Anticardiolipin Antibodies in Juvenile Rheumatoid Arthritis and Systemic Lupus Erythematosus

Background: Antiphospholipid antibody syndrome (APS) can either occur as a primary syndrome or associated with other autoimmune diseases such as systemic lupus erythematosus (SLE). Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in blood, measured by a standardized ELISA is the most acceptable laboratory criteria. APS IgG isotype, particularly IgG2 subclass is more strongly associated with thrombosis. Objectives: This study was done to determine the prevalence of IgG aCL and its subclasses in relation to APS symptoms, in a group of juvenile rheumatoid arthritis (JRA) and juvenile systemic lupus erythematosus (SLE) patients.   Methods: In this prospective study, 28 JRA and 16 SLE patients, aged 3-18 years, were enrolled. IgG aCL was assayed by standard aCL ELISA. IgG subclasses were also assayed by ELISA on sera with medium to high titers of aCL. ACL assay was performed on at least two occasions for each patient, over 3-6 months period of follow up.   Results: 29% (8/28) of JRA patients and 44% (7/16) of SLE patients had aCL. Six of SLE patients displayed APS related manifestations: hemolytic anemia, thrombocytopenia, arterial occlusion, valvular heart disease, livedo reticularis and pulmonary hypertension, but none of them had persistant medium or high titer of aCL. The lack of association of high titer of aCL with APS related symptoms was observed in two patients. The IgG subclasses were primarily IgG1 and IgG3.   Conclusion: The prevalence of IgG aCL in this group of pediatric SLE and JRA is not uncommon but it’s relation to clinical manifestations is not clear. IgG1 and IgG3 subclasses were not associated with thrombosis, which is in agreement with previous studies.     

Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome

OBJECTIVE: To evaluate the prevalence of diastolic dysfunction in patients with anticardiolipin antibodies (aCL) and to examine whether the antiphospholipid syndrome (APS) is associated with diastolic dysfunction independently of valvular abnormalities and systolic dysfunction. METHODS: Pulsed, continuous, colour Doppler echocardiography was performed in 179 subjects, of whom 15 were excluded from the analysis because of systolic dysfunction or severe valvular disease. The remaining 164 subjects included 29 patients with primary APS, 26 patients with secondary APS (APS in the presence of systemic lupus erythematosus (SLE)), and 30 patients with SLE and aCL but without APS; 43 patients with SLE without aCL and 36 normal volunteers served as control groups. RESULTS: The groups compared differed significantly in all measures of right ventricular function. There was a gradation of increasing diastolic function impairment as manifested by prolonged deceleration time (DT) and isovolumic relaxation time (IVRT) across the groups of patients with SLE without aCL, SLE with aCL, secondary APS, and primary APS. Differences in left ventricular diastolic function measures were less prominent. In regression analysis, DT increased by 19.6 ms (p=0.002) in the presence of primary APS and by 20.1 ms (p=0.038) in the presence of pulmonary hypertension. The titre of IgG aCL was the strongest predictor of a prolonged IVRT. CONCLUSION: Diastolic dysfunction, in particular of the right ventricle-that is, independent of valvular disease and systolic dysfunction, is a prominent feature of APS and may be related to the pathogenesis of the syndrome.     

Clinical manifestations and antiphosphatidylserine antibodies in patients with systemic lupus erythematosus: is there an association?

