Abstract
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), 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).
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.
Keywords: antiphospholipid syndrome, antiphospholipid antibodies, lupus anticoagulant, anticardiolipin, anti-beta-2 glycoprotein I antibodies, damage, cardiovascular disease, risk factors
Rheumatology key messages.
DIAPS was able to discriminate damage in a large multicentre cohort of primary aPL-positive patients.
Cardiovascular risk factors were associated with damage burden in aPL-positive patients.
Specific aPL profiles may help to identify patients more prone to accrue damage.
Introduction
APS is the most common acquired thrombophilia, characterized by thrombotic events and/or pregnancy morbidity in the presence of persistent aPL, namely lupus anticoagulant (LA), IgG and/or IgM anticardiolipin antibodies (aCL), and IgG and/or IgM anti-β-2 glycoprotein I antibodies (aβ2GPI). APS may develop in association with other autoimmune diseases, especially SLE, or without other autoimmune diseases (primary APS—PAPS) [1]. Recurrent thrombotic events are frequent in APS patients and may lead to damage. In patients with SLE, Ruiz-Irastorza et al. demonstrated that APS is a major predictor of irreversible organ damage and death [2]. Thus, quantifying damage associated with thrombosis and its treatment in APS patients is important for understanding disease severity and may help to predict outcomes.
Damage Index for APS (DIAPS) is an instrument developed for assessing damage accrual in thrombotic APS patients, which was initially validated in Latin American patients [3]. It was derived from the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) [4] and encompasses 37 items (22 from SDI and 15 newly added after applying the Delphi methodology). Each item may receive up to 2 points (range 0–74 points) [3]. All domains and items included in DIAPS are presented in Supplementary Table S1 (available at Rheumatology online). In the original study, DIAPS negatively correlated with quality of life measured by EuroQoL [3, 5]. More recently, Medina et al. found that DIAPS was able to capture damage accrual over a long-term follow-up in a similar population [6]. However, only a few papers evaluated DIAPS in other APS populations, mostly with a limited number of subjects [7–9].
APS is considered a rare disease, with an estimated prevalence of 50 cases per 100 000 population aged ≥18 years [10]. Therefore, implementing international multicentre efforts to conduct studies to understand the disease and its mechanisms is crucial. APS ACTION is an international clinical database and repository (prospective ‘registry’) that includes a large number of aPL-positive patients from different centres worldwide [11]. Studying DIAPS in this large international cohort may provide insights into risk factors associated with damage accrual in aPL-positive patients and may also verify the capability of DIAPS to capture damage burden in populations other than those initially reported.
Our primary objective was to quantify damage burden measured by DIAPS in aPL-positive patients with or without a history of thrombosis in a large international cohort. Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients.
Methods
Study design and patient selection
This is a cross-sectional analysis of baseline damage (measured by DIAPS) of the patients included in the APS ACTION Registry. We screened all patients (aged ≥18 years) registered in the APS ACTION Clinical Database as of April 2020. All patients were aPL positive according to the Updated Sapporo Classification Criteria [1] and tested within 1 year prior to enrolment.
The only exclusion criterion was autoimmune rheumatic diseases other than APS, given these diseases and their treatment, e.g. glucocorticosteroids (almost universally used) and cyclophosphamide, may be associated with damage [12–15], which could interfere with the analysis of the contribution of aPL positivity itself for damage accrual, leading to biases. However, we did not exclude patients that were using glucocorticoids to non-criteria manifestations related to APS or aPL-positivity (e.g. cytopenias).
All relevant information, such as demographic, thrombotic (including microvascular and catastrophic APS [CAPS] [16] events), non-thrombotic (including thrombocytopenia defined as <100 000 per microliter tested twice at least 12 weeks apart) and obstetrical APS manifestations and traditional cardiovascular disease (CVD) risk factors [17–20], was obtained at the baseline visit of APS ACTION. The aPL profile was obtained from local labs; high titres of aCL and aβ2GPI were defined as ≥80 units (highest ever), and patients were further classified as single, double or triple aPL-positive according to the number of positive aPL criteria, irrespective of isotype. Corticosteroid use was analysed binarily, as previous use (ever) or not (never). Study data were collected and managed using REDCap electronic capture tools hosted at Weill Cornell Medicine Clinical & Translational Science Center.
