Antibodies to Domain I ß2-Glycoprotein 1 in Patients with Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

The role of antiphospholipid antibodies (aPL), which are not included in the Sydney diagnostic criteria, in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) is poorly understood. The aim of this study was to determine the clinical significance of IgG antibodies for domain 1 of ß2-glycoprotein 1 (ß2-GP1), IgG anti-ß2-GP1DI, in patients with APS with and without SLE. The study included 187 patients with APS with or without SLE, 49 patients formed the comparison group, and 100 apparently healthy individuals formed the control group. IgG/IgM antibodies to cardiolipin (aCL) and IgG/IgM anti-ß2-GP1 were determined by enzyme immunoassay (ELISA) in patients with or without APS, and IgG anti-ß2-GP1DI was determined by chemiluminescence assay (CLA) in all patients and controls. IgG anti-ß2-GP1DI was detected in 37 (71%) of 52 patients with primary APS (PAPS), in 6 (50%) of 12 patients with probable APS, in 42 (71%) of 59 patients with SLE + APS, in 17 (26%) of 64 patients with SLE, in 1 (2%) of the comparison group, and in none of the control group. IgG anti-ß2-GP1DI was significantly associated with PAPS and SLE + APS compared with the patients with SLE (p = 0.0002 and 0.0001, respectively). The association of IgG anti-ß2-GP1DI with clinical manifestations of APS (thrombosis (p = 0.001) and obstetric pathology (p = 0.04)) was detected. There was a significant association of IgG anti-ß2-GP1DI with arterial thrombosis (p = 0.002) and with late gestational obstetric pathology (p = 0.01). High specificity of IgG anti-ß2-GP1DI depending on the diagnosis and clinical manifestations of APS despite low sensitivity was noted: specificity was 84% for thrombosis, 94% for obstetric pathology, and 89% for APS. Isolated IgG anti-ß2-GP1DI positivity was reported in 2% of 50 aPL-negative patients and was not associated with APS manifestations. The frequency of IgG anti-ß2-GP1DI detection was higher in the patients with APS compared to the patients with SLE, comparison group, and control (p < 0.05). Positive IgG anti-ß2-GP1DI values were significantly associated with thrombotic complications and with obstetric pathology (p = 0.002 and p = 0.01, respectively). Specificity of IgG anti-ß2-GP1DI for APS and its clinical manifestations (thrombosis and obstetric pathology) was higher than sensitivity (89, 94, and 84%, respectively).

[The analysis to data from Chinese Rheumatism Data Center external quality assurance program for autoantibodies in 2021].

To evaluate the data obtained from the external quality assurance program initiated by Chinese Rheumatism Data Center (CRDC-QAP) for autoantibodies detection in 2021, so as to assess the consensus and differences in cross-laboratory testing to autoantibodies in China. This is a retrospective study. After collecting data from the first half year (from May 15th to July 10th) and the second half year (from August 15th to November 19th) of CRDC-QAP program for autoantibody detection in 2021, it firstly analyzed the qualitative consensus of the cross-laboratory results. Secondly, it compared the positivity grade of numeric results according to the Sample to cut-off ratio (S/CO ratio) calculation. Finally, the mean and coefficient variation (CV) of numeric results from three major manufacturers were calculated. A total of 303 and 332 clinical labs voluntarily participated in the first half year and the second half year of CRDC-QAP program for autoantibody detection in 2021, respectively. Except for anti-ß2 glycoprotein type I (aß2-GPI) IgM, the cross-laboratory consensus of qualitative results for the other autoantibodies is greater than 96%. As for anti-cyclic citrullinated peptide antibody (anti-CCP) and anti mitochondrial antibody-M2 (AMA-M2), the numeric results from more than 90% laboratories showed the same positivity grade. More than 50% of laboratories used chemiluminescence immunoassay (CLIA) for quantitative evaluation of autoantibody. The CV of numeric results from different manufacturers showed certain differences(P<0.01) with the range from 0 to 238%. Although high consensus can be observed in term of qualitative result for autoantibody detection in cross-laboratory, there are still certain differences in numeric results in term of positivity grade and manufacturer-based CV.

