Notification Issue Date:

Medical Policy Bulletin

Title:Vectraź DA Blood Test for Rheumatoid Arthritis

Policy #:06.02.45

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.

The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.


Coverage is subject to the terms, conditions, and limitations of the member's benefit contract. The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

Vectraź DA Blood Test for Rheumatoid Arthritis is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Subject to the terms and conditions of the applicable benefit contract, Vectraź DA Blood Test for Rheumatoid Arthritis is not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.


Rheumatoid arthritis (RA) is a disorder characterized by chronic joint inflammation leading to painful symptoms, progressive joint destruction, and loss of function. The disorder is relatively common and is associated with a high burden of morbidity for affected individuals.

Treatment of RA has undergone a shift from symptom management to a more proactive strategy of minimizing disease activity and delaying disease progression. The goal of treatment is to reduce irreversible joint damage that occurs from ongoing joint inflammation and synovitis by keeping disease activity as low as possible. The availability of an increasing number of effective disease-modifying antirheumatic drugs has made achievement of remission, or sustained low disease activity, a feasible goal in a large proportion of individuals with RA. This treatment strategy has been called a “tight control” approach.

The concept of “tight control” in the management of RA has gained wide acceptance as evidence from clinical trials have demonstrated that outcomes are improved with a tight control strategy. In a tight control strategy, treatment targets are used that are mainly based on measures of disease activity. In a systematic review published in 2010, Schoels et al identified 7 trials that evaluated the efficacy of tight control. Four of these trials randomized individuals to either a tight control using treatment targets or to routine management. The treatment targets used were heterogeneous, including symptom-based measures, joint scores on exam, validated treatment activity measures, lab values, or combinations of these factors. In all four trials, there was a significant decrease in the disease activity score (DAS) and in the likelihood of achieving remission for individuals in the tight control group.

For a strategy of tight control to be successful, a reliable and valid measurement of disease activity is necessary. There are numerous disease activity measurements that can be used in clinical care. Composite measures include information from multiple sources, including individual self-report, physician examination and/or biomarker measurement. Composite measures are the most comprehensive but have the disadvantage of being more cumbersome and difficult to complete. Individual-reported measures are intended to be simpler, and rely only on information that individuals can provide expeditiously, but have the disadvantage of being more subjective. Measurements that rely only on biomarkers are objective and do not require individual input but do involve the cost and inconvenience of laboratory tests.

The most widely used and validated tool of assessment of disease activity in clinical research is the DAS28 score. This is a composite measure that includes examination of 28 joints for swelling and tenderness, combined with an individual report of disease activity and measurement of C-reactive protein (CRP) or erythrocyte sedimentation rate. This score has been widely validated and used for both research and clinical care and is often considered the criterion standard for measuring disease activity. However, it requires a thorough joint examination, individual-reported symptoms, and laboratory testing. Therefore, there have been many attempts to create a valid disease activity measure that is simpler. Some measures include only individual self-report and thus can be completed quickly in the setting of an office visit. An example of this type of measure is the Simplified Disease Activity Index (SDAI). Another approach is to use only serum biomarkers, which only requires a blood draw. The Vectra DA is this type of biomarker-based measure. Proponents of a biomarker approach have argued that this is simpler and avoids the subjectivity of physical examination and individual report.

There is a fairly large body of evidence comparing the performance of different disease activity measures in clinical care, including a number of systematic reviews. In a systematic review of disease activity measures sponsored by the American College of Rheumatology in 2012, more than 60 measurement instruments were identified. Through a 5-stage process that included review by an expert advisory panel in RA disease activity and detailed evaluation of psychometric properties, the workgroup selected 6 that were most useful and feasible for point-of-care clinical care. These were the Clinical Disease Activity Index (CDAI), DAS28, Individual Activity Scale (PAS), Individual Activity Scale II (PAS-II), Routine Assessment of Individual Index (RAPI) data with 3 measures, and the SDAI.

In another systematic review, Gaujoux-Viala et al compared 4 composite indices, DAS, DAS28, SDAI, and CDAI. In general, the concordance between measures was good, with kappa values around 0.7. An exception to this level of concordance was in the definition of remission, for which the DAS28 had lower levels of concordance with other measures, with kappa values ranging from 0.48 to 0.63. All of the measures had fair-to-good correlations with an independent health status measure, the Health Assessment Questionnaire, and with radiologic examination of joint structural damage.

