Viewpoint: Lupus anticoagulant detection and interpretation in antiphospholipid syndrome.

Lupus anticoagulant (LA) is a well-established risk factor for the clinical manifestations of antiphospholipid syndrome (APS). Accurate LA detection is an essential prerequisite for optimal diagnosis and management of patients with APS or aPL carriers. Variability remains a challenge in LA testing, with reliable detection influenced by multiple factors, including pre-analytical conditions, anticoagulation treatment, choice of tests and procedures performed, as well as interpretation of results, that can lead to false-positives or negatives. A standardised approach to LA testing, following current guidance, based on published data and international consensus, and with attention to detail, is required to underpin accurate detection of LA. Future work should focus on better characterisation of the nature of LA, which may ultimately lead to improved diagnosis and management of patients with APS and aPL carriers. This article reviews current practice and challenges, providing an overview on detection of LA.

Deciphering the clinical significance of longitudinal antiphospholipid antibody titers.

In antiphospholipid syndrome (APS), the risk of clinical manifestations increases with higher titers of antiphospholipid antibodies (aPL). Despite the adoption of aPL titers in the classification approach to aPL-positive subjects, the value of longitudinal monitoring of those titers in the follow-up is still debated, being well studied only in systemic lupus erythematosus (SLE). The literature suggests that the rate of aPL positivity decreases during follow-up in primary APS, estimating that seroconversion occurs in between 8.9 and 59% of patients over time. Negativisation of aPL occurs more frequently in asymptomatic aPL carriers than in patients with full-blown APS as well as in subjects with single aPL positivity or low aPL antibody titers. In patients with SLE, aPL typically behave fluctuating from positive to negative and back again in the course of follow-up. The few studies assessing the longitudinal course of aPL positivity with no associated systemic connective tissue disease reported a progressive decrement of aPL titers over time, in particular of antibodies against ß2 glycoprotein I (antiß2GPI) and cardiolipin (aCL) of IgG isotype. After a thrombotic event, aPL titers tend to decrease, as emerged from cohorts of both primary and secondary APS. Hydroxychloroquine has been identified as the most effective pharmacological agent to reduce aPL titers, with multiple studies demonstrating a parallel reduction in thrombosis rate. This review addresses available evidence on the significance of aPL titer fluctuation from clinical, therapeutic and pathogenic perspectives.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository ("Registry").

BACKGROUND: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. OBJECTIVES: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. PATIENTS/METHODS: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. RESULTS: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). CONCLUSION: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry.

OBJECTIVES: Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS: In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS: Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aß2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS: DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

16th International congress on antiphospholipid antibodies task force report on antiphospholipid syndrome laboratory diagnostics and trends.

Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-ß2 glycoprotein I (anti-ß2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of ß2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of ß2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16th International Congress on aPL, Manchester, UK, September 2019.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study.

Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-ß2 glycoprotein-I antibody (aß2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aß2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aß2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aß2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Anti-Neutrophil Extracellular Trap Antibodies in Antiphospholipid Antibody-Positive Patients: Results From the Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Clinical Database and Repository.

OBJECTIVE: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus. METHODS: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. RESULTS: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen. CONCLUSION: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens.

Fluctuation of Anti-Domain 1 and Anti-ß2 -Glycoprotein I Antibody Titers Over Time in Patients With Persistently Positive Antiphospholipid Antibodies.

OBJECTIVE: The present study was undertaken to longitudinally evaluate titers of antibodies against ß2 -glycoprotein I (anti-ß2 GPI) and domain 1 (anti-D1), to identify predictors of variations in anti-ß2 GPI and anti-D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry. METHODS: Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2-4 of follow-up) were included. Detection of anti-ß2 GPI and anti-D1 IgG antibodies was performed using chemiluminescence (BIO-FLASH; INOVA Diagnostics). RESULTS: Among 230 patients in the study cohort, anti-D1 and anti-ß2 GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti-D1 and anti-ß2 GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3-fold and 1.4-fold decreases in anti-D1 and anti-ß2 GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increases in anti-D1 and anti-ß2 GPI titers, respectively. Anti-D1 and anti-ß2 GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6-fold decrease in anti-D1 titers and a 2-fold decrease in anti-ß2 GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62-59.3) and 9.4 (95% CI 1.1-80.2), respectively. CONCLUSION: Treatment with HCQ and incident vascular events in aPL-positive patients predicted significant anti-D1 and anti-ß2 GPI titer fluctuations over time. Both anti-D1 and anti-ß2 GPI titers decreased around the time of thrombosis, with potential clinical relevance.

Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository.

OBJECTIVE: To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. METHODS: The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-ß2 -glycoprotein I [anti-ß2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). RESULTS: The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-ß2 GPI only. CONCLUSION: Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

Clinical and laboratory characteristics of Brazilian versus non-Brazilian primary antiphospholipid syndrome patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) clinical database and repository.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients. METHODS: We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS). RESULTS: We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ß2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white. CONCLUSIONS: Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event.

Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION): 10-Year Update.

PURPOSE OF REVIEW: APS ACTION is an international research network created to design and conduct large-scale, multicenter research in persistently antiphospholipid antibody (aPL)-positive patients. Given the expanding research activities of the network in the last decade since its creation, the purpose of this article is to review the scientific contributions of APS ACTION as well as future directions. RECENT FINDINGS: APS ACTION has achieved increased international collaboration with internal and external investigators for outcome, interventional, and mechanistic antiphospholipid syndrome (APS) studies. This has been linked to substantial progress in Core laboratory work, which has demonstrated that laboratories can achieve good agreement in performance of aPL assays by use of the same reagents, analyzer type, and protocols. APS ACTION will continue to identify gaps in the existing aPL/APS literature, design mechanistic studies to elucidate underlying mechanisms, and conduct prospective, large-scale clinical studies, all for the ultimate goal of early diagnosis and improved management of aPL-positive patients.

Identifying phenotypes of patients with antiphospholipid antibodies: results from a cluster analysis in a large cohort of patients.

OBJECTIVES: To identify the aggregation of patients with aPL into different subgroups sharing common features in terms of clinical and laboratory phenotypes. METHODS: We applied a hierarchical cluster analysis from the multiple correspondence analysis to determine subgroups of patients according to clinical and laboratory characteristics in a cohort of subjects with confirmed aPL positivity who presented to our outpatient clinics from 2006 to 2018. RESULTS: A total of 486 patients [403 women; age 41.7 years (26)] were included, resulting in five clusters. Cluster 1 (n= 150) presented with thrombotic events (65.3% with venous thrombosis), with triple aPL positivity found in 34.7% of them (the highest rate among the different clusters). All the patients from cluster 2 (n = 91) had a confirmed diagnosis of SLE and the highest rate of anti-dsDNA positivity (91.7%). Cluster 3 included 79 women with pregnancy morbidity. Triple positivity was present in 3.8%, significantly lower when compared with Cluster 1 (34.7% versus 3.8%, P <0.01). Cluster 4 included 67 patients, 28 (41.8%) of whom with APS. Thrombotic events were observed in 23.9% patients. Cluster 4 had the highest rate of cytopenia, with thrombocytopenia as high 41.8% with no anti-dsDNA antibodies. Cluster 5 included 94 asymptomatic aPL carriers. CONCLUSION: While clusters 1, 2, 3 and 5 corresponded to well-known entities, cluster 4 might represent a bridging condition between pure primary APS and defined SLE, with lower thrombotic risk when compared with primary APS but higher general features such as ANA and cytopenia (mainly thrombocytopenia).

Antiphospholipid Antibody Profile Stability Over Time: Prospective Results From the APS ACTION Clinical Database and Repository.

OBJECTIVE: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time. METHODS: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-ß2 glycoprotein-I (anti-ß2-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis. RESULTS: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate (P = 0.906) and multivariable analysis (P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, P = 0.002) the odds of an unstable aPL profile over time. CONCLUSION: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.

