Terapevticheskii arkhivTerapevticheskii arkhiv0040-36602309-5342LLC Obyedinennaya Redaktsiya3358310.26442/00403660.2019.05.000286Research ArticleLevel of N-terminal fragment of brain natriuretic peptide progenitor and atherosclerotic damage of brachocephalic arteries in patients with rheumatoid arthritis with inefficiency and/or injurability of basic anti - inflammatory treatmentGerasimovaE Vgerasimovaev@list.ruPopkovaT V-MartynovaA V-MarkelovaE I-NovikovaD S-KirillovaI G-V.A. Nasonova Scientific and Research Institute of Rheumatology15052019915343916042020Copyright © 2019, Consilium Medicum2019The high prognostic significance of the concentration of the N-terminal - pro-B-type natriuretic peptide (NT-proBNP) in the development of cardiovascular diseases (CVD) was identified for rheumatoid arthritis (RA) and general populations. Aim: to investigate the significance of NT-proBNP level in patients (pts) with RA with the ineffectiveness and/or intolerance of basic anti - inflammatory therapy; compare the level of NT-proBNP with atherosclerotic lesion of the brachiocephalic arteries (BCA), traditional risk factors and inflammatory markers. Materials and methods. The investigation enrolled 28 pts (24women/4men) with the lack of efficacy/resistance and/or intolerance of basic anti - inflammatory drugs (DMARDs); median age was 55 [46; 61] years, median disease duration 114 [60; 168] month; DAS28 6,2 [5.1; 7.0]; SDAI 35.0[23.9; 51.0], CDAI 30.0[21.0; 42.0], serum positivity for rheumatoid factor (RF) (100%)/anti - cyclic citrullinated peptide antibodies (ACCP) (86%). The study did not include RA pts with congestive heart failure. High incidence of traditional risk factors was found in RA pts: arterial hypertension - in 75%, dyslipidemia - 61%, smoking - 17%, overweight - 61%, family history of cardiovascular diseases - 36%, hypodynamia - 68%. Coronary artery disease was diagnosed in 11% RA pts. Lack of efficacy of 3 or more DMARDs was found in 46% of pts, intolerance to previous therapy with DMARDs - in 54% pts. 47% were receiving methotrexate (20 [18; 25] mg/week), 11% - leflunomide, 7% - sulfasalazine, 46% - glucocorticoids, 75% - non - steroidal anti - inflammatory drugs. The control group consisted of 20 healthy donors, comparable to pts by age and sex. Serum levels of of NT-proBNP were measured using electrochemiluminescence method Elecsys proBNP II (Roche Diagnostics, Switzerland). The determination of the intima - media thickness (IMT) BCA were assessed from duplex scanning. Atherosclerotic lesion of BCA was assessed by the presence of atherosclerotic plaque (IMT ≥1.2 mm). Results. NT-proBNP concentrations in RA pts proved to be higher (78.7 [41.4; 101.3] pg/ml) than those in the control group (55.3 [36.6; 67.3] pg/ml, p<0.05). RA pts were divided into two groups according to the level of NT-proBNP: >100 pg/ml - 1 group (n=6) and ≤100 pg/ml - 2 group (n=22). Groups of RA pts did not differ in gender, age, activity of RA, frequency of detection of traditional risk factors. Atherosclerotic lesion of the BCA was detected in 3 (50%) pts of the 1 group and in 8 (36%) pts of the 2 group (p>0.05). In RA pts the level of NT-proBNP correlated with age (r=0.39; p<0.05), with the IMT BCA (r=0.43; p<0.05). In RA pts of the 2 group, a correlation was observed between the concentration of NT-proBNP and the level of ACCP (r=0.42; p<0.05) and antibodies to modified citrullinated vimentin (anti-MCV; r=0.56; p<0.05). No association of NT-proBNP with PA activity (DAS28, CDAI, CDAI), inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), traditional