Analysis of Serbian Primary Antiphospholipid Syndrome Patients Confirmed a Strong Association Between Livedo Reticularis and Arterial Thrombosis: A National Cross-Sectional Cohort Study.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPLs) associated with thrombosis (arterial and/or venous) and/or obstetrical manifestations. However, various manifestations, which are considered to be noncriteria manifestations, are frequently found in APS. AIM: The purpose of this study was to evaluate whether noncriteria manifestations may be found more frequently in subjects with thrombotic and/or obstetrical APS ("criteria" manifestations) in a population of patients with primary APS (PAPS). This study presents the results from our national cohort. PATIENTS AND METHODS: This is a cross-sectional study of 360 PAPS patients. Data regarding the presence of thrombocytopenia, livedo reticularis, chorea, and valvulopathy were analyzed. The aPL analysis included the detection of anticardiolipin antibodies (aCLs: immunoglobulin G [IgG]/IgM), anti-ß 2 glycoprotein I (IgG/IgM), and lupus anticoagulant positivity. RESULTS: In our cohort, livedo reticularis was significantly related to arterial thromboses in the same way as valvular manifestations (valvular vegetations and valvular thickening and dysfunction not related to age) ( p = 0.0001, p = 0.013, respectively). Age was strongly related to all the noncriteria manifestations analyzed. Thrombocytopenia was significantly related to ß 2 glycoprotein I IgG and lupus anticoagulant positivity ( p = 0.043, p = 0.030, respectively), as well as to double and triple aPL positivity ( p = 0.041, p = 0.013 respectively). Moreover, in a multivariate model, livedo reticularis was strongly and independently related to arterial thrombosis in our cohort (odds ratio, 2.010; confidence interval, 1.229-3.288; p = 0.005). CONCLUSION: This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis, suggesting a more cautious approach regarding the presence of noncriteria manifestations, especially livedo reticularis, in APS.

Antiphospholipid Antibodies Increase the Risk of Fetal Growth Restriction: A Systematic Meta-Analysis.

Objective: Antiphospholipid syndrome (APS) is a chronic autoimmune disease with a high prevalence in females. Published data have identified pregnant women with APS may suffer from recurrent miscarriage, fetal death. However, the association between antiphospholipid antibody (aPL) and fetal growth restriction (FGR) remains controversial. This study aims to systematically review the literature on population-based studies investigating an association between aPL and FGR. Methods: The literature was searched on 1 November, 2021, using Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), following the MOOSE checklist. Study inclusion criteria focused on peer-reviewed published articles that reported an association between aPL and FGR. Quality assessment was performed based on the Newcastle-Ottawa scale. The between-study heterogeneity was assessed by the Q test. Publication bias was assessed by funnel plots. Results: Twenty-two studies (with 11745 pregnant women) were included in the final analysis. Pooled odds ratio for association of aPL, anticardiolipin antibodies (ACA), anti-beta2 glycoprotein 1 antibodies (ß2GP1), and FGR was 1.26 (95%CI 1.12, 1.40), 2.25 (95%CI 1.55, 2.94), and 1.31 (95% CI 1.12, 1.49), respectively. Lupus anticoagulant (LA) did not increase the chance of FGR (OR 0.82, 95%CI 0.54, 1.10). Conclusions: Our meta-analysis showed that aPL increased the risk of FGR. The risk of FGR varies with the aPL types. ACA and ß2GP1 are strongly associated with FGR. There are currently insufficient data to support a significant relationship between LA and FGR.

Antiphospholipid antibodies and osteonecrosis in systemic lupus erythematosus: a meta-analysis.

