To gather the perspectives of APS ACTION members regarding the strengths and limitations of Damage Index for Antiphospholipid Syndrome (DIAPS); and establish recommendations for the improvement of DIAPS.

APS ACTION members were invited to answer a survey regarding their satisfaction with DIAPS scoring system and individual items. The level of agreement (LoA) among members with the inclusion of individual items in DIAPS was calculated (LoA of <75% was considered disagreement). Respondents' open-ended comments about DIAPS limitations were also collected, which helped formulate our recommendations for DIAPS improvement.

Forty-two APS ACTION members (58.3%) answered the survey. Of them, 26 (61.9%) were satisfied, 4 (9.5%) were neutral, and 12 (28.6%) were dissatisfied with the current DIAPS scoring system. Fifteen items (39.5%) presented a LoA <75% regarding the inclusion in DIAPS. Respondents provided comments that were grouped under six main categories related to concerns about: a) definitions and attribution of damage (including causality and temporal relationship); b) scoring system; c) overlapping items; d) specific items (exclusion of redundant items and inclusion of additional ones); e) the need to incorporate multiple events; and f) feasibility and practicality. Finally, the APS ACTION "Damage" Working Group developed 7 recommendations that should be considered for the next generation DIAPS.

Approximately 60% of respondents were satisfied with DIAPS and its definitions; however, our survey demonstrated that there is substantial room to improve the current damage index for APS. Efforts for updating DIAPS should consider the APS ACTION "Damage" Working Group recommendations.

Background Antiphospholipid syndrome (APS) is a chronic autoimmune disorder characterized by thrombotic events and organ damage, often leading to significant morbidity and mortality. The Damage Index for Antiphospholipid Syndrome (DIAPS) was developed to quantify irreversible damage in these patients, providing a tool for better disease management. Objectives This study investigates the long-term accumulation of organ damage in patients with thrombotic APS. Specifically, it examines how damage severity differs between primary APS (PAPS) and secondary APS (SAPS) and how traditional cardiovascular risk factors contribute to disease progression. Understanding these interactions may help refine patient management strategies. Methods A retrospective analysis of 141 patients diagnosed with thrombotic APS was conducted using medical records. The DIAPS score was calculated for each patient, and its association with autoimmune comorbidities and cardiovascular risk factors was analyzed through statistical modeling. Results Among the 141 APS patients (86% female, mean age 52 years), systemic lupus erythematosus was the most frequent associated autoimmune disease (92%). Arterial hypertension was present in 39% of cases, dyslipidemia in 28%, and type 2 diabetes in 10%. Patients with SAPS had significantly higher DIAPS scores than those with PAPS (p=0.044). Hypertension and diabetes were linked to increased organ damage, while dyslipidemia influenced the relationship between APS-related autoimmunity and cumulative damage. Conclusions Patients with secondary APS experience more severe long-term damage compared to those with primary APS. Additionally, cardiovascular risk factors, particularly hypertension and diabetes, worsen disease progression. These findings underscore the need for a multidisciplinary approach that integrates autoimmune disease management with cardiovascular risk control to prevent irreversible complications in APS patients.

A treat-to-target (T2T) approach aims to the identification of a clinically relevant therapeutic target and applies tight control (periodic visits at prespecified time-points and treatment adjustments) to achieve it with the goal of improving disease outcomes. The application of a T2T strategy appears to be less feasible in APS compared to other autoimmune diseases. This is primarily explicable by the disease's kaleidoscopic clinical presentation, along with the lack of a definitive tool (biomarkers or scoring system) to assess disease activity, making it complex to recognize a singular, effective therapeutic target for APS patients. Nevertheless, the conceptualization of T2T strategies should be considered a key objective when managing APS, aiming to achieve optimal disease control (including lowering the risk for recurrences), to reduce damage accumulation, and, ultimately, to enhance patients' quality of life.

We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL).

Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression.

Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6 years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis.

This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

Despite anticoagulant therapy, a antiphospholipid syndrome (APS) has a higher rate of recurrent events, which can lead to damage accrual and a negative impact on life quality.

To evaluate the risk factors and APS subsets associated with damage accrual.

We conducted a retrospective single-center study. We reviewed the medical records of 282 APS patients, with a median age of 36 (IQR 30-46) years and a median of 195 (IQR 137-272) months. The primary endpoint was damage accrual during follow-up, defined as organ/tissue impairment present for at least six months or causing permanent loss. The secondary endpoints were early organ damage within six months of disease onset and death.

