ARTICLE
Auteur(s) :, Samia Esmat1, Hanan
EL Sherif2, Somaya Anwar2, Ibtsam
Fahmy3, Manal Elmenyawi4, Olphat
Shaker5
1Department of Dermatology,
2Department of Rheumatolgy,
3Department of Neurology,
4Department of Internal Medicine,
5Department of Biochemistry, Faculty of Medicine, Cairo
University, Egypt
accepté le 30 Août 2005
Behcet’s disease (BD) is a chronic relapsing disorder with
particular systemic features including thrombotic events, both
arterial and venous in origin [1]. The precise pathogenic mechanism
underlying the thrombotic tendency in Behcet’s disease is still
obscure, but vasculitic endothelial cell injury and/or dysfunction
with hypofibrinolysis have been suggested to play crucial roles
[2]. The fibrinolytic process operates in a complex manner in which
plasminogen activator binding kinetics may be altered
[3].Lipoprotein (a) (Lp(a)) is recognised as a cardiovascular risk
factor, implicated in atherogenic and thrombogenic processes [4].
This might occur via inhibition of plasminogen activation and
thereby interference with the fibrinolytic process [5]. Serum Lp
(a) levels are genetically determined by protein structure, little
influenced by diet, age and gender [6]. Previous reports have
indicated that it is influenced by disease states such as
rheumatoid arthritis and cancer [7, 8].Nitric oxide (NO) is another
molecule of key importance for the vascular system as well. It is
an important mediator of immunity and inflammation that is
responsible for the inhibition of platelet adhesion and endothelial
vasorelaxation [9]. It is generated from L-arginine by 3 different
nitric oxide synthase (NOS) isoforms in many cells. Type I neuronal
(nNOS), type II inducible (iNOS) and type III endothelial (eNOS).
Only one of them (iNOS) is a Ca2+ -independent isoform;
it can be induced by cytokines during inflammatory and infectious
processes and generates large amounts of NO [10].Since NO is
synthesized in the endothelium, it is considered to be an
interesting point of investigation in BD. It has a brief half-life
so measurement of the stable end product of NO metabolism, total
nitrite, in serum is usually used as a marker of NO production
[11].Changes in endothelial cell mediated production and release of
substances as a result of vasculitic damage have been reported to
be related to disease activity in BD [12]. The present study aimed
at assessment of serum levels of lipoprotein (a) and nitrites in
Behcet’s disease patients and studying their relations to clinical
features and disease activity.
Patients and methods
Subjects
The study was conducted on 30 cases of Behcet’s disease, randomly
recruited from the Rheumatology, Dermatology and Internal Medicine
Outpatient Clinics of Cairo University Hospitals. All patients
satisfied the criteria of the international Study Group for
Classification of Behcet’s Disease [13].
Fourteen age-matched healthy volunteers served as controls.
Clinical assessment
Each patient was subjected to thorough clinical evaluation, and
accordingly patients were allocated into two groups: active BD, and
inactive BD (active/inactive: 17/13). The disease was considered
active if worsening of at least two of the major clinical symptoms
was present at the time of the study (oral or genital ulcerations;
anterior/posterior or panuveitis; papulopustular skin lesions;
positive pathergy test). Patients showing no clinical or laboratory
disorders related to BD for at least one month were considered as
having inactive disease [14].
Vascular involvement was assessed by Doppler ultrasound.
No patients had received any systemic medications for at least
one month prior to the study.
Each patient and control was subjected to: complete blood count,
erythrocyte sedimentation rate (ESR); liver (bilirubin, SGOT, SGPT)
and kidney (urine analysis, serum urea and creatinine) function
tests, serum lipids (triglycerides (TG), total cholesterol, High
density lipoproteins (HDL) and low density lipoproteins (LDL)).
Serum levels of Lipoprotein(a) were estimated using IMUBIND
Lp(a), enzyme immunoassay (ELISA) according to the method of Craig
[15]. Kit was provided by American Diagnostica Incorporation.
