Association of anti-beta 2 glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus.

PURPOSE: Antiphospholipid antibodies (including anticardiolipin antibodies and circulating anticoagulant) are associated with thrombosis in systemic lupus erythematosus. Since it has been shown that beta 2 glycoprotein I (beta 2 gp I) acts as a cofactor of anticardiolipin antibody binding to cardiolipin, the presence and clinical meaning of anti-beta 2gp I antibodies in sera from patients with lupus were examined. PATIENTS AND METHODS: An enzyme-linked immunosorbent assay technique for the detection of anti-beta 2gp I antibodies was developed, and 47 lupus sera were studied retrospectively, as well as 88 healthy blood donors' sera. RESULTS: It was found that 17 of 47 patients with lupus (36%) had anti-beta 2gp I antibodies. Anti-beta 2gp I antibodies were statistically associated with anticardiolipin antibodies, thrombosis, and lupus anticoagulant. Eight of nine lupus patients with thrombosis had anti-beta 2gp I antibodies and lupus anticoagulant, and seven of them had anticardiolipin antibodies. Of 18 patients with anticardiolipin antibodies without anti-beta 2gp I antibodies or lupus anticoagulant, only one had thrombosis (due to nephrotic syndrome). Among anti-beta 2gp I-positive patients, 14 of 16 had lupus anticoagulant activity, whereas only three patients with lupus anticoagulant were anti-beta 2gp I-negative. CONCLUSIONS: The presence of anti-beta 2gp I antibodies is a new immunologic feature of lupus patients with thrombosis. In addition, since anti-beta 2gp I antibodies are closely associated with lupus anticoagulant activity, they may contribute to explain antiprothrombinase activity.     

Procoagulant effect of anti-beta2-glycoprotein I antibodies with lupus anticoagulant activity

Prothrombin time (PT) is routinely used to monitor oral anticoagulant treatment in patients with the antiphospholipid antibody syndrome (APS). The fact that PT is a phospholipid (PL)-dependent coagulation test raises the possibility that lupus anticoagulant (LA) might interfere with this test, thus complicating the control of anticoagulant treatment. The effect of 6 affinity-purified preparations of anti- (a)beta2-glycoprotein I (GPI) antibodies with LA activity on the PT was tested. Instead of prolonging PT as expected, the abeta2-GPI antibodies reduced the PT of both normal plasma and anticoagulated plasma by a mean of 2.4 seconds and 5.6 seconds, respectively. This effect was also observed using other 5 commercially available preparations of thromboplastin. The abeta2-GPI-mediated reduction in PT was dose-dependent and was lost upon removal of beta2-GPI. The failure of abeta2-GPI antibodies to express LA activity in PT was found to depend on the fact that calcium ions were added together with PL at the beginning of the assay. In fact, modification of the standard diluted Russell viper venom time (dRVVT) test by adding calcium ions together with PL resulted in a loss of abeta2-GPI anticoagulant activity. The procoagulant effect was not as evident in an assay that used stimulated monocytes as a source of thromboplastin. These results show that abeta2-GPI antibodies exhibit an 'in vitro' procoagulant effect in PT and an anticoagulant effect in dRVVT only when the interaction with their antigen and PL occurs in the absence of calcium ions.     

抗心磷脂抗体和抗β2糖蛋白Ⅰ抗体对系统性红斑狼疮血栓并发症的预测价值

目的 研究抗心磷脂抗体(ACA)及抗β2糖蛋白Ⅰ抗体(aβ,CPI)对系统性红斑狼疮(SLE)患者发生血栓并发症的预测价值.方法 对河北医科大学第二医院免疫风湿科2004年10月至2006年10月收治的45例活动期SLE患者用酶联免疫吸附法(ELIsA)检测ACA及aβ2GPI水平.分析它们与SLE患者血栓发生率的关系.结果 45例SLE患者中27例(60.0%)ACA阳性;其中10例并发血栓;ACA阴性的18例患者中1例并发血栓.ACA 阳性与阴性的SLE患者间血栓发生率差异有统计学意义(P＜0.05).ACA对预测SLE患者发生血栓的敏感性为90%,特异性为50%.45例患者中17例(37.8%)aβ2GPI阳性,其中8例并发血栓;aβ2GPI阴性的28例患者中3例并发血栓.aβ2GPI阳性与阴性的SLE患者闻的血栓发生率差异有统计学意义(P＜0.01).aβ2CPI预测SLE患者发生血栓的敏感性为72.7%,特异性为73.5%.结论 ACA、aβ2CPI均与LE的血栓形成相关,可用于预测SLE患者的血栓前状态.且aβ2CPI的特异性优于ACA,而敏感性不及ACA.     

