Anti-beta2-glycoprotein I: prevalence, clinical correlations, and importance of persistent positivity in patients with antiphospholipid syndrome and systemic lupus erythematosus

OBJECTIVE: Antibodies to beta2-glycoprotein I (anti-beta2-GPI) are found in a large percentage of patients with primary or secondary antiphospholipid syndrome (APS). Our aim was to identify the prevalence and clinical correlation of these antibodies in patients with APS and systemic lupus erythematosus (SLE), in comparison to anticardiolipin (aCL) and the lupus anticoagulant (LAC). We investigated whether serial samples improve clinical utility. METHODS: Serum samples for anti-beta2-GPI (IgG, IgM, IgA), aCL (IgG, IgM, IgA), and LAC (by dilute Russell viper venom time; RVVT) were collected from 418 consecutive patients with SLE or APS between October 2002 and March 2003. Clinical and serologic data of these patients were analyzed. RESULTS: A total of 185 (44.5%) patients were positive for anti-beta2-GPI, 55.3% were positive for aCL, and 31.1% for LAC. Anti-beta2-GPI was more common in Caucasians than in African Americans (p = 0.098). IgM and IgA were the most frequent isotypes of anti-beta2-GPI. aCL and anti-beta2-GPI were highly associated (p < 0.0001 to p = 0.0177, depending on isotype). A positive association was found between the presence of the LAC by dilute RVVT and anti-beta2-GPI IgG (p < 0.0001), IgM (p < 0.0001), and IgA (p = 0.0002) antibodies. Persistent positivity increased the association of venous and arterial thrombosis with anti-beta2-GPI (IgG and IgM isotypes). Pregnancy loss, seizures, and migraines were not associated with anti-beta2-GPI. IgA anti-beta2-GPI was not significantly associated with any manifestation of APS. CONCLUSION: The prevalence of anti-beta2-GPI IgM and IgA was very high in our population. Measurement of anti-beta2-GPI IgG is clinically useful in identifying patients with SLE at higher risk for venous and arterial thrombosis. Persistent positivity increased the association of IgG anti-beta2-GPI with venous thrombosis and anti-beta2-GPI IgM with arterial thrombosis. IgA anti-beta2-GPI was not significantly associated with APS manifestations.     

Isotypes of anti-beta2-glycoprotein I antibodies: association with thrombosis in patients with systemic lupus erythematosus

OBJECTIVE: To evaluate the association between isotypes of anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) and thrombosis and to identify antiphospholipid antibodies (aPL) that are most associated with thrombosis in patients with systemic lupus erythematosus (SLE). METHODS: IgG anticardiolipin antibody (aCL) and isotypes of anti-beta2-GPI were measured by ELISA, and clinical evidence of thrombosis was analyzed in 270 patients with SLE. RESULTS: IgG, IgM, and IgA anti-beta2-GPI were positive in 38.1, 13.7, and 34.8% of patients, respectively. Patients with a history of thrombosis were significantly more likely to have lupus anticoagulant (LAC), IgG aCL, and the 3 anti-beta2-GPI isotypes. Arterial thrombosis was associated with the presence of IgG aCL and the 3 anti-beta2-GPI isotypes, whereas venous thrombosis was associated with LAC, IgG aCL, and IgA anti-beta2-GPI. In stepwise multivariate logistic regression analysis, the variable that was associated with thrombosis was IgA anti-beta2-GPI. The occurrence of arterial thrombosis was associated with IgG aCL and that of venous thrombosis was related to IgA anti-beta2-GPI in stepwise multivariate analysis. The IgG, IgM, and IgA anti-beta2-GPI titers were closely correlated with IgG aCL titers. The IgA anti-beta2-GPI titers were also significantly correlated with those of IgG and IgM anti-beta2-GPI. CONCLUSION: The results suggest that anti-beta2-GPI isotypes are related to the occurrence of thrombosis, and measurements of IgA anti-beta2-GPI may be useful for predicting thrombotic episodes in patients with SLE.     

The value of IgA antiphospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus.

