Content uploaded by Pedro Gaspar
Author content
All content in this area was uploaded by Pedro Gaspar on Apr 15, 2024
Content may be subject to copyright.
Paper
Lupus
2024, Vol. 0(0) 1–12
© The Author(s) 2024
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/09612033241246360
journals.sagepub.com/home/lup
Predictors of damage accrual and its impact
on health-related quality of life of
thrombotic antiphospholipid syndrome:
Independent validation of the damage index
for antiphospholipid syndrome (DIAPS)
Pedro Gaspar
1,2,
*, Ana Sofia M Fernandes
3,
*, Ana Mafalda Abrantes
1,4
,In
ˆ
es Parreira
1
,
Inˆ
es Silva
1
, Ryan C Silva
1,5
, Mariana B Nobre
1
, Joana R Martins
1,5
and Catarina Mota
2,6
Abstract
Objectives: 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).
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords
Antiphospholipid syndrome, damage index, damage index for antiphospholipid syndrome, organ damage, quality of life
Date received: 21 March 2024; accepted: 25 March 2024
1
Internal Medicine Department, Hospital Santa Maria, Unidade Local de Sa´
ude Santa Maria, Lisbon, Portugal
2
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Centro Acad´
emico de Medicina de Lisboa, Universidade de Lisboa, Lisbon,
Portugal
3
Hospital Geral de Santo António, Unidade Local de Sa´
ude Porto, Oporto, Portugal
4
Instituto de Semiótica Cl´
ınica, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
5
Cl´
ınica Universit´
aria de Medicina 1, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
6
Cl´
ınica Universit´
aria de Medicina 2, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
*These authors contributed equally to this paper.
Corresponding author:
Pedro Gaspar, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Edif´
ıcio Egas Moniz, Av. Professor Egas
Moniz, Lisboa 1649-028, Portugal.
Email: pedrogaspar@edu.ulisboa.pt
Introduction
Thrombotic antiphospholipid antibody syndrome (APS)
cardinal features include arterial, venous and microvascular
thrombosis in the presence of persistently positive anti-
phospholipid antibodies (aPL).
1
Despite the current stan-
dard of care with vitamin K antagonists (VKA),
2
patients
experience recurrent thrombosis that leads to increased
morbidity and mortality.
3,4
The Damage Index for APS (DIAPS) was developed for
assessing damage accrual in thrombotic APS. It includes
37 items organized in 10 organ domains, 22 of which were
derived from the Systemic Lupus Erythematosus Interna-
tional Collaboration Clinics/American College of Rheu-
matology Damage Index (SDI). In their original study, the
authors applied the DIAPS to 156 patients with thrombotic
APS from several Latin American countries (Mexico,
Venezuela, El Salvador and Dominican Republic).
5
The
DIAPS demonstrated content, criterion and construct val-
idity as well as a significant correlation with health-related
quality of life (HR-QoL) as measured by 3-level 5-domain
EuroQol HR-QoL scale (EQ-5D-3L).
5
The clear association between APS evolving mani-
festations, damage acquisition and HR-QoL impairment
has been a matter of increasing interest.
6,7
Despite this,
both the risk factors for damage accrual and HR-QoL
impairment in APS have not been thoroughly explored,
and studies reporting a correlation between damage ac-
quisition, especially as measured by the DIAPS, and HR-
QoL are lacking.
5,8,9
On the one hand, HR-QoL has been
assessed unevenly throughout the studies and none of
them used the EQ-5D-3L as the original study.
8,10
On the
other hand, the majority of DIAPS studies were done in
Latin Americans,
9,10
which can hamper the generaliza-
tion of results as ethnicity influences patients’HR-QoL
perception.
11,12
In this study, we aim to explore the correlation between
the DIAPS and HR-QoL, using the EQ-5D-3L and 5L
scales, in a well-defined Portuguese APS cohort, hence
contributing with an independent validation of DIAPS in a
population with a distinct genetic background.
Methods
Patients
This study was conducted in two phases and included all
consecutive patients with thrombotic APS attending the
Immune-mediated Disease Clinic of Hospital Santa Maria,
Lisbon, Portugal, until April 2022. Only patients with
current follow-up were included. Both primary APS (pAPS)
and APS secondary to other autoimmune condition (sAPS)
were included, and all patients fulfilled the 2006 Sydney
classification criteria.
1
Patients with purely obstetric APS,
those under 18 years old and aPL carriers were not included
in the analysis. As we aimed to explore HR-QoL through a
questionnaire, we excluded mentally impaired patients,
those unable to answer independently, as well as non-
Portuguese speaking patients.
The study was approved by the Hospital Santa Maria’s
ethics committee (N°117/22) in accordance with the Hel-
sinki Declaration statements. Only data obtained as part of
routine clinical management were included. No patient
identifiable information is reported in this study. All patients
were given a verbal and explicit informed consent and only
patients who agreed to participate were included in this
study.
Phase 1 –Data collection and DIAPS assessment
Patients’demographics, medical disorders, clinical and
laboratory data were collected retrospectively from all
available medical records. All authors are actively involved
in the clinical follow-up of patients with APS. All infor-
mation is reported whenever available.
A protocol form was used to record the clinical and
laboratorial characteristics of the patients. Namely, it in-
cluded the following: (1) sex; (2) ethnicity; (3) age at
disease onset; (4) current age (defined as age at study entry);
(5) type of APS and associated underlying autoimmune
disease; (6) medical disorders; (7) cumulative clinical
manifestations (until entry the study); (8) treatment (taken
as ever-present); (9) accrual damage (accessed using the
DIAPS
5
); and (10) laboratory features.
Clinical manifestations were taken as recorded in
medical notes and confirmed according to established cri-
teria for each manifestation, using all available laboratory,
imaging and/or histopathological studies. As we aimed to
assess the impact of organ damage on HR-QoL, we grouped
both APS-related and non-related manifestations as medical
disorders to accurately represent the overall impact on the
specific organ. This approach included cerebrovascular
disease, cardiovascular disease and chronic kidney disease,
encompassing both acute and chronic events regardless of
their association with APS. See Supplemental Data 1 for a
detailed description of medical disorders and other defini-
tions. In our institution patients are requested to self-
nominate the race/ethnic group they belong to. We have
thus used the categories recorded in the hospital notes.
Accrued damage was assessed using DIAPS, beginning at
disease onset. We used DIAPS as described elsewhere.
5
Phase 2 –Quality of life assessment
We created a telephone questionnaire to assess the HR-QoL
using the Portuguese version of the EQ-D5-3L and
EuroQoL-Visual Analogue Scale (EQ-VAS), in accordance
with the original study.
5
We also applied the 5-level scale
2Lupus 0(0)
(EQ-D5-5L) as it is a more sensitive and recently validated
instrument.
13–15
Patients were contacted at least five times before being
excluded. This phase of the study was performed by PG,
ASMF, AMA, IP, IS, MBN, RCS and JRM. All members
were specifically trained for this task and attended joint
meetings led by the main researchers (PG and ASMF).
The full details of the questionnaire can be found in
Supplemental Data 2.Briefly, patients were first asked to rate
their health state from 1 (no problem) to 3 (severe impairment/
unable) in five dimensions: mobility, self-care, usual activities,
pain/discomfort and anxiety/depression. Then, we asked them
to re-rate each domain in a more sensitive way using the 5-
level scale: 1, no impairment; 2, mild; 3, moderate; 4, severe
impairment; and 5, unable. Lastly, we asked patients to classify
their current general health from 0 (‘worst possible health’)to
100 (‘best possible health’). The EQ-5D-index was calculated
for each patient using the Portuguese EQ-5D-3L
16
and EQ-
5D-5L value set.
