Classification Criteria For Antiphospholipid Syndrome Research Articles

Significance of Anti-Phosphatidylethanolamine Antibodies in the Pathogenesis of Recurrent Pregnancy Loss.

Anti-phosphatidylethanolamine antibody (aPE), an anti-phospholipid autoantibody (aPL), has been proposed as a factor in recurrent pregnancy loss (RPL). However, conflicting views exist on the pathogenicity of RPL, and aPE has not yet been included in the classification criteria for antiphospholipid syndrome (APS). Here, we aimed to determine the clinical importance of examining aPE. aPE (IgG, IgM) was measured in 1705 patients with a history of RPL and re-examined after a 12-week interval in patients who tested positive. Persistent positive patients were administered low-dose aspirin during the subsequent pregnancy and clinical outcomes depending on the presence, type, and persistence of aPE were evaluated. Among the patients positive for aPE IgG and aPE IgM in the first examination (n= 117; 6.87%, and n= 235; 13.6%, respectively), 31.5% and 37.6% were negative upon re-examination, respectively. Moreover, among the cases with known pregnancy outcome, the miscarriage rate in the cumulative positive aPE group was 32.6% (29/89), which did not differ significantly from that of the aPE negative group (27.7%; 80/209; P= 0.178). Alternatively, the miscarriage rate in the persistently positive group was 40.7% (22/54), which was significantly higher than that in the transient positive group, 20.0% (7/35) (P= 0.041). Particularly, this difference become more significant when focusing on aPE IgM, 46.9% (15/32) in the persistent, compared with 16.7% (4/24) in the transient positive group (P= 0.024). aPE IgM is suggested to serve as a pathogenic aPL together with anti-cardiolipin antibodies and lupus anticoagulants, particularly if these factors persist over an extended period of time.

OP0097 DEVELOPMENT OF NEW INTERNATIONAL CLASSIFICATION CRITERIA FOR ANTIPHOSPHOLIPID SYNDROME: PHASE III CASE COLLECTION RESULTS

Background:An international multi-disciplinary effort is underway to develop rigorous, new, consensus- and evidence-based classification criteria for Antiphospholipid Syndrome (APS). The methodological approach includes four phases; we have previously presented phases I and II (item generation and reduction), which resulted in 27 candidate criteria1organized in laboratory and clinical domains.Objectives:Phase III (item weighting/threshold identification) is currently underway; here we report initial Phase III case collection results.Methods:We used REDCap, a secure data system, for Phase III international case collection. The candidate criteria of 27 items at the end of Phase II was represented in a standardized case collection form. We asked international physicians interested in APS to provide and rate cases using a Likert scale (+3 to -3: highly likely to highly unlikely to be APS). Cases with higher scores (+2 or +3) were categorized as “highly likely” APS, whereas lower scores (+1 to -3) were categorized as “equivocal or unlikely” APS.Results:We collected 314 potential APS cases (mean age 43.8±14.4 years; 79% female; and 77% white) between 6/2019-8/2019 from 17 sites in Europe (47%), North America (41%), and South America (11%). Majority of cases were potential primary APS (64%); 137 were rated as “highly likely” and 177 as “equivocal or unlikely” APS. Lupus anticoagulant, antiβ2glycoprotein-I antibody IgG/M, anticardiolipin antibody IgG, arterial thrombosis, venous thromboembolism, microvascular disease, fetal loss between 16-34 weeks, severe preeclampsia, severe placental insufficiency, cardiac valve disease, and low platelet count occurred with higher frequency in the APS cases categorized as “highly likely” (Table).Conclusion:International collection of cases spanning the spectrum of “highly likely” to “equivocal or unlikely” APS provide “real world” assessment of patients being referred for APS evaluation. In next steps, proposed candidate criteria will be further refined, organized, and weighted, and a preliminary threshold for APS classification will be determined.

The IgA Isotype of Anti-β2 Glycoprotein I Antibodies Recognizes Epitopes in Domains 3, 4, and 5 That Are Located in a Lateral Zone of the Molecule (L-Shaped).