Serum concentration of nitrite is an index of nitric oxide (NO)
production because NO is an extremely unstable molecule rapidly
oxidized to nitrite. Serum levels of nitrite were measured
according to the method of Benjamin and Vallence [11].
Statistical methods
Data were processed on a personal computer, utilizing “SPSSWIN”
statistical package. Range, mean and standard deviation were given.
Chi-square, Student t-test and Mann Whitney U test were used when
appropriate. Two tailed analysis with P value less than 0.05 was
considered significant. Correlation analysis was performed using
pearson correlation.
Results
Among the 30 patients studied, there were 26 males and four
females. Their ages ranged from 17 to 55 years (mean: 32.83 ± 10.01
years). The disease duration ranged from 0.25 to 28 years (mean:
6.96 ± 7.00 years).
The general features and clinical manifestations of the studied
group are displayed in table 1( Table 1
).
Sixteen patients (53.3%) had vascular complications and all of
them were men. They suffered more venous than arterial events.
There was a high prevalence of deep venous thrombosis (12 patients
- 40%). Caval thrombosis involving different segments of either
superior or inferior vene cava was present in 4 patients (13.3%).
Superficial thrombophlebitis occurred in four patients. Arterial
events were evident in 4 patients (13.3%); arteritis associated
with aneurysm formation in 3 patients (10%), pulmonary aneurysms
complicated with haemoptysis and pulmonary embolism in 2 patients,
saccular aortic aneurysm leading to occlusion of the left external
iliac artery and proximal part of common femoral artery in one
patient (3.3%) and arterial thrombosis in one patient (3.3%).
Serum HDL were decreased in patients compared to the control
goup (P < 0.004) (table 2( Table 2
)). Serum HDL levels were significantly lower in BD patients with
vascular damage than the other Behcet’s disease patients (P <
0.012) (table 5( Table 5 )).
Serum Lp (a), TG and cholesterol concentrations were
significantly higher in Behcet’s disease patients than in controls
(P = 0.0001, P = 0.029 and P = 0.001 respectively) (table 2).
twelve of the patients (40%) had a serum Lp (a) > 0.30 gm/l.
Serum Lp (a) level showed a significant positive correlation
with serum cholesterol (r = 0.478), (P = 0.008) and LDL (r = 0.585,
0.0001), a significant inverse correlation with HDL (r = 0.598, P =
0.0001).
Comparison of the mean Lp (a) concentrations according to the
presence or absence of some disease parameters of the patient group
revealed that serum Lp (a) was significantly higher in patients
with vascular complications (P = 0.02) (table 3( Table 3 )).
Nitrites concentrations were decreased in patients compared to
controls (P = 0.0001) (table 2).
Comparison of the mean nitrite levels according to the presence
or absence of some clinical disease manifestations, showed that
serum nitrites were significantly lower in Behcet’s disease
patients with erythema nodosum (P = 0.008) (table 4( Table 4 )), and in active Behcet’s patients than in
inactive group (P = 0.04) (table 6( Table
6 )).
When BD patients with and without vascular complications were
compared, males were significantly more prevalent among patients
with vascular complications (P = 0.022). No significant differences
were found concerning age, disease duration, triglycerides,
cholesterol, smoking, hypertension and diabetes (table 5).
When the active and inactive BD groups were compared, ESR and
WBCs count were significantly elevated during activity while total
serum nitrite concentrations were significantly lower (P = 0.04)
(table 6).