The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-beta2-glycoprotein I antibodies

OBJECTIVE: We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-beta2-glycoprotein I antibodies (LA/abeta2GPI). METHODS: Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for abeta2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/abeta2GPI, LA and abeta2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT). RESULTS: Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/abeta2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/abeta2GPI, LA and abeta2GPI were 1.34 [95% confidence interval (CI) = 1.22-1.47], 1.36 (95% CI = 1.24-1.50) and 1.47 (95% CI = 1.31-1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests. CONCLUSION: Persistence of aCL positivity is associated with an increased risk of LA/abeta2GPI.     

Significance of anticardiolipin and anti-beta(2)-glycoprotein I antibodies in lupus nephritis

OBJECTIVE: To investigate whether anticardiolipin (aCL) and anti-beta(2)-glycoprotein I (anti-beta(2)GPI) antibodies are associated with lupus nephritis (group II patients), and whether there are differences in the prevalence of these two autoantibodies between group II patients and patients with non-nephritis SLE (group I) and primary antiphospholipid syndrome (PAPS) patients (group III). METHODS: IgG and IgM aCL were measured in 31 patients and anti-beta(2)GPI in 30 patients with systemic lupus erythematosus (SLE) nephritis and 25 without SLE nephritis and in 36 PAPS patients by validated enzyme immunoassays. Relationships of anti-double-stranded DNA (anti-dsDNA) antibodies and antibodies to the collagenous region of C1q (anti-C1q) with SLE nephritis were also examined. RESULTS: The prevalence and levels were higher for aCL, but not for anti-beta(2)GPI, antibodies in group II than in group I patients. Absolute values of aCL and anti-beta(2)GPI in all three patient groups correlated with each other. The prevalences of aCL, anti-dsDNA and anti-C1q antibodies were significantly higher in group II than in group I and group III patients. CONCLUSION: The observations in this paper suggest that raised levels of aCL antibodies are associated with lupus nephritis. We were not able to demonstrate an association between anti-beta(2)GPI antibodies and kidney disease either in patients with lupus or in patients with primary antiphospholipid syndrome. In SLE, we demonstrated that the presence of anticardiolipin antibodies in conjunction with elevated levels of anti-dsDNA and anti-C1q antibodies is highly specific for glomerulonephritis in patients with lupus.     

Clinical significance of anticardiolipin antibodies in juvenile idiopathic arthritis.

OBJECTIVE: Anticardiolipin antibodies (aCL) have been demonstrated in a large spectrum of autoimmune diseases. However, its occurrence in childhood, in particular in juvenile idiopathic arthritis (JIA), is not well established. The present study addressed the frequency and clinical significance of aCL in a group of JIA patients. METHODS: aCL (IgG and IgM isotypes), antinuclear antibodies (ANA), and rheumatoid factor (RF) were determined in 86 children with JIA (33 systemic, 31 polyarticular and 22 oligoarticular onset type). Thirty-two juvenile systemic erythematosus lupus patients (JSLE) and 52 healthy children formed the control groups. The disease activity and functional status of the JIA patients were scored to study their possible associations with the presence of aCL. RESULTS: Serum aCL levels above the normal range were detected in 28/86 JIA patients (32.5%), 12/32 JSLE patients (37.5%), and 3/52 healthy children (6%). Positive aCL levels were slightly or moderately elevated (usually below 30 GPL and 20 MPL). The presence of aCL was not associated with the presence of ANA or RF. Associations between aCL and clinical parameters, such as disease onset, duration, activity or severity could not be established. No JIA patient had vascular thrombosis, thrombocytopenia or "livedo reticularis". CONCLUSION: aCL occurred in low titers in JIA children, in a similar frequency to that observed in JSLE. No association with JIA clinical parameters or the clinical features classically linked to the antiphospholipid antibody syndrome were observed.     

