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Список литературы
1. Денисенко Л.Н., Деревянченко С.П., Матвеев С.В. Применение проблемного метода обучения совместно с деловой игрой для обучения студентов стоматологического факультета // Международный журнал экспериментального образования. 2016. № 4-2. С. 232-234.
2. Деревянченко С.П., Денисенко Л.Н., Колесова Т.В. Роль социально-бытовых и медико-биологических факторов в формировании заболеваний
полости рта у девочек разных поколений // Волгоградский научно-медицинский журнал. 2015. № 1. С. 40-42.
3. Деревянченко С.П., Маслак Е.Е., Колесова Т.В. Знания родителей о профилактике стоматологических заболеваний у детей дошкольного возраста // Актуальные вопросы стоматологии Сборник материалов электронной научно-практической конференции, посвященной 80-летию профессора В. Ю. Миликевича. Волгоградский государственный медицинский университет. 2012. С. 44-47.
4. Троицкая Ю.И., Деревянченко С.П. Формирование ценностных ориентаций в процессе профессиональной подготовке студентов - стоматологов // Журнал научных статей Здоровье и образование в XXI веке. 2012. Т. 14. №4. С. 330.
5. Деревянченко С.П., Залевская А.В., Деревянченко А.О. Привычки питания как фактор, снижающий стоматологическое здоровье младших школьников // Электронный научно-образовательный вестник Здоровье и образование в XXI веке. 2010. Т. 12. № 11. С. 527.
Егудина Е.Д.
к.мед.н., доцент, ассистент кафедры пропедевтики внутренней медицины ГУ «Днепропетровская
медицинская академия» МОЗ Украины
ПОРАЖЕНИЕ СОСУДОВ У ПАЦИЕНТОВ С СИСТЕМНОЙ СКЛЕРОДЕРМИЕЙ VASCULAR LESIONS IN PATIENTS WITH SYSTEMIC SCLEROSIS
Iegudina Ie.D.,
PhD, Associate professor of the department of the propedeutic of the internal medicine, SE "Dnepropetrovsk Medical Academy" of Health Ministry of Ukraine
АННОТАЦИЯ
Манифестное поражение сосудов наблюдается у 88% от числа больных ССД, клинические, инструментальные и морфологические признаки которого тесно связаны со степенью активности патологического процесса и длительностью болезни, с характером «вегетативного паспорта» (ваготонический и сим-патотонический тип вегетативной нервной системы), с серопозитивностью заболевания по антитопоизо-меразным антителам, антинуклеарному фактору, антителам к нативной дезоксирибонуклеиновой кислоте и кардиолипину. Ангиопатия при ССД сопровождается повышением легочного сосудистого сопротивления, развитием легочной гипертензии и изменениями процессов вазодилатации, при этом интегральные сосудистые клинические, инструментальные и морфологические параметры влияют на тяжесть склеродер-мической пневмопатии и нефропатии, выраженность пролиферации эндотелия, лимфогистиоцитарной инфильтрации и микротромбозирования сосудов. Иммунологические параметры, наряду с интегральным уровнем эндотелиальной сосудистой дисфункции, участвуют в патогенетических построениях васкулопа-тии при ССД и обладают у таких пациентов прогностической значимостью.
ABSTRACT
The manifest vascular lesion occurs in 88% of patients with SSc, clinical, instrumental and morphological features of which are closely related to the degree of activity of pathological process and the duration of the disease, the nature of the "vegetative passport" (vagotonic and simpathotonic type of autonomic nervous system), with seropositivity of the diseases on anti-topoisomerase antibodies, antinuclear factor, antibodies to native deoxyribonucleic acid and cardiolipin. Angiopathy in SSc is accompanied by an increase of pulmonary vascular resistance, development of pulmonary hypertension and change processes of vasodilation, while the integrated vascular clinical, instrumental and morphological parameters have an influence on the severity of scleroderma pneumopathy and nephropathy, severity of endothelial cell proliferation, lymphohistiocytic infiltration and microthrombosis of vessels. Immunological parameters, along with an integral level of vascular endothelial dysfunction, participate in the pathogenetic constructions of vasculopathy in SSc and have prognostic significance in these patients.
