And Primary Antiphospholipid Syndrome Research Articles

Eculizumab administration for myasthenia gravis also stabilizes thrombogenicity of catastrophic antiphospholipid syndrome

AbstractBackgroundThe co‐occurrence of myasthenia gravis and primary antiphospholipid syndrome (APS) is rare. Notably, both the diseases share common complement‐mediated mechanisms.Case PresentationA 36‐year‐old woman, who was previously diagnosed with myasthenia gravis and APS, developed multiple embolisms, involving the brain, kidney and spleen, with severe anemia and platelet reduction. She was diagnosed as catastrophic APS, and intensive immunotherapies, including plasma exchange, high‐dose corticosteroid and rituximab, were introduced. After these therapies, symptoms of both APS and myasthenia gravis worsened, consistent with elevation of immunoglobulin G anti‐beta‐2‐glycoprotein‐I antibody and anti‐acetylcholine receptor antibody. We started eculizumab, which resulted in stabilizing the disease activity of both diseases without notable adverse events.ConclusionsEculizumab can be effective for controlling multiple complement‐mediated pathophysiology.

Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus

BackgroundThere is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). ObjectivesOur aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. MethodsObservational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. Results133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. ConclusionsWe found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.

Therapeutic plasma exchange for refractory SLE: A comparison of outcomes between different sub-phenotypes.

Therapeutic plasma exchange (TPE) offers an alternative therapeutic modality for patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). However, there is conflicting evidence regarding its efficacy in different sub-phenotypes. This study aimed to investigate the main clinical characteristics and outcomes of patients with different phenotypes of SLE and APS treated with TPE at a tertiary care center. The database of the Blood and Apheresis Unit between 2001 and 2013 was screened for patients with SLE and primary APS. SLE disease activity index (SELENA-SLEDAI), the indications for treatment, complications, and outcomes were obtained from a review of medical records and phone calls. A total of 24 patients (SLE: 20, APS: 4) were recruited for the study. Mean ages of SLE (M/F: 1/19) and primary APS (PAPS) patients (M/F: 2/2) were 32.4±12.89 and 52.0±10.7 years, respectively. The main indications for TPE were hematologic, neurologic, and pulmonary involvement and APS-related symptoms. TPE was preferred in eight patients because of leucopenia and co-infection. SLEDAI was significantly decreased after TPE (16.7±8.3 before vs. 8.8±3.1 after, p=0.001). Both primary APS and SLE-related catastrophic APS (CAPS) patients had completely responded to TPE. The success rate of TPE in patients with thrombocytopenia was lower than patients with hemolytic anemia. The median (IQR 25%-75%) number of TPE sessions was 6.5 (5-10.5). In total, five patients experienced TPE-related major adverse events (catheter infections in three patients, bleeding in one patient, and hypotension in one patient). The median (IQR 25%-75%) follow-up time was 33.5 (6.75-81.25) months. In total, four patients died during follow up, of which three died during the period of TPE administration. Our data suggest that CAPS and other APS-related problems respond well to the TPE treatment. TPE should be kept in mind for the treatment of patients with other features of SLE, especially those resistant to other agents and in the presence of leucopenia.

Low-molecular-weight heparin and aspirin use in relation to pregnancy outcome in women with systemic lupus erythematosus and antiphospholipid syndrome: A cohort study

ABSTRACTObjective: To relate anticoagulant use to pregnancy complications in women with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). Methods: All ongoing pregnancies, 184, in two Dutch tertiary centers between 2000 and 2015. Results: LMWH and aspirin was prescribed in 15/109 SLE women without antiphospholipid antibodies (aPL), 5/14 with aPL, 11/13 with APS, 45/48 with primary APS. Main complications in the four treatment groups (no anticoagulant treatment, aspirin, LMWH, aspirin and LMWH) included hypertensive disorders of pregnancy (9.4%, 23.3%, 50%, 18.4%, respectively, p = 0.12) and preterm birth (16.7%, 34.3%, 75%, 36.8%, respectively, p < 0.001). Conclusion: Maternal and perinatal complications occurred frequently, despite LMWH and aspirin use.

Pure red cell aplasia and primary antiphospholipid syndrome: a unique association

Pure red cell aplasia (PRCA) is a disease with important relationships to autoimmune mechanisms. Although some autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have been associated with PRCA, until this point no studies have described the association between PRCA and primary antiphospholipid syndrome (APS). This is the first case report of PRCA associated with primary APS in a 39-year-old man with acute heart failure secondary to an anaemic condition that was diagnosed as pure red cell aplasia. The patient was later diagnosed with retinal artery and vein thromboses and bilateral deep venous thromboses of the femoral and popliteal veins. The most common causes of PRCA and other thrombophilias were ruled out in this investigation through complementary tests. This association with APS adds a new possibility to the study of PRCA pathophysiology.