17
Statistical analysis
We used STATA® version 16 for statistical analysis.
Continuous and categorical variables are presented as
median (interquartile range [IQR]) and number (%), re-
spectively. DIAPS, EQ-5D-3L and 5L indexes, and VAS
will also be presented as mean ± standard deviation (SD) for
comparison purposes with similar studies. Continuous
variables were compared using the Student’sttest or Mann-
Whitney U test after checking for normality, and categorical
variables using the Chi-square test or the Fisher’s exact test
when appropriate. We used univariable logistic regression
models to explore risk factors associated with the presence
of damage (DIAPS≥1) and with HR-QoL impairment. The
relationship between the DIAPS and QoL scales was per-
formed using a Spearman’s correlation test. To further in-
vestigate the association between DIAPS and HR-QoL, we
performed multivariable logistic regression adjusting for
demographics, medical disorders and clinical characteris-
tics. Variables were eligible for multivariable analysis
considering their clinical/biologic significance and/or their
statistically significant between-group differences and were
selected using a stepwise method. Only medical disorders
that were present in at least 10% of the cohort were included
in the model, hence enhancing the robustness of the effect
estimates. Significance was set as a two-sided αof less
than 0.05.
Results
Demographic and disease characteristics
From a total of 172 APS patients, 108 were included in this
study. The patient selection process is schematized in
Supplemental Figure 1. Patients’demographic, clinical and
laboratory characteristics are shown in Supplemental
Table 1. Most patients were female (65.7%) with pAPS
(75.9%), and 90.7% were white. sAPS (24.1%) was more
frequently associated with systemic lupus erythematosus
(SLE) (69.2%). The median age at disease onset was 42
(IQR 30–51) years, and patients were followed for a median
of 4 (IQR 2–11) years, ranging from one to 30 years. The
most common medical disorders were cerebrovascular
disease (n= 41, 38.0%), hypertension (n= 39, 36.1%) and
obesity (n= 35, 32.4%).
Most patients were lupus anticoagulant (LA) positive
(73.2%). IgM/IgG anticardiolipin antibodies, IgM/IgG anti-
ß2-glycoprotein I antibodies and triple positivity were found
in 50.0%, 32.4% and 15.7% of patients, respectively. By the
time of data collection, all patients were treated with an-
tithrombotic drugs (anticoagulation and/or antiplatelet
therapy). Most patients (88.9%) were on anticoagulation
therapy, mainly under VKA (79.6%). We recorded all
thrombotic and non-thrombotic cumulative manifestations
beginning with the disease onset (Supplemental Table 2).
According to the type of presenting event, most patients
(62.0%) were classified as having venous thrombotic APS,
whereas only five patients (4.6%) had a concomitant first
venous and arterial thrombosis. The most common
thrombotic manifestations were thromboembolic venous
disease (48.1%: lower limb deep vein thrombosis, 25.9%;
pulmonary embolism, 22.2%) and acute cerebral ischaemic
events (42.6%: stroke, 32.4%; transient ischaemic attack,
10.2%).
Damage assessment
Table 1 shows the prevalence of damage, its classification
and distribution of affectation of each DIAPS domain for all
patients. Damage (DIAPS≥1) was present in 48.2% of
patients. In the total sample, the mean DIAPS was 1.48 ±
1.99, and absolute values ranged from 0 (n= 56) to 8 (n= 4).
Among patients with damage, the mean DIAPS was 3.08 ±
1.83. The neuropsychiatric domain was the most affected
(24.2%), followed by the peripheral vascular (20.3%).
Overall, vascular venous insufficiency (12.0%) and is-
chaemic stroke with hemiparesis (9.3%) were the most
affected items.
Patients were categorized into two groups according to
whether they had damage or not. Risk factors for damage
(DIAPS≥1) were assessed (Table 2). Neither sex, age
(current and at disease onset), medical disorders, type of
APS, type of first thrombotic event and aPL profile were
associated with damage. Treatment with DOAC, but not
VKA nor antiplatelet therapy, was associated with increase
odds for damage. See Supplemental Table 3 for a detailed
comparison between the designated groups.
Gaspar et al. 3
Table 1. Distribution of damage by each DIAPS domain.
N= 108
Damage assessment DIAPS ≥1, n(%) 52 (48.2) | 52 (100.0)
DIAPS all patients | patients with damage
Median (IQR) 0 (0; 2) | 2 (2;4)
Mean±SD 1.48±1.99 | 3.08±1.83
Minimum; maximum 0; 8 | 2; 8
0 56 (51.6) | 0 (0.0)
2 35 (32.4) | 35 (67.3)
4 10 (9.3) | 10 (19.2)
6 3 (2.8) | 3 (5.8)
8 4 (3.7) | 4 (7.7)
DIAPS domains and items Peripheral vascular, n(%) 22 (20.3)
Deep vein thrombosis 8 (7.4)
Intermittent claudication 1 (0.9)
Tissue loss (minor) 0
Tissue loss (major) 0
Vascular venous insufficiency 13 (12.0)
Pulmonary, n(%) 9 (8.3)
Pulmonary infarction 8 (7.4)
Pulmonary arterial hypertension 1 (0.9)
Chronic thromboembolic pulmonary hypertension 0
Respiratory insufficiency 0
Cardiovascular, n(%) 6 (5.6)
Coronary artery bypass 0
Myocardial infarction 3 (2.8)
Cardiomyopathy 0
aPL associated heart disease (asymptomatic; symptomatic) 2 (1.9)
aPL associated heart disease requiring valve replacement 1 (0.9)
Neuropsychiatric, n(%) 26 (24.2)
Cognitive impairment 3 (2.8)
Seizures 6 (5.6)
Ischaemic stroke with hemiparesis 10 (9.3)
Ischaemic stroke with hemiplegia 0
Multi-infarct dementia 1 (0.9)
Cranial neuropathy 2 (1.9)
Sudden neurosensorial hearing loss 0
Transverse myelitis 0
Optic neuropathy 4 (3.7)
Peripheral neuropathy 0
Abnormal movements 0
Dystonia -
Chorea -
Parkinsonism -
Ophthalmologic, n(%) 1 (0.9)
Retinal vaso-occlusive disease 1 (0.9)
Blindness 0
Renal, n(%) 10 (9.2)
Chronic renal failure 5 (4.6)
Proteinuria 4 (3.7)
Renal thrombotic microangiopathy 1 (0.9)
Musculoskeletal, n(%) 1 (0.9)
Avascular necrosis 1 (0.9)
Cutaneous, n(%) -
Chronic cutaneous ulcers 0
Gastrointestinal, n(%) 3 (2.8)
Mesenteric thrombosis 2 (1.9)
Budd Chiari syndrome 0
Cirrhosis of the liver 1 (0.9)
Endocrine, n(%) -
Adrenal insufficiency 0
Hypopituitarism 0
Infertility, n(%) 2 (1.9)
There are no missing data. aPL, antiphospholipid antibodies, IQR, interquartile range; DIAPS, damage index for antiphospholipid syndrome; SD, standard
deviation.
4Lupus 0(0)
Table 2. Univariate logistic regression for damage (DIAPS≥1) and impairment of at least one EQ-5D-3L and -5L domain.
