The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome

Thrombocytopenia is frequently found in patients with the antiphospholipid syndrome (APS), yet data concerning clinical associations of thrombocytopenia in patients with APS are still scarce. We evaluated possible associations between thrombocytopenia and various APS-related manifestations in a large group of APS patients. Three hundred and seven APS patients were retrospectively evaluated, 259 women and 48 men. Most patients had primary APS (PAPS) (n=173, 56.1%). APS was associated with systemic lupus erythematosus (SLE) in 104 patients (33.9%). All patients underwent detailed medical interview and routine physical examination. Further data were obtained from patients' medical files regarding the expression of various clinical manifestations of the disease. There were 90 patients with thrombocytopenia (29.3%), the rate was significantly higher in SLE compared to PAPS patients (41.9% vs. 23.1%, p=0.001). Similar rates of thrombocytopenia were found in male (29.2%) and female (29.3%) patients. Significant associations were found between thrombocytopenia and cardiac valves thickening and dysfunction, epilepsy, chorea, arthritis, livedo reticularis and skin ulcerations. In contrast, the rates of thrombotic episodes as well as obstetric complications were similar in patients with and without thrombocytopenia. Our data suggest the presence of thrombocytopenia may be a risk factor for cardiac, neurological, articular and cutaneous complications in APS.     

Primary antiphospholipid syndrome: a distinct entity?

Although antiphospholipid syndrome (APS) was first fully described in the context of connective tissue diseases such as systemic lupus erythematosus (SLE), it was soon recognised that the condition can exist on its own. APS appears to represent a clinical spectrum, both in terms of APS features and the presence of other autoimmune conditions. The clinical and serological characteristics of "primary" APS (PAPS) are similar to those of secondary APS, although the clinical features are more commonly recognised in the presence of another autoimmune or inflammatory condition. Furthermore, patients with PAPS may subsequently develop SLE. It is important to identify PAPS, since it is likely to be a contributing factor for a significant proportion of patients with a variety of vascular, neurological and other conditions. It may emerge as more common than secondary APS.     

Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI.

Increased prevalence of anti-phospholipid antibodies (aPL) and increased levels of lipid peroxidation have been described in patients with HIV infection. To assess the binding specificity and avidity of aPL antibodies in HIV infection, sera from 44 HIV-1 infected patients were evaluated for antibodies to cardiolipin (aCL), phosphatidyl serine (aPS), phosphatidyl inositol (aPI) and phosphatidyl choline (aPC) using enzyme linked immunosorbent assay (ELISA) methods. Sera from 30 patients with systemic lupus erythematosus (SLE), but without features of anti-phospholipid syndrome (APS) (SLE/non APS), six with SLE and secondary APS, (SLE/APS) and 11 with primary APS (PAPS) were also evaluated as controls. The resistance of the aPL antibody binding to dissociating agents was evaluated by treating the ELISA wells, after serum incubation with 2 M urea or 0.6 M NaCl for 10 min. An anti-beta2-glycoprotein-I (beta2-GPI) ELISA was used to assess serum reactivity against beta2-GPI, a plasma protein considered as the true antigen of aCL antibodies occurring in APS and SLE patients. The prevalence of aCL, aPS, aPI and aPC antibodies in HIV-1 infection was 36%, 56%, 34% and 43% respectively, which was comparable to that found in SLE/APS and PAPS patients and significantly higher than that observed in SLE/non-APS patients. Anti-beta2-GPI antibodies occurred in 5% of HIV-1 infected vs. 17% in SLE/non-APS (P=0.11), 50% in SLE/APS (P=0.009) and 70% in PAPS patients (P=0.0014). A significant decrease of aPL binding after urea and NaCl treatment was observed in the sera of HIV-1-infected, compared to that of APS patients, indicating that aPL antibodies from HIV-1 infected individuals have low resistance to dissociating agents. In conclusion, aPL antibodies (1) occur in HIV-1 infection; (2) tend to recognize various phospholipids but not beta2-GPI; and (3) are of low resistance to dissociating agents-a finding probably reflecting low antibody avidity. Finally, these, like the autoimmune-type aCL antibodies, tend to recognize the oxidized CL-a finding probably indicating autoantibody generation as a result of neoepitope formation by oxidized PLs.     