Background: Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with presence of anti-phospholipid antibodies (aPL). The APS classification criteria only consider the aPL of IgG/IgM isotype, however testing of aPL of IgA isotype is recommended when APS is suspected and consensus aPL are negative. IgA anti-βeta-2 glycoprotein-I (B2GP1) has been clearly related with occurrence of thrombotic events. Antibodies anti-B2GP1 of IgG/M isotypes recognize an epitope in Domain 1 (R39-G43), the epitopes that recognize IgA anti-B2GP1 antibodies are not well-identified.Aim: To determine the zones of B2GP1 recognized by antibodies of IgA isotype from patients with APS symptomatology and positive for IgA anti-B2GP1.Methods: IgA antibodies to Domain-1(D1) and Domain-4/5(D4/5) of B2GP1 (ELISA) and epitope mapping on oligopeptide arrays of B2GP1 were evaluated in sera from a group of 93 patients with at least one thrombotic and with isolated positivity for IgA anti-B2GP1 antibodies (negative for other aPL).Results: A total of 47 patients (50.5%) were positive for anti-D4/5 and 23(25%) were positive for anti-D1. When peptide arrays were analyzed, three zones of B2GP1 reactivity were identified for more than 50% of patients. The center of these zones corresponds to amino acids 140(D3), 204(D4), and 264(D5). The peptides recognized on D3 and D4 contain amino acid sequences sharing high homology with proteins of microorganism that were previously related with a possible APS infectious etiology. In the three-dimensional structure of B2GP1, the three peptides, as the R39-G43 epitope, are located on the right side of the molecule (L-shape). The left side (J-shape) does not bind the antibodies.Conclusions: Patients with thrombotic APS clinical-criteria, and isolated IgA anti-B2GP1 positivity appear to preferentially bind, not to the D1 or D4/5 domains of B2GP1, but rather to three sites in D3, D4, and D5. The sites on D3 and D4 were previously described as the target identified by human monoclonal antibodies derived from patients that were capable of inducing APS in animal models. The localization of these epitopes opens a new route to explore to increase understanding of the patholophysiology of the APS and to propose new alternatives and therapeutic targets.

Has lupus anticoagulant testing had its day?

Antibodies against phosphatidylserine–prothrombin complexes (PS–PT) are one type of antiphospholipid antibody that is responsible for lupus anticoagulant activity. Anti-PS–PT antibodies are not currently included in the classification criteria for antiphospholipid syndrome (APS), but should they replace lupus anticoagulant testing to improve the diagnosis of APS?

Intrauterine fetal deaths related to antiphospholipid syndrome: a descriptive study of 65 women

ObjectiveAlthough one of the three obstetric manifestations of antiphospholipid syndrome (APS) is intrauterine fetal death (IUFD), little is known about it in this context. We report the first large series of patients with APS and IUFD.MethodsWe retrospectively analyzed the history and clinical data of women at four French hospitals. All had (1) APS diagnosis (Sydney criteria) and (2) IUFD at or after 10 weeks of gestation (weeks) between 2000 and 2016.ResultsThe study included 65 women. Their median age at the index IUFD was 29 years (IQR 26–33); 38 (58%) were primigravidas. The index IUFD was the first APS clinical manifestation in 48 women (74%). Overall, 35% had a triple-positive antibody profile.IUFD occurred at a median gestational age of 24 weeks (IQR 18–27) and was associated with maternal obstetric complications in 16 women (25%), namely, preeclampsia (n = 12), hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP) (n = 6), and/or placental abruption (n = 5). Half of the 50 women with available data had a small-for-gestational-age fetus.Overall, including during the follow-up period of 4 years (IQR 2–9), 28 women (43%) had at least one thrombosis, and 29% were diagnosed with systemic lupus erythematosus (SLE). Ultimately, 54 women (83%) had at least one live birth. Only one woman had three consecutive early miscarriages.ConclusionIUFD was most often the inaugural sign of APS. Of the APS classification criteria, IUFD, preeclampsia, and thromboses were common in this cohort, while the “3 consecutive early miscarriages” criterion was met only once. With treatment, most of the women successfully had at least one live birth.

