Description of Procedure or Service

Definition

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder which results from a complex interaction between genes and environment, leading to a breakdown of immune tolerance and synovial inflammation in a characteristic symmetric pattern, and usually leads, if uncontrolled, to destruction of joints due to erosion of cartilage and bone, causing joint deformities (Firestein, 2017).

Vectra DA is an multi-biomarker disease activity (MBDA) blood test which employs an algorithm to combine the levels of 12 serum biomarkers into a single score from 1 to 100 to provide an objective measure of RA disease activity intended for use in conjunction with existing symptom-based disease activity measures with the objective of improving long-term outcomes for RA patients(van der Helm-van Mil, Knevel, Cavet, Huizinga, & Haney, 2013).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

The use of a multi-biomarker disease activity score for rheumatoid arthritis (e.g., Vectra DA score) is considered investigational. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When a multi-biomarker disease activity score for rheumatoid arthritis (Vectra DA) is covered

Not applicable.

When a multi-biomarker disease activity score for rheumatoid arthritis (Vectra DA) is not covered

The use of a multi-biomarker disease activity score for rheumatoid arthritis (e.g., Vectra DA score) is considered investigational.

Policy Guidelines

Background

RA affects over 1.3 million people in the US and over 4 million worldwide. Despite the availability of potent biologic treatments, substantial disease activity persists in many patients, with accompanying progressive bone and soft tissue damage, extra-articular consequences, disability, and increased mortality (Centola et al., 2013).

Improved outcomes as a result of intense management and tight control of disease activity have been demonstrated by several studies, such as TICORA, CAMERA, BeSt, and FinRACO. Frequent disease activity measurement and treatment adjustment are used to reach a specific target disease activity level leading to greater reduction in disease activity, increased rates of remission, and improved radiographic outcomes (Curtis et al., 2012; Goekoop-Ruiterman et al., 2005; Grigor et al., 2004) . The American College of Rheumatology (ACR) (Singh et al., 2012), the European League Against Rheumatism (EULAR) (Combe et al., 2007), and the Treat to Target task force (Smolen et al., 2010), as well as the Physician Quality Reporting System have incorporated these findings into their recommendations for frequent disease activity monitoring for all patients(Centola et al., 2013). Thus, measurement of disease activity and reliable assessment of remission have become important for the optimal management of patients with RA. However, there is no current gold standard for disease activity assessment in RA. Multiple measures are used, each with varying strengths and weaknesses, such that no single ‘best’ measure of disease activity could be recommended in U.S. or international RA guidelines (Centola et al., 2013).

Disease activity indices are based on different clinical, laboratory, and physical measures. Most of these, including the Disease Activity Score (DAS) (van der Heijde et al., 1990), the modified DAS in 28 joints (DAS28) (Prevoo et al., 1995), the Simplified Disease Activity Index (SDAI) (Smolen et al., 2003), the Clinical Disease Activity Index (CDAI) (Aletaha et al., 2005), and the Routine Assessment of Patient Index Data 3 (RAPID3) (Pincus, Swearingen, Bergman, & Yazici, 2008; Pincus, Yazici, Bergman, Maclean, & Harrington, 2007), rely on either clinical evaluation of tender and swollen joints, patient-reported outcomes (PROs), or both (Curtis et al., 2012) in the assessment of disease activity. However, studies have shown that these clinical measures are not sufficiently sensitive since they cannot exclude the presence of active disease as evidenced by imaging-detected inflammation or radiological progression (Brown et al., 2006; Klarenbeek et al., 2011; Lillegraven et al., 2012; Rezaei et al., 2012; Saleem et al., 2009). These findings indicate that patients can have subclinical disease despite displaying few clinical signs and symptoms (van der Helm-van Mil et al., 2013).

Protein biomarkers can provide complementary, objective, and reliable measurements reflecting underlying pathophysiological processes. Erythrocyte sedimentation rate (ESR) and CRP measurements are currently incorporated into clinical disease activity measures, including the DAS and SDAI (Centola et al., 2013). However, these biomarkers are non-specific indicators of inflammation that can be elevated due to age, anemia and the presence of immunoglobulins, and that can be unexpectedly low or even normal in patients with active disease, possibly due to underlying genetics(Keenan, Swearingen, & Yazici, 2008; Rhodes et al., 2010; Sokka & Pincus, 2009). Therefore, ESR and CRP measurement may not be useful in all RA patients, and other biomarkers may provide additional information about disease state. Previous research studies have reported that other protein biomarkers implicated in the pathophysiology of joint disease are also correlated with disease activity (Centola et al., 2013; Chambers, MacFarlane, Whicher, & Dieppe, 1983; Hammer et al., 2007; Klimiuk et al., 2002; Mease, 2011).

