rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2010-820rsp-953Research ArticleСтатьиArticlesВлияние терапии ритуксимабом на функцию эндотелия и другие маркеры атеросклерозау пациентов с активным ревматоидным артритомImpact of rituximab therapy on endothelial function and other markers of atherosclerosisin patients with active rheumatoid arthritisВолковА. В.VolkovAleksandr Vital'evichsandyvlk@yahoo.comLinevaO GLinevaO G-KuzikyantsK KhKuzikyantsK Kh-ЛукинаГ. В.LukinaG V-НасоновЕвгений ЛьвовичNasonovE L-ВолковА. В.VolkovAleksandr Vitalyevichsandyvlk@yahoo.com <mailto:sandyvlk@yahoo.com>LinevaO GLinevaO G-KuzikyantsK KhKuzikyantsK Kh-ЛукинаГ. В.LukinaG V-НасоновЕвгений ЛьвовичNasonovE L-201015122010486№6 (2010)3136Copyright © Волков А.В., Lineva O.G., Kuzikyants K.K., Лукина Г.В., Насонов Е.Л., Волков А.В., Lineva O.G., Kuzikyants K.K., Лукина Г.В., Насонов Е.Л., 20102010Волков А.В., Lineva O.G., Kuzikyants K.K., Лукина Г.В., Насонов Е.Л., Волков А.В., Lineva O.G., Kuzikyants K.K., Лукина Г.В., Насонов Е.Л.Volkov A.V., Lineva O.G., Kuzikyants K.K., Lukina G.V., Nasonov E.L., Volkov A.V., Lineva O.G., Kuzikyants K.K., Lukina G.V., Nasonov E.L.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/953

Эндотелиальная дисфункция играет ключевую роль в патогенезе атеросклероза. Увеличение риска развития сердечно-сосудистых заболеваний у больных ревматоидным артритом (РА) свидетельствует о значении воспаления в возникновении и прогрессировании атеросклероза. Ритуксимаб (РТМ, моноклональные антитела к CD20-позитивным B-лимфоцитам) применяется для лечения пациентов с активным РА. Цель. Оценить влияние РТМ на эндотелиальную функцию у пациентов с активным РА. Материал и методы. В исследование было включено 20 пациентов с активным РА (DAS 28>5,0), средний возраст 50 (41,5; 63) лет, средняя длительность заболевания 95,7 (24; 144) мес. Всем пациентам назначался внутривенно РТМ (1 курс - 2 инфузии в дозе 1000 мг с интервалом 2 нед). Для оценки функции эндотелия использовался метод поток-зависимой вазодилатации (ПЗВД) плечевой артерии, которая проводилась всем пациентам на скрининге (до первой инфузии), а также на 2, 8, 16 и 24-й неделях после второй инфузии. Результаты. В исследуемой группе пациентов до применения РТМ не было выявлено статистически значимых отклонений показателей ПЗВД от таковых в группе контроля, сопоставимой по полу и возрасту. ПЗВД коррелировала с возрастом (r=-0,44, p=0,049), длительностью заболевания (r=0,6, p=0,017), уровнем холестерина (r=0,48, p=0,045), толщиной комплекса интима-медиа общих сонных артерий (r=0,52, p=0,023), а также наличием кардиоваскулярных факторов риска (r=0,51, p=0,027). После проведения курса лечения РТМ не было выявлено статистически значимых различий ПЗВД между исходным значением и на 8, 16, 24-й неделях (12,8±5,7; 11,3±5,2; 14,3±7,1; 12,5±5,2% соответственно). Все пациенты были разделены на 2 группы в зависимости от реакции (увеличение или уменьшение ПЗВД в динамике). Пациенты первой группы (10 человек) демонстрировали достоверное увеличение показателя с 10,74±5,75 (на скрининге) до 14,17±5,13% (на 24-й неделе; p<0,05). Снижение ПЗВД во второй группе (10 пациентов) также было статистически достоверным (с 14,87±5,15 до 10,88±4,89%). 4 больных из второй группы к 24-й неделе имели дисфункцию эндотелия. У пациентов с улучшением функции эндотелия отмечались более длительное течение РА (144±111 против 47±38 мес), меньший исходный уровень С-реактивного белка (26,5 против 35,6 мг/л), а также меньший показатель ПЗВД на скрининге (10,1±5,8 против 14,9±5,2%). Различий между группами по возрасту, активности заболевания (DAS 28) и наличию кардиоваскулярных факторов риска и/или атеросклероза сонных артерий не обнаружено. Заключение. Наше исследование показало, что применение РТМ в целом не влияет на функцию эндотелия у пациентов с активным РА. Обнаруженная разнонаправленная реакция постокклюзионной гиперемии диктует необходимость широкого внедрения методов оценки состояния сердечно-сосудистой системы у больных РА.

