rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2013-636rsp-774Research ArticleСтатьиArticlesМногопараметрический анализ биомаркеров в лабораторной диагностике раннего ревматоидного артитаMultiparameter analysis of biomarkers in the laboratory diagnosis of early rheumatoid arthritisНовиковА. А.NovikovAleksandr Aleksandrovichirramnlab@rambler.ruАлександроваЕлена НиколаевнаAleksandrovaE N-GerasimovA NGerasimovA N-ЧеркасоваМ. В.CherkasovaM V-КаратеевДмитрий ЕвгеньевичKarateevD E-ЛучихинаЕ. Л.LuchikhinaE L-НасоновЕвгений ЛьвовичNasonovE L-201315042013512№2 (2013)111116Copyright © Новиков А.А., Александрова Е.Н., Gerasimov A.N., Черкасова М.В., Каратеев Д.Е., Лучихина Е.Л., Насонов Е.Л., 20132013Новиков А.А., Александрова Е.Н., Gerasimov A.N., Черкасова М.В., Каратеев Д.Е., Лучихина Е.Л., Насонов Е.Л.Novikov A.A., Aleksandrova E.N., Gerasimov A.N., Cherkasova M.V., Karateev D.E., Luchikhina E.L., Nasonov E.L.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/774

Цель разработать многопараметричесий диагностический индекс (МДИ) для лабораторной диагностики раннего ревматоидного артрита (РА). Материал и методы. Обследовано 102 пациента с ранним РА: 79 женщин и 23 мужчины; возраст (МЕ [25-й; 75-й перцентили]) 51 [41; 62] год, длительность 4 [2,5; 6,0] мес, DAS28 5,4 [4,1; 5,9]. Группу сравнения (n=616) составили: 27 пациентов с системной красной волчанкой, 15 с синдромом Шегрена, 25 с анки-лозирующим спондилоартритом, 33 с остеоартритом, 20 с OVERLAP-синдромом; 9 с подагрическим, 22 с псориатическим и 168 с недифференцированным артритами, а также 297 здоровых доноров, сопоставимых по полу и возрасту с обследованными больными. Концентрации 36 биомаркеров измеряли с использованием иммунонефелометрического метода, иммуноферментного анализа и технологии «xMAP». Прогноз значений одной переменной по другим проводили при помощи метода многомерной линейной регрессии (многофакторного анализа). Результаты. Выделены наиболее «сильные» факторы прогнозирования наличия раннего РА, а именно: концентрации интерлейкина 6, С-реактивного белка, гранулоцитарно-макрофагальный колониестимулирующий фактор, интерферон γ (ИФ^), ИФ^-индуцибельный белок, антитела к циклическому цитруллиниро-ванному пептиду и создан кандидатный МДИ для раннего РА (МИРРА). После тщательной валидации МИРРА может рассматриваться как высокоточный серологический тест для ранней диагностики РА. Заключение. Создание МДИ с более высокой диагностической точностью, по сравнению с рутинно используемыми биомаркерми, крайне важно для ранней диагностики РА, позволяющей начать активную противоревматическую терапию, способную эффективно затормозить прогрессирующее поражение суставов.

Subjects and methods. 102 patients with early RA (79 women and 23 men; median age 51 years [41 to 62, 25th to 75th percentile]; disease duration 4 months [2.5 to 6.0]; DAS28 5.4 [4.1 to 5.9]) were examined. A comparison group consisted of 616 patients including 27 with systemic lupus erythematosus, 15 with Sjö gren’s syndrome, 25 with ankylosing spondyloarthritis; 33 with osteoarthritis, 20 with overlap syndrome, 9, 22, and 168 patients with gouty, psoriatic, and undifferentiated arthritis, respectively; as well as 297 healthy donors matched with the examinees for gender and age. The concentrations of 36 biomarkers were measured by an immunonephelometric method, enzyme immunoassay, and xMAP technology. The values of one variable from others were predicted using a multiple linear regression method (multivariate analysis). Results. The strongest predictors of early RA, such as the concentrations of interleukin-6, C-reactive protein, granulo-cyte-macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN^-inducible protein, anti-cyclic citrullinated peptide antibodies, were identified and a candidate for MDI was developed for early RA (MIRRA). After thorough validation, MIRRA may be regarded as a precision serological assay for the early diagnosis of RA. Conclusion. The development of MDI having a higher diagnostic precision than routinely used biomarkers is imperative for early RA diagnosis that allows one to initiate active antirheumatic therapy that is able to effectively delay progressive joint injury.