Antiphospholipid Syndrome With Isolated Isotype M Anticardiolipin and/or Anti-B2GPI Antibody Is Associated With Stroke.

Background and Purpose- International classification criteria for antiphospholipid syndrome (APS) include IgM (immunoglobulin M), aCL (anticardiolipin), and aB2GPI (anti-β2-glycoprotein-I) antibodies, but their relevance is still debated. We aimed to assess whether patients with isolated IgM aCL and/or aB2GPI at diagnosis have specific characteristics and outcomes. Methods- We retrospectively included APS patients with isolated IgM antiphospholipid antibodies (isolated-IgM-APS) and compared them to APS patients with IgG and IgM, or IgG alone and/or lupus anticoagulant (nonisolated-IgM-APS). Results- Among the 168 APS patients included, 24 (14.3%) had isolated IgM. Median follow-up was 92.5 months (36-151.5). Isolated-IgM-APS patients were 9.5 years older. At diagnosis, stroke was more frequent in isolated-IgM-APS after adjustment for cardiovascular risk factors (odds ratio, 3.8; 95% CI, 1.3-11.5). IgM isotype remained isolated in 17 of 24 (70.8%) patients over time. Global relapse-free survival did not differ between the two groups. In thrombotic APS, monotherapy with antiplatelet agents was more frequently used in isolated-IgM-APS group with 14 of 20 versus 28 of 134 patients ( P<0.0001), with a higher relapse rate with antiplatelet agent alone compared to vitamin K antagonists, especially for patients presenting with a stroke (hazard ratio, 7.37; 95% CI, 1.19-19.0). Conclusions- Isolated IgM APS patients should not be disregarded because they represent 14.3% of an APS population. They have some characteristics: older age at diagnosis and a strong association with stroke. Clinicians must be aware of this situation because antiplatelet agent do not seem to well prevent relapses compared to vitamin K antagonist.

The clinical value of assays detecting antibodies against domain I of β2-glycoprotein I in the antiphospholipid syndrome.

As the clinical symptoms of the antiphospholipid syndrome (APS) frequently occur irrespective of the syndrome, diagnosis predominantly depends on the laboratory assays measuring the level or function of antiphospholipid antibodies (aPLs). β2-glycoprotein I (β2GPI) is increasingly accepted as the most important target of aPLs. Anti-β2GPI antibodies constitute a heterogeneous population, but current in vivo and in vitro evidence show that especially the first domain (DI) of β2GPI contains an important pathogenic epitope. This epitope containing Glycine40-Arginine43 (G40-R43) has proven to be cryptic and only exposed when β2GPI is in its open conformation. A previous study demonstrated a highly variable exposure of the cryptic epitope in commercial anti-β2GPI assays, with implications on correct patient classification. Unexpectedly, recent unpublished data revealed impaired exposure of the pathogenic epitope in the commercially available anti-DI chemiluminescence immunoassay (CIA) assay detecting specific antibodies directed to DI. In this review we summarize the laboratory and clinical performance characteristics of the different anti-DI assays in published data and conclude with inconsistent results for both the correlation of anti-DI antibodies with clinical symptoms and the added value of anti-DI antibodies in the classification criteria of APS. Additionally, we hypothesize on possible explanations for the observed discrepancies. Finally, we highly advise manufacturers to use normal pooled plasma spiked with the monoclonal anti-DI antibodies to verify correct exposure of the cryptic epitope.

Obstetric antiphospholipid syndrome

The present clinical and laboratory classification criteria for antiphospholipid syndrome (APS) were established in Sydney, Australia, in 2006. In this review, we focus on the obstetric subset of APS (OAPS),...