DIAPS calculation
All data needed to calculate DIAPS were retrospectively retrieved from the baseline assessment of the APS ACTION Registry. All 22 items derived from the SLICC/ACR-DI were routinely recorded by the APS ACTION registry since its inception. The 15 newly added items were either already collected in a structured fashion as part of the aPL/APS-related history (vascular venous insufficiency, abnormal movements, aPL-associated heart valve disease with or without valve replacement, renal thrombotic microangiopat, chronic cutaneous ulcers), or were collected as part of the general medical history (researchers are formally instructed to fulfil an open ended-form with all relevant medical conditions that developed between the current and the last visit, which occur every 12 ± 3 months). Since all information collected in DIAPS is critical and should be entered in the APS ACTION database, clinical information was considered absent if not properly recorded. Information not readily available, namely optic neuropathy, multi-infarct dementia and chronic thromboembolic pulmonary hypertension, was treated using regression imputation to conservatively predict the actual data, based on the presence, respectively, of multiple sclerosis-like symptoms and blindness; cognitive dysfunction and stroke; and pulmonary hypertension and pulmonary embolism. Calculation of DIAPS was performed as previously published by Amigo et al. [3]. Due to the nature of the registry and since there was no specification whether DIAPS items should be scored only after aPL identification/APS diagnosis in the original paper, we analysed all the damage burden present at the baseline assessment of APS ACTION, as long as it was attributed to aPL/APS by the researcher.
Since DIAPS was initially validated only for thrombotic APS, we divided aPL-positive patients into two groups and performed different analyses to understand the contribution of different clinical and laboratory characteristics in damage burden for each scenario: (i) a thrombotic group, and (ii) a non-thrombotic group (including obstetric APS and aPL-positive patients without criteria manifestations).
Thrombotic group
To be included in the thrombotic group, a patient must have presented with at least one episode of thrombosis documented by imaging or histopathology, irrespective of its site (arterial, venous or microvascular) [1]. We further divided thrombotic PAPS patients into two groups according to high damage (DIAPS ≥3) vs low damage (DIAPS <3). The definition of high damage was based on the median values of DIAPS found in our cohort (high damage DIAPS ≥p50 vs low damage DIAPS <p50); those values were supported by a recent paper published by Medina et al., who also defined DIAPS ≥3 as severe damage in their cohort [6]. Groups were then compared regarding demographics, clinical and laboratory characteristics (including aPL profile) to identify variables associated with the presence of high damage.
Non-thrombotic group
To be included in the non-thrombotic group, a patient must not have presented with any history of documented thrombosis. Since DIAPS was not initially validated for use in non-thrombotic patients, we further classified non-thrombotic patients according to the presence (DIAPS >0) or absence of damage (DIAPS = 0), to understand if DIAPS was able to capture damage in this scenario. Groups were then compared regarding demographics, clinical and laboratory characteristics to identify variables associated with the presence of damage.
Ethical statement
This is a retrospective non-interventional analysis of multicentre APS ACTION registry patients. All patients included in the APS ACTION registry signed a written informed consent form following local ethical approvals at each institution. All procedures followed the principles embodied in the Declaration of Helsinki and were in accordance with local statutory requirements of each centre involved.
Statistical analysis
No sample size was calculated, as it was a convenience sample. We screened all 826 aPL-positive patients included in the APS ACTION Registry when data were locked.
Data are expressed as the mean and standard deviation (SD) or median and interquartile range (IQR), as appropriate. The significance level was defined as 5%. Statistical analysis was performed using the χ2 test and Fisher’s exact test for categorical variables, and the Mann–Whitney U-test and Student’s t-test for continuous variables, as appropriate. Normality was tested using graphical analyses and the Shapiro–Wilk test. Multivariate analyses were performed using variables with P < 0.10 in the univariate analyses. Statistical analyses were performed with SPSS Statistics 22.0 (IBM Corp., Armonk, NY, USA).
