Positive antiphospholipid antibodies and pulmonary embolism in a patient with adalimumab-induced lupus.

It is known that administration of tumor necrotic factor (TNF) inhibitors induces lupus. The case of a Crohn's disease patient who had been treated with adalimumab (ADA) and showed positive anti-DNA and antiphospholipid antibodies and developed pulmonary embolism is presented. Fortunately, early diagnosis and intervention helped her survive. Although ADA was withdrawn, the Crohn's disease did not recur, and the autoantibodies became negative without any steroid therapy. It is important to recognise that administration of TNF inhibitors may be associated with antiphospholipid syndrome. It is necessary to perform therapeutic interventions such as TNF inhibitor withdrawal and prompt anticoagulant therapy when such pathology is suspected.

Ophthalmologic manifestations in patients with antiphospholipid antibodies: Beware of iatrogenic complications.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by several clinical manifestations such as venous and arterial thrombosis associated with persistent antiphospholipid antibodies (aPL). Several studies confirmed that retinal vein occlusion was the most common APS ocular manifestation. The purpose of this study was to identify ophthalmologic manifestations in a homogeneous cohort of well-defined persistently aPL-positive patients and to determine variables associated with these manifestations. METHODS: APL-positive patients were selected from two research programs. All ophthalmologic manifestations including those related to APS were recorded. RESULTS: A total of 117 patients were included and 10 of them had APS-related ophthalmologic manifestations (glaucoma, hydroxychloroquine-related maculopathy, anterior acute uveitis, anterior ischemic optic neuropathy). Systemic Lupus Erythematosus (SLE) (OR = 3.4[95%CI; 0.9-12.7), corticosteroids (OR = 9.0 [95%CI; 2.2-37.7]) and aPL-related nephropathy (OR = 7.1 [95%CI; 1.7-30.0]) were significatively associated with the risk of APS-related ophthalmologic manifestations. CONCLUSION: Most of ocular manifestations in this study were iatrogenic related to corticosteroids or hydroxychloroquine. Patients with SLE, small vessel thrombosis in general, or with aPL-related nephropathy in particular, seemed at higher risk to develop APS-related ophthalmologic manifestations thus deserving adequate monitoring.

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.

Antiphospholipid antibody-activated NETs exacerbate trophoblast and endothelial cell injury in obstetric antiphospholipid syndrome.

Despite the widespread use of antiplatelets and anticoagulants, women with antiphospholipid syndrome (APS) may face pregnancy complications associated with placental dysplasia. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many autoimmune diseases, including vascular APS; however, their role in obstetric APS is unclear. Herein, we investigated the role of NETs by quantifying cell-free DNA and NET marker levels. Live-cell imaging was used to visualize NET formation, and MAPK signalling pathway proteins were analysed. Cell migration, invasion and tube formation assays were performed to observe the effects of NETs on trophoblasts and human umbilical vein endothelial cells (HUVECs). The concentrations of cell-free DNA and NETs in sera of pregnant patients with APS were elevated compared with that of healthy controls (HCs) matched to gestational week. APS neutrophils were predisposed to spontaneous NET release and IgG purified from the patients (APS-IgG) induced neutrophils from HCs to release NETs. Additionally, APS-IgG NET induction was abolished with inhibitors of reactive oxygen species, AKT, p38 MAPK and ERK1/2. Moreover, NETs were detrimental to trophoblasts and HUVECs. In summary, APS-IgG-induced NET formation deserves further investigation as a potential novel therapeutic target in obstetrical APS.

Antiphosphatidylserine Antibody as a Cause of Multiple Dural Venous Sinus Thromboses and ST-Elevation Myocardial Infarction.