Objectives: The present meta-analysis aimed to assess the relationship between antiphospholipid antibodies (aPLs) or antiphospholipid antibody syndrome (APS) and the incidence of osteonecrosis (ON) in systemic lupus erythematosus (SLE) patients.Methods: MEDLINE/Pubmed, EMBASE, Web of science, the Chinese Biomedical Literature Database (CBM), the Wan-Fang Database, and the China National Knowledge Infrastructure (CNKI) were searched from their inception up until 26 December 2020. Studies in English were included. Case-control studies and cohort studies were included. Studies pertaining to the link between aPLs or APS and ON patients were slated for inclusion in the current analysis.Results: Twenty-two studies involving a total of 3054 SLE patients were included. The positivities of anticardiolipin antibody (ACL), IgG ACL, IgM ACL, LA and APS in SLE is not associated with ON. One study showed that IgG or IgM ß2GP1 had no association with ON. No publication bias was detected. The quality of this evidence was low because of the high risk of bias across studies, and therefore robust inferences cannot be made.Conclusion: SLE patients demonstrated a weak association between aPLs and ON. The nature of the association between aPLs and ON in SLE needs to be investigated in-depth in future research.

[Seronegative antiphospholipid syndrome: Myth or reality?] / Syndrome des antiphospholipides « séronégatif ¼ : mythe ou réalité ?

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetrical manifestations and the persistent presence, at least 12 weeks apart, of antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL) and/or anti-ß2 glycoprotein I antibodies (aß2GPI). The finding of patients with clinical profile highly suggestive of APS but who are negative for conventional biological criteria has led to the concept of seronegative APS. In the last few years, new antigen targets and methodological approaches have been employed to more clearly identify this syndrome in patients with thrombosis or obstetrical complications without conventional aPL. Although seronegative APS is still controversial, there is increasing recognition of the existence of this subgroup. However, clinical relevance of non conventional aPL need to be confirmed by efforts toward standardizing new biological tools and longitudinal studies involving large cohort of patients.

Brain stem infarction in a 6-year-old boy with Down syndrome.

Infarct locations in children with arterial ischemic stroke have primarily been reported to be lobar or in the basal ganglia, and those in patients with Down syndrome (DS) and antiphospholipid syndrome (APS) are typically wide and multiple. No solitary brain stem infarctions have ever been reported in children with DS until now. Here, we report a case of brain stem infarction in a 6-year-old boy with DS who had no cardiac, renal, or intestinal complications. He exhibited ataxic gait and medial longitudinal fasciculus (MLF) symptoms at first presentation. Neuroimaging revealed a localized and isolated lesion in the midbrain. Although he did not satisfy the diagnostic criteria of APS, he showed persistently elevated levels of anticardiolipin antibody (21 U/mL; normal value <10 U/mL). Although he had the risks of a multiple vascular systems disorder, DS, and persistently elevated levels of antiphospholipid antibodies, his lesion was not similar to any of the previously reported cerebral infarctions in DS or in APS. To our knowledge, this is the first report of limited solitary brain stem infarction in a child with DS.

Epidemiological, clinical and immune factors that influence the persistence of antiphospholipid antibodies in leprosy

Abstract Introduction: Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. Objectives: To determine whether epidemiological, clinical and immunological factors played a role in the longterm persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. Methods: The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. Results: Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-β2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82-0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0-0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03-7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. Conclusion: Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.

Cirugía cardiaca en pacientes con lupus eritematoso sistémico: características clínicas y desenlaces / Cardiac surgery in systemic lupus erythematosus patients: Clinical characteristics and outcomes

