Preview

Научно-практическая ревматология

Расширенный поиск

Создание и применение диагностического индекса, основанного на многопараметрическом анализе биомаркеров, для определения активности ревматоидного артрита

https://doi.org/10.14412/1995-4484-2014-72-78

Полный текст:

Аннотация

Ревматоидный артрит (РА) – гетерогенное заболевание, в основе патогенеза которого лежит сложное сочетание генетически детерминированных и приобретенных дефектов регуляторных механизмов, ограничивающих gатологическую активацию иммунной системы в ответ на потенциально патогенные и нередко на физиологические стимулы. Современные противоревматические препараты позволяют эффективно подавлять воспалительный процесс и в значительной мере сдерживать прогрессирование болезни. Однако их потенциал может быть реализован в полной мере лишь при использовании соответствующей тактики лечения, при этом регулярный контроль активности заболевания является ключевым компонентом ведения больных РА. Количественная оценка статуса пациента дает возможность разрабатывать стандартизованные показания для применения противоревматической терапии. Применение для оценки активности заболевания клинических индексов не позволяет добиться полной объективности получаемых результатов. Создаются диагностические индексы, основанные на многопараметрическом анализе биомаркеров. Накопление информации об особенностях белкового профиля при РА привело к созданию индекса для определения активности заболевания, основанного на измерении концентраций биомаркеров, ассоциирующихся со значениями как клинических индексов, так и их компонентов (multi-biomarker disease activity, MBDA) – VECTRA DA. В настоящее время MBDA является единственным клинически апробированным лабораторным индексом, который может быть использован для мониторинга активности РА, прогнозирования степени прогрессирования деструктивного поражения суставов, эффективности проводимой терапии.

Об авторах

А. А. Новиков
ФГБУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» РАМН, Москва, Россия
Россия


Елена Николаевна Александрова
ФГБУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» РАМН, Москва, Россия
Россия


Евгений Львович Насонов
ФГБУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» РАМН, Москва, Россия
Россия