BACKGROUND Antiphospholipid syndrome (APS) is an autoimmune disease characterized by antibodies directed against phospholipids on plasma membranes. Through unclear mechanisms, APS confers hypercoagulability. APS may cause recurrent thromboses in the arterial and venous vasculature. We report a case of primary APS resulting in cerebral venous thrombosis and ST-elevation myocardial infarction (STEMI) for which only antiphosphatidylserine (aPS) IgM antibody was positive after extensive investigation. CASE REPORT A 48-year-old male was admitted after a witnessed generalized seizure with subsequent confusion. Imaging demonstrated thrombosis of multiple central nervous system (CNS) sinuses, including the superior sagittal sinus and bilateral transverse sinuses. The patient was heparinized with aggressive hydration, which proved inadequate, prompting endovascular thrombectomy. Three months later, despite anticoagulation therapy, the patient developed a STEMI when International Normalized Ratio (INR) was 1.8. Echocardiogram (ECHO) and PAN CT scan were normal. Initial coagulation studies demonstrated normal anticardiolipin antibody, prothrombin time, partial thromboplastin time, and platelet count. Outpatient coagulation studies revealed normal antithrombin III, protein C/S, hemoglobin electrophoresis, homocysteine, anti-ß2 glycoprotein 1 antibodies, and D-Dimer. Factor V Leiden, JAK 2 mutation, prothrombin gene mutation, and tests for paroxysmal nocturnal hemoglobinuria (PNH) were negative. A positive phosphatidylserine IgM was detected. The patient was continued on warfarin (10 mg daily) with a target INR of 3.0-3.5 and clopidogrel (75 mg daily). CONCLUSIONS Despite extensive investigation, this patient only showed evidence of elevated aPS IgM antibodies, likely contributing to his CNS venous sinus thromboses and STEMI. It is important to screen for antiphosphatidylserine antibodies in cases of unprovoked thrombosis when standard thrombophilia analysis is unrevealing. This will assist in identifying pathogenicity and help prevent recurrence of subsequent thromboses.

Antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies and anti-ß2-glycoprotein 1 antibodies. APS can present with a variety of clinical phenotypes, including thrombosis in the veins, arteries and microvasculature as well as obstetrical complications. The pathophysiological hallmark is thrombosis, but other factors such as complement activation might be important. Prevention of thrombotic manifestations associated with APS includes lifestyle changes and, in individuals at high risk, low-dose aspirin. Prevention and treatment of thrombotic events are dependent mainly on the use of vitamin K antagonists. Immunosuppression and anticomplement therapy have been used anecdotally but have not been adequately tested. Pregnancy morbidity includes unexplained recurrent early miscarriage, fetal death and late obstetrical manifestation such as pre-eclampsia, premature birth or fetal growth restriction associated with placental insufficiency. Current treatment to prevent obstetrical morbidity is based on low-dose aspirin and/or low-molecular-weight heparin and has improved pregnancy outcomes to achieve successful live birth in >70% of pregnancies. Although hydroxychloroquine and pravastatin might further improve pregnancy outcomes, prospective clinical trials are required to confirm these findings.

Arterial stenosis in antiphospholipid syndrome: Update on the unrevealed mechanisms of an endothelial disease.

First described in 1983, antiphospholipid syndrome (APS) is an autoimmune condition characterized by the occurrence of recurrent arterial and/or venous thrombosis, and/or pregnancy morbidity, in the setting of persistent presence of antiphospholipid antibodies (aPL). While thrombosis is the most well-known pathogenic mechanism in this disorder, the relevance of some other mechanisms such as arterial stenosis is being increasingly recognized. Arterial stenosis has been first described in the renal arteries in patients with APS, however intracranial and coeliac arteries can also be involved with various and treatable clinical manifestations. The underlying pathophysiology of this stenotic arterial vasculopathy is not fully understood but some recent studies revealed new insights into the molecular mechanism behind this endothelial cell activation in APS. In this review, we discuss these newly discovered mechanisms and highlight the diagnostic and therapeutic modalities of the APS related arterial stenosis.

Comorbid association of antiphospholipid antibodies and migraine: A systematic review and meta-analysis.