The multiple-biomarker disease activity score was developed by screening 396 candidate biomarkers, selecting the 12 most correlated to RA clinical disease activity (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], MMP-3, CRP, serum amyloid A [SAA], leptin, and resistin) and creating an algorithm to generate a composite score (Centola et al., 2013). It has been shown to correlates significantly (r=0.72; p<0.001) with disease activity, (Centola et al., 2013; Curtis et al., 2012; Hambardzumyan et al., 2015; van der Helm-van Mil et al., 2013) and is validated for clinical use in the USA as a disease activity marker in RA(Bakker et al., 2012; Hirata et al., 2013). The MBDA score was found to reflect current clinical disease activity and capable of tracking changes in disease activity over time. Remission based on the MBDA score was a significant predictor of radiographic non-progression, whereas remission defined by traditional DAS28-CRP or ACR/EULAR criteria was not(van der Helm-van Mil et al., 2013). Furthermore, the MBDA test was useful in assessing the risk of radiographic progression among patients who met clinical remission criteria(van der Helm-van Mil et al., 2013). MBDA results may provide an important adjunct to clinical assessment, however, further studies are needed to confirm its clinical utility in the management of RA.

Applicable Federal Regulations

There are no U.S. Food and Drug Administration (FDA)-approved MBDA tests for measuring disease activity in RA. Commercially available tests are laboratory-developed tests that are not subject to FDA approval.

Guidelines and Recommendations

Taylor and Maini (2017) published a review on investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis. The authors stated that “the combined use of multiple markers may provide advantages over the use of single markers for predicting disease activity and progression… Emerging data indicate that a MBDA test may provide a useful adjunct to clinical assessment to identify progression-free remission and assess subclinical disease.” Fleischmann et al (2016) assessed the ability of a multi-biomarker disease activity (MBDA) test (Vectra DA) to reflect clinical measures of disease activity in patients enrolled in the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) trial. In the AMPLE trial, patients with active rheumatoid arthritis (RA) who were naive to biologic agents and had an inadequate response to methotrexate were randomized (1:1) to receive subcutaneous abatacept (125 mg every week) or subcutaneous adalimumab (40 mg every 2 weeks), with background methotrexate, for 2 years. The MBDA score was determined using serum samples collected at baseline, month 3, and years 1 and 2. The authors noted that “no association between the MBDA score and disease activity defined by the CDAI, SDAI, DAS28-CRP, or RAPID-3 in the abatacept and adalimumab treatment groups was observed.” They concluded that “The MBDA score did not reflect clinical disease activity in patients enrolled in AMPLE and should not be used to guide decision-making in the management of RA, particularly for patients who receive abatacept or adalimumab as the first biologic agent” Li et al (2013) evaluated the impact of multi-biomarker disease activity (MBDA) blood test for rheumatoid arthritis (RA) on treatment decisions made by health care providers (HCPs) in 101 patients. HCPs completed surveys before and after viewing the MBDA test result, recording dosage and frequency for all planned RA medications and physician global assessment of disease activity. Frequency and types of change in treatment plan that resulted from viewing the MBDA test result were determined. The researchers concluded that “the addition of the MBDA test to clinical assessment led to meaningful changes in the treatment plans of 38% of RA patients being cared for by HCPs in office practice. Even though treatment was potentially improved, the overall quantity of drug use was minimally affected.” The study did not report on whether the changes in clinical management due to the MBDA test resulted in improved clinical outcomes.

Practice Guidelines and Position Statements

American College of Rheumatology (ACR)

In 2012, The American College of Rheumatology (ACR) convened a Working Group to comprehensively evaluate the validity, feasibility, and acceptability of available RA disease activity measures and derive recommendations for their use in clinical (Anderson et al., 2012). The Working Group recommended that “the Clinical Disease Activity Index, Disease Activity Score with 28-joint counts (erythrocyte sedimentation rate or C-reactive protein), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with 3 measures, and Simplified Disease Activity Index because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity states; have remission criteria; and are feasible to perform in clinical settings.” ACR (Singh et al., 2016) also noted that “the WG recognizes that there is currently no ideal measure of disease activity, and acknowledges that some measures excluded in our review may later be found to possess adequate, or even superior, psychometric properties to the 6 recommended measures… Nevertheless, based on available evidence and expert opinion, we believe we have identified measures that are currently the most reliable, valid, feasible, and acceptable measures of disease activity in RA.”