Список литературы

1. <div><p>Насонов ЕЛ, редактор. Ревматология. Национальное руководство. Москва: ГЭОТАР-Медиа; 2008: С. 290–331. [Nasonov EL, editor. Revmatologiya. Natsional'noe rukovodstvo. Moscow: GEOTAR-Media; 2008: P. 290–331.]</p><p>Bakker MF, Jacobs JW, Verstappen SM, et al. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis. 2007;66(30):56–60.</p><p>Verstappen S, Jacobs J, van der Veen M, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66(11):1443–9. DOI: http://dx.doi.org/10.1136/ard.2007.071092. Epub 2007 May 22.</p><p>Mease PJ. Improving the routine management of rheumatoid arthritis: the value of tight control. J Rheumatol. 2010;37(8):1570–8. DOI: 10.3899/jrheum.091064. Epub 2010 Jul 1.</p><p>Smolen JS, Aletaha D, Bijlsma J, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–7. DOI: 10.1136/ard.2009.123919. Epub 2010 Mar 9.</p><p>Олюнин ЮА. Оценка статуса больных ревматоидным артритом. Научно-практическая ревматология. 2012;50(1):9–13. [Olyunin YA. Otsenka statusa bol'nykh revmatoidnym artritom. Rheumatology Science and Practice. 2012;50(1):9–13.]. DOI: http://dx.doi.org/10.14412/1995-4484-2012-497.</p><p>Wells G, Becker JC, Teng J, et al. Validation ofthe 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68(6):954–60. DOI: 10.1136/ard.2007.084459. Epub 2008 May 19.</p><p>Fransen J, van Riel P. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005; 23(5 Suppl 39):S93–9.</p><p>Pincus T, Swearingen CJ, Bergman M, Yazici Y. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index categories. J Rheumatol. 2008;35(11):2136–47. DOI: http://dx.doi.org/10.3899/jrheum.080182. Epub 2008 Sep 15.</p><p>Uhlig T, Kvien TK, Pincus T. Test-retest reliability of disease activity coreset measures and indices in rheumatoid arthritis. Ann Rheum Dis. 2009;68(6):972–5. DOI: 10.1136/ard.2008.097345. Epub 2008 Oct 28.</p><p>Ranzolin A, Brenol J, Bredemeier M, et al. Association of concomitant fibromyalgia with worse disease activity score in 28 joints, health assessment questionnaire, and short form 36 scores in patients with rheumatoid arthritis. Arthritis Rheum. 2009;61(6):794–800. DOI: 10.1002/art.24430.</p><p>Leeb BF, Andel I, Sautner J, et al. The DAS28 in rheumatoid arthritis and fibromyalgia patients. Rheumatology (Oxford). 2004;43(12):1504–7. DOI: http://dx.doi.org/10.1093/rheumatology/keh322. Epub 2004 Jul 13.</p><p>Marhadour T, Jousse-Joulin S, Chale’s G, et al. Reproducibility of joint swelling assessments in long-lasting rheumatoid arthritis: influence on Disease Activity Score-28 values (SEA-Repro study part I). J Rheumatol. 2010;37(5):932–7. DOI: 10.3899/jrheum.090879. Epub 2010 Apr 1.</p><p>Sokka T, Pincus T. Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35%–45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol. 2009;36(7):1387–90. DOI: 10.3899/jrheum.080770. Epub 2009 May 1.</p><p>Rhodes B, Merriman ME, Harrison A, et al. A genetic association study of serum acute-phase C-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation. PLoS Med. 2010;7(9):e1000341. DOI: http://dx.doi.org/10.1371/journal.pmed.1000341.</p><p>Keenan RT, Swearingen CJ, Yazici Y. Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol. 2008;26(5):814–9.</p><p>Doherty NS, Littman BH, Reilly K, et al. Analysis of changes in acute-phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two-dimensional gel electrophoresis. Electrophoresis. 1998;19(2):355–63. DOI: http://dx.doi.org/10.1002/elps.1150190234.</p><p>Hueber W, Tomooka BH, Zhao X, et al. Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines. Ann Rheum Dis. 2007;66(6):712–9. DOI: http://dx.doi.org/10.1136/ard.2006.054924. Epub 2006 Aug 10.</p><p>Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631–9. DOI: http://dx.doi.org/10.1056/NEJMoa055373.</p><p>Zethelius B, Berglund L, Sundstrum M, et al. Use of Multiple Biomarkers to Improve the Prediction of Death from Cardiovascular Causes. N Engl J Med. 2008;358(20):2107–16. DOI: http://dx.doi.org/10.1056/NEJMoa0707064.