Salaffi et al compared the responsiveness of numerous disease activity measures, including individual self- report measures and composite indices, over a 6-month period of treatment with disease-modifying drugs. The composite indices evaluated were DAS28, SDAI, CDAI, and the Mean Overall Index for RA. The individual-reported measures evaluated were the Clinical Arthritis Index, the Rheumatoid Disease Activity Index, the Routine Assessment of Individual Index Data (RAPID3), and PAS. Across all measures, there was wide variability in internal responsiveness, with the highest value obtained for the DAS28 measure. There were some differences in responsiveness between the measures, but all were considered suitable for use in clinical care. When comparing the individual-reported measures with the composite measures, there was no difference in internal or external responsiveness.


The Vectra DA test (Crescendo Bioscience, South San Francisco, CA) consists of 12 individual biomarkers. These are:
  • Interleukin-6 (IL-6)
  • Tumor necrosis factor receptor type I (TNFRI)
  • Vascular cell adhesion molecule 1 (VCAM-1)
  • Epidermal growth factor (EGF)
  • Vascular endothelial growth factor A (VEGF-A)
  • YKL-40
  • Matrix metalloproteinase 1 (MMP-1)
  • Matrix metalloproteinase 3 (MMP-3)
  • CRP
  • Serum amyloid A (SAA)
  • Leptin
  • Resistin

Multibiomarker Disease Activity (MBDA) tests for disease activity in rheumatoid arthritis (RA) are best evaluated in the framework of a prognostic test, as they provide prognostic information that assists in treatment decisions. Assessment of a prognostic tool typically focuses on 3 categories of evidence: (1) technical performance; (2) clinical validity (i.e,, statistically significant association between the test result and health outcomes); and (3) clinical utility (i.e., demonstration that use of the prognostic information clinically can alter clinical management and/or improve health outcomes compared with patient management without use of the prognostic tool). In some cases, it is important to evaluate whether the test provides incremental information above the standard workup to determine whether the test has utility
in clinical practice.

Eastman et al described aspects of the technical performance of the MBDA Vectra test in 2012. The 12 individual biomarkers in the Vectra test were measured using multiplexed sandwiched immunoassays with biomarker-specific capture antibodies. The total MBDA score had good reproducibility over time, with a coefficient of variation of less than 2%. Cross-reactivity by serum rheumatoid factor, other RA antibodies, and/or common RA therapies, was minimal.

Centola et al published a study on the development of the Vectra DA test in 2013. This publication described a multistage process for development and validation of the score. In the first phase, the screening phase, proteins were identified that could be readily measured and had the potential to be associated with RA disease activity. A comprehensive total of 130 candidate biomarkers were selected. In the second phase, 4 separate patient cohorts were used to refine the biomarkers by their correlations with multiple measures of disease activity. In the final phase, assay optimization and training, the biomarkers with the greatest predictive ability were optimized for multiplex assay. In addition, the combined cohorts of patients were used for algorithm training using a number of statistical techniques. The final model included 12 individual biomarkers and an algorithm that generated a score between 0 and 100.

Evidence for the clinical validity of the Vectra DA test consists of studies that correlate the score with other measures of disease activity, including the DAS28 score. These studies show a positive correlation that is in the moderate range, with reported r values ranging from 0.46 to 0.72. One study reported a kappa value of 0.34 for the DAS28 and Vectra DA, indicating a moderate level of agreement above chance. There is also some evidence that the Vectra DA score correlates with response to treatment. For discriminating levels of disease activity, 2 studies that used the DAS28 as the criterion standard reported an AUC in the moderate to high range, with values ranging from 0.7 to 0.86 for different populations.

Another study compared the discriminatory ability of Vectra DA versus the DAS28 using radiographic disease progression as the reference standard and reported that the AUC was higher for Vectra DA compared with DAS28.

To demonstrate clinical utility, there should be evidence that the MBDA score is at least as good a measure of disease activity as other available measures. This could be demonstrated directly by an RCT that compared a management strategy using Vectra DA score with an alternate management strategy using another measure of disease activity and that reported clinical outcomes such as symptoms, functional status, quality of life, or disease progression on radiologic imaging. Indirect measures of clinical utility could be obtained from high-quality evidence that clinical validity of the MBDA is equivalent to other measures used in clinical care, together with guidance on the optimal use of the score in decision making, i.e., evidence linking management changes to specific results on the MBDA score.

One RCT was identified that tested the impact of the Vectra DA score on simulated decision making by experienced rheumatologists. A total of 81 rheumatologists without previous experience with the Vectra DA test were randomized to decision making with and without the Vectra DA score, using 3 validated clinical vignettes representing typical clinical care in RA. A quality score for each vignette was calculated using predefined criteria. Quality scores in the group receiving the Vectra DA score improved by 3% compared with the control group (p=0.02). The largest benefits in the Vectra DA group were improvements in the quality of disease activity and treatment decisions of 12% (p<0.01), and more appropriate use of biologics and disease-modifying drugs (p<0.01).