BACKGROUND: Antiphospholipid antibodies (aPLs) namely anticardiolipin (aCL) antibody, anti-ß2-glycoprotein I (ß2GPI) antibody and lupus anticoagulant (LA) are autoantibodies produced against anionic phospholipids and proteins on plasma membranes. Migraine is a primary headache disorder which has growing evidences of autoimmune-mediated pathogenesis and previous studies suggested the presence of aPLs in migraine patients. AIMS: The aim of this study was to evaluate the comorbid association between aPLs (aCL, anti-ß2GPI and LA) and migraine compared to healthy controls. METHODS: Studies were searched through PubMed, ISI Web of Science and Google Scholar databases without restricting the languages and year (up to October 2016) and were selected based on the inclusion criteria. Two authors independently extracted data from the included studies. All analyses were conducted by using random effects model to calculate the odds ratio (OR) and 95% confidence interval (CI). Quality assessment was carried out by using the modified Newcastle-Ottawa Scale (NOS). Publication bias was evaluated via visualization of funnel plots, Begg's and Egger's tests. RESULTS: The database searches produced 1995 articles, 13 of which were selected (912 migraineurs and 822 healthy controls). 8.59%, 15.21% and 4.11% of the migraineurs exhibited aCL, anti-ß2GPI and LA which was 4.83, 1.63 and 3.03 times higher, respectively, than healthy controls. A significant presence of aCL (OR: 3.55, 95% CI: 1.59-7.95; p=0.002) or anti-ß2GPI antibodies (OR: 2.02, 95% CI: 1.20-3.42; p=0.008) was observed in migraine patients, however, LA was not significantly associated (OR: 2.02, 95% CI: 0.50-8.37; p=0.320). Majority of the studies (n=10 of 13) demonstrated NOS score of 7 or above and no significant publication bias was observed. CONCLUSION: Migraine might be an autoimmune-associated neurologic disorder. The presence of aCL or anti-ß2GPI antibodies was significant in migraine patients compared to healthy controls, suggesting an involvement of these autoantibodies in migraine attack.

Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase.

OBJECTIVES: Hydroxychloroquine (HCQ) has been used for decades to treat patients with rheumatic diseases, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis or the antiphospholipid syndrome (APS). We hypothesise that HCQ might target endosomal NADPH oxidase (NOX), which is involved in the signal transduction of cytokines as well as antiphospholipid antibodies (aPL). METHODS: For in vitro experiments, monocytic cells were stimulated with tumour necrosis factor α (TNFα), interleukin-1ß (IL-1ß) or a human monoclonal aPL and the activity of NOX was determined by flow cytometry. The expression of genes known to be induced by these stimuli was quantified by quantitative reverse transcription PCR. Live cell imaging was performed by confocal laser scanning microscopy. Finally, the effects of HCQ on NOX-induced signal transduction were analysed in an in vivo model of venous thrombosis. RESULTS: HCQ strongly reduces or completely prevents the induction of endosomal NOX by TNFα, IL-1ß and aPL in human monocytes and MonoMac1 cells. As a consequence, induction of downstream genes by these stimuli is reduced or abrogated. This effect of HCQ is not mediated by direct interference with the agonists but by inhibiting the translocation of the catalytic subunit of NOX2 (gp91phox) into the endosome. In vivo, HCQ protects mice from aPL-induced and NOX2-mediated thrombus formation. CONCLUSIONS: We describe here a novel mechanism of action of HCQ, that is, interference with the assembly of endosomal NOX2. Since endosomal NOX2 is involved in many inflammatory and prothrombotic signalling pathways, this activity of HCQ might explain many of its beneficial effects in rheumatic diseases including the APS.

Cutaneous manifestations in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a hypercoagulable state that leads to thrombosis and recurrent pregnancy loss related to the presence of antiphospholipid antibodies (LAC, anticardiolipin, antiA2-glycoprotein). Among cutaneous manifestations, livedo reticularis is the most frequent form of APS. In the literature, there are rare cases associated with diffuse skin necrosis (widespread skin necrosis) and intravascular thrombosis in the small vessels of the dermis. We describe the case of a 44-year-old man with positive anticardiolipin antibodies and protein S deficiency that developed scattered, bullous skin lesions, haemorrhagic in appearance with signs of necrosis as first clinical manifestation of antiphospholipid syndrome.

Antithrombotic treatment for stroke associated with antiphospholipid antibodies.

