mp-564 - mp-564 - Medical Policies
Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis
Policy Number: MP-564
Latest Review Date: July 2020
Policy Grade: B
The use of a multi-biomarker disease activity score for rheumatoid arthritis (RA) (e.g., Vectra® DA score) is considered not medically necessary and investigational in all situations.
DESCRIPTION OF PROCEDURE OR SERVICE:
Assessment of disease activity in rheumatoid arthritis (RA) is an important component of management because a main goal of treatment is to maintain low disease activity or remission. There are a variety of available instruments for measuring RA disease activity. These use combinations of physical exam findings, radiologic results, and serum biomarkers to construct a disease activity score. A Multi-biomarker Disease Activity (MBDA) instrument is a disease activity measure that is comprised entirely of serum biomarkers. The Vectra test is a commercially available MBDA blood test that measures 12 biomarkers to construct a disease activity score. Concentrations of these 12 biomarkers are entered into a proprietary formula which, after adjustment by age, gender and adiposity (i.e., leptin) levels, generates a disease activity score (“adjusted MBDA score”) that ranges from one (low disease activity) to 100 (high disease activity).
RA is characterized by chronic joint inflammation leading to painful symptoms, progressive joint destruction and loss of function. The disorder is relatively common and associated with a high burden of morbidity for affected patients.
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 anti-rheumatic drugs has made achievement of remission, or sustained low disease activity, a feasible goal in a large proportion of patients 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. Evidence from clinical trials has demonstrated that outcomes are improved with a tight control strategy, in which treatment targets are mainly based on measures of disease activity. In a systematic review, Schoels et al (2010) identified seven studies that evaluated the efficacy of tight control. Four of these trials randomized patients to tight control using treatment targets or to routine management, two studies compared different treatment targets, and one study compared results from a targeted treatment with historical controls. The treatment targets were heterogeneous, including symptom-based measures, joint scores on the exam, validated treatment activity measures, lab values, or combinations of these factors. In all four trials that randomized patients to tight control or routine management, there was a significant decrease in the Disease Activity Score (DAS) or its 28 joints version (DAS28) and in the likelihood of achieving remission for patients in the tight control group.
According to American College of Rheumatology (ACR) guidelines, initial treatment of patients with RA is monotherapy (usually a disease-modifying ant rheumatic drug). Treatment may progress to combination therapy if disease activity remains moderate or high despite monotherapy. Combination therapy may consist of additional disease-modifying ant rheumatic drugs or the addition of tumor necrosis factors or non-tumor necrosis factors biologics.
Selection of Disease Activity Assessment Tools
For a strategy of tight control to be successful, a reliable and valid measurement of disease activity is necessary. Numerous measurements exist that assess various aspects of RA disease activity, including patient self-report of symptom severity and functional capacity, physician examination of joints for swelling and tenderness, laboratory testing of serum biomarkers, and imaging. Various assessment tools exist that range from those that rely only on single types of measurements, to composite tools that combine information from multiple measurement sources. These assessment tools vary in their psychometric properties and their feasibility of implementation and these trade-offs must be considered in their selection for use. For example, although composite tools are more comprehensive, in some cases they may be less feasible for regular use.
Based on a systematic review (2019) of the psychometric properties of 46 tools, an ACR working group determined that the following 11 measures of disease activity fulfilled a minimum standard for regular use in most clinical settings: Disease Activity Score (DAS), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28 joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), Multibiomarker Disease Activity Score (MBDA score, Vectra DA), Rheumatoid Arthritis Disease Activity Index (RADAI),Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), and the Simplified Disease Activity Index (SDAI). Additionally, using a modified Delphi process, the ACR working group further identified the following five measures as “preferred” for regular use in most clinic settings: the DAS28-ESR/CRP, CDAI, DSAI, RAPID3, and Patient Activity Scale-II.