Antibodies to age‐β2glycoprotein I in patients with anti‐phospholipid antibody syndrome

Anti‐phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of ‘anti‐phospholipid antibodies’ (aPL). The main target antigen of the antibodies is β₂glycoprotein I (β₂GPI). Post‐translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose‐modified β₂GPI (G‐β₂GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme‐linked immunosorbent assay (ELISA) using a G‐β₂GPI. Nine of 15 consecutive PAPS out‐patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G‐β₂GPI (anti‐G‐β₂GPI) by ELISA. The occurrence of anti‐G‐β₂GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti‐G‐β₂GPI. Of note, aG‐β₂GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti‐β₂GPI test. Moreover, in APS patients, anti‐G‐β₂GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G‐β₂GPI is a target antigen of humoral immune response in patients with APS, suggesting that β₂GPI glycation products may contain additional epitopes for anti‐β₂GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.     

Classification of primary antiphospholipid syndrome as systemic lupus erythematosus: Analysis of a cohort of 214 patients

Objectives

To assess the limitations of the SLICC (Systemic Lupus International Collaborating Clinics) classification criteria for systemic lupus erythematosus (SLE), in patients with primary antiphospholipid syndrome (PAPS).

Pregnancy outcomes in patients with systemic autoimmunity

The impact of maternal systemic autoimmune diseases on pregnancy outcome is not unequivocally defined. We analysed the pregnancy outcome of 221 pregnancies from 181 autoimmune patients, consecutively followed in a single Italian reference centre from 2001 to 2009. All patients were prospectively followed with monthly visits. Pregnancy outcome was compared with the previous obstetrical history. The patient population comprised five groups: primary antiphospholipid syndrome (PAPS, 39 pregnancies), antiphospholipid syndrome associated with a rheumatic disease (APS/RD, 17 pregnancies), other RD (92 pregnancies), isolated autoantibodies (autoAbs) in the absence of a definite autoimmune disease (aAbs, 38 pregnancies) and reactive arthritis or spondyloarthropathies (35 pregnancies). Of these patients, 50.6% had previous pregnancy complications with an anamnestic live-birth rate of 43.4%. In these patients, complications dropped to 28.2% (44/156). This percentage was very similar to that observed in the 221 pregnancies (29.9%, 66/221) with a live-birth rate of 87.3%. Mean neonatal weight was 3018 ± 611 g; mean gestational age at delivery was 38.17 ± 2.79 weeks. Thus, 10.4% of pregnancies resulted in preterm delivery and 10.9% newborns had low weight at delivery. APS/RD patients had the worse outcome: 17.6% resulted in miscarriage, 14.3% resulted in growth restriction and 50% resulted in preterm delivery. This result was mainly due to patients with APS/systemic lupus erythematosus (SLE) that had the lowest gestational age at delivery (30.8 ± 3.56 weeks) and the lowest newborn weight (1499 ± 931 g). Results confirm that a strict follow-up and targeted treatments significantly improve pregnancy outcomes in autoimmune patients with PAPS, SLE and isolated autoAbs. The pregnancy outcome in patients with APS/SLE remains unsatisfactory.     

Antinucleosome antibodies in primary antiphospholipid syndrome: a hint at systemic autoimmunity?

BACKGROUND: Antinucleosome antibodies (anti-NCS) are reported to be highly sensitive and specific for systemic lupus erythematosus (SLE) and to correlate with disease activity. They may appear in early stages of the disease, in particular before anti-dsDNA antibodies, being a potential marker for identifying patients susceptible to SLE. Patients with primary antiphospholipid syndrome (PAPS) may develop full-blown SLE but there is no evidence for markers predictive for that. AIM: To evaluate whether anti-NCS may be predictors for full-blown or lupus like disease (LL) in a cohort of PAPS patients. METHODS: A multicentric cohort of 105 PAPS patients was tested for IgG/IgM anti-NCS by using a home made assay with H1-stripped chromatin as antigen. RESULTS: Eighty-one out of 105 (77%) of the patients were positive for anti-NCS; medium-high titre results were present only in 49/105 (46%). Anti-NCS were more frequently detected in PAPS+LL, but no relationship with clinical/serological features was found, except for a weak correlation with anti-dsDNA antibodies. Two PAPS patients evolved into full-blown SLE during the follow-up and displayed high titre anti-NCS many years before. CONCLUSIONS: Our findings suggest that anti-NCS might be added to the mosaic of autoimmune phenomena characterizing PAPS patients and in particular those with more chance to evolve to SLE.     