The current mainstay of treatment of thrombotic antiphospholipid syndrome (APS) is long term warfarin; however, the optimal antithrombotic treatment for APS-related ischaemic stroke or transient ischaemic attacks (TIA) remains uncertain, as does the optimal intensity of anticoagulation. The risk of bleeding with increasing anticoagulant intensity needs to be balanced against the risk of profound permanent disability and death, or irreversible neurological deterioration as a result of recurrent stroke/TIA. Several experts recommend a target INR of 3.5 (range 3.0­4.0) for stroke associated with persistent antiphospholipid antibodies (aPL) which meet International consensus Updated Sapporo (Sydney) classification criteria, with a similar approach in patients with aPL-associated TIA. However, current guidelines recommend a target INR of 2.5 (2.0­3.0) in these patients. Prospective adequately powered clinical studies are required to determine the optimal antithrombotic approach including the potential role of oral direct inhibitors of coagulation for patients with aPL-associated stroke.

Diagnosis and classification of the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses, often multiple, and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL). Some estimates indicate that the incidence of the APS is around 5 new cases per 100,000 persons per year and the prevalence around 40-50 cases per 100,000 persons. The aPL are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis and 6% of patients with pregnancy morbidity. The original classification criteria for the APS were formulated at a workshop in Sapporo, Japan, in 1998, during the 8th International Congress on aPL. The Sapporo criteria, as they are often called, were revised at another workshop in Sydney, Australia, in 2004, during the 11th International Congress on aPL. At least one clinical (vascular thrombosis or pregnancy morbidity) and one laboratory (anticardiolipin antibodies, lupus anticoagulant or anti-ß2-glycoprotein I antibodies) criterion had to be met for the classification of APS.

A possible coagulation-independent mechanism for pregnancy loss involving ß(2) glycoprotein 1-dependent antiphospholipid antibodies and CD1d.

PROBLEM ß(2) glycoprotein1 (ß(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-ß(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound ß(2) GP1. Anti-ß(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-ß2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-ß2GP1 mAbs. CONCLUSIONS ß(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.

The association of antiphospholipid antibodies with intrauterine fetal death: a case-control study.

INTRODUCTION: Over the past few decades it has been recognized that antiphospholipid antibodies are associated with pregnancy loss. Other placenta-mediated pregnancy complications have also been associated with the presence of antiphospholipid antibodies. Most studies have measured antiphospholipid antibodies near the time of the event investigated. OBJECTIVES: To investigate the association of antiphospholipid antibodies and a history of intrauterine fetal death (IUFD) in a case-control design. MATERIALS AND METHODS: A case-control study of 105 women with a history of IUFD after 22 gestational weeks and 262 controls with live births. The prevalence of lupus anticoagulant, anticardiolipin- and anti-ß2-glycoprotein 1 antibodies were measured 3-18years after the event of IUFD. RESULTS: Total 9.5% of women with a history of IUFD and 5.0% of controls had at least one positive test for antiphospholipid antibodies (OR 2.0; 95% confidence interval (CI) 0.9-4.8). Women with a history of IUFD were significantly more often positive for lupus anticoagulant compared to controls (OR 4.3; 95% CI 1.0-18.4). The association of lupus anticoagulant with a history of IUFD was confined to women positive for other antiphospholipid antibodies in addition to lupus anticoagulant. Being positive for anti-ß2-glycoprotein 1 or anticardiolipin antibodies alone was not significantly associated with a history of IUFD. CONCLUSIONS: Women with a history of IUFD after 22 gestational weeks were more often lupus anticoagulant positive. The association was confined to women with multiple positivity for antiphospholipid antibodies, although firm conclusions on the importance of multiple positivity cannot be made from this study.

A unique preliminary study on placental apoptosis in mice with passive immunization of anti-phosphatidylethanolamine antibodies and anti-factor XII antibodies.

