Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus

OBJECTIVE: To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to beta 2-glycoprotein I (beta 2GPI), and to search for a relationship between the presence of IgG and/or IgM anti-beta 2GPI antibody and clinical manifestations in SLE patients. METHODS: IgG and IgM anti-beta 2GPI in 308 Japanese SLE patients were measured using phospholipid-independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined. RESULTS: The values of anti-beta 2GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti-beta 2GPI assay was more useful in distinguishing beta 2GPI-dependent aCL from beta 2GPI-independent aCL. The presence of IgG anti-beta 2GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti-beta 2GPI may fluctuate with disease activity. CONCLUSION: The results suggest that pathogenic aCL is directed against structurally altered beta 2GPI and that enzyme immunoassay for anti-beta 2GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.     

Celiac disease associated with systemic lupus erythematosus

Celiac disease in children has been occasionally reported to be associated with various disorders such as arthritis, cutaneous vasculitis and diabetes mellitus. We report on a 12-year-old girl with celiac disease, diagnosed at 1 year of age, who developed systemic lupus erythematosus. This association has not yet been reported in children.     

Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies but not with antibodies against oxidized low-density lipoprotein

The prevalence and clinical significance of antibodies against beta2-glycoprotein I (anti-beta2GPI) and antibodies against oxidized low-density lipoprotein (anti-ox-LDL) were evaluated as potential indicators of arterial disease in patients with systemic lupus erythematosus (SLE) and SLE with secondary antiphospholipid syndrome (APS). IgG anti-beta2GPI and IgG anti-ox-LDL were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples from 118 patients with SLE, including 40 with secondary APS. IgG anti-beta2GPI were positive in 17% (20/118) of SLE patients. The presence and titres of IgG anti-beta2GPI were strongly associated with a history of arterial thrombosis. Haemolytic anaemia was also significantly associated with the presence of IgG anti-beta2GPI. The prevalence of IgG anti-ox-LDL was 53% (63/118), but there was no association with arterial thrombosis. No correlation between the values of anti-ox-LDL and those of anti-beta2GPI was found. These results suggest that IgG anti-beta2GPI could be a marker for arterial thrombosis in SLE patients, while IgG anti-ox-LDL were not associated with arterial disease in this group of lupus patients.     

Anticardiolipin antibodies are associated with pulmonary hypertension in patients with mixed connective tissue disease or systemic lupus erythematosus

Anticardiolipin antibodies (aCL) were studied in relation to pulmonary hypertension (PH) in 22 patients with mixed connective tissue disease (MCTD) or systemic lupus erythematosus (SLE). The mean pulmonary arterial pressure (mPAP) values were similar in the 12 MCTD and 10 SLE patients: 26 +/- 11 and 25 +/- 11 mm Hg, respectively. However, the frequency of PH was higher in SLE (60%) than in MCTD patients (33%). The titers of aCL were significantly higher in SLE (38 +/- 27 IU/ml) than in MCTD (17 +/- 7 IU/ml; p < 0.02). Two SLE patients with high titers of aCL had multiple cerebral infarction and transverse myelitis, and deep vein thrombosis, respectively. A significant correlation between the titers of aCL and mPAP was observed in patients with MCTD (p < 0.05), but not in patients with SLE.     

Lupus anticoagulants in patients with systemic lupus erythematosus

Lupus anticoagulants (LA) and anticardiolipin antibodies (aCL) are known as thrombosis-related antiphospholipid antibodies. LA is not as well characterized as aCL, and the relation between LA and aCL is not clarified. Since standardized method for the detection of LA has not been established, we measured LA activities in outpatients with SLE by using two different methods (KCT and dRVVT), and analyzed the characteristics of LA in SLE. LA was detected in 29.8% of all samples (14.3% in both methods, 15.5% in one method). IgG-aCL and IgM-aCL was detected in 38% and 20%, respectively, of all LA positive samples. Though a good correlation was observed between LA activities and IgG-aCL levels, a considerable number of LA positive samples were negative for aCL. This indicated the presence of factors with LA activity other than aCL. On the contrary there was also a high percentage of LA negative samples with positive aCL (42.4% in IgG-aCL, 47.4% in IgM-aCL), suggesting the presence of aCL with poor or low LA activity. These findings showed the heterogeneity of antiphospholipid antibodies both in LA and in aCL. The platelet function tests showed increased platelet adhesiveness and normal platelet aggregation in LA positive patients with SLE even in the inactive phase. The serum levels of factors such as protein C, protein S, antithrombin III and thrombomodulin were within normal range. Clinical features such as hemolytic anemia, thrombosis and abortion were more frequently observed in LA positive population than in LA negative population. The clinical features tend to be different between patients with dRVVT-LA and those with KCT-LA, though not significant. Because of the heterogeneity in LA, a combination of more than two different methods including dRVVT was recommended for the detection and the evaluation of LA.     

