mrjСовременная ревматологияModern Rheumatology Journal1996-70122310-158XIMA-PRESS, LLC10.14412/1996-7012-2018-4-16-22mrj-857Research ArticleОБЗОРЫREVIEWSСтратификация больных и выбор терапии на основании профилей экспрессии генов в крови при ревматоидном артритеPatient stratification and choice of therapy based on blood gene expression profiles in rheumatoid arthritisЧетинаE. В.ChetinaE. V.

Елена Васильевна Четина.

115522, Москва, Каширское шоссе, 34А.

etchetina@mail.ruМарковаГ. А.MarkovaG. A.ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой».РоссияV.A. Nasonova Research Institute of Rheumatology.Russian Federation2018051220181241622Copyright © Четина E.В., Маркова Г.А., 20182018Четина E.В., Маркова Г.А.Chetina E.V., Markova G.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://mrj.ima-press.net/mrj/article/view/857

Ревматоидный артрит (РА) – хроническое воспалительное заболевание неизвестной этиологии, при котором повреждаются разные участки иммунной системы и другие ткани, а также происходит деструкция суставов. Современные способы терапии направлены на подавление воспаления и снижение уровня боли, однако они не влияют на патофизиологические и биохимические механизмы, участвующие в разрушении сустава. Более того, больные РА представляют собой исключительно гетерогенную группу, поэтому не все они одинаково отвечают на лечение. В связи с этим необходима персонифицированная терапия. Однако в настоящее время оценка больного, включающая клинические, иммунологические и радиологические показатели, не позволяет предсказать ответ на антиревматическое лечение приблизительно в половине случаев. Тем не менее исследования последних лет свидетельствуют о том, что стратификация больных в соответствии с уровнем провоспалительных генов в крови способна помочь прогнозировать ответ на антиревматическую терапию.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology, in which different parts of the immune system and other tissues are involved and joint destruction also occurs. Current therapy methods are aimed at suppressing inflammation and reducing pain; however, they do not affect the pathophysiological and biochemical mechanisms involved in joint destruction. Moreover, RA patients are an exclusively heterogeneous group, so not all of them respond equally well to treatment. In this regard, there is a need for personalized therapy. However, the patient's assessment, including clinical, immunological, and radiological parameters, does not currently allow the response to anti-rheumatic treatment to be predicted in about half of the cases. Just the same, recent studies suggest that patient stratification according to the blood level of proinflammatory genes can help predict a response to antirheumatic therapy.

ревматоидный артритэкспрессия геновкитайская традиционная медицинафактор некроза опухоли αинтерферон типа 1стратификация больныхответ на терапиюrheumatoid arthritisgene expressiontraditional Chinese medicinetumor necrosis factor-αtype 1 interferonpatient stratificationresponse to therapyReferencesTchetina EV. «High» and «Low» Gene Expression Signatures in Rheumatoid Arthritis: an Emerging Approach for Patient Stratification and Therapy Choice. Editorial. Int J Orthopaedics. 2015;2(2):219-26. doi:10.6051/j.issn.2311-5106.2015.02.35Tchetina EV. «High» and «Low» Gene Expression Signatures in Rheumatoid Arthritis: an Emerging Approach for Patient Stratification and Therapy Choice. Editorial. Int J Orthopaedics. 2015;2(2):219-26. doi:10.6051/j.issn.2311-5106.2015.02.35Paula FS, Alves JD. Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biologics. 2014;8:1-12. doi: 10.2147/BTT.S35475. Epub 2013 Dec 9.Paula FS, Alves JD. Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis. Biologics. 2014;8:1-12. doi: 10.2147/BTT.S35475. Epub 2013 Dec 9.Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009 Feb 21;373(9664):659-72. doi: 10.1016/S0140-6736(09)60008-8. Epub 2009 Jan 20.Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009 Feb 21;373(9664):659-72. doi: 10.1016/S0140-6736(09)60008-8. Epub 2009 Jan 20.Viatte S, Plant D, Bowes J, et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann Rheum Dis. 2012 Dec;71(12): 1984-90. doi: 10.1136/annrheumdis-2011-201225. Epub 2012 Jun 1.Viatte S, Plant D, Bowes J, et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann Rheum Dis. 2012 Dec;71(12): 1984-90. doi: 10.1136/annrheumdis-2011-201225. Epub 2012 Jun 1.Kurreeman F, Liao K, Chibnik L, et al. Genetic basis of autoantibody positive and negative rheumatoid arthritis risk in a multiethnic cohort derived from electronic health records. Am J Hum Genet. 