Ключевые слова: склеродермия, сосуды, ангиопатия, течение, патогенез.
Keywords: scleroderma, vessels, angiopathy, course, pathogenesis.
Introduction. Among rheumatological disease the part of systemic sclerosis (SSc) is about 2%, [22], and the number of such patients is increasing everywhere [16]. One of the main manifestations of SSc is a vascular lesion [20,17], the morphological study of the skin and internal organs reveals the signs of angiopathy in all cases in these patients [19]. Vascular pathology in SSc include primary and secondary (associated with pulmonary pathology) pulmonary hypertension [11], digital arteritis with necrosis of the phalanges [18], chronic kidney disease with changes in glomerular ar-terioles and capillaries [20,12], affection of carotid and coronary arteries [1,2].
Variants of the clinical course of cardiovascular disease in these patients are not studied enough, it remains little-known the nature of the relationship between the morphological manifestations of skin and kidney angiopathy, the role of the immune system disorders and vascular endothelial function in the patho-genesis constructions of scleroderma angiopathy. The preceding became the purpose and objectives of this study.
Materials and methods. The study included 65 patients with SSc in the age from 15 to 67 years (mean age 39,5 ± 1,67 years), among whom there were 9,5% of men and 90.5% women. The duration of the clinical manifestation of the disease was 9,0 ± 0,95 years. All surveyed have chronic form of the pathological process, I degree activity ascertained in 38.4% of cases, II - in 36.9%, III - to 24.7%. The limited cutaneous form was diagnosed in 45.1% of patients, the diffuse - in 27.7%, lesion of skeletal muscle - at 40.9%, joints - at 81.2%, theart - at 78.5%, lung - at 58.4%, esophageal -at 61.5%, liver - in 27.6%, kidney - at 31.7%, the central nervous system - at 32.1%, peripheral - at 37.5%, sclerodactyly was found in 18.6% of cases, Raynaud's syndrome - in 93,4%, Sjogren's syndrome - in 17,9%, CREST-syndrome - 7.9%.
Patients underwent electrocardiography (devices "MIDAK-EK1T", Ukraine and «Bioset-8000", Germany), echocardiography ( «Acuson-Aspen-Siemens», Germany and "the HD-11-XE-Philips», The Netherlands), X-ray examination of joints and lungs ( «Mul-tix-Compact-Siemens", Germany), esophagogastros-copy (fiberscope «Olympus-GIF-Q20», Japan), sonography of internal organs (scanner «Envisor-Philips» (Netherlands)), the ultrasonic doppler of the blood vessels (angiography «Aplia- XG-Toshiba », Japan), bio-microscopy of conjunctiva vessels (slit lamp «Haag-Streit-Bern-900», Switzerland). Determine the mean peripheral arterial pressure (MAP) and pulmonary artery pressure (PAP), total peripheral resistance (TPR) and pulmonary vascular resistance (PVR), vascular vegetative index (VVI), intravessels (IVI), vessels (VI) and extravessels indexes (EVI), the initial diameter of the brachial artery (CI), the degree of vasodilatation (AD), the diameter during the time of vasodilation (DV) and the index of vascular tension (IVT), set the initial vegetative tone ( "vegetative passport") of the patients, distributing them to eutonics, vagotonics and sympa-thotonics.
We studied the clinical course index of the
angiopathy (Q) by the formula: {Q=(E:E)x Vy }, where E - sum of points of all clinical signs of SSc, E -the number of signs, Y - the degree of disease activity. Determined also instrumental vascular index (VI-¥), wherein each average signs of the patients (X) with its standard deviation (q) were evaluated at 1 point in the case {<X + q}, at {X + q^X + 2q} - 2 points, at {X + 2q~X + 3q} - 3 points, at {> X + 3q} - 4 points. Calculated T to one patient according to the formula: {¥ = (A + 2B + 3C + 4A): E}, where «A, B, C, A» - the number of patients, respectively, with 1, 2, 3 and 4 points, «E "- the number of indicators. To determine the integral index of endothelial vascular dysfunction (0) first in patients determined rate of change (A) vasoconstrictors indicators - vascular endothelial growth factor (VEGF), endothelin-1 (ET1 and thromboxane A2 (TxA2), and vasodilator prostacyclin (PgI2) according to the formula: {X =[(F:-F2): q] 2, where F1 and F2 - figures of the sick and the healthy, q
- standard deviation in healthy. Then calculated © by
the formula: {©=^(K + A + M):N }, «K» - VEGF,
«A» - ET1, «M» - TxA2, «N» - PgI2 (endothelial dysfunction was diagnosed when 0> 5 units). Laboratory parameters were studied in 30 healthy subjects as a control group(13 men and 17 women. aged 18-65 years).
