Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis

POLICY NUMBER

A.2.04.119

DESCRIPTION

Assessment of disease activity in rheumatoid arthritis is an important component of management with a goal of treatment to maintain low disease activity or achieve remission. There are a variety of instruments for measuring rheumatoid arthritis disease activity. The instruments use combinations of physical exam findings, radiologic results, and serum biomarkers to construct a disease activity score. A multibiomarker disease activity instrument is a disease activity measure that is comprised entirely of serum biomarkers. The Vectra test is a commercially available multibiomarker disease activity 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 1 (low disease activity) to 100 (high disease activity).

Rheumatoid Arthritis

Rheumatoid arthritis (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. Most epidemiological studies and clinical trials on RA have predominantly focused on White patients. As a result, there are limited data informing the epidemiology and clinical outcomes of patients from other races and ethnicities with RA.

TreatmentTreatment 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 the achievement of remission, or sustained low disease activity, a feasible goal for 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 and colleagues identified 7 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 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 4 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 the American College of Rheumatology (ACR) guidelines, initial treatment of patients with RA is monotherapy (usually a disease-modifying antirheumatic drug). Treatment may progress to combination therapy if disease activity remains moderate or high despite monotherapy. Combination therapy may consist of additional disease-modifying antirheumatic drugs or the addition of tumor necrosis factor inhibitors or non-tumor necrosis factor 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-reporting 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 5 measures as “preferred” for regular use in most clinic settings: the DAS28-ESR/CRP, CDAI, DSAI, RAPID3, and Patient Activity Scale-II.

Vectra Test

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 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), 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 1 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.

The ACR working group's systematic review reported by England and colleagues (2019) graded feasibility of the RA disease activity measurement tools. Any measure not commercially available or requiring advanced imaging was graded as infeasible. All other measures started with 4 points (ie, “++++”) and were downgraded by 1-point for each of the following implementation considerations: requiring a provider joint count, requiring a laboratory test, not possible to complete during a routine clinic visit, and not possible to complete on the same day as the clinic visit. The ACR Working Group downgraded the feasibility of the Vectra DA by 3 points (ie, score of “++++" decreased to “+"). This was 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.

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 (Labcorp, formerly Crescendo Bioscience and Myriad) is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the 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.

POLICY

The use of a multibiomarker disease activity score for rheumatoid arthritis (eg, Vectra score) is considered investigational in all situations.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

07/17/2014: Approved by Medical Policy Advisory Committee.

07/23/2015: Code Reference section updated for ICD-10.

09/14/2015: Policy description updated. Policy statement unchanged. Investigative definition updated in Policy Guidelines section.

06/07/2016: Policy number A.2.04.119 added.

08/01/2016: Policy description updated regarding instruments for measuring RA disease activity. Policy statement unchanged. Code Reference section updated to add CPT code 81490.

07/11/2017: Policy description updated regarding the Vectra DA test scores. Policy statement unchanged.

07/06/2018: Policy title changed from "Vectra DA Blood Test for Rheumatoid Arthritis" to "Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis." Policy description updated regarding treatment and assessment tools. Policy statement unchanged.

07/15/2019: Policy reviewed; no changes.

07/14/2020: Policy description updated regarding disease activity assessment tools and the Vectra test. Policy statement updated to change "Vectra® DA score" to "Vectra score."

08/26/2021: Policy description updated regarding tests. Policy statement unchanged.

07/13/2022: Policy description updated. Policy statement unchanged.

07/31/2023: Policy description updated. Policy statement unchanged.

07/12/2024: Policy reviewed; no changes.

08/20/2025: Policy description updated regarding tests. Policy statement unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.119

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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