Objetivos: Estudiar las características clínicas y desenlaces de los pacientes con lupus eritematoso sistémico (LES) intervenidos de cirugía cardiaca. Métodos: Se realizó un estudio retrospectivo de 30 pacientes con LES y cirugía cardiaca en un solo centro. Se registraron comorbilidades, características demográficas, clínicas, serológicas, riesgo cardiovascular, tratamiento, tipo de cirugía, complicaciones postoperatorias, mortalidad e histología. Resultados: La duración de LES al momento de la cirugía fue de 2 años. El procedimiento más frecuente fue recambio valvular (53%), seguido de ventana pericárdica (37%). Al menos una complicación postoperatoria se presentó en el 63% (principalmente infecciones). Un pinzamiento aórtico≥76 min se asoció con al menos una complicación (OR 6,4; IC 95% 1,1-35,4, p=0,03). La mortalidad temprana ocurrió en 5 pacientes (17%) y tardía en 3 (10%); siendo las causas principales sepsis e insuficiencia cardiaca. La actividad de la enfermedad se asoció a la realización de ventana pericárdica (OR 12,6; IC 95% 1,9-79; p=0,007), presencia de linfopenia≤1.200 (OR 10,1; IC 95% 1,05-97; p=0,04), edad≤30 años (OR 7,7; IC 95% 1,2-46,3; p=0,02) y NYHA clase III (OR 7,0; IC 95% 1,1-42, p=0,03). El desarrollo de infección postoperatoria se asoció con estancia hospitalaria≥2 semanas (OR 54,9; IC 95% 5,0-602,1; p=0,001), estancia en UCI≥10 días (OR 20; IC 95% 1,6-171,7, p=0,01), duración de ventilación mecánica ≥ 5 días (OR 16,9, IC 95% 1,5-171,7, p = 0,01) y PSAP≥50mmHg (OR 7,8; IC 95% 1,4-41,2; p=0,01). Conclusiones: La cirugía cardiaca en LES se asocia a alta morbimortalidad

Objectives: To study the clinical characteristics and outcomes in systemic lupus erythematosus (SLE) patients who underwent cardiac surgery. Methods: Retrospective analysis of 30 SLE patients who underwent cardiac surgery at a single center. Demographics, comorbidities, clinical and serologic characteristics, cardiovascular risk scores and treatment were recorded. Type of surgery, postoperative complications, mortality and histology were analyzed. Results: Disease duration at surgery was 2 years. Valve replacement was the procedure most frequently performed (53%), followed by pericardial window (37%). At least one postoperative complication developed in 63% (mainly infections). An aortic cross-clamp time≥76minutes was associated with at least one postoperative complication (OR 6.4, 95% CI 1.1-35.4, p=.03). Early death occurred in 5 patients (17%) and late in 3 (10%); main causes were sepsis and heart failure. Disease activity was associated with pericardial window (OR 12.6, 95% CI 1.9-79, p=.007); lymphopenia≤1.200 (OR 10.1, 95% CI 1.05-97, p=.04); age≤30 years (OR 7.7, 95% CI 1.2-46.3, p=.02); and New York Heart Association class III (OR 7.0, 95% CI 1.1-42, p=.03). Postoperative infection was associated with length of hospital stay≥2 weeks (OR 54.9, 95% CI 5.0-602.1, p=.001); intensive care unit stay≥10 days (OR 20, 95% CI 1.6-171.7, p=.01); duration of mechanical ventilation≥5 days (OR 16.9, 95% CI 1.5-171.7, p=.01); and pulmonary artery systolic pressure≥50mmHg (OR 7.8, 95% CI 1.4-41.2, p=.01). Conclusions: Cardiac surgery in SLE confers high morbidity and mortality. SLE-specific preoperative risk scores should be designed to identify prognostic factors

Assessment of diagnostic methods for the detection of anticardiolipin and anti-ßeta2 glycoprotein I antibodies in patients under routine evaluation for antiphospholipid syndrome.

