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Increased Levels of Oxidative Stress Markers, Soluble CD40 Ligand, and Carotid Intima-Media Thickness Reflect Acceleration of Atherosclerosis in Male Patients with Ankylosing Spondylitis in Active Phase and without the Classical Cardiovascular Risk Factors

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Abstract

Objective The primary aim of the study was to assess levels of oxidative stress markers, soluble CD40 ligand (sCD40L), serum pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF) as well as carotid intima-media thickness (IMT) in patients with ankylosing spondylitis (AS) with active phase without concomitant classical cardiovascular risk factors. Material and methods The observational study involved 96 male subjects: 48 AS patients and 48 healthy ones, who did not differ significantly regarding age, BMI, comorbid disorders, and distribution of classical cardiovascular risk factors. In both groups, we estimated levels of oxidative stress markers, lipid profile, and inflammation parameters as well as sCD40L, serum PAPP-A, and PlGF. In addition, we estimated carotid IMT in each subject. Results The study showed that markers of oxidative stress, lipid profile, and inflammation, as well as sCD40L, PlGF, and IMT, were significantly higher in the AS group compared to the healthy group. Conclusion Our results demonstrate that ankylosing spondylitis may be associated with increased risk for atherosclerosis.
Research Article
Increased Levels of Oxidative Stress Markers, Soluble
CD40 Ligand, and Carotid Intima-Media Thickness Reflect
Acceleration of Atherosclerosis in Male Patients with Ankylosing
Spondylitis in Active Phase and without the Classical
Cardiovascular Risk Factors
Agata Stanek,
1
Armand Cholewka,
2
Tomasz Wielkoszyński,
3
Ewa Romuk,
3
Karolina Sieroń,
4
and Aleksander Sieroń
1
1
School of Medicine with the Division of Dentistry in Zabrze, Department of Internal Medicine, Angiology and Physical Medicine,
Medical University of Silesia, Batorego St., 15, 41-902 Bytom, Poland
2
Department of Medical Physics, Chelkowski Institute of Physics, University of Silesia, 4 Uniwersytecka St., 40-007 Katowice, Poland
3
School of Medicine with the Division of Dentistry in Zabrze, Department of Biochemistry, Medical University of Silesia,
Jordana 19 St., 41-808 Zabrze, Poland
4
School of Health Sciences in Katowice, Department of Physical Medicine, Chair of Physiotherapy, Medical University of Silesia,
Medyków St., 12, 40-752 Katowice, Poland
Correspondence should be addressed to Agata Stanek; astanek@tlen.pl
Received 15 June 2017; Accepted 12 July 2017; Published 14 August 2017
Academic Editor: Adrian Doroszko
Copyright © 2017 Agata Stanek et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. The primary aim of the study was to assess levels of oxidative stress markers, soluble CD40 ligand (sCD40L), serum
pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF) as well as carotid intima-media thickness
(IMT) in patients with ankylosing spondylitis (AS) with active phase without concomitant classical cardiovascular risk factors.
Material and methods. The observational study involved 96 male subjects: 48 AS patients and 48 healthy ones, who did not
dier signicantly regarding age, BMI, comorbid disorders, and distribution of classical cardiovascular risk factors. In both
groups, we estimated levels of oxidative stress markers, lipid prole, and inammation parameters as well as sCD40L, serum
PAPP-A, and PlGF. In addition, we estimated carotid IMT in each subject. Results. The study showed that markers of oxidative
stress, lipid prole, and inammation, as well as sCD40L, PlGF, and IMT, were signicantly higher in the AS group compared
to the healthy group. Conclusion. Our results demonstrate that ankylosing spondylitis may be associated with increased risk
for atherosclerosis.
1. Introduction
Ankylosing spondylitis (AS) is a chronic inammatory
arthritis aecting primarily the axial skeleton and sacroiliac
joints [1, 2].
Several epidemiological studies conrmed the high risk
of cardiovascular morbidity and mortality in AS patients,
which is associated with an increase of risk for atherosclerosis
independent of traditional risk factors that may be connected
with the disease activity, functional and mobility limitations,
structural damage, and inammation [3, 4].
Inammation, on the one hand, has an important role in
dierent stages of atherogenesis, and, on the other, attenuates
established cardiovascular risk factors [5, 6].
During inammation and phagocytosis reactions, reac-
tive oxygen species (ROS) may be released into the extracel-
lular space and injure the surrounding tissue and thereby
result in the production of acute-phase proteins [7].
Hindawi
Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 9712536, 8 pages
https://doi.org/10.1155/2017/9712536
Moreover, according to the theory of oxidative stress,
atherosclerosis results from the oxidative modication of
low-density lipoproteins (LDL) in the arterial wall by ROS
[8]. Modied ox-LDL is generally accepted to be an impor-
tant elicitor of promitotic, proinammatory, and atherogenic
eects in vascular cells [9]. What is more, ox-LDL may inter-
act with dierent molecules and form proatherogenic com-
plexes (e.g., ox-LDL/CRP and ox-LDL/β2-glycoprotein 1)
that may not only perpetuate vascular inammation but also
trigger autoimmune responses, accelerating the development
of atherosclerosis [10, 11].
In addition, high titers of antibodies of ox-LDL have been
reported in patients with myocardial infarction [12], athero-
slerosis [13], and rheumatoid disease [9].
It has been demonstrated that the CD40L concentration
is increased in patients with occlusive carotid artery disease
and may be also a predictor of cardiovascular events [14, 15].
On the other hand, it has been also reported that the pla-
cental growth factor (PlGF) plays an important role in ath-
erosclerosis by stimulating the angiogenesis and atherogenic
migration of monocytes/macrophages into the arterial wall
[16]. It seems to be more eective during the early phase of
atherogenesis, because anti-PlGF antibody treatment signi-
cantly inhibits early lesions but is ineective during the more
advanced stages of plaque development [17].
The other marker of atherogenesis is serum pregnancy-
associated plasma protein-A (PAPP-A). It has been shown
that its circulating concentrations are higher in patients with
acute coronary syndrome than in patients with chronic stable
angina and in healthy subjects. Furthermore, increased
serum PAPP-A concentration is associated with the presence
and extent of stable coronary heart disease as well as predic-
tive of future ischemic cardiac events, and the need for percu-
taneous coronary intervention or coronary artery bypass
graft surgery [18, 19].
On the other hand, a few papers postulate that oxidative
stress might be involved both in AS disease onset and pro-
gression [2024].
Taking this data into account, the primary aim of the
study was to assess levels of oxidative stress markers,
sCD40L, PAPP-A, and PlGF as well as carotid IMT in AS
patients with active phase without concomitant classical
cardiovascular risk factors.
2. Materials and Methods
2.1. Participants. The research protocol has been reviewed
and approved by the Bioethical Committee of the Medical
University of Silesia in Katowice (Permission number
KNW/022/KB/103/16), and all the subjects we analyzed gave
their informed, written consent for inclusion in the observa-
tional study. It was carried out in accordance with the Decla-
ration of Helsinki (1964). The study involved 96 male
subjects: 48 patients with ankylosing spondylitis (AS group,
mean age 46.06 ±1.44 years) and 48 healthy subjects (control
group, mean age 46.63 ±1.50 years), who did not dier sig-
nicantly regarding age, BMI, comorbiding disorders, and
distribution of classical cardiovascular risk factors. All the
patients included in the observational study fullled the
modied New York Criteria for denite diagnosis of AS,
which served as the basis for the ASAS/EULAR recommen-
dations [25]. Enrollment in the study was performed in the
AS group of male patients, with denite diagnosis of AS
who did not suer from any other diseases, had no associated
pathologies, and whose attending physician did not apply
disease-modifying antirheumatic drugs (DMARDs), biologic
agents, or steroids. The AS patients were treated with
NSAIDs, which doses were not altered within one month
before the beginning of the study. All the patients with AS
were HLAB27 positive, and they exhibited III and IV radio-
graphic grades of sacroiliac joint disease. The BASDAI was
5.35 ±1.64 and the BASFI was 5.13 ±2.17. The AS patients
did not suer from any other diseases. Similarly, the healthy
subjects had no acute or chronic diseases, nor did they use
any medication. The demographic data of the subjects is
shown in Table 1.
