Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya30847Editorial articleПередовая статьяPleiotropic effects of statins in systemic sclerosisПлейотропные эффекты статинов при системной склеродермииAlekperovRizvan TairovichАлекперовРизван Таирович

д-р мед. наук, ст. науч. сотр. лаб. микроциркуляции и воспаления; Научно-исследовательский институт ревматологии РАМН

ralekperov@list.ruKorzenevaElizaveta Grigor'evnaКорзеневаЕлизавета Григорьевна

канд. биол. наук, мл. науч. сотр. лаб. микроциркуляции и воспаления; Научно-исследовательский институт ревматологии РАМН

AleksandrovaElena NikolaevnaАлександроваЕлена Николаевна

д-р мед. наук, рук. лаб. клинической иммунологии; Научно-исследовательский институт ревматологии РАМН

aleksandrova@irramn.ruNovikovAleksandr AleksandrovichНовиковАлександр Александрович

канд. биол. наук, ст. науч. сотр. лаб. клинической иммунологии, тел.: 8-499-115-93-77; Научно-исследовательский институт ревматологии РАМН

Anan'evaLidiya PetrovnaАнаньеваЛидия Петровна

д-р мед. наук, рук. лаб. микроциркуляции и воспаления; Научно-исследовательский институт ревматологии РАМН

lpana@yandex.ruAlekperovR T

Research Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow

KorzenevaE G

Research Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow

AlexandrovaE N

Research Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow

NovikovA A

Research Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow

AnanyevaL P

Research Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow

Научно-исследовательский институт ревматологии РАМНResearch Institute of Rheumatology of the Russian Academy of Medical Sciences, Moscow15052011835NO5 (2011)ТОМ 83, №5 (2011)414710042020Copyright ©; 2011, Consilium MedicumCopyright ©; 2011, ООО "Консилиум Медикум"2011Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/30847

Aim. To study anti-inflammatory and angioprotective properties of statins in patients with systemic sclerosis (SS). Material and methods. Fifty SS patients enrolled in the trial were divided into two groups: the study group included 30 patients who received standard therapy and atorvastatin in a dose 10-40 mg/day, the control group (n = 20) received standard therapy alone. The blood of the patients was studied with enzyme immunoassay for concentrations of highly sensitive C-reactive protein (hs-CRP), IL-6, VCAM-1, E-selectin, WF antigen, VEGF-A, VEGF-R2. The tests were made before the treatment and after 12 months of the treatment. Results. The levels of hs-CRP, IL-6, VCAM-1, E-selectin, WF antigen, VEGF-A and VEGF-R2 were significantly higher in the study group than in healthy donors. The controls also had elevated levels of the above substances except IL-6 and VEGF-A which elevated but not significantly. A 12-month treatment in the study group resulted in a significant lowering of hs-CRP, IL-6, WF antigen, E-selectin, VEGF-A and VEGF-R2, the number of patients with elevated IL-6, WF antigen, VEGF-R2 also reduced while in the controls the parameters did not change. Conclusion. Atorvastatin has anti-inflammatory and angioprotective effects in SS patients.

Цель исследования. Изучить противовоспалительные и ангиопротективные свойства статинов у больных системной склеродермией (ССД). Материалы и методы. В исследование включили 50 больных ССД, которые были разделены на 2 группы: в основной группе (n = 30) дополнительно к терапии назначали аторвастатин в дозе 10-40 мг/сут, в контрольной (n = 20) лечение оставалось без изменений. В крови определяли содержание высокочувствительного С-реактивного белка (вч-СРБ), интерлейкина-6 (ИЛ-6), молекул адгезии сосудистых клеток VCAM-1, E-селектина, антигена фактора Виллебранда (Аг:ФВ), фактора А роста эндотелия сосудов (VEGF-A) и растворимых рецепторов 2-го типа к фактору A роста эндотелия сосудов (VEGF-R2) методом иммуноферментного анализа. Исследования проводили в начале и через 12 мес лечения. Результаты. Содержание вч-СРБ, ИЛ-6, VCAM-1, E-селектина, Аг:ФВ, VEGF-A и VEGF-R2 у больных основной группы было достоверно выше, чем у здоровых доноров. В контрольной группе эти показатели также были повышены, за исключением ИЛ-6 и VEGF-A, уровень которых был существенно, но недостоверно выше, чем у здоровых. Через 12 мес в основной группе наблюдалось достоверное снижение уровней вч-СРБ, ИЛ-6, Аг:ФВ, E-селектина, VEGF-A и VEGF-R2. В основной группе также отмечалось достоверное уменьшение числа больных с повышенными уровнями ИЛ-6, Аг:ФВ и VEGF-R2. В контрольной группе уровень и частота повышения исследуемых показателей оставались практически без изменений и не отличались от исходных. Заключение. Аторвастатин проявляет противовоспалительные и ангиопротективные свойства у больных ССД.