risk factors and therapy was found. Conclusion. The level of NT-proBNP in the blood of RA pts with ineffectiveness and/or intolerance to basic anti - inflammatory therapy is higher than in the control group. In every fifth RA patient, the concentration of NT-proBNP was higher than 100 pg/ml. The association of NT-proBNP with age and immunological parameters (ACCP and anti-MCV) was demonstrated. The correlation between the concentration of NT-proBNP and the IMT BCA may indicate the possible role of this biomarker in the progression of atherosclerotic lesions of arteries in RA pts. The significance of NT-proBNP in the development of early manifestations of atherosclerosis in RA requires further study.N-terminal-pro-B-type natriuretic peptiderheumatoid arthritisatherosclerotic damage of brachocephalic arteriestraditional risk factorscardiovascular diseasesN-концевой фрагмент предшественника мозгового натрийуретического пептида В-типаревматоидный артритатеросклеротическое поражение брахиоцефальных артерийтрадиционные факторы рискасердечно-сосудистые заболевания[Попкова Т.В., Новикова Д.С., Насонов Е.Л. Атеросклероз при ревматических заболеваниях. В кн.: Ревматология: клинические рекомендации. Под ред. Е.Л. Насонова. M.: ГЭОТАР-Медиа, 2010: 678-702.][Corrales A, Dessein P.H, Tsang L, et al. Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross - sectional study. Arthritis Res Ther. 2015;17:55. doi: 10.1186/s13075 -015-0576-7][Попкова Т.В., Новикова Д.С., Насонов Е.Л. Сердечно - сосудистые заболевания при ревматоидном артрите: новые данные. Научно - практическая ревматология. 2016;54(2):122-8. doi: 10.14412/1995-4484-2016-122-128][Navarro-Millán I, Yang S, Du Vall S.L, et al. Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration. Ann Rheum Dis. 2016;75:341-7. doi: 10.1136/annrheumdis-2013-204987][Pope J.E, Nevskaya T, Barra L, Parraga G. Carotid artery atherosclerosis in patients with active rheumatoid arthritis: predictors of plaque occurrence and progression over 24 weeks. Open Rheumatol J. 2016;10:49-59. doi: 10.2174/1874312901610010049][Rudolf Berger, Deddo Moertl, Sieglinde Peter, et al. N-Terminal Pro-B-Type Natriuretic Peptide-Guided, Intensive Patient Management in Addition to Multidisciplinary Care in Chronic Heart Failure. J Am Coll Cardiol. 2010;55:645. doi: 10.1016/j.jacc.2009.08.078][Roger V.L. Epidemiology of heart failure. Circ Res. 2013;113:646-59. doi: 10.1161/circresaha.113.300268][Cameron V.A, Rademaker M.T, Ellmers L.J, et al. Atrial and brain natriuretic peptide expression after myocardial infarction in sheep: ANP is synthesized by fibroblast infiltration the infarct. Endocrinology. 2000;141:4690-7. doi: 10.1210/endo.141.12.7847][Di Angelantonio E, Chowdhury R, Sarwar N, Ray K.K, Gobin R, Saleheen D, Thompson A, Gudnason V, Sattar N, Danesh J. B-type natriuretic peptides and cardiovascular risk: systematic review and meta - analysis of 40 prospective studies. Circulation. 2009;120:2177-87. doi: 10.1161/ circulationaha.109.884866][Morrow D.A, Cannon C.P, Jesse R.L, Newby L.K, Ravkilde J, Storrow A.B, Wu A.H.B, Christenson R.H, for the NACB Writing Group. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Circulation. 2007;115:e356-e375. doi: 10.1161/ CIRCULATIONAHA.107.182882][Vergaro G, Januzzi J.L. Jr, Cohen Solal A, et al. NT-proBNP prognostic value is maintained in elderly and very elderly patients with chronic systolic heart failure. Int J Cardiol. 