Using biochemical analyzer «Olympus-AU-640" (Japan ") were investigated in serum creatinine levels, fibrinogen (FG), C-reactive protein (CRP), circulating immune complexes (CIC) and rheumatoid factor (RF). Levels of antibodies to native deoxyribonucleic acid (aDNA), cardiolipin (aCL), cyclic citrullinated peptide antibodies (aCCP), VEGF indicators, ET1, TxA2, cyclic guanosine monophosphate (cGMP), E-selectin (Esel), P-selectin (Psel ) (reader «PR2100 Sanofi diagnostic pasteur», France) were investigated by immune-enzyme analysis. The levels of anti- topoisomerase antibodies (aScl70) and antinuclear factor (ANF) were determined by immunoblotting method. Seropositivity for aScl70 was determined in 83.5% of cases, for ANF
- in 63.9% by aDNA - in 67.2%, by RF - in 67.9%, by aCCP - in 27.1%. During the evaluation of renal function was used defining glomerular filtration rate by MDRD eGFR formula by determining serum creatinine level.
In 37 patients (32 women and 5 men) aged 15 to 67 years (mean age 42,8 ± 2,03 years) performed skin biopsy, and in 8 of them with urinary syndrome - kidney biopsy, which was carried out against the background of ataralgezia with ultrasound kidney control. We used the technique of «True-Cut» («the present cutoff") with «Biopty-Bard» high-speed pistol. Microscopic examination was performed on a microscope «Olympus-AX40» from a digital video camera «Olym-pus-DP50». Damage of the individual kidney structures (glomeruli, tubules, stroma and vessels) were scored (from 0 to 3). The average damage (0) was calculated by the formula: {0 = (a + 2p + 3y) :( a + p + y + 5)}, where «a, p, y» - the number of patients with respectively 1, 2 and 3 points, and «5» - the number of patients with the absence of this sign.
Statistical analysis of the results was carried out by computer variations, non-parametric, correlation, regression, single (ANOVA) and multivariate (ANOVA / MANOVA) analysis of variance (program «Microsoft Excel» and «Statistica-Stat-Soft», USA). Determine the average value, standard errors and deviations, parametric Pearson correlation coefficients and nonpara-metric Kendall criteria, Brown-Forsythe variance criteria, multiple regression, Student's, Wilcoxon-Rao, McNemar- Fisher's criteria and the accuracy of the statistics.
Results. In the process of clinical and instrumental examination the signs of angiopathy were set at 88.2% of patients with SSc who formed the experimental group, the control group wasformed by other patients. The distribution of the experimental group in frequency of clinical signs of the disease is closely associated with vascular disorders, it was as follows: Raynaud's syndrome, peripheral neuropathy, hypertension (MAP> 15 mmHg), encephalopathy, pulmonary hypertension (PAP> 20 mmHg), glomerulonephritis, telangiectasia, antiphospholipid syndrome, uveitis, capillaritis of the hands and feet are correlated as 50:38:34:30:28:22:18:16:12:10. The defeat of the oi-rfice of the aorta was detected in 55.6% of patients, the left common carotid artery - at 27.3%, right - at 28.1%, the left internal carotid artery - at 36.9%, right - at 24.6% . Indicator MAP was 108,8 ± 2,71 mmHg, PAP
- 12,2 ± 0,47 mmHg, the ratio of MAP / PBP - 11,7 ± 0,67%, TPR - 2,3 ± 0,10 dinxsecxcm-8, PVR - 222,3 ±10,65 din xsecxcm-5, PVR/TPR - 9,0 ± 0,52%, VVI -15,9 ± 0,79 r.u., DI - 4,4 ± 0,02 mm and AD - 12,1 ± 0 , 71%, DV - 5,5 ± 0,04 mm, IVT - 1,4 ± 0,10 r.u.