The subjects from both groups were asked to abstain from
alcohol, drugs, and any immunomodulators, immunostimu-
lators, hormones, vitamins, minerals, or other substances
with antioxidant properties for 4 weeks before the study. All
the subjects were also asked to refrain from the consumption
of caeine 12 hours prior to laboratory analysis.
2.2. Blood Sample Collection. Blood samples of all the subjects
were collected in the morning before the rst meal. Samples
of whole blood (5 ml) were drawn from a basilic vein of each
subject and then collected into tubes containing ethylenedi-
aminetetraacetic acid (Sarstedt, S-monovette with 1.6 mg/
ml EDTA-K
3;
catalogue number 04.1931) and into tubes with
a clot activator (Sarstedt, S-monovette, catalogue number
Table 1: Demographic data of the study subjects.
Characteristic AS patients
(n=48)
Healthy
subjects
(n=48)
pvalue
Sex (M/F) 48/0 48/0
Age (years), mean (SD) 46.06 ±1.44 46.63 ±1.50 0.096
BMI (kg/m
2
), mean (SD) 24.5 ±4.4 23.8 ±5.7 0.674
Smoking (yes/no) 0/48 0/48
BASDAI 5.35 ±1.64 ——
BASFI 5.13 ±2.17 ——
HLA B27 antigen (yes/no) 48/0 ——
Cerebral/coronary/peripheral
vascular disease (yes/no) 0/48 0/48
Hypertension (yes/no) 0/48 0/48
Diabetes mellitus (yes/no) 0/48 0/48
Hyperlipidemia (yes/no) 0/48 0/48
Medication
NSAID (yes/no) 48/0 ——
DMARD (yes/no) 0/48 ——
Biological agents (yes/no) 0/48 ——
SD: standard deviation; BMI: body mass index; BASDAI: the Bath
Ankylosing Spondylitis Disease Activity Index; BASFI: the Bath
Ankylosing Spondylitis Functional Index; HLA B27 antigen: human
leukocyte B27 antigen; NSAID: nonsteroidal anti-inammatory drug;
DMARD: disease-modifying antirheumatic drug.
2 Oxidative Medicine and Cellular Longevity
04.1934). The blood samples were centrifuged (10 min., 900
g,4
°
C), and then the plasma and serum were immediately
separated and stored at the temperature of 70
°
C, until bio-
chemical analyses were performed. In turn, the red blood
cells retained from removal of EDTA-plasma were rinsed
with isotonic salt solution and then 10% of hemolysates were
prepared for further analyses. Hemoglobin concentration in
hemolysates was determined by standard cyanmethemoglo-
bin method. The inter- and intra-assay coecients of varia-
tions (CV) were, respectively, 1.1% and 2.4%.
2.3. Biochemical Analyses
2.3.1. Oxidative Stress Marker Analyses
(1) Determination of Activity of Antioxidant Enzymes. The
plasma and erythrocyte superoxide dismutase (SOD
E.C.1.15.1.1) activity was determined by the Oyanagui
method [26]. Enzymatic activity was expressed in nitrite unit
(NU) in each mg of hemoglobin (Hb) or ml of blood plasma.
One nitrite unit (1 NU) means a 50% inhibition of nitrite ion
production by SOD in this method. SOD isoenzymes (SOD-
Mn and SOD-ZnCu) were measured using potassium
cyanide as the inhibitor of the SOD-ZnCu isoenzyme. The
inter- and intra-assay coecients of variations (CV) were,
respectively, 2.8% and 5.4%.
The catalase (CATE.C.1.11.1.6.) activity in erythrocytes
was measured by Aebi [27] kinetic method and expressed in
IU/mgHb. The inter- and intra-assay coecients of variations
(CV) were, respectively, 2.6% and 6.1%.
The erythrocyte glutathione peroxidase (GPxE.C.1.11.1.9.)
activity was assayed by Paglia and Valentines kinetic method
[28], with t-butyl peroxide as a substrate and expressed as
micromoles of NADPH oxidized per minute and normalized
to one gram of hemoglobin (IU/gHb). The inter- and intra-
assay coecients of variations (CV) were, respectively, 3.4%
and 7.5%.
The activity of glutathione reductase in erytrocytes
(GRE.C.1.6.4.2) was assayed by Richterichs kinetic
method [29], expressed as micromoles of NADPH utilized
per minute and normalized to one gram of hemoglobin
(IU/gHb). The inter- and intra-assay coecients of varia-
tions (CV) were, respectively, 2.1% and 5.8%.
(2) Determination of Nonenzymatic Antioxidant Status.
The total antioxidant capacity of plasma was measured as
the ferric reducing ability of plasma (FRAP) according to
Benzie and Strain [30] and calibrated with the use of
Trolox and expressed in μmol/l. The inter- and intra-
assay coecients of variations (CV) were, respectively,
1.1% and 3.8%.
The serum concentration of protein sulfhydryl (PSH)
was determined by Koster et. als method [31] using dithio-
nitrobenzoic acid (DTNB) and expressed in μmol/l. The
inter- and intra-assay coecients of variations (CV) were,
respectively, 2.6% and 5.4%.
The serum concentration of uric acid (UA) was deter-
mined by a uricase-peroxidase method [32] on the Cobas
Integra 400 plus analyzer and expressed as mg/dl. The inter-
and intra-assay coecients of variations (CV) were, respec-
tively, 1.4% and 4.4%.
(3) Determination of Lipid Peroxidation Products and TOS.
The intensity of lipid peroxidation in the plasma and the
erythrocytes was measured spectrouorimetrically as a thio-
barbituric acid-reactive substances (TBARS) according to
Ohkawa et al. [33]. The TBARS concentrations were
expressed as malondialdehyde (MDA) equivalents in μmol/l
in plasma or nmol/gHb in erythrocytes. The inter- and
intra-assay coecients of variations (CV) were, respectively,
2.1% and 8.3%.
The serum concentrations of oxidized low-density lipo-
protein (ox-LDL) and antibodies to ox-LDL (ab-ox-LDL)
were measured with the use of ELISA kits (catalogue num-
bers BI-20022 and BI-20032, Biomedica, Poland) according
to the manufacturers instructions. The ox-LDL and the ab-
ox-LDL concentrations were expressed in ng/ml and mU/
ml, respectively. The inter- and intra-assay coecients of
variations (CV) for ox-LDL were 5.8% and 9.4%, respectively,
and for ab-ox-LDL4.1% and 8.7%, respectively.
The serum total oxidant status (TOS) was determined
with the method described by Erel [34] and expressed in
μmol/l. The inter- and intra-assay coecients of variations
(CV) were, respectively, 2.2% and 6.4%.
2.3.2. Determination of Inammatory State Parameters. The
erythrocyte sedimentation rate (ESR) was determined
immediately in whole blood with EDTA by the classical
Westergren method.
The high-sensitivity C-reactive protein (hs-CRP) (cata-
logue number EIA 4584) concentration in serum was
determined by latex immunoturbidimetric method (BioSys-
tems, Spain) and expressed in mg/l. The inter- and intra-
assay coecients of variations (CV) were, respectively,
2.3% and 5.5%.
The serum ceruloplasmin (CER) oxidase activity was
measured with the use of the p-phenylenediamine kinetic
method by Richterich [29] and expressed in mg/dl after a cal-
ibration with pure ceruloplasmin isolated from a healthy
donor serum pool. The inter- and intra-assay coecients of
variations (CV) were, respectively, 3.1% and 6.1%.