BACKGROUND: We assessed the performance characteristics and correlations of the traditional enzyme-linked immunosorbent assay (ELISA) and chemiluminescence immunoassay (CIA) for detecting IgG and IgM antibodies to cardiolipin (aCL) and beta2 glycoprotein (anti-ß2GPI) antibodies in patients under routine evaluation for APS. METHODS: Patients (n = 216) referred to ARUP Laboratories for lupus anticoagulant (LAC) and/or aCL or anti-ß2GPI IgG/IgM antibodies evaluation were assessed by ELISA and CIA methods. Diagnostic accuracies, correlations between methods and specific clinical manifestations in APS were investigated. RESULTS: The areas under the curve (%) for APS using LAC with CIA (74, 95% CI: 65-82) or ELISA (70, 95% CI: 61-79) aPLs were comparable. The overall agreements and linear regression correlations between methods for aPL antibody of the same specificity were variable: aCL IgG 87.3%; R2 = 0.7491, aCL IgM 71.6%; R2 = 0.2656, anti-ß2GPI IgG 77.2%; R2 = 0.7688 and anti-ß2GPI IgM 81.7%; R2 = 0.3305. CONCLUSIONS: With inclusion of LAC, the ELISA and CIA show comparable performance for the diagnosis of APS. However, correlations of APS-specific manifestations were dependent on method of detecting the aPL antibodies suggesting platforms may not be used interchangeable.

Revisiting the Phadia/EliA cut-off values for anticardiolipin and anti-ß2-glycoprotein I antibodies: a systematic evaluation according to the guidelines.

Background Phadia/EliA fluorescence enzyme immunoassays are widely used automated assays for anticardiolipin (aCL) and anti-ß2-glycoprotein I (aß2GPI) antibodies. To date, cut-off values for these assays have not been evaluated systematically and the evidence behind manufacturer's recommended cut-off values is not clear. Objective To determine Phadia/EliA cut-off values for antiphospholipid antibodies (aPL) according to the procedures suggested by guidelines. Methods A total of 266 blood donors (135 females and 131 males) were included. The pre-handling and analysis of the samples were performed according to the International Society on Thrombosis and Hemostasis (ISTH) guideline for solid phase aPL assays. Cut-off values and corresponding 90% confidence intervals (CI) for each antibody were established and outliers were handled according to the Clinical and Laboratory Standards Institute (CLSI) guideline for reference intervals. Samples from 377 consecutive patients, referred to our thrombophilia center with evidence of thrombosis or pregnancy morbidity were included for aPL testing. Results The in-house 99th (97.5th) percentile cut-off values were 11 (8.7), 12 (6.9) 8.5 (5.0) AU/mL for aß2GPI IgG, IgM and IgA, and 21 (13) GPL-U/mL and 41 (25) MPL-U/mL for aCL IgG and IgM, respectively. The prevalence of positive results (%) defined by these cut-off values in patients with evidence of thrombosis or pregnancy morbidity was 9.5 (12.2), 1.6 (2.9), and 7.0 (9.9), and 0.8 (3.8) for aß2GPI IgG, IgM, and aCL IgG and IgM respectively. The use of in-house 99th percentile cut-off values compared to the manufacturer suggested cut-off values resulted in 1 and 39 fewer samples for aß2GPI and aCL to be classified as positive for aPL, respectively. Conclusions We present Phadia/EliA cut-off values with 90% CI for aPL determined systematically according to the ISTH and CLSI guidelines. These values are different from values previously determined, suggesting variation of aPLs in different populations. Our findings indicate the need for each laboratory to determine/validate assay specific cut-off values for aPL.

Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis.

