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.

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.

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.

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.

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.

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 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.

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry.

OBJECTIVE: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. METHODS: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. RESULTS: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. CONCLUSIONS: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

The Clinical Relevance of Noncriteria Antiphospholipid Antibodies.

While lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-ß2 glycoprotein I (anti-ß2GPI) antibodies represent the best available and the most widely used tests in the investigation for antiphospholipid syndrome (APS), evidence gathered in recent years indicates that other antiphospholipid antibodies (aPL) specificities may also play a role in the syndrome. Several autoantibodies have been shown to be complexed with phospholipids other than cardiolipin, or to some domains of ß2GPI, or else directed to other proteins of the coagulation cascade, and these have also been proposed to be of relevance to APS, and their diagnostic value and clinical utility are the focus of current research.

Clinical utility of the global anti-phospholipid syndrome score for risk stratification: a pooled analysis.

Objective: Recently, our group conceived a risk score for clinical manifestations of APS (the global APS score, or GAPSS) that takes into account the combination of independent cardiovascular risk factors and the aPL positivity profile. These include hyperlipidaemia, arterial hypertension, aCL, anti-ß2 glycoprotein-I, aPS-PT and the LA. A complementary version, the adjusted GAPSS (aGAPSS), which excludes aPS-PT, was also designed. The aim of our study was to systematically review the literature to assess the clinical utility of the GAPSS and aGAPSS for risk stratification of any APS clinical manifestation. Methods: We pooled data from available cohort studies, including a total of 10 studies, comprising 2273 patients, in which the GAPSS has been applied. A search strategy was developed a priori to identify an available cohort that reported findings which investigated the clinical utility of GAPSS or aGAPSS. Results: Seven studies used the GAPSS in their cohort, whereas three studies used the aGAPSS. In brief, we found a statistically significant difference in the cumulative GAPSS and aGAPSS between patients that experienced an arterial and/or venous thrombotic event [cumulative mean GAPSS (s.d.) 10.6 (4.74) and aGAPSS 7.6 (3.95)], patients without any thrombotic manifestation [cumulative GAPSS 7.01 (5.46) and aGAPSS 4.9 (4.33)] and patients with pregnancy morbidity [cumulative GAPSS 8.79 (2.59) and aGAPSS 6.7 (2.8)]. The highest levels of GAPSS were found in patients that experienced arterial thrombosis [mean GAPSS 12.2 (5.2)] and patients that experienced any recurrences of clinical manifestations of APS [mean GAPSS 13.7 (3.1)]. Conclusion: GAPSS may represent a useful tool to assess the thrombosis or pregnancy loss risk in aPL-positive patients, switching from the concept of aPL as a sole diagnostic antibody to aPL as risk factors for clinical events.

Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.

Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes -measured by proton magnetic resonance spectroscopy in APS-mice. Using 111In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy.

The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review.

BACKGROUND: Around 10% of all thrombotic cerebrovascular events (CVE) occur in young population and in a large proportion of those the trigger remains undetermined. Antiphospholipid antibodies (aPL) are recognised risk factors for ischaemic stroke and recurrent thrombotic events; however, the frequency of aPL in young people with CVE is still an unresolved issue. OBJECTIVES: To estimate the frequency of aPL in young adults with CVE and to determine whether aPL-positive young individuals are at greater risk of CVE when compared with individuals without aPL by systematically reviewing the literature. METHODS: Medline reports published between 1970 and 2013 investigating the presence of aPL in young patients (<50 years old) with CVE were included. The median frequency for positive aPL, including lupus anticoagulant, anticardiolipin antibodies (aCL) and antibodies against ß2Glycoprotein I (anti-ß2GPI), was calculated for stroke and transient ischaemic attacks. FINDINGS: This systematic review is based on available data from 5217 patients and controls from 43 studies analysing the frequency of aPL in young patients with CVE. The overall aPL frequency was estimated as 17.4% (range 5%-56%) for any CVE, 17.2% (range 2%-56%) for stroke and 11.7% (range 2%-45%) for transient ischaemic attack (TIA). The presence of aPL increased the risk for CVE by 5.48-fold (95% CI 4.42 to 6.79). Based on available data, the frequency of aPL in young patients with CVE can be estimated at 17%, rising up to 22% for aCL in patients with stroke. The presence of aPL seems to confer a fivefold higher risk for stroke or TIA when compared with controls. However, variability in test reproducibility and cut-off definition still represent an important methodological limitation for the current diagnostic testing for aPL. These observations should be confirmed by appropriately designed population studies.

Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment.