2.3.3. Determination of Lipid Prole. Total, HDL-, and LDL-
cholesterol (T-Chol, HDL-Chol, and LDL-Chol, resp.) and
triglicerydes (TG) concentrations in serum were estimated
using routine techniques (Cobas Integra 400 plus analyzer,
Roche Diagnostics, Mannheim, Germany). The concentra-
tions were expressed in mg/dl. The inter- and intra-assay
coecients of variations (CV) were, respectively, 2.8% and
5.4% for T-Chol, 3.2% and 5.4% for HDL-Chol, 2.6% and
6.5% for LDL-Chol, and 2.5% and 7.6% for TG.
The triglycerides/HDL-cholesterol (TG/HDL) and
LDL-cholesterol/HDL-cholesterol (LDL/HDL) ratios were
calculated.
2.3.4. Determination of PAPP-A, Soluble CD40 Ligand, and
PlGF. Serum pregnancy-associated plasma protein-A
(PAPP-A) (catalogue number EIA-4512), soluble CD40
3Oxidative Medicine and Cellular Longevity
Ligand (sCD40L) (catalogue number EIA4851), and pla-
cental growth factor (PlGF) (catalogue number EIA-4529)
concentrations were assayed by ELISA methods with
DRG Instruments GmbH (Germany) kits. All assays were
performed according to the manufacturers instructions.
The PAPP-A and sCD40L concentrations were expressed in
ng/ml, the PlGF concentrationin pg/ml. The inter- and
intra-assay coecients of variations (CV) were, respectively,
6.8% and 10.2% for PAPPA-A, 5.1% and 9.4% for sCD40L,
and 6.2% and 12.1% for PlGF.
2.4. Assay of Intima-Media Thickness. A high-resolution
Doppler ultrasonography was performed with a Logic-5
device with a high-frequency (11 MHz and 15 MHz) linear
probe. The sonographer was an angiologist who was unaware
of subjects clinical state. Measurement of intima-media
thickness (IMT) was performed in the right and left common
carotid arteries, and the average of the 2 measurements was
calculated. The IMT was expressed in mm.
2.5. Assay of Activity of Ankylosing Spondylitis. The activity of
ankylosing spondylitis was measured by the Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) and the Bath
Ankylosing Spondylitis Functional Index (BASFI).
The BASDAI has six questions related to fatigue, back
pain, peripheral pain, peripheral swelling, local tenderness,
and morning stiness (degree and length). Other than the
item relating to morning stiness, all questions were scored
from 0 (none) to 10 (very severe) using a visual analogue
scale (VAS). The sum was calculated as the mean of two
morning stiness items and the four remaining items [35].
The BASFI is the mean score of ten questions addressing
functional limitations and the level of physical activity
at home and work, assessed on VAS scales (0 = easy,
10 = impossible) [36].
2.6. Statistical Analyses. Statistical analyses were undertaken
using the statistical package of Statistica 10 Pl software. For
each parameter, the indicators of the descriptive statistics
were determined (mean value and standard deviation
(SD)). The normality of the data distribution was checked
using the Shapiro-Wilk test, while the homogeneity of the
variance was checked by applying the Levene test. In order
to compare the dierences between the control group and
the AS group, an independent sample Studentst-test was
used or alternatively the MannWhitney Utest. Correlations
between particular parameters were statistically veried by
means of Spearmans nonparametric correlation test. Dif-
ferences at the signicant level of p<0 05 were considered
statistically signicant.
3. Results
3.1. Oxidative Stress. In AS patients, there was a signicantly
higher activity of antioxidant enzymes: plasma SOD, along
with erythrocyte SOD, erythrocyte CAT, erythrocyte GPx,
and erythrocyte GR, was observed in comparison to the
healthy subjects. But the plasma activity of SOD-Mn and
SOD-CuZn isoenzymes in both groups did not dier signi-
cantly. What is more, in AS patients, a signicantly lower
concentration of the parameters of nonenzymatic antioxi-
dants, FRAP, PSH, and UA, was observed in comparison to
the healthy subjects (Table 2).
Furthermore, a signicantly higher concentration of lipid
peroxidation products plasma MDA, along with erythrocyte
MDA, ox-LDL, and ab-ox-LDL, was noted in AS patients in
comparison to the control group of the healthy subjects. In
addition, in AS patients, the concentration of TOS was signif-
icantly higher in comparison to the control group (Table 3).
3.2. Lipid Prole, Inammatory Parameters, and Carotid
Intima-Media Thickness. In AS patients, there was a signi-
cantly higher concentration of the lipid prole parameters:
T-Chol, LDL-Chol, and TG as well as TG/HDL ratio and
LDL/HDL ratio were noted in comparison to the control
group. But only the concentration of HDL-Chol in both
groups did not dier signicantly. What is more, also the
concentrations of sCD40L and PlGF as well as carotid IMT
Table 2: Parameters of enzymatic antioxidant status (superoxide dismutase (SOD), its isoenzymes: manganese superoxide dismutase
(SOD-Mn) and copper-zinc superoxide dismutase (SOD-CuZn), catalase (CAT), glutathione peroxidase (GPx), and glutathione
reductase (GR) activity) and nonenzymatic antioxidant status (ferric reducing ability of plasma (FRAP), protein sulfhydryl (PSH), and
uric acid (UA) concentration, as well as activity of ceruloplasmin (CER)) in ankylosing spondylitis (AS) patients and healthy subjects.
Parameter AS patients (n=48) Healthy subjects (n=48)p
SOD (p) (NU/ml) 12.67 ±1.98 10.93 ±2.55 <0.001
SOD-Mn (p) (NU/ml) 5.08 ±2.00 4.59 ±1.88 0.223
SOD-CuZn (p) (NU/ml) 7.64 ±2.31 6.79 ±1.99 0.055
SOD (e) (NU/mgHb) 105.85 ±22.60 95.50 ±19.18 0.017
CAT (e) (IU/mgHb) 410.98 ±63.56 352.55 ±77.21 <0.001
GPx (e) (IU/gHb) 27.23 ±6.43 24.49 ±5.00 0.022
GR (e) (IU/gHb) 1.67 ±0.58 1.38 ±0.43 0.007
FRAP (p) (μmol/l) 550.38 ±76.98 642.17 ±105.67 <0.001
PSH (s) (μmol/l) 474.46 ±192.06 559.07 ±215.14 0.045
UA (s) (mg/dl) 4.73 ±1.39 5.84 ±1.53 <0.001
Values are expressed as means ±standard deviations (SD) of the means; p: plasma; s: serum; e: erythrocyte lysates.
4 Oxidative Medicine and Cellular Longevity
were signicantly higher in AS patients in comparison to the
healthy group. The concentration of PAPP-A in both groups
did not dier signicantly. Furthermore, in AS patients, a
signicantly higher concentration of all the examined
parameters of inammatory state, ESR, hs-CRP, and CER,
was observed in comparison to the healthy subjects (Table 4).
3.3. Signicant Relationships among the Estimated
Parameters in AS Patients. In the AS group, a high, statisti-
cally signicant correlation was observed between acute
phase proteins (hs-CRP versus CER; r=0 59,p<0 05), total
SOD activity in erythrocytes and ceruloplasmin (r=0 52,
p<005), and glutathione cycle enzyme activities in eryth-
rocytes (POX versus GR; r=066,p<0 05) as well as
between uric acid concentration and FRAP activity in
plasma (r=065,p<0 05). Mild but still statistically signif-
icant correlations were shown between CRP concentration
and SOD-CuZn and SOD-Mn plasma activities (r=035,
p<005), erythrocyte MDA concentration and SOD
erythrocyte activity (r=035,p<005), sCD40L and PlGF
concentration (r=0 51,p<005), plasma MDA and T-Chol
(r=030,p<0 05), and TOS and TG/HDL ratio (r=037,
p=0001). Also, a high correlation between BASFI and
BASDAI was observed (r=0 67,p<0 05) in AS patients.
Unfortunately, no statistically signicant correlations
between AS activity parameters (BASFI and BASDAI) and
oxidative stress parameters as well as carotid IMT and oxida-
tive stress parameters were obtained.