2018 Nov 15;271:324-30. doi: 10.1016/j.ijcard.2018.04.006][Provan S, Angel K, Semb A.G, et al. NT-proBNP predicts mortality in patients with rheumatoid arthritis: results from 10-year follow - up of the EURIDISS study. Ann Rheum Dis. 2010 Nov;69(11):1946-50. doi: 10.1136/ard.2009.127704][Breunig M, Kleinert S, Lehmann S, et al. Simple screening tools predict death and cardiovascular events in patients with rheumatic disease. Scand J Rheumatol. 2018;47(2):102-9. doi: 10.1080/03009742.2017.1337924 Epub 2017 Aug 16][Redfield M, Rodeheffer R, Jacobsen S, Mahoney D, Bailey K, Burnett J. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976-82.][Alehagen U, Goetze J.P, Dahlström U. Reference intervals and decision limits for Btype natriuretic peptide (BNP) and its precursor (Nt - proBNP) in the elderly. Clin Chim Acta. 2007;382:8-14. doi.org/10.1016/j.cca. 2007.03.005][Passino C, Poletti R, Fontana M, et al. Clinical relevance of non - cardiac determinants of natriuretic peptide levels. Clin Chem Lab Med. 2008;46:1515-23. doi: 10.1515/CCLM.2008.293][Khan A.M, Сheng S, Maqnusson M, et al. Cardiac natriuretic peptides, obesity, and insulin resistance: evidence from two community - based studies. J Clin Endocrinol Metab. 2011;96:3242-9. doi: 10.1210/jc.2011-1182][Vergaro G, Januzzi J, Cohen Solal A, et al. NT-proBNP prognostic value is maintained in elderly and very elderly patients with chronic systolic heart failure. Int J Cardiol. 2018 Nov 15;271:324-30. doi: 10.1016/j.ijcard. 2018.04.006][Schultz M, Faber J, Kistorp C, et al. N-terminal - pro-B-type natriuretic peptide (NT-pro-BNP) in different thyroid function states. Clin Endocrinol (Oxf). 2004;60:54-9][Avouac J, Meune C, Chenevier-Gobeaux C, et al. Inflammation and disease activity are associated with high circulating cardiac markers in rheumatoid arthritis independently of traditional cardiovascular risk factors. J Rheumatol. 2014;41(2):248-55. doi: 10.3899/jrheum.130713][Södergren A, Karp K, Bengtsson C, Möller B, Rantapää-Dahlqvist S, Wållberg-Jonsson S. The extent of subclinical atherosclerosis is partially predicted by the inflammatory load: a prospective study over 5 years in patients with rheumatoid arthritis and matched controls. J Rheumatol. 2015;42:935-42. doi: 10.3899/jrheum.140694][Targońska-Stępniak B, Piotrowski M, et al. Prospective assessment of cardiovascular risk parameters in patients with rheumatoid arthritis. Cardiovasc Ultrasound. 2018;16(1):18. doi: 10.1186/s12947-018-0136-9][Кириллова И.Г., Новикова Д.С., Попкова Т.В. и др. Уровень N-концевого натрийуретического пептида и диастолическая дисфункция у больных ранним ревматоидным артритом до назначения базисных противовоспалительных препаратов. Терапевтический архив. 2016;88(5):19-26. doi: 10.17116/terarkh201688519-26][De Filippi C.R, Christenson R.H, Gottdiener J.S, et al. Dynamic cardiovascular risk assessment in elderly people. The role of repeated n - terminal pro - b - type natriuretic peptide testing. J Am Coll Cardiol. 2010;55:441-50. doi: 10.1016/j.jacc.2009.07.069][Zhou W, Ni Z, Yu Z, et al. Brain natriuretic peptide is related to carotid plaques and predicts atherosclerosis in pre - dialysis patients with chronic kidney disease. Eur J Intern Med. 2012;23:539-44. doi: 10.1016/j.ejim. 2012.06.001][Odden M.C, Shlipak M.G, Whitson H.E, et al. Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. Atherosclerosis. 2014 Nov;237(1):336-42. doi: 10.1016/j.atherosclerosis. 