Objective: Antiphospholipid antibodies are a group of heterogeneous autoantibodies which have been reported in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) in association with thrombosis, fetal loss, and thrombocytopenia. In this study, we aimed to reveal the prevalence and correlation of IgG, IgA, and IgM isotypes of antibodies to cardiolipin (aCL) and antiphosphatidylserine (aPS) with clinical and laboratory manifestations of SLE patients. Methods: Fifty-nine SLE patients and 41 healthy controls were included. Fifteen of patients (25.4%) had secondary APS. aCL and aPS antibody assays were performed by enzyme-linked immunosorbent assay. Results: All isotypes of aCL and aPS antibodies except IgG were higher in patients with or without APS than those in the healthy controls (p<0.001). The most significant associations were found among migraine and IgA aCL (p<0.001), livedo reticularis and both IgM aCL and IgM aPS (p<0.001), migraine and IgM aCL (p<0.01), pulmonary involvement and IgM aCL (p<0.01), migraine and IgA aPS (p<0.01), and both thrombosis and migraine with IgM aPS (p<0.01). Conclusion: A relatively high prevalence of aCL and aPS antibodies was found in our SLE patients. It seems that isotypes of IgM aCL, IgM aPS, IgA aCL, and IgA aPS antibodies are correlated well with migraine and IgM aPS with thrombosis in SLE patients with secondary APS. The assessment of both IgM and IgA isotypes of aPS and aCL antibodies may be helpful in predicting these manifestations.     

The prevalence of antibodies to anionic phospholipids in patients with the primary antiphospholipid syndrome, systemic lupus erythematosus and their relatives and spouses

OBJECTIVES: Antiphospholipid antibodies (aPL) have been associated with syndromes involving thrombosis, fetal loss and thrombocytopenia. Genetic and environmental conditions are among the factors attributed to the cause of autoimmune diseases such as the antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The aim of this study was to determine whether these factors determine the prevalence of aPL. METHODS: Three groups of patients were tested for the presence of IgG, IgM and IgA anticardiolipin (aCL), antiphosphatidylinositol (aPI), antiphosphatidylglycerol (aPG) and antiphosphatidylserine (aPS) antibodies: (i) patients with primary APS (PAPS); (ii) patients with SLE and secondary APS; and (iii) patients with SLE without APS. First-degree relatives and spouses of patients with SLE/APS were also tested for circulating aPL. RESULTS: IgG aPL were particularly prevalent in patients with PAPS. IgG aPI and aCL were more prevalent in patients with PAPS than the IgM equivalents (P < 0.0001). Notably, none of the patients with PAPS had IgA aPL. A significantly higher number of relatives of patients with SLE/APS possessed IgG aPL than the normal controls. Except for aPG (P < 0.03), the prevalence of these antibodies in the relatives was not significantly different from patients with SLE/APS. The relatives also had significantly higher prevalence of IgG aPI, aPS and aCL antibodies than IgM aPL antibodies. In contrast, the prevalence of IgG aPL in the spouses was no different than in the healthy controls. CONCLUSIONS: Genetic factors, shared by patients and their relatives, seem to have some effect on the prevalence of aPL in the subjects studied, while environmental factors shared by spouses appear to have no influence.     

Longitudinal study of antinuclear and anticardiolipin antibodies in pregnant women with systemic lupus erythematosus and antiphospholipid syndrome