Results
Patients’ characteristics
Of the 826 patients screened, 586 aPL-positive patients without other autoimmune rheumatic systemic diseases were included. The flowchart of patient inclusion and exclusion is presented in Fig. 1. The majority of the patients were female (71.0%) and white (66.9%), with a mean age of 51.5 (13.3) years. Out of the 586 included patients, 412 (70.3%) had previous thrombotic events (the thrombotic group), while 174 (29.7%) did not (the non-thrombotic group). Clinical and laboratory characteristics of the included patients are summarized in Table 1.
Figure 1.
Flow diagram of patient selection. DIAPS: Damage Index for Antiphospholipid Syndrome; PAPS: primary APS
Table 1.
Demographic, clinical and laboratory characteristics of aPL-positive patients
| Thrombotic PAPS |
Non-thrombotic patients |
|||||
|---|---|---|---|---|---|---|
| (n = 412) |
(n = 174) |
|||||
| Characteristic | Patients with high damage (DIAPS ≥3) | Patients with low damage (DIAPS <3) | P-value | Patients with damage (DIAPS >0) | Patients without damage (DIAPS = 0) | P-value |
| (n = 36) | (n = 138) | |||||
| (n = 110) | (n = 302) | |||||
| Demographics | ||||||
| Age, mean (s.d.), years | 54.9 (13.2) | 51.4 (13.6) | 0.022 | 52.5 (12.6) | 48.8 (12.7) | 0.260 |
| Female, n (%) | 59 (53.6) | 204 (67.5) | 0.008 | 31 (86.1) | 122 (88.4) | 0.774 |
| White, n (%) | 72 (65.5) | 198 (65.6) | 0.522 | 27 (75.0) | 95 (68.8) | 0.533 |
| Cardiovascular disease risk factors, n (%) | ||||||
| Hypertension | 50 (45.5) | 89 (29.5) | 0.002 | 16 (44.4) | 21 (15.2) | <0.001 |
| Diabetes | 8 (7.3) | 18 (6.0) | 0.628 | 2 (5.6) | 5 (3.6) | 0.635 |
| Hyperlipidaemia | 42 (38.2) | 79 (26.2) | 0.018 | 11 (30.6) | 11 (8.0) | 0.001 |
| Obesity | 40 (36.7) | 66 (21.9) | 0.002 | 8 (22.2) | 27 (19.6) | 0.723 |
| Criteria manifestations, n (%) | ||||||
| Arterial event | 60 (54.5) | 145 (48.0) | 0.266 | NA | NA | NA |
| Venous event | 82 (74.5) | 165 (54.6) | <0.001 | NA | NA | NA |
| Microvascular event or CAPS | 14 (12.7) | 24 (7.9) | 0.138 | NA | NA | NA |
| Obstetric event | 19/59 (32.2) | 55/204 (27) | 0.826 | 8 (22.2) | 51 (37.0) | 0.096 |
| Non-criteria manifestations, n (%) | ||||||
| Livedo | 20 (18.2) | 36 (11.9) | 0.101 | 3 (8.3) | 12 (8.7) | >0.999 |
| Thrombocytopenia | 24 (21.8) | 45 (14.9) | 0.096 | 7 (19.4) | 23 (16.6) | 0.694 |
| Autoimmune haemolytic anaemia | 3 (2.7) | 8 (2.6) | 0.965 | 0 | 4 (2.9) | 0.582 |
| aPL profile, n (%) | ||||||
| LA | 92/104 (88.5) | 261/291 (89.7) | 0.727 | 31/35 (88.6) | 100/136 (73.6) | 0.061 |
| aCL | 76/109 (69.7) | 198/289 (68.5) | 0.816 | 26/35 (74.3) | 90/135 (66.7) | 0.388 |
| High titres (≥80) | 60/109 (55.0) | 147/289 (50.9) | 0.457 | 17/35 (48.6) | 58/135 (43.0) | 0.552 |
| aβ2GPI | 66/101 (65.3) | 147/264 (55.7) | 0.094 | 24/34 (70.6) | 78/129 (60.5) | 0.278 |
| High titres (≥80) | 35/101 (34.7) | 59/264 (22.3) | 0.016 | 15/34 (44.1) | 56/129 (43.4) | 0.941 |
| Single positive | 24/94 (25.5) | 75/248 (30.2) | 0.439 | 5/32 (15.7) | 43/123 (35.0) | 0.042 |
| LA only | 19/94 (20.2) | 64/248 (25.8) | 0.315 | 4/32(12.5) | 26/123 (21.1) | 0.301 |
| Double positive | 23/94 (24.5) | 56/248 (22.6) | 0.658 | 8/32 (25.0) | 31/123 (25.2) | 0.963 |
| Triple positive | 47/94 (50.0) | 117/248 (47.2) | 0.554 | 18/32 (56.3) | 49/123 (39.8) | 0.076 |
| Treatment | ||||||
| Corticosteroid use (ever), n (%) | 24 (21.8) | 24 (8.0) | <0.001 | 5 (13.9) | 11 (8.0) | 0.329 |
Bold text represents statistically significant differences. aβ2GPI: anti-β-2 glycoprotein I; aCL: anticardiolipin; CAPS: catastrophic APS; DIAPS: Damage Index for Antiphospholipid Syndrome; LA: lupus anticoagulant; NA: not applicable; PAPS: primary APS.