PROBLEM: Antiphospholipid antibodies have been investigated both in humans and in animal models. In contrast, there are fewer reports describing anti-phosphatidylethanolamine (aPE) antibodies in humans, and there are no reports of animal studies with aPE till date. Clinically, FXII deficiency or anti-FXII antibodies are sometimes associated with aPE in patients with recurrent pregnancy loss. Therefore, we asked whether aPE and/or anti-FXII in mice could cause fetal resorption, placental thrombosis and apoptosis. Moreover, antibodies to respective target antigens (LDC27 or IPP30) could cause pregnancy failure as well. METHODS OF STUDY: Animal models were used to carry out these objectives. All the animals were immunized with different antibodies by passive immunization. Placental samples were used for various observations. RESULTS AND CONCLUSIONS: Mice with passive immunization of aPE (or anti-LDC27) and aFXII (or anti-IPP30) produced a slight increase in fetal resorption, but markedly induced thrombosis and hemorrhage in the placenta associated with lower platelet counts and increased placental apoptosis. In addition, fewer mitotic cells, less trophoblast giant cell invasion, and more shrunken cells in the deciduas were seen. Our study supports the pathogenic role of aPE and aFXII in pregnancy complications and also suggests a beneficial role of LDC27 and IPP30 antigens on pregnancy failures.

Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin.

PROBLEM Women with antiphospholipid antibodies (aPL) are at risk of miscarriage and pre-eclampsia, obstetrical disorders associated with reduced trophoblast invasion and spiral artery transformation. aPL target the placenta by binding beta(2) -glycoprotein I (ß(2) GPI) on the trophoblast. In this study, we determined whether aPL alter the trophoblast secretion of angiogenic factors and evaluated the effect of low molecular weight heparin (LMWH) on this response. METHOD OF STUDY First-trimester trophoblast was treated with anti-ß(2) GPI antibodies with or without LMWH. Angiogenic factor secretion was measured by enzyme-linked immunosorbent assay. RESULTS Trophoblast cells produced more vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and soluble endoglin following exposure to anti-ß(2) GPI Abs, and this occurred in both a MyD88-dependent and MyD88-independent manner. LMWH was unable to reverse the effects of the anti-ß(2) GPI Abs on trophoblast VEGF secretion, but enhanced PlGF. Strikingly, LMWH upregulated soluble fms-like tyrosine kinase receptor-1 (sFlt-1) secretion independently of aPL. CONCLUSION This study demonstrates that aPL perturb the secretion of trophoblast angiogenic factors. LMWH does not reverse this effect but exacerbates sFlt-1 secretion, a potent anti-angiogenic factor. These findings may help to explain why women with antiphospholipid syndrome, who are treated with heparin to prevent early pregnancy loss, remain at increased risk of developing late obstetrical complications, such as pre-eclampsia.

First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss.

The objective of this study was to assess pregnancy outcome in women with a history of refractory antiphospholipid antibody-associated pregnancy loss(es) who were treated with early low-dose prednisolone in addition to aspirin and heparin. Eighteen women with antiphospholipid antibodies who had refractory pregnancy loss(es) were given prednisolone (10 mg) from the time of their positive pregnancy test to 14 weeks' gestation. Before low-dose prednisolone was given as treatment, 4 (4%) of 97 pregnancies had resulted in live births. Among 23 pregnancies supplemented with prednisolone, 9 women had 14 live births (61%), including 8 uncomplicated pregnancies. The remainder were complicated by preterm delivery, preeclampsia, and/or small-for-gestational-age infants. There were 8 first-trimester miscarriages and 1 ectopic pregnancy. There were no fetal deaths after 10 weeks' gestation and no evidence of maternal morbidity. The addition of first-trimester low-dose prednisolone to conventional treatment is worthy of further assessment in the management of refractory antiphospholipid antibody-related pregnancy loss(es), although complications remain elevated.

Antiphospholipid antibodies and the brain: a consensus report.

This report discusses the difference between antiphospholipid antibodies (aPL) as a predictor for first and recurrent ischemic stroke, whether or not concomitant systemic lupus erythematosus (SLE) increases aPL-associated risk, and the association of aPL with other neurological manifestations. The neurological manifestations covered in this report were selected because they are among the most common, including cognitive dysfunction, headache, multiple sclerosis and seizures/epilepsy. Recommendations are made regarding further research that is needed to clarify remaining uncertainties.