Usefulness of a Diluted Prothrombin Time for Accurately Diagnosing Antiphospholipid Syndrome

The usefulness of lupus anticoagulant (LA) and several antibodies for predicting thrombosis was assessed in patients with idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), lupus like disease (LLD), recurrent abortion and primary antiphospholipid syndrome (APS). LA was measured using the diluted Russell Viper Venom test (DRVVT) and the diluted prothrombin time (dPT). In healthy volunteers, the median (range) of the DRVVT and dPT ratio were 0.97 (0.88 - 1.08) and 1.05 (0.85 - 1.29), re- spectively. The positive percent of dPT ratio was high in patients with ITP, SLE, recurrent abortion and primary APS. The sensitivity for thrombosis was highest for the dPT ratio and the specificity for thrombosis was highest for the DRVVT ra- tio. The sensitivity and the Odd's ratio for both the dPT and DRVVT ratio were high. A positive predictive value in DRVVT and a negative predictive value in dPT were high. The receiver operating characteristic (ROC) curve analysis in- dicates that the dPT ratio might be more useful for predicting thrombosis than the DRVVT ratio. The DRVVT and dPT ratios are useful for both the diagnosis of APS as well as predicting thrombosis.

Cross-reactivity between anti-cardiolipin, anti-high-density lipoprotein and anti-apolipoprotein A-I IgG antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome.

Atherosclerosis is an important complication of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). One suggested mechanism may be the action of autoantibodies directed against plasma lipoproteins. We studied the presence and patterns of cross-reactivity between antibodies directed against cardiolipin, high-density lipoprotein (HDL) and apolipoprotein A-I (Apo A-I) in patients with SLE and APS. Sera from 50 patients (25 SLE and 25 APS) and 10 healthy controls together with three human immunoglobulin G anti-cardiolipin (CL) monoclonal antibodies (IS4, CL1 and CL24) were assessed for the presence of autoantibodies binding cardiolipin, HDL and Apo A-I. Classical inhibition assays were performed to study interference by HDL and Apo A-I in the binding of the human monoclonal antibody to CL. To determine the cross-reactivity patterns between these autoantibodies, sera from 12 patients were incubated on ELISA plates coated with the three different molecules and the captured antibodies were then tested for their activity towards each of the other antigens. All three monoclonals bound to CL. IS4 and CL1 also bound to HDL but only IS4 bound to Apo A-I. Anti-cardiolipin titres were higher in patients with APS than SLE and in healthy controls (P<0.03 and P<0.009 respectively). Titres of antibodies to HDL were higher in patients with SLE and APS than in controls (P<0.009 and P<0.03 respectively). There were no significant differences with respect to the presence of antibodies binding to Apo A-I. In the SLE population, anti-HDL antibody titres correlated with anti-Apo A-I (r=0.563, P<0.004), but not in patients with APS. In the cross-reactive assay, 11/12 (91.7%) of the samples containing isolated anti-CL antibodies reacted to HDL and 2/12 (16.7%) to Apo A-I. Samples containing isolated anti-HDL antibodies also reacted with CL and Apo A-I (7/12 and 3/12 respectively). All samples collected after incubation with Apo A-I bound to HDL and 6/12 (50%) to CL. There were no differences in the cross-reactivity patterns between patients with SLE and APS. Patients with SLE and APS have antibodies directed against HDL and Apo A-I. A high percentage of these antibodies cross-react with CL, suggesting the presence of different groups of antibodies with different targets. The study of the interaction between the immune response and the lipoprotein components and the correct characterization of the reactivity patterns of autoantibodies may be of relevance in the study of atherosclerosis in patients with SLE and APS.

Acquired HDL Deficiency Associated With Apolipoprotein A-I Reactive Monoclonal Immunoglobulins