2014.09.012][Gan L, Feng C, Liu C, et al. Association between serum N-terminal pro-B-type natriuretic peptide levels and characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography. Exp Ther Med. 2016 Aug;12(2):667-75. doi: 10.3892/etm. 2016.3371][Клинические рекомендации Российского кардиологического общества 2018 г. Сердечная недостаточность: хроническая (ХСН) и острая декомпенсированная (ОДСН). Диагностика, профилактика и лечение. http://scardio.ru/content/Guidelines/ Chronic%20(CHF)%20and%20acute%20decompensated%20(ADHF).pdf][Targońska-Stępniak B, Majdan M. Amino - terminal pro - brain natriuretic peptide as a prognostic marker in patients with rheumatoid arthritis. Clin Rheumatol. 2011;30:61-9. doi: 10.1007/s10067-010-1622-0][Tomáš L, Lazúrová I, Oetterová M, et al. Left ventricular morphology and function in patients with rheumatoid arthritis. Wien Klin Wochenschr. 2013 May;125(9-10):233-8. doi: 10.1007/s00508-013-0349-8][Schau T, Gottwald M, Arbach O, et al. Increased Prevalence of Diastolic Heart Failure in Patients with Rheumatoid Arthritis Correlates with Active Disease, but Not with Treatment Type. J Rheumatol. 2015 Nov;42(11): 2029-37. doi: 10.3899/jrheum.141647][Yokoe I, Kobayashi H, Kobayashi Y, et al. Impact of tocilizumab on N-terminal pro - brain natriuretic peptide levels in patients with active rheumatoid arthritis without cardiac symptoms. Scand J Rheumatol. 2018 Sep;47(5):364-70. doi: 10.1080/03009742.2017.1418424][Lianza A.C, Aikawa N.E, Moraes J.C, et al. Long - term evaluation of cardiac function in juvenile idiopathic arthritis under anti-TNF therapy. Clin Exp Rheumatol. 2014 Sep-Oct;32(5):754-9.][Breunig M, Kleinert S, Lehmann S, et al. Simple screening tools predict death and cardiovascular events in patients with rheumatic disease. Scand J Rheumatol. 2018 Mar;47(2):102-9. doi: 10.1080/03009742.2017.1337 924][Giles J.T, Fert-Bober J, Park J, et al. Myocardial citrullination in rheumatoid arthritis: a correlative histopathologic study. Arthritis Res Ther. 2012 Feb 24;14(1):R39. doi: 10.1186/ar3752][Tsuchida K, Tanabe K. Plasma brain natriuretic peptide concentrations and the risk of cardiovascular events and death in general practice. J Cardiol. 2008;52:212-23. doi: 10.1016/j.jjcc.2008.07.007][Brune K, Katus H.A, Moecks J, et al. N-terminal pro-B-type natriuretic peptide concentrations predict the risk of cardiovascular adverse events form anti - inflammatory drugs: a pilot study. Clin Chem. 2008;54:1149-57. doi: 10.1373/clinchem.2007.097428][Mirjafari H, Welsh P, Verstappen S.M, еt al. N-terminal pro - brain - type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR). Ann Rheum Dis. 2014;73(4):684-90. doi: 10.1136/annrheumdis-2012-202848][Ma K.K, Ogawa T, de Bold A.J. Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro - infl ammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase. J Mol Cell Cardiol. 2004; 36:505-13. doi: 10.1016/j.yjmcc.2004.01.001][Emdin M, Passino C, Prontera C, Iervasi A, Ripoli A, Masini S, et al. Cardiac natriuretic hormones, neuro - hormones, thyroid hormones and cytokines in normal subjects and patients with heart failure. Clin Chem Lab Med. 2004;42:627-36.][Passino C, Poletti R, Fontana M, et al. Clinical relevance of non - cardiac determinants of natriuretic peptide levels. Clin Chem Lab Med. 2008;46(11):1515-23. doi: 10.1515/CCLM.2008.293][Shaw S.M, Fildes J.E, Puchałka C.M, et al. BNP directly immunoregulates the innate immune system of cardiac transplant recipients in vitro. Transpl Immunol. 2009 Jan;20(3):199-202. doi: 10.1016/j.trim.2008.08.010][Kobayashi H, Kobayashi Y, Yokoe I, et al. Magnetic Resonance Imaging-Detected Myocardial Inflammation and Fibrosis in Rheumatoid Arthritis: Associations With Disease Characteristics and N-Terminal Pro-Brain Natriuretic Peptide Levels. Arthritis Care Res (Hoboken). 2017 Sep;69(9):1304-11. doi: 10.1002/acr.23138]