2011 Jan 7;88(1): 57-69. doi: 10.1016/j.ajhg.2010.12.007.Kurreeman F, Liao K, Chibnik L, et al. Genetic basis of autoantibody positive and negative rheumatoid arthritis risk in a multiethnic cohort derived from electronic health records. Am J Hum Genet. 2011 Jan 7;88(1): 57-69. doi: 10.1016/j.ajhg.2010.12.007.Berglin E, Johansson T, Sundin U, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis. 2006 Apr;65(4):453-8. Epub 2005 Sep 21.Berglin E, Johansson T, Sundin U, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis. 2006 Apr;65(4):453-8. Epub 2005 Sep 21.Del Val del Amo N, Ibanez Bosch R, Fito Manteca C, et al. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: relation with disease aggressiveness. Clin Exp Rheumatol. 2006 May-Jun;24(3):281-6.Del Val del Amo N, Ibanez Bosch R, Fito Manteca C, et al. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: relation with disease aggressiveness. Clin Exp Rheumatol. 2006 May-Jun;24(3):281-6.Van der Helm-van Mil AH, De Cessie S, Van Dongen H, et al. A prediction rule for disease outcome in patients with Recentonset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 2007 Feb;56(2):433-40.Van der Helm-van Mil AH, De Cessie S, Van Dongen H, et al. A prediction rule for disease outcome in patients with Recentonset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 2007 Feb;56(2):433-40.Van Dongen H, van Aken J, Lard LR, et al. Efficacy of methotrexate treatment in patients with probable rheumatoidarthritis: A doubleblind, randomized, placebo-controlled trial. Arthritis Rheum. 2007 May;56(5):1424-32.Van Dongen H, van Aken J, Lard LR, et al. Efficacy of methotrexate treatment in patients with probable rheumatoidarthritis: A doubleblind, randomized, placebo-controlled trial. Arthritis Rheum. 2007 May;56(5):1424-32.Thurlings RM, Boumans M, Tekstra J, et al. Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients. Arthritis Rheum. 2010 Dec;62(12):3607-14. doi: 10.1002/art.27702.Thurlings RM, Boumans M, Tekstra J, et al. Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients. Arthritis Rheum. 2010 Dec;62(12):3607-14. doi: 10.1002/art.27702.Mesko B, Poliska S, Nagy L. Gene expression profiles in peripheral blood for the diagnosis of autoimmune diseases. Trends Mol Med. 2011 Apr;17(4):223-33. doi: 10.1016/j.molmed.2010.12.004. Epub 2011 Mar 8.Mesko B, Poliska S, Nagy L. Gene expression profiles in peripheral blood for the diagnosis of autoimmune diseases. Trends Mol Med. 2011 Apr;17(4):223-33. doi: 10.1016/j.molmed.2010.12.004. Epub 2011 Mar 8.Burska AN, Roget K, Blits M, et al. Gene expression analysis in RA: towards personalized medicine. Pharmacogenomics J. 2014 Apr;14(2):93-106. doi: 10.1038/tpj. 2013.48. Epub 2014 Mar 4.Burska AN, Roget K, Blits M, et al. Gene expression analysis in RA: towards personalized medicine. Pharmacogenomics J. 2014 Apr;14(2):93-106. doi: 10.1038/tpj. 2013.48. Epub 2014 Mar 4.Serikawa KA, Jacobsen S, Lundsgaard D, et al. Detection of gene expression signatures related to underlying disease and treatment in rheumatoid arthritis patients. Mod Rheumatol. 2013 Jul;23(4):729-40. doi: 10.1007/s10165-012-0723-9. Epub 2012 Aug 8.Serikawa KA, Jacobsen S, Lundsgaard D, et al. Detection of gene expression signatures related to underlying disease and treatment in rheumatoid arthritis patients. Mod Rheumatol. 2013 Jul;23(4):729-40. doi: 10.1007/s10165-012-0723-9. Epub 2012 Aug 8.Van Baarsen LG, Wijbrandts CA, Timmer TC, et al. Synovial tissue heterogeneity in rheumatoid arthritis in relation to disease activity and biomarkers in peripheral blood. Arthritis Rheum. 2010 Jun;62(6): 1602-7. doi: 10.1002/art.27415.Van Baarsen LG, Wijbrandts CA, Timmer TC, et al. Synovial tissue heterogeneity in rheumatoid arthritis in relation to disease activity and biomarkers in peripheral blood. Arthritis Rheum. 2010 Jun;62(6): 1602-7. doi: 10.1002/art.27415.He Y, Lu A, Zha Y, Tsang I. Differential effect on symptoms treated with traditional Chinese medicine and western combination therapy in RA patients. Complement Ther Med. 2008 Aug;16(4):206-11. doi: 10.1016/j.ctim.2007.08.005. Epub 2008 Jan 24.He Y, Lu A, Zha Y, Tsang I. Differential effect on symptoms treated with traditional Chinese medicine and western combination therapy in RA patients. Complement Ther Med. 2008 Aug;16(4):206-11. doi: 10.1016/j.ctim.2007.08.005. Epub 2008 Jan 24.Lu C, Zha Q, Chang A, et al. Pattern differentiation in Traditional Chinese Medicine can help define specific indications for biomedical therapy in the treatment of rheumatoid arthritis. J Altern Complement Med. 2009 Sep;15(9):1021-5. doi: 10.1089/acm.2009.0065.Lu C, Zha Q, Chang A, et al. Pattern differentiation in Traditional Chinese Medicine can help define specific indications for biomedical therapy in the treatment of rheumatoid arthritis. J Altern Complement Med. 2009 Sep;15(9):1021-5. doi: 10.1089/acm.2009.0065.Jiang M, Xiao C, Chen G, et al. Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis. Front Med. 2011 Jun;5(2):219-28. doi: 10.1007/s11684-011-0133-y. Epub 2011 Jun 22.Jiang M, Xiao C, Chen G, et al. Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis. Front Med. 2011 Jun;5(2):219-28. doi: 10.1007/s11684-011-0133-y. Epub 2011 Jun 22.Chen G, Lu C, Zha Q, et al. A networkbased analysis of traditional Chinese medicine cold and hot patterns in rheumatoid arthritis. Complement Ther Med. 2012 Feb- Apr;20(1-2):23-30. doi: 10.1016/j.ctim.2011.10.005. Epub 2011 Nov 3.Chen G, Lu C, Zha Q, et al. A networkbased analysis of traditional Chinese medicine cold and hot patterns in rheumatoid arthritis. Complement Ther Med. 2012 Feb- Apr;20(1-2):23-30. doi: 10.1016/j.ctim.2011.10.005. Epub 2011 Nov 3.Gonzalo-Gil E, Galindo-Izquierdo M. Role of transforming growth factor-beta (TGF) beta in the physiopathology of rheumatoid arthritis. Reumatol Clin. 2014 May-Jun;10(3):174-9. doi: 10.1016/j.reuma.2014.01.009. Epub 2014 Mar 28.Gonzalo-Gil E, Galindo-Izquierdo M. Role of transforming growth factor-beta (TGF) beta in the physiopathology of rheumatoid arthritis. Reumatol Clin. 2014 May-Jun;10(3):174-9. doi: 10.1016/j.reuma.2014.01.009. Epub 2014 Mar 28.Zhang Y, Qiu H, Zhang H, et al. Vascular endothelial growth factor A (VEGFA) polymorphisms in Chinese patients with rheumatoid arthritis. Scand J Rheumatol. 2013;42(5): 344-8. doi: 10.3109/03009742.2013.787454. Epub 2013 Jul 15.Zhang Y, Qiu H, Zhang H, et al. Vascular endothelial growth factor A (VEGFA) polymorphisms in Chinese patients with rheumatoid arthritis. Scand J Rheumatol. 2013;42(5): 344-8. doi: 10.3109/03009742.2013.787454. Epub 2013 Jul 15.Miao CG, Yang YY, He X, et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal. 2013 Oct;25(10):2069-78. doi: 10.1016/j.cellsig.2013.04.002. Epub 2013 Apr 17.Miao CG, Yang YY, He X, et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal. 2013 Oct;25(10):2069-78. doi: 10.1016/j.cellsig.2013.04.002. Epub 2013 Apr 17.Hao Q,Wang L, Tang H. Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells. Am J Physiol Cell Physiol. 2009 Apr;296(4): C821-7. doi: 10.1152/ajpcell.00504.2008. Epub 2009 Jan 28.Hao Q,Wang L, Tang H. Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells. Am J Physiol Cell Physiol. 2009 Apr;296(4): C821-7. doi: 10.1152/ajpcell.00504.2008. Epub 2009 Jan 28.Lee HS, Woo SJ, Koh HW, et al. Regulation of apoptosis and inflammatory responses by insulin-like growth factor binding protein 3 in fibroblast-like synoviocytes and experimental animal models of rheumatoid arthritis. Arthritis Rheumatol. 2014 Apr; 66(4):863-73. doi: 10.1002/art.38303.Lee HS, Woo SJ, Koh HW, et al. Regulation of apoptosis and inflammatory responses by insulin-like growth factor binding protein 3 in fibroblast-like synoviocytes and experimental animal models of rheumatoid arthritis. Arthritis Rheumatol. 2014 Apr; 66(4):863-73. doi: 10.1002/art.38303.Page TH, Smolinska M, Gillespie J, et al. Tyrosine kinases and inflammatory signalling. Curr Mol Med. 2009 Feb;9(1):69-85.Page TH, Smolinska M, Gillespie J, et al. Tyrosine kinases and inflammatory signalling. Curr Mol Med. 2009 Feb;9(1):69-85.Dirven L, Klarenbeek NB, van den Broek M, et al. Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy. Clin Rheumatol. 2013 May;32(5): 585-90. doi: 10.1007/s10067-012-2136-8. Epub 2012 Dec 9.Dirven L, Klarenbeek NB, van den Broek M, et al. Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy. Clin Rheumatol. 2013 May;32(5): 585-90. doi: 10.1007/s10067-012-2136-8. Epub 2012 Dec 9.Lindblad SS, Mydel P, Hellvard A, et al. The N-methyl-d-aspartic acid receptor antagonist memantine ameliorates and delays the development of arthritis by enhancing regulatory T cells. Neurosignals. 2012;20(2): 61-71. doi: 10.1159/000329551. Epub 2011 Dec 1.Lindblad SS, Mydel P, Hellvard A, et al. The N-methyl-d-aspartic acid receptor antagonist memantine ameliorates and delays the development of arthritis by enhancing regulatory T cells. Neurosignals. 2012;20(2): 61-71. doi: 10.1159/000329551. Epub 2011 Dec 1.Olsen NJ, Moore JH, Aune TM. Gene expression signatures for autoimmune disease in peripheral blood mononuclear cells. Arthritis Res Ther. 2004;6(3):120-8. Epub 2004 Apr 29.Olsen NJ, Moore JH, Aune TM. Gene expression signatures for autoimmune disease in peripheral blood mononuclear cells. Arthritis Res Ther. 2004;6(3):120-8. Epub 2004 Apr 29.Baccala R, Kono DH, Theofilopoulos AN. Interferons as pathogenic effectors in autoimmunity. Immunol Rev. 2005 Apr;204:9-26.Baccala R, Kono DH, Theofilopoulos AN. Interferons as pathogenic effectors in autoimmunity. Immunol Rev. 2005 Apr;204:9-26.Raychaudhuri S. Recent advances in the genetics of rheumatoid arthritis. Curr Opin Rheumatol. 