Detrimental roles of TNF-alpha in the antiphospholipid syndrome and de novo synthesis of antiphospholipid antibodies induced by biopharmaceuticals against TNF-alpha.

Antiphospholipid syndrome (APS) is an autoimmune disease that is characterized by arterial and/or venous thrombosis and/or recurrent pregnancy losses. Obstetric APS (OAPS) is considered as a distinct entity from vascular APS (VAPS). In the absence of any additional disease, APS is designated as primary (PAPS), while the term secondary APS (SAPS) is used when other diseases are associated. Catastrophic APS (CAPS) is characterized by the rapid development of multiple thrombosis in various vital organs. The presence of antiphospholipid antibodies (aPL Abs) is considered as a laboratory criterion for APS diagnosis. aPL Abs cause an increase in systemic and decidual TNF-alpha levels in experimental model of APS (eAPS), while paradoxically, administration of TNF-alpha blockers has been associated with de novo synthesis of aPL Abs in patients with various autoimmune diseases. While eAPS provides evidence for the fact that application of TNF-alpha blockers has beneficial effects, lack of randomized prospective studies is the main obstacle for consideration of TNF-alpha blockers administration as a therapeutic option not for all, but at least for selected cases of APS patients despite compelling evidence for detrimental roles of TNF-alpha for both VASP and OAPS. This article represents a review of previously published reports on detrimental roles of TNF-alpha in APS, reports on the application of anti-TNF-alpha agents in eAPS and articles that reported de novo synthesis of aPL Abs induced by biopharmaceuticals against TNF-alpha.

Immunotherapeutic strategies in antiphospholipid syndrome.

Antiphospholipid syndrome is an autoimmune condition, characterised by the persistent presence of antiphospholipid antibodies and either thrombosis or obstetric morbidity. The cornerstone of therapy is long-term anticoagulation to reduce morbidity and mortality; however, better understanding of the immunological pathways may direct us to develop future therapeutic strategies. We provide an overview of the current understanding of the immunopathogenesis of this perplexing condition and its associated morbidities and current evidence for some of the immunotherapeutic strategies.

Pregnancy success rate and response to heparins and/or aspirin differ in women with antiphospholipid antibodies according to their Global AntiphosPholipid Syndrome Score.

BACKGROUND: The current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS. METHODS: One-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients' GAPSS into low risk (< 6), medium risk (6-11), and high risk (≥12). RESULTS: The live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late. Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS <6, n = 72), a medium risk group (GAPSS 6-11, n = 66) and a high risk group (GAPSS ≥12, n = 5). When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p < 0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p < 0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p < 0.001). CONCLUSIONS: GAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC.

Marginal zone lymphoma-associated antiphospholipid antibodies successfully treated with bendamustine rituximab.

A 46-year-old man presented with splenomegaly, abdominal adenopathy and profoundly elevated prothrombin time and partial thromboplastin time. He was diagnosed with marginal zone lymphoma (MZL) and small lymphocytic lymphoma, and the abnormal coagulation studies were secondary to the presence of a lupus anticoagulant. Optimal upfront therapy for MZL has not been established, and the incidence of antiphospholipid antibodies (APLA) in this patient population is rare. Following treatment with six cycles of bendamustine and rituximab with 2 years of rituximab maintenance, our patient remained in remission and his coagulation studies normalised. This report describes a case of successful treatment of APLA associated with MZL that resolved after treatment of the lymphoma.

Treatment options for patients who have antiphospholipid syndromes.

The antiphospholipid thrombosis syndrome, associated with anticardiolipin (aCL) or subgroup antibodies, can be divided into one of six subgroups (I-VI). There is little overlap (about 10% or less) between these subtypes, and patients usually conveniently fit into only one of these clinical types. Although there appears to be no correlation with the type, or titer, of aCL antibody and type of syndrome, the subclassification of thrombosis and aCL antibody patients into these groups is important from the therapy standpoint. This article also reviews the clinical presentations associated with each of these six subgroups.

Aspirin and reproductive outcomes.