Tuberculosis among Filipino patients with systemic lupus erythematosus

A retrospective review of the clinical records of 54 patients with systemic lupus erythematosus (SLE) and documented tuberculosis (TB) infection seen at the University of Santo Tomas Hospital was accomplished. There were 53 women and one man, with a mean age of 32.2 +/- 10 years and a total of 57 TB occurrences. Pulmonary involvement was recorded in 42 (74%): upper lungfield in 25, mid to lower lungfield in 7, and miliary pattern or diffuse infiltrates in 10. TB arthritis was noted in 8, osteomyelitis in 4, and soft tissue abscesses in 4. Central nervous system involvement consisted of brain abscesses (tuberculomas) in two and meningitis in one. Two patients each had TB lymphadenitis, genitourinary TB, ileocecal TB, and TB peritonitis. Hepatobiliary and cutaneous TB occurred in one patient each. Eight of 10 patients with disseminated or miliary TB died primarily of respiratory failure; six of these eight patients also had some form of extrapulmonary involvement. Using the Wilcoxon rank-sum test, there were significant differences in the mean SLE Disease Activity Index (SLEDAI) and Severity of Disease Index (SDI) scores between those with limited TB (SLEDAI 24 +/- 7 SD; SDI 19 +/- 18 SD) versus those with extensive TB (SLEDAI 41 +/- 16 SD; SDI 36 +/- 21 SD), P < .05. There was no significant difference in the average daily prednisone dose (mg) between those with limited TB (25 +/- 17 SD) versus those with extensive TB (31 +/- 16 SD). The contributory role of tuberculous infection in the morbidity and mortality of patients with SLE must be emphasized, especially in areas endemic for TB.     

Increased risk of malignancy in patients with systemic lupus erythematosus

BACKGROUND: Systemic lupus erythematosus is a chronic, multisystem, autoimmune disorder that primarily affects women. Morbidity and mortality have improved for lupus patients during the last 15 years. An increased risk of malignancy in patients with lupus has been shown in some, but not all studies. The purpose of this study was to ascertain cancer risk in lupus patients by linking two disease registries. METHODS: Participants in the Chicago Lupus Cohort included 616 women with lupus who were residents of Cook County, Illinois. They were seen during 1985-1995 at 4 University, inner city, and suburban inpatient and outpatient clinics in Chicago. Malignancies occurring in these subjects during the study interval, 1985-1995, were identified from the Illinois State Cancer Registry by matching name, birthdate, and social security number. Standardized incidence ratios (SIRs) were estimated for all malignancies in this cohort of lupus patients using age, gender, and all race or race-stratified specific cancer incidence data from Cook County, Illinois. RESULTS: The registry linkage study with the Illinois State Cancer Registry documented that 30 women with lupus had a malignancy. The expected number of malignancies for women in the lupus cohort was 15.0. There were 8 cases of breast cancer and 4 each of lung and cervical cancer. In the remaining 14 women, 12 different types of cancers were noted. The SIR and 95% confidence interval (CI) for malignancy for all women with lupus in the study were 2.0 (1.4, 2.9) and lung cancer was the only individual cancer increased in all women--SIR and 95% CI were 3.1 (1.3, 7.9). In the analysis stratified by race, the risk of malignancy (SIR and 95% CI) was increased in Caucasian women, 2.3 (1.4, 3.9). Breast cancer was the only individual cancer increased in Caucasian women with lupus with an SIR and 95% CI of 2.9 (1.4, 6.4). CONCLUSIONS: Lupus patients have an increased risk of malignancy. Breast, lung, and gynecological malignancies were the most common malignancies observed in the cohort and breast cancer was significantly increased in Caucasian women.     

Hyperprolactinemia in males with systemic lupus erythematosus

Alanine dehydrogenase [EC 1. 4. 1. 1] was purified to homogeneity from a crude extract of Enterobacter aerogenes ICR 0220. The enzyme had a molecular mass of about 245 kDa and consisted of six identical subunits. The enzyme showed maximal activity at about pH 10.9 for the deamination of L-alanine and at about pH 8.7 for the amination of pyruvate. The enzyme required NAD+ as a coenzyme. Analogs of NAD+, deamino-NAD+ and nicotinamide guanine dinucleotide served as coenzymes. Initial-velocity and product inhibition studies suggested that the deamination of L-alanine proceeded through a sequential ordered binary-ternary mechanism. NAD+ bound first to the enzyme, followed by L-alanine, and the products were released in the order of ammonia, pyruvate, and NADH. The Km were 0.47 mM for L-alanine, 0.16 mM for NAD+, 0.22 mM for pyruvate, 0.067 mM for NADH, and 66.7 mM for ammonia. The Km for L-alanine was the smallest in the alanine dehydrogenases studied so far. The enzyme gene was cloned into Escherichia coli JM109 cells and the nucleotides were sequenced. The deduced amino acid sequence was very similar to that of the alanine dehydrogenase from Bacillus subtilis. However, the Enterobacter enzyme has no cysteine residue. In this respect, the Enterobacter enzyme is different from other alanine dehydrogenases.     