2010 Mar;22(2):109-18. doi: 10.1097/BOR.0b013e328336474d.Raychaudhuri S. Recent advances in the genetics of rheumatoid arthritis. Curr Opin Rheumatol. 2010 Mar;22(2):109-18. doi: 10.1097/BOR.0b013e328336474d.Sigurdsson S, Padyukov L, Kurreeman FA, et al. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 2007 Jul;56(7):2202-10.Sigurdsson S, Padyukov L, Kurreeman FA, et al. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 2007 Jul;56(7):2202-10.Van der Pouw Kraan TC, Wijbrandts CA, Van Baarsen LG, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis. 2007 Aug;66(8): 1008-14. Epub 2007 Jan 12.Van der Pouw Kraan TC, Wijbrandts CA, Van Baarsen LG, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis. 2007 Aug;66(8): 1008-14. Epub 2007 Jan 12.Reynier F, Petit F, Paye M, et al. Importance of correlation between gene expression levels: application to the type I interferon signature in rheumatoid arthritis. PLoS One. 2011;6(10):e24828. doi: 10.1371/journal.pone.0024828. Epub 2011 Oct 17.Reynier F, Petit F, Paye M, et al. Importance of correlation between gene expression levels: application to the type I interferon signature in rheumatoid arthritis. PLoS One. 2011;6(10):e24828. doi: 10.1371/journal.pone.0024828. Epub 2011 Oct 17.Cantaert T, Van Baarsen LG, Wijbrandts CA, et al. Type I interferons have no major influence on humoral autoimmunity in rheumatoid arthritis. Rheumatology (Oxford). 2010 Jan;49(1):156-66. doi: 10.1093/rheumatology/kep345. Epub 2009 Nov 23.Cantaert T, Van Baarsen LG, Wijbrandts CA, et al. Type I interferons have no major influence on humoral autoimmunity in rheumatoid arthritis. Rheumatology (Oxford). 2010 Jan;49(1):156-66. doi: 10.1093/rheumatology/kep345. Epub 2009 Nov 23.Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307-36.Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307-36.Tak PP. IFN-β in rheumatoid arthritis. Front Biosci. 2004 Sep 1;9:3242-7.Tak PP. IFN-β in rheumatoid arthritis. Front Biosci. 2004 Sep 1;9:3242-7.Vervoordeldonk MJ, Aalbers CJ, Tak PP. Interferon β for rheumatoidarthritis: new clothes for an old kid on the block. Ann Rheum Dis. 2009 Feb;68(2):157-8. doi: 10.1136/ard.2008.097899.Vervoordeldonk MJ, Aalbers CJ, Tak PP. Interferon β for rheumatoidarthritis: new clothes for an old kid on the block. Ann Rheum Dis. 2009 Feb;68(2):157-8. doi: 10.1136/ard.2008.097899.Hay N, Sonnenberg N. Upstream and downstream of mTOR. Genes Dev. 2004 Aug 15;18(16):1926-45.Hay N, Sonnenberg N. Upstream and downstream of mTOR. Genes Dev. 2004 Aug 15;18(16):1926-45.Yoshimura N, Ohmoto Y, Yasui H, et al. The direct effect of FK506 and rapamycin on interleukin 1(beta) and immunoglobulin production in vitro. Transplantation. 1994 Jun 27; 57(12):1815-8.Yoshimura N, Ohmoto Y, Yasui H, et al. The direct effect of FK506 and rapamycin on interleukin 1(beta) and immunoglobulin production in vitro. Transplantation. 1994 Jun 27; 57(12):1815-8.Foey AD, Feldmann M, Brennan FM. CD40 ligation induces macrophage IL-10 and TNA-alpha production: differential use the PI3K and p42/44 MAPR-pathways. Cytokine. 2001 Nov 21;16(4):131-42.Foey AD, Feldmann M, Brennan FM. CD40 ligation induces macrophage IL-10 and TNA-alpha production: differential use the PI3K and p42/44 MAPR-pathways. Cytokine. 2001 Nov 21;16(4):131-42.Carlson RP, Hartman DA, Tomchek LA, et al. Rapamycin, a potential disease-modifying antiarthritic drug. J Pharmacol Exp Ther. 1993 Aug;266(2):1125-38.Carlson RP, Hartman DA, Tomchek LA, et al. Rapamycin, a potential disease-modifying antiarthritic drug. J Pharmacol Exp Ther. 1993 Aug;266(2):1125-38.Migita K, Eguchi K, Aoyagi T, et al. The effects of the immunosuppressant rapamycin on the growth of rheumatoid arthritis synovial fibroblast. Clin Exp Immunol. 1996 Apr;104(1):86-91.Migita K, Eguchi K, Aoyagi T, et al. The effects of the immunosuppressant rapamycin on the growth of rheumatoid arthritis synovial fibroblast. Clin Exp Immunol. 1996 Apr;104(1):86-91.Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem. 2005 Feb 4;280(5): 3583-9. Epub 2004 Nov 15.Sugatani T, Hruska KA. Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem. 2005 Feb 4;280(5): 3583-9. Epub 2004 Nov 15.Tchetina E, Demidova NV, Semyonova LA, et al. Differential expression of mammalian target of rapamycin (mTOR) in the peripheral blood of early-stage rheumatoid arthritis patients as a prognostic marker of the disease activity and knee joint destruction: a two year followup study. Ann Rheum Dis. 2010;69(Suppl 3):675.Tchetina E, Demidova NV, Semyonova LA, et al. Differential expression of mammalian target of rapamycin (mTOR) in the peripheral blood of early-stage rheumatoid arthritis patients as a prognostic marker of the disease activity and knee joint destruction: a two year followup study. Ann Rheum Dis. 2010;69(Suppl 3):675.Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010 Sep 25; 376(9746):1094-108. doi: 10.1016/S0140-6736(10)60826-4.Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010 Sep 25; 376(9746):1094-108. doi: 10.1016/S0140-6736(10)60826-4.Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford). 2004 Oct;43(10):1252-5. Epub 2004 Jul 6.Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford). 2004 Oct;43(10):1252-5. Epub 2004 Jul 6.Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006 Jan;54(1):26-37.Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006 Jan;54(1):26-37.Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial. Lancet. 2008 Aug 2;372(9636):375-82. doi: 10.1016/S0140-6736(08)61000-4. Epub 2008 Jul 16.Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial. Lancet. 2008 Aug 2;372(9636):375-82. doi: 10.1016/S0140-6736(08)61000-4. Epub 2008 Jul 16.Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000 Nov 30; 343(22):1586-93.Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000 Nov 30; 343(22):1586-93.Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumour necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo- controlled, 52-week trial. Arthritis Rheum. 2004 May;50(5):1400-11.Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumour necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo- controlled, 52-week trial. Arthritis Rheum. 2004 May;50(5):1400-11.Maini RN, Breedveld FC, Kalden JR, et al. Anti-tumour necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004 Apr;50(4):1051-65.Maini RN, Breedveld FC, Kalden JR, et al. Anti-tumour necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004 Apr;50(4):1051-65.Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, doubleblind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006 Sep;54(9):2793-806.Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, doubleblind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006 Sep;54(9):2793-806.Emery P, Fleischmann R, Filipowicz- Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, doubleblind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006 May;54(5):1390-400.Emery P, Fleischmann R, Filipowicz- Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, doubleblind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006 May;54(5):1390-400.Tchetina EV, Demidova NV, Karateev DE, Nasonov EL. Rheumatoid factor positivity is associated with increased joint destruction and up-regulation of matrix metalloproteinase 9 and cathepsin K gene expression in the peripheral blood in rheumatoid arthritis patients treated with methotrexate. Int J Rheumatol. 2013;2013:457876. doi: 10.1155/2013/457876. Epub 2013 Nov 14.Tchetina EV, Demidova NV, Karateev DE, Nasonov EL. Rheumatoid factor positivity is associated with increased joint destruction and up-regulation of matrix metalloproteinase 9 and cathepsin K gene expression in the peripheral blood in rheumatoid arthritis patients treated with methotrexate. Int J Rheumatol. 2013;2013:457876. doi: 10.1155/2013/457876. Epub 2013 Nov 14.Weinblatt ME. Efficacy of methotrexate in rheumatoid arthritis. Br J Rheumatol. 1995 Nov;34 Suppl 2:43-8.Weinblatt ME. Efficacy of methotrexate in rheumatoid arthritis. Br J Rheumatol. 1995 Nov;34 Suppl 2:43-8.Katchamart W, Trudeau J, Phumethum V, Bombardier C. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2009 Jul; 68(7):1105-12. doi: 10.1136/ard.2008.099861. Epub 2008 Dec 3.Katchamart W, Trudeau J, Phumethum V, Bombardier C. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2009 Jul; 68(7):1105-12. doi: 10.1136/ard.2008.099861. Epub 2008 Dec 3.Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23.Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23.Van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs from bench to bedside. Nat Clin Pract Rheumatol. 2007 Jan; 3(1):26-34.Van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs from bench to bedside. Nat Clin Pract Rheumatol. 2007 Jan; 3(1):26-34.Blits M, Jansen G, Assaraf YG, et al. Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis. Arthritis Rheum. 2013 Nov;65(11):2791-802. doi: 10.1002/art.38094.Blits M, Jansen G, Assaraf YG, et al. Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis. Arthritis Rheum. 