Eighty (28.4%) patients presented damage accrual; 52.5% developed damage within six months of APS onset, and 41.3% had more than one organ involved. Neuropsychiatric involvement, affecting 38.8% of the patients, was the most frequent, followed by peripheral vasculopathy and renal involvement, 35% either. Death happened in 7 (2.5 %) patients; damage accrual was associated with a 6-fold risk of death [OR 6.7 (95% CI 1.3-35.1), p = 0.03]. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual with 5-fold and 4-fold higher risk, respectively [(OR 4.9 (95% CI 2.1-11.7), p < 0.0001 and (OR 3.8 (95% CI 1.5-10.1), p = 0.007]. The cumulative incidence of damage accrual increased by 5.7-fold and 3.6-fold in patients with microangiopathy and non-criteria manifestations.

APS patients had a higher frequency of damage accrual. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual.

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.

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.

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), aβ2GPI 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).

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.

Life-long anticoagulation increases bleeding risk in patients with antiphospholipid syndrome (APS). The Damage Index for Antiphospholipid Syndrome does not include bleeding events in damage accrual.

We aimed to characterize the prevalence, severity, and damage associated with bleeding events in patients with APS.

This was a single-center retrospective analysis of patients with thrombotic APS (2006 Sydney criteria). Bleeding events were reviewed up to 43 years and classified according to the ISTH definitions into 2 groups: 1) major bleedings and 2) nonmajor bleedings (minor bleedings and clinically relevant nonmajor bleedings). Damage events were recorded as bleeding events a) resulting in permanent (>6 months) decrease in organ function and b) complicated by total/partial organ resection.

Among 197 patients (2412 patient-years [PYs] of follow-up), all of whom had been exposed to antithrombotic therapy, 40.6% experienced 167 bleedings (6.9 events per 100 PYs), of whom 61.3% had nonmajor bleedings (77.2% of bleedings: 42.6% minor, 57.4% clinically relevant nonmajor) and 38.8% had major bleedings (22.8% of bleedings; 1.6 events per 100 PYs). Soft/connective tissue was affected in 44.3% of bleedings, and 94.6% were nonmajor bleedings. Central nervous system was affected in 20.9% of bleedings, and 62.9% were major bleedings. Bleeding events were spontaneous in 90.4% of cases, and thrombocytopenia was likely involved in 62.2% of bleedings. Damage occurred in 11.4% of bleedings and affected 7.6% of patients. Most of the damage was associated with central nervous system events (8.4% of all bleedings).

Approximately 40% of patients experienced at least 1 bleeding, and almost 8% of patients were left with organ damage not recognized by the current version of the Damage Index for Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid binding proteins. The result is an increased risk of thrombotic events, pregnancy morbidity, and various other autoimmune and inflammatory complications. Although antiphospholipid syndrome was first recognized in patients with lupus, the stand alone presentation of antiphospholipid syndrome is at least equally common. Overall, the diagnosis appears to affect at least one in 2000 people. Studies of antiphospholipid syndrome pathogenesis have long focused on logical candidates such as coagulation factors, endothelial cells, and platelets. Recent work has shed light on additional potential therapeutic targets within the innate immune system, including the complement system and neutrophil extracellular traps. Vitamin K antagonists remain the mainstay of treatment for most patients with thrombotic antiphospholipid syndrome and, based on current data, appear superior to the more targeted direct oral anticoagulants. The potential role of immunomodulatory treatments in antiphospholipid syndrome management is receiving increased attention. As for many systemic autoimmune diseases, the most important future direction is to more precisely identify mechanistic drivers of disease heterogeneity in pursuit of unlocking personalized and proactive treatments for patients.

This study assessed patient-reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life.

Patients completed Patient-Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1-10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression.

Of 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43-0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF.

Individuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs.

To identify the different clinical phenotypes of antiphospholipid syndrome (APS) by using cluster analysis and describe cumulative damage of disease clusters.

This retrospective study includes patients with APS (±systemic lupus erythematosus (SLE)). Two-step cluster analysis was applied by considering clinical data. Damage was calculated for all patients by applying damage index for APS (DIAPS).

A total of 237 patients (198 females; median age of 43 years; median follow-up of 9.5 years) were classified into four clusters. Cluster 1 (n = 74) consisted of older patients with arterial-predominant thrombosis, livedo reticularis, and increased cardiovascular risk; cluster 2 (n = 70) of SLE+APS patients with thrombocytopenia and heart valve disease; cluster 3 (n = 59) of patients with venous-predominant thrombosis, less extra-criteria manifestations; and cluster 4 (n = 34) of patients with only pregnancy morbidity with lower frequency of extra-criteria features and cardiovascular risk. Patients with SLE+APS (n = 123) had the highest mean DIAPS. Regarding clusters, 1 and 2 had high cumulative damage. While cumulative survival rates of clusters did not differ, cluster 2 and 3 had lower survival rates at further years. There was no correlation between DIAPS and mortality.

SLE+APS patients with extra-criteria manifestations and older APS patients with arterial thrombosis and increased cardiovascular risk have higher cumulative damage. Effective treatment of SLE disease activity and control of cardiovascular risk may help to reduce cumulative damage in these patients.