Table 1 The general features and clinial manifestations
of Behcet’s disease patients
|
Item
|
Number of patients (30)
|
Percentage of cases
|
|
Mean age
|
32.83 ± 10.01 years
|
-
|
|
Mean age of onset
|
25.87 ± 7.9 years
|
-
|
|
Mean disease duration
|
6.96 ± 7.00 years
|
-
|
|
Male: female ratio
|
26 : 4
|
-
|
|
Oral ulcers
|
30
|
100
|
|
Genital ulcers
|
27
|
90
|
- Skin lesions:
- papulopustular
- erythema nodosum like
- dermal vasculitis
|
|
|
|
Skin pathergy test
|
18
|
60
|
- Eye findings:
- anterior uveitis
- posterior uveitis
- retinal vasculitis
- optic neuropathy
- papilloedema
|
|
|
|
Vascular findings
|
16
|
53.3
|
|
Cardiac manifestations
|
3
|
10
|
|
Chest manifestations
|
8
|
26.7
|
- Neurological manifestations:
- - ataxia
- - migraine
- - pyramidal tract signs
- - cranial nerve
- - stroke
- - aseptic meningitis
|
|
- 53.3
- 3.3
- 43.3
- 20
- 16.7
- 13.3
- 3.3
|
|
Articular manifestation
|
13
|
43.3
|
|
Gastrointestinal manifestations
|
2
|
6.7
|
Table 2 Comparison between Behcet’s disease patients
and controls
|
Item
|
|
|
P
|
|
240.90 ± 170.64
|
66.79 ± 10.37
|
0.0001*
|
|
8.99 ± 3.87
|
25.38 ± 2.68
|
0.0001*
|
|
36.37 ± 13.83
|
49.64 ± 12.54
|
0.004*
|
|
116.27 ± 68.73
|
73.14 ± 26.78
|
0.029*
|
|
293.27 ± 114.19
|
177.57 ± 20.65
|
0.001*
|
Table 5 Determination of possible risk factors for
Behcet’s disease patients with vascular complications
|
Item
|
- BD with vascular affection
- (n = 16)
|
- BD without vascular affection
- (n = 14)
|
P
|
|
Age
|
31.75 ± 9.69
|
34.07 ± 10.59
|
0.254
|
|
Disease duration
|
6.56 ± 6.83
|
7.41 ± 7.42
|
0.452
|
|
Sex (male)
|
16
|
10
|
0.0221
|
|
Smoking
|
7
|
8
|
0.271
|
|
Hypertension
|
4
|
2
|
0.152
|
|
Diabetes
|
3
|
1
|
0.231
|
|
HDL
|
30.13 ± 6.05
|
43.50 ± 16.78
|
0.012*
|
|
Cholesterol
|
307.13 ± 126.54
|
277.43 ± 100.54
|
0.361
|
|
TG
|
114.94 ± 25.99
|
117.79 ± 98.76
|
0.706
|
|
Lp (a)
|
280.62 ± 127.26
|
195.50 ± 205.19
|
0.02*
|
Table 3 Comparison of mean lipoprotein (a) levels
(mg/l) according to the presence or absence of some disease
parameters in Behcet’s patients
|
Item
|
Present
|
Absent
|
P
|
|
Genital ulcers
|
248.37 ± 173.34
|
173.67 ± 155.00
|
0.163
|
|
Erythema nodosum
|
295.50 ± 277.38
|
227.25 ± 137.89
|
0.292
|
|
Eye problems
|
207.53 ± 136.62
|
274.27 ± 198.14
|
0.253
|
|
Cardiac
|
311.67 ± 119.46
|
223.21 ± 178.82
|
0.192
|
|
Chest
|
213.22 ± 129.88
|
252.76 ± 187.03
|
0.093
|
|
Vascular1
|
280.62 ± 127.26
|
195.50 ± 205.19
|
0.022
|
|
Neurological
|
253.12 ± 217.92
|
226.93 ± 98.81
|
0.343
|
|
Articular
|
236.00 ± 219.62
|
244.65 ± 128.71
|
0.392
|
|
Gastrointestinal
|
179.75 ± 130.60
|
250.30 ± 176.17
|
0.251
|
Table 4 Comparison of mean nitrite levels (Mmol/l)
according to the presence or absence of some disease prameters in
Behcet’s patients
|
Item
|
Present
|
Absent
|
P
|
|
Genital ulcers
|
9.26 ± 3.96
|
6.60 ± 1.75
|
0.266
|
|
Erythema nodosum
|
6.52 ± 1.65
|
9.61 ± 4.03
|
0.008*
|
|
Eye problems
|
8.74 ± 4.14
|
9.27 ± 3.66
|
0.716
|
|
Cardiac
|
9.02 ± 4.18
|
8.98 ± 3.88
|
0.985
|
|
Chest
|
8.18 ± 5.21
|
9.29 ± 3.35
|
0.496
|
|
Vascular
|
8.61 ± 4.14
|
9.43 ± 3.64
|
0.570
|
|
Neurological
|
9.50 ± 3.89
|
8.41 ± 3.89
|
0.450
|
|
Articular
|
9.33 ± 4.61
|
8.73 ± 3.32
|
0.681
|
|
Gastrointestinal
|
10.85 ± 5.78
|
8.70 ± 3.56