DIAPS ≥1 EQ-5D impairment
3L 5L
OR (95%CI) p-value OR (95%CI) p-value OR (95%CI) p-value
Demographics
Male sex 1.43 (0.64–3.18) 0.376 0.30 (0.12–0.74) 0.009 0.43 (0.17–1.13) 0.086
Current age (y)
a
1.02 (0.99–1.05) 0.211 0.99 (0.96–1.03) 0.746 1.00 (0.86–1.04) 0.872
Age at APS onset (y)
a
0.99 (0.97–1.02) 0.547 0.98 (0.95–1.01) 0.166 0.99 (0.96–1.02) 0.479
Age at APS diagnosis (y)
a
1.01 (0.98–1.04) 0.595 0.99 (0.96–1.02) 0.430 1.00 (0.96–1.03) 0.868
Time of follow-up (y)
a
1.08 (1.01–1.15) 0.019 1.07 (0.99–1.67) 0.092 1.06 (0.97–1.16) 0.166
Ethnicity
White 4.27 (0.84–20.62) 0.080 0.31 (0.04–2.55) 0.275 0.41 (0.05–2.40) 0.407
Non-white
b
0.24 (0.05–1.19) 3.25 (0.39–26.92) 2.45 (0.29–20
Medical disorders
Hypertension 1.98 (0.89–4.40) 0.092 1.87 (0.71–4.92) 0.207 1.27 (0.47–3.44) 0.639
Cerebrovascular disease 1.22 (0.56–2.66) 0.617 1.05 (0.43–2.59) 0.909 1.09 (0.41–2.88) 0.862
Obesity 1.21 (0.54–2.72) 0.637 1.51 (0.57–4.00) 0.408 1.36 (0.48–3.84) 0.565
Depression
c
2.13 (0.67–6.85) 0.202 - - - -
Diabetes mellitus 0.85 (0.22–3.35) 0.816 1.18 (0.23–6.07) 0.841 0.89 (0.17–4.60) 0.886
Hypothyroidism
c
3.52 (0.68–18.30) 0.134 - - - -
Cardiovascular disease 4.58 (0.50–42.42) 0.180 1.35 (0.14–12.64) 0.792 1.02 (0.11–9.65) 0.983
Chronic kidney disease
d
- - 1.00 (0.10–10.04) 1.000 0.76 (0.08–7.67) 0.815
Clinical characteristics
Type of APS
Primary 0.60 (0.25–1.47) 0.266 0.19 (0.04–0.87) 0.032 0.26 (0.06–1.19) 0.083
Secondary 1.66 (0.68–4.04) 5.26 (1.15–23.99) 3.97 (0.84–17.84)
First thrombotic event
Arterial 1.14 (0.53–2.44) 0.740 0.90 (0.38–2.16) 0.822 0.86 (0.34–2.22) 0.761
Venous 0.82 (0.38–1.79) 0.617 1.43 (0.59–3.47) 0.424 1.48 (0.57–3.81) 0.419
aPL profile (ever-present)
LA 1.20 (0.51–2.82) 0.676 0.72 (0.26–2.01) 0.532 1.03 (0.36–2.94) 0.960
AC (IgG/IgM) 1.34 (0.63–2.87) 0.442 1.65 (0.68–3.98) 0.269 1.59 (0.61–4.10) 0.341
aß2GPI (IgG/IgM) 0.87 (0.39–1.94) 0.726 1.95 (0.71–5.38) 0.196 1.36 (0.48–3.84) 0.565
Triple positive 2.24 (0.76–6.56) 0.143 2.84 (0.61–13.32) 0.185 2.11 (0.45–10.02) 0.346
Current treatment
Anticoagulation 2.00 (0.56–7.09) 0.283 0.57 (0.12–2.77) 0.484 0.76 (0.15–3.75) 0.736
VKA 0.72 (0.28–1.85) 0.502 0.41 (0.11–1.51) 0.178 0.56 (0.15–2.08) 0.385
DOAC 8.56 (1.01–72.14) 0.048 2.46 (0.29–20.95) 0.410 1.86 (0.22–15.97) 0.571
Antiplatelet therapy 0.87 (0.34–2.23) 0.777 1.64 (0.50–5.37) 0.411 1.19 (0.36–3.96) 0.775
Hydroxychloroquine 1.47 (0.62–3.46) 0.377 13.74 (1.77–106.6) 0.012 10.14 (1.30–79.24) 0.027
Steroids 1.55 (0.63–3.81) 0.342 5.04 (1.1–23.05) 0.037 3.71 (0.80–17.14) 0.093
Immunossupressants
e
2.24 (0.76–6.56) 0.143 6.40 (0.81–50.76) 0.079 4.80 (0.60–38.36) 0.139
DIAPS≥1 - - 1.22 (0.51–2.93) 0.657 1.15 (0.45–2.93) 0.777
DIAPS
a
- - 1.43 (0.84–2.42) 0.188 1.34 (0.77–2.33) 0.308
Data are shown as odds ratio (OR) and 95% confidence interval (CI). aß2GPI, anti-ß2 glycoprotein I; ACL, anticardiolipin; aPL, antiphospholipid antibodies;
APS, antiphospholipid syndrome; CNS, central nervous system; DIAPS, damage index for antiphospholipid syndrome; DOAC, direct oral anticoagulant;
LA, lupus anticoagulant; VKA, vitamin K antagonist. See Supplemental Data 1 for further detail on medical disorders definitions.
a
Per one-unit increase OR.
b
Patients were consulted and asked to self-denominate themselves appropriately. These included African Portuguese (n= 4, 3.7%), Latino (n= 4, 3.7%), and
East Asians (n= 2, 1.9%).
c
All patients with depression and hypothyroidism had at least one EQ-5D-3 L and 5L domain impaired, hence excluded from this analysis.
d
All patients with chronic kidney disease had damage (DIAPS≥1), hence excluded from the analysis.
e
Included azathioprine (n= 11), methotrexate (n= 5), mycophenolate mofetil (n= 4), rituximab (n= 3), cyclophosphamide (n= 3), adalimumab (n= 1),
belimumab (n= 1) and sulfasalazine (n= 3).
Gaspar et al. 5
Quality of life assessment
HR-QoL as measured by the EQ-5D-3L showed at least
some impairment (level >1) in mobility in 30.6% of pa-
tients, self-care in 17.6%, usual activities in 36.1%, paint/
discomfort in 57.4% and anxiety/depression in 52.8% of
patients (Table 3). The mean EQ-5D-3L index was 0.659 ±
0.261. The prevalence of impairment (level >1) in the EQ-
5D-5L was higher in all five domains but the EQ-5D-5L
index (0.826 ± 0.204) increased. Compared to patients with
no damage, the proportion of patients reporting mobility
and usual activities impairment was significantly higher
among patients with damage using the EQ-5D-3L scale
(Figure 1(a)). The overall pattern of affectation remained
approximately unchanged when we use the EQ-5D-5L
scale, but the difference in the proportion of patients re-
porting usual activities impairment was lost (Figure 1(b)).
DIAPS and its items correlated with the 3- and 5-level
EQ-5D scales and indexes in a similar fashion (Table 4). The
DIAPS neuropsychiatric domain showed a positive corre-
lation with mobility, self-care and usual activities impair-
ment assessed with both scales, as well as a negative
correlation with the EQ-5D-3L and -5L indexes. The pe-
ripheral vascular domain was positively correlated with the
EQ-5D-5L mobility and pain/discomfort domains, but only,
and weakly, with the mobility domain of the EQ-5D-3L
scale. Total DIAPS showed a significant positive correlation
Table 3. Health-related quality of life assessment.