Endothelial dysfunction plays a key role in the pathogenesis of atherosclerosis. An increased cardiovascular risk in patients with rheumatoid arthritis (RA) suggests that inflammation is of importance for the occurrence and progression of atherosclerosis. Rituximab (RTM, monoclonal antibodies to CD20-positive B lymphocytes) is used to treat patients with active RA. Objective. To evaluate the effect of RTM on endothelial function in patients with active RA. Subjects and methods. The study enrolled 20patients with active RA (DAS 28 >5.0); their mean age was 50 (range 41.5 to 63) years; mean disease duration was 95.7 (range 24 to 144) months. Intravenous RTM was used (as a course of 2 infusions in a dose of 1000 mg at a 2-week interval) in all the patients. Brachial artery flow-dependent vasodilation (FDVD) that was carried out in all the patients at screening (before the first infusion) and also at 2, 8, 16, and 24 weeks after the second infusion was employed to evaluate endothelial function. Results. Before RTM therapy, the study group of patients showed no statistically significant deviations of FDVD values from those in the gender- and age-matched control group. FDVD correlated with age (r=-0.44; p=0.049), disease duration (r = 0.6; p=0.017), cholesterol level (r=0.48; p=0.045), common carotid artery intima-media thickness (r=0.52; p=0.023), and cardiovascular risk factors (r=0.51; p=0.027). No statistically significant differences were found in the baseline value of FDVD and those observed after a course of RTM therapy and at weeks 8, 16, 24 (12.8±5.7, 11.3±5.2, 14.3±7.1, and 12.5±5.2%, respectively). All the patients were divided into 2 groups according to their response (an increase or a reduction in FDVD over time). Group 1 patients (n=10) demonstrated a significant increase in this index from 10.74±5.75 (at screening) to 14.17±5.13% (at week 24) (p<0.05). In Group 2 patients (n = 10), the reduction in FDVD was also statistically significant (from 14.87±5.15 to 10.88±4.89%). Four patients from Group 2 had endothelial dysfunction by week 24. Patients with improved endothelial function were found to have a longer RA duration (144±111 versus 47±38 months), a lower baseline C-reactive protein level (26.5 versus 35.6 mg/l), and a lower screening FDVD index ((10.1±5.8 versus 14.9±5.2%). No group differences found in age, disease activity (DAS 28), and cardiovascular risk factors and/or carotid artery atherosclerosis. Conclusion. Our study has shown that the use of RTM generally fails to affect endothelial function in patients with active RA. The found heterodirectional postocclusive reactive hyperemia makes it necessary to widely introduce methods for evaluating the cardiovascular system in patients with RA.