According to Wilcoxon-Rao multivariate analysis, the integrated clinical and instrumental vascular indices are affected by the degree of disease activity, the type of autonomic nervous system, indicators aScl70 and aCL. To assess the influence of various factors on the clinical features of scleroderma angiopathy, we selected those that are both significant correspond to the results of one-way variance analysis Brown-Forsythe and nonparametric correlation Kendall analysis. It turned out that with the degree of activity of SSc associated the development of uveitis and leukocytoclastic enantemy, with the duration of the pathological process
- values of MAP, PAP and AD, with the level of aScl70 and aDNA - capillaritis of the hands and feet, with the aCCP - the presence of telangiectasia and dyscircula-tory encephalopathy.
Patients of experimental and control groups were significantly different from each other in their "vegetative passport" (in the presence of angiopathy -sympa-thotonics prevailed, and among other patients - vago-tonics) that McNemar-Fisher analysis showed, thus making ln6,2 ± 0,27 r.u. and ln6,5 ± 0,67 r.u.
Discussion. According to the results of the varia-tional, variance and correlation analysis, the rate AD> 4 r.u. (> X + q study group) reflects the severity of systemic angiopathy, which has a certain practical significance. The development of Raynaud's syndrome and pulmonary hypertension directly depends from indicator PVR, the formation of peripheral neuropathy - from the changes of the carotid arteries, the emergence of
leukocytoclastic enantemy - from VI values. Given such complex statistical calculations made the following conclusions: 1) the presence of Raynaud's syndrome with SSc is a risk factor for high PVR, and lesions of the peripheral nervous system is a risk factor for the involvement in the process of carotid arteries; 2) indicator VI> 9 points (> X + q study group) refers to prognosis negative features of leukocytoclastic enan-temy.
As shown by Brown-Forsythe of variance and Kendall correlation analysis, fibrinogenemia defines in these patients the level of pBP, the serum concentration of aScl70 - pAP. In this regard, the values of FG> 8 g/l are a risk factor for arterial hypertension, and positivity for aScl70 - lung hypertension.
According to multivariate Wilcoxon-Rao analysis of variance, integrated morphological signs of vascular skin lesions are affected by the duration of the disease, indicators aScl70 and aCL. As the single-factor analysis of the Brown-Forsythe, the duration of the disease affects the degree of thickening of the vessel walls, proliferation of the intima and the appearance of extravasation of red blood cells, the values aScl70 - levels of lymphohistiocytic infiltration and fibrinoid swelling of the vascular wall, parameter aCL - endothelial proliferation, the degree of vascular trombosis, aDNA - the nature of mucoid swelling.
SSc characterized by violation of vascular endothelial function [4, 6], and as an example, vasospastic Raynaud's syndrome, in the genesis of which is involved vascular endothelial dysfunction with hyper ET1 and ESel [15, 13]. To a greater extent pulmonary and renal vessels react on changes in endothelial dysfunction in these patients [8,7]. with the development of pulmonary hypertension, lesion of renal arterioles and capillaries [5]. Vascular endothelial dysfunction in SSc appears appropriate dysregulation of angiogenesis due to enhanced synthesis of VEGF [14].
We have established in patients with SSc direct correlation of Pearson between the levels in the serum of aCL and TxA2, CRP and HCys, ANF - and VEGF. The content of VEGF directly correlated with the values of Q, ¥ and 0. In addition, as demonstrated by the analysis of Kendall, the parameters Q and T inversely correlated with the values of PGI2, only Q has positive correlation with the ET1 and TxA2, ¥ - with cGMP, 0 - with Esel. Dispersion-correlation of telangiectasia, glomerulonephritis and hypertension are related to index 0. Last is directly correlated with the pBP, pAP, the degree of narrowing of carotid arteries, endothelial proliferation and fibrinoid swelling of the skin vessels.