An in vitro assay for detection of glomerular binding IgG autoantibodies in patients with systemic lupus erythematosus

The deposition of anti-dsDNA antibodies in the glomerulus is believed to play a critical role in the pathogenesis of nephritis in SLE. However, an absolute correlation between serum levels of anti-dsDNA antibodies and renal disease has not been found. Recently a glomerular binding assay (GBA) has been developed to detect IgG binding to isolated rat glomeruli. We have used the GBA to study sera from four groups of SLE patients: (A) + anti-dsDNA antibodies, active nephritis; (B) - anti-dsDNA antibodies, active nephritis; (C) + anti-dsDNA antibodies, no nephritis; and (D) - anti-dsDNA antibodies, no nephritis. The serum anti-dsDNA antibodies in group A and group C patients could not be distinguished on the basis of isotype, charge, or cross-reactivity with histones. Nevertheless, the mean intensity of glomerular immunofluorescence was significantly higher in group A than in the three other patient groups and distinguished between patients with serum anti-dsDNA antibodies who had nephritis and those without clinically apparent nephritis. GBA reactivity was unaffected by DNase treatment of sera, but was partially inhibited by preincubation with dsDNA. These findings are consistent with the hypothesis that some anti-dsDNA antibodies cross-react with glomerular components and that the presence of this cross-reactivity is associated with, and may be responsible for, the development of nephritis. In addition, we have identified a group of SLE patients with renal disease and typical renal histopathology and immune deposits who do not have serum anti-dsDNA antibodies or antibodies that directly bind to glomeruli in the GBA. The mechanism of renal immune deposition in these patients remains to be determined.     

A case of systemic lupus erythematosus associated with spinal epidural hematoma

A 47 year-old Japanese female who showed transverse myelopathy (TM) due to spinal epidural hematoma diagnosed by MRI in the course of systemic lupus erythematosus (SLE) was reported. She was admitted to Keio University Hospital due to paraplegia, anesthesia of lower extremity, urinary disturbance. Neurological examination revealed transverse disturbance of Th 10. Lumbar spinal cord MRI showed irregular mass that located at epidural region of 9th-11th thoracic vertebrae. When the laminectomy of 9th-11th thoracic vertebrae was performed, hematoma (4.5 cm x 1.5 cm in size) was confirmed and removed completely. Post operative condition was stable and symptoms had been improving gradually. It has been reported that TM associated with SLE was closely related to myelitis. In this case, epidural hematoma was a major cause of TM and MRI was very useful for her diagnosis and treatment. This is the rare case of SLE associated with spinal epidural hematoma and was thought as a important case to consider the cause of neurological complication of SLE.     

Tyrosine phosphorylation in peripheral lymphocytes from patients with systemic lupus erythematosus

A comparative study of tyrosine phosphorylation was performed on peripheral blood lymphocytes from systemic lupus erythematosus (SLE) patients and from healthy donors. Freshly isolated SLE lymphocytes presented an elevated tyrosine phosphorylation level when compared to healthy donors lymphocytes (p = 0.005). Among all phosphorylated proteins, those called p120, p110, p80 and p55-p60 were more phosphorylated. The level of tyrosine phosphorylation of p120 and p110 proteins discriminated significantly (p = 0.0048, respectively, p = 0.02) between SLE patients and healthy donors. Lymphocytes form SLE patients and healthy donors were then stimulated by cross-linking T cell antigens (CD3, CD4, CD8) to further distinguish the signal transduction between normal and pathologic lymphocytes. No statistical differences in the tyrosine phosphorylation pattern, following CD4 or CD8 cross-linking, were observed between SLE patients and healthy donors lymphocytes. CD3 cross-linking induced an effect on tyrosine phosphorylation different in SLE patients versus healthy donors lymphocytes. Thus, the lymphocytes of SLE patients were refractile in anti-CD3 stimulation in comparison with the healthy donors lymphocytes. Chi-square analysis demonstrated that a significantly larger number of healthy donors responded to anti-CD3 stimulation compared to SLE patients (p = 0.03). The high frequency of tyrosine phosphorylation of p110 and p80 proteins, following CD3 stimulation, in normal versus SLE lymphocytes, suggested that these proteins could be involved in abnormal signal transduction in SLE cells.     