N= 108
EQ-5D-3L
Mobility impairment 33 (30.6)
Self-care impairment 19 (17.6)
Usual activities impairment 39 (36.1)
Pain/Discomfort impairment 62 (57.4)
Anxiety/Depression impairment 57 (52.8)
EQ-5D-3L Index 0.657 (0.884; 0.482)
Mean±SD 0.659±0.261
Minimum; maximum 0.344; 1.000
EQ-5D-5L
Mobility impairment 39 (36.1)
Self-care impairment 21 (19.4)
Usual activities impairment 46 (42.6)
Pain/Discomfort impairment 68 (63.0)
Anxiety/Depression impairment 63 (58.3)
EQ-5D-5L Index 0.873 (0.964; 0.770)
Mean±SD 0.826±0.204
Minimum; maximum 0.050; 1.000
Visual analogic Scale 72.5 (87.5; 50)
Mean±SD 69.23±21.91
Minimum; maximum 0; 100
Data shows the impairment of the 3- and 5-level EQ-5D scales domains
regardless of their severity (level ≥1). See the Methods section for addi-
tional details.
Figure 1. Distribution and comparison of the proportion of patients reporting A) EQ-5D-3L and B) EQ-5D-5L domains impairment
between patients with (DIAPS≥1) and without damage. A/D, anxiety/depression; MO, mobility; P/D, pain/discomfort; SC, self-care;
UA, usual activities. *p< .050.
6Lupus 0(0)
with mobility, usual activities and pain/discomfort domains
of the 3- and 5-level EQ-5D scales, and a negative corre-
lation with both indexes. This echoes what we found in the
univariable logistic regression analysis (Table 5). Regarding
patients’health-related QoL perception, only the peripheral
vascular domain showed a significant negative correlation
with the VAS (r = 0.212, p= .028). Total DIAPS did not
significantly correlate with the VAS (r = 0.172, p= .075).
In a univariable analysis (Table 5), the presence of
damage was significantly associated with impairment of
mobility, usual activities and pain/discomfort. Being male
reduced the odds of impairment of all EQ-5D domains but
did not reach statistical significance in the self-care and
anxiety/depression domains. Increasing age was associated
with compromised mobility and self-care, while being white
did not affected the risk of impairment of all five quality of
life domains. Regarding medical disorders, hypertension
and cerebrovascular disease were the ones that most fre-
quently showed a significant difference in between-groups
differences in all EQ-5D domains (Supplemental Tables 4 to 8).
Table 4. DIAPS items and EQ-5D-3L and -5L health status domains correlation.
Mobility Self-care
Usual
activities
Pain/
Discomfort
Anxiety/
Depression VAS EQ-5d index
Peripheral vascular 0.196/
0.043
0.249/
0.009
0.045/
0.641
0.046/
0.637
0.090/0.355
0.111/0.253
0.179/0.064
0.225/0.019
0.172/0.076
0.147/0.129
0.212/
0.028
0.212/
0.028
0.170/
0.079
0.227/
0.018
3L
5L
Pulmonary 0.016/0.868
0.018/
0.856
0.035/0.719
0.024/0.804
0.019/
0.843
0.076/
0.432
0.083/0.393
0.092/0.342
0.121/0.211
0.128/0.188
0.054/0.578
0.054/0.578
0.072/0.461
0.133/0.171
3L
5L
Cardiovascular 0.052/
0.592
0.047/
0.626
0.102/
0.295
0.108/
0.268
0.019/0.848
0.001/
0.992
0.094/0.335
0.083/0.395
0.058/0.551
0.076/0.438
0.096/0.323
0.096/0.323
0.006/0.950
0.006/
0.951
3L
5L
Neuropsychiatric 0.322/
0.001
0.289/
0.003
0.293/
0.002
0.331/
0.001
0.266/0.006
0.263/0.006
0.144/0.138
0.137/0.159
0.053/0.584
0.031/0.753
0.086/
0.378
0.086/
0.378
0.280/
0.003
0.235/
0.015
3L
5L
Ophthalmologic 0.064/
0.511
0.071/
0.466
0.207/
0.032
0.178/0.066
0.126/0.192
0.130/0.180
0.079/0.418
0.007/0.947
0.101/0.299
0.104/0.286
0.139/
0.152
0.139/
0.152
0.116/
0.232
0.020/
0.835
3L
5L
Renal 0.038/
0.694
0.066/
0.495
0.131/
0.178
0.138/
0.154
0.073/0.450
0.049/0.613
0.021/0.830
0.001/0.999
0.095/0.329
0.134/0.168
0.041/
0.674
0.041/
0.674
0.033/0.732
0.043/0.658
3L
5L
Musculoskeletal 0.064/
0.511
0.071/
0.466
0.045/
0.647
0.047/
0.627
0.126/0.192
0.130/0.180
0.079/0.418
0.007/0.947
0.085/0.383
0.023/0.813
0.042/0.665
0.042/0.665
0.047/
0.629
0.017/
0.860
3L
5L
Cutaneous -
-
-
-
-
-
-
-
-
-
-
-
-
-
3L
5L
Gastrointestinal 0.009/0.926
0.007/0.939
0.078/
0.422
0.083/
0.396
0.011/
0.911
0.017/
0.860
0.083/0.391
0.003/0.977
0.068/0.485
0.054/0.582
0.010/0.918
0.010/0.918
0.090/0.357
0.035/0.723
3L
5L
Endocrine -
-
-
-
-
-
-
-
-
-
-
-
-
-
3L
5L
DIAPS 0.264/
0.006
0.273/
0.004
0.137/0.157
0.146/0.132
0.248/0.009
0.226/0.019
0.221/0.022
0.215/0.026
0.034/0.729
0.070/0.474
0.172/
0.075
0.172/
0.075
0.231/
0.016
0.209/
0.030
3L
5L
Data are shown as Spearman’s coefficient/p-value. Data are shown in bold if significant. EQ-5D-3L, Euro-Quality of Life five domain three level scale; EQ-
5D-5L, Euro-Quality of Life five domain five level scale; DIAPS, Damage Index for Antiphospholipid Syndrome; VAS, Visual Analogue Scale.
Gaspar et al. 7
Table 5. Univariate logistic regression for all EQ-5D-3L domains impairment (moderate to severe).