Antiphospholipid syndrome (APS) is an autoimmune condition that is associated with thrombosis and morbidity in pregnancy. The exact mechanisms by which these associations occur appear to be heterogeneous and are not yet well understood. The aim of this study was to identify and analyze publications in recent years to better understand the diagnosis and its contribution to monitoring APS among women with recurrent miscarriage (RM). This systematic review and meta-analysis was conducted using the PubMed and Web of Knowledge databases, with articles published between 2010 and 2014, according to the PRISMA statement. Of the 85 identified studies, nine were selected. Most of the studies reported an association between recurrent miscarriage and specific antiphospholipid antibodies, as anticardiolipin antibodies (aCL), lupus anticoagulant (LA), anti-ß2-glycoprotein I antibodies (aß2GPI) and antiphosphatidylserine (aPS), which showed a relationship with RM. The main result of the meta-analysis revealed association between antiphospholipid antibodies (aPLs) and/or APS compared to the patients with RM (OR: 0.279; 95% CI: 0.212-0.366) and APS cases compared to the patients with RM (OR: 0.083; 95% CI: 0.036-0.189). High heterogeneity among these studies (I2=100.0%, p <0.001) was observed. In addition, there was no significant publication bias across studies according to Begg's test (p=0.230), although Egger's test (p=0.037) suggests significant publication bias. The funnel plot was slightly asymmetrical. Systematic review and meta-analysis demonstrated a positive association between antiphospholipid antibodies and/or antiphospholipid syndrome in patients with recurrent miscarriage.

Solid Phase Immunoassay for the Detection of Anticardiolipin Antibodies.

The anticardiolipin (aCL) test was first developed in the 1980s and proved to be a valuable addition to the lupus anticoagulant assay for identifying patients with a disorder that came to be later known as the antiphospholipid syndrome (APS). Although the test has relatively poor specificity for APS diagnosis, particularly at low positive levels, it has continued to play a major role in the identification and management of these patients because of its high sensitivity and ability to be measured in both serum and plasma, and despite concomitant presence of anticoagulants normally given to APS patients. In this chapter we outline the procedure for producing essential assay components and for performing the aCL ELISA, which can be used to determine the presence of IgG, IgM and IgA aCL antibodies in human samples. We also provide general guidelines that will facilitate optimal performance of the aCL ELISA assay.

Non-Criteria or Seronegative Obstetric Antiphospholipid Syndrome?

BACKGROUND: Obstetric antiphospholipid syndrome (Obs-APS) is one of the most commonly identified causes of recurrent pregnancy loss and its accurate diagnosis is a requirement for optimal treatment. Some patients do not fulfill the revised Sapporo classification criteria, the original APS classification criteria, and are considered to be non-criteria Obs-APS. In these patients with non-criteria, there is controversy about their inclusion within the spectrum of APS and eventually their treatment as having Obs-APS. A subset of patients may also have clinical characteristics of Obs-APS even though lupus anticoagulant (LA), anticardiolipin antibodies, and anti-ß2-glycoprotein I (aß2GPI) antibodies are consistently negative. These patients are recognized as seronegative Obs-APS. We reviewed evidence of non-criteria Obs-APS and discuss a case of a woman with a diagnosis of active systemic lupus erythematosus (SLE) and non-criteria Obs-APS with four consecutive pregnancy losses. After an accurate diagnosis the patient received prenatal counseling and benefited from the optimal treatment of Obs-APS that led to a successful pregnancy. The applicability of this successful experience about outcomes in women with non-criteria, or seronegative, Obs-APS is also evaluated.

Controversias del síndrome de anticuerpos antifosfolipídicos en obstetricia / Controversies concerning the antiphospholipid syndrome in obstetrics

El síndrome de anticuerpos antifosfolipídicos es una enfermedad autoinmune no inflamatoria, caracterizada por eventos trombóticos recurrentes y/o complicaciones obstétricas, asociados a la presencia de anticuerpos antifosfolipídicos circulantes: anticuerpos anticardiolipina, anti-β2 glucoproteína-i y/o anticoagulante lúpico. Los anticuerpos antifosfolipídicos son un grupo heterogéneo de autoanticuerpos asociados con morbilidad obstétrica, como pérdida gestacional recurrente, muerte fetal, parto pretérmino asociado a insuficiencia placentaria como enfermedad hipertensiva del embarazo y/o restricción del crecimiento intrauterino. Los procesos fisiopatológicos relacionados con la morbilidad obstétrica no se han comprendido del todo, involucrándose múltiples eventos inmunológicos, entre ellos los inflamatorios, la activación del complemento, el desbalance de los factores angiogénicos y, en alguna proporción de los casos, se ha demostrado trombosis e infarto. Debido a la controversia en los criterios clínicos y de laboratorio, así como a la repercusión en la mejora de los resultados perinatales en pacientes que inician tratamiento, decidimos llevar a cabo esta revisión sobre los conceptos de síndrome de anticuerpos antifosfolipídico relacionado con complicaciones obstétricas y síndrome de anticuerpos antifosfolipídico seronegativo, así como su manejo en obstetricia (AU)