Decreased bone mineral density in premenopausal patients with systemic lupus erythematosus

To study bone mineral density (BMD) in premenopausal adult female patients with systemic lupus erythematosus (SLE) and its relation with clinical parameters, 56 SLE patients (mean age 31 years, mean disease duration 6.3 years) and 15 normal controls were studied. BMD at the lumbar vertebrae (L2-L4) was measured by dual energy X-ray absorptiometry (DEXA). Classification of BMD was made according to the WHO criteria in 1994. Correlation between BMD and clinical parameters was calculated. It was found BMD in the SLE patients (0.942 +/- 0.136 g/cm2) was lower than in the control group (1.055 +/- 0.080 g/cm2) (P < 0.01). According to the WHO criteria, 17 patients (30%) had normal BMD, 22 patients (40%) had osteopenia and 17 patients (30%) had osteoporosis. BMD was inversely correlated with disease duration in SLE patients (p < 0.005). The minimal disease duration for a female SLE patient to develop osteopenia was 3.5 years. In conclusion, SLE patients have lower lumbar BMD than normal controls. SLE patients with longer disease duration have lower BMD. In order to achieve early prevention of osteoporosis, we suggest that female SLE patients with disease duration for more than 3.5 years should take a BMD examination.     

Soluble tumor necrosis factor receptors in patients with systemic lupus erythematosus

OBJECTIVE: To study the variations of type II soluble receptors for tumor necrosis factor (sR-TNF) in patients with systemic lupus erythematosus and investigate their use in the clinical setting. PATIENTS AND METHODS: Twenty-six patients with systemic lupus were followed for a mean 3 years. sR-TNF and other immunological parameters (C reactive protein, anti-DNA antibodies, C3 and C4 complement fractions, soluble receptors for interleukin 2) were measured in sera at different points of the disease course. The systemic lupus activity measure (SLAM) was determined at each point, and confronted with the biology results. The study was cross sectional for the group and longitudinal for the patients. RESULTS: sR-TNF was the immunological parameter which correlated best with SLAM. It also correlated with sedimentation rate, C reactive protein, thrombopenia, anemia, creatinine level, anti-DNA antibodies and sR-IL2. The longitudinal study pointed out however that this finding is not consistent for each patient. CONCLUSION: A rise in sR-TNF related to systemic lupus activity but is of limited practical interest for individual patient follow-up.     

Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus

The anti-DNA response is a hallmark of systemic lupus erythematosus (SLE). The precise mechanisms leading to anti-DNA antibody (Ab) production remain to be studied. Nonetheless, it is becoming clear that anti-DNA Abs cause inflammatory lesions not only via deposition of circulating immune complexes (IC) consisting of anti-DNA Ab and antigens (Ags), but also via in situ IC formation by cationic anti-DNA Abs. It is intriguing that cationic anti-DNA Abs are encoded by a unique germline Vkappa gene, A30, which encodes an extraordinary cationic light chain, whereas somatic mutations did not induce a cationic shift of electrical charge in human lupus nephritis, suggesting that the usage of a specific germline gene may confer the cationic charge (or pathogenicity) on anti-DNA Abs and that somatic mutations induce the affinity maturation of Abs. Whether cationic anti-DNA Abs will develop depends at least partly on the presence or absence of the germline A30 gene, since patients who lack this gene in the germline Vkappa repertoire did not develop severe lupus nephritis. Receptor editing, a mechanism for changing the affinity of the B cell Ag receptor [surface immunoglobulin (Ig) receptor] to avoid self-reactivity actually seems defective in patients with SLE because normal B cells edited the A30 gene, whereas SLE B cells express A30 mRNA. Thus, along with the importance of somatic mutations, polymorphisms of Ig Vkappa locus, and genetic predisposition, the failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.     

Sera from patients with systemic lupus erythematosus demonstrate enhanced IgG binding to endothelial cells pretreated with tumour necrosis factor alpha

Fluorescence flow cytometry and indirect immunofluorescence were used to detect circulating IgG antiendothelial cell antibodies (IgG-AECA) in the sera of patients suffering from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and progressive systemic sclerosis (PSS). Pretreatment of endothelial cells with tumour necrosis factor alpha (TNF alpha), but not with interferon gamma (IFN gamma), increased the IgG binding from sera of some patients with active SLE. In contrast, no change in binding activity to cytokine-stimulated endothelial cells was observed in the RA and PSS sera. The results of this study suggested that the enhanced binding of IgG from the sera of patients with SLE to endothelial cells stimulated with TNF alpha may be due to the ability of this cytokine to increase the expression of potential antigens on the surface of these cells. Hence, TNF alpha may play a role in the immune-mediated vascular damage associated with SLE.