The objective of this study was to perform a longitudinal follow-up of antinuclear antibodies (ANAs) and anticardiolipin antibodies titers (aCL) throughout pregnancy in a group of patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) patients during their therapy for the prevention of fetal loss and to examine their relationship with pregnancy outcome. Thirty patients and 15 controls were followed in the study. Fifteen patients had SLE (group I) and 15 had APS (group II, of which seven patients had primary APS and eight had APS secondary to SLE). All patients were receiving therapy for the prevention of fetal loss with prednisone and aspirin as part of an ongoing clinical trial in lupus pregnancy. If there was a history of previous thrombosis, heparin was added. Blood samples were taken at the 1st, 2nd, and 3rd trimesters (T) of pregnancy in order to assess the presence of IgG and IgM aCL antibodies (ELISA), anti-dsDNA ( C. luciliae) ANAs (HEp-2 cells), and immunospecific antibodies (antiextractable nuclear antigens). We collected 90 samples from patients and 45 samples from healthy controls. Group I (SLE) ANAs were positive in 100% during the 1st T, 67% in the 2nd T, and 67% in the 3rd T, with various immunofluorescence patterns. In five patients, aCL antibodies were detected without a history of APS (one in 1st T, three in 2nd T, and one in 3rd T). Fetal loss was observed in two patients, in one of whom it was associated with nephritis, high titers of ANAs, and anti-dsDNA. Another patient had pulmonary hemorrhage with anti-dsDNA and aCL. In group II, all but one patient with primary APS were negative to ANAs. In secondary APS, by contrast, 6/8 patients (75%) had positive ANAs at least during the 1st T. All seven patients with primary APS and 6/8 with secondary APS had aCL during pregnancy. In 9/15 (60%) patients from the APS group with a history of previous fetal loss, aCL became negative during pregnancy and they had live births. The disappearance of aCL was associated with improved fetal survival (relative risk, or RR, 0.67). ANAs in the control group were positive in 7% at low titers, and all of them were negative for aCL. Despite treatment, ANAs are prevalent during pregnancy in SLE patients and APS secondary to SLE. During pregnancy in SLE, aCL titers may appear. Decreasing titers and/or disappearance of aCL correlated with improved fetal prognosis in a subset of patients with APS.     

Asymptomatic cerebrovascular lesions detected by magnetic resonance imaging in patients with systemic lupus erythematosus lacking a history of neuropsychiatric events.

OBJECTIVE: To clarify the extent of asymptomatic cerebrovascular involvement in systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Cerebral magnetic resonance imaging (MRI) findings and ultrasonography findings of 100 patients with SLE lacking present or past clinical neurologic deficits were compared with 66 age-matched volunteers to determine the combined intima-media thickness (IMT) of the common carotid artery, and tests for anti-cardiolipin antibodies (aCL). RESULTS: Thirty-eight patients, but only 2 controls, showed imaging abnormalities. Among 23 SLE patients with cerebrovascular lesions by MRI who underwent single-photon emission computed tomography (SPECT), 14 showed hypoperfusion of the lesion. The IMT value and prevalence of aCL did not differ between the 55 SLE patients tested and controls. SLE disease activity index (SLEDAI) as assessed by a quantitative clinical index was significantly greater in patients with brain lesions than in those without. CONCLUSION: The prevalence of asymptomatic brain lesions in SLE patients is highs and shows a relationship to disease activity.     

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.     

Value of IgA anticardiolipin and anti-beta2-glycoprotein I antibody testing in patients with pregnancy morbidity

OBJECTIVE: To study the prevalence of IgA antiphospholipid antibodies, particularly anticardiolipin antibodies (aCL) and anti-beta(2)-glycoprotein I (abeta(2)GPI), in a cohort of patients with pregnancy morbidity. PATIENTS AND METHODS: Serum samples from four groups of patients were studied by an in house enzyme linked immunosorbent assay (ELISA). Group I: 28 patients with primary antiphospholipid syndrome (PAPS) (median age 32.5 years, range 25-34). Twelve patients had a history of thrombosis. All were positive for IgG/M aCL or lupus anticoagulant (LA), or both. Group II: 28 patients with unexplained pregnancy morbidity (median age 35 years, range 23-48). Seven had history of thrombosis. Nine patients were positive for IgG/M aCL. None from this group fulfilled Sapporo criteria for APS. Group III: 28 patients with systemic lupus erythematosus (SLE) (median age 34 years, range 25-52). Eleven had a history of thrombosis. Twenty one patients had IgG/M aCL and/or LA, but only 19 fulfilled Sapporo criteria for APS. RESULTS: IgA aCL were found in 12, 6, and 14 patients from the groups with PAPS, unexplained pregnancy morbidity, and SLE, respectively. Most patients had these antibodies together with IgG/IgM aCL. Three patients from the group with unexplained pregnancy morbidity and two with SLE had IgA aCL alone. IgA abeta(2)GPI was present in one patient from each group. All IgA abeta(2)GPI were present together with IgG and/or IgM abeta(2)GPI. CONCLUSIONS: The prevalence of IgA aCL is high in patients with pregnancy morbidity, although IgA aCL are usually present together with IgG and/or IgM aCL. IgA abeta(2)GPI are not useful in identifying additional women with APS and pregnancy morbidity.     

Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome

OBJECTIVE: To determine the prevalence of anti-high-density lipoprotein (anti-HDL) antibodies and to establish a possible relationship between anti-HDL, anticardiolipin antibodies (aCL), anti-beta(2)-glycoprotein I (anti-beta(2)GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). METHODS: Thirty-two patients with SLE and 36 with primary APS were enrolled in a cross-sectional study. Twenty age- and sex-matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti-beta(2)GPI, and antiprothrombin antibodies and IgG anti-HDL were measured by enzyme-linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL(2), and HDL(3) were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence. RESULTS: Levels of total HDL, HDL(2), and HDL(3) were reduced in patients with SLE compared with controls (mean +/- SD 0.51 +/- 0.3, 0.37 +/- 0.3, and 0.14 +/- 0.1 mmoles/liter, respectively, versus 1.42 +/- 0.9, 1.01 +/- 0.7, and 0.40 +/- 0.2). Patients with SLE and primary APS had higher titers of anti-HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti-HDL titers (r = -0.48, P = 0.005) whereas in the primary APS population, IgG anti-beta(2)GPI was the only independent predictor of PON activity (r = -0.483, P = 0.003). In the SLE group, anti-HDL was inversely correlated with TAC (r = -0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02). CONCLUSION: IgG anti-HDL and IgG anti-beta(2)GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low-density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.     

Antiphospholipid antibodies (aPL) in systemic lupus erythematosus. Are they specific tools for the diagnosis of aPL syndrome?

OBJECTIVE--Antiphospholipid antibody (aPL) specificity for aPL-related events was evaluated in systemic lupus erythematosus (SLE). METHODS--A study was carried out on 105 patients affected with SLE comparing the prevalence of lupus anticoagulant (LA) and IgG and IgM anticardiolipin antibodies (aCL) between patients with and without features of antiphospholipid syndrome (APS). Antiphospholipid antibody profile was subsequently evaluated in the aPL positive patients with and without aPL-related events, thus excluding the patients with complications of APS possibly due to factors other than aPL. RESULTS--LA showed a strong association with thrombosis and livedo reticularis, and IgG aCL with thrombosis and neurological disorders, while no clinical features were associated with IgM aCL. A considerable number of aPL positive patients with no aPL-related manifestations was also observed, suggesting the low specificity of aPL assays (54.4%). When studying the 60 aPL positive patients, LA was specific (91.3%) for the diagnosis of aPL-related thrombosis, whereas aCL were not specific, although IgG aCL mean levels were higher in patients with arterial thrombosis than in those without APS features. CONCLUSIONS--LA but not aCL positivity is a specific tool for the diagnosis of thrombotic complications due to aPL in SLE.     

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.     

Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus?