OBJECTIVE: It is recognized that the presence of IgG and IgM anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC) is associated with thrombosis in patients with antiphospholipid syndrome (APS). Some reports have shown that testing for IgA anticardiolipin and anti-beta2-glycoprotein antibodies (anti-beta2-GPI) provides extra diagnostic help in patients with APS, while other authors could not support this data. We designed this cross sectional study to determine the prevalence of IgA aCL, anti-beta2-GPI, and antiprothrombin antibodies and to study their clinical significance in a large cohort of patients with systemic lupus erythematosus (SLE). METHODS: This study comprised 134 SLE patients (126 women; median age 37.5 yrs, range 16-72). The median duration of the disease was 9 years, range 0.1-38. Of these, 55 (41%) had a history of thrombotic events: 22 (40%) presented an arterial event, 22 (40%) a venous event, and 11 (20%) both arterial and venous events. Of 49 women who had been pregnant, 18 (37%) gave a history of recurrent pregnancy loss. Thrombocytopenia was present in 14/127 patients (11%). Forty patients (30%) were diagnosed as APS secondary to SLE, 23 (17%) had IgG/M aCL and/or LAC without clinical features of APS, and 71 (53%) were SLE patients who were repeatedly negative for IgG/M aCL or LAC. IgG, IgM, IgA aCL and anti-beta2-GPI were detected by ELISA. Antibodies directed to prothrombin were detected by 2 ELISA using prothrombin coated on irradiated plates (aPT) and phosphatidylserine/prothrombin complex (aPS/PT) as antigen. RESULTS: IgA aCL were found in 18/134 (13%) patients. Of these, 3 (17%) had IgA aCL as well as IgG/M aCL, and 2 (11%) had IgG/M aCL and anti-beta2-GPI. Of the 18 patients positive for IgA aCL, 8 were also positive for LAC. Of these, one (5%) patient had IgA aCL as well as other isotype of aCL, and 7 (39%) patients had both aCL and anti-beta2-GPI. None of these patients had binding of IgA aPT or aPS/PT. Of the entire group of 18 patients, 5 (28%) had IgA aCL as the sole aPL. Four of 5 of these patients were diagnosed as SLE but had no antiphospholipid (aPL) related clinical manifestations. We found no association between the presence of IgA aCL and clinical manifestations of APS. IgA anti-beta2-GPI were found in 8/134 (6%) patients. Of these, one (12.5%) had IgA anti-beta2-GPI as well as IgG/M anti-beta2-GPI and aCL. Of the 8 patients positive for IgA anti-beta2-GPI, 6 (75%) were also positive for LAC. Of these, one (12.5%) patient presented with IgA anti-beta2-GPI along with other isotypes of aCL, and 4 (50%) patients with aCL and other isotype of anti-beta2-GPI. One patient (12.5%) had IgA anti-beta2-GPI along with LAC only, and one patient (12.5%) who was diagnosed as SLE had no aPL related clinical manifestation but had IgA anti-beta2-GPI as the sole aPL. CONCLUSION: IgA aCL and anti-beta2-GPI are found in SLE, usually along with IgG and/or IgM isotypes. Testing for IgA aCL and anti-beta2-GPI is not a helpful screening test and does not contribute to the recognition of APS in SLE. IgA aPT and aPS/PT are not present in patients with SLE, therefore there is no need to test for these antibodies.     

IgG anti-beta2-glycoprotein I antibodies in adult patients with systemic lupus erythematosus: prevalence and diagnostic value for the antiphospholipid syndrome

OBJECTIVE: To investigate the prevalence of serum anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies and other antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). To study their diagnostic value for the antiphospholipid syndrome (APS). METHODS: Anti-beta2-GPI and IgG anticardiolipin (aCL) were determined in sera from 102 consecutive patients with SLE using ELISA. Serum and plasma tests were also done for lupus anticoagulant (LAC), syphilis, and antibodies to dsDNA. Clinical and laboratory features of APS were observed. RESULTS: Prevalences were 23.5% for aCL and 18.6% for anti-beta2-GPI. Correlations between the presence of aCL and anti-beta2-GPI and between their titers were statistically significant (p<0.0001). No associations were found between anti-beta2-GPI and disease activity criteria (SLEDAI, ECLAM, dsDNA). Anti-beta2-GPI were significantly associated with LAC (p = 0.005), APS (p = 0.005), and a high aCL titer (aCL > 5 SD; p< or =0.001). LAC was the best diagnostic criterion for APS. CONCLUSION: These data suggest that determination of anti-beta2-GPI in addition to aCL and LAC is unlikely to improve the diagnosis of APS in patients with SLE.     

Antiphospholipid antibodies may be a new prognostic parameter in aggressive non-Hodgkin's lymphoma

OBJECTIVES: Patients with malignancies have an increased prevalence of antiphospholipid antibodies (APA). The aim of this study was to determine the prevalence of IgG, IgM, and IgA anticardiolipin antibodies (aCL) and anti-beta-2 glycoprotein I antibodies (anti-beta2-GPI) in patients with non-Hodgkin's lymphoma (NHL), and to investigate their clinical and prognostic significance. METHODS: The study group included 86 patients with NHL. Enzyme-linked immunosorbent assay kits were used to measure the concentrations of aCL and anti-beta2-GPI, and coagulation tests, to measure lupus anticoagulant (LAC) activity. Blood was collected at diagnosis in all patients and at follow-up in 15. Median follow-up time was 1.9 yr. RESULTS: Elevated APA levels were found in 35 patients (41%) at diagnosis: one patient aCL IgG, five patients aCL IgM, five aCL IgA, one anti-beta2-GPI IgG, 14 anti-beta2-GPI IgM, and 19 anti-beta2-GPI IgA; LAC activity was found in three of 67 patients (4.5%). There was no significant correlation between elevated APA levels and patient's age or sex, disease stage or grade, bone marrow involvement, B symptoms, serum lactate dehydrogenase levels, serum beta2 microglobulin levels, International Prognostic Index (IPI) score, performance status, type of treatment, or response to treatment. There was a correlation between elevated APA and absence of extranodal disease (P = 0.045). A strong negative correlation was found between elevated APA at diagnosis and survival time. Two-year survival was 90 +/- 5% for patients without APA at diagnosis compared with 63 +/- 11% for patients with an elevated APA levels (P = 0.0025). APA added to the predictive value of IPI for event-free and overall survival. CONCLUSIONS: APA are elevated in 41% of NHL patients at diagnosis and are correlated with shortened survival. Their level may serve as an independent prognostic variable in aggressive NHL.     