systemic sclerosisstatinsinflammationendothelial dysfunctionangiogenic factorsсистемная склеродермиястатинывоспалениедисфункция эндотелияангиогенные факторыГусева Н. Г. Системная склеродермия и псевдосклеродермические синдромы. М.: Медицина, 1993.Varga J., Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J. Clin. Invest. 2007; 117: 557-567.Leroy E. C. Systemic sclerosis: a vascular perspective. Rheum. Dis. Clin. N. Am. 1996; 22: 695-708.Koch A. E., Kronfield-Harrington L. B., Szechnech A. et al. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Pathobiology 1993; 61: 239-246.Claman H. N., Giorno R. C., Seibold J. R. Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin". Arthr. and Rheum. 1991; 34: 1495-1501.White B. Immunologic aspects of scleroderma. Curr. Opin. Rheumatol. 1995; 7: 541-545.Freedman R. R., Girgis R., Mayes M. D. Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma. J. Rheumatol. 2001; 28(l): 119-121.Goto K., Kasuya Y., Maysuki N. et al. Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in vascular smooth muscle. Proc. Natl. Acad. Sci. USA 1989; 86: 3915-3918.Anderson M. E., Moore T. L., Hollis S. et al. Endothelial-dependent vasodilation is impaired in patients with systemic sclerosis, as assessed by low dose iontophoresis. Clin. Exp. Rheumatol. 2003; 21: 403.La Civita L., Rossi M., Vagheggini G. et al. Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis. Ann. Rheum. Dis. 1998; 57: 52-55.Schlez A., Kittel M., Braun S. et al. Endothelium-dependent regulation of cutaneous microcirculation in patients with systemic scleroderma. J. Invest. Dermatol. 2003; 120: 332-334.Boin F., Wigley F. M. Understanding, assessing and treating Raynaud's phenomenon. Curr. Opin. Rheumatol. 2005; 17: 752-760.Thompson A. E., Shea B., Welch V. et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthr. and Rheum. 2001; 44(8): 1841-1847.Fisher M., Grotta J. New uses for calcium channel blockers: therapeutic implications. Drugs 1993; 46: 961-975.Nannini C., West C. P., Erwin P. J., Matteson E. L. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthr. Res. Ther. 2008; 10: R124.Mayes M. D., Lacey J. V., Beebe-Dimmer J. et al. Prevalence, incidence, sutvival, and disease characteristics of systemic sclerosis in a large US population. Arthr. and Rheum. 2003; 48(8): 2246-2255.Steen V. D., Medsger T. A. Changes in causes of death in systemic sclerosis, 1972-2002. Ann. Rheum. Dis. 2007; 66: 940-944.The long-term intervention with pravastatin in ischemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 1998; 339: 1349-1357.Sacks F. M., Pfeffer M. A., Moye L. A. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 1996; 335: 1001-1009.Node K., Fujita M., Kitakaze M. et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopatic dilated cardiomyopathy. Circulation 2003; 108: 839- 843.Kobashigava J. A., Katznekson S., Laks H. et al. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 1995; 333(10): 621-627.Wenke K., Meiser B., Thiery J. et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997; 96: 1398-1402.Kwak B. R., Mulhaupt F., Mach F. Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. Autoimmune Rev. 2003; 2: 332-338.Vaughan C. J., Gotto A. M., Basson C. T. The evolving role of statins in the management of atherosclerosis. J. Am. Coll. Cardiol. 2000; 35: 1-10.Ridker P. M., Rifai N., Pfeffer M. A. et al. Longterm effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999; 100: 230-235.Bernot D., Benoliel A. M., Peiretti F., Lopez S. Effect of atorvastatin on adhesive phenotype of human endothelial cells activated by tumor necrosis factor alpha. J. Cardiovasc. Pharmacol. 2003; 41: 316-324.Zapolska-Downar D., Siennicka A., Kaczmarczyk M. et al. Simvastatin modulates TNFalpha-induced adhesion molecules expression in human endothelial cells. Life Sci. 2004; 75: 1287- 1302.Romano M., Diomede L., Sironi M. et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab. Invest. 2000; 80: 1095-1100.Wang H. R., Li J. J., Huang C. X. et al. Fluvastatin inhibits the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappaB in human endothelial cells stimulated by C-reactive protein. Clin. Chim. Acta 2005; 353: 53-60.Nawawi H., Osman N. S., Yusoff K., Khalid B. A. Reduction in serum levels of adhesion molecules, interleukin-6 and C-reactive protein following short-term low-dose atorvastatin treatment in patients with non-familial hypercholesterolemia. Horm. Metab. Res. 2003; 35: 479-485.Ascer E., Bertolami M. C., Venturinelli M. L. et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177: 161-166.Xu Z. M., Zhao S. P., Li Q. Z. et al. Atorvastatin reduces plasma MCP-1 in patients with acute coronary syndrome. Clin. Chim. Acta 2003; 338: 17-24.Rezaie-Majd A., Maca T., Bucek R. A. et al. Simvastatin reduces expression or cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1194-1199.