ревматоидный артритритуксимабсердечно-сосудистые заболеванияатеросклерозэндотелиальная функцияпоток-зависимая вазодилатацияrheumatoid arthritisrituximabcardiovascular diseasesatherosclerosisendothelial functionflow-dependent vasodilationReferences<div><p>Pincus T., Callahan L. What is the natural history of rheumatoid arthritis? Rheum Dis Clon North Am 1993; 19: 123-46.</p><p>Symmons D., Jones M., Scott D. et al. Long term mortality outcomes in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25(6): 1072-7.</p><p>Lopes-Gongo F., Oliver Minario D., De la Torre I. et al. Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthr Rheum 2009; 61(4): 419-24.</p><p>Solomon D.H., Karlson E.W., Rimm E.B. et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107: 1303-7.</p><p>Del Rincon I., Williams K., Stern M.P. et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthr Rheum 2001; 44: 2737-45.</p><p>Verma S., Buchanan M.R., Anderson T.J. Endothelial function testing as a biomarker of vascular disease. Circulation 2003; 108(17): 2054-9.</p><p>Witte D., Westerink J., Konning E. et al. Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations? J Am Coll Cardiol 2005; 45(12): 1987-93.</p><p>Насонов Е.Л., Панюкова Е.В., Александрова Е.Л. С-реактивный белок - маркер воспаления при атеросклерозе (новые данные). Кардиология 2002; 42(7): 53-60.</p><p>Насонов Е.Л. Проблема атеротромбоза в ревматологии. Вестн РАМН 2003; 7: 6-10.</p><p>Sattar N., McCarey D.W., Capell H., McInnes I.B. Explaining how «high-grade» systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003; 108: 2957-63.</p><p>Gonzalez-Gay M.A., Gonzalez-Juanatey C., Ollier W.E. Endothelial dysfunction in rheumatoid arthritis: influence of HLA-DRB1 alleles. Ann Rheum Dis 2004; 63(1): 31-5.</p><p>Widlansky M., Gokce N., Keaney J. et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-60.</p><p>Vaudo G., Marchesi S., Gerli R. Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis 2004; 63(1): 31 - 5.</p><p>Van Doornum S., McColl G., Jenkins A. et al. Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular function. Arthr Rheum 2003; 48(1): 72-80.</p><p>Bosello S., Santoliquido A., Zoli A. et al. TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis. Clin Rheumatol 2008; 27(7): 833-9 [Epub. 2007 Dec 13].</p><p>Kerekes G., Soltesz P., Der H. et al. Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol 2009; 28(6): 705-10[Epub. 2009 Mar 25].</p><p>Gonzalez-Juanatey C., Llorca J., Vazquez-Rodriguez T. et al. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthr Rheum 2008; 59(12): 1821-4.</p><p>Gonzalez-Juanatey C., Llorca J., Sanchez-Andrade A. et al. Short-term adalimumab therapy improves endothelial function in patients with rheumatoid arthritis refractory to infliximab. Clin Exp Rheumatol 2006; 24(3): 309-12.</p><p>Garces S.P., Parreira Santos M.J., Vinagre F.M. et al. Anti-tumour necrosis factor agents and lipid profile: a class effect? Ann Rheum Dis 2008; 67: 895-6.</p><p>Насонов Е.Л. Новые направления в лечении ревматоидного артрита: место РТМ. Consilium Medicum 2008; 10(2): 7-14.</p><p>Aubry M.C., Riehle D.L., Edwards W.D. et al. B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis: preliminary observations. Cardiovasc Pathol 2004; 13(4): 233-6.</p><p>Touboul P.-J., Hennerici M.G., Mears S. et al. Mannheim Intima-Media Thickness Consensus. Cerebrovasc Dis 2004; 18: 346-9.</p><p>Deanfield J., Donald A., Ferri C. et al. Endothelium function and dysfunction. A statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypert 2005; 23: 7-17.</p><p>Situnayake R.D., Kitas G. Dyslipidemia and rheumatoid arthritis. Ann Rheum Dis 1997; 56: 341-2.</p><p>Doornum S., McColl G., Wicks I.P. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology 2005; 44(11): 1428-32.</p><p>Benjamin E., Larson M., Keyes M. et al. Clinical correlates and heritability of flow-mediated dilatation in the community. The Framingham Heart Study. Circulation 2004; 109: 613-9.</p><p>Van Halm V., Nielen M.M., Nurmohamed M.T. et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis 2007; 66: 184-8.</p><p>Rossner S., Lofmark C. Dyslipoproteinaemia in patients with active, chronic polyarthritis. A study on serum lipoproteins and triglyceride clearance (intravenous fat tolerance test). Atherosclerosis 1977; 28: 41-52.</p><p>Sattar N., Crompton P., Cherry L. et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthr Rheum 2007; 56: 831-9.