 190193, 1986 25. Asherson RA, Khamashta MA, Baguley E, Oakley CM, Rowel1 NR, Hughes GRV: Myocardial infarction and antiphospholipid antibodies in SLE and related disorders. Q J Med 73: 1103-1 115, 1989 26. Harris EN: A reassessment of the antiphospholipid syndrome. J Rheumatol 17:733-735, 1990 27. Montalban J, Barquinero J, Ordi J: Antiphospholipid antibodies and stroke (abstract). Clin Exp Rheumatol 6:209A, 1988 28. Lechner K, Pabinger-Fasching I: Lupus anticoagulants and thrombosis. Hemostasis 15:254262, 1985 29. Lockshin MD, Druzin ML, Goei S: Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 313:152-156, 1985 30. Harris EN, Asherson RA, Gharavi AE: Thrombocytopenia in SLE and related autoimmune disorders: association with anticardiolipin antibody. Br J Haematol 59:227-230, 1985 31. Khamashta MA, Cervera R, Asherson RA, Font J, Gil A, Coltart DJ, Vazquez JJ, Pare C, Ingelmo M, Oliver J, Hughes GRV: Association of antibodies against phospholipids with heart valve disease in systemic lupus erythematosus. Lancet 335:1541-1544, 1990 32. Leung W-H, Wong K-L, Lau C-P, Wong C-K, Liu H-W: Association between antiphospholipid antibodies and cardiac abnormalities in patients with systemic lupus erythematosus. Am J Med 89:411-418, 1990 33. Hams EN, Gharavi AE, Hughes GRV: Antiphospholipid antibodies. Clin Rheum Dis 11:591409, 1985 34. Hughes GRV, Asherson R, Khamashta MA: Antiphospholipid antibodies: their clinical significance. Topical Rev 16:1 4 , 1990 35. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda-Vriesman FJC, Barbui T, Zwaal RFA, Bevers EM: Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 335:1544-1547, 1990 36. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA: Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta-2glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 87:4120-4124, 1990 37. Shousboe I: Beta-2-glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood 66:108&1091, 1985 38. Nimpf J, Bevers EM, Bomans PHH: Prothrombinase activity of human platelets is inhibited by beta-2-glycoprotein I. Biochim Biophys Acta 884: 142-149, 1986 39. Rivkin E, Lahita RG: Isolation of a cDNA clone with homology to apolipoprotein A1 using sera from an SLE patient (abstract). Arthritis Rheum 34 (suppl 9):S162, 1991 40. Ilowite NT, Samuel P, Ginzler E, Jacobson MS: Dyslipoproteinemia in pediatric systemic lupus erythematosus. Arthritis Rheum 31:8594?63, 1988 41. Arvanis C, Toutozas P, Yatzidis T: Fatal myocardial infarction in systemic lupus erythematosus: a report of a case of a young female patient. Vasc Dis J 1:258-260, 1964 42. Miller J, Condes CA, Duppish IM: Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus. Am J Cardiol 35:309-314, 1975 43. Jensen G, Sigurd B: Systemic lupus erythematosus and acute myocardial infarction. Chest 64:653454, 1973 44. Rosenthal T, Neufeld H, Kishon Y: Myocardial infarction in a young woman with systemic lupus erythematosus. Angiology 31573-575. , 1980 ---45. Gladman DD, Urowitz MB: Morbidity in systemic lupus erythematosus. J Rheumatol 14 (suppl 13):223-226, 1987 LAHITA ET AL 46. Bulkley BH, Roberts WC: The heart in SLE and the changes induced by corticosteroid therapy. Am J Med 58:243-264, 1975 47. Haider YS, Roberts WC: Coronary artery disease in systemic lupus erythematosus: qualification of degrees of narrowing in 22 necropsy patients (21 women) aged 1G37 years. Am J Med 70:775-781, 1981 48. Rosner S, Ginzler EM, Diamond HS, Weiner M, Schlesinger M, Fries JF, Wasner C, Medsger TA Jr, Ziegler G, Klippel JH, Hadler NM, Albert DA, Hess EV, Spencer-Green G, Grayzel A, Worth D, Hahn BH, Barnett EV: A multicenter study of outcome in systemic lupus erythematosus. 11. Causes of death. Arthritis Rheum 25:612417, 1982 49. Urowitz MB, Bookman AM, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA: The bimodal mortality pattern of SLE. Am J Med 60:221-225, 1976 50. Bulkley BH, Roberts WC: The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. Am J Med 58:243-264, 1978 51. Spiera H, Rothenberg RR: Myocardial infarction of four young patients with SLE. J Rheumatol 10:464-466, 1983 52. Rossner S: Further studies on serum lipoproteins in connective tissue diseases. Atherosclerosis 31:93-99, 1978 53. Hamsten A, Norberg R, Bjorkholm M: Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cerebrovascular events. Lancet I: 113-1 16, 1986 54. Norberg R, Ernerudh J, Hamsten A: Phospholipid antibodies in cardiovascular disease. Acta Med Scand 715:93-98, 1987 55. Brown JH, Doherty CC, Allen DC, Morten P: Fatal cardiac failure due to myocardial microthrombi in systemic lupus erythematosus. Br Med J [Clin Res] 296:1505, 1988 56. Asherson RA, Harris N, Gharavi A, Hughes GRV: Myocardial infarction in systemic lupus erythematosus and “lupus-like’’ disease (letter). Arthritis Rheum 29: 1292-1293, 1986 57. Coenen JL, Nikkels RE: A patient with probable systemic lupus erythematosus, lupus anticoagulant and myocardial infarction. Neth J Med 35:253-259, 1989 58. Petri M, Perez-Gutthann S, Spence D, Hochberg MC: Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med 93513-519, 1992 59. Minick CR, Murphy GE: Experimental induction of atherosclerosis by the synergy of allergic injury to arteries and lipid rich diet. I. Effect of repeated injections of mouse serum in rabbits fed a dietary cholesterol supplement. J Exp Med 124:635452, 1966 60. Minick CR, Murphy GE: Experimental induction of athero/ arteriosclerosis by the synergy of allergic injury to arteries and lipid rich diet. 11. Effect of repeatedly injecting foreign protein in rabbits fed a lipid-rich cholesterol-poor diet. Am J Pathol 73~265-300,1973 61. Hardin MJ, Minick CR, Murphy GE: Experimental induction of atherosclerosis by the synergy of allergic injury to arteries and lipid rich diet. 111. The role of earlier acquired fibromuscular intimal thickening in the pathogenesis of later developing arteriosclerosis. Am J Pathol 73:301-327, 1973 62. Minick CR, Fabricant CG, Fabricant J, Litrenta MM: Atherol arteriosclerosis induced by infection with a Herpes virus. Am J Pathol96:673-706, 1979 63. Cines DB, Lyss AP, Bina M, Corkey R, Kefalides NA, Friedman HM: Fc and C3 receptors induced by Herpes simplex virus on cultured human endothelial cells. J Clin Invest 69:123-128, 1982 64. Freidman HN, Macarak EJ, MacGregor RR, Wolfe J, Kefalides NA: Virus infection of endothelial cells. J Infect Dis 143:22G 273, 1981
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