Antiphospholipid antibody syndrome is a non-inflammatory autoimmune disease characterized by recurrent thrombotic events and/or obstetric complications associated with the presence of circulating antiphospholipid antibodies (anticardiolipin antibodies, anti-β2 glycoprotein-i antibodies, and/or lupus anticoagulant. Antiphospholipid antibodies are a heterogeneous group of autoantibodies associated with recurrent miscarriage, stillbirth, fetal growth restriction and premature birth. The diversity of the features of the proposed placental antiphospholipid antibodies fingerprint suggests that several disease processes may occur in the placentae of women with antiphospholipid antibody syndrome in the form of immune responses: inflammatory events, complement activation, angiogenic imbalance and, less commonly, thrombosis and infarction. Because of the disparity between clinical and laboratory criteria, and the impact on perinatal outcome in patients starting treatment, we reviewed the aspects of antiphospholipid antibody syndrome related to obstetric complications and seronegative antiphospholipid antibody syndrome, and their treatment in obstetrics (AU)

Novel diagnostic and therapeutic frontiers in thrombotic anti-phospholipid syndrome.

The anti-phospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity, associated with a persistent positivity for anti-phospholipid antibodies (aPL). The current classification criteria for APS include three laboratory tests: lupus anti-coagulant (LA), anti-cardiolipin (aCL), and anti-ß2 glycoprotein-I (ß2GPI). To date, the therapeutic approach for thrombotic APS mainly centers on long-term anti-coagulation with a vitamin K antagonist (VKA). APS management may represent a challenge for the treating physicians. Patients with different aPL profiles need a tailored risk-stratified approach. Moreover, in patients with recurrent thrombotic events despite therapy with VKA, or in those with microvascular involvement, new therapeutic options are highly needed. In this review, we aim to elucidate recent findings about new aPL specifities, available risk scoring models, and novel therapeutic approaches in APS management.

Novel enzyme immunoassay system for simultaneous detection of six subclasses of antiphospholipid antibodies for differential diagnosis of antiphospholipid syndrome.

: Antiphospholipid syndrome, which often complicates systemic lupus erythematosus (SLE), features high occurrence of arterial and/or venous thrombosis and recurrent fetal loss. However, which antibody subclass contributes to which clinical event remains uncertain. We newly developed an up-to-date enzyme immunoassay system using the AcuStar automated analyzer (Instrumentation Laboratory, Bedford, Massachusetts, USA) for parallel detection of six subclasses of antiphospholipid antibodies (aPLs): anticardiolipin antibodies (aCL) of IgG, IgM, and IgA and anti-ß2-glycoprotein I antibodies (aß2GPI) of IgG, IgM, and IgA. They were measured in 276 healthy volunteers and 138 patients with SLE: 45 with thromboembolic complications (29 arterial; 16 venous) and 93 without. Lupus anticoagulant activity in their plasma was measured according to the guidelines recommended by the Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies. aCL/ß2GPI was measured with a standard ELISA kit commonly used in Japan. The positive results of IgG aCL, IgA aCL, and IgG aß2GPI were closely associated with thromboembolic complications, whereas IgM aCL and IgM aß2GPI were not. receiver operating characteristic analysis revealed that the accuracy of predicting thromboembolic complications based on the composite test results of the former three antibodies were obviously higher than by each alone. Regarding agreement with the test results of lupus anticoagulant activity, IgG aß2GPI showed the closest match. Patients with SLE frequently possess various combinations of the six aPL subclasses, and this antibody spectrum is closely associated with thromboembolic events in these patients. This new automated enzyme immunoassay system allows simultaneous analysis of the profile of aPL subclasses for the differential diagnosis of antiphospholipid antibody syndrome in its early stage.