IgA anti-β2 glycoprotein I antibodies: Experience from a large center

ObjectiveIgG and IgM antibodies directed at β2-glycoprotein I are included in the classification criteria for the antiphospholipid syndrome (APS) while the IgA antibodies against β2-glycoprotein I (IgA aβ2GPI) are not. Conflicting data about the significance of IgA aβ2GPI and APS manifestation can be found and more studies are necessary in order to define the diagnostic value of IgA aβ2GPI. In the present article, we investigated the possible role of IgA aβ2GPI as marker of APS. MethodsA cohort of 314 patients with APS and systemic autoimmune disease was investigated for the presence of IgA aβ2GPI and its association with clinical manifestation of APS. ResultsEighty-nine patients presented IgA aβ2GPI, 68 cases associated with others antiphospholipid antibodies (aPL) and in 21 cases being the only aPL present. In primary APS IgA aβ2GPI are highly coincidental with other aPL (92,2%) while most of the isolated IgA aβ2GPI were present in the SLE group (16/21).No association between IgA aβ2GPI and APS manifestations: thrombosis and pregnancy morbidity was found, while a positive association between IgA aβ2GPI and the presence of anti-nDNA, anti-RNP, anti-Sm, anti-SSA, anti-SSB antibodies was encountered. ConclusionOur study does not show association between IgA aβ2GPI and APS manifestations and does not support the inclusion of IgA aβ2GPI as a classification criteria for APS.

'Non-Criteria' Neurologic Manifestations of Antiphospholipid Syndrome: A Hidden Kingdom to be Discovered.

Neurological manifestations or disorders associated with the central nervous system are among the most common and important clinical characteristics of antiphospholipid syndrome (APS). Although in the most recently updated (2006) APS classification criteria, the neurological manifestations encompass only transient ischemic attack and stroke, diverse 'non-criteria' neurological disorders or manifestations (i.e., headache, migraine, bipolar disorder, transverse myelitis, dementia, chorea, epileptic seizures, multiple sclerosis, psychosis, cognitive impairment, Tourette's syndrome, parkinsonism, dystonia, transient global amnesia, obsessive compulsive disorder and leukoencephalopathy) have been observed in APS patients. To date, the underlying mechanisms responsible for these abnormal neurological manifestations in APS remain unclear. In vivo experiments and human observational studies indicate the involvement of thrombotic events and/or high titers of antiphospholipid antibodies in the neuro-pathogenic cascade of APS. Although different types of neurologic manifestations in APS patients have successfully been treated with therapies involving anti-thrombotic regimens (i.e., anticoagulants and/or platelet antiaggregants), antineuralgic drugs (i.e., antidepressants, antipsychotics and antiepileptics) and immunosuppressive drugs alone or in combination, evidence-based guidelines for the management of the neurologic manifestations of APS remain unavailable. Therefore, further experimental, clinical and retrospective studies with larger patient cohorts are warranted to elucidate the pathogenic linkage between APS and the central nervous system in addition to randomized controlled trials to facilitate the discovery of appropriate medications for the 'non-criteria' neurologic manifestations of APS.

Assessment of the independent associations of IgG, IgM and IgA isotypes of anticardiolipin with thrombosis in SLE

ObjectiveThe Sydney classification criteria for antiphospholipid syndrome include lupus anticoagulant or moderate-to-high titre anticardiolipin IgG or IgM. We explored the association of all anticardiolipin isotypes, lupus anticoagulant and the combination...

The association between antiphospholipid antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature.

In a previous systematic literature search, we demonstrated that the frequencies of antiphospholipid antibodies (aPL) in general-population patients with pregnancy morbidity (PM), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke (ST) are 6%, 10%, 11%, and 14%. To determine the association between aPL and clinical outcomes, we conducted a follow-up analysis of the 120 studies included in the original paper. Based on the analysis of 81 studies, a significant difference in the frequency of aPL criteria tests between patients and controls emerged considering all the outcomes together (10% versus 3%). In particular, a significant difference was reported for overall PM, pregnancy loss (PrL), late PrL, severe preeclampsia (PEC), ST, MI, and DVT. No difference emerged for early PrL, intrauterine growth restriction (IUGR), PEC, eclampsia (EC), and HELLP. A positive association was found in more than half of the studies for overall PrL, severe PEC, HELLP, ST, MI, and DVT and in less than half for early and late PrL, PEC, EC, and IUGR. The positive association between aPL and clinical outcomes included in the antiphospholipid syndrome classification criteria is not supported by every study, being particularly inconsistent for early PL, IUGR, PEC, EC, and HELLP.