We retrospectively studied a large cohort of patients with primary antiphospholipid syndrome (APS) from 4 different referral centers to analyze the clinical and serologic features and, specifically, to determine the number of patients going on to develop systemic lupus erythematosus (SLE) or other autoimmune disease after long-term follow-up. The study included 128 unselected patients with primary APS who fulfilled the Sapporo International Criteria from 4 different tertiary hospitals in the United Kingdom, Mexico, and Spain. The patients had attended the referral centers between January 1987 and July 2001. We reviewed clinical and serologic characteristics according to a pre-established protocol. We used univariate analysis with the chi-squared or Fisher exact test and logistic regression to analyze possible factors related to the coexistence of SLE and APS. Ninety-seven female and 31 male patients fulfilled the criteria, with a median age of 42 +/- 12 years (range, 16-79 yr), and with a mean follow-up of 9 +/- 3 years (range, 2-15 yr). The main manifestations included deep vein thrombosis in 62 patients (48%), arterial thrombosis in 63 (49%) patients, pregnancy loss in 177/320 (55%) cases, and pulmonary embolism in 37 (30%) patients. Other clinical manifestations were migraine in 51 (40%) patients, thrombocytopenia in 48 (38%), livedo reticularis in 47 (37%), and valvular disease in 27 (21%). Serologic findings were anticardiolipin antibodies (aCL) IgG positive in 110 (86%) patients, aCL IgM in 36 (39%), lupus anticoagulant in 71 (65%), antinuclear antibodies in 47 (37%), and positive Coombs test in 5 (4%) patients. During the follow-up and after a median disease duration of 8.2 years (range, 1-14 yr), 11 (8%) patients developed SLE, 6 (5%) developed lupus-like disease, and 1 (1%) developed myasthenia gravis. The remaining 110 patients (86%) continued to have primary APS. After the univariate analysis, a family history of lupus, the presence of Raynaud phenomenon, migraine, psychiatric features, multiple sclerosis-like features, hemolytic anemia, low C3 and C4, and Coombs positivity conferred a statistically significant risk for the subsequent development of SLE (p < 0.05). Only the presence of Coombs positivity had statistical significance (odds ratio, 66.4; 95% confidence interval, 1.6-2714; p = 0.027) after the logistic regression evaluation. The current study confirms that progression from primary APS to SLE or lupus-like disease is unusual, even after a long follow-up. Only 3 patients developed anti-dsDNA antibodies. The presence of a positive Coombs test might be a marker for the development of SLE in patients with primary APS.     

Comparison between the standard anticardiolipin antibody test and a new phospholipid test in patients with connective tissue diseases

OBJECTIVE: Antiphospholipid (aPL) antibodies are present in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS) and are associated with recurrent thromboses, thrombocytopenia, and pregnancy losses. The presence of aPL antibodies is routinely tested using a standardized ELISA that utilizes cardiolipin as antigen (aCL ELISA). This test, although sensitive, is frequently positive in patients with nonrelated autoimmune disorders and some infectious diseases, making the test less specific. Thus there is a need for more specific tests for aCL with equivalent sensitivity to the standard assay. We evaluated the diagnostic utility of a new aPL antibody test kit with a unique phospholipid mixture designed to be more specific than the standard anticardiolipin ELISA. METHODS: aPL antibodies (IgG, IgM) were measured by both a standard ELISA and a new ELISA kit (APhL ELISA Kit, Louisville APL Diagnostics, Inc., Louisville, KY, USA) in the baseline serum from patients enrolled in a 5 year inception cohort, prospective study of early rheumatoid diseases: rheumatoid arthritis (N = 70), SLE (70), scleroderma (45), inflammatory myositis (36), and early undifferentiated connective tissue disease (CTD) (165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjogren's syndrome (44) was also defined. Serum from 200 blood donors (BD) served as controls. Patients with known APS (33) and antinuclear cytoplasmic antibody positive renal vasculitis (52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The kit was 90.9% sensitive for detecting APS. Seven patients missed by the kit all had standard aCL values < 40 PL units. Assuming controls do not have APS, the kit was 99.5% specific vs 96.0% for the standard assay. For the patients with CTD, the kit never detected a patient that was not also detected by the standard aCL assay. CONCLUSION: The APhL ELISA Kit appears to be more specific than the standard aCL ELISA without adding potential false positive results. The new test may be useful for followup study for patients found to be aCL positive by standard assays to increase specificity for aCL screening.     