</p><p>Van Bussel BC, Ferreira I, van de Waarenburg MP, et al. Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and an electrochemiluminescense-based multi-array platform. PLoS One. 2013;8(3):e58576. DOI: http://dx.doi.org/10.1371/journal.pone.0058576.</p><p>Zhang Z. An In Vitro Diagnostic Multivariate Index Assay (IVDMIA) for ovarian cancer: harvesting the power of multiple biomarkers. Rev Obstet Gynecol. 2012;5(1):35–41.</p><p>Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptorpositive breast cancer. J Clin Oncol. 2006;24(23):3726–34. DOI: http://dx.doi.org/10.1200/JCO.2005.04.7985. Epub 2006 May 23.</p><p>Kolberg JA, Jorgensen T, Gerwien RW, et al. Development of a type 2 diabetes risk model from a panel of serum biomarkers from the Inter 99 cohort. Diabetes Care. 2009;32(7):1207–12. DOI: 10.2337/dc08-1935.</p><p>Rioja I, Hughes FJ, Sharp CH, et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor alpha, tumor necrosis factor receptor superfamily member 9, and macrophage colony-stimulating factor. Arthritis Rheum. 2008;58(8):2257–67. DOI: http://dx.doi.org/10.1002/art.23667.</p><p>Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635. DOI: http://dx.doi.org/10.1371/journal.pone.0060635.</p><p>Holton W. Bioinformatics: literature searchlight. Environ Health Perspect. 2004;112(15):A872. DOI: http://dx.doi.org/10.1289/ehp.112-a872a.</p><p>Nolan JP, Sklar LA. Suspension array technology: evolution of the flat-array paradigm. TRENDS in Biotechnology. 2002;20(1):9–12. DOI: http://dx.doi.org/10.1016/S0167-7799(01)01844-3.</p><p>Benjamini Y, Hochberg M. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Statist Soc: Series B (Statistical Methodology). 1995;57:289–300.</p><p>Tibshirani R. Regression shrinkage and selection via the lasso. J Royal Statist Soc: Series B (Statistical Methodology). 1996;58:267–88.</p><p>Zou H, Hastie T. Regularization and variable selection via the elastic net. J Royal Statist Soc: Series B (Statistical Methodology). 2005;67:301–20.</p><p>Firestein G, Panayiand G, Wollheim F. Rheumatoid arthritis. Oxford: Oxford University Press; 2006. P. 173–92.</p><p>Brozik M, Rosztoczy I, Meretey K, et al. Interleukin 6 levels in synovial fluids of patients with different arthritides: correlation with local IgM rheumatoid factor and systemic acute phase protein production. J Rheumatol. 1992;19(1):63–8.</p><p>Dasgupta B, Corkill M, Kirkham B, et al. Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol. 1992;19(1):22–5.</p><p>Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634–5. DOI: http://dx.doi.org/10.1126/science.1071924.</p><p>Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10):578–82. DOI: 10.1038/nrrheum.2009.181.</p><p>Moss M, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008;4(6):300–9. DOI: http://dx.doi.org/10.1038/ncprheum0797.</p><p>Xu JW, Ma J, Li TF, et al. Expression of epidermal growth factor and transforming growth factor alpha in interfacial membranes retrieved at revision total hip arthroplasty. Ann Rheum Dis. 2000;59(10):822–7. DOI: http://dx.doi.org/10.1136/ard.59.10.822.</p><p>Hiraoka K, Sasaguri Y, Komiya S, et al. Cell proliferation-related production of matrix metalloproteinases 1 (tissue collagenase) and 3 (stromelysin) by cultured human rheumatoid synovial fibroblasts. Biochem Int. 1992;27(6):1083–91.</p><p>Huh YH, Kim SH, Kim SJ, et al. Differentiation status-dependent regulation of cyclooxygenase-2 expression and prostaglandin E2 production by epidermal growth factor via mitogen-activated protein kinase in articular chondrocytes. J Biol Chem. 2003;278(11):9691–7. DOI: http://dx.doi.org/10.1074/jbc.M211360200.</p><p>Wang Y, Ripperger J, Fey GH, et al. Modulation of hepatic acute phase gene expression by epidermal growth factor and Src protein tyrosine kinases in murine and human hepatic cells. Hepatology. 1999;30(3):682–97. DOI: http://dx.doi.org/10.1002/hep.510300318.</p><p>Brenchley PE. Antagonising angiogenesis in rheumatoid arthritis. Ann Rheum Dis. 2001;60(3):71–4.