4. Discussion
Briey, in this observational study, we viewed signicantly
higher oxidative stress parameters, levels of inammatory
state, and lipid prole parameters, sCD40L, and PlGF as well
as values of TG/HDL, LDL/HDL ratio, and carotid IMT in
AS patients with active phase (BASDAI and BASFI),
compared to the healthy subjects.
In the available literature, only a few, unequivocal reports
concerning the prooxidant-antioxidant status in patients
with ankylosing spondylitis have been published.
In the study [20], in patients with ankylosing spondylitis,
a signicantly lower plasma total antioxidant status (TAS)
was demonstrated, as well as higher values of the total
oxidant status (TOS) and oxidative stress index (OSI), in
comparison to the control group of healthy volunteers. That
study did not reveal any signicant correlation between
the values of the above parameters and the activity of the
disease process.
In another study [22], no signicant dierences were
demonstrated to occur in the activity of SOD, nitric oxide
(NO) metabolites, and the concentration of MDA, between
the group of patients with AS in the active form and the
group of patients with inactive process. The activity of
SOD, NO metabolites, and the concentration of MDA also
failed to demonstrate statistically signicant dierences when
compared to the control group of healthy subjects, whereas
the activity of CAT and the concentration of MDA in
patients with an active form of the disease were signicantly
higher, in relation to other groups of subjects studied.
In the study [37], all antioxidant enzyme activities were
lower, but the MDA level was higher in patients with AS
when compared to the control group.
Table 3: Oxidative stress parameters: malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), antibodies to oxidized low-
density lipoprotein (ab-ox-LDL), and total oxidant status (TOS) concentration in ankylosing spondylitis (AS) patients and healthy subjects.
Parameter AS patients (n=48) Healthy subjects (n=48)p
MDA (p) (μmol/l) 2.51 ±0.63 2.25 ±0.47 0.025
MDA (e) (nmol/gHb) 0.17 ±0.03 0.15 ±0.03 <0.001
ox-LDL (s) (ng/ml) 268.48 ±105.83 162.98 ±63.29 <0.001
ab-ox-LDL (s) (mU/ml) 479.82 ±328.39 323.82 ±210.26 0.007
TOS (s) (μmol/l) 26.99 ±10.65 16.50 ±6.87 <0.001
Values are expressed as means ±standard deviations (SD) of the means; p: plasma; s: serum; e: erythrocyte lysates.
Table 4: Parameters of lipid prole (total cholesterol (T-Chol), low-
density lipoprotein cholesterol (LDL-Chol), high-density lipoprotein
cholesterol (HDL-Chol), triglicerydes (TG) concentration, TG/HDL,
and LDL/HDL ratio), concentration of PAPP-A, soluble CD40
ligand (sCD40L), PlGF, and value of carotid intima-media
thickness (IMT), as well as parameters of inammatory state
(erythrocyte sedimentation rate (ESR) value, high sensitivity C-
reactive protein (hs-CRP), and ceruloplasmin (CER)
concentration) in ankylosing spondylitis (AS) patients and
healthy subjects.
Parameter AS patients
(n=48)
Healthy subjects
(n=48)p
T-Chol (s) (mg/dl) 217.73 ±35.48 187.09 ±18.57 <0.001
LDL-Chol (s) (mg/dl) 140.49 ±33.64 112.57 ±22.89 <0.001
HDL-Chol (s) (mg/dl) 61.10 ±18.08 57.49 ±15.16 0.291
TG (s) (mg/dl) 190.48 ±47.30 139.74 ±47.66 <0.001
TG/HDL ratio 3.37 ±1.13 2.57 ±1.23 <0.001
LDL/HDL ratio 2.55 ±1.1 2.02 ±0.58 <0.05
PAPP-A (s) (ng/ml) 17.82 ±16.22 14.24 ±4.35 0.281
sCD40L (s) (ng/ml) 8.93 ±3.74 5.54 ±2.37 <0.001
PlGF (s) (pg/ml) 25.8 ±8.99 19.77 ±3.27 <0.001
Carotid IMT (mm) 1.1 ±0.13 0.55 ±0.08 <0.001
ESR 27.13 ±21.55 5.94 ±3.91 <0.01
hs-CRP (s) (mg/l) 14.92 ±15.55 1.58 ±2.00 <0.001
CER (s) (mg/dl) 48.12 ±12.67 38.68 ±4.84 <0.001
Values are expressed as means ±standard deviations (SD) of the means;
s: serum.
5Oxidative Medicine and Cellular Longevity
The next paper [38] reported that ESR, CRP, and lipid
peroxidation products were higher in patients with AS than
in healthy subjects, but vitamins A, C, E, and β-carotene con-
centrations in plasma, reduced glutathione, and glutathione
peroxidase activity values in erythrocyte were lower in
patients with AS than in healthy subjects. But the authors
estimated only some chosen parameters of prooxidant-
antioxidant status. Furthermore, the level of oxidative stress
was shown to be correlated with the intensity of inamma-
tion in patients with AS [21].
Contrastingly, there are many papers, which reported
increased cardiovascular risk in AS patients [3943].
In the current study, a signicant increase in acute-phase
protein concentration (hs-CRP and CER) was observed in AS
patients compared to the healthy subjects. A signicant pos-
itive correlation between hs-CRP and CER was shown as well
as a signicant negative correlation between hs-CRP and
plasma SOD-CuZn.
Some researchers found that increased AS disease activity
was associated with decreases in lipid levels and the decrease
in HDL-Chol levels, which tended to be almost twice as large
as the decrease in total cholesterol levels, resulting in a more
atherogenic lipid prole [43, 44].
However, in the study [45] in AS patients, the authors did
not observe a signicant dierence in T-Chol, LDL-Chol,
HDL-Chol, and TG concentration compared to healthy
subjects. But in AS patients, the values of HDL/LDL ratio,
complex intima-media, and TOS concentration as well as
inammatory state parameters were signicantly higher than
in controls. In this study, a signicant increase in T-Chol,
LDL-Chol, and TG as well as TG/HDL and LDL/HDL ratio
was observed in comparison to the healthy subjects. But
HDL-Chol concentration did not dier between AS patients
and healthy subjects. In addition, the carotid IMT in AS
patients was also signicantly higher in comparison to the
healthy subjects.
A high level of cholesterol, especially in LDL, may acti-
vate thrombocytes and cause the release of substances that
activate phospholipase A
2
. Then, the accumulated arachi-
donic acid is metabolized to leukotriene by a lipoxygenase
pathway and thromboxane, prostaglandin, and MDA by a
cyclooxygenase pathway. During this metabolism, ROS
may be produced, and under insucient antioxidant capac-
ity, they may also trigger lipid peroxidation [44]. What is
more, it was shown that the TG/HDL ratio estimates ath-
erogenic small, dense low-density lipoprotein cholesterol
and predicts arterial stiness and hard cardiovascular
events in adults [46, 47]. In our study, we observed a
signicant positive correlation between TOS and TG/
HDL ratio.
Additionally, it was also shown that an increase in serum
LDL levels leads to an increase in the adherence of circulating
monocytes to arterial endothelial cells and at the same time
to an increased rate of entry of LDL into the intima [48]. It
is also possible that TG enrichment may alter the physico-
chemical properties of LDL, which is considerably more
susceptible to oxidation [49].
In this study, we also observed the increased concentra-
tion of lipid peroxidation products in plasma and erythrocyte.
MDA is one the most abundant aldehydes, resulting from
peroxidation of arachidonic, eicosapentaenoic, and docosa-
hexaenoic acid [50, 51]. MDA reacts with lysine residues by
forming Schibases [52] and plays a major role in LDL mod-
ication and their deviation towards macrophages [48].
In the current study, a signicantly higher concentration
of MDA in plasma as well as in erythrocytes in AS patients
was observed compared to healthy subjects. A positive corre-
lation between plasma MDA and T-Chol as well as erythro-
cyte MDA and SOD in AS patients was also shown. We did
not observe any correlation between MDA and other esti-
mated parameters. The explanation of this fact may be that
TBARS assay does not measure MDA exclusively, because
it reacts to compounds other than MDA [51].