DIAPS
The mean DIAPS value of thrombotic PAPS patients was 1.94 (1.46) and the median DIAPS was 2 (IQR 1–3, min 0, max 9). Of the 412 patients in this group, 348 (84.5%) presented with damage (DIAPS >0) and 110 (26.7%) with high damage (DIAPS ≥3) at the baseline evaluation. The peripheral vascular domain was the most commonly affected: 260 (63.1%) patients presented at least one item from this domain. This was followed by the neuropsychiatric (n = 107, 30.0%) and the cardiovascular (n = 57, 13.8%) domains. All domains were significantly more frequent in patients with high damage, except for gastrointestinal and endocrine (Table 2).
Table 2.
Frequency of DIAPS domains affected in thrombotic PAPS and non-thrombotic aPL-positive patients
| Thrombotic PAPS |
Non-thrombotic patients |
|||||
|---|---|---|---|---|---|---|
| (n = 412) |
(n = 174) |
|||||
| Patients with high damage (DIAPS ≥3) | Patients with low damage (DIAPS <3) | P-value | Patients with damage (DIAPS >0) | Patients without damage (DIAPS = 0) | P-value | |
| (n = 110) | (n = 302) | (n = 36) | (n = 138) | |||
| Peripheral vascular, n (%) | 83 (75.5) | 177 (58.6) | 0.002 | 1 (2.8) | 0 (0.0) | 0.207 |
| Pulmonary, n (%) | 19 (17.3) | 4 (1.3) | <0.001 | 0 (0.0) | 0 (0.0) | NA |
| Cardiovascular, n (%) | 36 (32.7) | 21 (7.0) | <0.001 | 13 (36.1) | 0 (0.0) | <0.001 |
| Neuropsychiatric, n (%) | 65 (59.1) | 42 (13.9) | <0.001 | 22 (61.1) | 0 (0.0) | <0.001 |
| Ophthalmologic, n (%) | 4 (3.6) | 0 (0.0) | 0.005 | 0 (0.0) | 0 (0.0) | NA |
| Renal, n (%) | 19 (17.3) | 5 (1.7) | <0.001 | 4 (11.1) | 0 (0.0) | 0.002 |
| Musculoskeletal, n (%) | 2 (1.8) | 0 (0.0) | 0.019 | 1 (2.8) | 0 (0.0) | 0.207 |
| Cutaneous, n (%) | 20 (18.2) | 4 (1.3) | <0.001 | 3 (8.3) | 0 (0.0) | 0.008 |
| Gastrointestinal, n (%) | 3 (2.7) | 2 (0.7) | 0.121 | 0 (0.0) | 0 (0.0) | NA |
| Endocrine, n (%) | 0 (0.0) | 0 (0.0) | NA | 0 (0.0) | 0 (0.0) | NA |
Bold text represents statistically significant differences. DIAPS: Damage Index for Antiphospholipid Syndrome; NA: not available; PAPS: primary antiphospholipid syndrome.
Patients from the non-thrombotic aPL-positive group had a mean DIAPS value of 0.28 (0.61) and median DIAPS value of 0 (IQR 0–0, min 0, max 3). Thirty-six (20.7%) had some type of damage (DIAPS >0) at baseline. The neuropsychiatric (n = 22, 12.6%) and the cardiovascular (n = 13, 7.5%) domains were the most frequently affected in this group. When compared with patients without damage, the cardiovascular, neuropsychiatric, renal and cutaneous domains were significantly associated with the presence of damage (Table 2).