Pregnancy outcomes in patients with systemic autoimmunity

The impact of maternal systemic autoimmune diseases on pregnancy outcome is not unequivocally defined. We analysed the pregnancy outcome of 221 pregnancies from 181 autoimmune patients, consecutively followed in a single Italian reference centre from 2001 to 2009. All patients were prospectively followed with monthly visits. Pregnancy outcome was compared with the previous obstetrical history. The patient population comprised five groups: primary antiphospholipid syndrome (PAPS, 39 pregnancies), antiphospholipid syndrome associated with a rheumatic disease (APS/RD, 17 pregnancies), other RD (92 pregnancies), isolated autoantibodies (autoAbs) in the absence of a definite autoimmune disease (aAbs, 38 pregnancies) and reactive arthritis or spondyloarthropathies (35 pregnancies). Of these patients, 50.6% had previous pregnancy complications with an anamnestic live-birth rate of 43.4%. In these patients, complications dropped to 28.2% (44/156). This percentage was very similar to that observed in the 221 pregnancies (29.9%, 66/221) with a live-birth rate of 87.3%. Mean neonatal weight was 3018 ± 611 g; mean gestational age at delivery was 38.17 ± 2.79 weeks. Thus, 10.4% of pregnancies resulted in preterm delivery and 10.9% newborns had low weight at delivery. APS/RD patients had the worse outcome: 17.6% resulted in miscarriage, 14.3% resulted in growth restriction and 50% resulted in preterm delivery. This result was mainly due to patients with APS/systemic lupus erythematosus (SLE) that had the lowest gestational age at delivery (30.8 ± 3.56 weeks) and the lowest newborn weight (1499 ± 931 g). Results confirm that a strict follow-up and targeted treatments significantly improve pregnancy outcomes in autoimmune patients with PAPS, SLE and isolated autoAbs. The pregnancy outcome in patients with APS/SLE remains unsatisfactory.     

Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: Are they different entities?

Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features.Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria.Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished.The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.     

Pulmonary Hypertension,Antiphospholipid Antibodies,and Syndromes

Antiphospholipid antibodies have been associated with two types of pulmonary hypertension (PHT), the thromboembolic type, after deep venous thromboses in the lower limbs complicated by pulmonary embolism and the “primary” plexogenic type. The PHT may occur in the absence of any other manifestations of the antiphospholipid syndrome (APS), and cases have been recorded with very high levels of antiphospholipid antibodies. It may also accompany systemic lupus erythematosus (SLE) and may manifest with or without other features of the APS. It may also form part of the clinical presentation of a “primary” APS. Its prevalence is of the order of 1.8–3.5% of the manifestations of the APS depending on the series. Primary “idiopathic” PHT has long been regarded as an “immunological” disorder. Its manifestations are essentially to the primary type seen with the connective tissue disorders such as SLE, APS, mixed connective tissue disease, calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia variety of systemic sclerosis and Sjögren’s syndrome. The high prevalence of PHT in patients with human immunodeficiency virus infection who demonstrate low CD4 counts points to a close relationship between the T regulatory cells (Treg) and the development of PHT, and this hypothesis is discussed in this review. Genetic and chromosomal aspects of PHT are also discussed.     

The PTPN22*R620W polymorphism does not confer genetic susceptibility to antiphospholipid syndrome in the Spanish population

In this work, we proposed to determine the association of the PTPN22*R620W SNP with primary antiphospholipid syndrome (PAPS) in a case-control association study of Spanish Caucasian individuals. A total of 81 PAPS patients were compared with 81 blood-donor healthy control subjects. PTPN22 SNP (R620W) genotyping was performed by using a polymerase chain reaction-restricted fragment length polymorphism assay. No statistically significant differences were found between control subjects and PAPS patients for the PTPN22*R620W genotypes (P = 0.214). No statistically significant differences were found according to either the presence or absence of antiphospholipid antibodies or the clinical manifestations associated to PAPS. Our results indicate that this functional PTPN22*R620W polymorphism is not associated to PAPS; it seems not to be a risk factor in our Spanish population. The effect of the PTPN22 SNP on clinical manifestations and presence of antiphospholipid antibodies in APS warrants further investigations.     

