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IL-17 AND THE FEATURES OF THE COURSE OF PSORIATIC DISEASE AND THE FORMATION OF ATHEROSCLEROSIS IN PATIENTS WITH PSORIATIC ARTHRITIS
Khimion L.
MD, Dr., Full Professor, Head of Department of Family Meicine (Institute of Family Meicine) Shupyk National Medical Academy of Postgraduate Education, Kyiv Ukraine,
Boiko A. p.h.d. student
Shupyk National Medical Academy of Postgraduate Education, Kyiv Ukraine,
ABSTRACT
The study of the connection of psoriasis and cardiovascular diseases is paid much attention by domestic and foreign scientists. The article is devoted to the study of the relationship of traditional risk factors (RF) for cardiovascular diseases (CVD) with the activity of the inflammatory process and atherosclerosis in patients with psoriatic arthritis (PsA). The study included 52 patients with PsA who did not have atherosclerotic CVD, diabetes, chronic kidney disease and other serious diseases, did not take statins, the control group consisted of 20 patients with psoriasis (PS) and 20 practically healthy individuals who had no signs of rheumatic, infectious and other inflammatory diseases were screened. It was revealed that in patients with PsA, the severity of the atherosclerotic process is more compared with patients with PS (the RF profiles were the same). The content of IL-17 in serum significantly correlates with the clinical and laboratory characteristics of PsA (PASI index, DAS28), which confirms the role of this cytokine in the immunopathogenesis of psoriatic arthritis and has an indirect effect on the severity of atherosclerotic process.
Keywords: psoriatic arthritis, psoriasis, cardiovascular diseases, dyslipidemia, atherosclerosis, C-reactive protein, uric acid, IL-17.
Introduction. Psoriatic arthritis (PsA) is a chronic, progressive systemic disease associated with psoriasis, with a predominant localization of the inflammatory process in the tissues of the musculoskeletal system. Particular interest in PsA is associated with an increase in the number of patients with this pathology and severe disabling consequences [1,2].
According to current concepts, PsA is regarded as a systemic autoimmune disease of a multifactorial nature. In this disease, violations of both cellular and humoral immunity are observed. In PsA, as with other
spondylarthritis, changes in the balance of pro- and anti-inflammatory cytokines are observed, which form a regulatory network and participate in the pathogenetic mechanisms of this type of arthritis [3]. Significant expression of cytokines-regulators of inflammation (interleukin (IL) -1, IL-8, tumor necrosis factor alpha (TNF-a), regulators of T-cell immune response (IL-2, IL-10, IL-12), regulators B-cell immune response (IL-4, IL-6, IL-16), as well as still insufficiently studied cytokines - IL-17, IL-20, etc. [4].
According to current data in the pathogenesis of psoriasis and PsA, interleukin-17 plays a key role.
Some researchers have found a significant increase in the amount of this cytokine in the serum of patients with psoriasis and dog. This revealed the ability of IL-17 to activate the synthesis of IL-1 and IL-6, which in turn have a destructive potential in the inflammatory process, as well as the synthesis of metalloproteinases (MMP-9), leading to tissue remodeling and the release of type II collagen degradation products . The role of IL-17 in regulating the function of chondrocytes and synoviocytes, stimulation of granulopoiesis has been revealed [5, 6,7].
IL-17 is crucial for the maintenance of hypertension and vascular dysfunction caused by angiotensin II and may be a therapeutic target for this common disease [8].
According to the results of one-dimensional and multivariate meta-analysis in patients with rheumatoid arthritis treated with biological drugs, IL-17 is a major predictor of microvascular dysfunction and arterial elasticity. This study suggests that IL-17 may play an important role in the development of endothelial dysfunction and cardiovascular disease in rheumatoid arthritis [9].
The experimental approach during the study demonstrated the causal relationship between skin production of IL-17A in the skin and systemic vascular dysfunction. The data demonstrate the possible role of IL-17A in the binding of skin and vascular diseases, the spread of cytokines and the active influence of neutro-philic granulocytes embedded in the vessel wall to cause vascular oxidative stress, inflammation and dysfunction, leading to arterial hypertension. Dermal overexpression of IL-17A causes systemic endothelial dysfunction, vascular oxidative stress, hypertension, and increases mortality, mainly caused by myeloperoxidase + CD11b + GR1 + F4 / 80 inflammatory cells. Depletion of GR-1 + immune cells or neutralization of IL-17A cytokines by biological agents attenuates the vascular phenotype in K14-IL-17Aind / + mice [10].