It is known that chronic kidney disease is observed in 1/3 of the number of patients with SSc [20], and for its very typical, though non-specific, changes in blood vessels [3], and biopsy reveal necrotizing glomerulonephritis with severe lymphohistiocytic infiltration of glomerular arterioles and capillaries [12]. According to our data, the chronic scleroderma nephropathy occurs with splitting and thickening of the glomerular capillary loops, the proliferation of the endothelium of the capillaries and arterioles, with lymphohistiocytic, plasmo-cytic and neutrophil their infiltration, with fibrinoid swelling and necrosis, hyalinosis, elastofibrosis and
sclerosis of vessels, as well as perivascular sclerosis, with deposition in capillaries and arterioles IgA, IgG, IgM, C3- and C1q-complement components, as reflected in Fig. 1. 0 vessels amounted to 0,76 ± 0,070 r.u., glomeruli - 0,95 ± 0,077 r.u., tubules - 1,28 ± 0,122
Further statistical processing of the obtained data showed variance directly correlation of capillary endothelium proliferation and neutrophil infiltration from Q, and plasmatic impregnation and IgG deposition - from Taking into account of the statistical data was made the following conclusion: the value 0> 9 r.u. (> X ± ç SSc patients) indicate about the severity of fibrinoid swelling of the walls of arterioles and IgA deposition in them.
Conclusions.
1. The manifest vascular lesion occurs in 88% of patients with SSc, clinical, instrumental and morphological features of which are closely related to the degree of activity of pathological process and the duration of the disease, the nature of the "vegetative passport" (vagotonic simpatotonic type of autonomic nervous system), with seropositivity of the disease by aScl, ANF, aDNA.
2. Angiopathy in SSc accompanied by an increase in PVR, the development of pulmonary hypertension and changes in the processes of the vasodilation, while the integrated vascular parameters Q, ¥ and © affect the severity of scleroderma pneumopathy and nephrop-athy, severity of endothelial cell proliferation, lympho-histiocytic infiltration and microtrombosis of vessels.
3. Indicators aScl, ANF and FG, along with integral level of endothelial dysfunction 0, are involved in the pathogenestic constructions of vasculopathy in SSc and in these patients have prognostic significance.
r.u., kidney stroma - 1,25 ± 0,107 r.u., in this case revealed a positive parametric correlation of Pearson criteria between 0 vessels and glomeruli. In addition, according to the results of the non-parametric Kendall analysis, 0 vessels directly related to the capillaritis of
References
1. Ciccone M.M., Scicchitano P., Zito A. et al. (2015) Evaluation of differences in carotid intima-media thickness in patients affected by systemic rheumatic diseases. Intern. Emerg. Med., 10 (7): 823-830.
2. Dadoniene J., Cypiene A., Ryliskyte L. et al.
(2015) Skin autofluorescence in systemic sclerosis is related to the disease and vascular damage: a cross-sectional analytic study of comparative groups. Dis. Markers., 20 (15): 837470.
3. De Groot K. (2014) Renal manifestations in rheumatic diseases. Internist, 48 (8): 779-785.
4. Denton C.P. (2015) Systemic sclerosis: from pathogenesis to targeted therapy. Clin. Exp. Rheumatol., 33 (4): 3-7.
5. Dimitroulas T., Sarafidis P., Roma V. (2010) Scleroderma renal crisis accompanied by new-onset pulmonary arterial hypertension: an acute systemic en-dothelial injury? Case report and literature. Inflamm. Allergy Drug. Targets., 9 (4): 313-318.
6. Ferrante A., Guggino G., Di Liberto D. et al.
(2016) Endothelial progenitor cells: Are they displaying a function in autoimmune disorders? Mech. Ageing. Dev., 3 (5): 122-128.
7. González-Suárez I., Arpa J., Ríos-Blanco J.J. (2016) Brain microvasculature involvement in ANCA positive vasculitis. Cerebrovasc. Dis., 41 (5-6): 313-321.
8. Guo L., Li M., Chen Y. et al. (2015) Anti-endothelin receptor type a autoantibodies in systemic
the hands and feet.
Fig. 1. Absolute frequency of morphological features of vessels lesion in renal biopsy in patients with
scleroderma nephropathy.