In the late 1980s and early 1990s, researchers hypothesized that aspirin could be used to prevent or delay the onset of preeclampsia. This hypothesis was tested in numerous trials which showed limited, but positive results. Subsequently, aspirin has been used in an attempt to improve pregnancy outcomes in women who have both antiphospholipid antibodies and a history of recurrent loss, and has also been used in an attempt to improve the success of in vitro fertilization. In theory, aspirin has both positive and negative effects on reproduction. Aspirin, which suppresses cyclooxygenase, has the potential to interfere with implantation, but also has the potential to support the maintenance of pregnancy. Aspirin is prescribed with increasing frequency to reduce the risk of maternal thrombosis and reduce the risk of miscarriage and poor pregnancy outcome. Aspirin alone, however, is not considered sufficient to prevent thrombosis and even in women with the antiphospholipid syndrome, the question as to whether low-dose aspirin improves pregnancy outcomes has not been answered affirmatively. Aspirin has potential risks. Aspirin inhibits platelet function and can contribute to maternal and fetal bleeding. Aspirin crosses the placenta. Although aspirin has not been associated with other congenital anomalies, it has been associated with an increased risk of vascular disruptions, particularly gastroschisis and possibly premature closure of the ductus arteriosus. Nonetheless, large trials demonstrate low-dose aspirin's relative safety and generally positive effects on reproductive outcomes.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles.

INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Diagnosing antiphospholipid syndrome: 'extra-criteria' manifestations and technical advances.

First described in the early 1980s, antiphospholipid syndrome (APS) is a unique form of acquired autoimmune thrombophilia in which patients present with clinical features of recurrent thrombosis and pregnancy morbidity and persistently test positive for the presence of antiphospholipid antibodies (aPL). At least one clinical (vascular thrombosis or pregnancy morbidity) and one lab-based (positive test result for lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein 1 antibodies) criterion have to be met for a patient to be classified as having APS. However, the clinical spectrum of APS encompasses additional manifestations that can affect many organs and cannot be explained exclusively by patients being in a prothrombotic state; clinical manifestations not listed in the classification criteria (known as extra-criteria manifestations) include neurologic manifestations (chorea, myelitis and migraine), haematologic manifestations (thrombocytopenia and haemolytic anaemia), livedo reticularis, nephropathy and valvular heart disease. Increasingly, research interest has focused on the development of novel assays that might be more specific for APS than the current aPL tests. This Review focuses on the current classification criteria for APS, presenting the role of extra-criteria manifestations and lab-based tests. Diagnostic approaches to difficult cases, including so-called seronegative APS, are also discussed.

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.

OBJECTIVE: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. METHODS: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-ß2 -glycoprotein I (anti-ß2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control. RESULTS: Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-ß2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-ß2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice. CONCLUSION: In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.

Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions.

OBJECTIVE: Antiphospholipid antibodies (aPL) interfere with several physiologic functions of human trophoblasts, including reducing their ability to migrate, decreasing their production of angiogenic factors, and inducing an inflammatory response. This may provide the underlying mechanism by which aPL responses lead to recurrent pregnancy loss or preeclampsia in women with obstetric antiphospholipid syndrome (APS). Although treatment with heparin may reduce the rate of recurrent pregnancy loss, the risk of preeclampsia remains high. Therefore, alternative treatments are needed for the management of pregnant patients with APS. Since aspirin-triggered lipoxins (ATLs) have immune and angiogenic modulatory properties, the objective of this study was to determine the effects of the ATL 15-epi-lipoxin A4 on the function of aPL-altered human trophoblasts in the first trimester of pregnancy. METHODS: A first-trimester human trophoblast cell line (HTR8) was treated with mouse anti-human ß2 -glycoprotein I monoclonal antibodies (aPL) in the presence or absence of the ATL 15-epi-lipoxin A4 . Trophoblast migration and interactions with endometrial endothelial cells were measured using Transwell and coculture assays. Trophoblast secretion of cytokines and angiogenic factors was measured by enzyme-linked immunosorbent assay. RESULTS: Treatment of HTR8 cells with ATL reversed the aPL-induced decrease in trophoblast migration, an effect that appeared to be regulated through restoration of interleukin-6 production. Using a model of spiral artery transformation, aPL and sera from APS patients with pregnancy morbidity disrupted trophoblast-endothelial cell interactions, and treatment with ATL restored the stability of the cocultures. In contrast, ATL treatment did not resolve the proinflammatory and antiangiogenic responses of trophoblasts induced by aPL. CONCLUSION: These findings indicate that ATLs may have some benefits in terms of preventing the effects of aPL on trophoblast function, which raises the possibility of the use of ATLs as an adjuvant therapy in women with aPL.