Atherosclerosis and antiphospholipid syndrome

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and β2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to β-2 Glycoprotein (anti-β2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-β2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.     

IgG autoantibodies against beta2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that [beta2-glycoprotein I (beta2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of beta2GPI/oxLDL complexes and IgG autoantibodies against beta2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The beta2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-beta2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with beta2GPI in SLE and APS patients. In contrast, anti-beta2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against beta2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.     

Renal Involvement in the Antiphospholipid Syndrome (APS)—APS Nephropathy

Although the kidney represents a major target organ in antiphospholipid syndrome (APS), renal involvement in APS was poorly recognized until recently. The most well-recognized renal manifestations of APS are the renal artery thrombosis/stenosis, renal infarction, hypertension, renal vein thrombosis, end-stage renal disease, increased allograft vascular thrombosis, some types of glomerular disease, and a small-vessel vaso-occlusive nephropathy, recently defined as APS nephropathy. APS nephropathy was first described in primary APS patients, characterized by acute thrombotic lesions in glomeruli and/or arterioles (thrombotic microangiopathy) and chronic vascular lesions such as fibrous intimal hyperplasia of arterioles and interlobular arteries, organized thrombi with or without recanalization, and fibrous arterial and arteriolar occlusions or focal cortical atrophy. APS nephropathy was also detected in further studies including patients with systemic lupus erythematosus (SLE)-related APS and SLE/non-APS patients with positive antiphospholipid antibodies, independently of lupus nephritis. The same histologic lesions, especially thrombotic mictroangiopathy, were also observed in patients with catastrophic APS. The most frequent clinical and laboratory characteristics of APS nephropathy in all the above groups of patients are hypertension (often severe), proteinuria (ranging from mild to nephrotic range), hematuria, and acute or chronic renal insufficiency.     

Cardiac manifestations in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease associated with arterial and venous thrombotic events and recurrent fetal loss. Cardiac manifestations in APS primarily include accelerated atherosclerosis leading to cardiovascular disease. There is increased cardiovascular mortality in APS. Cardiovascular risk is even higher in secondary APS in lupus patients. Several traditional and disease-related, autoimmune-inflammatory risk factors are involved in APS-associated atherosclerosis and its clinical manifestations. Antiphospholipid antibodies (APA), lupus anticoagulant, anti-oxLDL and other antibodies have been implicated in vascular events underlying APS. The primary and secondary prevention of atherosclerosis and CAD in these diseases includes drug treatment, such as the use of statins and aspirin, as well as lifestyle modifications. Apart from atherosclerosis and CVD, other cardiac manifestations may also be present in these patients. Among these conditions, valvular disease including thickening and vegetations is the most common. APA are involved in the pathogenesis of Libman-Sacks endocarditis usually associated with SLE. In addition, ventricular dysfunction, intracardiac thrombi and myxomas, pulmonary hypertension may also exist in APS patients. Early diagnosis of APS, thorough examination of the heart, control of traditional risk factors by lifestyle modifications and pharmacotherapy, probably anti-inflammatory treatment, and close follow-up of APS patients may help to minimize cardiovascular risk in these individuals.     

TSGA10 - A target for autoantibodies in autoimmune polyendocrine syndrome type 1 and systemic lupus erythematosus

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.     

Thrombotic microangiopathic hemolytic anemia with reduction of ADAMTS13 activity: initial manifestation of childhood-onset systemic lupus erythematosus

Severe manifestations of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and thrombotic thrombocytopenic purpura (TTP) are characterized by multiorgan thrombotic microangiopathy. We describe reduction of ADAMTS13 activity and the development of systemic autoimmunity in all 8 children initially diagnosed with acquired noncongenital TTP during an 8.5-year period. Median age at diagnosis was 12.0 years (range, 2.6-17.3 years). ADAMTS13 activity was absent (<5%) in 6 patients; 3 patients had a detected inhibitor. SLE was diagnosed concurrently in 3 patients, and 4 patients were diagnosed within 5 years. Six of the children diagnosed with SLE had absent ADAMTS13 activity at diagnosis. In 6 patients with SLE, immune-mediated nephritis developed by 46 months. All surviving patients with SLE developed antiphospholipid antibodies, including some with a lupus anticoagulant. Patients with SLE did not have TTP recurrences once daily immunosuppressive regimens were started. An evaluation for SLE/APS is warranted in children and adolescents with reduced ADAMTS13 activity and thrombotic microangiopathy.     