Billing/Coding/Physician Documentation

Information This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81490

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Aletaha, D., Nell, V. P., Stamm, T., Uffmann, M., Pflugbeil, S., Machold, K., & Smolen, J. S. (2005). Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther, 7(4), R796-806. doi:10.1186/ar1740

Anderson, J., Caplan, L., Yazdany, J., Robbins, M. L., Neogi, T., Michaud, K., Kazi, S. (2012). Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken), 64(5), 640-647. doi:10.1002/acr.21649

Bakker, M. F., Cavet, G., Jacobs, J. W., Bijlsma, J. W., Haney, D. J., Shen, Y., Welsing, P. M. (2012). Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis, 71(10), 1692-1697. doi:10.1136/annrheumdis-2011-200963

Brown, A. K., Quinn, M. A., Karim, Z., Conaghan, P. G., Peterfy, C. G., Hensor, E., Emery, P. (2006). Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum, 54(12), 3761-3773. doi:10.1002/art.22190

Centola, M., Cavet, G., Shen, Y., Ramanujan, S., Knowlton, N., Swan, K. A., Curtis, J. R. (2013). Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis. PLoS One, 8(4). doi:10.1371/journal.pone.0060635

Chambers, R. E., MacFarlane, D. G., Whicher, J. T., & Dieppe, P. A. (1983). Serum amyloid-A protein concentration in rheumatoid arthritis and its role in monitoring disease activity. Ann Rheum Dis, 42(6), 665-667.

Combe, B., Landewe, R., Lukas, C., Bolosiu, H. D., Breedveld, F., Dougados, M., Yazici, H. (2007). 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, 66(1), 34-45. doi:10.1136/ard.2005.044354

Curtis, J. R., van der Helm-van Mil, A. H., Knevel, R., Huizinga, T. W., Haney, D. J., Shen, Y., Weinblatt, M. E. (2012). Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken), 64(12), 1794-1803. doi:10.1002/acr.21767

Firestein, G. (2017). Pathogenesis of rheumatoid arthritis - UpToDate. In P. L. Romain (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/pathogenesis-ofrheumatoid-arthritis?source=search_result&search=ra&selectedTitle=6~150.

Fleischmann, R., Connolly, S. E., Maldonado, M. A., & Schiff, M. (2016). Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab. Arthritis Rheumatol, 68(9), 2083- 2089. doi:10.1002/art.39714

Goekoop-Ruiterman, Y. P., de Vries-Bouwstra, J. K., Allaart, C. F., van Zeben, D., Kerstens, P. J., Hazes, J. M., Dijkmans, B. A. (2005). Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum, 52(11), 3381-3390. doi:10.1002/art.21405

Grigor, C., Capell, H., Stirling, A., McMahon, A. D., Lock, P., Vallance, R., Porter, D. (2004). Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet, 364(9430), 263-269. doi:10.1016/s0140- 6736(04)16676-2

Hambardzumyan, K., Bolce, R., Saevarsdottir, S., Cruickshank, S. E., Sasso, E. H., Chernoff, D., van Vollenhoven, R. F. (2015). Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis, 74(6), 1102-1109. doi:10.1136/annrheumdis-2013-204986

Hammer, H. B., Odegard, S., Fagerhol, M. K., Landewe, R., van der Heijde, D., Uhlig, T., Kvien, T. K. (2007). Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis, 66(8), 1093-1097. doi:10.1136/ard.2006.064741

Hirata, S., Dirven, L., Shen, Y., Centola, M., Cavet, G., Lems, W. F., Allaart, C. F. (2013). A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford), 52(7), 1202-1207. doi:10.1093/rheumatology/kes362

Keenan, R. T., Swearingen, C. J., & Yazici, Y. (2008). Erythrocyte sedimentation rate and Creactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol, 26(5), 814-819.

Klarenbeek, N. B., Koevoets, R., van der Heijde, D. M., Gerards, A. H., Ten Wolde, S., Kerstens, P. J., Allaart, C. F. (2011). Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis. Ann Rheum Dis, 70(10), 1815-1821. doi:10.1136/ard.2010.149260

Klimiuk, P. A., Sierakowski, S., Latosiewicz, R., Cylwik, J. P., Cylwik, B., Skowronski, J., & Chwiecko, J. (2002). Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis, 61(9), 804-809.