Factors associated with increased damage
In the thrombotic group, patients with high damage were more likely to be older (54.9 [13.2] vs 51.4 [13.6] years, P = 0.022), male (46.4% vs 32.5%, P = 0.008) and to have hypertension (45.5% vs 29.5%, P = 0.002), hyperlipidaemia (38.2% vs 26.2%, P = 0.018) and obesity (36.7% vs 21.9%, P = 0.002) (Table 1). High titres of aβ2GPI correlated with the presence of high damage (34.7% vs 22.3%, P = 0.016). Also, corticosteroid use was associated with high damage (21.8% vs 8.0%, P < 0.001).
In the non-thrombotic group, patients who presented with damage at baseline also presented more frequently with hypertension (44.4% vs 15.2%, P < 0.001) and hyperlipidaemia (30.6% vs 8.0%, P = 0.001). Patients without damage (DIAPS = 0) were more often single aPL positive, when compared with those with damage (DIAPS >0).
Multivariate analyses are presented in Table 3.
Table 3.
Risk factors associated with damage in aPL-positive patients, in the multivariate analysis
| Thrombotic PAPS (n = 412) |
Non-thrombotic patients (n = 174) |
|||
|---|---|---|---|---|
| High damage (DIAPS ≥3) |
Presence of damage (DIAPS >0)
|
|||
| Variable | OR (95% CI) | Adjusted P-value | OR (95% CI) | Adjusted P-value |
| Hyperlipidaemia | 1.82 (1.05, 3.15) | 0.032 | 4.32 (1.37, 13.65) | 0.001 |
| Obesity | 2.14 (1.23, 3.71) | 0.007 | — | — |
| aβ2GPI high titres (≥80) | 2.33 (1.36, 4.02) | 0.002 | — | — |
| Corticosteroids use | 3.73 (1.80, 7.75) | <0.001 | — | — |
| Hypertension | 2.75 (0.92, 2.69) | 0.097 | 4.55 (1.82, 11.35) | 0.001 |
| Single positivity | — | — | 0.24 (0.08, 0.77) | 0.016 |
Bold text represents statistically significant differences. aβ2GPI: anti-β-2 glycoprotein I; DIAPS: Damage Index for Antiphospholipid Syndrome; OR: odds ratio; PAPS: primary antiphospholipid syndrome.
Discussion
This is the first study to evaluate damage measured by DIAPS in a multiethnic international cohort of primary aPL-positive patients. We independently assessed the use of DIAPS in a cohort including patients from 27 centres located in 14 different countries (USA, Brazil, Canada, Italy, Spain, UK, France, Greece, Japan, China, and others) and we found that this score was able to capture damage in aPL-positive patients both with and without a history of thrombosis [7–9, 21].
The majority (85%) of our thrombotic PAPS patients presented with some type of damage, and approximately one-fourth presented with high damage. In a recently published study, Medina et al. found rates of severe organ damage higher than ours, affecting 59.7% of thrombotic PAPS patients, with a median DIAPS value of 3 (IQR 2–5) [6]. However, these high rates of organ damage measured by DIAPS contrast with previous studies assessing irreversible damage in APS patients using different definitions. Erkan et al. identified organ damage in 38% of patients after 10 years of follow-up [21]. Grika et al. reported that 29% of 135 patients experienced damage assessed by SDI, after 7.5 year of follow-up [22]. Finally, Dall’Ara et al. described damage in 20% of 35 PAPS patients [23]. Therefore, our findings reinforce that DIAPS may be a more sensitive tool, capturing a broad spectrum of damage-related clinical complications in APS patients.
In thrombotic PAPS patients, the most affected domains of DIAPS varied widely across different studies. Data from the other four studies that provided information on this matter are compared with our data in Fig. 2 [6–9]. Even though this heterogeneity may arise from differences between populations, it may also reflect the consequence of different screening strategies adopted in different clinical facilities.
Figure 2.