2013 Nov;65(11):2791-802. doi: 10.1002/art.38094.Tchetina EV, Demidova NV, Karateev DE, Nasonov EL. Methotrexate therapy monitoring by mTOR, autophagy-related ULK1, caspase 3, cdk-inhibitor p21, TNFalpha, and osteoclast-specific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of early rheumatoid arthritis patients. Ann Rheum Dis. 2012;71(Suppl 3):653.Tchetina EV, Demidova NV, Karateev DE, Nasonov EL. Methotrexate therapy monitoring by mTOR, autophagy-related ULK1, caspase 3, cdk-inhibitor p21, TNFalpha, and osteoclast-specific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of early rheumatoid arthritis patients. Ann Rheum Dis. 2012;71(Suppl 3):653.Tchetina EV, Demidova NV, Karateev DE. Positive correlation of Ulk1 and MMP-9 versus negative correlation of mTOR and TNFα baseline gene expressions in the peripheral blood with the disease activity and joint destruction indices registered in rheumatoid arthritic patients after treatment. Ann Rheum Dis. 2014;73(Suppl 2). doi:10.1136/annrheumdis- 2014-eular.3992.Tchetina EV, Demidova NV, Karateev DE. Positive correlation of Ulk1 and MMP-9 versus negative correlation of mTOR and TNFα baseline gene expressions in the peripheral blood with the disease activity and joint destruction indices registered in rheumatoid arthritic patients after treatment. Ann Rheum Dis. 2014;73(Suppl 2). doi:10.1136/annrheumdis- 2014-eular.3992.Rustenburg F, Baggen JM, Verweij CL, et al. Responsiveness to anti-tumour necrosis factor alpha therapy is related to pre-treatment tissue inflammation levels in rheumatoid arthritis patients. Ann Rheum Dis. 2008 Apr;67(4):563-6. Epub 2007 Nov 27.Rustenburg F, Baggen JM, Verweij CL, et al. Responsiveness to anti-tumour necrosis factor alpha therapy is related to pre-treatment tissue inflammation levels in rheumatoid arthritis patients. Ann Rheum Dis. 2008 Apr;67(4):563-6. Epub 2007 Nov 27.Wijbrandts CA, Dijkgraaf MG, Kraan MC, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium. Ann Rheum Dis. 2008 Aug;67(8):1139-44. Epub 2007 Nov 29.Wijbrandts CA, Dijkgraaf MG, Kraan MC, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium. Ann Rheum Dis. 2008 Aug;67(8):1139-44. Epub 2007 Nov 29.Marotte H, Maslinski W, Miossec P. Circulating tumour necrosis factor-alpha bioactivity in Rheumatoid Arthritis patients treated with infliximab: link to clinical response. Arthritis Res Ther. 2005;7(1):R149-55. Epub 2004 Dec 1.Marotte H, Maslinski W, Miossec P. Circulating tumour necrosis factor-alpha bioactivity in Rheumatoid Arthritis patients treated with infliximab: link to clinical response. Arthritis Res Ther. 2005;7(1):R149-55. Epub 2004 Dec 1.Kim TH, Choi SJ, Lee YH, et al. Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets. Joint Bone Spine. 2014 Jul;81(4):325-30. doi: 10.1016/j.jbspin.2014.01.013. Epub 2014 Feb 20.Kim TH, Choi SJ, Lee YH, et al. Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets. Joint Bone Spine. 2014 Jul;81(4):325-30. doi: 10.1016/j.jbspin.2014.01.013. Epub 2014 Feb 20.Tanino M, Matoba R, Nakamura S, et al. Prediction of efficacy of anti-TNF biologic agent, infliximab, for rheumatoid arthritis patients using a comprehensive transcriptome analysis of white blood cells. Biochem Biophys Res Commun. 2009 Sep 18;387(2):261-5. doi: 10.1016/j.bbrc.2009.06.149. Epub 2009 Jul 3.Tanino M, Matoba R, Nakamura S, et al. Prediction of efficacy of anti-TNF biologic agent, infliximab, for rheumatoid arthritis patients using a comprehensive transcriptome analysis of white blood cells. Biochem Biophys Res Commun. 2009 Sep 18;387(2):261-5. doi: 10.1016/j.bbrc.2009.06.149. Epub 2009 Jul 3.Sekiguchi N, Kawauchi S, Furuya T, et al. Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients following treatment with an anti-TNF-alpha monoclonal antibody, infliximab. Rheumatology (Oxford). 2008 Jun;47(6):780-8. doi: 10.1093/rheumatology/ken083. Epub 2008 Apr 3.Sekiguchi N, Kawauchi S, Furuya T, et al. Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients following treatment with an anti-TNF-alpha monoclonal antibody, infliximab. Rheumatology (Oxford). 2008 Jun;47(6):780-8. doi: 10.1093/rheumatology/ken083. Epub 2008 Apr 3.Van Baarsen LG, Wijbrandts CA, Gerlag DM, et al. Pharmacogenomics of infliximab treatment using peripheral blood Genes Immun. 2010 Dec;11(8):622-9. doi: 10.1038/gene.2010.34. Epub 2010 Jun 17.Van Baarsen LG, Wijbrandts CA, Gerlag DM, et al. Pharmacogenomics of infliximab treatment using peripheral blood Genes Immun. 2010 Dec;11(8):622-9. doi: 10.1038/gene.2010.34. Epub 2010 Jun 17.Meugnier E, Coury F, Tebib J, et al. Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-alpha treatments. Physiol Genomics. 2011 Apr 12;43(7):365-71. doi: 10.1152/physiolgenomics.00127.2010. Epub 2011 Jan 25.Meugnier E, Coury F, Tebib J, et al. Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-alpha treatments. Physiol Genomics. 