However, so far, there are no reports estimating ox-LDL
and ab-ox-LDL concentration in ankylosing spondylitis. In
the present study, a signicantly higher concentration of
ox-LDL as well as ab ox-LDL in AS patients was observed
compared to healthy subjects.
In the study [53], it was shown that antibodies to ox-LDL
were correlated signicantly with ESR and CRP in patients
with early rheumatoid arthritis and suggested that the
occurrence of these antibodies must be related to inamma-
tion. However, in the current study, no correlation was
observed between ox-LDL and ab-ox-LDL and other esti-
mated parameters.
In our study, we observed a signicantly higher levels of
sCD40L and PlGF as well as a positive correlation between
them. Furthermore, in this study, the level of PAPP-A did
not dier between AS patients and healthy subjects. It may
be connected with the fact that PAPP-A is expressed in
unstable but not in stable atherosclerotic plaques [18].
The study proved that increased oxidative stress, the
levels of sCD40L and PlGF, the disturbance of lipids, and
the inammation process may enhance atherogenesis in
AS patients.
However, the study has some limitations. First, it
involved only 48 AS patients and thus a greater number of
patients should be examined. Second, patients in dierent
stages of AS should be involved in the study.
5. General Conclusion
Our results demonstrate that increased oxidative stress,
higher serum concentrations of PlGF and sCD40L, and
increased IMT may reect the acceleration of atherosclerosis
in male AS patients in active phase and without concomitant
classical cardiovascular risk factors.
Conflicts of Interest
The authors declare that there is no conict of interests
regarding the publication of this paper.
Acknowledgments
This work was support by a grant from the Medical
University of Silesia (KNW-1-045/K/7/K).
6 Oxidative Medicine and Cellular Longevity
References
[1] J. Braun and J. Sieper, Ankylosing spondylitis,Lancet,
vol. 369, no. 9570, pp. 13791390, 2007.
[2] L. E. Dean, G. T. Jones, A. G. MacDonald, C. Downham,
R. D. Sturrock, and G. J. Macfarlane, Global prevalence
of ankylosing spondylitis,Rheumatology, vol. 53, no. 4,
pp. 650657, 2014.
[3] C. Han, D. W. Robinson, M. V. Hackett, L. C. Paramore, K. H.
Fraeman, and M. V. Bala, Cardiovascular disease and risk
factors in patients with rheumatoid arthritis, psoriatic arthritis,
and ankylosing spondylitis,Journal of Rheumatology, vol. 33,
no. 4, pp. 21672172, 2006.
[4] N. Bodnár, G. Kerekes, I. Seres et al., Assessment of sublinical
vascular disease associated with ankylosing spondylitis,The
Journal of Rheumatology, vol. 38, no. 4, pp. 723729, 2011.
[5] P. Libby, P. M. Ridker, and G. K. Hansson, Inammation in
atherosclerosis: from pathophysiology to practice,Journal of
the American College of Cardiology, vol. 54, no. 23, pp. 2129
2138, 2009.
[6] R. Ross, Atherosclerosis: an inammatory disease,New
England Journal of Medicine, vol. 340, no. 2, pp. 115126,
1999.
[7] B. V. Kural, A. Orem, G. Cimşit, Y. E. Yandi, and M.
Calapoglu, Evaluation of the atherogenic tendency of lipids
and lipoprotein content and their relationships with oxidant-
antioxidant system in patients with psoriasis,Clinica Chimica
Acta, vol. 328, no. 1-2, pp. 7182, 2003.
[8] G. Vogiatzi, D. Tousoulis, and C. Stefanadis, The role of oxi-
dative stress in atherosclerosis,Hellenic Journal of Cardiology,
vol. 50, no. 5, pp. 402409, 2009.
[9] B. H. Hahn, J. Grossman, W. Chen, and M. McMahon, The
pathogenesis of atherosclerosis in autoimmune rheumatic dis-
eases: roles of inammation and dyslipidemia,Journal of
Autoimmunity, vol. 28, no. 2-3, pp. 6975, 2007.
[10] E. Galkina and K. Ley, Immune and inammatory mecha-
nisms of atherosclerosis,Annual Review of Immunology,
vol. 27, pp. 165197, 2009.
[11] E. Matsuura, L. R. Lopez, Y. Shoenfeld, and P. R. Ames,
β2-glycoprotein I and oxidative inammation in early ath-
erogenesis: a progression from innate to adaptive immu-
nity?Autoimmunity Reviews, vol. 12, no. 2, pp. 241249,
2012.
[12] M. Puurunen, M. Mänttäri, V. Manninen et al., Antibody
against oxidized low density lipoprotein predicting myocardial
infarction,Archives of Internal Medicine, vol. 154, no. 22,
pp. 26052609, 1994.
[13] E. Maggi, G. Finardi, M. Poli et al., Specicity autoantibodies
against oxidized LDL as an additional marker for atheroscle-
rotic risk,Coronary Artery Disease, vol. 4, no. 12, pp. 1119
11122, 1993.
[14] J. Balla, M. T. Magyar, D. Bereczki et al., Serum levels of plate-
let released CD40 ligand are increased in early onset occlusive
carotid artery disease,Disease Markers, vol. 22, no. 3,
pp. 133140, 2006.
[15] M. Yuan, H. Fu, L. Ren, H. Wang, and W. Guo, Soluble CD40
ligand promotes macrophage foam cell formation in the etiol-
ogy of atherosclerosis,Cardiology, vol. 131, no. 1, pp. 11-12,
2015.
[16] P. Pervanidou, G. Chouliaras, A. Akalestos et al., Increased
placental growth factor (PlGF) concentrations in children
and adolescents with obesity and the metabolic syndrome,
Hormones, vol. 13, no. 3, pp. 369374, 2014.
[17] C. Roncal, I. Buysschaert, N. Gerdes et al., Short-term delivery
of anti-PlGF antibody delays progression of atherosclerotic
plaques to vulnerable lesions,Cardiovascular Research,
vol. 86, no. 1, pp. 2936, 2010.
[18] J. Lund, Q. P. Qin, T. Ilva et al., Circulating pregnancy-
associated plasma protein a predicts outcome in patients with
acute coronary syndrome but no troponin I elevation,Circu-
lation, vol. 108, no. 16, pp. 19241926, 2003.
[19] T. Mueller, B. Dieplinger, W. Poelz, and M. Haltmayer,
Increased pregnancy-associated plasma protein-a as a marker
for peripheral atherosclerosis: results from the Linz peripheral
arterial disease study,Clinical Chemistry, vol. 52, no. 6,
pp. 10961103, 2006.
[20] M. Karakoc, O. Altindag, K. Keles, N. Soran, and S. Selek,
Serum oxidative-antioxidative status in patients with anky-
losing sponydilitis,Rheumatolology International, vol. 27,
no. 12, pp. 11311134, 2007.
[21] L. D. Kozaci, I. Sari, A. Alacacioglu, S. Akar, and N. Akkoc,
Evaluation of inammation and oxidative stress in ankylos-
ing spondylitis: a role for macrophage migration inhibitory
factor,Modern Rheumatology, vol. 20, no. 1, pp. 3439,
2010.
[22] S. Ozgocmen, S. Sogut, O. Ardicoglu, E. Fadillioglu, I.
Pekkutucu, and O. Akyol, Serum nitric oxide, catalase, super-
oxide dismutase, and malondialdehyde status in patients with
ankylosing spondylitis,Rheumatology International, vol. 24,
no. 2, pp. 8083, 2004.
[23] D. Solmaz, D. Kozacı,İ. Sarıet al., Oxidative stress and
related factors in patients with ankylosing spondylitis,
European Journal of Rheumatology, vol. 3, no. 1, pp. 20
24, 2016.
[24] A. Stanek, G. Cieślar, E. Romuk et al., Decrease in antioxidant
status in patients with ankylosing spondylitis,Clinical Bio-
chemistry, vol. 43, no. 6, pp. 565570, 2010.