Antiphospholipid antibodies in pediatric systemic lupus erythematosus.

OBJECTIVE: Antiphospholipid antibodies (aPLs) have been extensively studied in adults with systemic lupus erythematosus (SLE) and have been associated with arterial and venous thrombosis, thrombocytopenia, neurologic disorders, and recurrent fetal loss. In contrast, very little is known about the frequency and clinical significance of aPLs in pediatric SLE. This study was designed to determine the frequency of aPLs in pediatric SLE and the temporally associated clinical manifestations. DESIGN: We studied 29 consecutive patients with onset of SLE in childhood seen in the Pediatric Rheumatology Clinic at the University of Pittsburgh, Children's Hospital, between 1985 and 1992. We defined aPL as the presence of a lupus anticoagulant (LAC), immunoglobulin G or immunoglobulin M anticardiolipin antibodies (aCLs), or a biologic false-positive serologic test for syphilis determined by a VDRL test. Clinical manifestations were temporally correlated to the presence of aPLs if they occurred within 6 months. RESULTS: Overall, 19 (65%) of 29 children with SLE had one of the three laboratory abnormalities defining aPL. LAC was detected in 16 (62%) of 26, aCL in 18 (66%) of 27, and false-positive VDRL test results in 11 (39%) of 28. Twenty-five of the 29 patients had all three tests performed. In 10 patients, all three tests were abnormal. The presence of thrombosis in 7 patients (4 venous, 2 arterial, and 1 both) was associated with a positive aPL, specifically aCL. The presence of an aPL was significantly associated with anti-double-stranded DNA antibodies, but not with neuropsychiatric manifestations or with thrombocytopenia. The presence of an aCL was significantly associated with hemolytic anemia. A prolonged prothrombin time, in the setting of an LAC (all with a prolonged activated partial thromboplastin time), was associated with life-threatening disease in 6 of 15 patients. CONCLUSION: Sixty-five percent of 29 consecutive pediatric patients with SLE had evidence of aPL. The presence of aPL, specifically aCL, was significantly associated with thrombotic events. The presence of a prolonged prothrombin time in the setting of an LAC may be a marker of more serious disease in pediatric SLE.

Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune etiologies.

We have investigated clinical effectiveness of intravenous immunoglobulin G infusion (IVIg) on antiphospholipid antibody titers in five women with evidence of antiphospholipid antibody-associated recurrent spontaneous abortions and one with antinuclear antibody who became refractory to conventional autoimmune treatment during pregnancy and experienced pregnancy complications. Three women developed intrauterine growth retardation and three had complicated twin pregnancies with rising autoantibody titers. Antiphospholipid antibody and antinuclear antibody titers were tested pre and 2 weeks after each IVIg infusion. We report that: (i) IgG antiphospholipid antibody titers were significantly suppressed after each IVIg infusion (P < 0.05); (ii) IgM antiphospholipid antibody titers were also significantly suppressed after each IVIg infusion (P < 0.0001); (iii) decreased titers of autoantibodies paralleled increased levels of maternal IgG which lasted for at least 30 days; the autoantibodies showed a definite rise again prior to the next infusion; (iv) antinuclear antibody titers were effectively suppressed; and (v) rising autoantibody titers combined clinical manifestation of intrauterine growth retardation and women with complicated twin pregnancies. We conclude that IVIg infusion effectively suppresses IgM and IgG autoantibodies to phospholipids and antinuclear antibody in autoimmune women with a history of recurrent spontaneous abortions and refractory to conventional anticoagulation or immunosuppressive treatment.

