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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 novel multi-biomarker test to assess rheumatoid arthritis disease activity. Arthritis Care & Research. 2012; 64 (12):1794-1803.

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.

References:

1. Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan K, Turner M, Sutton C, Smith D, Haney D, Chernoff D, Hesterberg L, Carulli J, Taylor P, Shadick N, Weinblatt M, Curtis J. Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis. PLOS ONE 2013 Apr 9;8(4):e60635. doi:10.1371/journal.pone.0060635.

2. Curtis JR, et al. Validation of a novel multi-biomarker test to assess rheumatoid arthritis disease activity. Arthritis Care & Research. 2012; 64 (12):1794-1803.

3. Hambardzumyan K, Bolce R, Saevarsdottir S, Cruickshank SE, Sasso EH, Chernoff D, Forslind K, Petersson I, Geborek P, van Vollenhoven RF. Pre-treatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis 2014. doi:10.1136/annrheumdis-2013-204986

4. 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.

5. van der Helm-van Mil AHM, Knevel R, Cavet G, Huizinga TWJ, and Haney DJ. An Evaluation of Molecular and Clinical Remission in Rheumatoid Arthritis by Assessing Radiographic Progression. Rheumatology (Oxford). 2013. doi:10.1093/rheumatology/kes378.

Frequently asked questions

How was Vectra DA developed and validated?

The 12 biomarkers in Vectra DA were selected from a pool of 396 candidate biomarkers. The multistep development process involved over 1,900 serum samples from more than 1,700 patients. Vectra DA was validated against the DAS28-CRP in seropositive (AUROC = 0.77; P<0.001) and seronegative patients (AUROC = 0.70; P<0.001).1,2

Where is the Vectra DA test performed?

Vectra DA is a laboratory-developed test. Crescendo has a California-licensed CLIA-certified laboratory dedicated to testing blood specimens for the Vectra DA test, with results reported within approximately 5-7 calendar days from shipping of the specimen to Crescendo Bioscience. However, results may be available as soon as 72 hours from shipping date. Vectra DA is only available from Crescendo's Clinical Laboratory.
Crescendo is also a College of American Pathologists (CAP) - Accredited Laboratory and has a New York State Clinical Laboratory Evaluation Program (CLEP) laboratory permit to provide services to physicians/patients in New York.

How often should I order Vectra DA for each of my patients?

Vectra DA can be considered anytime you assess disease activity. The frequency of the assessment, therefore, may vary for each patient and each physician.

How do I order a Vectra DA test?

Vectra DA specimen collection kits, which can be ordered through Customer Service or your local Crescendo Representative, include everything needed to order a test, collect a blood specimen, and send the specimen to our CLIA laboratory for processing. Included in the kit is information on sample collection and shipping. Specimens for up to 5 patients can be shipped in each Vectra DA kit. Customer Service can be reached toll-free at 1-877-RHEUMDX (1-877-743-8639) or customerservice@crescendobio.com

How often should I order Vectra DA for each of my patients?

Vectra DA can be considered when you assess disease activity for a patient with RA. The frequency of the assessment, therefore, may vary for each patient and each physician.

When should I order Vectra DA in relation to a scheduled appointment?

Vectra DA can be a valuable complement to your clinical judgment in the assessment of RA disease activity. Vectra DA is most valuable when current test results are available at the time of the patient visit. If you would like to have the results available at the time of the scheduled office visit, patients should have blood drawn for Vectra DA at least 2 weeks prior to the visit.

Which of my RA patients may benefit from Vectra DA?

Vectra DA can be used in any adult patient with RA. Test results are intended to aid in the assessment of disease activity in RA patients when used in conjunction with standard clinical assessment. This test is not intended or validated to diagnose RA.

Can I use Vectra DA to confirm a diagnosis of RA?

Vectra DA is not intended or validated for the diagnosis or confirmation of RA.

How is Vectra DA different than CRP testing?

CRP is a single biomarker that is a non-specific measure of inflammation, whereas, Vectra DA measures 12 key proteins (including CRP) that are associated with RA disease activity. Multivariate regression analysis indicates that Vectra DA is an independent predictor of DAS28CRP, even after adjusting for CRP (P<0.001). Vectra DA has been shown to identify patients with clinically-relevant RA disease activity that can be missed by CRP. High Vectra DA scores have been associated with an increased risk of radiographic progression even when CRP is low.3

Does Medicare cover Vectra DA?

Medicare fully covers Vectra DA with no copayment or deductible. (Medicare Advantage plans may require a copay.)

Will Medicare Advantage plans cover Vectra DA?

Medicare Advantage plans do cover Vectra DA. However, patients enrolled in Medicare Advantage plans may have out-of-pocket costs such as copays and deductibles. Please call us at 1-877-RHEUMDX (1-877-743-8639), option 1, from 7 am to 4 pm PST for more information.