Насонов Е. Л. Перспективы применения статинов в ревматологии. Рус. мед. журн. 2003; 11(23): 1273-1276.Abeles A. M., Pillinger M. H. Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy? Arthr. and Rheum. 2006; 54(2): 393-407.Jury E. C., Ehrenstein M. R. Statins: immunomodulators for autoimmune rheumatic disease? Lupus 2005; 14: 192-196.Derk C. T., Jimenez S. A. Statins and the vasculopathy of systemic sclerosis: Potential therapeutics agents? Autoimmunity Rew. 2005; 1: 25-32.McCarey D. W., McInnes I. B., Madhok R. et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomized placebo-controlled trial. Lancet 2004; 363: 2015- 2021.Kanda H., Yokota K., Kubo K. et al. Simvastatin reduces the disease activity in patients with rheumatoid arthritis [abstract]. Arthr. and Rheum. 2004; 50 (Suppl. 9): S387.Kotyla P. J., Sliwinska-Kotyla B., Kucharz E. J. TNF alpha as potential target in the treatment of SLE: a role of HMG-CoA reductase inhibitor simvastatin. J. Rheumatol. 2006; 33: 2361.Ferreira G. A., Navarro T. P., Telles R. W. et al. Atorvastatin therapy improves endothelial-dependent vasodilatation in systemic lupus erythematosus patients: an 8 weeks controlled trial. Rheumatology 2007; 46: 1560-1565.Masi A. T., Rodnan G. P., Medsger T. A. et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthr. and Rheum. 1980; 23(5): 581-590.Smith G. P., Chan E. S. Molecular pathogenesis of skin fibrosis: insight from animal models. Curr. Rheumatol. Rep. 2010; 12(1): 26-33.Smith E. A., Kahaleh M. B., LeRoy E. C. The acute phase response in scleroderma. Differing responses to intravenous PGE1. Clin. Exp. Rheumatol. 1986; 4(4): 341-345.Blann A. D., Illingworth K., Jayson M. I. Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud's phenomenon. J. Rheumatol. 1993; 20(8): 1325-1330.Stuart R. A., Littlewood A. J., Maddison P. J., Hall N. D. Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. Clin. Exp. Rheumatol. 1995; 13(1): 17-22.Scala E., Pallota S., Frezzolini A. et al. Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement. Clin. Exp. Immunol. 2004; 138: 540-546.Алекперов Р. Т., Баранов А. А., Абайтова Н. Е. Клинические ассоциации С-реактивного белка при системной склеродермии. Тер. арх. 2006; 78(6): 30-35.Allanore Y., Borderie D., Lemarechal H. et al. Correlation of serum collagen I carboxyterminal telopeptide concentrations with cutaneous and pulmonary involvement in systemic sclerosis. J. Rheumatol. 2003; 30(1): 68-73.Akesson A., Scheja A., Lundin A., Wollheim F. A. Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthr. and Rheum. 1994; 37(5): 729-735.Bolster M. B., Ludwicka A., Sutherland S. E. et al. Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis. Arthr. and Rheum. 1997; 40: 743-751.Hasegawa M., Sato S., Fujimoto M. et al. Serum levels of interleukin-6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp 130 in patients with systemic sclerosis. J. Rheumatol. 1998; 25(2): 308-313.Matucci-Cerinic M., Pignone A., Biagini M., Lotti T. Markers of disease activity in systemic sclerosis. Clin. Dermatol. 1994; 12: 291-297.Denton C. P., Bickerstaff M. C., Shiwen X. et al. Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis. Br. J. Rheumatol. 1995; 34(11): 1048-1054.Distler O., Distler J. H., Scheid A. et al. Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ. Res. 2004; 95: 109-116.Davies C. A., Jeziorska M., Freemont A. J., Herrick A. L. The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum. Pathol. 2006; 37: 190-197.Choi J. J., Min D. J., Cho M. L. et al. Elevated vascular endothelial growth factor in systemic sclerosis. J. Rheumatol. 2003; 30: 1529-1533.Abou-Raya A., Abou-Raya S., Helmi M. 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-COA) reductase inhibitors (statins): a potentially valid addition to the therapeutic armamentarium of systemic sclerosis. Ann. Rheum. Dis. 2006; 65(Suppl. II): 38.Kuwana M., Kaburaki J., Okazaki Y. et al. Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis. Arthr. and Rheum. 2006; 54(6): 1946-1951.Furukawa S., Yasuda S., Amengual O. et al. Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis: a pilot study. Ann. Rheum. Dis. 2006; 65: 1118- 1120.Del Papa N., Cortiana M., Comina D. P. et al. Clinical and biological evidences of improvement of vascular endothelial function by simvastatin in patients with systemic sclerosis. Ann. Rheum. Dis. 2007; 66 (Suppl. II): 207.