Specificity and sensitivity of anti-beta2-glycoprotein I as compared with anticardiolipin antibody and lupus anticoagulant in Thai systemic lupus erythematosus patients with clinical features of antiphospholipid syndrome

Antibodies to beta(2)-glycoprotein I (anti-beta(2)-GPI) have been reported to have stronger association with clinical antiphospholipid syndrome (APS) than anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). We investigated the sensitivity and specificity of ELISA for anti-beta(2)-GPI in Thai systemic lupus erythematosus (SLE) patients with clinical features of APS and compared the results with IgG/IgM aCL and LAC to find the test with the best association. The hospital records of 151 Thai SLE patients whose sera had been sent for either IgG/IgM anticardiolipin antibodies or lupus anticoagulant testing were reviewed. Sera of patients either without complete clinical records or those with APS-related manifestations other than vascular thrombosis and pregnancy morbidity (according to the international consensus statement on preliminary classification criteria for definite APS) were excluded. For the remaining subjects (112 patients), their sera were tested for anti-beta(2)-GPI antibody, IgG and IgM anticardiolipin, and lupus anticoagulant. The sensitivity and specificity of each method were compared by using the chi-square test. Among the 112 (74.2%) SLE patients in the study, 35 (31.3%) presented with preliminary clinical criteria for APS (i.e., vascular thrombosis and pregnancy morbidity) whereas 77 (68.7%) did not. The sensitivity and specificity of anti-beta(2)-GPI determination were 57.1 and 79.2%, respectively, whereas those of IgG aCL were 25.7 and 94.8%, of IgM aCL were 5.7 and 98.7%, and of LAC were 44.8 and 77.3%, respectively. The accuracy of the four tests showed similar association with clinical APS (accuracy of test = 72.3, 73.2, 69.6, and 68.3%, respectively). Concerning the sensitivity, specificity, and difficulty of the methods, the combination of anti-beta(2)-GPI and IgG aCL tests was the best for the diagnosis of APS in Thai SLE patients.     

Prevalence of antibodies to beta2-glycoprotein I in systemic lupus erythematosus and their association with antiphospholipid antibody syndrome criteria: a single center study and literature review

OBJECTIVE: To determine the prevalence of anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) in patients with systemic lupus erythematosus (SLE), and to assess their association with and predictive value for the clinical classification criteria of the antiphospholipid antibody syndrome (APS). METHODS: One hundred thirty-three consecutive patients with SLE were recruited from 2 lupus clinics in the University of Toronto. Serum and plasma samples were tested for IgG anticardiolipin antibodies (aCL), prolonged partial thromboplastin time (PTT), a panel of lupus anticoagulant (LAC) assays, and anti-beta2-GPI (IgG, IgM, IgA). Normal ranges for the assays were established using 129 healthy controls. A literature review from 1992 to 2000 was performed using beta2-GPI, SLE, APS, thrombosis, and recurrent pregnancy loss as key search words. RESULTS: The distribution of anti-beta2-GPI antibodies (of any isotype) in each group were as follows: all patients with SLE, 36.8%; SLE with clinical features of APS, 40.4%; SLE without clinical features of APS, 34.9%; and healthy controls, 3%. The positive predictive values of prolonged PTT, IgG aCL, and anti-beta2-GPI for at least one clinical feature of APS in SLE were 59.3, 50.0, and 38.8%, respectively. There were 27 patients with SLE who had antibodies to beta2-GPI but a normal PTT and negative aCL and LAC. Six (20.7%) of these had a history of thrombosis and/or recurrent pregnancy loss. Twelve studies (including ours) were identified in which patient groups were similar and the same antibody isotype was measured. No agreement was apparent after reviewing the literature regarding an association of anti-beta2-GPI IgG and clinical features of APS in patients with SLE. CONCLUSION: Antibodies to beta2-GPI were frequently seen (35%) in our SLE population. The prevalence of anti-beta2-GPI was similar in those with (19/47) and without (39/86) APS. Anti-beta2-GPI did, however, identify 6 patients with clinical features of APS who were negative for aCL and prolonged PTT. Our results indicate that anti-beta2-GPI may provide additional information for the diagnosis of APS in SLE, but do not supercede other established assays. However, when we attempted to place our results in the context of other reports, the literature review revealed that secondary diagnoses of patient groups and assay techniques are too variable among different investigators to allow useful comparison. Thus, no conclusions could be drawn regarding anti-beta3-GPI and clinical features of secondary APS in SLE.     