According to Hoanglan Nguyen, Valorie L. Chias-son, intensive treatment of IL-17 endothelial cells caused a significant increase in phosphorylation of the endothelial nitric oxide (NO) threonine 495 synthase inhibitor (eNOS Thr495). Of the kinases known for eNOS Thr495 phosphorylation, only inhibition of Rho kinase prevented IL-17-induced increase. IL-17 caused a threefold increase in the RhoA activator of the Rho kinase, and this was prevented by the neutralizing IL-17 antibody. In isolated muscle aortas, IL-17 significantly increased the phosphorylation of eNOS Thr495, induced the expression of RhoA, and decreased NO-dependent relaxation responses, which were all prevented by either neutralizing the IL-17 antibody or inhibiting Rho kinase. In mice, IL-17 treatment for 1 week significantly increased systolic blood pressure, and this was associated with decreased NO-dependent aortic responses to relaxation, increased eNOS Thr495 phosphorylation, and increased RhoA expression. Inhibition of Rho kinase prevented hypertension caused by IL-17. These data demonstrate that IL-17 activates RhoA / Rho kinase, leading to endothelial dysfunction and hypertension. IL-17 or Rho kinase inhibitors may
be useful as antihypertensive agents in autoimmune diseases associated with IL-17[11].
In modern literature, there is a rather large number of studies devoted to the search for additional RFs of CVD, the definitions of which may improve the assessment and prognosis in patients with PsA with different levels of cardiovascular risk. However, until now, there is no clear answer to many of the key issues that could significantly improve the effectiveness of prevention programs and significantly reduce the high mortality and morbidity rates of CVD in patients with PsA.
Aim. To determine the relationship of serum IL-17 with the features of the course of psoriatic disease and the formation of atherosclerosis in patients with PsA.
Materials and methods. The study included 52 patients with PsA who did not have atherosclerotic CVD, diabetes mellitus, chronic kidney disease, and others. severe illness, did not take statins. As a comparison group, 20 people from PS were compared, compared by age and sex. As a control group, 20 practically healthy individuals who had no signs of rheumatic, infectious and other inflammatory diseases were screened. The selection of the control group was done according to the gender and age of the examined patients. The selected patients, at the time of inclusion in the study, had no hypertension and did not take anti-hypertensive medications. All patients were provided with a complex of clinical and instrumental and laboratory examinations, a survey. Anthropometry, blood pressure measurements, questionnaires for the detection of bad habits (smoking, alcohol abuse), anthropometry were used to detect RF, and in order to assess the presence of depression and / or anxiety disorders, patients used the Hospital Alert and Depression Scale (HADS), which was designed to initially detect anxiety and depression in patients (screening) in general medical practice. The burden of heredity was determined by the presence of an atherosclerotic disease or a major RF (high blood pressure, diabetes, and DLP) in relatives of the first-line patient (mother or father) who manifested before the age of 55 in men and women up to the age of 65 years. The PASI (Psoriasis Area Severity Index) calculator was used to assess the degree of skin lesions. All patients with PsA determined the Disease Activity Score (DAS28) index for CRP, and was assessed at an average level of two years. The Alcohol Use Disorder (AUDIT) questionnaire was used for determining the risk group and the number of people who use the health-hazardous amount of alcohol. Identification Test, developed on the basis of the WHO Cooperative Project (1989). Tobacco use was assessed during an interview with the patient in accordance with the Order of the Ministry of Health of Ukraine dated 03.08.2012 № 601 "On Approval and Implementation of Medical-Technological Documents on Standardization of Medical Aid in the Termination of the Use of Tobacco Products".
All patients and controls were provided with a complex of clinical and laboratory and instrumental research. A general clinical examination included: a complete physical examination, a determination of the severity of psoriasis, an articular examination. Laboratory
grams, according to the GCP prior to the data processing. The results base and data preparation for mathematical processing were performed in MS Excel 2013.
Results. The average age of patients with PsA was 39,62 ± 5.8 years (25 (48,07%) women and 27 (51,92%) men), patients with PS (comparison group) 32,3 ± 5.63 years ( 8 (40%) women and 12 (60%) men), respectively, the control group included 11 women (55%) and 9 men (45%), mean age 32,3 ± 5,63, respectively. The duration of PsA ranged from 3 to 20 years. (Table 1). The polyarthritic variant of joint syndrome was observed in 48,0% (25 persons), oligoarthritic -30,76% (16 persons), spinal arthritis - 21,24% (11 persons). An increase in CHD was detected in 73.9% of patients with PsA (mean 5,23 ± 1.01). In terms of the activity of the articular process, remission was observed in 9,61% of patients, with an average degree of activity in 51,92%, and a high rate in 17,3%. All PsA patients had PS skin lesions.
The analysis of the prevalence and severity index of skin lesions in psoriasis (PASI index) revealed a significant difference between the PsA group (Table 1) and the comparison group and the control group. A significantly higher PASI index of moderate severity (>10> 20 points) of the skin was found in the PsA group compared to the PS and the control group (p <0.05).