Mobility Self-care Usual activities Pain/discomfort Anxiety/depression
3L 5 L 3L 5 L 3L 5 L 3L 5 L 3L 5 L
Male sex 0.24 (0.08–0.69)** 0.28 (0.11–0.73)** 0.45 (0.14–1.48) 0.54 (0.18–1.60) 0.17 (0.05–0.49)** 0.19 (0.07–0.49)** 0.35 (0.15–0.79)* 0.40 (0.17–0.91)* 0.47 (0.21–1.06) 0.46 (0.21–1.04)
Age
a
1.04 (1.01–1.08)* 1.04 (1.01–1.08)* 1.04 (0.99–1.09) 1.05 (1.00–1.09)* 1.02 (0.99–1.06) 1.03 (0.99–1.07) 1.01 (0.98–1.04) 1.02 (0.99–1.05) 0.98 (0.95–1.01) 0.97 (0.95–1.01)
Age at APS onset (y)
a
1.02 (0.99–1.05) 1.01 (0.99–1.04) 1.02 (0.98–1.06) 1.02 (0.98–1.05) 1.00 (0.98–1.03) 1.01 (0.98–1.04) 0.99–1.02) 1.00 (0.97–1.02) 0.98 (0.95–1.00) 0.97 (0.94–0.99)*
Time of follow-up (y)
a
1.03 (0.87–1.10) 1.04 (0.99–1.11) 1.04 (0.97–1.12) 1.07 (0.99–1.14) 1.03 (0.97–1.10) 1.04 (0.98–1.11) 1.07 (0.99–1.14) 1.07 (1.00–1.15)* 1.03 (0.97–1.10) 1.06 (0.99–1.13)
Ethnicity (white) 1.03 (0.25–4.25) 1.35 (0.33–5.57) 0.84 (0.16–4.31) 0.96 (0.19–4.90) 0.53 (0.14–1.96) 0.46 (0.12–1.73) 0.55 (0.13–2.25) 0.39 (0.08–1.96) 0.25 (0.05–1.24) 0.32 (0.06–1.58)
Cerebrovascular disease 1.57 (0.68–5.62) 1.45 (0.65–3.24) 4.72 (1.63–13.70)** 4.44 (1.61–12.26)** 1.22 (0.55–2.74) 1.09 (0.50–2.39) 0.91 (0.42–2.01) 0.62 (0.28–1.39) 1.06 (0.49–2.31) 1.41 (0.63–3.12)
Hypertension 3.09 (1.32–7.22)** 2.78 (1.22–6.29)* 7.17 (2.34–21.99)** 6.56 (2.28–18.89)*** 2.32 (1.03–5.26)* 2.43 (1.09–5.42)* 1.31 (0.59–2.91) 1.29 (0.56–2.93) 0.91 (0.41–1.99) 0.75 (0.34–1.66)
Obesity 1.89 (0.81–4.45) 1.53 (0.67–3.51) 2.2 (0.80–5.99) 2.25 (0.85–5.97) 1.53 (0.67–3.51) 1.43 (0.64–3.23) 1.17 (0.52–2.66) 1.44 (0.61–3.38) 0.92 (0.41–2.07) 0.93 (0.41–2.10)
Depression 1.31 (0.40–4.26) 1.94 (0.63–6.00) 2.11 (0.58–7.61) 1.18 (0.51–6.47) 1.39 (0.44–4.34) 1.01 (0.33–3.15) 1.39 (0.43–4.47) 1.55 (0.45–5.32) 6.53 (1.39–30.80)* -
e
Diabetes mellitus 0.63 (0.12–3.19) 0.88 (0.21–3.71) 1.38 (0.26–7.22) 2.25 (0.51–9.85) 0.88 (0.21–3.71) 0.65 (0.15–2.75) 0.92 (0.23–3.64) 1.19 (0.28–5.06) 1.13 (0.29–4.46) 0.88 (0.22–3.49)
Hypothyroidism 1.4 (0.31–6.24) 1.86 (0.44–7.88) 0.65 (0.08–5.62) 0.57 (0.07–4.91) 1.07 (0.24–4.73) 0.79 (0.18–3.51) 5.73 (0.68–48.29) 4.48 (0.53–37.79) 6.99 (0.83–59.00) 5.50 (0.65–46.38)
Cardiovascular disease 3.65 (0.58–22.96) 2.79 (0.45–17.48) -
c
-
c
2.79 (0.45–17.48) 5.81 (0.63–53.83) 3.10 (0.34–28.74) 2.44 (0.26–22.60) 1.36 (0.22–8.49) 1.08 (0.17–6.71)
Chronic kidney disease 2.35 (0.32–17.48) 1.81 (0.24–13.39) -
c
-
c
1.81 (0.24–13.39) 1.36 (0.18–10.06) 2.29 (0.23–22.74) 1.80 (0.18–17.91) 0.29 (0.03–2.84) 0.23 (0.03–2.25)
Type of APS (secondary) 2.49 (0.99–6.23)
b
3.30 (1.32–8.20)** 2.15 (0.74–6.21) 2.36 (0.85–6.56) 3.30 (1.32–8.20)** 2.77 (1.12–6.88)* 5.78 (1.83–18.24)** 6.30 (1.75–22.66)** 1.98 (0.79–4.96) 3.02 (1.10–8.30)*
First event (arterial) 1.54 (0.58–4.07) 1.26 (0.57–2.77) 4.99 (1.65–15.12)** 3.44 (0.16–9.41)* 1.74 (0.79–3.85) 1.45 (0.67–3.14) 0.94 (0.43–2.03) 0.62 (0.28–1.36) 0.71 (0.33–1.52) 0.97 (0.41–1.90)
Triple positive 1.75 (0.60–5.09) 1.72 (0.60–4.90) 1.00 (0.26–3.91) 0.87 (0.23–3.35) 1.72 (0.60–4.90) 1.24 (0.44–3.51) 1.97 (0.64–6.04) 1.50 (0.49–4.62) 1.01 (0.36–2.84) 1.02 (0.36–2.93)
Anticoagulation 0.58 (0.17–1.97) 0.77 (0.23–2.60) 0.37 (0.10–1.39) 0.28 (0.08–0.99)*
d
0.77 (0.23–2.60) 0.71 (0.21–2.38) 0.96 (0.28–3.24) 1.24 (0.37–4.22) 0.52 (0.15–1.85) 0.43 (0.11–1.68)
Antiplatelet therapy 2.28 (0.87–5.99) 1.64 (0.63–4.24) 2.88 (0.97–8.52) 3.21 (1.12–9.17)* 2.07 (0.80–5.35) 1.84 (0.71–4.72) 1.09 (0.42–2.82) 1.04 (0.39–2.74) 1.38 (0.53–3.56) 1.32 (0.50–3.48)
Hydroxychloroquine 2.40 (0.98–5.84) 3.00 (1.25–7.21)* 2.35 (0.84–6.62) 2.51 (0.93–6.82) 7.02 (2.74–17.98)*** 4.53 (1.81–11.32)** 7.09 (2.26–11.18)** 7.63 (2.14–27.30)** 1.68 (0.70–4.01) 2.31 (0.92–5.84)
Steroids 1.36 (0.53–3.50) 1.88 (0.76–4.67) 1.68 (0.56–5.00) 1.89 (0.66–5.37) 3.85 (1.51–9.79)** 3.25 (1.28–8.27)* 5.51 (1.74–17.47)** 6.03 (1.67–21.74)** 1.21 (0.49–2.98) 1.75 (0.67–4.50)
Immunosuppressants
f
1.39 (0.43–3.85) 2.29 (0.80–6.52) 1.56 (0.45–5.44) 1.95 (0.60–6.32) 3.05 (1.06–8.83)* 2.18 (0.76–6.26) 7.02 (1.52–32.48)* 5.38 (1.16–24.91)* 1.01 (0.36–2.84) 1.88 (0.61–5.78)
DIAPS≥13 (1.27–7.08)* 2.78 (1.23–6.27)* 2.09 (0.76–5.83) 2.00 (0.75–5.31) 2.34 (1.05–5.24)* 1.8 (0.83–3.89) 2.21 (1.01–4.83)* 1.99 (0.90–4.42) 0.69 (0.33–1.48) 0.6 (0.28–1.30)
DIAPS 1.70 (1.12–2.58)* 1.79 (1.16–2.74)** 1.26 (0.80–1.98) 1.21 (0.77–1.89) 1.79 (1.16–2.74)** 1.61 (1.06–2.44)** 1.83 (1.12–2.99)* 1.67 (1.02–2.74)* 1.07 (0.73–1.57) 1.01 (0.69–1.49)
Data are shown as odds ratio (OR) and 95% confidence interval (CI). APS, antiphospholipid syndrome; DIAPS, damage index for antiphospholipid syndrome. See Supplemental Data 1 for further detail on
medical disorders definitions. *p< .050, **p< .010; ***p< .001.
a
Per one-unit increase OR.
b
p= .051.
c
None of patients with cardiovascular and chronic kidney disease had impairment in the self-care domain of the 3L and 5L EQ-5D scales; hence, they were excluded from the analysis.
d
p= .049.
e
All patients with depression had impairment in the anxiety/depression domain of the EQ-5D-5L scale, hence excluded from this analysis.
f
Included azathioprine (n= 11), methotrexate (n= 5), mycophenolate mofetil (n= 4), rituximab (n= 3), cyclophosphamide (n= 3), adalimumab (n= 1), belimumab (n= 1), and sulfasalazine (n= 3).