IgA anticardiolipin and anti-beta2-glycoprotein I are the most prevalent isotypes in African American patients with systemic lupus erythematosus.

BACKGROUND: Ethnicity plays a role in the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies in patients with systemic lupus erythematosus (SLE). Few studies have been done in the African American population. METHODS: Serum samples from 100 African American patients with SLE were tested for IgG, IgM, and IgA aCL and anti-beta2-GPI antibodies by enzyme-linked immunosorbent assay (ELISA). Computerized clinical data on these patients were reviewed with a specific focus on clinical manifestations of antiphospholipid syndrome (APS). RESULTS: Positivity for at least one isotype of aCL antibodies was found in 33% of the patients, whereas 28% were positive for at least one isotype of anti-beta2-GPI antibodies. IgA was the most prevalent isotype for both antibodies; 24% of the patients in the aCL ELISA and 19% in the anti-beta2-GPI ELISA were positive for IgA. Positivity for both aCL and anti-beta2-GPI in the same patient was seen more frequently with the IgA isotype. Fewer than half of the patients positive for aCL antibodies had medium-to-high levels of antibodies. A few patients had presented thrombotic manifestations, and these patients were positive for aCL (P = 0.01) and anti-beta2-GPI antibodies (P = 0.02). No other manifestations of APS could be significantly correlated with the presence of these antibodies. CONCLUSIONS: Our results show that IgA is the most prevalent isotype among the African American patients with SLE studied. The predominance of the IgA isotype and the low prevalence of medium-to-high levels of aCL antibodies may account for the low frequency of clinical manifestations of APS in these patients.     

Do antibodies to beta2-glycoprotein 1 contribute to the better characterization of the antiphospholipid syndrome?

The aim of this study was to determine if the measurement of anti-beta2-glycoprotein I antibodies (abeta2-GPI) in serum levels contributes to the better characterization of the clinical situation of patients with antiphospholipid syndrome (APS). For this purpose abeta2-GPI of both isotypes was measured in 42 patients with APS and 32 SLE patients without APS. Clinical records of all patients were thoroughly reviewed. The presence of abeta2-GPI was correlated with the clinical manifestations of APS and compared with the presence of anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) activity. There was a positive correlation between levels of aCL and abeta2-GPI for both IgG and IgM isotypes (rho of Spearman=0.82 and 0. 64 respectively, P=0.0001). Both antibodies presented significantly higher titres in LA positive patients (P<0.05). The specificity for APS was 91% for IgG abeta2-GPI vs 75% for IgG aCL and 87% for IgM abeta2-GPI vs 81% for IgM aCL. 68% of patients with thrombosis of 100% of patients with thrombocytopenia showed positive tests for all three markers (aCL, LA, abeta2-GPI). Simultaneous presence of circulating LA and high titres of both aCL and abeta2-GPI identify a subset of patients with primary APS (PAPS) who have a more severe clinical course of the disease. Although the specificity of abeta2-GPI IgG is higher than that of aCL IgG, when all three tests are performed abeta2-GPI testing provides only additional information to that of aCL and LA. Therefore, we concluded that the abeta2-GPI test should not be considered as a substitute for conventional LA or aCL assays. However, performance of abeta2-GPI seems to be important in PAPS with high aCL titres, to alert the physician about the risk for the worst course of the illness.     

High avidity anti-beta 2-glycoprotein I antibodies in patients with antiphospholipid syndrome

OBJECTIVE: To evaluate avidity of IgG anti-beta 2-glycoprotein I antibodies (anti-beta2-GPI) in patients with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) in relation to thrombosis, and to demonstrate a possible affinity maturation of IgG anti-beta 2-GPI during the disease course. METHODS: 64 sera from 32 patients (18 with primary or secondary APS, 14 with SLE without APS) and their respective IgG fractions or affinity purified anti-beta 2-GPI were studied by anticardiolipin (aCL) and anti-beta 2-GPI enzyme linked immunosorbent assay and by chaotropic assay. RESULTS: Six, 12, and 14 patients had high, low, and heterogeneous avidity IgG anti-beta 2-GPI, respectively. In 12 patients an increase in antibody avidity was observed over a period of between four and 12 years. More patients with APS were in the high avidity than in the low avidity anti-beta 2-GPI group, while the opposite was observed for SLE alone (both p<0.05). The most common clinical feature among patients with high avidity anti-beta 2-GPI was thrombosis, mainly venous thrombosis (p<0.05 and p<0.02, respectively, v the low avidity anti-beta 2-GPI group). CONCLUSIONS: Patients with APS with or without SLE may have anti-beta2-GPI of high, low, or heterogeneous avidity. High avidity anti-beta 2-GPI appear to be associated with thrombosis and APS, while in pure SLE low avidity anti-beta 2-GPI may prevail. Monitoring of avidity may help elucidate the role of anti-beta 2-GPI affinity maturation in the pathogenesis of APS.     