In a study using physician surveys, Li et al examined the impact of a MBDA score on treatment decisions for patients with RA. This study examined the treatment decisions made by 6 health care providers, all who had shown previous interest in using the MBDA score. A total of 108 patients were enrolled who were at least 18 years old, had a diagnosis of RA, completed a MBDA test, and had a survey completed by a physician. Surveys of treatment decisions were done before and after the results of the MBDA score was provided. After receiving the MBDA score, treatment plans were changed in 38 of 101 cases (38%; 95% CI, 29% to 48%). Changes in treatment decisions were a change in the type of drug in 21 of 38 cases, and a change in the dose or route of administration of a drug in 17 of 38 cases. There was no data collected on outcomes associated with the different treatment decisions.

There is some limited evidence that treatment decisions can be influenced by the Vectra DA score. This evidence comes from simulated cases and/or surveys of physician behavior. There are no RCTs that compare use of the Vectra DA score with an alternative method of measuring disease activity, and as a result there is no direct evidence that Vectra DA improves outcomes. Other disease activity measures have been associated with improvements in health outcomes in clinical trials. Thus, the evidence from RCTs on other measures, together with the correlation of Vectra DA with these measures, is indirect evidence that outcomes may be improved with use of the Vectra DA test. However, there is insufficient evidence to determine whether Vectra DA is as good as other, more established disease activity measures in improving outcomes.


Assessment of disease activity in rheumatoid arthritis (RA) is an important component of treatment management, as one of the main goals of treatment is to maintain low disease activity or remission. There are a variety of available instruments for measuring RA disease activity. One potential approach is the use of a Multibiomarker Disease Activity (MBDA) score. The Vectra DA test is a commercially available MBDA blood test that uses 12 biomarkers to construct a disease activity score ranging from 0 to 100. It is one of numerous disease activity measures that are available for RA. Other disease activity scores (e.g., Disease Activity Score with 28 joints [DAS28]) have been more extensively validated and have been widely used in research and clinical care.

Evidence of validity for the Vectra DA measure consists of numerous studies that correlate Vectra DA with disease progression, response to therapy, and/or other previously validated disease activity measures such as the DAS28. These studies establish that the Vectra DA score is a predictor of disease progression and that decreases in the score are correlated with disease response. They also show moderate correlations of Vectra with the DAS28. A smaller number of studies evaluate clinical utility by examining changes in decision making associated with use of Vectra, but these are limited by the design of using simulated cases or physician surveys and do not report any outcome data. This limited body of evidence on the Vectra DA test is not sufficient to determine whether it is as good as or better than other disease activity measures, and it is possible that it is not as accurate as the DAS28 for use as a measure of disease activity in individuals with RA.

Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640- 647.

Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. 2012;71(10):1692-1697.

Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635.

Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2012;64(12):1794-1803.

Eastman PS, Manning WC, Qureshi F, et al. Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis. J Pharm Biomed Anal. 2012;70:415-424.

Gaujoux-Viala C, Mouterde G, Baillet A, et al. Evaluating disease activity in rheumatoid arthritis: which composite index is best? A systematic literature analysis of studies comparing the psychometric properties of the DAS, DAS28, SDAI and CDAI. Joint Bone Spine. 2012;79(2):149-155.

Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis. 2014.

Hirata S, Li W, Defranoux N, et al. A multi-biomarker disease activity score tracks clinical response consistently in individuals with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. Mod Rheumatol. 2014:1-6.

Li W, Sasso EH, Emerling D, et al. Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use. Curr Med Res Opin. 2013;29(1):85-92.

Markusse IM, Dirven L, van den Broek M, et al. A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study. J Rheumatol. 2014;41(11):2114-2119.

Peabody JW, Strand V, Shimkhada R, et al. Impact of rheumatoid arthritis disease activity test on clinical practice. PLoS One. 2013;8(5):e63215.

Salaffi F, Ciapetti A, Gasparini S, et al. The comparative responsiveness of the individual self-report questionnaires and composite disease indices for assessing rheumatoid arthritis activity in routine care. Clin Exp Rheumatol. 2012;30(6):912-921.

Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. 2010;69(4):638-643.

Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology (Oxford). 2012;51 Suppl 6:vi28-36.


Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD - 10 Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD -10 Diagnosis Code Number(s)

This service is experimental/investigational for all diagnoses.

HCPCS Level II Code Number(s)


Revenue Code Number(s)


Coding and Billing Requirements

Policy History

Revisions from 06.02.45
03/25/2020This policy has been reissued in accordance with the Company's annual review process.
05/08/2019This policy has been reissued in accordance with the Company's annual review process.
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Vectraź DA Blood Test for Rheumatoid Arthritis.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date: 02/01/2016
Version Issued Date: 02/01/2016
Version Reissued Date: 03/25/2020

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