Antimalarial agents and lupus.

Antimalarials are under-utilized, disease-modifying agents that are useful in the management of lupus erythematosus. Antimalarials can promote a remission in non-organ-threatening lupus and decrease its risk of dissemination. They are especially useful for cutaneous and inflammatory joint disease and have modest actions in improving serositis, fatigue, and cognitive dysfunction. As agents that do not depress the bone marrow or promote opportunistic infections, antimalarials have potential applications in combination with other antilupus medications and with each other.

Effects of unfractionated and low molecular weight heparin on antiphospholipid antibody binding in vitro.

OBJECTIVE: To compare the efficacy of unfractionated heparin and low molecular weight heparin in the in vitro binding of antiphospholipid antibodies obtained from the sera of patients with recurrent pregnancy loss. METHODS: Women with immunoglobulin (Ig) G antibodies to the phospholipids cardiolipin and phosphatidylserine were selected based on a positive test by a standard enzyme-linked immunosorbent assay (ELISA). The sera were reassayed for antiphospholipid antibodies in a modified ELISA using increasing doses of unfractionated heparin or low molecular weight heparin (0, 16, 32, 64, 128, and 256 IU). Sera were fractionated by unfractionated and low molecular weight heparin affinity chromatography to compare the binding avidity and antiphospholipid antibody activity. RESULTS: All sera demonstrated a dose-dependent inhibition in measured antiphospholipid antibody activity with the addition of unfractionated or low molecular weight heparin. Levels of IgG cardiolipin and IgG phosphatidylserine were significantly inhibited in the presence of 32 IU of low molecular weight heparin (P <.001 and P <.05, respectively) and in the presence of 64 IU of unfractionated heparin (P <.001 and P <.05, respectively). Antiphospholipid antibody binding activity in serum as measured in the ELISA was maximally reduced 76-89% with 256 IU of either heparin derivative. Affinity chromatography with unfractionated or low molecular weight heparin columns absorbed 72% and 66% of IgG cardiolipin activity, respectively, and 46% and 54% of IgG phosphatidylserine activity, respectively. CONCLUSION: These data suggest that low molecular weight heparin and unfractionated heparin reduce the in vitro binding of antiphospholipid antibodies on a per unit basis. Both heparins demonstrate binding activity similar to that of antiphospholipid antibodies in vitro.

Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials.

OBJECTIVE: To explore the effects of interventions given to improve pregnancy outcome in women with antiphospholipid antibodies. DATA SOURCES: Cochrane Controlled Trials Register, Cochrane Collaboration Pregnancy and Childbirth Group's Specialized Register of Controlled Trials, EMBASE, and MEDLINE were searched in December 1999. STUDY SELECTION: Randomized or quasi-randomized controlled trials of therapy for pregnancy loss associated with antiphospholipid antibodies were identified. TABULATION, INTEGRATION, AND RESULTS: Trial selection, data extraction, and quality assessment were performed by two authors independently. Quantitative analysis of summary data was performed using the fixed- and random-effects models with heterogeneity assessments. Pregnancy loss and adverse neonatal outcomes were the main outcome measures. Ten trials (n = 627) fulfilled the inclusion criteria (of which four lacked adequate allocation concealment). Three trials of aspirin alone showed no significant reduction in pregnancy loss (relative risk [RR] 1.05, 95% confidence interval [CI] 0.66, 1.68). Heparin combined with aspirin (two trials, 140 patients) significantly reduced pregnancy loss compared with aspirin alone (RR 0.46, 95% CI 0.29, 0.71). Prednisone and aspirin resulted in a significant increase in prematurity (RR 4.83, 95% CI 2.85, 8.21) but no significant reduction in pregnancy loss (RR 0.85, 95% CI 0.53, 1.36). CONCLUSION: Combination therapy with aspirin and heparin may reduce pregnancy loss in women with antiphospholipid antibodies by 54%. Further large, randomized controlled trials with adequate allocation concealment are necessary to exclude significant adverse effects.