ранний ревматоидный артритбиомаркерымногопараметрический диагностический индексearly rheumatoid arthritisbiomarkersmultiparameter diagnostic indexReferences<div><p>Насонов Е.Л., Каратеев Д.Е., Балабанова Р.М. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. М.: ГЭОТАР-Медиа, 2008;290-331.</p><p>O’Dell J.R. Treating rheumatoid arthritis early: a window of opportunity? Arthr Rheum 2002;46:283-5.</p><p>Scott D.L. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthr Rheum 2002;46:286-90.</p><p>Насонов Е.Л. Почему необходима ранняя диагностика и лечение ревматоидного артрита? Рус мед журн 2002;10:1009-10.</p><p>Orozco C., Olsen N.G. Identification of patients with early rheumatoid arthritis: challenges and future directions. Clin Devel Immunol 2006;13:295-7.</p><p>Krabben A., Huizinga T.W., van der Helm-van Mil A.H. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Ann Rheum Dis 2012;71:238-41.</p><p>Arnett F.C., Edworthy S.M., Bloch D.A. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 1988;31:315-24.</p><p>Van Venrooij W.J., van Beers J.J., Pruijn G.J. Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann NY Acad Sci 2008;1143:268-85.</p><p>Miossec P., Verweij C.L., Klareskog L. et al. Biomarkers and personalized medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies. Ann Rheum Dis 2011;70:1713-8.</p><p>Gibson D.S., Rooney M.E., Finnegan S. et al. Biomarkers in rheumatology, now and in the future. Rheumatology (Oxford) 2012;51:423-33.</p><p>Александрова Е.Н., Новиков А.А., Насонов Е.Л. Современные стандарты лабораторной диагностики ревматических заболеваний. М., 2012;6-9.</p><p>Schellekens G.A., Visser H., de Jong B.A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthr Rheum 2000;43:155-63.</p><p>Schellekens G.A., de Jong B.A., van den Hoogen F.H. et al. Citrulline is an еssential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101:273-81.</p><p>Bang H., Luthke K., Gauliard A. et al. Mutated citrullinated vimentin (MCV) as a candidate autoantigen for diagnosis and monitoring of disease activity in rheumatoid arthritis. Ann Rheum Dis 2006;65:144.</p><p>Aletaha D., Neogi T., Silman A. et al. 2010 rheumatoid arthritis classification criteria. Arthr Rheum 2010;62:2569-81.</p><p>Taylor P., Gartemann J., Hsieh J. et al. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. SAGE-Hindawi Access to Research Autoimmune Diseases Volume 2011, Article ID 815038.</p><p>Dayer E., Dayer J., Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nat Clin Pract Rheumatol 2007;3:512-20.</p><p>de Seny D., Fillet M., Ribbens C. et al. Monomeric calgranulins measured by SELDI-TOF mass spectrometry and calprotectin measured by ELISA as biomarkers in arthritis. Clin Chem 2008;54:1066-75.</p><p>Hueber W., Tomooka B.H., 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;66:712-9.</p><p>Новиков А.А., Александрова Е.Н., Диатроптова М.А. и др. Роль цитокинов в патогенезе ревматоидного артрита. Науч-практич ревматол 2010;2:71-82.</p><p>Firestein G.S. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol 2005;11:39-44.</p><p>Wener M. Multiplex, megaplex, index, and complex: the present and future of laboratory diagnostics in rheumatology. Arthr Res Ther 2011;13:134.</p><p>Zhou X., Fragala M.S., McElhaney J. et al. Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Curr Opin Clin Nutr Metab Care 2010;13:541-7.</p><p>Bossuyt P.M. The thin line between hope and hype in biomarker research. JAMA 2011;305:2229-30.</p><p>Katz M.H. Multivariable analysis: a primer for readers of medical research. Ann Intern Med 2003;138:644-50.</p><p>Cavet G., Centola M., Shen Y. et al. Development of a multi-biomarker test for rheumatoid arthritis (RA) disease activity. Ann Rheum Dis 2010;69:148.</p><p>Герасимов А.Н. Медицинская статистика: Учебное пособие. М.: Медицинское информационное агентство, 2007; 480 с.</p><p>Alex P., Szodoray P., Knowlton N. et al. Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis. Clin Exp Rheumatol 2007;25:584-92.</p><p>Meyer P., Hodkinson B., Ally M. et al. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Hindawi Publishing Corporation Mediators of Inflammation Vol. 2010, Article ID 158514.</p><p>Deane K., O’Donnell C., Hueber W. et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthr Rheum 2010;62:3161-72.