Significance of fully automated tests for the diagnosis of antiphospholipid syndrome.

Antiphospholipid antibodies (aPLs) can vary both immunologically and functionally, thus it is important to effectively and correctly identify their presence when diagnosing antiphospholipid syndrome. Furthermore, since many immunological/functional tests are necessary to measure aPLs, complete examinations are often not performed in many cases due to significant burden on the testing departments. To address this issue, we measured aPLs defined according to the classification criteria (anticardiolipin antibody: aCL) IgG/IgM and anti-ß2 glycoprotein I antibody (aß2GPI) (IgG/IgM) as well as non-criteria antibodies (aCL IgA, aß2GPI IgA and aß2GPI domain I), in a cohort of 211 patients (61 APS, 140 disease controls and 10 healthy individuals). APLs were measured using a fully automated chemiluminescent immunoassay instrument (BIO-FLASH®/ACL AcuStar®) and with conventional ELISA tests. We demonstrated that both sensitivity and accuracy of diagnosis of aCL IgG and aß2GPI IgG were high, in agreement with the past reports. When multiple aPLs were examined, the accuracy of diagnosis increased. The proportion of APS patients that were positive for 2 or more types of aPLs (47/61, 77%) was higher than that of patients with systemic lupus erythematosus (SLE)(3/37, 9%), those with non-SLE connective tissues diseases (1/53,2%), those with other diseases or healthy volunteers. Based on these findings, it was concluded that the fully automated chemiluminescent immunoassay instrument, which allows the simultaneous evaluation of many types of aPLs, offers clear advantages for a more complete, more rapid and less labor-intensive alternative to running multiple ELISA and could help in better diagnosis for suspected APS patients.

Diagnóstico en el síndrome antifosfolipídico: desde una perspectiva histórica a la aparición de nuevos autoanticuerpos / Diagnosis of antiphospholipid syndrome: From an historical perspective to the emergence of new autoantibodies

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Validation of a New Panel of Automated Chemiluminescence Assays for Anticardiolipin Antibodies in the Screening for Antiphospholipid Syndrome.

BACKGROUND: Antibodies anticardiolipin (aCL) and anti-ß2-glycoprotein I (aß2GPI) are two of three laboratory criteria of antiphospholipid syndrome (APS). All of assays of antiphospholipid antibodies (aPL), coagulation assays as well as ELISAs, show methodological shortcomings, that affect their sensitivity and specificity. Therefore, we decided to validate these parameters for a new chemiluminescent examination (CLIA). METHODS: aCL and aß2GPI antibodies were measured by ELISAs (AIDA, Bad Kreuznach, Germany) and aß2GPI with CLIA kits (Werfen, Barcelona, Spain). RESULTS: When we evaluated both assays, the coefficient of variation for CLIA was slightly lower (9.04 - 12.74%) than for ELISA (11.05 - 15.3%) and the LOD was 0.2 U/L. The dilution series showed significant linearity for all CLIA methods, aCL IgG, aCL IgM, aß2GPI IgG, and aß2GPI IgM (0 - 3000 U/L), and method comparison studies revealed good agreement with the currently used ELISA (Kappa values ranging 0.534 - 0.936) without determination of aß2GPI IgG. The determination aß2GPI IgG by CLIA method shows higher positivity in 31 samples. These new aCL IgG, aCL IgM, aß2GPI IgG, and aß2GPI IgM tests have excellent analytical characteristics and allow fully automated and simultaneous analysis on an analyzer. CONCLUSIONS: Chemiluminescent determination of an automated analyzer can improve the fundamental parameters of tests such as reproducibility between laboratories.