To the Editor: Immunoglobulins (Igs) directed at components of lipoproteins to cause altered lipoprotein metabolism have been described in patients with multiple myeloma,1,2⇓ xanthomatosis,3 benign gammopathies,4 rheumatoid arthritis,5 systemic lupus erythematosus (SLE), and primary antiphospholipid syndrome (APS).6,7⇓ In most cases, hyperlipidemia results from Igs reactive with apolipoprotein (apo) B present on very low–density lipoproteins and LDLs. Less common have been associations of Igs with hypolipidemia or reactive with HDLs. Here we describe two patients who developed low HDL-cholesterol (HDL-C) levels (<5th percentile) associated with benign gammopathy and the presence of serum Igs reactive with apo A-I. Patient 1 (P1) was a morbidly obese (body mass index, 48 kg/m2), 45-year-old woman with mild normocytic, normochromic anemia (hematocrit, 33 g/L; hemoglobin, 11.6 g/L) and low HDL-C (0.22 mmol/L [8 mg/dL]). Serum Ig levels were elevated. Antinuclear antibodies were detected but were nonreactive with dsDNA, Sm, RNP, SSA, SSB, SCL-70, and histone. Anticardiolipin and anti–β2-glycoprotein I antibodies were negative. Immunofixation electrophoresis (IFE) identified monoclonal IgGκ and IgGλ bands. No Igs or light chains were detected in her urine. Serum lipid levels showed that HDL-C was in the low-normal to normal range between 1992 and 1996 (1.0 to 1.4 mmol/L) but at the time of presentation …

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

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). 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. 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). 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.

Anti-β2 Glycoprotein I Antibodies Prevent the De-activation of Platelets and Sustain their Phagocytic Clearance

Exposure to phosphatidylserine (PS) tags dying and senescent cells for removal and identifies activated platelets. In this study we followed the fate of PS-exposing platelets in the presence of antibodies purified from Systemic Lupus Erythematosus (SLE) and primary Anti-phospholipid Syndrome (APS) patients' sera by β2GPI affinity chromatography. Thrombin-activated platelets exposed PS and associated to β2GPI. Both events were required for recognition by antibodies. Human monocyte-derived macrophages phagocytosed activated platelets only. Each macrophage internalized an average of 3.16±0.2 platelets after 60min at 37°C. Phagocytosis did not increase after longer incubations (4.65±0.26 platelets internalized by each macrophage after 300min). Recognition of platelets by anti-β2GPI antibodies significantly increased phagocytosis (P< 0.01). Upon withdrawal of thrombin, platelets downregulated PS (PS exposure t1/2: 242min) and the ability to be recognized by macrophages. Purified β2GPI bound to PS-exposing platelets (association t1/2: 250min). Phosphatidyl serine exposure and β2GPI association had virtually identical kinetics. Antibody binding prolonged the exposure of the β2GPI/PS complex (t1/2: >1200min). The ability to phagocytose opsonized platelets was accordingly sustained (5.3±0.2 opsonized platelets were internalized by each macrophage after 60min and 9.4±0.3 after 300min). Anti-β2GPI antibodies therefore poise activated platelets in a PS-exposing status, preventing the recycling of their function and favoring their phagocytic clearance.

Poly(ADP-ribose) polymerase alleles in French Caucasians are associated neither with lupus nor with primary antiphospholipid syndrome. GRAID Research Group. Group for Research on Auto-Immune Disorders.

To investigate the putative involvement of poly(ADP-ribose) polymerase (PARP) alleles in systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). This study of French Caucasians included 171 unrelated patients with SLE, 88 unrelated patients with primary APS, and 193 ethnically matched healthy controls. The SLE group comprised 89 patients with sporadic SLE and 82 patients with familial SLE. Patients' and controls' DNA were genotyped for the various alleles of a polymorphic CA dinucleotide repeat located within the promoter region of PARP. No statistically significant difference was observed for the distribution of PARP alleles between the healthy control group and each patient group or the pooled SLE patient group. The study findings strongly suggest that these alleles do not influence susceptibility to SLE or primary APS in French Caucasians.

A human monoclonal antiphospholipid antibody that is representative of serum antibodies and is germline encoded

To investigate the origins of antiphospholipid antibodies associated with thrombosis and other disorders that are found in patients with systemic lupus erythematosus and primary antiphospholipid syndrome (APS). Characterization, idiotypic study, and nucleotide sequencing of a human monoclonal antiphospholipid antibody generated from a patient with primary APS. Identification of the germline genes from which the antibody is derived. A human monoclonal antibody, BH1, was generated. This antibody has ligand-binding properties that closely resemble those of the serum antiphospholipid antibodies found in our patient and in other individuals with APS: it recognizes negatively charged phospholipids, and has lupus anticoagulant activity; it does not bind to neutral phospholipids, or to single-stranded or double-stranded DNA. The relevance of BH1 to the patient's serum antibodies is supported by our idiotypic studies. BH1 is encoded by a new germline VH gene, and by a lambda light chain gene that displays > 99% homology with the V lambda III.1 germline gene. Serum antiphospholipid antibodies associated with thrombosis may be encoded by either germline or only slightly mutated variable-region genes.