The Vectra Test is a commercially available multibiomarker disease activity (MBDA) test that is an approach to measuring RA disease activity that uses only serum biomarkers obtained through a laboratory blood draw. The manufacturer describes Vectra as a complement to clinical judgment. Although not explicitly stated, it appears that the test may be used as an adjunct to other disease activity measures, to potentially identify patients at high risk of progression who would, therefore, benefit from a more aggressive treatment strategy.
The Vectra test measures the serum concentrations of the following 12 biomarkers: 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), and Matrix Metalloproteinase 3 (MMP-3), C-reactive protein (CRP), Serum Amyloid A (SAA), Leptin, and Resistin. The concentrations of these 12 biomarkers are measured in serum and, combined with age, gender and adiposity (i.e., leptin) information, are entered in a proprietary formula to generate a score on a scale of one to 100 that represents the level of RA disease activity:
Categories of scores were constructed to correlate with the DAS28-CRP scale:
- 45-100: high disease activity
- 30-44: moderate disease activity
- 1-29: low disease activity
Prior to December 2017, the Vectra test was originally referred to as Vectra DA and the original MBDA score did not include adiposity (i.e., leptin) adjustment. However, as the current, commercially available version of the test includes the leptin-adjusted MBDA score (now called the "adjusted MBDA score"), the focus of this policy will primarily be on the leptin-adjusted Vectra test.
In the ACR working group's systematic review reported by England et al (2019), they also graded feasibility of RA disease activity measurement tools from "– to ++++ with + to ++++ meeting minimum feasibility for regular use. Scoring was as follows: measures started with a score of ++++; any measure not commercially available or requiring advanced imaging was graded -; requiring a provider joint count reduced feasibility by +; requiring a laboratory test reduced feasibility by +; number of items and time to completion were considered and score was reduced by + if not feasible in a routine clinic visit or by ++ if not feasible on the same day as the clinic visit." The ACR Working Group graded the feasibility of the Vectra DA as "+", due to its requirement of a laboratory test and because its result is not available on the same day as the clinic visit. Although the current, commercially available version of the Vectra test was not assessed in the 2019 ACR guideline, because it requires the same laboratory testing that is not available on the same days as the clinic visit, likely it would have a similar feasibility rating as the older version.
This policy has been updated regularly with searches of the MEDLINE database. The most recent literature review was updated through April 15, 2020.
Summary of Evidence
For individuals who have RA who receive the current commercially available Vectra test ("adjusted MBDA score") as an adjunct or as a replacement of other disease activity measures, the evidence includes one study that analyzed archived serum samples using combined data from an RCT and a cohort study. The relevant outcomes are test validity, other test performance measures, symptoms, change in disease status, functional outcomes, and quality of life. Analyses comparing Vectra with other previously validated disease activity measures such as the DAS28 or to radiographic progression, consisted mostly of correlations. However, the PPV’s that individuals with Vectra moderate- to high-risk disease scores had radiographic progression were low, at 3.9% and 9.3%, respectively. Additionally, due to numerous relevance, design and conduct limitations of this study, the body of evidence on the Vectra test is insufficient to determine whether it is as good as or better than other disease activity measures. Additionally, there is no evidence evaluating Vectra as an adjunct to other disease activity measures. The evidence is insufficient to determine the effects of the technology on health outcomes.
Original Vectra DA test
For individuals who have rheumatoid arthritis who receive the original Vectra DA test as an adjunct or as a replacement of other disease activity measures, the evidence includes analyses of archived serum samples from RCTs and prospective cohort studies. Relevant outcomes are test validity, other test performance measures, symptoms, change in disease status, functional outcomes, and quality of life. Analyses comparing Vectra DA with other previously validated disease activity measures such as the DAS28 or to radiographic progression, consisted mostly of correlations, with only one study providing sensitivity, specificity, and positive and negative predictive values. The positive predictive value from this study was 21%. Other analyses of archived serum samples evaluated the use of Vectra DA to predict treatment response. Results from those analyses were inconsistent. The body of evidence on the Vectra DA test is insufficient to determine whether it is as good as or better than other disease activity measures. Additionally, there is no evidence evaluating Vectra DA as an adjunct to other disease activity measures. The evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
American College of Rheumatology
In its 2019 guidelines on the treatment of rheumatoid arthritis, the American College of Rheumatology identified the following 11 measures of disease activity as fulfilling a minimum standard for regular use in most clinical settings: Disease Activity Score (DAS), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28 joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), Multibiomarker Disease Activity Score (MBDA score, Vectra DA), Rheumatoid Arthritis Disease Activity Index (RADAI),Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), Simplified Disease Activity Index (SDAI). Although the original Vectra DA test is included in this list, the current commercially available version of the test that is now called Vectra and that includes the leptin-adjusted MBDA score (now called the "adjusted MBDA score") was not addressed in the 2019 ACR guideline. This is because evidence on Vectra with the adjusted MBDA score was published subsequent to the ACR review end date.