</p><p>Choy E., Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 2009; 68: 460-9.</p></div><br /><div><p>Pincus T., Callahan L. What is the natural history of rheumatoid arthritis? Rheum Dis Clon North Am 1993; 19: 123-46.</p><p>Symmons D., Jones M., Scott D. et al. Long term mortality outcomes in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25(6): 1072-7.</p><p>Lopes-Gongo F., Oliver Minario D., De la Torre I. et al. Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthr Rheum 2009; 61(4): 419-24.</p><p>Solomon D.H., Karlson E.W., Rimm E.B. et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107: 1303-7.</p><p>Del Rincon I., Williams K., Stern M.P. et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthr Rheum 2001; 44: 2737-45.</p><p>Verma S., Buchanan M.R., Anderson T.J. Endothelial function testing as a biomarker of vascular disease. Circulation 2003; 108(17): 2054-9.</p><p>Witte D., Westerink J., Konning E. et al. Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations? J Am Coll Cardiol 2005; 45(12): 1987-93.</p><p>Насонов Е.Л., Панюкова Е.В., Александрова Е.Л. С-реактивный белок - маркер воспаления при атеросклерозе (новые данные). Кардиология 2002; 42(7): 53-60.</p><p>Насонов Е.Л. Проблема атеротромбоза в ревматологии. Вестн РАМН 2003; 7: 6-10.</p><p>Sattar N., McCarey D.W., Capell H., McInnes I.B. Explaining how «high-grade» systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003; 108: 2957-63.</p><p>Gonzalez-Gay M.A., Gonzalez-Juanatey C., Ollier W.E. Endothelial dysfunction in rheumatoid arthritis: influence of HLA-DRB1 alleles. Ann Rheum Dis 2004; 63(1): 31-5.</p><p>Widlansky M., Gokce N., Keaney J. et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-60.</p><p>Vaudo G., Marchesi S., Gerli R. Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis 2004; 63(1): 31 - 5.</p><p>Van Doornum S., McColl G., Jenkins A. et al. Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular function. Arthr Rheum 2003; 48(1): 72-80.</p><p>Bosello S., Santoliquido A., Zoli A. et al. TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis. Clin Rheumatol 2008; 27(7): 833-9 [Epub. 2007 Dec 13].</p><p>Kerekes G., Soltesz P., Der H. et al. Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis. Clin Rheumatol 2009; 28(6): 705-10[Epub. 2009 Mar 25].</p><p>Gonzalez-Juanatey C., Llorca J., Vazquez-Rodriguez T. et al. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthr Rheum 2008; 59(12): 1821-4.</p><p>Gonzalez-Juanatey C., Llorca J., Sanchez-Andrade A. et al. Short-term adalimumab therapy improves endothelial function in patients with rheumatoid arthritis refractory to infliximab. Clin Exp Rheumatol 2006; 24(3): 309-12.</p><p>Garces S.P., Parreira Santos M.J., Vinagre F.M. et al. Anti-tumour necrosis factor agents and lipid profile: a class effect? Ann Rheum Dis 2008; 67: 895-6.</p><p>Насонов Е.Л. Новые направления в лечении ревматоидного артрита: место РТМ. Consilium Medicum 2008; 10(2): 7-14.</p><p>Aubry M.C., Riehle D.L., Edwards W.D. et al. B-Lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis: preliminary observations. Cardiovasc Pathol 2004; 13(4): 233-6.</p><p>Touboul P.-J., Hennerici M.G., Mears S. et al. Mannheim Intima-Media Thickness Consensus. Cerebrovasc Dis 2004; 18: 346-9.</p><p>Deanfield J., Donald A., Ferri C. et al. Endothelium function and dysfunction. A statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypert 2005; 23: 7-17.</p><p>Situnayake R.D., Kitas G. Dyslipidemia and rheumatoid arthritis. Ann Rheum Dis 1997; 56: 341-2.</p><p>Doornum S., McColl G., Wicks I.P. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology 2005; 44(11): 1428-32.</p><p>Benjamin E., Larson M., Keyes M. et al. Clinical correlates and heritability of flow-mediated dilatation in the community. The Framingham Heart Study. Circulation 2004; 109: 613-9.</p><p>Van Halm V., Nielen M.M., Nurmohamed M.T. et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis 2007; 66: 184-8.</p><p>Rossner S., Lofmark C. Dyslipoproteinaemia in patients with active, chronic polyarthritis. A study on serum lipoproteins and triglyceride clearance (intravenous fat tolerance test). Atherosclerosis 1977; 28: 41-52.</p><p>Sattar N., Crompton P., Cherry L. et al. Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study. Arthr Rheum 2007; 56: 831-9.</p><p>Choy E., Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 2009; 68: 460-9.</p></div><br />

The authors declare that there are no conflicts of interest present.