Antiphospholipid antibodies and infertility.

Since the late 1980s some publications have proposed that antiphospholipid antibodies (aPL) may have some relationship with infertility, considering reported deleterious effects that aPL exert on trophoblast proliferation and growth. Although not included in current classification criteria for antiphospholipid syndrome, many physicians investigate for aPL in patients with a history of infertility, including antibodies not listed in classification criteria, and most of those patients will receive anticoagulant therapy if any of those antibodies have a result considered positive. A review of literature was conducted searching for studies that investigated the association of aPL and infertility and if aPL positivity alters in vitro fertilization (IVF) outcome. The definition of infertility, routine work-up to exclude other causes of infertility, definition of IVF failure as inclusion criteria and control populations were heterogeneous among studies. Most of them enrolled women over 40 years of age, and exclusion of other confounding factors was also inconsistent. Of 29 studies that assessed aPL positivity rates in infertile women, the majority had small sample sizes, implying a lack of power, and 13 (44.8%) reported higher frequency of aPL in infertile patients compared to controls, but most of them investigated a panel of non-criteria aPL tests, whose clinical significance is highly controversial. Only two studies investigated all three criteria tests, and medium-high titer of anticardiolipin cut-off conforming to international guidelines was used in one study. Considering IVF outcome, there was also disparity in this definition: few studies assessed the live birth rate, others the implantation rate. Of 14 publications that addressed the relationship between aPL and IVF outcome, only two described a detrimental effect of these autoantibodies. In conclusion, available data do not support an association between aPL and infertility, and aPL positivity does not seem to influence IVF outcome. Well-designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile should be performed to test whether clinically relevant aPL do-or not-exert an effect on human fertility.

SAT0234 Valvular heart disease in antiphospholipid syndrome

BackgroundAntiphospholipid syndrome (APS) is defined by the presence of venous or arterial thrombosis, recurrent pregnancy loss and anti-phospholipid antibodies (aPLs). Echocardiographic studies have disclosed heart valve abnormalities in about a...

AB0393 Comparison of multi-line dot assay and enzyme-linked immunosorbent assay for detection of autoantibody profile in antiphospholipid syndrome

BackgroundDiagnosis of antiphospholipid syndrome (APS) still remains a laboratory challenge due to the great diversity of antiphospholipid antibodies (aPL) and their significance regarding APS classification criteria. Standardized enzyme-linked immunosorbent assay...

The significance of antiphospholipid antibodies tests

Antiphospholipid syndrome (APS) is an autoimmune disease defined by the presence of antiphospholipid antibodies (APL) in plasma of patients with thrombosis and/or pregnancy morbidity. In the classification criteria of APS, the presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL) or anti-β2-glycoprotein I antibodies (aβ2GPI) is necessary to diagnose APS. Recently, we defined "antiphospholipid score (aPL-S)" and evaluate the predictive value for thrombosis. In the study, aPL-S may be a predictive marker for developing thrombosis in patients with autoimmune diseases. In this article, we explain various APL assays for diagnosing APS in a clinical practice, introduce the study of "aPL-S", and discuss the significance of APL tests not only for a diagnosis of APS but also for a predictive marker of thrombosis in patients with autoimmune diseases.

Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study

AbstractThe updated Sapporo classification criteria for antiphospholipid syndrome (APS) only include thrombosis or pregnancy morbidity as clinical criteria. To test this notion, we studied 55 patients (80% women) with hematologic manifestations. All fulfilled the laboratory criteria for primary APS. Thirty-five patients (64%) had thrombocytopenia, 14 (25%) had autoimmune hemolytic anemia, and 6 (11%) had both. Twenty-five patients (22 women, 88%) also fulfilled one clinical criterion for APS after a median follow-up of 13.2 years (range, 1.45-37 years), whereas the remaining 30 patients (22 women, 73%) have not had any thrombotic event nor pregnancy morbidity after a median follow-up of 5.4 years (range, 0.12-24 years). No patient developed systemic lupus erythematosus during follow-up. The hematologic manifestation was asynchronous with the APS onset in 84% of patients. The response to treatment was similar regardless of the APS status. Patients with definite APS were more frequently positive for the lupus anticoagulant (63%) than lupus anticoagulant-positive patients without APS (30%; odds ratio, 3.5; 95% confidence interval, 1.07-11.4; P < .02). Anticardiolipin or anti–β2-glycoprotein-I antibodies were highly prevalent among the study groups. Our study suggests that, depending upon their antiphospholipid profile, patients with hemocytopenias appear to comprise a peculiar subset of patients with APS; some develop thrombotic and/or obstetric APS whereas others continue with hematologic APS.