90K immunostimulatory glycoprotein in children with juvenile idiopathic arthritis

Objectives: To assess whether circulating levels of 90K glycoprotein are increased in children with juvenile idiopathic arthritis (JIA) at different stages of the disease, compared to healthy controls and to evaluate potential over time changes in its concentrations following treatment with the antitumor-necrosis factor (TNF) drug etanercept.

Methods: 90K glycoprotein, C-reactive protein, erythrocyte sedimentation rate, TNF, antinuclear antibodies, rheumatoid factor and the Juvenile Arthritis Disease Activity Score were assessed in 71 children: 23 with newly diagnosed JIA, 23 with established and active JIA and 25 healthy controls. Patients, eligible for anti-TNF treatment, underwent a similar clinical/laboratory assessment after 6- and 12-month etanercept therapy.

Results: At baseline, significant differences were found in 90K levels between the three study groups: JIA at onset (157.7 [131.4–241.5] μg/ml), JIA on treatment (90.0 [68.8–120.2] μg/ml) and control group (58.0 [44.5–79.0] μg/ml), (p for trend <.001), with the JIA at onset group showing the highest values. In the JIA on treatment group, following one-year etanercept treatment, a significant reduction in 90K was detected already at 6 months (74.3 [56.0–104.1] μg/ml p?=?.001) and a further decline was observed at 12 months (49.3 [46.0–67.6] μg/ml p?Conclusion: Our study showed that 90K glycoprotein levels are increased in JIA children compared to healthy controls, suggesting a potential pathogenetic role in the JIA. Besides, 12 months of therapy with etanercept can reduce 90K levels.     

Serum anti-beta2-glycoprotein-I and anticardiolipin antibodies during thrombosis in systemic lupus erythematosus patients

PURPOSE: Antibodies to beta2-glycoprotein-I are more strongly associated with clinical antiphospholipid syndrome than are anticardiolipin antibodies. We previously found a decrease in anticardiolipin antibodies at the time of thrombosis in 6 patients with systemic lupus erythematosus (SLE). We therefore sought to determine the prevalence and levels of antibodies to beta2-glycoprotein-I and to cardiolipin before, during, and after thrombosis in patients with SLE, and to compare them with patients who did not have thrombosis. METHODS: We studied 24 patients with SLE who had at least one episode of thrombosis and 102 patients with SLE without thrombosis. Serum anticardiolipin antibodies were measured by conventional enzyme-linked immunosorbent assay (ELISA) using newborn calf serum as the blocking agent. Serum anti-beta2-glycoprotein-I antibodies were measured by ELISA on nonirradiated plates, using purified human beta2-glycoprotein-I without phospholipid. RESULTS: All patients with thrombosis had anti-beta2-glycoprotein-I antibodies, compared with only 17% of controls (P <0.0001). We observed a significant decrease in serum anti-beta2-glycoprotein-I levels at the time of thrombosis, as compared with previous and subsequent samples. The prevalence and levels of IgG and IgM anticardiolipin antibodies were similar in patients with and without thrombosis. A decrease in IgG or IgM anticardiolipin titers occurred during thrombosis in 6 patients. Anticoagulant, corticosteroid, and immunosuppressive treatments did not appear to affect anti-beta2-glycoprotein-I levels at the time of thrombosis. CONCLUSION: Anti-beta2-glycoprotein-I antibodies are strongly associated with thrombosis in patients with SLE. The decrease of anti-beta2-glycoprotein-I levels at the time of thrombosis may indicate a pathogenic role. This antibody may also be a marker of predisposition for thrombosis in these patients.     