[25] S. van der Linden, H. A. Valkenburg, and A. Cats, Evaluation
of diagnostic criteria for ankylosing spondylitis. A proposal for
modication of the New York criteria,Arthritis Rheumatol-
ogy, vol. 27, no. 4, pp. 361368, 1984.
[26] Y. Oyanagui, Revaluation of assay methods and establish-
ment of kit for superoxide dismutase activity,Analytical
Biochemistry, vol. 142, no. 2, pp. 290296, 1984.
[27] H. Aebi, Catalase in vitro,Methods in Enzymology, vol. 105,
pp. 121126, 1984.
[28] D. Paglia and W. Valentine, Studies of the quantities and
qualitative characterization of erythrocyte glutathione peroxi-
dase,Journal of Laboratory and Clinical Medicine, vol. 70,
no. 1, pp. 158169, 1967.
[29] R. Richterich, Clinical Chemistry: Theory and Practice,
Academic Press, New York, 1969.
[30] I. F. F. Benzie and J. J. Strain, The ferric reducing ability of
plasma (FRAP) as a measure of antioxidant power: the FRAP
assay,Analytical Biochemistry, vol. 239, no. 1, pp. 7076,
1996.
[31] J. F. Koster, P. Biemond, and A. J. Swaak, Intracellular and
extracellular sulphydryl levels in rheumatoid arthritis,Annals
of the Rheumatic Diseases, vol. 45, no. 1, pp. 4446, 1986.
[32] Y. Zhao, X. Yang, W. Lu, H. Liao, and F. Liao, Uricase based
methods for determination of uric acid in serum,Microchi-
mica Acta, vol. 164, no. 1, pp. 16, 2009.
7Oxidative Medicine and Cellular Longevity
[33] H. Ohkawa, N. Ohishi, and K. Yagi, Assay for peroxides in
animal tissue by thiobarbituric acid reaction,Analytical
Biochemistry, vol. 95, no. 2, pp. 351358, 1979.
[34] O. Erel, A new automated colorimetric method for measuring
total oxidant status,Clinical Biochemistry, vol. 38, no. 12,
pp. 11031111, 2005.
[35] S. Garrett, T. Jenkinson, L. G. Kennedy, H. Whitelock, P.
Gaisford, and A. Calin, A new approach to dening disease
status in ankylosing spondylitis: the Bath Ankylosing Spon-
dylitis Disease Activity Index,Journal of Rheumatology,
vol. 21, no. 12, pp. 22862291, 1994.
[36] A. Calin, S. Garrett, H. Whitelock et al., A new approach to
dening functional ability in ankylosing spondylitis: the devel-
opment of the Bath Ankylosing Spondylitis Functional Index,
The Journal of Rheumatology, vol. 21, no. 12, pp. 22812285,
1984.
[37] O. V. Mitrofanova, V. V. Bagirova, and S. I. Krasikov, Levels
of lipid peroxidation products and activity of antiradical
defense enzymes in blood of patients with Bechterew disease,
Terapevtichesky Arkhiv, vol. 74, no. 5, pp. 6669, 2002.
[38] M. Nazıroğlu, S. Akkuş, and H. Celik, Levels of lipid peroxi-
dation and antioxidant vitamins in plasma and erythrocytes
of patients with ankylosing spondylitis,Clinical Biochemistry,
vol. 44, no. 17-18, pp. 14121415, 2011.
[39] R. Agca, S. C. Heslinga, V. P. van Halm, and M. T. Nurmo-
hamed, Atherosclerotic cardiovascular disease in patients
with chronic inammatory joint disorders,Heart, vol. 102,
no. 10, pp. 790795, 2016.
[40] K. Eriksson, L. Jacobsson, K. Bengtsson, and J. Askling, Is
ankylosing spondylitis a risk factor for cardiovascular disease,
and how do these risks compare with those in rheumatoid
arthritis?Annals of the Rheumatic Diseases, vol. 76, no. 2,
pp. 364370, 2016.
[41] S. C. Heslinga, I. A. OeverVan den, A. M. SijlVan et al.,
Cardiovascular risk management in patients with active
ankylosing spondylitis: a detailed evaluation,BioMed Central
Musculoskeletal Disorders, vol. 16, no. 80, 2016.
[42] A. Bremander, I. F. Petersson, S. Bergman, and M. Englund,
Population-based estimates of common comorbidities and
cardiovascular disease in ankylosing spondylitis,Arthritis
Care & Research, vol. 63, no. 4, pp. 550556, 2011.
[43] S. Mathieu, L. Gossec, M. Dougados, and M. Soubrier,
Cardiovascular prole in ankylosing spondylitis: a systematic
review and meta-analysis,Arthritis Care & Research,
vol. 63, no. 4, pp. 557563, 2011.
[44] V. P. Halmvan, J. C. Denderenvan, M. J. Peters et al.,
Increased disease activity is associated with a deteriorated
lipid prole in patients with ankylosing spondylitis,Annals
of the Rheumatic Diseases, vol. 65, no. 11, pp. 14731477, 2006.
[45] A. Kucuk, A. Uğur Uslu, A. Icli et al., The LDL/HDL ratio and
atherosclerosis in ankylosing spondylitis,Zeitschrift für
Rheumatologie, vol. 76, no. 1, pp. 5863, 2016.
[46] A. Cordero, E. Andrés, B. Ordoñez et al., The trigliceryde/
high-density lipoprotein cholesterol ratio for predicting the
rst coronary event in men,American Journal of Cardiology,
vol. 104, no. 10, pp. 13931397, 2009.
[47] E. M. Urbina, P. R. Khoury, C. E. McCoy, L. M. Dolan, S. R.
Daniels, and T. R. Kimball, Triglyceride to HDL-C ratio and
increased arterial stiness in children, adolescents, and young
adults,Pediatrics, vol. 131, no. 4, pp. e1082e1090, 2013.
[48] J. Steinberg, Low density lipoprotein oxidation and its patho-
logical signicance,Journal of Biological Chemistry, vol. 272,
no. 34, pp. 2096320966, 1997.
[49] L. E. Schreier, H. Mosso, G. I. Lopez, L. Siri, and R. W.
Wikinski, Low density lipoprotein composition and oxidabil-
ity in atherosclerotic cardiovascular disease,Clinical Chemis-
try, vol. 29, no. 5, pp. 479487, 1999.
[50] H. Esterbauer, R. J. Schaur, and J. Zollner, Chemistry and
biochemistry of 4-hydroxynonenal, malonaldehyde and related
aldehydes,Free Radical Biology and Medicine, vol. 11, no. 1,
pp. 81128, 1991.
[51] A. Ayala, M. F. Muroz, and S. Arguelles, Lipid peroxidation:
production, metabolism, and signaling mechanisms of malon-
dialdehyde and 4-hydroxy-2-nonenal,Oxidative Medicine
and Cellular Longevity, vol. 2014, Article ID 360438, 31 pages,
2014.
[52] H. Esterbauer, Cytotoxicity and genotoxicity of lipid-
oxidation products,American Journal of Clinical Nutrition,
vol. 57, 5 Supplement, pp. 779S786S, 1993.
[53] L. Paimela, T. Helve, M. Leirisalo-Repo et al., Clinical signif-
icance of antibidies against oxidized low density lipoprotein in
early RA,Annals of the Rheumatic Diseases, vol. 55, no. 8,
pp. 558-559, 1996.
8 Oxidative Medicine and Cellular Longevity
... Measurements were made using a Logic-5 ultrasound system with a 11-15 MHz vascular transducer. The IMT was presented in mm [28]. ...