Antiphospholipid antibodies in the connective tissue diseases: their relation to the antiphospholipid syndrome and forme fruste disease

Anticardiolipin antibodies (aCL) were measured in the sera of patients with different connective tissue diseases and spondyloarthropathies. Elevated antibody binding was found in systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, primary sicca syndrome, dermatopolymyositis and psoriatic arthritis but not in ankylosing spondylitis. The 15 highest binding SLE patients included 10 with Raynaud's phenomenon, 5 with livedo reticularis, 7 with vasculitis, 3 with major thrombotic episodes and 3 with spontaneous abortions. aCL were also measured in patients with these clinical features in isolation. Seven of 18 patients with multiple thromboses and 3/22 with multiple spontaneous abortions had raised aCL binding. Normal or near normal levels were found in patients with idiopathic thrombocytopenia, livedo reticularis, a single cerebral thrombosis and uncomplicated myocardial infarction.     

HLA-DPB1 alleles association of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus

Our objective was to determine the HLA-DPB1 allele associations of anticardiolipin (aCL) and anti-beta2GPI (a(beta)2GPI) antibodies, and of clinical manifestations of the antiphospholipid syndrome (APS), in systemic lupus erythematosus (SLE). We studied 577 European patients with SLE. aCL and a(beta)2GPI antibodies were measured by ELISA. Molecular typing of HLA-DPB1 locus was performed by polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. aCL showed positive association with -DPB1*1501 (P = 0.005, OR = 7.4), and -DPB1*2301 (P = 0.009, OR = 3.3). a(beta)2GPI showed positive association with -DPB1*0301 (P = 0.01, OR = 1.9), and -DPB1*1901 (P = 0.004, OR = 8.1). In addition, livedo reticularis was associated with -DPB1*1401, and Raynaud's phenomenon with -DPB1*2001. In conclusion, HLA-DPB1 locus may contribute to the genetic predisposition to develop antiphospholipid antibodies and clinical manifestations of the APS in patients with SLE.     

Validation of the Sapporo criteria for antiphospholipid syndrome

OBJECTIVE: To test the Sapporo criteria for the classification of the antiphospholipid syndrome (APS). METHODS: We classified 243 consecutive patients who had clinical diagnoses of primary APS (n = 49), secondary APS (n = 26), systemic lupus erythematosus (SLE) without clinical APS (n = 131), and lupus-like disease without clinical APS (n = 37). RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value were 0.71, 0.98, 0.95, and 0.88, respectively. False-negative findings were the result of patients being classified on the basis of minor criteria that were not included in the Sapporo criteria, such as livedo reticularis, thrombocytopenia, low-titer IgG or IgM anticardiolipin antibody, IgA anticardiolipin antibody, and anti-beta2-glycoprotein I antibody. Some patients with false-negative results were true seronegative cases. CONCLUSION: The Sapporo criteria for APS compare favorably with the American College of Rheumatology criteria for SLE and are usable for clinical studies.     

Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study

OBJECTIVE: To evaluate whether premenopausal women with antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE) have increased prevalence of atherosclerosis after adjustment has been made for known cardiovascular risk factors. METHODS: We evaluated premenopausal women with APS in comparison with age-matched groups of patients with SLE [positive or negative for anticardiolipin (aCL) antibodies] or rheumatoid arthritis (RA), and healthy subjects. Thirty-three subjects in each group were assessed for cardiovascular risk factors, including a detailed lipid profile. Ultrasonography of carotid and femoral arteries assessed the intima-media thickness (IMT) and the presence of atherosclerotic plaque. RESULTS: Atherosclerotic plaques were detected in 5, 2, 4, 1 and 1 subject in the five groups respectively. APS patients had significantly more affected vessels than RA patients and healthy controls (P=0.042 and P=0.016, respectively), but not compared with SLE patients. No consistent differences in IMT, traditional cardiovascular risk factors or lipid parameters were detected among the five groups. The odds for atherosclerosis independently increased 1.19-fold per year of increasing age [95% confidence interval (CI) 1.08-1.31; P=0.001), 1.019-fold per 1 mg/dl increase in low-density lipoprotein (LDL) (95% CI 1.003-1.036; P=0.020), 1.035-fold per additional 1 g of methylprednisolone equivalent cumulative corticosteroid dose (95% CI, 0.996-1.074; P=0.074), and 4.35-fold in the presence of APS or SLE (95% CI 0.75-25.2; P=0.10). Neither aCL nor anti-beta(2)GPI antibodies were associated with atherosclerosis. CONCLUSION: Premenopausal APS and SLE women have an increased prevalence of carotid and femoral plaque that is not accounted for by other predictors of atherosclerosis, including age, lipid parameters and cumulative steroid dose.     