Prevalence of lupus anticoagulant and anticardiolipin antibodies in a healthy population

This study was designed to explore the incidence of lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) and their relationship to each other in a healthy population of 499 blood donors. Plasma samples were tested for LA activity and IgG, IgM and polyvalent ACA. Prolongation of the kaolin clotting time of a mixture of 80% normal plasma and 20% test plasma compared to the normal (dKCT) was used to detect LA activity. A normal distribution of dKCT was found with the mean 3.5 seconds ±SD 10.6 seconds. Forty subjects (8%) were greater than 10% of the normal control; among these, 18 (3.6%) were outside the 95% confidence limits. The median age (29.3) and sex (M = 12, F = 28) of the 40 subjects with prolonged KCT were significantly different (ρ < 0.001) from the group as a whole, younger females predominating. The frequency distribution of IgG, IgM and polyvalent ACA was skewed and the majority did not have detectable levels. ACA concentration falling within 95% of the population group were regarded as normal. Applying this definition, abnormal IgG ACA was greater than 4.33 U/ml, IgM ACA greater than 3.55 U/ml and polyvalent ACA greater than 4.55 U/ml with a prevalence of 4.6%, 4.6% and 5.6% respectively. Of the subjects with positive ACA of any class there was no significant association with either age or sex or the presence of LA. Only three plasma samples had both activities. Neither ACA nor LA were associated with antinuclear antibodies (ANA) or rheumatoid factor (Rh factor). Thus, in a healthy population LA is found predominantly in younger females and neither LA or ACA appear to identify subjects with other autoimmune parameters such as ANA or Rh factor or, for that matter, each other.     

Lupus anticoagulant and anticardiolipin antibodies in systemic lupus erythematosus

The lupus anticoagulant (LA) is an acquired autoantibody of the IgG or IgM type that acts on platelet factor III, inhibiting the generation of the prothrombin activator complex. It is prevalent in 5-10% of SLE cases and, in contradistinction to the name anticoagulant, it may be associated with thrombotic events, recurrent abortion or intrauterine death. Anti-cardiolipin antibody like LA, is an anti-phospholipid antibody and also causes recurrent thrombotic events. Mention has been made of a possible cross-reactivity between anti-phospholipid antibodies and anti-DNA antibodies. The optimal treatment for this problem is at present unknown.     

Studies of natural anticoagulant proteins and anticardiolipin antibodies in patients with the lupus anticoagulant

Components of the natural anticoagulant system (NAS) and anticardiolipin antibodies were examined in 21 patients with lupus anticoagulant (LA), 13 of whom had past histories of thrombotic episodes. No relationship could be shown between the antigenic levels of protein C and S (PC, PS) and a history of thrombosis. Inhibition of the anticoagulant activity of activated protein C (APC) was observed using plasma from 20/21 patients when phospholipid vesicles were used as the surface for the coagulation reaction. This effect was not affected by the addition of PS. When platelet membranes were employed only 2/21 patients demonstrated inhibition of APC. Under the latter condition, PS functional activity was inhibited in 7/21 patients, six of whom had a past history of thrombosis.
Reduced antithrombin III or heparin cofactor II levels were observed in a total of 4/21 patients and may have contributed to the development of thrombosis in three of these patients. Antibodies specifically directed against these proteins were not detected suggesting the possibility of an associated constitutional deficiency. Anticardiolipin antibodies, though elevated in 17/21 patients, did not serve as a useful marker for an increased risk of thrombosis, and the level did not correlate with inhibition of the activity of APC or PS.
We conclude that the mechanism of thrombosis in patients with LA is multi-factorial. A subset of patients in whom LA specifically inhibits PS function may represent patients who are at significant risk from thrombosis.     

Antinuclear antibody, lupus anticoagulant, and anticardiolipin antibody in women with idiopathic habitual abortion. A controlled, prospective study of forty-four women

In a controlled, prospective study of 44 consecutive women with idiopathic habitual abortion, only 5% had symptoms of rheumatic disease. Patients did not differ from control subjects in the frequency of positive results on tests for antinuclear antibody or anti-double-stranded DNA. Levels of C3 and C4 were higher in the habitual aborters. No patients had anti-Ro. The antiphospholipid antibody results were analyzed using 2 methods: the frequency of antiphospholipid antibodies was 9% by lupus anticoagulant using the Russell viper venom time (95% confidence interval 22-2.5) and 11% by anticardiolipin antibody assay (95% confidence interval 25-3.7), which was not significantly different from that in control subjects. However, the mean levels in the aborters (although within the normal range) were significantly higher than those in control subjects for anti-double-stranded DNA (P = 0.004), lupus anticoagulant (by Russell viper venom time; P = 0.05), and anticardiolipin antibody (P = 0.0007), when examined by multiple linear regression analysis corrected for age and concurrent pregnancy. Of the 3 patients with antiphospholipid antibodies and subsequent successful pregnancies, only 1 was treated with prednisone and aspirin. We conclude that, in the majority of women, subclinical lupus, anti-Ro, the lupus anticoagulant, and anticardiolipin antibodies are not associated with idiopathic habitual abortion.     