European League Against Rheumatism
The European League Against Rheumatism (2017) updated its guidelines on the management of early arthritis. The League recommended that arthritis activity be assessed at one- to three-month intervals to determine target treatment. “Monitoring of disease activity should include tender and swollen joint counts, patient and physician global assessments, erythrocyte sedimentation rate, and C reactive protein, usually by applying a composite measure.” Composite measures recommended include the Disease Activity Score with 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index. One item on the research agenda recommended by the League was to evaluate new biomarkers and multibiomarkers for the prognosis and treatment in early arthritis.
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence published guidance on the management of adult patients with rheumatoid arthritis in 2018. There is no discussion on the use of a multibiomarker disease activity blood test to monitor patients with rheumatoid arthritis.
U.S. Preventive Services Task Force Recommendations
Vectra DA, Rheumatoid Arthritis, RA, Multi-biomarker Disease Activity (MBDA)
APPROVED BY GOVERNING BODIES:
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The Vectra® test (Crescendo Bioscience) is available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Autoimmune (rheumatoid arthritis), analysis of 12 biomarkers using immunoassays, utilizing serum, prognostic algorithm reported as a disease activity score
Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
Unlisted chemistry procedure
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- Bouman CAM, van der Maas A, van Herwaarden N, Sasso EH, van den Hoogen FHJ, den Broeder AA. A multi-biomarker score measuring disease activity in rheumatoid arthritis patients tapering adalimumab or etanercept: predictive value for clinical and radiographic outcomes. Rheumatology (Oxford). Jun 1 2017; 56(6):973-980.
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- Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. Jun 2017; 76(6):948-959.
- Crescendo Bioscience. Vectra DA Patient Guide: Understanding results. n.d.; https://vectrascore.com/know-your-results/. Accessed May 18, 2020.
- Crescendo Biosciences, Inc. Vectra Technical Specifications. May 2019. https://vectrascore.com/clinicians/vectra-testdescription/.Accessed May 7, 2020
- Curtis, JJ, Brahe, CC, Lund Hetland, MM, Hambardzumyan, KK, Saevarsdottir, SS, Wang, XX, Flake Ii, DD, Sasso, EE, Huizinga, TT. Predicting risk for radiographic damage in rheumatoid arthritis: comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies. Curr Med Res Opin, 2019 Feb 20; 1-11:1-11.
- Curtis, JJ, Xie, FF, Yang, SS, Danila, MM, Owensby, JJ, Chen, LL. Uptake and Clinical Utility of Multibiomarker Disease Activity Testing in the United States.. J. Rheumatol., 2018 Nov 18; 46(3).
- 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.
- Curtis JR, Wright GC, Strand V, et al. Reanalysis of the Multi-Biomarker Disease Activity Score for Assessing Disease Activity in the Abatacept Versus Adalimumab Comparison in Biologic-Naive Rheumatoid Arthritis Subjects with Background Methotrexate Study: Comment on the Article by Fleischmann et al. Arthritis Rheumatol. Apr 2017; 69(4):863-865.
- Davis JM, 3rd. Editorial: The Multi-Biomarker Disease Activity Test for rheumatoid arthritis: is it a valid measure of disease activity? Arthritis Rheumatol. Sep 2016; 68(9):2061-2066.