Comparative analysis of the most affected domains of DIAPS in PAPS patients according to different published studies. DIAPS: Damage Index for Antiphospholipid Syndrome; PAPS: primary APS
Another notable finding of our study is that the presence of traditional CVD risk factors was associated with higher damage in both thrombotic and non-thrombotic aPL-positive patients. In the pathogenesis of APS, the ‘two hit hypothesis’ is used to explain the clinical observation that the sole presence of aPL ('first hit'), even if persistent, is not sufficient for inducing thrombotic events. A ‘second hit’ capable of triggering damage to the vessel wall and activation of the endothelial cells and the coagulation cascade is, therefore, needed to create a prothrombotic environment that leads to clot formation [24–28]. In our patients with higher damage, the presence of CVD risk factors, namely male gender, older age, hypertension, hyperlipidaemia and obesity, may have acted as the ‘second hit’ and facilitated thrombotic recurrence, which results in increased damage accrual over time and may explain the higher DIAPS values in this group, when compared with patients without those risk factors. In their cluster analysis study, Uludağ et al. identified a cluster (n = 74) that consisted of older patients with CVD risk factors and predominance of arterial events; this cluster showed a mean DIAPS of 2.24 (1.44), which ranked second among the four identified clusters in terms of damage [9]. This may provide further evidence that CVD risk factors could play an important role in damage accrual. However, in contrast to our study, this paper included both PAPS and SLE-associated APS patients, which may introduce confounding factors. Renal manifestations are more frequent in SLE patients and treatment with either corticosteroids or cyclophosphamide may itself lead to irreversible damage, namely avascular necrosis or infertility, respectively [12–15]. Thus, the inclusion of SLE patients negatively impacts interpretation and precludes us from drawing definite conclusions about the importance of CVD risk factors in damage progression in their cohort. A recent study published by Torricelli et al. showed that high risk PAPS and APS with lupus show differences in damage kinetics during disease evolution [7]. Thus, prospective studies analysing the kinetics of damage accrual in PAPS patients with CVD risk factors are required.
A further finding was that high titres of aβ2GPI correlated with high damage in thrombotic PAPS patients and that single aPL positivity negatively correlated with damage in the non-thrombotic group. This reinforces the importance of aβ2GPI and high-risk profiles in APS pathogenesis [29]. Curiously, lupus anticoagulant and triple positivity, important risk factors for thrombotic recurrence in patients with APS, were not associated with increased damage in our cohort, which raises concern about DIAPS content validity. An updated version of the damage index for APS may be needed to address this issue. Also, previous corticosteroid use was an independent risk factor for high damage in patients with PAPS, similar to what was previously demonstrated for SLE patients [13, 30, 31].
Our study has limitations. First, this is a cross-sectional study with retrospective analysis of records from a database; future studies using prospective data from APS ACTION may provide more conclusive data on the impact of CVD risk factors on damage accrual in PAPS patients. Second, referral bias should be considered, since APS ACTION centres are mostly tertiary referral academic centres, which may have led to selection bias and reduced external validity. Also, the exclusion of SLE and other autoimmune diseases associated with APS may limit its external validity. However, our study also has strengths. APS ACTION has the largest active APS cohort in the world. Among the studies that analysed damage in aPL-positive patients, this is the largest one to date, with almost 600 participants. Furthermore, we are able to include patients from all continents, except Africa.
In conclusion, DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. A significant proportion of patients with thrombotic PAPS presented with severe organ damage, and the most frequently affected domains were peripheral vascular, neuropsychiatric and cardiovascular. Neuropsychiatric and cardiovascular domains were also relevant to non-thrombotic patients. Selected traditional CVD risk factors, corticosteroid use, and the presence of high titres of aβ2GPI correlated with higher damage in thrombotic primary APS patients. Also, hypertension and obesity positively correlated and single positivity negatively correlated with damage in the non-thrombotic group. Prospective studies are needed to understand the kinetics of damage accrual in PAPS patients with CVD risk factors.
Supplementary Material
Acknowledgements
The APS ACTION registry was created using REDCAP provided by the Clinical and Translational Science Center at Weill Cornell Medical College (CTSC grant UL1 TR000457). We want to thank JoAnn Vega, CCRC, for her administrative support as the APS ACTION Global Lead Coordinator. Please see Supplementary Data S1 (available at Rheumatology online) for the full list of APS ACTION Members in this study.