Anti-CCP antibodies in Brazilian children and adults with juvenile idiopathic arthritis

Patients with juvenile idiopathic arthritis (JIA) may need further care in the adult clinic as this disease frequently has continuous inflammatory activity during adult life. To identify which pediatric JIA patients will need continuing care into adulthood. We compared the clinical, serological, and demographic data of 45 JIA patients followed up by the pediatric clinic to those of 49 JIA patients in the adult rheumatology clinic. Patients in the adult clinic have older age at disease onset (p?<?0.0001) and higher prevalence of positive anti-cyclic citrullinated peptide (CCP) (p?=?0.05). No differences were observed in JIA form, presence of rheumatoid factor (RF), uveitis, and gender. Anti-CCP and older age at disease onset may identify pediatric JIA patients that will need further care in the adult clinic.     

Incidence of juvenile idiopathic arthritis in children in Estonia: a prospective population-based study

OBJECTIVE: To study the incidence rate of juvenile idiopathic arthritis (JIA) and its clinical subtypes in Estonia, to follow the course of the disease in newly diagnosed patients for 2 years, and to find the frequency of human leucocyte antigens (HLA) B27, DR1 and DR4 in JIA patients. METHOD: A population-based study involving prospective registration of new cases of JIA in 1998-2000 and their clinical follow-up for 2 years. RESULTS: In 1998-2000, 162 new cases of JIA were diagnosed. The mean annual incidence rate of JIA was 21.7 per 100 000 children aged 0-15 years (22.9 in girls and 19.3 in boys). During the investigation period, the incidence rate rose 3.5-fold. Oligoarthritis was the most frequent subtype (mean annual incidence rate of 11.7 per 100 000), followed by seronegative polyarthritis (4.4 per 100 000). HLA-DR1, B27 and DR4 were found respectively in 44.4, 28.6 and 11.1% of cases in which the analysis was performed. In HLA-B27-positive patients, inflammation markers of blood remained at a high level for a longer period compared with HLA-B27-negative patients. CONCLUSIONS: This is the first population-based study on the epidemiology of juvenile arthritis in Estonia in which the new classification criteria defined by the International League of Associations for Rheumatology (ILAR) have been used. In addition to environmental factors, an increase in awareness among family doctors is a probable reason for the rise in incidence during the study period. HLA-B27 might have predictive value as a marker of chronicity of inflammation.     

Risk of arterial thrombosis in patients with anticardiolipin antibodies and lupus anticoagulant

The relationship between arterial or venous thrombosis and the levels of anticardiolipin antibodies (aCL) and/or existence of lupus anticoagulant (LA) was studied. The 141 patients with systemic lupus erythematosus (SLE) were divided into four groups: aCL single positive (25 cases), LA single positive (11 cases), aCL and LA double positive (25 cases), aCL and LA double negative (80 cases). The prevalence of thrombosis was higher in aCL and LA double positive patients (21/25 cases, 84.0%, P  < 0.01) than that in aCL single positive patients (4/25 cases, 16.0%), LA single positive patients (1/11 cases, 9.1%) and double negative patients (3/80 cases, 3.8%). Furthermore, in these double positive patients, all patients (10/10 cases) with a high positive level of aCL (>10 units/ml) had arterial thrombosis, whereas only 2/15 patients (13.3%) with a low positive level of aCL (3–10 units/ml) were affected. Venous thrombosis was frequently found in the low positive group (9/15 cases, 60.0%). On the contrary, none of 105 LA negative patients had arterial thrombosis and only seven (6.7%) had venous thrombosis. These findings indicate that a high aCL activity combined with a LA positive result might be a risk factor for arterial thrombosis.