Association of IgA Anti-ß2 Glycoprotein I with Clinical and Laboratory Manifestations of Systemic Lupus Erythematosus

IgA isotypes of anticardiolipin and anti-ß(2) glycoprotein I (anti-ß(2)-GPI) are omitted from the revised antiphospholipid syndrome (APS) classification criteria. Multiple studies have found a high prevalence of IgA anti-ß(2)-GPI in systemic lupus erythematosus (SLE). We determined the frequency and associations of IgA anti-ß(2)-GPI in a cohort of patients with SLE. anti-ß(2)-GPI was measured in 796 patients with SLE (93% women, 53% white, 38% African American, mean age 45 yrs). IgA anti-ß(2)-GPI (> 20 phospholipid units) was found in 20%. Using a cohort database, associations with cumulative thrombotic and other manifestations were determined. of patients with SLE who demonstrated IgA anti-ß(2)-GPI positivity, about 6% had transient ischemic attack (p = 0.070), 4% had superficial thrombophlebitis (p = 0.647), 20% had deep venous thrombosis (p = 0.003), 4% had other venous thrombosis (p = 0.827), 12% had stroke (p = 0.050), and 1% had myocardial infarction (p = 0.397). IgG anti-ß(2)-GPI has the strongest association with thrombosis in SLE. However, IgA anti-ß(2)-GPI was more strongly associated with deep venous thrombosis and with stroke than was IgM. These results indicate that assessment of IgA anti-ß(2)-GPI is associated with thrombosis in SLE, and that the classification criteria for APS should be revised to include IgA anti-ß(2)-GPI in patients with SLE.

Antiphospholipid antibody profile: implications for the evaluation and management of patients

According to the classification criteria of antiphospholipid syndrome, lupus anticoagulant, anticardiolipin and anti-beta(2) glycoprotein I antibody assays are independent risk factors for the occurrence of vascular thrombosis and pregnancy loss. However, it is generally accepted that patients carrying multiple positivity have more a severe disease and higher recurrence rate despite treatment. On the other hand, the diagnostic value of a positive result in one only assay is more controversial, particularly in the presence of clinical manifestations such as deep vein thrombosis or early miscarriages, which are rather common in the general population. In this review we speculate on current and future strategies to interpret different antiphospholipid antibody profiles in the clinical practice.

Lupus et syndrome des anticorps antiphospholipides. Critères de diagnostic et de suivi

There are no internationally validated diagnostic criteria for systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APLS). However, classification criteria have been edicted and clinicians use (and abuse) of these criteria for the diagnosis of SLE or APLS. ACR classification criteria for SLE have been published in 1982 and (partially) revised in 1997 in order to integrate recent technical immunological methods for the diagnosis. ACR criteria give a (too) large part to dermatologic manifestations and a (too) limited part to other visceral manifestations (pulmonary, neurologic and psychiatric for instance). APLS classification criteria have been revised in 2006 but still exclude non thrombotic manifestations, such as thrombopenia, endocarditis or chorea. As these criteria are for classification only, it is not a must for a clinician that his (or her) patient fulfils these criteria to propose the diagnosis of SLE or APLS and treat the patient as so. The follow-up of patients with SLE or APLS is based on a series of recommendations formulated either by a standing-committee of EULAR as for SLE or a national official bureau such as the French High Authority of Health. After a careful survey of the international literature, the committees made recommendations on the prognostic value of various biochemical and immunological parameters which must be used in order to predict flares in SLE. No recommendation are available for APLS.