2011 Apr 12;43(7):365-71. doi: 10.1152/physiolgenomics.00127.2010. Epub 2011 Jan 25.Van Baarsen LG, Wijbrandts CA, Rustenburg F, et al. Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther. 2010;12(1):R11. doi: 10.1186/ar2912. Epub 2010 Jan 22.Van Baarsen LG, Wijbrandts CA, Rustenburg F, et al. Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther. 2010;12(1):R11. doi: 10.1186/ar2912. Epub 2010 Jan 22.Mavragani CP, La DT, Stohl W, Crow MK. Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-alpha/beta ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort. Arthritis Rheum. 2010 Feb;62(2):392-401. doi: 10.1002/art.27226.Mavragani CP, La DT, Stohl W, Crow MK. Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-alpha/beta ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort. Arthritis Rheum. 2010 Feb;62(2):392-401. doi: 10.1002/art.27226.Smiljanovic B, Grü n JR, Biesen R, et al. The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines. J Mol Med (Berl). 2012 Nov;90(11):1295-309. doi: 10.1007/s00109-012-0907-y. Epub 2012 May 19.Smiljanovic B, Grü n JR, Biesen R, et al. The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines. J Mol Med (Berl). 2012 Nov;90(11):1295-309. doi: 10.1007/s00109-012-0907-y. Epub 2012 May 19.Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3372-7. Epub 2005 Feb 22.Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3372-7. Epub 2005 Feb 22.Ducreux J, Durez P, Galant C, et al. Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23. doi: 10.1002/art.38202.Ducreux J, Durez P, Galant C, et al. Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23. doi: 10.1002/art.38202.Mitani Y, Takaoka A, Kim SH, et al. Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling. Genes Cells. 2001 Jul;6(7):631-40.Mitani Y, Takaoka A, Kim SH, et al. Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling. Genes Cells. 2001 Jul;6(7):631-40.Sanayama Y, Ikeda K, Saito Y, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheumatol. 2014 Jun;66(6): 1421-31. doi: 10.1002/art.38400.Sanayama Y, Ikeda K, Saito Y, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheumatol. 2014 Jun;66(6): 1421-31. doi: 10.1002/art.38400.Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001; 19:163-96.Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001; 19:163-96.Takeuchi T, Miyasaka N, Tatsuki Y, et al. Inhibition of plasma IL-6 in addition to maintenance of an efficacious trough level of infliximab associated with clinical remission in patients with rheumatoid arthritis: analysis of the RISING Study. Ann Rheum Dis. 2012 Sep; 71(9):1583-5. doi: 10.1136/annrheumdis-2011-201069. Epub 2012 May 5.Takeuchi T, Miyasaka N, Tatsuki Y, et al. Inhibition of plasma IL-6 in addition to maintenance of an efficacious trough level of infliximab associated with clinical remission in patients with rheumatoid arthritis: analysis of the RISING Study. Ann Rheum Dis. 2012 Sep; 71(9):1583-5. doi: 10.1136/annrheumdis-2011-201069. Epub 2012 May 5.Sellam J, Marion-Thore S, Dumont F, et al. Whole-blood transcriptomic profiling highlights several pathophysiological pathways associated with rituximab response in rheumatoid arthritis: Data from the SMART trial. Arthritis Rheumatol. 2014 Aug;66(8): 2015-25. doi: 10.1002/art.38671.Sellam J, Marion-Thore S, Dumont F, et al. Whole-blood transcriptomic profiling highlights several pathophysiological pathways associated with rituximab response in rheumatoid arthritis: Data from the SMART trial. Arthritis Rheumatol. 2014 Aug;66(8): 2015-25. doi: 10.1002/art.38671.Lee YH, Bae SC, Song GG. Meta-analysis of gene expression profiles to predict response to biologic agents in rheumatoid arthritis. Clin Rheumatol. 2014 Jun;33(6): 775-82. doi: 10.1007/s10067-014-2547-9. Epub 2014 Mar 5.Lee YH, Bae SC, Song GG. Meta-analysis of gene expression profiles to predict response to biologic agents in rheumatoid arthritis. Clin Rheumatol. 2014 Jun;33(6): 775-82. doi: 10.1007/s10067-014-2547-9. Epub 2014 Mar 5.Raterman HG, Vosslamber S, de Ridder S, et al. The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther. 2012 Apr 27;14(2):R95. doi: 10.1186/ar3819.Raterman HG, Vosslamber S, de Ridder S, et al. The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther. 2012 Apr 27;14(2):R95. doi: 10.1186/ar3819.Sellam J, Marion-Thore S, Dumont F, et al. Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial. Arthritis Rheumatol. 2014 Aug;66(8): 2015-25. doi: 10.1002/art.38671.Sellam J, Marion-Thore S, Dumont F, et al. Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial. Arthritis Rheumatol. 