References:
1. Graudal NA, et al. Radiographic progression in rheumatoid arthritis. Arthritis Rheum. 1998;41(8):1470-1480.
2. van der Pouw Kraan TC, et al. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues.
Arthritis Rheum. 2003;48:2132-2145.
3. Sokka T, et al. 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):1387-1390.
4. Grigor C, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA Study): a single-blind randomised controlled trial. Lancet. 2004;364:263-269.
5. Rantalaiho V, et al, for the FIN-RACo Trial Group. Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial.
Arthritis Res Ther. 2010;12(3):R122.
6. Verstappen SMM, et al, on behalf of the Utrecht Rheumatoid
Arthritis Cohort study group. 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;66:1443-1449.
7. Goekoop-Ruiterman YPM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the
BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52(11):3381-3390.
8. Saag KG, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.
9. Combe B, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
Ann Rheum Dis. 2007;66:34-45.
10. Smolen JS, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69:631-637.
11. Shen Y, Dirven L. Cavet G, et al. Serum biomarker combinations to assess disease activity in the BeSt study. Presented at: EULAR 2010 Annual European
Congress of Rheumatology; June 16-19, 2010: Rome, Italy. Supported by
Crescendo Bioscience, Inc.
12. van Dinther-Janssen AC, Horst E, Koopman G, et al. The VLA-4/VCAM-1 pathway is involved in lymphocyte adhesion to endothelium in rheumatoid synovium. J Immunol. 1991;147(12):4207-4210.
13. Tokuhira M, Hosaka S, Volin MV, et al. Soluble vascular cell adhesion molecule 1 mediation of monocyte chemotaxis in rheumatoid arthritis. Arthritis Rheum. 2000;43(5):1122-1133.
14. Seemayer CA, Kuchen S, Kuenzler P, et al. Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. Am J Pathol. 2003;162(5):1549-1557.
15. Koch AE, Burrows JC, Haines GK, Carlos TM, Harlan JM, Leibovich SJ. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest. 1991;64(3):313-320.
16. 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):822-827.
17. Hiraoka K, Sasaguri Y, Komiya S, Inoue A, Morimatsu M. Cell proliferation-related production of matrix metalloproteinases 1 (tissue collagenase) and 3 (stromelysin) by cultured human rheumatoid synovial fibroblasts. Biochem Int. 1992;27(6):1083-1091.
18. Huh YH, Kim SH, Kim SJ, Chun JS. 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):9691-9697.
19. 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):682-697.
20. Afuwape AO, Kiriakidis S, Paleolog EM. The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis. Histol Histopathol. 2002;17(3):961-972.
21. Koch AE, Harlow LA, Haines GK, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994;152(8):4149-4156.
22. Niida S, Kaku M, Amano H, et al. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med. 1999;190(2):293-298.
23. Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol. 1998;16(3-4):249-284.
24. Smolen JS, Maini RN. Interleukin-6: a new therapeutic target. Arthritis Res Ther. 2006;8(suppl 2):S5.
25. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology. 2010;49(1):15-24.
26. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634-1635.
27. Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009;10:578-582.
28. Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci. 2006;11:529-543.
29. 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;267:1008-1014.
30. Suzuki K, Enghild JJ, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin). Biochemistry. 1990;29:10261-10270.
31. Okada Y, Takeuchi N, Tomita K, Nakanishi I, Nagase H. Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. Ann Rheum Dis. 1989;48(8):645-653.
32. 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;268:25803-25810.
33. Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M. Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997;237(1):46-54.
34. De Ceuninck F, Gaufillier S, Bonnaud A, Sabatini M, Lesur C, Pastoureau P. YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun. 2001;285:926-931.
35. 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(pt 3):651-659.
36. 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):291-296.
37. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432.
38. 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):1426-1433.
39. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543-546.
40. Holloway WR, Collier FM, Aitken CJ, et al. Leptin inhibits osteoclast generation. J Bone Miner Res. 2002;17(2):200-209.
41. 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):976-989.
42. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307-312.
43. 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):824-834.
44. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174:5789-5795.
45. 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):520-526.
46. 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):1851-1854.
47. Zhang N, Ahsan MH, Purchio AF, West DB. 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):8125-8134.
48. Kisilevsky R, Tam SP. Acute phase serum amyloid A, cholesterol metabolism, and cardiovascular disease. Ped Pathol Mol Med. 2002;21(3):291-305.
49. Kumon Y, Suehiro T, Hashimoto K, Nakatani K, Sipe JD. Local expression of acute phase serum amyloid A mRNA in rheumatoid arthritis synovial tissue and cells. J Rheumatol. 1999;26:785.
50. O'Hara R, Murphy EP, Whitehead AS, FitzGerald O, Bresnihan B. Acute-phase serum amyloid A production by rheumatoid arthritis synovial tissue. Arthritis Res. 2000;2:142.
51. Weinhold B, Ruther U. Interleukin-6-dependent and independent regulation of the human C-reactive protein gene. Biochem J. 1997;327:425-429.
52. Zhang D, Jiang SL, Rzewnicki D, Samols D, Kusher I. C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem J. 1995;310:143-148.