Antiphospholipid antibodies in young women with and without oral contraceptive use.

The role of thrombophilia in the elevated risk of thromboembolism during oral contraceptive use has been established. We performed a cross-sectional study among young women to survey the occurrence of antiphospholipid antibodies among users and non-users of oral contraceptives. Serum levels of immunoglobulin (Ig)G, IgA and IgM isotypes of anti-beta2-glycoprotein I and anticardiolipin antibodies were measured by validated enzyme-linked immunosorbent assay methods. Combining all types of antiphospholipid antibodies, pill-users had an elevated antibody titre more than twice as frequently as non-users (odds ratio, 2.3; 95% confidence interval, 1.1-5.1). The higher frequency of elevated antibody titre was related most commonly to IgG type anti-beta2-glycoprotein I antibodies. Oral contraceptive use increases the risk of elevated antiphospholipid antibody levels among asymptomatic young women.

Combined plasmapheresis and immunosuppression as rescue treatment of a patient with catastrophic antiphospholipid syndrome occurring despite anticoagulation: a case report.

We report the case of a 33-year-old female with known primary antiphospholipid syndrome who, despite full-dose oral anticoagulation, presented with myocardial infarction, acute respiratory distress syndrome, purulent bronchitis, and septic shock. Antiphospholipid antibodies and anti-beta2-glycoprotein-1 titres were markedly elevated. The patient was diagnosed with catastrophic antiphospholipid syndrome and treated with unfractionated intravenous heparin. However, she developed thromboembolism of the right foot and skin marmoration of her extremities during heparin therapy, and therefore plasmapheresis, immunoglobulins, cyclophosphamide, and methylprednisone under a broad spectrum of anti-infective therapy were instituted. This treatment led to a rapid decrease of antiphospholipid antibody and anti-beta2-glycoprotein-1 titres, and the patient's condition gradually improved. Upon discharge from the hospital, pulmonary infiltrates had markedly regressed, and she was feeling well. Given the high mortality of catastrophic antiphospholipid syndrome, this report emphasizes the need for rapid diagnosis and effective multimodal treatment in an intensive care unit setting for these patients.

Increased titer of anti-beta2-glycoprotein I IgG antibody among factor V Leiden carriers during oral contraceptive use.

The risk of thromboembolism during oral contraceptive (OC) use is increased among factor V Leiden (FVL) carriers compared to women with wild-type genotype of the gene for coagulation factor V (FV). The carrier frequency in the general population is too high for FVL alone to be responsible for the reported association. Additional risk factors may be required to explain the increased risk of thromboembolism of carriers during OC use. We conducted a case-control study to compare the titer of anti-beta2-glycoprotein I immunoglobulin G (IgG) and the frequency of elevated titer of IgG type anti-beta2-glycoprotein I antibody between FVL carriers and individuals with FV wild-type genotype with and without pill use. An asymptomatic population of 313 unrelated nonpregnant women were screened for FVL and for the presence of anti-beta2-glycoprotein I IgG antibody. Sixty-six women were FVL carriers and 247 had normal genotype. One-hundred and thirty-five women used OC at the time of screening and 178 did not. Among FVL carriers, OC pill users had a higher mean anti-beta2-glycoprotein I IgG titer than nonusers (9.2 SGU/mL vs. 4.7 SGU/mL, p = 0.0485). Among women with FV wild-type genotype, there was no significant difference in anti-beta2-glycoprotein I IgG titers between users and nonusers of OCs (6.4 SGU/mL and 6.0 SGU/mL, respectively; p = 0.7010). The odds of an elevated anti-beta2-glycoprotein I IgG titer during OC use in FVL heterozygous women was 2.41 (95% confidence interval: 0.79-7.39) relative to users with-type genotype. FVL may contribute to the development of elevated titer of IgG type anti-beta2-glycoprotein I antibody during OC use. The elevated titer of IgG type anti-beta2-glycoprotein I antibody may select women among FVL carriers during OC use with an increased risk of thromboembolism.