- 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.
- Fleischmann R, Connolly SE, Maldonado MA, et al. Estimating disease activity using multi-biomarker disease activity scores in patients with rheumatoid arthritis treated with abatacept or adalimumab. Arthritis Rheumatol. Apr 25 2016.
- Fleischmann R, Connolly SE, Maldonado MA, et al. Reply. Arthritis Rheumatol. Apr 2017; 69(4):867-868.
- 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. Jun 2015; 74(6):1102-1109.
- Hambardzumyan K, Bolce RJ, Saevarsdottir S, et al. Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial. RMD Open. 2016; 2(1):e000197.
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- Hirata S, Dirven L, Shen Y et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology 2013; 52(7): 1202-1207.
- Hirata S, Li W, Defranoux N, et al. A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. Mod Rheumatol. May 2015; 25(3):344-349.
- Hirata S, Li W, Kubo S, et al. Association of the multi-biomarker disease activity score with joint destruction in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha inhibitor treatment in clinical practice. Mod Rheumatol. Mar 30 2016:1-7.
- Krabbe S, Bolce R, Brahe CH, et al. Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage. Scand J Rheumatol. Sep 2017; 46(5):353-358.
- 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.
- Li W, Sasso EH, van der Helm-van Mil AH, et al. Relationship of multi-biomarker disease activity score and other risk factors with radiographic progression in an observational study of patients with rheumatoid arthritis. Rheumatology (Oxford). Feb 2016; 55(2):357-366.
- 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. Nov 2014; 41(11):2114-2119.
- National Institute for Health and Care Excellence. Rheumatoid arthritis in adults: management [NG100]. July 2018, https://www.nice.org.uk/guidance/ng100. Accessed May 19, 2020.
- Peabody JW, Strand V, Shimkhada R et al. Impact of rheumatoid arthritis disease activity test on clinical practice. PLoS One 2013; 8(5):e63215.
- Rech J, Hueber AJ, Finzel S, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis. Oct 19 2015.
- Reiss WG, Devenport JN, Low JM, et al. Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis. Rheumatol Int. Feb 2016; 36(2):295-300.
- Salaffi F, Ciapetti A, Gasparini S et al. The comparative responsiveness of the patient 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.
- Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. Nov 4 2009; 101(21):1446-1452.
- Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. Jan 2016; 68(1):1-26.
- Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology (Oxford) 2012; 51 Suppl 6:vi28-36.
- van der Helm-van Mil AH, Knevel R, Cavet G, Huizinga TW, Haney DJ. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression. Rheumatology (Oxford). May 2013; 52(5):839-846.
Medical Policy Panel, April 2014
Medical Policy Group, September 2014 (1): New policy, previously only listed on the Investigational Listing; remains investigational
Medical Policy Administration Committee, October 2014
Available for comment September 23 through November 6, 2014
Medical Policy Panel, April 2015
Medical Policy Group, May 2015 (3): Updates to Description, Key Points, Current Coding – added CPT code 81490 that will be effective 01/01/16, - and References; no change to policy statement.
Medical Policy Group, November 2015: 2016 Annual Coding Update. Verified new code 81490 included on policy.
Medical Policy Panel, June 2016
Medical Policy Group, June 2016 (3): 2016 Updates to Description, Key Points, & References; no change to Policy statement.
Medical Policy Panel, June 2017
Medical Policy Group, July 2017 (3): 2017 Updates to Description, Key Points and References. No change to policy statement.
Medical Policy Panel, June 2018
Medical Policy Group, July 2018 (3): 2018 Updates to Title, Description, Key Points and References. Added Key Words- multi-biomarker disease activity (MBDA). No change to policy statement.
Medical Policy Panel, June 2019
Medical Policy Group, June 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.
Medical Policy Panel, June 2020
Medical Policy Group, July 2020 (9): 2020 Updates to Description, Key Points, References. No change to policy statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
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As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
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