8Lupus 0(0)
Hypertension was significantly associated with mobility, self-
care and usual activities domains, and cerebrovascular disease
with self-care impairment (Tab le 5 ). sAPS increased the risk for
impairment of all HR-QoL domains expect for self-care do-
main. Notably, treatment with hydroxychloroquine, systemic
steroids and immunosuppressants, were also significantly as-
sociated with the impairment of usual activities and pain/
discomfort domains.
We performed a multivariable logistic regression anal-
ysis to investigate the association between DIAPS and HR-
QoL impairment (Supplemental Table 9). After adjusting
for sex, age, medical disorders, type of APS, type of first
thrombotic event and treatment, the DIAPS lost its sig-
nificant effect on HR-QoL deterioration as measured by the
3-level (per one unit increase OR 1.29, 95% CI 0.69–2.42,
p= .296) and 5-level (per one unit increase OR 1.20, 95% CI
0.65–2.23, p= .557) EQ-5D scales.
Discussion
In this study we report a detailed characterization on the
prevalence and risk factors associated with damage ac-
quisition, as measured by the DIAPS, and HR-QoL im-
pairment, assessed by both the EQ-5D-3L and -5L scales,
and demonstrate a significant correlation between them in a
well-defined thrombotic APS cohort.
In thrombotic APS, the prevalence of damage and its
severity varies across different studies. Torricelli et al.
18
followed a group of 100 APS patients (50% associated to
SLE) over 10 years and showed that the mean DIAPS
increased over time in both pAPS (1.72 [SD 1.17] to
2.04 [SD 1.50]) and sAPS (0.82 [SD 0.96] to 2.24 [SD
1.61]). Only 4% and 16% of patients were free of damage at
the end of the study, respectively.
18
In a single-centre ret-
rospective study including 197 APS patients followed for a
median of 10 (IQR 6–17) years aiming to assess the rela-
tionship between damage acquisition and mortality, the
authors showed that cumulative damage developed in 143
(73.6%) patients with a mean cumulative DIAPS of 1.6 (SD
1.7) (median 1, IQR 0–2).
19
Recently, DIAPS was evaluated
in a multi-ethnic international cohort comprising 826 aPL-
positive patients from the APS Alliance for Clinical Trials
and International Networking (APS ACTION) registry.
20
Among the 412 pAPS group, 348 (84.5%) presented with
damage and 110 (26.7%) with high damage (DIAPS≥3) at
the baseline evaluation; the mean DIAPS value was 1.94
(1.46) and the median DIAPS was 2 (IQR 1–3, min 0, max
9).
20
In our study, the mean cumulative DIAPS was 1.48
(1.99) (median 0, IQR 0–2; Table 1) which is line with
previously reported findings.
5,10,18–20
However, it is worth
noting that only approximately 48% of our patients pre-
sented with damage. This heterogeneity may stem from
variations between populations, local patient referencing
practices or differences in study methodologies.
Additionally, the shorter follow-up time observed in our
study may contribute to these differences as the demo-
graphic characteristics, such as a female preponderance,
predominantly primary type of APS, and distribution of
thrombotic manifestations, are consistent with existing
literature. Our patients were followed for a median of 4
(IQR 2–11) years. Studies with longer follow-up have re-
ported organ damage in up to 98.5% of patients.
10
The most affected domains of DIAPS also exhibit var-
iation. Consistent with previous studies,
8,10,21
our findings
indicate that the neuropsychiatric domain is the most af-
fected, followed by the peripheral vascular domain. Con-
trary reports were found by Torricelli et al.
18
and in the APS
ACTION cohort,
20
who reported the peripheral vascular
domain as the most affected. Overall, these results are
consistent with the fact that damage is expected from the
main thrombotic manifestations (i.e. deep vein thrombosis,
pulmonary embolism and acute cerebral ischaemic
events),
5,10
as we observe in our study.
Risk factors for damage acquisition as measured by the
DIAPS have been scarcely explored. In the APS ACTION
cohort, the presence of classical cardiovascular (CVD) risk
factors, namely, male sex, older age, hypertension, hyper-
lipidaemia and obesity, were associated with higher dam-
age.
20
This is reinforced in a cluster analysis conducted by
Uluda˘
g et al., where the authors identified a group (n= 74)
comprising older patients with CVD risk factors and a
higher incidence of arterial events who exhibited a mean
DIAPS of 2.24 ± 1.44, ranking second among the four
clusters identified in terms of damage.
22
In our study,
however, we did not observe any significant association
between medical disorders (such as hypertension, obesity,
diabetes and cardiovascular disease), as well as sex and age,
with damage accrual (Table 2). These findings align with
Medina et al.’s who also reported no such association.
10
Interestingly, we observed that triple positivity was not
associated with damage. Even though this finding was also
reported by other research groups,
10
including the APS
ACTION cohort,
20
this contrasts with the known impor-
tance of triple positivity as a risk factor for thrombosis
recurrence, thus more likely damage accrual, in APS.
23
HR-QoL is recognized as an outcome of interested in
rheumatic diseases in parallel to standard measures of
treatment efficacy. Both disease-associated manifestations
and damage can potentially contribute to HR-QoL im-
pairment. However, studies reporting a correlation between
damage acquisition, especially as measured by the DIAPS,
and HR-QoL outcomes are lacking. One of the anticipated
limitations of the DIAPS is related to the fact that ethnicity
influences patients’HR-QoL perception
11,12
and that the
score was developed and validated in an ethnic restricted,
although multicentric, cohort of Latin American patients.
5
Despite the distinct genetic background and, presumably,
cultural differences between our patients (mainly whites
Gaspar et al. 9
with European ancestry) and the original study (mainly
Latin Americans), our results are globally comparable to
Amigo et al.’s
5
; the DIAPS correlated with the mobility,
usual activities, pain/discomfort EQ-5D-3L domains, and
the EQ-5D-3L index. This trend remained in the 5-level
scale. Nevertheless, when adjusting for demographics and
clinical characteristics, the DIAPS lost its association with
both the 3- and 5-level EQ-5D scales. Even though this
highlights the importance of additional determinants of HR-
QoL impairment, results should be interpreted carefully due
to the limited sample size.
APS affects predominantly young patients and the mean
age of onset, and its consequences are highly variable,
ranging from mild thrombocytopenia to the sudden onset of
permanent disability following a stroke with hemiplegia.
Erkan et al.
24
analysed a group of 39 pAPS patients over
10 years and reported that around 20% of them were unable
to perform everyday activities due to cognitive dysfunction
or aphasia. Zuily et al. reported that a history of arterial
thrombosis significantly impaired HR-QoL in both physical
and mental health domains in APS patients: myocardial
infarction affected mainly physical health; mental health
domain was predominantly affected by peripheral arterial
thrombosis and cerebral ischaemic events.