The main clinical and demographic characteristics of the examined patients are presented in Table 1.
Table 1.
Clinico-demographic characteristics of patients included in the study
Indicator PsA PS Control group
n=52 without PsA n=20 n=20
Age, years 39,62±4,8 32,3±5,63 30,75±2,13
Women,( n/%) 25 (48,07%)* 8 (40%) 11 (55%)
Men,(n/%) 27 (51,92%) 12 (60%) 9 (45%)
Average duration of the disease 10,42±0,34* 4,1±0,57 -
DAS 28, points - -
Remission <2,6 5 (9,61%) - -
Low activity level >2,6<3,2 11 (21,15%) - -
Average degree of activity >3,2<5,1 27 (51,92%) - -
High degree of activity >5,1 9 (17,3%) - -
PASI, points 14,36±1,12* 7,2±1,05 -
Low activity level < 10 points n, % 9(17,31%)* 13(65%) -
Average degree of activity >10<20 points n, % 36 (69,23%)* 4 (20%) -
High degree of activity >20 points n, % 7 (13,46%) 3 (15%) -
research included determination of lipid, purine and high-sensitivity CRP indices.
In order to determine the state of the vascular wall, a duplex ultrasonic scan of carotid arteries (CA) was performed for all patients. According to the recommendations of the European Society of Cardiology, scanning of the CA was carried out in three planes - two longitudinal (front and rear) and one transverse. the thickness of the intima-media complex (IMT) was evaluated in the zone of maximal thickening in the orientation of the scanning plane of the longitudinal axis of the vessel. It was calculated the average value of the IMT of the right and left general CA as the mean of 9 measurements in 3 positions; the diagnostic criterion for thickening IMT was considered to be >0.9 mm, the presence of an atherosclerotic plaque, with a local thickening of TIMC of> 1.5 mm and more, or a thickening of more than 50% or 0.5 mm relative to other areas of IMT.
IL-17 was determined by enzyme-linked immunosorbent assay using a set of reagents manufactured by CJSC ELISA Kit: IL-17 (Human IL-17 (Interleukin 17) ELISA Kit), cat. No. E-EL-H0105, sensitivity: 18.75 pg / ml, measurement range: 31.25-2000 pg / ml.
The mathematical processing of the results was carried out in the IBM SPSS 20 and Statistica 10.0 pro-
Note: * the difference between the groups is significant p <0.05.
According to the results of the initial examination of patients, the frequency of detection of CVD behavioral RF (smoking, alcohol abuse, sedentary lifestyle) in the group of patients with PsA revealed a significant difference in smoking frequency (at any time in the last 10 years) and susceptibility to psycho-emotional overload in groups patients with skin lesions and control group. The frequency of combination of CVD RF in PsA patients is shown in Table 2.
According to the results of the analysis of lipid metabolism, a significant difference was observed between the mean levels of TC in the group of patients
with PSA (Table 2) compared with the control group. The median levels of TC, TG, LDL cholesterol, LDL cholesterol were significantly higher in patients with PsA, and VLDL cholesterol levels were significantly lower than those in the PS and control groups (p <0.05).
The increase in the levels of high-sensitivity CRP and US in the group of patients with PsA was noted in 76,92% (40 persons) and 21,15% (11 persons) respectively (Table 2).
Table 2.
Cardiovascular risk factors and state of the vascular wall in the examined patients
Indicator PsA n=52 PS without PsA n=20 Control group n=20
Smoking (at any time in the last 10 years), n,% of people 69,23% (6 ociö) * 52,63% (10 ociö) # 40% (8 ociö)
Hypodynamia, n, % of people 46,15% (24 ociö) 47,3% (9 ociö) # 30% (6 ociö)
Adiposity, n, % of people 17,3% (9 ocoön) 15,78% (3 ocoön) 5% (1 ocoön)
Stress, n, % of people 92,3% (48 ociö) * 84,2% (16 ociö) # 50% (10 ociö)
The heredity of cardiovascular disease is encumbered, n,% of people 69,23% (36 ociö) * 42,1% (8 ociö) 40% (8 ociö)
Incidence of DLP, % 82,26% (43 ociö)* 62,5% (20 ociö) 15% (3 ocoön)
TCh, mmol / l 5,37±0,2* 4,17±0,44 3,2±0,1
TG, mmol / l 2,45±0,2* 1,52±0,1# 1,32±0,2
HDL cholesterol, mmol / l 1,19±0,1 0,76±0,1# 1,32±0,1
LDL cholesterol, mmol / l 3,45±0,8* 2,43±0,3# 3,12±0,3
VLDL cholesterol, mmol / l 0,81±0,4*# 0,5±0,1# 0,62±0,1
Index of atherogenicity, c.u. 3,69±0,9*# 2,47±0,2# 2,7±0,2
CRP, (mg/l) 16,94±1,79*# 4,45±0,53# 0,77±0,2
UA (mkmmol / l) 402,85±15,24*# 326,68±15,59# 187,83±8,2
Fibrinogen 2,94±1,02 1,97±0,77# 1,9±0,2
SCORE 3,11±0,33*# 2,43±0,11# 1,71±0,11
<2 CVD RF, % <2 CVD RF, % 13,05%* 15,1%
3-5 CVD RF, % 3-5 CVD RF, % 69,56%* 68,1%
>5 CVD RF, % >5 CVD RF, % 17,39%* 16,8%
Average value TIM CA, mm 0,94±0,02*# 0,7±0,01# 0,64±0,02
TIMC> 0.9 45,83%*# 22, 58% 5%
Number of atherosclerotic plaques CA 7,61% (4 ociö)* # 0 0
Note: * the difference between the groups of patients is significant, p <0.05, # difference with rupture control is reliable, p <0.05.