OBJECTIVE: Statins may have beneficial vascular effects in systemic lupus erythematosus (SLE) beyond their cholesterol-lowering action, although the mechanisms involved are not completely understood. We investigated potential mechanisms involved in the efficacy of fluvastatin in preventing atherothrombosis in SLE. METHODS: Eighty-five patients with SLE and 62 healthy donors were included in the study. Selected patients (n=27) received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start and at the end of treatment. Monocytes from five patients were treated in vitro with fluvastatin. RESULTS: Increased prothrombotic and inflammatory variables were found in patients with SLE. SLE monocytes displayed altered mitochondrial membrane potential and increased oxidative stress. Correlation and association analyses demonstrated a complex interplay among autoimmunity, oxidative stress, inflammation and increased risk of atherothrombosis in SLE. Fluvastatin treatment of patients for 1 month reduced the SLE Disease Activity Index and lipid levels, oxidative status and vascular inflammation. Array studies on monocytes demonstrated differential expression in 799 genes after fluvastatin treatment. Novel target genes and pathways modulated by fluvastatin were uncovered, including gene networks involved in cholesterol and lipid metabolism, inflammation, oxidative stress and mitochondrial activity. Electron microscopy analysis showed increased density volume of mitochondria in monocytes from fluvastatin-treated patients, who also displayed higher expression of genes involved in mitochondrial biogenesis. In vitro treatment of SLE monocytes confirmed the results obtained in the in vivo study. CONCLUSIONS: Our overall data suggest that fluvastatin improves the impairment of a redox-sensitive pathway involved in processes that collectively orchestrate the pathophysiology of atherothrombosis in SLE.

The global anti-phospholipid syndrome score in primary APS.

OBJECTIVE: The aim of this study was to evaluate the clinical relevance of the global APS score (GAPSS) in a cohort of primary APS patients. METHODS: This study included 62 consecutive patients with primary APS. Data on clinical manifestations, conventional cardiovascular risk factors and aPL profile were collected. The GAPSS was calculated for each patient by adding together the points corresponding to the risk factors, based on a linear transformation derived from the ß regression coefficient as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for aCL IgG/IgM, 4 for anti-ß2 glycoprotein I IgG/IgM, 3 for aPS-PT IgG/IgM and 4 for LA. RESULTS: Higher GAPSS values were seen in patients who experienced thrombosis alone when compared with those with pregnancy loss alone [11.5 (S.D. 4.6) and 8.7 (S.D. 3.2), P = 0.04]. Patients with both thrombosis and pregnancy loss showed higher GAPSS than those with pregnancy loss alone [12.5 (S.D. 4.6) vs 8.7 (S.D. 3.2), P = 0.02]. Higher GAPSS values were also shown after subgrouping for the site of thrombosis when compared with pregnancy loss alone [12.2 (S.D. 5.2) for arterial thrombosis, 12.0 (S.D. 4.0) for venous vs 8.7 (S.D. 3.2), P = 0.02 and P = 0.04, respectively]. Patients with thrombotic recurrences showed higher GAPSS values when compared with those without recurrence [13.7 (S.D. 3.1) vs 9.4 (S.D. 3.9), P = 0.02]. This was also seen when comparing recurrences vs no recurrences independently of the site of the thrombotic event [13.9 (S.D. 3.6) vs 11.0 (S.D. 4.3), P = 0.01 for arterial and 13.6 (S.D. 2.18) vs 8.91 (S.D. 3.6), P < 0.01 for venous thrombosis]. GAPSS values ≥11 were strongly associated with a higher risk of recurrence [odds ratio (OR) 18.27 (95% CI 3.74, 114.5) for a cut-off of 11, OR 20.64 (95% CI 3.92, 185.92) for a cut-off of 12 and 21.64 (95% CI 3.89, 189.56) for a cut-off of 15]. GAPSS values ≥11 seemed to have the best risk accuracy in terms of sensitivity and specificity. CONCLUSION: The GAPSS is demonstrated to be a valid tool for a substantial improvement in risk stratification for thrombosis in primary APS.

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment.

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10).

New tests to detect antiphospholipid antibodies: antiprothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies.

Antiprothrombin antibodies have been proposed as potential new biomarkers for thrombosis and/or pregnancy morbidity in the setting of the antiphospholipid syndrome (APS). Antiprothrombin antibodies are commonly detected by ELISA, using prothrombin coated onto irradiated plates (aPT), or prothrombin in complex with phosphatidylserine (aPS/PT), as antigen. Although these antibodies can co-exist in the same patient, aPT and aPS/PT seem to belong to different populations of autoantibodies. Early research explored the role of antibodies to prothrombin as potential antigenic targets for the lupus anticoagulant (LA). To date their clinical significance is being investigated and their potential role in identifying patients at higher risk of developing thrombotic events or pregnancy morbidity is being probed.

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.