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Objective. Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects the axial skeleton, leading to joint disability. Our study aims at investigating the change of oxidative and antioxidative stress linked biomarkers in AS. Methods. This systematic review and meta-analysis was performed following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Web of Science, and Cochrane Library databases till May 2020 were searched. Only articles published in English were included. Two reviewers screened relevant studies, extracted data, and assessed the quality of included studies using the Newcastle-Ottawa scale independently. Either random or fixed effect model was adopted base on the heterogeneity testing by statistic. Standardized mean difference (SMD) and 95% confidence intervals (CI) of oxidative and antioxidative markers were calculated. value <0.05 was considered statistically significant. Results. A total of 22 studies including 931 AS patients and 917 healthy controls met the selection criteria. Significantly increased levels of all oxidative stress markers except myeloperoxidase, and significantly decreased levels of total antioxidant status (, 95% CI -2.35 to -0.03, ) and paraoxonase 1(, 95% CI -1.78 to -0.24, ) in serum were observed in AS patients when compared with healthy controls. However, there were no significant differences of all oxidative and anti-oxidative stress biomarkers in erythrocytes. Additionally, the levels of malondialdehyde (, 95% CI 0.21 to 0.81, ) and advanced oxidation protein products (, 95% CI 0.58 to 1.31, ) in serum were significantly higher in active patients when compared with inactive AS patients. Conclusion. This meta-analysis demonstrated an overall increase of oxidative markers and decrease of antioxidative markers in AS, suggesting that oxidative stress may play an important role in the pathogenesis of AS. 1. Introduction Ankylosing spondylitis (AS) is the major subtype of spondyloarthropathies involving predominantly the sacroiliac joints and axial skeleton and can lead to impairments in joint structures, new bone formation, and disability [1]. Furthermore, other specific organs and systems such as eyes, skin, kidneys, gastrointestinal tract, and cardiovascular system can be affected with the development of AS, resulting in decreased quality of life [2]. Although the etiology of AS is still unclear, it has been reported that oxidative stress may play an important role in the pathogenesis of AS [3, 4]. Oxidative stress refers to the imbalance of oxidative and antioxidative systems, resulting in an increase of reactive oxygen species (ROS) [5]. ROS including nitric oxide, superoxide, and hydroxyl radical anion can be produced in normal cellular metabolism and is crucial for cell proliferation, differentiation, apoptosis, and signal transduction with a low concentration [6]. However, oxidative stress happens when the speed of the increase of ROS exceeds the capacity of antioxidant to eliminate them, triggering oxidative damage to lipids, proteins, and DNA [5]. Various byproducts would be produced in oxidative damage such as malondialdehyde (MDA) and advanced oxidation protein products (AOPP). MDA is a marker of lipid peroxidation [7], which can work as secondary mediators to cause further damage [8]. AOPP, a marker of protein oxidation products with earlier formation and greater stability in the process of oxidative damage, can also demonstrate oxidative stress [3]. On the contrary, antioxidants such as catalase, superoxide dismutase (SOD), and paraoxonase (PON) can protect against oxidative damage [9]. For example, SOD can convert superoxidative radicals to hydrogen peroxide by disproportionation, and then hydrogen peroxide can be reduced to water and oxygen by CAT [10]. Therefore, the concentrations of antioxidants also reflect the oxidative stress state. Oxidative stress is associated with inflammation, the pathological hallmark of AS [11]. On one hand, inflammatory cells can promote the release of various enzymes to induce oxidative stress [12]. On the other hand, a number of ROS accumulating at the site of inflammation can enhance proinflammatory responses by activating the inflammatory signal pathways [13]. The interconnected relationship between bone inflammation and oxidative stress in AS contributes to bone resorption [8, 14]. Acting as both cause and effect, inflammatory cytokines and oxidative stress can promote the formation and activation of osteoclast to enhance bone loss in AS [8]. Signal pathways activated by proinflammatory cytokines and oxidative stress products also play a key role in the progression of bone mass loss in AS [14]. In addition, new bone formation is another pathological feature of AS. Although the role of oxidative stress in new bone formation is still unclear, it is reported that ROS is related to the activation of Wnt/Beta-catenin and BMP/Smad pathways which are involved in the progression of new bone formation in AS [15, 16]. Up to now, the levels of oxidative and antioxidative biomarkers in serum and erythrocytes of AS patients have been assessed in several studies. However, the results in different studies were inconsistent. Thus, we aimed to investigate the change of oxidative and antioxidative stress linked biomarkers in AS and to explore the potential role of oxidative stress in the pathogenesis of AS. To our knowledge, this is the first meta-analysis of oxidative and antioxidative biomarkers in AS. 2. Methods 2.1. Literature Search Strategy This systematic review and meta-analysis was performed following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in INPLASY (registration number: INPLASY202050066). PubMed, Web of Science, and Cochrane Library databases till May 2020 were searched following the protocol. The search terms are as follows: (“oxidative” or “oxidation” or “oxidant” or “oxidat” or “antioxidant” or “antioxidative” or “antioxidat” or “redox”) AND (“spondylitis, ankylosing” or “spondyloarthritis ankylopoietica” or “ankylosing spondylarthritis” or “ankylosing spondylarthritides” or “spondylarthritides, ankylosing” or “spondylarthritis, ankylosing” or “ankylosing spondylitis” or “spondylarthritis ankylopoietica” or “bechterew disease” or “bechterew’s disease” or “bechterew s disease” or “marie strumpell disease” or “marie strumpell disease” or “rheumatoid spondylitis” or “spondylitis, rheumatoid” or “spondylitis ankylopoietica” or “ankylosing spondyloarthritis” or “ankylosing spondylarthritides” or “spondylarthritides, ankylosing” or “spondyloarthritis, ankylosing” or “axial spondyloarthritis” or “peripheral spondyloarthritis” or “radiographic axial spondyloarthritis”). There was no language restriction when searching the above databases. Two independent reviewers searched the above databases and screened the titles and abstracts. In addition, references of searched studies were reviewed to identify additional relevant studies. After that, full texts of relevant studies were reviewed. Any disagreements between two reviewers were resolved by the third author. 2.2. Inclusion and Exclusion Criteria Studies were included when they met the following criteria: (1) case-control or cohort study, (2) measurement of oxidative or antioxidative stress biomarkers in any type of samples from AS patients and healthy controls, and (3) English language. Exclusion criteria are as follows: (1) reviews, case reports, letters, meeting, and abstracts; (2) insufficient data; and (3) animal or in vitro study. 2.3. Data Extraction The data of studies meeting the selection criteria were extracted by two authors independently. Any disagreements between two reviewers were resolved by the third author. The following data were extracted: first author, publication year, country of studies, age, gender, sample size and source, type of markers, the concentration of oxidative or antioxidative markers, diagnostic criteria, and disease activity. The Newcastle-Ottawa scale (NOS) was used to assess the quality of included studies. 2.4. Statistical Analysis The parameters reported in two or more studies were stratified based on the type of markers and sample source (serum or erythrocytes). Then, meta-analysis of the following biomarkers was conducted: total oxidant status (TOS), malondialdehyde (MDA), myeloperoxidase (MPO), advanced oxidation protein products (AOPP), nitric oxide (NO), total antioxidant status (TAS), paraoxonase (PON), arylesterase (ARE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thiol, and glutathione reductase (GR). Standardized mean difference (SMD) and 95% confidence intervals (CIs) of oxidative and antioxidative markers were calculated. Median, range, or interquartile interval was transformed into mean and SD according to the method of Hozo et al. [17]. The heterogeneity among included studies was calculated using the statistic. The random effect model was adopted if the heterogeneity was high ( or ); otherwise, fixed effect model was adopted. The publication bias was assessed by Egger’s test. Sensitivity analysis was conducted for oxidative and antioxidative biomarkers measured in more than three studies by excluding a study one by one and repeating the meta-analysis. Statistical analyses were performed using STATA software (version 15.1, StataCorp, College Station, US). value<0.05 was considered statistically significant. 3. Results The study selection process was shown in Figure 1. Primary search generated 392 records, and 98 of duplications were removed. After screening the titles and abstracts, 255 articles were excluded. 39 full-text articles were assessed, and 17 articles were excluded because of data insufficiency and irrelevance of content or article type. Finally, 22 studies with 931 AS patients and 917 healthy controls were included in the systematic review and meta-analysis.