25
In our study,
we observed that having arterial thrombosis was also highly
associated with HR-QoL impairment, particularly in the
self-care domain. Since most of the arterial thrombosis
affected the central nervous system (Supplemental Table 2),
we were not surprised to find that cerebrovascular ischaemic
disease, encompassing both acute cerebral ischaemic le-
sions (stroke and transient ischaemic attacks) and micro-
vascular central nervous system involvement, were also a
risk factor for self-care impairment. Current treatment
recommendations suggest adding antiplatelet therapy to
VKA in cases of recurrent thrombosis and/or thrombosis of
arterial nature.
2,26
This could explain why we also observe
an association between the exposure to antiplatelet therapy
and the risk of EQ-5D self-care domain impairment.
The relationship between APS and SLE seems to be
bidirectional regarding HR-QoL impairment. Patients with
thrombotic APS or SLE with thromboembolic event have
poorer HR-QoL scores than aPL-positive SLE patients
without thrombosis.
27
Patients with SLE-associated APS
report a greater impact on HR-QoL compared with
pAPS.
25,28
We also found SLE to be highly associated with
the impairment of most EQ-5D domains, mostly leading to
impairment in the usual activities and pain/discomfort
domains. The concordant association between the expo-
sure to hydroxychloroquine, steroids, and immunosup-
pressants with HR-QoL impairment, follows the current
treatment recommendations for SLE.
29
Anticoagulation with warfarin or another VKA remains
the cornerstone of APS treatment.
2
Reports are that the use
of anticoagulation can potentially contribute to HR-QoL
impairment. Hernandez-Molina et al.
21
showed that patients
with APS on VKA reported lower HR-QoL especially with
regard to their physical functioning, intimate relationships,
burden to others and pain domains. The RAPS trial
30
showed a small improvement in the VAS in the rivarox-
aban group compared to the VKA group (mean difference
6.5, 95% CI 1.4–11.5; p= .013). These results can be
explained by either the burden of the treatment itself (i.e.
need to frequent monitoring, medication unpredictability
and fear of side effects, bleeding associated organ
damage)
28,31,32
or the burden of its indication, for example,
thromboembolic events, as we showed for cerebrovascular
ischaemic disease. In our study the exposure to anti-
coagulation were not associated with the risk of impairment
of any of EQ-5D domains. In fact, we observe a non-
significant trend towards a protective effect in almost all
domains even though the exposure to direct oral antico-
agulants (DOAC), but not to VKA, was associated with the
risk of having damage (Table 2). In a recent meta-analysis of
randomized control trials, the use of DOAC compared with
VKA was associated with increased odds of recurrent ar-
terial thrombotic events (OR 5.43; 95% CI 1.87–15.75; p<
.001), especially stroke.
33
However, to explore the recur-
rence rate, risk factors and related damage was beyond the
scope of the current work.
Correlation between the peripheral vascular domain and
the VAS, but not the EQ-5D-3L index, illustrates how
patients may take into consideration more than just the
functional consequences of vascular damage. The Aberdeen
Varicose Vein Questionnaire
34
and the Chronic Venous
Insufficiency Questionnaire
35
are two validated HR-QoL
instruments specific for chronic venous disease that cor-
relate with the EQ-5D-5L score, and consider cosmetic
effects of varicose veins and associated psychological
distress.
36
Contrary to cerebral ischaemic events, which
often disables patients from the beginning, and are well
captured by the EQ-5D indexes (Table 4), post-thrombotic
syndrome is a long-term sequela of deep vein thrombosis.
37
It is likely that symptoms arising from post-thrombotic
syndrome, particularly pain and aesthetic repercussions,
would be captured by the VAS. This is particularly true in
our cohort since the great majority of accrued damage in this
domain referred to venous events, namely, venous vascular
insufficiency (Table 1). Notably, however, we observe a
correlation between the peripheral vascular domain and the
EQ-5D-5L index as well as with the pain/discomfort do-
main using the 5-level scale. This shows that not only the 5-
level version of EuroQoL is more sensitive, but also that
pain, presumably associated with post-thrombotic syn-
drome, may be the main reason why these patients have
impaired HR-QoL. An APS-specific HR-QoL questionnaire
could be an elegant solution for better accounting HR-QoL
in studies involving APS patients in the future, but it is
currently an unmet need.
6
10 Lupus 0(0)
We acknowledge some potential limitations. First, in line
with the known relatively low prevalence of APS, the small
number of patients compromise the generalizability. Sec-
ond, as data were collected retrospectively in a real-world
scenario, we cannot assure that all damage events were
accurately reported in the medical records. This could ex-
plain the surprisingly low prevalence of cognitive impair-
ment in our patients compared to what is known for APS.
38
Third, we did not collect other variables that might impact
QoL (e.g. education level, socioeconomic status, healthcare
access). In particular, we did not take into account disease
activity in SLE, which has been associated with decrease in
HR-QoL.
39,40
Fourth, we did not have a baseline QoL
assessment (i.e. before damage has evolved) with which our
results could be compared to. However, this study does offer
potentially valuable data on an understudied patient pop-
ulation and reveals a correlation between damage acqui-
sition and QoL. Future studies should overcome these
caveats.
In conclusion, cumulative damage, as measured by the
DIAPS, is associated with impaired HR-QoL in thrombotic
APS patients. Impaired HR-QoL in APS is multifactorial
and related to damage as well as to clinical and demographic
characteristics. While this work acts as an external vali-
dation of the DIAPS and contributes to generalizing its
applicability, it also highlights the need for appropriate tools
for evaluating QoL in APS patients, both for everyday
clinical practice and for their application in clinical trials.
Acknowledgements
We thank the participants for their involvement in the study.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with re-
spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, au-
thorship, and/or publication of this article.
ORCID iD
Pedro Gaspar https://orcid.org/0000-0002-6965-3435
Supplemental Material
Supplemental material for this article is available online.
References
1. Miyakis S, Lockshin MD, Atsumi T, et al. International
consensus statement on an update of the classification criteria
for definite antiphospholipid syndrome (APS). J Thromb
Haemostasis 2006; 4(2): 295–306.
2. Tektonidou MG, Andreoli L, Limper M, et al. EULAR rec-
ommendations for the management of antiphospholipid syn-
drome in adults. Ann Rheum Dis 2019; 78(10): 1296–1304.
3. Tektonidou MG. Prognostic factors and clustering of serious
clinical outcomes in antiphospholipid syndrome. QJM 2000;
93(8): 523–530.
4. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and
mortality in the antiphospholipid syndrome during a 10-year
period: a multicentre prospective study of 1000 patients. Ann
Rheum Dis 2015; 74(6): 1011–1018.
5. Amigo MC, Goycochea-Robles MV, Espinosa-Cuervo G,
et al. Development and initial validation of a damage index
(DIAPS) in patients with thrombotic antiphospholipid syn-
drome (APS). Lupus 2015; 24(9): 927–934.
6. Gaspar P, Cohen H and Isenberg DA. The assessment of
patients with the antiphospholipid antibody syndrome: where
are we now? Rheumatology 2020; 59(7): 1489–1494.
7. Desnoyers M, Dufrost V, Wahl D, et al. Health-related quality
of life in antiphospholipid syndrome: current knowledge and
future perspectives. Curr Rheumatol Rep 2020; 22(6): 20.