IgG reactivity to phospholipid-bound beta(2)-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome.

BACKGROUND AND OBJECTIVE: Autoantibodies to beta(2)-glycoprotein I (beta(2)-GPI) and/or prothrombin (FII) have been involved in the expression of lupus anticoagulant (LA) activity, an in vitro phenomenon associated with an increased risk of arterial and/or venous thromboembolic events. However, LA activity sustained by anti-FII antibodies has a much weaker association with thrombosis than LA activity sustained by anti-beta(2)-GPI antibodies. Because assays aimed at detecting LA activity are now commercially available, we evaluated the relative sensitivity to anti-FII and anti-beta(2)-GPI antibodies of a commercial LA assay in a consecutive series of patients with the clinical suspicion of anti-phospholipid antibody (APA) syndrome. DESIGN AND METHODS: One hundred and ten consecutive patients with the clinical suspicion of APA syndrome (primary in 39) and 36 healthy controls were evaluated for the presence of LA activity (LA, Staclot, Stago), anticardiolipin antibodies (Quanta Lite aCL IgG, IgM, Inova Diagnostics), and IgG binding to solid-phase and/or phospholipid (PL)-bound beta(2)-GPI and FII by ELISA assays developed an optimized in our laboratory. Odds ratios for the association of IgG binding activity with LA and the aCL IgG status were calculated. In LA patients, dependency of LA potency (as assessed by clotting time prolongation in absence or presence of hexagonal phospholipid) on autoantibody titers was analyzed by the generalized linear model. Total IgG fractions were purified from selected patients to evaluate their ability to inhibit prothrombin activation at low FII concentration. RESULTS: Anticardiolipin antibodies (aCL) of the IgG or IgM type were found in 64 and 23 patients and LA activity in 49 patients. Anti-beta(2)-GPI and anti-FII (solid-phase and PL-bound) IgG titers exceeding by more than 3 standard deviations the mean values observed in control subjects were found in 46 and 47 patients and in 56 and 30 patients respectively, with the highest titers detected in the subgroup of patients with both LA and aCL IgG. The relative risk of LA for patients free of anti-FII and/or anti-beta(2)-GPI IgG was 0.03 after stratification for the aCL IgG status. Anti-beta(2)-GPI (solid-phase and PL-bound) IgG (RR 34.4 and 12.6) and anti-FII (solid-phase) IgG (RR 6.33) were all associated with LA activity. However, when taking into account co-existence of anti-FII and anti-beta(2)-GPI IgG in the same patients, the relative risk of LA for patients with isolated anti-FII IgG (solid-phase and/or PL-bound) was 0.50, whereas it ranged from 4.24 to 8.70 for all the antibody combinations including anti-beta(2)-GPI IgG. Anti-beta(2)-GPI (PL-bound) and aCL IgG titers were the only significant predictors of LA potency determined in absence phospholipid (anti-beta(2)-GPI IgG) or in presence of hexagonal phospholipid (aCL IgG). Total IgG fractions purified from 12 patients (6 with anti-FII IgG) did not significantly inhibit factor II activity up to a 150-fold molar excess. INTERPRETATION AND CONCLUSIONS: These results highlight the high prevalence of anti-FII and anti-beta(2)-GPI IgG in patients with the clinical suspicion of APA syndrome and particularly in the subgroup of patients with LA activity. The fraction of LA activity which can be quenched by addition of hexagonal phospholipid is, however, only dependent on IgG directed to PL-bound beta(2)-GPI. Other antibodies associated with anticardiolipin IgG may explain residual clotting time prolongation observed in the presence of hexagonal phospholipid.     

Prevalence and isotype distribution of antiphospholipid antibodies in Chilean patients with systemic lupus erythematosus (SLE)