1 - hyalinosis 2 - splitting and thickening of the capillary loops, 3 - elastofibrosis, 4 - perivascular sclerosis, 5 - wall sclerosis, 6 - IgA deposits in capillaries, 7 - deposits of IgG in capillaries, 8 - fibrinoid swelling, 9 -fibrinoid necrosis, 10 - IgM deposits in capillaries, 11 - neutrophilic infiltration of capillaries, 12 - the proliferation of capillary endothelium, 13 - C3 deposits in the capillaries, 14 - plasmatic impregnation of arterioles, 15 - the proliferation of the endothelium of arterioles, 16 - dysmucoidosis, 17 - C1q deposits in the capillaries, 18 - IgG deposits in the arterioles, 19 - lymphohistiocytic infiltration, 20 - IgA deposits in arterioles, 21 - IgM deposits in arterioles, 22 - C3 deposits in arterioles, 23 - C1q deposits in arterioles.
lupus erythematosus-associated pulmonary arterial hypertension. Arthritis Rheumatol., 67 (9): 2394-2402.
9. Hegner B., Schaub T., Catar R. et al. (2016) Intrinsic deregulation of vascular smooth muscle and myofibroblast differentiation in mesenchymal stromal cells from patients with systemic sclerosis. PLoS One., 11 (4): 0153101.
10. Ho Y.Y., Lagares D., Tager A.M., Kapoor M. (2014) Fibrosis - a lethal component of systemic sclerosi. Nat. Rev. Rheumatol., 10 (7): 390-402.
11. Karabay C.Y., Karaahmet T., Tigen K. et al. (2011) Cardiovascular involvement in patients with systemic sclerosis: insights from electromechanical characteristics of the heart. Anadolu Kardiyol. Derg., 11 (7): 643-647.
12. Kubota K., Ueno T., Mise K. et al. (2015) ANCA-associated vasculitis in a patient with systematic sclerosis and Sjogren's syndrome: a case report. Case Rep. Nephrol. Dial., 5 (2): 113-117.
13. Latuskiewicz-Potemska J., Chmura-Skirlin-ska A., Gurbiel R.J., Smolewska E. (2016) Nailfold capillaroscopy assessment of microcirculation abnormalities and endothelial dysfunction in children with primary or secondary Raynaud syndrome. Clin. Rheumatol., 35 (8): 1993-2001.
14. Manetti M., Guiducci S., Matucci-Cerinic M. (2016) The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem? Arthritis Res. Ther., 18 (5): 36-46.
15. Overbury R., Murtaugh M.A., Fischer A., Frech T.M. (2015) Primary care assessment of capil-laroscopy abnormalities in patients with Raynaud's phenomenon. Clin. Rheumatol., 34 (12): 2135-2140.
16. Ramos-Casals M., Brito-Zeron P., Kostov B.
(2015) Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun. Rev., 14 (8): 670-679.
17. Sharma A., Dhooria A., Aggarwal A. Rathi M. (2016) Connective tissue disorder-associated vascu-litis. Curr. Rheumatol. Rep., 18 (6): 31-41.
18. Sharp C.A., Akram Q., Hughes M., Muir L.
(2016) Differential diagnosis of critical digital ischemia in systemic sclerosis: Report of five cases and review of the literature. Semin. Arthritis Rheum., 46 (2): 209216.
19. Srivastava R., Jyoti B., Bihari M., Pradhan S. (2016) Progressive systemic sclerosis with intraoral manifestations: A case report and review. Indian J. Dent., 7 (2): 99-104.
20. Visconti L., Atteritano M., Buemi M., San-toro D. (2014) Renal and extra-renal involvement in sclerodermia. G. Ital. Nefrol., 31 (5): 120-126.
21. Wang Y.J., Huang X.L., Yan J.W. et al. (2015) The association between vibration and vascular injury in rheumatic diseases: a review of the literature. Autoimmunity, 48 (1): 61-68.
22. Yang Z., Ren Y., Liu D. et al. (2016) Prevalence of systemic autoimmune rheumatic diseases and clinical significance of ANA profile: data from a tertiary hospital in Shanghai, China. APMIS, 124 (9): 805-811.