Li, W., Sasso, E. H., Emerling, D., Cavet, G., & Ford, K. (2013). Impact of a multi-biomarker disease activity test on rheumatoid arthritis treatment decisions and therapy use. Curr Med Res Opin, 29(1), 85-92. doi:10.1185/03007995.2012.753042

Lillegraven, S., Prince, F. H., Shadick, N. A., Bykerk, V. P., Lu, B., Frits, M. L., Solomon, D. H. (2012). Remission and radiographic outcome in rheumatoid arthritis: application of the 2011 ACR/EULAR remission criteria in an observational cohort. Ann Rheum Dis, 71(5), 681-686. doi:10.1136/ard.2011.154625

Mease, P. J. (2011). The potential roles for novel biomarkers in rheumatoid arthritis assessment. Clin Exp Rheumatol, 29(3), 567-574.

Pincus, T., Swearingen, C. J., Bergman, M., & Yazici, Y. (2008). RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index categories. J Rheumatol, 35(11), 2136-2147.

Pincus, T., Yazici, Y., Bergman, M., Maclean, R., & Harrington, T. (2007). A proposed continuous quality improvement approach to assessment and management of patients with rheumatoid arthritis without formal joint counts, based on quantitative routine assessment of patient index data (RAPID) scores on a multidimensional health assessment questionnaire (MDHAQ). Best Pract Res Clin Rheumatol, 21(4), 789-804. doi:10.1016/j.berh.2007.02.009

Prevoo, M. L., van 't Hof, M. A., Kuper, H. H., van Leeuwen, M. A., van de Putte, L. B., & van Riel, P. L. (1995). Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum, 38(1), 44-48.

Rezaei, H., Saevarsdottir, S., Forslind, K., Albertsson, K., Wallin, H., Bratt, J., van Vollenhoven, R. F. (2012). In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial. Ann Rheum Dis, 71(2), 186- 191. doi:10.1136/annrheumdis-2011-200038

Rhodes, B., Merriman, M. E., Harrison, A., Nissen, M. J., Smith, M., Stamp, L., Vyse, T. J. (2010). A genetic association study of serum acute-phase C-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation. PLoS Med, 7(9), e1000341. doi:10.1371/journal.pmed.1000341

Saleem, B., Brown, A. K., Keen, H., Nizam, S., Freeston, J., Karim, Z., Emery, P. (2009). Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: A clinical and imaging comparative study. Arthritis Rheum, 60(7), 1915-1922. doi:10.1002/art.24596

Singh, J. A., Furst, D. E., Bharat, A., Curtis, J. R., Kavanaugh, A. F., Kremer, J. M., Saag, K. G. (2012). 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken), 64(5), 625-639. doi:10.1002/acr.21641

Singh, J. A., Saag, K. G., Bridges, S. L., Jr., Akl, E. A., Bannuru, R. R., Sullivan, M. C., McAlindon, T. (2016). 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken), 68(1), 1-25. doi:10.1002/acr.22783

Smolen, J. S., Aletaha, D., Bijlsma, J. W., Breedveld, F. C., Boumpas, D., Burmester, G., van der Heijde, D. (2010). Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis, 69(4), 631-637. doi:10.1136/ard.2009.123919

Smolen, J. S., Breedveld, F. C., Schiff, M. H., Kalden, J. R., Emery, P., Eberl, G., Tugwell, P. (2003). A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford), 42(2), 244-257.

Sokka, T., & Pincus, T. (2009). 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, 36(7), 1387-1390. doi:10.3899/jrheum.080770

Taylor, P., & Maini, R. (2017). Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis. In J. O'Dell (Ed.), UpToDate. Waltham. MA. Retrieved from https://www.uptodate.com/contents/investigational-biologic-markers-in-the-diagnosis-andassessment-of-rheumatoid-arthritis.

van der Heijde, D. M., van 't Hof, M. A., van Riel, P. L., Theunisse, L. A., Lubberts, E. W., van Leeuwen, M. A., van de Putte, L. B. (1990). Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis, 49(11), 916-920.

van der Helm-van Mil, A. H. M., Knevel, R., Cavet, G., Huizinga, T. W. J., & Haney, D. J. (2013). An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression. In Rheumatology (Oxford) (Vol. 52, pp. 839-846).

Policy Implementation/Update Information

1/1/19 New policy developed. The use of a multi-biomarker disease activity score for rheumatoid arthritis (e.g., Vectra DA score) is considered investigational. BCBSNC does not provide coverage for investigational services or procedures. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (an)