</p><p>Paramalingam S., Thumboo J, Vasoo S. et al. In vivo proand anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singapore 2007;36:96-9.</p><p>Hitchon C.A., Alex P., Erdile L.B. et al. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol 2004;31:2336-46.</p><p>Kokkonen H., Soderstrom I., Rocklov J. et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthr Rheum 2010;62:383-91.</p><p>Jorgensen K.T., Wiik A., Pedersen M. et al. Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors. Ann Rheum Dis 2008;67:860-6.</p><p>Poulsom H., Charles P. Antibodies to citrullinated vimentin are a specific and sensitive marker for the diagnosis of rheumatoid arthritis. Clin Rrev Allerg Immun 2008;34:410.</p><p>Raza K., Mathsson L., Buckley C.D. et al. Antimodified citrulli-nated vimentin (MCV) antibodies in patients with very early synovitis. Ann Rheum Dis 2010;69:6278.</p><p>Bizzaro N. Antibodies to citrullinated peptides: a significant step forward in the early diagnosis of rheumatoid arthritis. Clin Chem Lab Med 2007;45:150-7.</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;19:22-5.</p><p>Hanaoka R., Kasama T., Muramatsu M. et al. A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthr Res Ther 2003;5:74-81.</p><p>Müller B., Paulukat J., Nold M. et al. Interferon-gamma induces expression of interleukin-18 binding protein in fibroblast-like synoviocytes. Rheumatology (Oxford) 2003;42:442-5.</p><p>Koch A.E., Kunkel S.L., Harlow L.A. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992;90:772-9.</p><p>Chandra P.E., Sokolove J., Hipp B.G. et al. Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. Arthr Res Ther 2011;13:102.</p><p>Rantapä ä-Dahlqvist S. Diagnostic and prognostic significance of autoantibodies in early rheumatoid arthritis. Scand J Rheumatol 2005;34:83-96.</p><p>Zeng X., Ai M., Tian X. et al. Diagnostic value of anticyclic citrullinated peptide antibody in patients with rheumatoid arthritis. J Rheumatol 2003;30:1451-5.</p><p>Niewold T., Harrison M., Paget S. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. Q J Med 2007;100:193-201.</p><p>http://www.cap.org/apps/docs/committees/technology/ivdmia.pdf</p></div><br /><div><p>Насонов Е.Л., Каратеев Д.Е., Балабанова Р.М. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. М.: ГЭОТАР-Медиа, 2008;290-331.</p><p>O’Dell J.R. Treating rheumatoid arthritis early: a window of opportunity? Arthr Rheum 2002;46:283-5.</p><p>Scott D.L. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthr Rheum 2002;46:286-90.</p><p>Насонов Е.Л. Почему необходима ранняя диагностика и лечение ревматоидного артрита? Рус мед журн 2002;10:1009-10.</p><p>Orozco C., Olsen N.G. Identification of patients with early rheumatoid arthritis: challenges and future directions. Clin Devel Immunol 2006;13:295-7.</p><p>Krabben A., Huizinga T.W., van der Helm-van Mil A.H. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Ann Rheum Dis 2012;71:238-41.</p><p>Arnett F.C., Edworthy S.M., Bloch D.A. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 1988;31:315-24.</p><p>Van Venrooij W.J., van Beers J.J., Pruijn G.J. Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann NY Acad Sci 2008;1143:268-85.</p><p>Miossec P., Verweij C.L., Klareskog L. et al. Biomarkers and personalized medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies. Ann Rheum Dis 2011;70:1713-8.</p><p>Gibson D.S., Rooney M.E., Finnegan S. et al. Biomarkers in rheumatology, now and in the future. Rheumatology (Oxford) 2012;51:423-33.</p><p>Александрова Е.Н., Новиков А.А., Насонов Е.Л. Современные стандарты лабораторной диагностики ревматических заболеваний. М., 2012;6-9.</p><p>Schellekens G.A., Visser H., de Jong B.A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthr Rheum 2000;43:155-63.</p><p>Schellekens G.A., de Jong B.A., van den Hoogen F.H. et al. Citrulline is an еssential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101:273-81.</p><p>Bang H., Luthke K., Gauliard A. et al. Mutated citrullinated vimentin (MCV) as a candidate autoantigen for diagnosis and monitoring of disease activity in rheumatoid arthritis. Ann Rheum Dis 2006;65:144.</p><p>Aletaha D., Neogi T., Silman A. et al. 2010 rheumatoid arthritis classification criteria. Arthr Rheum 2010;62:2569-81.