2014 Aug;66(8): 2015-25. doi: 10.1002/art.38671.Tchetina EV, Kuzikyants KH, Devyataikina AY, et al. Rituximab therapy monitoring by mTOR, autophagy-related ULK1, caspase 3, cdk-inhibitor p21, TNFalpha, and osteoclastspecific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of rheumatoid arthritis patients. Ann Rheum Dis. 2012;71(Suppl 3):668.Tchetina EV, Kuzikyants KH, Devyataikina AY, et al. Rituximab therapy monitoring by mTOR, autophagy-related ULK1, caspase 3, cdk-inhibitor p21, TNFalpha, and osteoclastspecific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of rheumatoid arthritis patients. Ann Rheum Dis. 2012;71(Suppl 3):668.Julia A, Barcelo M, Erra A, et al. Identification of candidate genes for rituximab response in rheumatoid arthritis patients by microarray expression profiling in blood cells. Pharmacogenomics. 2009 Oct;10(10): 1697-708. doi: 10.2217/pgs.09.99.Julia A, Barcelo M, Erra A, et al. Identification of candidate genes for rituximab response in rheumatoid arthritis patients by microarray expression profiling in blood cells. Pharmacogenomics. 2009 Oct;10(10): 1697-708. doi: 10.2217/pgs.09.99.Smolen JS, Van Der Heijde DM, St Clair EW, et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006 Mar;54(3):702-10.Smolen JS, Van Der Heijde DM, St Clair EW, et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006 Mar;54(3):702-10.Emery P, Genovese MC, Kavanaugh AF, et al. Adalimumab plus methotrexate results in less frequent and less severe radiographic progression than methotrexate alone at all levels of clinical response in early rheumatoid arthritis. Ann Rheum Dis. 2006;65(Suppl 2):88.Emery P, Genovese MC, Kavanaugh AF, et al. Adalimumab plus methotrexate results in less frequent and less severe radiographic progression than methotrexate alone at all levels of clinical response in early rheumatoid arthritis. Ann Rheum Dis. 2006;65(Suppl 2):88.Lequerre T, Bansard C, Vittecoq O, et al. Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia. Arthritis Res Ther. 2009;11(3):R99. doi: 10.1186/ ar2744. Epub 2009 Jun 29.Lequerre T, Bansard C, Vittecoq O, et al. Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia. Arthritis Res Ther. 2009;11(3):R99. doi: 10.1186/ ar2744. Epub 2009 Jun 29.Tsubaki T, Arita N, Kawakami T, et al. Characterization of histopathology and geneexpression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens. Arthritis Res Ther. 2005;7(4): R825-36. Epub 2005 Apr 25.Tsubaki T, Arita N, Kawakami T, et al. Characterization of histopathology and geneexpression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens. Arthritis Res Ther. 2005;7(4): R825-36. Epub 2005 Apr 25.Higgs BW, Liu Z, White B, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011 Nov;70(11): 2029-36. doi: 10.1136/ard.2011.150326. Epub 2011 Jul 28.Higgs BW, Liu Z, White B, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011 Nov;70(11): 2029-36. doi: 10.1136/ard.2011.150326. Epub 2011 Jul 28.Grassi F, Cristino S, Toneguzzi S, et al. CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients. J Cell Physiol. 2004 May; 199(2):244-51.Grassi F, Cristino S, Toneguzzi S, et al. CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients. J Cell Physiol. 2004 May; 199(2):244-51.Brö mme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential offtarget effects. Expert Opin Investig Drugs. 2009 May;18(5):585-600. doi: 10.1517/13543780902832661 .Brö mme D, Lecaille F. Cathepsin K inhibitors for osteoporosis and potential offtarget effects. Expert Opin Investig Drugs. 2009 May;18(5):585-600. doi: 10.1517/13543780902832661 .Kim KS, Choi HM, Lee YA, et al. Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis. Rheumatol Int. 2011 Apr;31(4):543-7. doi: 10.1007/s00296-010-1592-1. Epub 2010 Jul 28.Kim KS, Choi HM, Lee YA, et al. Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis. Rheumatol Int. 2011 Apr;31(4):543-7. doi: 10.1007/s00296-010-1592-1. Epub 2010 Jul 28.Reynolds RJ, Cui X, Vaughan LK, et al. Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis. Rheumatol Int. 2013 Jan;33(1):129-37. doi: 10.1007/s00296-011-2355-3. Epub 2012 Jan 12.Reynolds RJ, Cui X, Vaughan LK, et al. Gene expression patterns in peripheral blood cells associated with radiographic severity in African Americans with early rheumatoid arthritis. Rheumatol Int. 2013 Jan;33(1):129-37. doi: 10.1007/s00296-011-2355-3. Epub 2012 Jan 12.Liu Z, Sokka T, Maas K, et al. Prediction of disease severity in patients with early rheumatoid arthritis by gene expression profiling. Hum Genomics Proteomics. 2009 Apr 27; 2009. pii: 484351. doi: 10.4061/2009/484351.Liu Z, Sokka T, Maas K, et al. Prediction of disease severity in patients with early rheumatoid arthritis by gene expression profiling. Hum Genomics Proteomics. 2009 Apr 27; 2009. pii: 484351. doi: 10.4061/2009/484351.

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