</p><p>Murakami M, Iwai S, Hiratsuka S, et al. Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood. 2006;108(6):1849–56. DOI: http://dx.doi.org/10.1182/blood-2006-04-016030.</p><p>Klimiuk P, Sierakowski S, Latosiewicz R, et al. Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis. 2002;61(9):804–9. DOI: http://dx.doi.org/10.1136/ard.61.9.804.</p><p>Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci. 2006;11:529–43. DOI: http://dx.doi.org/10.2741/1817.</p><p>Flannery CR, Lark MW, Sandy JD. Identification of a stromelysin cleavage site within the interglobular domain of human aggrecan: evidence for proteolysis at this site in vivo in human articular cartilage. J Biol Chem. 1992;267(2):1008–14.</p><p>Suzuki K, Enghild JJ, Morodomi T, et al. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry. 1990;29(44):10261–70. DOI: http://dx.doi.org/10.1021/bi00496a016.</p><p>Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem. 1993;268(34):25803–10.</p><p>Kirkpatrick RB, Emery JG, Connor JR, et al. Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997;237(1):46–4. DOI: http://dx.doi.org/10.1006/excr.1997.3764.</p><p>De Ceuninck F, Gaufillier S, Bonnaud A, et al. YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun. 2001;285(4):926–31. DOI: http://dx.doi.org/10.1006/bbrc.2001.5253.</p><p>Ling H, Recklies AD. The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha. Biochem J. 2004;380(3):651–9. DOI: http://dx.doi.org/10.1042/BJ20040099.</p><p>Kotzin BL, Falta MT, Crawford F, et al. Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc Natl Acad Sci USA. 2000;97(1):291–6. DOI: http://dx.doi.org/10.1073/pnas.97.1.291.</p><p>Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32. DOI: http://dx.doi.org/10.1038/372425a0.</p><p>Reseland JE, Syversen U, Bakke I, et al. Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res. 2001;16(8):1426–33. DOI: http://dx.doi.org/10.1359/jbmr.2001.16.8.1426.</p><p>Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543–6. DOI: http://dx.doi.org/10.1126/science.7624777.</p><p>Holloway WR, Collier FM, Aitken CJ, et al. Leptin inhibits osteoclast generation. J Bone Miner Res. 2002;17(2):200–9. DOI: http://dx.doi.org/10.1359/jbmr.2002.17.2.200.</p><p>Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138(5):976–89. DOI: http://dx.doi.org/10.1016/j.cell.2009.06.051.</p><p>Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–12. DOI: http://dx.doi.org/10.1038/35053000.</p><p>Thommesen L, Stunes AK, Monjo M, et al. Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem. 2006;99(3):824–34. DOI: http://dx.doi.org/10.1002/jcb.20915.</p><p>Bokarewa M, Nagaev I, Dahlberg L, et al. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174(9):5789–95.</p><p>Oshima K, Nampei A, Matsuda M, et al. Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun. 2005;331(2):520–6. DOI: http://dx.doi.org/10.1016/j.bbrc.2005.03.210.</p><p>Shetty GK, Economides PA, Horton ES, et al. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care. 2004;27(10):2450–7. DOI: http://dx.doi.org/10.2337/diacare.27.10.2450.</p><p>Косыгина АВ. Адипоцитокины в научной и клинической практике. Ожирение и метаболизм. 2011;(1):32–9. [Kosygina AV. Adipotsitokiny v nauchnoy i klinicheskoy praktike. Ozhirenie i metabolizm. 2011;(1):32–9.]</p><p>Benigni F, Fantuzzi G, Sacco S, et al. Six different cytokines that share GP130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1. Blood. 1996;87(5):1851–4.</p><p>Zhang N, Ahsan MH, Purchio AF, et al. Serum amyloid A-luciferase transgenic mice: response to sepsis, acute arthritis, and contact hypersensitivity and the effects of proteasome inhibition. J Immunol. 2005;174(12):8125–34.</p><p>Kisilevsky R, Tam SP. Acute phase serum amyloid A, cholesterol metabolism, and cardiovascular disease. Ped Pathol Mol Med. 2002;21(3):291–305. DOI: http://dx.doi.org/10.1080/02770930290056523.</p><p>Kumon Y, Suehiro T, Hashimoto K, et al. Local expression of acute phase serum amyloid A mRNA in rheumatoid arthritis synovial tissue and cells. J Rheumatol. 