Contributor Information
Gustavo G M Balbi, Universidade de São Paulo, São Paulo, São Paulo, Brazil; Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.
Yasaman Ahmadzadeh, Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY, USA.
Maria G Tektonidou, National and Kapodistrian University of Athens, Athens, Greece.
Vittorio Pengo, University Hospital Padova, Padova, Italy.
Savino Sciascia, Center of Research of Immunopathology and Rare Diseases, University of Turin, Turin, Italy.
Amaia Ugarte, Hospital Universitario Cruces, País Vasco, Barakaldo, Spain.
H Michael Belmont, Hospital for Joint Diseases, New York University, New York, NY, USA.
Chary Lopez-Pedrera, Rheumatology Service, IMIBIC/Reina Sofia Hospital, University of Cordoba, Cordoba, Spain.
Paul R Fortin, CHU de Québec-Université Laval, Québec, Québec, Canada.
Denis Wahl, Université de Lorraine, INSERM, DCAC, Nancy, France; Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, CHRU-Nancy, Nancy, France.
Maria Gerosa, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Guilherme R de Jesús, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
Lanlan Ji, Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China.
Tatsuya Atsumi, Hokkaido University Hospital, Sapporo, Japan.
Maria Efthymiou, Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
D Ware Branch, University of Utah and Intermountain Healthcare, Salt Lake City, UT, USA.
Cecilia Nalli, Rheumatology and Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.
Esther Rodriguez Almaraz, Hospital Universitario, 12 de Octubre, Madrid, Spain.
Michelle Petri, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ricard Cervera, Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain.
Jason S Knight, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Bahar Artim-Esen, Istanbul University School of Medicine, İstanbul, Turkey.
Rohan Willis, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, TX, USA.
Maria Laura Bertolaccini, Academic Department of Vascular Surgery, King’s College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK.
Hannah Cohen, Haemostasis Research Unit, Department of Haematology, University College London, London, UK.
Robert Roubey, University of North Carolina, Chapel Hill, NC, USA.
Doruk Erkan, Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY, USA.
Danieli Castro Oliveira de Andrade, Universidade de São Paulo, São Paulo, São Paulo, Brazil.
for AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (APS ACTION):
JoAnn Vega, Guillermo Pons-Estel, Bill Giannakopoulos, Steve Krilis, Guilherme de Jesus, Roger Levy, Flavio Signorelli, Danieli Andrade, Gustavo Balbi, Ann E Clarke, Leslie Skeith, Paul R Fortin, Lanlan Ji, Zhouli Zhang, Chengde Yang, Hui Shi, Stephane Zuily, Denis Wahl, Maria G Tektonidou, Cecilia Nalli, Laura Andreoli, Angela Tincani, Cecilia B Chighizola, Maria Gerosa, Pierluigi Meroni, Vittorio Pengo, Chunyan Cheng, Giulia Pazzola, Savino Sciascia, Silvia Foddai, Massimo Radin, Stacy Davis, Olga Amengual, Tatsuya Atsumi, Imad Uthman, Maarten Limper, Philip de Groot, Guillermo Ruiz - Irastorza, Amaia Ugarte, Ignasi Rodriguez-Pinto, Ricard Cervera, Jose Pardos-Gea, Esther Rodriguez Almaraz, Maria Angeles Aguirre Zamorano, Chary Lopez-Pedrera, Bahar Artim-Esen, Maria Laura Bertolaccini, Hannah Cohen, Maria Efthymiou, Ian Mackie, Giovanni Sanna, Jason Knight, Yu Zuo, Michelle Petri, Rebecca K Leaf, Robert Roubey, Thomas Ortel, Rohan Willis, Nina Kello, Michael Belmont, Steven Levine, Jacob Rand, Medha Barbhaiya, Doruk Erkan, Jane Salmon, Michael Lockshin, Ali A Duarte Garcia, and D Ware Branch
Supplementary material
Supplementary material is available at Rheumatology online.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Contribution statement
All authors provided critical review, relevant edits and feedback to direct content during multiple rounds of review. In addition, all authors have read and approved the final version of this manuscript.
Funding
No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: The authors declare that they have no competing interests regarding this paper.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.