Table 3.
PiBHi iHTep.ieHidHy 17 y oöGTOKeHHx xBopux Ha ncA Ta nC
Indicator PsA, PS
n=52 without PsA, n=20
DAS 28, points
Remission <2,6 26,00±1,01 -
Low activity level >2,6<3,2 134,80±2,03 -
Average degree of activity >3,2<5,1 169,20±6,85 -
High degree of activity >5,1 180,33±3,44 -
PASI, points
Low activity level < 10 points n, % - 61,09±0,81
Average degree of activity >10<20 points n, % - 91,75±1,11
High degree of activity >20 points n, % - 147,81±1,04
In the comparative analysis of lipid metabolism indexes, it was found that the average levels of TC, TG, and LDL cholesterol in patients with PsA significantly exceeded the corresponding indices in patients with PS and indicators of healthy individuals in the control group. In this correlation analysis, the greatest influence on IMT CA was found on DAS 28, TC, LDL cholesterol, CRP, FG, PASI, IL-17 (r = 0,54, 0,68, 0,67, 0,53, 0,52, 0,43, 0,36 in accordance). In the group of patients with DAS 28 of medium and high activity (>3,2), a strong correlation between the IMT CA and the level of UA (r = 0,61) was found. The level of HDL cholesterol was associated with a strong feedback with CRP and a median power of reverse linkage with UA
levels. There was a direct correlation between the level of FG and CRP and UA in the average strength (r = 0,54, 0,48, respectively). The given analysis in the group of patients with PS revealed: a direct connection of average strength between IMT CA, TC, LDL cholesterol, CRP (r = 0,37, 0,39, 0,38, respectively). The results of the correlation analysis confirm the relationship of inflammation with dyslipidemia, which plays a significant role in the progression of atherosclerotic vascular lesions and the subsequent formation of CVD. A correlation was found between IL-17 and DAS 28 (r = 0,48), between IL-17 and PASI (r = 0.61), between IL-17 and CRP (r = 0,38) and the direct relationship between TC and IL-17 (r = 0,37) (Table 4).
(Table 4).
Results of correlation analysis of levels of interleukin-17 and laboratory indices of PsA (Table 4)._
Correlating signs Correlation coefficient Significance level, р
Level IL-17 and PASI 0,61 р<0,05
Level IL-17 and DAS 28 0,48 р<0,05
Level IL-17 and TIMC 0,36 р<0,05
Level IL-17 and CRP 0,38 р<0,05
According to the results of ultrasound examination of carotid arteries, it was found that patients with PsA and PS have a greater severity of atherosclerotic process than healthy peers, which is confirmed by the higher average values of IMT in the group of patients with PsA (0,93 ± 0,02) p <0.05 compared with the group control (0,68 ± 0,02), with IMT > 0,9 detected in 45,83% of patients with PsA, which is proven complementary RF CDV and in 22,58% of patients with PS, which is significantly higher than the control group indicator (5%). It should be noted that the presence of atherosclerotic plaques is diagnosed in 6,25% of patients with PsA.
Conclusions: 1) In patients with PsA there is a significant increase in the number of IL-17 in the serum compared with healthy age-appropriate persons and patients with PS, which indicates the informative use of determining the level of IL-17 as a diagnostic criterion for psoriatic arthritis.
2) The content of IL-17 in serum significantly correlates with the clinical and laboratory characteristics of PsA (PASI index, DAS28), which confirms the role of this cytokine in the immunopathogenesis of psoriatic arthritis and has an indirect effect on the severity of atherosclerotic process.
3) The highest severity of atherosclerotic CA lesion (the largest IMT CA and the presence of atherosclerotic plaques) was found in patients with PsA with prolonged high activity of arthritis and high levels of IL-17 in serum.
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