1999;26(4):785.</p><p>O’Hara R, Murphy EP, Whitehead AS, et al. Acute-phase serum amyloid A production by rheumatoid arthritis synovial tissue. Arthritis Res. 2000;2(2):142. Epub 2000 Feb 24. DOI: http://dx.doi.org/10.1186/ar78.</p><p>Eastman PS, Manning WC, Qureshi F, et al. Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis. J Pharm Biomed Anal. 2012;70:415–24. DOI: 10.1016/j.jpba.2012.06.003. Epub 2012 Jun 12.</p><p>Hirata JR, van der Helm-van M, Knevel R, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care. Res (Hoboken). 2012;64(12):1794–803.</p><p>Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford). 2013;52(7):1202–7. DOI: http://dx.doi.org/10.1093/rheumatology/kes362.</p><p>Ma MH, Ramanujan S, Haney DJ, et al. Biomarker signatures in rheumatoid arthritis patients with low disease activity: the REMIRA study. Ann Rheum Dis. 2011;70(3):537.</p><p>Van der Helm-van Mil AH, Knevel R, Cavet G, et al. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression. Rheumatology (Oxford). 2013;52(5):839–46. DOI: http://dx.doi.org/10.1093/rheumatology/kes378.</p><p>Li W, Haney DJ, Cavet G, Huizinga T, et al. The Multi-Biomarker Disease Activity Test (Vectra® DA) estimates risk of radiographic progression for patients with rheumatoid arthritis from the leiden early arthritis clinic. Arthritis Rheum. 2013;65(10):1788.</p><p>Maijer KI, de Hair MJH, Li W, et al. Evaluation of a Multi-Biomarker Disease Activity (Vectra® DA Algorithm) in Early Rheumatoid Arthritis and Unclassified Arthritis Patients. Ann Rheum Dis. 2013;72(3):389.</p><p>Li W, Sasso EH, Emerling D, et al. Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use. Curr Med Res Opin. 2013;29(1):85–92.</p><p>Hambardzumyan K, Saevarsdottir S, Bolce R, et al. In early rheumatoid arthritis, the 12 individual biomarkers that comprise the Multiple Biomarker Disease Activity score relate differentially to clinical response and radiographic progression: results from a randomized trial. Arthritis Rheum. 2013;65(10):1789.</p><p>Jurgens MS, Bijlsma JW, Jacobs JW, et al. Response to MTX Plus Prednisone in CAMERA II Using a Multi-Biomarker Disease Activity Test (Vectra® DA) and DAS28-ESR. Ann Rheum Dis. 2013;72(3):395.</p><p>Krabbe S, Bolce R, Brahe C, et al. Early changes in a Multi-Biomarker Disease Activity score after starting adalimumab treatment predict change in MRI inflammation at 6 months. Arthritis Rheum. 2013;65(Suppl 10):1436.</p><p>Hirata S, Li W, Defranoux N, et al. Repeated high or low Multi-Biomarker Disease Activity (VECTRA® DA Algorithm) scores associated with radiographic outcomes in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. Arthritis Rheum. 2013;65(Suppl 10):1453.</p><p>Hanami K, Hirata S, Tasaka H, et al. Behavior of the multi-biomarker disease activity (vectra® da algorithm) score and components in patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis. 2013;72(3):391.</p><p>Yamaoka K, Kubo S, Sonomoto K, et al. Correlation of a Multi-Biomarker Disease Activity (VECTRA DA) score with clinical disease activity and its components with radiographic progression in rheumatoid arthritis patients treated with tofacitinib. Arthritis Rheum. 2012;64(10):2162.</p></div><br />


Для цитирования:


Новиков А.А., Александрова Е.Н., Насонов Е.Л. Создание и применение диагностического индекса, основанного на многопараметрическом анализе биомаркеров, для определения активности ревматоидного артрита. Научно-практическая ревматология. 2014;52(1):72-78. https://doi.org/10.14412/1995-4484-2014-72-78

For citation:


Novikov A.A., Aleksandrova E.N., Nasonov E.L. ELABORATION AND APPLICATION OF THE DIAGNOSTIC INDEX BASED ON MULTIVARIATE ANALYSIS OF BIOMARKERS TO DETERMINE THE ACTIVITY OF RHEUMATOID ARTHRITIS. Rheumatology Science and Practice. 2014;52(1):72-78. (In Russ.) https://doi.org/10.14412/1995-4484-2014-72-78

Просмотров: 954


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 1995-4484 (Print)
ISSN 1995-4492 (Online)