Previous studies have demonstrated that ethnicity plays a role in the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2 glycoprotein I (abeta2-GPI) antibodies in systemic lupus erythematosus (SLE) patients. Few studies have been done in Latin American populations. Serum samples from 129 Chilean SLE patients were tested for IgG, IgM and IgA aCL and abeta2-GPI by ELISA. Clinical data were reviewed with the focus on clinical manifestations of antiphospholipid syndrome (APS). Positivity for at least one isotype of aCL was found in 30% of patients, while only 10% were positive for at least one isotype of abeta2-GPI. IgG was the most prevalent isotype for aCL (16%), and the isotype distribution was similar (4%) for abeta2-GPI. In general, the presence of aCL was significantly associated with the presence of abeta2-GPI, but a number of samples were positive for only one antibody, some of them associated with clinical manifestations of APS. ACL antibodies at medium-high titers were significantly correlated with thrombosis (P = 0.0007) and fetal loss (P = 0.009); however, the sensitivity of abeta2-GPI for detecting thrombosis and fetal loss was lower than aCL (19 and 17% vs 56 and 50%, respectively), and the specificity slightly higher (91 and 90% vs 84 and 82%). In Chilean SLE patients, aCL and abeta2-GPI antibodies are important in the evaluation of patients with APS. However, the utility of abeta2-GPI antibodies was limited by the low prevalence of these antibodies in comparison with other ethnic groups. Further studies are needed to define the basis of the observed differences among ethnic groups.     

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.     

Anti-beta2-glycoprotein I autoantibodies, in vitro thrombin generation, and the antiphospholipid syndrome

OBJECTIVE: Thrombin plays a pivotal role in the regulation of hemostasis. We examined the effect of antiphospholipid (aPL) antibodies, in particular those with specificity for beta2-glycoprotein I (beta2-GPI), on in vitro thrombin generation, and examined the association with clinical manifestations of the antiphospholipid syndrome (APS). METHODS: We studied plasma samples from 59 patients with aPL antibodies determined by the presence of either elevated anticardiolipin (aCL) antibodies or lupus anticoagulant (LAC). Direct antibody binding of IgG, IgM, and IgA to beta2-GPI and prothrombin (PT) was determined by ELISA. Affinity purification of total IgG and IgG anti-B2-GPI antibodies was performed using staphylococcal protein A and phospholipid liposomes. A chromogenic assay was used to determine the effect of plasma samples and purified autoantibodies on in vitro thrombin generation. RESULTS: Thirty-three of 59 (56%) plasma samples inhibited in vitro generation of thrombin and 7/59 (12%) accelerated thrombin formation. There was a strong negative correlation between thrombin generation and IgG aCL (r = -0.72, p < 0.001) and IgG anti-beta2-GPI (r = -0.71, p < 0.001) antibody levels, and a weaker correlation with LAC (r = -0.46, p = 0.001). This association was not found with anti-PT antibodies and could not be attributed to concurrent therapy with warfarin. Additional experiments with affinity purified IgG antibodies indicated a dose dependent inhibition of thrombin generation, which was restricted to anti-beta2-GPI antibodies. Patients with a history of core clinical manifestations of the APS [venous and arterial thrombosis, recurrent (> or = 2) fetal loss] had significantly greater inhibition of in vitro thrombin generation (mean +/- SEM Z score: -3.38 +/- 0.51 vs -1.42 +/- 0.56; p = 0.01) and higher levels of IgG aCL (mean +/- SEM Z score: 8.39 +/- 1.12 vs 5.39 +/- 0.88; p = 0.04) and IgG anti-beta2-GPI antibodies (mean +/- SEM Z score: 4.49 +/- 0.69 vs 2.26 +/- 0.54; p = 0.01). Odds ratios for these variables and clinical manifestations of the APS were 5.43, 4.17, and 3.28, respectively. CONCLUSION: aPL antibodies may accelerate or inhibit the rate of in vitro thrombin formation. The predominant effect is inhibition that is restricted to IgG anti-beta2-GPI antibodies and it is strongly associated with clinical manifestations of the APS.     

Raynaud's phenomenon and antiphospholipid antibodies in systemic lupus erythematosus: is there an association?

OBJECTIVE: To evaluate the association of IgG and IgM antibodies directed against different negatively charged phospholipids (that is, anticardiolipin (aCL), antiphosphatidylinositol, antiphosphatidylserine, and antiphosphatidic acid) and anti-beta(2)-glycoprotein I (abeta(2)GPI), with Raynaud's phenomenon in patients with systemic lupus erythematosus (SLE). METHODS: Ninety three patients with SLE (81 female), 40 with and 53 without Raynaud's phenomenon, were included in the study. IgG and IgM antiphospholipid antibodies and abeta(2)GPI were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: Fifty patients (54%) were positive for IgG and/or IgM antibodies to one or more phospholipid antigens or to beta(2)GPI. The prevalence of all autoantibodies evaluated, either IgG or IgM, was higher in patients without than in those with Raynaud's phenomenon. A negative association was found between IgG aCL and Raynaud's phenomenon (p=0.038), whereas autoantibodies other than aCL were not significantly associated with Raynaud's phenomenon. CONCLUSION: Our results demonstrate no positive association between antiphospholipid antibodies and Raynaud's phenomenon in SLE and indicate that measurement of anti-negatively charged phospholipid antibodies other than aCL is not useful as a serological marker predictive for Raynaud's phenomenon.     

Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus

OBJECTIVE: Different prevalences of antiphospholipid antibodies (aPL) have been reported in different populations of patients with systemic lupus erythematosus (SLE). Chinese are generally believed to have lower risk of vascular thrombosis. We examined the prevalence of aPL including lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies, the level of thrombotic risk, and the association of aPL with thrombotic and pregnancy outcomes in a Chinese cohort with SLE at the university lupus clinic during the period 1986-2003. METHODS: aPL were measured in 272 SLE patients, and medical records were reviewed for vascular thrombosis and pregnancy outcomes. RESULTS: The prevalence of LAC, IgG aCL, and IgG anti-beta2-GPI antibodies was 22.4%, 29.0%, and 7.7%, respectively. There were 38 episodes of thrombosis after a mean duration of followup of 11.0 +/- 6.8 SD years, giving a thrombotic rate of 1.26/100 patient-years. All aPL were shown to be associated with vascular thrombosis. IgG anti-beta2-GPI antibodies were found to be associated with recurrent thrombosis [8.0/100 patient-years or 25.0% (7/28)]. Patients taking hydroxychloroquine were found to have fewer thrombotic complications than those who were not (OR 0.17, 95% CI 0.07-0.44; p < 0.0001). LAC was the strongest factor associated with recurrent miscarriages [relative risk 12.3, 95% CI 1.22-123.31; p = 0.03). The diagnosis of secondary antiphospholipid syndrome was satisfied in 8.9% of patients. CONCLUSION: The lifetime and recurrent thrombotic rates in our patients with aPL were not particularly different from those in the literature. However, the lower prevalence of aPL in our cohort may suggest a role of other prothrombotic factors in predisposition to thrombosis.     

Anticardiolipin and anti-beta2glycoprotein-I antibodies in patients with systemic lupus erythematosus: comparison between Colombians and Spaniards

We studied the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2glycoprotein I (anti-beta2GPI) antibodies in two populations of patients with systemic lupus erythematosus (SLE), 160 Colombians and 160 Spaniards. All sera were tested in our laboratory by enzyme-linked immunosorbent assay (ELISA) for IgG, IgM, and IgA aCL, as well as IgG and IgM anti-beta2GPI. Positive results for at least 1 of the 3 aCL isotypes were found in 40 Colombians (25%) and 55 Spaniards (34%). IgG aCL was the predominant isotype in both populations. Positive results for at least 1 of the anti-beta2GPI isotypes were found in 34 Colombians (21%) and 29 Spaniards (18%). IgG anti-beta2GPI was the dominant isotype in Colombians, while IgM was predominant in Spaniards. Positivity for anti-beta2GPI in aCL-positive patients was present in 77% in the Colombian group and 50% in the Spaniard group. Among Colombians, IgG aCL and anti-beta2GPI correlated with thrombosis, fetal loss, and thrombocytopenia. Among Spaniards, IgG aCL and IgG anti-beta2GPI correlated with thrombosis, fetal loss, and livedo reticularis. For detecting thrombosis and fetal loss, aCL ELISA was more sensitive than anti-beta2GPI in Spaniards, and anti-beta2GPI ELISA was more specific than aCL in both populations.     

High titer of anti-phosphatidylserine-prothrombin complex antibodies in patients with cutaneous polyarteritis nodosa

OBJECTIVE: To investigate possible correlations between cutaneous polyarteritis nodosa (CPN) and antiphospholipid syndrome-associated antibodies. METHODS: Sixteen patients were referred with CPN features. To investigate the possible role of antiphospholipid antibodies (aPL) in CPN, we measured serum lupus anticoagulant (LAC), IgG and IgM anticardiolipin (aCL) and anti-phosphatidylserine-prothrombin complex (anti-PS/PT) antibodies, and anti-beta(2)-glycoprotein I-dependent cardiolipin (anti-beta(2)GPI/CL) antibodies in the 16 CPN patients, 8 microscopic polyangiitis (MPA) patients, 33 systemic lupus erythematosus (SLE) patients, and 23 healthy controls. LAC was determined according to the Subcommittee on Lupus Anticoagulant/Phospholipid Dependent Antibody guidelines. Anti-PS/PT, aCL, and anti-beta(2)GPI/CL antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: Anti-PS/PT antibodies and/or LAC were detected in all CPN patients, but not in any controls. Serum IgM anti-PS/PT antibody was found in 13 (81.3%) CPN patients. The mean +/- SD serum anti-PS/PT IgM level (19.9 +/- 12.4 units/ml) in CPN patients was significantly elevated compared with SLE patients (5.7 +/- 5.9 units/ml). IgG anti-PS/PT antibody was detected in 5 (31.3%) CPN patients, but not in any controls. The IgG PS/PT antibody titers were similar in CPN patients (12.3 +/- 12.0 units/ml) and SLE patients (13.8 +/- 14.3 units/ml). Three (18.8%) CPN patients were positive for IgG aCL antibody and 2 (12.5%) for IgM aCL antibody. No MPA patients had aPL. CPN skin manifestations included livedo reticularis (14 [87.5%]). Direct immunofluorescence (DIF) revealed C3 within the affected vessels in 7 (77.8%) of 9 CPN patients. CONCLUSION: Our study demonstrated that presence of anti-PS/PT antibodies and/or LAC could serve as markers in CPN patients. CPN could be dependently associated with the presence of anti-PS/PT antibody. Clinicians need to recognize these titers to permit early accurate diagnosis and treatment. We believe that anti-PS/PT antibodies will become widely recognized as a new factor when diagnosing CPN.     