Antiphospholipid antibody tests: spreading the net

OBJECTIVE: To examine the hypothesis that testing for new antiphospholipid antibody specificities may help to identify the antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) with thrombosis who are repeatedly negative for anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). METHODS: Three groups of patients with SLE were studied: (a) SLE/APS (n = 56): 51 female, mean (SD) age 46 (11) years, fulfilling 1999 Sapporo criteria for the APS; (b) SLE/thrombosis (n = 56): 53 female, age 42.6 (12) years, all with a history of thrombosis and persistently negative for aCL and/or LA; (c) SLE only (n = 56): 53 female, age 40 (11) years, without a history of thrombotic events. aCL and LA were retested in all samples. All patients were tested for anti-beta(2)-glycoprotein I (anti-beta(2)GPI) and antiprothrombin antibodies (aPT) by coating prothrombin on irradiated plates or using phosphatidylserine-prothrombin complex as the antigen (aPS-PT). RESULTS: Anti-beta(2)GPI were only present in patients from the SLE/APS group, all of whom were also positive for aCL. aPT and aPS-PT were also more commonly found in SLE/APS than in SLE/thrombosis or SLE only groups (54% v 5%, p<0.0001 or v 16%, p<0.0001 for aPT and 63% v 2%, p<0.0001 or v 11%, p<0.0001 for aPS-PT, respectively). No differences were found between SLE/thrombosis and SLE only groups (p = 1.5 for beta(2)GPI, p = 0.1 for aPT, and p = 0.1 for aPS-PT). CONCLUSION: Testing for aPT in patients with SLE with thrombosis, but persistently negative for aCL and LA, may be helpful in some selected cases. Anti-beta(2)GPI are not present in patients who are negative for aCL.     

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.     

Prevalence and clinical correlates of anti-phospholipid antibodies in South Africans with systemic lupus erythematosus

OBJECTIVE: To determine the prevalence and clinical correlates of anti-phospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), lupus anti-coagulant (LA), anti-beta2-glycoprotein 1 (abeta2GP1), and anti-prothrombin (aPT) antibodies, in Black South African patients with systemic lupus erythematosus (SLE). METHODS: A cross-sectional study of 100 SLE patients in whom clinical characteristics, including features of the anti-phospholipid syndrome (APS), disease activity, and damage were documented, and sera tested for aCL, abeta2GP, and aPT of all isotypes, and LA. RESULTS: Positive aCL, abeta2GPI, aPT, and LA were found in 53, 84, 20, and 2 patients, respectively. Immunoglobulin (Ig)A aCL and IgG abeta2GPI were the commonest aCL (49.1%) and abeta2GPI (47%) isotypes, respectively. IgA abeta2GPI were associated with both a history of thrombosis alone (p<0.05) and a history of any clinical feature, thrombosis, and/or spontaneous abortion of the APS (p<0.05); IgA aCL were associated with a history of any clinical APS event (p<0.05); and abeta2GPI of any isotype were associated with a history of arthritis (p<0.001). CONCLUSION: Our findings provide further evidence that screening for abeta2GPI and IgA aCL isotypes may improve the risk assessment for APS in SLE patients of African extraction. Further prospective studies are warranted to determine the clinical utility of these tests and to elucidate the genetic basis for the increased IgA aPL response in SLE patients of African extraction.