Development of a New International Antiphospholipid Syndrome Classification Criteria Phase I/II Report: Generation and Reduction of Candidate Criteria.

OBJECTIVE: An international multidisciplinary initiative, jointly supported by the American College of Rheumatology and European Alliance of Associations for Rheumatology, is underway to develop new rigorous classification criteria to identify patients with high likelihood of antiphospholipid syndrome (APS) for research purposes. The present study was undertaken to apply an evidence- and consensus-based approach to identify candidate criteria and develop a hierarchical organization of criteria within domains. METHODS: During phase I, the APS classification criteria steering committee used systematic literature reviews and surveys of international APS physician scientists to generate a comprehensive list of items related to APS. In phase II, we reviewed the literature, administered surveys, formed domain subcommittees, and used Delphi exercises and nominal group technique to reduce potential APS candidate criteria. Candidate criteria were hierarchically organized into clinical and laboratory domains. RESULTS: Phase I generated 152 candidate criteria, expanded to 261 items with the addition of subgroups and candidate criteria with potential negative weights. Using iterative item reduction techniques in phase II, we initially reduced these items to 64 potential candidate criteria organized into 10 clinical and laboratory domains. Subsequent item reduction methods resulted in 27 candidate criteria, hierarchically organized into 6 additive domains (laboratory, macrovascular, microvascular, obstetric, cardiac, and hematologic) for APS classification. CONCLUSION: Using data- and consensus-driven methodology, we identified 27 APS candidate criteria in 6 clinical or laboratory domains. In the next phase, the proposed candidate criteria will be used for real-world case collection and further refined, organized, and weighted to determine an aggregate score and threshold for APS classification.

Clinical and laboratory characteristics of Brazilian versus non-Brazilian primary antiphospholipid syndrome patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) clinical database and repository

Abstract Background: Antiphospholipid syndrome (APS) is characterized by episodes of thrombosis, obstetric morbidity or both, associated with persistently positive antiphospholipid antibodies (aPL). Studying the profile of a rare disease in an admixed population is important as it can provide new insights for understanding an autoimmune disease. In this sense of miscegenation, Brazil is characterized by one of the most heterogeneous populations in the world, which is the result of five centuries of interethnic crosses of people from three continents. The objective of this study was to compare the clinical and laboratory characteristics of Brazilian vs. non-Brazilian primary antiphospholipid syndrome (PAPS) patients. Methods: We classified PAPS patients into 2 groups: Brazilian PAPS patients (BPAPS) and PAPS patients from other countries (non-BPAPS). They were compared regarding demographic characteristics, criteria and non-criteria APS manifestations, antiphospholipid antibody (aPL) profile, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS). Results: We included 415 PAPS patients (88 [21%] BPAPS and 327 [79%] non-BPAPS). Brazilian patients were significantly younger, more frequently female, sedentary, obese, non-white, and had a higher frequency of livedo (25% vs. 10%, p < 0.001), cognitive dysfunction (21% vs. 8%, p = 0.001) and seizures (16% vs. 7%, p = 0.007), and a lower frequency of thrombocytopenia (9% vs. 18%, p = 0.037). Additionally, they were more frequently positive for lupus anticoagulant (87.5% vs. 74.6%, p = 0.01), and less frequently positive to anticardiolipin (46.6% vs. 73.7%, p < 0.001) and anti-ß2-glycoprotein-I (13.6% vs. 62.7%, p < 0.001) antibodies. Triple aPL positivity was also less frequent (8% vs. 41.6%, p < 0.001) in Brazilian patients. Median aGAPSS was lower in the Brazilian group (8 vs. 10, p < 0.0001). In the multivariate analysis, BPAPS patients still presented more frequently with livedo, cognitive dysfunction and sedentary lifestyle, and less frequently with thrombocytopenia and triple positivity to aPL. They were also less often white. Conclusions: Our study suggests a specific profile of PAPS in Brazil with higher frequency of selected non-criteria manifestations and lupus anticoagulant positivity. Lupus anticoagulant (not triple positivity) was the major aPL predictor of a classification criteria event.