Anti-beta2-glycoprotein I in childhood immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) etiology is not clarified. Phospholipid antigen antibodies (aPls) occur in ITP patient sera. We studied predictive values of elevated anti-beta2-glycoprotein I (anti-beta2-GP1) or anticardiolipin antibody (aCl) concentrations for secondary ITP detection, comparing levels with steroid therapy responsiveness in three groups of children and adolescents. Participants' antinuclear antibodies, aCls (IgM, IgG) and anti-beta2-GPI (IgG) were assessed. Significantly higher aCl (IgM), aCl (IgG) and anti-beta2-GPI (IgG) mean concentrations occurred in chronic ITP cases compared with acute or control cases. Of chronic ITP cases, 77.8% showed elevated IgG aCl serum concentrations, and all presented increased IgG anti-beta2-GPI serum levels. Significant positive correlation between increased levels of IgG anti-beta2-GPI and increased IgG aCl serum concentrations was determined; these increased IgG concentrations significantly correlated with steroid therapy resistance. A total of 76.1% of ITP cases had positive aPls (all chronic ITP cases, five acute ITP cases). Elevated aCl or anti-beta2-GPI serum IgG isotype concentrations occurred in all nine splenectomized ITP children with positive aPls (three showed increased IgM aCl levels). Follow-up of the initially studied ITP children (2000-2004) revealed 16.7% developed clinical and laboratory criteria of systemic lupus erythrematosus (one acute ITP in remission, six chronic ITP); elevated IgG aCl serum concentrations were found at study start in these seven cases, and six had increased anti-beta2-GPI. IgG classes of both aCls and anti-beta2-GPI may be determinant cofactors for the developing risk of antiphospholipid syndrome or autoimmune diseases in ITP. Great attention should be paid to both assays as predictors for steroid therapy response.     

Antiphospholipid antibodies in patients with coronary heart disease and the disturbances of glucose tolerance

Experimental and clinical reports suggest the role of antiphospholipid antibodies (aPL) in the pathogenesis of atherosclerosis and arterial thrombosis. The aim of our study was to evaluate IgM and IgG anti-beta2-glycoprotein I (anti-beta2-GPI), as well as IgG antiphosphatydylserine (aPS) antibodies in 80 consecutive patients (mean age 58.6+/-8.3 years) referred for coronary angiography, dependent on the extent of atherosclerotic lesions in coronary vessels and the disturbances of glucose tolerance. Antiphospholipid antibodies were measured by ELISA. The mean values of aPS and anti-beta2-GPI did not differ significantly between patients with 1- (n = 17), 2- (n = 15) or 3-vessel disease (n = 14) and subjects without significant changes in coronary arteries (n = 34), as well as between patients with unstable (n = 12) and effort angina (n = 68). Significantly higher levels of IgG anti-beta2-GPI were found in the subgroup with type 2 diabetes in comparison with the subjects with impaired glucose tolerance (median 3,8 (1.9 -9.3) U/ml vs 2,8 (1.5-5.0) U/ml, p = 0.027). Current smokers (n = 11) had significantly higher values of aPS than non smokers (55.8 +/- 30.7 - 64.7) U/ml vs 38.7 (5.7 +/- 82.6) U/ml, p = 0.017). Abnormal aPS values were found in 34 subjects (42,5%): 16 (6 diabetics) with normal angiograms (47.0%), 9 (26.5%) with 1-vessel disease, 3 (8,8%) with 2-vessel disease and 6 (17,6%) with 3- vessel disease. Increased IgG anti- (2-GPI levels were found in 8 (10%), and IgM anti-beta2-GPI - in 4 patients (5%). All subjects with high IgM anti-beta2-GPI values, as well as 5 persons with high IgG anti-beta2-GPI levels (62.5%) had significant coronary artery lesions. Multiple regression analysis revealed that factors independently influencing the levels of aPS were: patient's age (Beta = -0.8417, p = 0.0003) and glycaemia 120 min. after glucose load (Beta = 0.6453, p = 0.025). CONCLUSIONS: our results do not confirm an association between aPS or/and anti-beta2-GPI antibodies and the extent of atherosclerotic lesions in coronary vessels, although they suggest an increased membrane phospholipids immunogenicity in relatively young patients with elevated postload glycaemia, as well as cigarette smokers.