Aspirin-Interleukin-3 Interrelationships in Patients With Anti-Phospholipid Syndrome

PROBLEM: Previously we reported on the generation of experimental anti-phospholipid syndrome (APS) in mice. These models were employed to evaluate the efficacy of various novel therapeutic modalities including interleukin-3 (IL-3) and low dose aspirin. The efficacy of the latter was found to be interrelated. Low dose aspirin is capable of inhibiting the activity of the enzyme cyclooxygenase which is responsible for the metabolism of arachidonic acid towards the production of prostaglandins. This shifts the metabolism of arachidonic acid to the other pathway and leads to an overproduction of leukotrienes. The leukotrienes act as stimulators of IL-3 production, a positive cytokine in pregnancy which enhances placental and fetal development. In the current study we evaluated the IL-3 levels in pregnant women with APS and expanded our knowledge on the interrelationships between aspirin, arachidonic acid metabolites and IL-3 in the human system. METHODS: IL-3 levels were recorded in the serum of pregnant women with APS and compared to a control pregnant group. In addition peripheral blood mononuclear cells from healthy subjects were incubated with different concentrations of aspirin or with arachidonic acid metabolites (Leukotriene B4, C4 or PGE₂), and IL-3 production in the culture fluids was evaluated. RESULTS: Serum level of IL-3 in pregnant patients with primary APS, APS secondary to SLE and SLE was lower in comparison to the control group. The in vitro studies revealed that only low dose aspirin (10 mg/μl) stimulated IL-3 production while higher doses of the drug failed to induce the cytokine generation. Leukotriene B4 and C4 were stimulatory whereas PGE₂ acted as inhibitor of IL-3 production. CONCLUSIONS: The serum level of IL-3 is decreased to pregnant women with primary or secondary APS. Low dose aspirin is capable of stimulating EL-3 production in vitro most probably through an elevation of leukotriene production, which may explain its beneficial activity in preventing the manifestations of APS.     

The effects of IgG purified from women with SLE and associated pregnancy loss on rat embryos in culture

PROBLEM: Recurrent fetal loss occurs in approximately 1% of women. Autoimmune causes have been suggested as a factor in some of these cases. High rates of intrauterine fetal growth retardation and increased incidence of prematurity is associated with systemic lupus erythematosus (SLE) and the anti-phospholipid syndrome (APS). Autoantibodies from sera of SLE/APS patients affect reproductive outcome in pregnant mice, as was studied in vivo, where injection of immunoglobulin (Ig)G purified from patients with APS to mice caused fetal resorptions and growth retardation. METHODS: In order to investigate the direct effect of IgG purified from women with SLE or APS on the growth and viability of embryos, we cultured 11.5-day old-rat embryos in their yolk sacs in the presence of IgG purified from SLE and APS patients. RESULTS: IgG purified from SLE and recurrent pregnancy loss (RPL) patients affected directly the embryo and yolk sac reducing their growth. The purified IgG positive for anti-cardiolipin/anti-DNA antibodies reduced yolk sac and embryonic growth more than sera negative for these antibodies. CONCLUSION: Various antiphospholipid antibodies affect differently the growth and development of the embryo and the placenta.     

Oxidized low-density lipoprotein/beta2-glycoprotein I complexes and autoantibodies to oxLig-1/beta2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome

Oxidized low-density lipoprotein (oxLDL) interacts with beta2-glycoprotein I (beta2-GPI) via oxLDL-derived specific ligands (oxLig-1) forming complexes. The prevalence and significance of oxLDL/alpha2-GPI complexes and antibodies to oxLig-1/alpha2-GPI were evaluated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The oxLDL/beta2-GPI complex was 69% positive (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, 62% in 40 patients with SLE with secondary APS, and 60% in 50 control patients with SLE without APS. IgG anti-oxLig-1/beta2-GPI antibody was positive in 31 (32%) of 97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti-oxLig-1/beta2-GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive value). These results confirm that oxLDL/beta2-GPI complexes are common in SLE and suggest a possible immunogenic role in APS. In contrast, IgG anti-oxLig-1/beta2-GPI antibodies not only are associated with but also are clinically useful risk factors for APS.