</p><p>Taylor P., Gartemann J., Hsieh J. et al. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. SAGE-Hindawi Access to Research Autoimmune Diseases Volume 2011, Article ID 815038.</p><p>Dayer E., Dayer J., Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nat Clin Pract Rheumatol 2007;3:512-20.</p><p>de Seny D., Fillet M., Ribbens C. et al. Monomeric calgranulins measured by SELDI-TOF mass spectrometry and calprotectin measured by ELISA as biomarkers in arthritis. Clin Chem 2008;54:1066-75.</p><p>Hueber W., Tomooka B.H., 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;66:712-9.</p><p>Новиков А.А., Александрова Е.Н., Диатроптова М.А. и др. Роль цитокинов в патогенезе ревматоидного артрита. Науч-практич ревматол 2010;2:71-82.</p><p>Firestein G.S. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol 2005;11:39-44.</p><p>Wener M. Multiplex, megaplex, index, and complex: the present and future of laboratory diagnostics in rheumatology. Arthr Res Ther 2011;13:134.</p><p>Zhou X., Fragala M.S., McElhaney J. et al. Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research. Curr Opin Clin Nutr Metab Care 2010;13:541-7.</p><p>Bossuyt P.M. The thin line between hope and hype in biomarker research. JAMA 2011;305:2229-30.</p><p>Katz M.H. Multivariable analysis: a primer for readers of medical research. Ann Intern Med 2003;138:644-50.</p><p>Cavet G., Centola M., Shen Y. et al. Development of a multi-biomarker test for rheumatoid arthritis (RA) disease activity. Ann Rheum Dis 2010;69:148.</p><p>Герасимов А.Н. Медицинская статистика: Учебное пособие. М.: Медицинское информационное агентство, 2007; 480 с.</p><p>Alex P., Szodoray P., Knowlton N. et al. Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis. Clin Exp Rheumatol 2007;25:584-92.</p><p>Meyer P., Hodkinson B., Ally M. et al. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Hindawi Publishing Corporation Mediators of Inflammation Vol. 2010, Article ID 158514.</p><p>Deane K., O’Donnell C., Hueber W. et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthr Rheum 2010;62:3161-72.</p><p>Paramalingam S., Thumboo J, Vasoo S. et al. In vivo proand anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singapore 2007;36:96-9.</p><p>Hitchon C.A., Alex P., Erdile L.B. et al. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol 2004;31:2336-46.</p><p>Kokkonen H., Soderstrom I., Rocklov J. et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthr Rheum 2010;62:383-91.</p><p>Jorgensen K.T., Wiik A., Pedersen M. et al. Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors. Ann Rheum Dis 2008;67:860-6.</p><p>Poulsom H., Charles P. Antibodies to citrullinated vimentin are a specific and sensitive marker for the diagnosis of rheumatoid arthritis. Clin Rrev Allerg Immun 2008;34:410.</p><p>Raza K., Mathsson L., Buckley C.D. et al. Antimodified citrulli-nated vimentin (MCV) antibodies in patients with very early synovitis. Ann Rheum Dis 2010;69:6278.</p><p>Bizzaro N. Antibodies to citrullinated peptides: a significant step forward in the early diagnosis of rheumatoid arthritis. Clin Chem Lab Med 2007;45:150-7.</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;19:22-5.</p><p>Hanaoka R., Kasama T., Muramatsu M. et al. A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthr Res Ther 2003;5:74-81.</p><p>Müller B., Paulukat J., Nold M. et al. Interferon-gamma induces expression of interleukin-18 binding protein in fibroblast-like synoviocytes. Rheumatology (Oxford) 2003;42:442-5.</p><p>Koch A.E., Kunkel S.L., Harlow L.A. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992;90:772-9.</p><p>Chandra P.E., Sokolove J., Hipp B.G. et al. Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. Arthr Res Ther 2011;13:102.</p><p>Rantapä ä-Dahlqvist S. Diagnostic and prognostic significance of autoantibodies in early rheumatoid arthritis. Scand J Rheumatol 2005;34:83-96.</p><p>Zeng X., Ai M., Tian X. et al. Diagnostic value of anticyclic citrullinated peptide antibody in patients with rheumatoid arthritis. J Rheumatol 2003;30:1451-5.</p><p>Niewold T., Harrison M., Paget S. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. Q J Med 2007;100:193-201.</p><p>http://www.cap.org/apps/docs/committees/technology/ivdmia.pdf</p></div><br />

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