Will health insurance cover Vectra DA?

Medicare fully covers Vectra DA with no copayment or deductible. (Medicare Advantage plans may require a copay.) For patients who are covered under employer-sponsored health plans, until the insurance company provides a positive coverage statement, we will not know for sure if it will be covered by that insurance company. However, insurance companies may still pay for the test without a formal coverage policy. If one of your patients should face a challenge with reimbursement, we offer comprehensive reimbursement services through the Crescendo Access & Reimbursement Essentials (CARE) program to meet the needs of each patient.

Crescendo will bill for the test, as the provider of service, so your office will not be required to bill or collect for Vectra DA. Your patient may receive an Explanation of Benefits (EOB) from their insurance company. Crescendo Bioscience may be identified as the test provider on the EOB. Please note: the EOB is not a bill. If your patient owes anything, Crescendo Bioscience will bill them directly.

Our experienced reimbursement specialists are available from 7 am to 4 pm PST, Monday through Friday, to answer any questions from you, your staff, or your patients. Simply call 1-877-RHEUMDX (1-877-743-8639).

Does Crescendo Bioscience provide financial assistance?

Crescendo provides financial assistance programs for uninsured and underinsured patients through the Crescendo Access & Reimbursement Essentials (CARE) program. For patients who have no insurance or have insurance that does not cover the test, Vectra DA may be provided at no cost based on financial eligibility. For those who have insurance* and cannot afford the out-of-pocket costs, financial assistance may also be available.

*Not valid for services reimbursed under Medicare, Medicaid, or similar federal or state programs.

Before or after Vectra DA testing, patients can contact Crescendo to see if they qualify for financial assistance. Crescendo will mail or fax the CARE financial assistance application form or it can be downloaded here.

How do I receive the results of a Vectra DA test?

Vectra DA test reports are available via fax or mail, or through the VectraViewTM portal, based on your preference. Results are available within approximately 5-7 calendar days from shipping of the specimen to Crescendo Bioscience. However, results may sometimes be available as soon as 72 hours from shipping date. The report provides the Vectra DA score and score history, which can be used to enhance patient counseling.

Can results of the test be sent directly to my patients?

Vectra DA test results will be returned to the ordering physician by fax, mail, or via Vectra View portal within approximately 5-7 calendar days from shipping of the specimen to Crescendo Bioscience. However, results may be available as soon as 72 hours from shipping date. Crescendo will send Vectra DA test results directly to patients upon their request. Crescendo encourages patients who request their test results directly to reach out to their rheumatologist to evaluate their Vectra DA score in the context of their condition and medical history.

How should I interpret Vectra DA test scores?

Vectra DA categorizes RA disease activity into:

High = >44

Moderate = 30 to 44

Low = 1 to <30

The Vectra DA cutoffs were selected to correspond to cutoffs on the DAS28-CRP scale.4

High Vectra DA scores have been associated with a higher risk of radiographic progression – low/moderate scores have been identified with a lower risk. 3,5

These thresholds are provided as a guide and a complement to your clinical judgment to help inform patient management. If you have questions or would like assistance in interpreting a Vectra DA result, please contact Crescendo Bioscience at 1-877-RHEUMDX (1-877-743-8639).

What is the effect of IL-6 therapy (tocilizumab) on Vectra DA?

Tocilizumab is designed to specifically target and inhibit IL-6 signaling. IL-6 is one of the 12 biomarkers included in Vectra DA. Change in the Vectra DA score during tocilizumab treatment may underestimate the change in clinical response due to increases in IL-6.

Can the Vectra DA score be affected by the flu, vaccination, or other situations that affect the immune system?

As with other inflammatory measures such as ESR and CRP, physicians should be aware of the possibility that factors other than RA may affect the Vectra DA score. Although the effect of the following situations on the Vectra DA score has not been evaluated, the literature indicates that proteins included in the Vectra DA test could be affected by:

  • A current infection, especially if associated with systemic symptoms
  • A recent vaccination
For more information, contact Medical Affairs by contacting Customer Service at 1-877-743-8639.

What are the benefits of using the VectraView online portal?

VectraView is a free, HIPAA-secured, online portal for both physicians and office staff.

VectraView provides practices with population management capabilities including a view of the aggregate results for all of a practice’s tested patients and the ability to generate patient lists based on disease activity, last Vectra DA test date, change in Vectra DA score or other attributes of interest. Ancillary tools include the ability for practices/providers to enter medications and clinical assessments and plot these in relation to each other and Vectra DA scores. Additionally it provides health care professionals with a user-friendly, seamless way to order Vectra DA tests and review Vectra DA test results.