|
0.310
|
Table 6 Comparison between active and inactive groups
of Behcet’s disease patients
|
Item
|
|
|
P
|
|
Lp (a)
|
275.94 ± 191.78
|
195.08 ± 131.57
|
0.155
|
|
Nitrite2
|
7.86 ± 3.45
|
10.47 ± 4.01
|
0.041
|
|
ESR
|
52.76 ± 30.82
|
23.31 ± 16.32
|
0.0081
|
|
HB
|
11.78 ± 1.62
|
12.11 ± 2.13
|
0.453
|
|
WBCs
|
8.23 ± 1.99
|
6.59 ± 1.63
|
0.0241
|
|
Platelets
|
344.65 ± 137.12
|
267.15 ± 72.22
|
0.221
|
Discussion
Lp (a) has been associated with both antifibrinolytic and
atherogenic effects. It is structurally related to LDL [4]. It has
been reported through in vitro studies that the serum levels of Lp
(a) can interfere with process of plasminogen-plasmin conversion,
resulting in decreased generation of plasmin and attenuation of
clot lysis at the endothelial surface [16]. Due to its marked
structural homology with plasminogen [4], Lp (a) competes with it
for binding the fibrin fragments located in the plasma membrane of
endothelial cells, platelets and macrophages [5, 17].
Inflammation causes alteration of lipoprotein and vascular
endothelial structure and functions to favor atherogenesis and
increases the concentration of atherogenic proteins in serum.
Lipoprotein(a) is known to be an acute phase protein and is
significantly correlated with acute phase reactants [18].
In the present study, elevated serum Lp(a) concentrations, TG
and cholesterol were noticed in Behcet’s disease patients compared
to the controls. HDL concentrations were lower in patients than in
the control group. In addition, Lp(a) levels were directly
correlated with serum cholesterol and inversely with HDL. Örem et
al. [19] and Gurbuz et al. [20] reported increased plasma Lp(a)
levels and reduced HDL-C concentrations [19] in the BD
patients.
The prevalence of vascular involvement in BD varies from 7.7 to
43% according to the ethnicity of the studied population [21-23].
In this study, 53.3% (16/30) prevalence of vascular lesions was
obtained; all of the affected patients were males. None of the four
female patients in the study had vascular complications. Out of the
26 male patients, twelve (46.2%) had deep vein thrombosis while
four (13.3%) had arterial events. This indicates that males are a
high risk group for vascular affection in BD. Ames et al. reported
that BD patients had a 14-fold relative risk of undergoing a venous
occlusion and a 5.4-fold relative risk of suffering an arterial
event in gender-adjusted data of BD. They reported that male
patients had a higher risk of vein thrombosis while arterial
occlusions were more common in females patients [24].
In this study, significantly higher Lp(a) levels in BD patients
with vascular complications was observed compared to other
patients. Twelve of the patients (40%) had a serum Lp(a) greater
than 0.3 gm/l; the value at which the atherogenic and thrombogenic
risks were considered to be increased [25]. A similar observation
was reported by Glueck and coworkers in patients with a history of
thrombophlebitis [26]. In another report, increased Lp(a) was
associated with elevated PAI-1 in the patients with thrombotic
complications leading them to speculate that Lp(a) has a possible
role in defective fibrinolysis related to the pathophysiology of
vasculitis in certain instances [19].