53. Macintyre SS, Schultz D, Kushner I. Biosynthesis of C-reactive protein. Ann NY Acad Sci. 1982;389:76-87.
54. van der Meer IM, Oel HH, Hofman A, Pols HA, de Jong FH, Witteman JC. Soluble Fas, a mediator of apoptosis, C-reactive protein, and coronary and extracoronary atherosclerosis. The Rotterdam Coronary Calcification Study. Atherosclerosis. 2006;189(2):464-469.
55. Knowlton N, et al. Rheumatoid factor interferes with multiplex immunoassays in rheumatoid arthritis patients. Presented at: EULAR 2010 Annual European Congress of Rheumatology; June 16-19, 2010; Rome, Italy.
56. Eastman S, et al. Assay development for precise measurement of disease activity serum biomarkers. Presented at: EULAR 2010 Annual European Congress of Rheumatology; June 16-19, 2010; Rome, Italy.
57. Fleischmann R, et al, on behalf of the InFoRM Study Group. RA population characteristics in InFoRM: a longitudinal observational study. Presented at: EULAR 2010 Annual European Congress of Rheumatology; June 16-19, 2010; Rome, Italy.
58. Ramanujan S, et al. Multi-protein biomarker panel integrates critical pathophysiologic mechanisms in measurement of RA disease activity. Presented at: EULAR 2010 Annual European Congress of Rheumatology; June 16-19, 2010; Rome, Italy.
59. Bakker MF, et al. Performance of serum biomarkers and a pre-specified multivariate biomarker-based test to measure disease activity in early rheumatoid arthritis treated according to the CAMERA protocol. Presented at: EULAR 2010 Annual European Congress of Rheumatology; June 16-19, 2010; Rome, Italy.
60. Curtis JR, et al. Validation of a Multi-Biomarker Test for Rheumatoid Arthritis (RA) Disease Activity (Vectra(TM) DA) in a Multi-Cohort Study. Presentation 1782. ACR/ARHP 2010 Annual Scientific Meeting; November 6-11, 2010. Atlanta, GA, USA.
61. Inoue E, et al. Comparison of Disease Activity Score (DAS)28-erythrocyte sedimentation rate and DAS28-C-reactive protein threshold values. Ann Rheum Dis. 2007;66:407-409.
62. Cavet G, Centola M, Shen Y, et al. Development of a multi-biomarker test for rheumatoid arthritis (RA). Ann Rheum Dis. 2010; 69(suppl 3):148.
VCAM-1 (vascular cell adhesion molecule-1) is an adhesion molecule expressed by endothelial and synovial cells. VCAM-1 may contribute to cellular recruitment to synovial tissue, as well as to cartilage invasion and destruction by fibroblasts. Vectra DA measures the soluble form of VCAM-1.12-15
EGF (epidermal growth factor) is a growth factor secreted by macrophages, fibroblasts, and endothelial cells in RA joint tissue. EGF is associated with proliferation and differentiation of stromal cells (fibroblasts, chondrocytes, endothelial cells) and can induce production of inflammatory mediators and proteinases in these cells. EGF may also modulate the hepatic acute-phase response.16-19
VEGF-A (vascular endothelial growth factor A) is a potent angiogenic growth factor and vascular permeability factor expressed by various synovial cells including fibroblasts and macrophages. VEGF-A promotes inflammation, fluid accumulation, and bone erosion.20-22 
IL-6 (interleukin 6) is a cytokine produced by multiple cells, including leukocytes, fibroblasts, and skeletal cells in RA. IL-6 is a major driver of RA inflammation, cartilage degradation, bone erosion, and the hepatic acute-phase response.23-25
TNF-RI (tumor necrosis factor receptor, type 1) is a receptor for TNF-α that is expressed on the membranes of numerous cell types. TNF-RI-mediated signaling contributes to multiple effects of TNF-α, including induction of cell death. Vectra DA measures the soluble form, TNF-RI, which binds to and neutralizes TNF-α.26,27
MMP-1 (matrix metalloproteinase-1 or collagenase-1) is a collagen-degrading enzyme that contributes to cartilage destruction in RA, and to leukocyte invasion and angiogenesis in the synovial tissue.28
MMP-3 (matrix metalloproteinase-3 or stromelysin-1) is an enzyme that degrades glycosaminoglycan components of cartilage and also activates the collagenase MMP-1.29-31
YKL-40, or human cartilage glycoprotein 39, is secreted primarily by chondrocytes and differentiated macrophages. YKL-40 may promote chondrocyte and fibroblast proliferation and antagonize cartilage destruction. YKL-40 reactive T cells have been found in RA patients, suggesting that they may contribute to RA autoimmunity.32-36
Leptin is a hormone secreted by adipose tissue, synovial tissue, and bone. A satiety factor associated with obesity, leptin can also activate leukocytes and regulate bone remodeling.37-41
Resistin is also a hormone associated with the adipose tissue. Like leptin, it can be secreted by synovial tissue and bone and promotes inflammation and bone remodeling. Resistin has been associated with obesity and diabetes.42-45
SAA (serum amyloid) is a major acute-phase protein secreted by the liver in response to inflammation. Like CRP, elevated SAA may be associated with cardiovascular risk. SAA may also be produced by synovial fibroblasts and chondrocytes, and may induce proinflammatory activation of fibroblasts, macrophages, and T cells.46-50 
CRP (C-reactive protein) is another major acute-phase protein secreted by the liver in response to inflammation. Elevated CRP levels are associated with an elevated risk of cardiovascular disease.51-54