... Increased blood levels of sCD40L and PIGF were observed in these patients. Importantly, these patients were not burdened with classic cardiovascular risk factors [59]. Whole-body cryotherapy decreases the levels of Inflammatory, oxidative stress, and atherosclerosis plaque markers in male patients with active phase ankylosing spondylitis in the absence of classical cardiovascular risk factors [60]. ...
... Few publications have examined AS and CD40. One of them describes an increased risk of atherosclerosis in AS patients through analysis of many factors, including increased level of soluble CD40 ligand (Stanek et al., 2017). ...
Article
While the recent literature on Whole-Body Cryotherapy pointed to its beneficial systemic effects on inflammatory markers in rheumatoid arthritis, it was not clear whether it could also have more localized effects, with the attainment of analgesic thresholds on hands that are usually protected during protocols. Twenty-five young, healthy subjects (12 males aged 25.1 ± 3.5 years and 13 females aged 23.5 ± 2.6 years) agreed to participate in this study. Two study groups were defined: (1) a control group with a hand fully gloved and (2) an experimental group with a partially ungloved hand during the WBC session. In both groups, the achievement of analgesic thresholds of skin temperature was established through thermal imaging, focused on the measurement of temperatures at the different joint locations. Using a new protocol with direct exposure of the hands during the last 40 s of a standard WBC session of 3 min at −110 °C made it possible to respect this risk/benefit balance. Infrared thermography analyses revealed that for all regions of interest (except MCP and IP, CMP for thumb), there was a clinically meaningful reduction of skin temperature in participants from the experimental group. The thermal analysis suggests that a protocol of Whole-Body Cryotherapy at −110 °C where hands must be ungloved during 40 s could be a useful tool for the management of hand rheumatoid arthritis by achieving local antalgic thresholds.
Article
Full-text available
Background Ankylosing spondylitis (AS) is an inflammatory disease with documented elevated cardiovascular (CV) risk due to systemic inflammation and a higher prevalence of CV risk factors. CV risk management (CV-RM) could be an effective method to reduce CV mortality and morbidity in AS patients. We assessed CV risk and evaluated guideline adherence according to the Dutch CV-RM guideline. Methods This study was conducted with a cohort of consecutive AS patients eligible for treatment with a tumor necrosis factor (TNF) -α inhibitor. Data from the Dutch National Institute for Public Health and Environment was used to compare the prevalence of CV risk factors in AS patients with the Dutch background population. Results In total, 254 consecutive AS patients were included. The prevalences of hypertension (41% vs 31%) and smoking (43% vs 27%) were substantially higher in AS patients as compared to the general Dutch background population. Of 138 AS patients older than 40 years the 10-years CV risk could be calculated. Fifty-one of these 138 patients (37%) had an indication for CV risk treatment. CV risk treatment was initiated in 42 of the 51 (82%), however, in only 12 of the 51 (24%) patients treatment targets for either hypertension or hypercholesterolemia were reached. Conclusion The increased rates of hypertension and smoking illustrate the importance of CV-RM in AS patients. Although the majority of all AS patients eligible for CV-RM received CV risk medication, CV-RM remains a challenge for treating physicians, as treatment targets were not achieved in three-quarter of the eligible patients.
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Objectives In ankylosing spondylitis (AS) patients, cardiac and vascular involvement may manifest as atherosclerosis and coronary artery disease. Systemic inflammation, oxidative stress, increased low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol constitute a significant risk for atherosclerosis. This study investigated the relationship between carotid intima–media thickness (CIMT), LDL/HDL ratio, total oxidant status (TOS; an indicator of oxidative stress) and ischemic modified albumin (IMA; an ischemic marker in AS patients). Patients and methods Sixty AS patients were diagnosed using the Modified New York Criteria; 54 age- and gender-matched participants were included as controls. CIMT, LDL/HDL ratio, TOS and IMA were measured using the most appropriate methods. Results IMA was higher in AS patients compared to controls (p < 0.0001). TOS was also increased in AS patients (p = 0.005); as was CIMT (p < 0.0001). The LDL/HDL ratio was also greater in AS patients compared to controls (p = 0.047). A positive correlation was found between CIMT and LDL/HDL ratio among AS patients. Conclusion Elevated CIMT, IMA and TOS levels suggest an increased risk of atherosclerotic heart disease in AS patients. The LDL/HDL ratio was higher in AS patients compared to controls, and there was a correlation between LDL/HDL ratio and CIMT, albeit statistically weak. Therefore, the LDL/HDL ratio is not a reliable marker to predict atherosclerotic heart disease in AS patients.
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Aims To assess and compare the incidence of cardiovascular (CV) events, by CV phenotype, between patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA) and the general population. Methods Using linkages of national and population-based registers, we identified one cohort of prevalent patients with AS (n=5358), one with RA (n=37 245) and one with matched general population subjects (n=25 006). These cohorts were identified in 2006 through 2011 and were followed in 31 December 2012, for first ever occurrence of acute coronary syndromes (ACS), deep venous thromboembolism, pulmonary embolism and stroke, respectively. For each outcome, we calculated incidence rates standardised to the age and sex distribution of the AS cohort, as well as relative risks using Cox proportional hazards models. Results Based on 69 ACS events during 20 251 person-years of follow-up of the patients with AS, and 966 events during 127 014 person-years in the RA cohort, the age/sex-adjusted relative risks for ACS compared with the general population was 1.3 (95% CI 1.0 to 1.7) for AS and 1.7 (1.4 to 2.0) for RA. For thromboembolic events, the corresponding risks were 1.4 (1.1 to 1.9) in AS and 1.8 (1.5 to 2.1) in RA. Finally, for stroke, the relative risks were 1.5 (1.1 to 2.0) in AS and 1.5 (1.2 to 1.8) in RA, compared with the general population. Conclusions Prevalent patients with AS are at a 30%–50% increased risk of incident CV events. When compared with patients with RA, this level of increase was similar for stroke, but only half as high for ACS and thrombotic events.
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Inflammatory joint disorders (IJD), including rheumatoid arthritis (RA), ankylosing spondylitis (ASp) and psoriatic arthritis (PsA), are prevalent conditions worldwide with a considerable burden on healthcare systems. IJD are associated with increased cardiovascular (CV) disease-related morbidity and mortality. In this review, we present an overview of the literature. Standardised mortality ratios are increased in IJD compared with the general population, that is, RA 1.3-2.3, ASp 1.6-1.9 and PsA 0.8-1.6. This premature mortality is mainly caused by atherosclerotic events. In RA, this CV risk is comparable to that in type 2 diabetes. Traditional CV risk factors are more often present and partially a consequence of changes in physical function related to the underlying IJD. Also, chronic systemic inflammation itself is an independent CV risk factor. Optimal control of disease activity with conventional synthetic, targeted synthetic and biological disease-modifying antirheumatic drugs decreases this excess risk. High-grade inflammation as well as anti-inflammatory treatment alter traditional CV risk factors, such as lipids. In view of the above-mentioned CV burden in patients with IJD, CV risk management is necessary. Presently, this CV risk management is still lacking in usual care. Patients, general practitioners, cardiologists, internists and rheumatologists need to be aware of the substantially increased CV risk in IJD and should make a combined effort to timely initiate CV risk management in accordance with prevailing guidelines together with optimal control of rheumatic disease activity. CV screening and treatment strategies need to be implemented in usual care.
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Objective Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine and sacroiliac joints of unknown etiology. Recent studies have reported increased oxidative stress, which is implicated in the pathogenesis of a number of diseases, in AS. The purpose of this study was to investigate oxidative stress and related factors in AS.
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Aim: To study lipid peroxidation (LPO) in Bechterev's disease (BD) treated with antiinflammatory and antioxidant drugs. Material and methods: LPO was estimated in 75 BD patients before medication and during this treatment. 30 healthy volunteers served control. Results: Levels of LPO products was high but activity of antioxidant defense enzymes low in BD patients. Conclusion: Antiinflammatory drugs meloxicam, indometacin and an antioxidant drug triovit depressed LPO activity, improve the patients' condition and results of functional tests.