8. Radin M, Foddai SG, Cecchi I, et al. Quality of life in patients
with antiphospholipid antibodies differs according to anti-
phospholipid syndrome damage index (DIAPS). Eur J Intern
Med 2021; 92: 134–136.
9. Martinez-Martinez LA, Chacon-Perez MJNN and Amigo
MC. AB0466 damage index in patients with thrombotic
antiphospholipid syndrome: retrospective cohort study (Ab-
stract). Ann Rheum Dis 2016; 75(Suppl 2): 1065.
10. Medina G, Cim´
eAk
´
e EA, Vera-Lastra O, et al. Damage index
for antiphospholipid syndrome during long term follow-up:
correlation between organ damage accrual and quality of life.
Lupus 2021; 30(1): 96–102.
11. Carpenter DM. Racial/ethnic differences in quality of life for
people living with arthritis who see a primary care physician.
Open Rheumatol J 2011; 5(1): 24–29.
12. Bolen J, Schieb L, Hootman JM, et al. Differences in the
prevalence and impact of arthritis among racial/ethnic groups
in the United States. National Health Interview Survey. 2010;
7(3A64).
13. Ferreira LN, Ferreira PL, Ribeiro FP, et al. Comparing the
performance of the EQ-5D-3L and the EQ-5D-5L in young
Portuguese adults. Health Qual Life Outcome 2016; 14(1):
89.
14. Herdman M, Gudex C, Lloyd A, et al. Development and
preliminary testing of the new five-level version of EQ-5D
(EQ-5D-5L). Qual Life Res 2011; 20(10): 1727–1736.
15. Janssen MF, Birnie E, Haagsma JA, et al. Comparing the
standard EQ-5D three-level system with a five-level version.
Value Health 2008; 11(2): 275–284.
16. Ferreira LN, Ferreira PL, Pereira LN, et al. The valuation of
the EQ-5D in Portugal. Qual Life Res 2014; 23(2): 413–423.
17. Ferreira PL, Antunes P, Ferreira LN, et al. A hybrid modelling
approach for eliciting health state preferences: the Portuguese
EQ-5D-5L value set. Qual Life Res 2019; 28(12): 3163–3175.
Gaspar et al. 11
18. Torricelli AK, Ugolini-Lopes MR, Bonf´
a E, et al. Anti-
phospholipid syndrome damage index (DIAPS): distinct
long-term kinetic in primary antiphospholipid syndrome and
antiphospholipid syndrome related to systemic lupus eryth-
ematosus. Lupus 2020; 29(3): 256–262.
19. Gaspar P, Farinha F, Sayar Z, et al. A one-point increase in the
damage index for antiphospholipid syndrome (DIAPS) pre-
dicts mortality in thrombotic antiphospholipid syndrome.
Clin Exp Rheumatol. 2023; 41(3): 605–612.
20. Balbi GGM, Ahmadzadeh Y, Tektonidou MG, et al. Damage
measured by Damage Index for Antiphospholipid Syndrome
(DIAPS) in antiphospholipid antibody-positive patients in-
cluded in the APS ACTION registry. Rheumatology. 2023;
63(3): 772–779.
21. Hern´
andez-Molina G, Gonz´
alez-P´
erez I, Pacheco-Molina C,
et al. Quality of life in patients with antiphospholipid syn-
drome is related to disease burden and anticoagulant therapy.
Int J Rheum Dis 2017; 20(6): 755–759.
22. Uluda˘
g¨
O, Çene E, Gurel E, et al. Description of damage in
different clusters of patients with antiphospholipid syndrome.
Lupus 2022; 31(4): 433–442.
23. Chayoua W, Kelchtermans H, Moore GW, et al. Identification
of high thrombotic risk triple-positive antiphospholipid
syndrome patients is dependent on anticardiolipin and anti
β2glycoprotein I antibody detection assays. J Thromb Hae-
mostasis 2018; 16(10): 2016–2023.
24. Erkan D, Yazici Y, Sobel R, et al. Primary antiphospholipid
syndrome: functional outcome after 10 years. J Rheumatol;
27(12): 2817–2821.
25. Zuily S, Rat AC, Regnault V, et al. Impairment of quality of
life in patients with antiphospholipid syndrome. Lupus 2015;
24(11): 1161–1168.
26. Cohen H, Sayar Z, Efthymiou M, et al. Management of
anticoagulant-refractory thrombotic antiphospholipid syn-
drome. Lancet Haematol 2020; 7(8): e613–e623.
27. Balitsky AK, Peeva V, Su J, et al. Thrombovascular events
affect quality of life in patients with systemic lupus eryth-
ematosus. J Rheumatol 2011; 38(6): 1017–1019.
28. Georgopoulou S, Efraimidou S, MacLennan SJ, et al. Anti-
phospholipid (Hughes) syndrome: description of population
and health-related quality of life (HRQoL) using the SF-36.
Lupus 2015; 24(2): 174–179.
29. Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR
recommendations for the management of systemic lupus
erythematosus: 2023 update. Ann Rheum Dis 2024; 83(1):
15–29.
30. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus
warfarin to treat patients with thrombotic antiphospholipid
syndrome, with or without systemic lupus erythematosus
(RAPS): a randomised, controlled, open-label, phase 2/3,
non-inferiority trial. Lancet Haematol 2016; 3(9): e426–e436.
31. De Oliveira Vaz C, De Moraes Mazetto Fonseca B,
Nascimento Silva Vasconcelos PE, et al. Self-perceived
quality of life of primary antiphospholipid syndrome pa-
tients using vitamin K antagonist. Lupus 2021; 30(5):
707–714.
32. Gaspar P, Mittal P, Cohen H, et al. Bleeding events in
thrombotic antiphospholipid syndrome: prevalence, severity,
and associated damage accrual. Res Pract Thromb Haemost
2024; 8(1): 102327.
33. Khairani CD, Bejjani A, Piazza G, et al. Direct oral anticoag-
ulants vs vitamin K antagonists in patients with antiphospholipid
syndromes. J Am Coll Cardiol 2023; 81(1): 16–30.
34. Garratt AM, Macdonald LM, Ruta DA, et al. Towards
measurement of outcome for patients with varicose veins.
Qual Saf Health Care 1993; 2(1): 5–10.
35. Launois R, Reboul-Marty J and Henry B. Construction and
validation of a quality of life questionnaire in chronic lower
limb venous insufficiency (CIVIQ). Qual Life Res 1996; 5(6):
539–544.
36. Kuet ML, Lane TR, Anwar MA, et al. Comparison of disease-
specific quality of life tools in patients with chronic venous
disease. Phlebol J Venous Dis 2014; 29(10): 648–653.
37. Farrell JJ, Sutter C, Tavri S, et al. Incidence and interventions
for post-thrombotic syndrome. Cardiovasc Diagn Ther 2016;
6(6): 623–631.
38. Hassan F, Naffaa ME, Saab A, et al. Cognitive impairment in
anti-phospholipid syndrome and anti-phospholipid antibody
carriers. Brain Sci 2022; 12(2): 222.
39. Riaz MM, Shen L, Lateef A, et al. Differential impact of
disease activity and damage on health-related quality of life in
patients with systemic lupus erythematosus. Lupus 2022;
31(9): 1121–1126.
40. Chaigne B, Chizzolini C, Perneger T, et al. Impact of disease
activity on health-related quality of life in systemic lupus
erythematosus –a cross-sectional analysis of the Swiss
Systemic Lupus Erythematosus Cohort Study (SSCS). BMC
Immunol 2017; 18(1): 17.
12 Lupus 0(0)