Etingin and his associates [27] showed that Lp(a) stimulates
plasminogen activator inhibitor-1 (PAI-1) secretion from
endothelial cells. While Aitchison et al., reported reduced tissue
plasminogen activators and increased PAI-1 secretions from
endothelial cells in patients with Behcet’s disease with a possible
deficiency in endothelial heparin-like activity [28]. These two
effects may cause decreased fibrinolytic activity independently, or
in combination. However, no direct link currently exists with
intravascular coagulation. Caplice et al., suggested that Lp(a)
through its apolipoprotein (A) moiety may promote thrombosis by
binding and inactivating tissue factor pathway inhibitor in a
concentration dependent manner as well [29].
BD patients have a high atherogenic potential as marked by the
significantly lower HDL, and higher cholesterol and triglicerides
concentrations compared to controls. The significantly high level
of serum Lp(a) and its significant negative correlation with HDL
suggests that it is another important atherogenic factor in BD. Its
significantly higher level in BD patients with vascular occlusion,
introduces Lp(a) as an important risk factor for thrombosis in
these patients.
Serum level of Lp(a) was higher in the group with active BD
compared to inactive group, but the diference was not statistically
significant. A 23% decrease of plasma Lp(a) was obtained by Orem et
al., 1995 during disease activity [30]. These fluctuations of
plasma LP(a) might increase the risk of thrombogenic complications
in patients with active BD.
Nitric oxide-generating cells and proinflammatory cytokines
including interleukin 1β (IL-1β), IL-2, IL-6 and tumor necrosis
factor, have been reported to be implicated in BD pathogenesis
[31]. These cytokines may be involved in the upregulation of
endothelial cells; they also induce iNOS.
In this study, the serum level of nitrites was found to be lower
in Behcet’s disease patients compared to controls and when
correlated to the clinical findings a significant decrease was
obtained in patients during activity and in those with erythema
nodosun-like lesions.
The decreased nitrite levels observed in the active period may
be due to rapid transformation of NO to peroxynitrite produced as a
result of the interaction of NO with superoxide anion [32].
Peroxynitrite, is itself a powerful oxidizing cytotoxic agent that
may also yield the hydroxy radical [33].
It might be postulated that nitric oxide production may be
decreased as one of the consequences of the endothelial dysfunction
in Behçet’s disease [34]. On the other hand, being responsible for
endothelial vasorelaxation and inhibition of platelet aggregation
during inflammation [9], the decrease in NO production might play
an important role in the development of thrombotic events or other
pathophysiological changes occurring in patients with Behcet’s
disease. This was evidenced by the significant association found in
this work between decreased serum nitrite with disease activity and
erythema nodosum lesions. Leucocytoclastic vasculitis is a
characteristic pathological feature in erythema nodosum like
lesions of BD compared to erythema nodosum associated with other
systemic diseases [35].
Other different studies were carried out to determine the
possible association of BD, antioxidant status and the nitric oxide
levels with controversial results. One study reported the absence
of any significant differences that suggest the importance of NO in
BD [36]. Other authors reported a significant decrease in nitrite
concentrations in the serum [14] as well as in tears (in BD with
uveiits) [32] during disease activity. Others found a significant
increase in serum NO metabolite levels [37, 38]. They stated that
NO might have critical biological activities in the vasculitic
events during disease activity. These controversies in nitrite
levels might be related to the instability of NO and its changes
during different states of disease activity.
We could therefore conclude that increased serum lipoprotein(a)
and decreased nitrite levels may contribute to vascular damage and
endothelial defects important in the etiopathogenesis of BD. Lp (a)
is a significant risk factor for atherogenesis and thrombosis in
those patients. Decreased nitrites can be considered as a marker of
disease activity that might be related to endothelial
dysfunction.
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