Medical Policy: 02.04.68 

Original Effective Date: September 2017 

Reviewed: September 2017 

Revised:  

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy 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 will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

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.

 

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.

 

Assessment of disease activity in rheumatoid arthritis 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 rheumatoid arthritis disease activity. They use combinations of physical exam findings, radiologic results, and serum biomarkers to construct a disease activity score. There are more than 60 methods of measuring disease activity in individuals with RA. An expert panel on RA determined the following 6 measures were the most useful and feasible in a clinical setting: Clinical Disease Activity Index [CDAI], Disease Activity Score with 28 joints (DAS28), Patient Activity Scale, Patient Activity Scale II, Routine Assessment of Patient Index Data 3 (RAPID3), and Simplified Disease Activity Index (SDAI).

 

A multibiomarker disease activity (MBDA) instrument is a disease activity measure that is comprised entirely of serum biomarkers. The Vectra DA test is a commercially available MBDA blood test that uses 12 biomarkers to construct a disease activity score ranging from 1 (low disease activity) to 100 (high disease activity).

 

Vectra DA Test 

The Vectra DA test consists of 12 individual biomarkers:

  • Interleukin-6
  • Tumor necrosis factor receptor type I
  • Vascular cell adhesion molecule 1
  • Epidermal growth factor
  • Vascular endothelial growth factor A
  • YKL-40
  • Matrix metalloproteinase 1
  • Matrix metalloproteinase 3
  • C-reactive protein
  • Serum amyloid A
  • Leptin
  • Resistin

The Vectra DA test scores range from 1 to 100. 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

For individuals who have rheumatoid arthritis who receive the Vectra DA test, the evidence includes post hoc analyses of archived serum samples from randomized controlled trials and prospective cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, change in disease status, functional outcomes, and quality of life. Evidence from the available studies has correlated Vectra DA with disease progression and other previously validated disease activity measures such as the Disease Activity Score with 28 joints (DAS28). These studies have shown that the Vectra DA score has moderate correlations with other disease activity measures (eg, DAS28). Other post hoc analyses of archived serum samples have evaluated the use of MBDA to measure treatment response. Correlation of MBDA scores with other disease activity measures differed by the duration and type of treatment. A smaller number of studies have evaluated clinical utility by examining changes in decision making associated with the use of Vectra, but these studies are limited by the design because they used archived serum samples, simulated cases, or physician surveys and did not report any health outcomes data. This 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, and it is uncertain whether it is as accurate as the DAS28. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

American College of Rheumatology 

In the 2015 American College of Rheumatology guidelines on the treatment of rheumatoid arthritis, ACR endorsed the following measures of disease activity: Patient Activity Scale, Routine Assessment of Patient Index Data 3, Clinical Disease Activity Index, Disease Activity Score 28, and Simplified Disease Activity Index. The guidelines indicated that other measures are available to clinicians, but that including the new measures was out of scope.

 

Systemic Lupus Erythematosus (SLE) 

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease (CTD) that can be difficult to diagnose because patients often present with diverse, nonspecific symptoms that overlap with other CTDs; to further complicate matters, commonly used laboratory tests are not highly accurate. Moreover, similar symptoms may also present themselves in patients with fibromyalgia.

 

In 1997 the American College of Rheumatology (ACR) updated criteria for the classification of SLE.  The ACR classification criteria are as follows:

  1. Malar rash
  2. Discoid rash
  3. Photosensitivity
  4. Mouth or nose ulcers (usually painless)
  5. Arthritis (nonerosive) in two or more peripheral joints, along with tenderness, swelling, or effusion
  6. Serositis: Pleuritis or pericarditis
  7. Renal disorder: excessive protein in the urine, or cellular casts in the urine
  8. Neurologic disorder: seizures and/or psychosis, in the absence of offending drugs or known metabolic derangements
  9. Hematologic disorders: hemolytic anemia, leukopenia, lymphopenia or thrombocytopenia
  10. Immunologic disorder: antibodies to double stranded DNA (anti-dsDNA), antibodies to Smith nuclear antigen (anti-Sm), positive antiphospholipid antibody or false positive serologic test for syphilis known to be positive for at least 6 months
  11. Abnormal antinuclear antibody (ANA) test in the absence of drugs known to induce it

These criteria were originally developed for research, but they have been widely adopted in clinical care. Individuals who meet 4 or more of the 11 criteria are diagnosed with SLE. If a patient meets fewer than four of the criteria, lupus can still be diagnosed by clinical judgment and it is recommended that a rheumatologist confirm the diagnosis.

 

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC), an international group of researchers, developed revised criteria for diagnosing SLE.These criteria include more laboratory tests than the earlier ACR criteria, including elements of the complement system. Patients are classified as having SLE if they satisfy 4 or more of the 18 criteria below, including at least 1 clinical criterion and 1 immunologic criterion, or they have biopsy-confirmed nephritis compatible with SLE and with ANA or antidsDNA antibodies. In a sample of 690 patients, the SLICC criteria had a sensitivity of 97% and a specificity of 84% for diagnosing SLE, whereas the ACR criteria applied to the same sample had a sensitivity of 83% and a specificity of 96%. It is not clear how well-accepted the SLICC recommendations are in the practice setting. The SLICC criteria are outlined below.

 

Clinical and Immunologic Criteria 

Clinical Criteria 
  • Acute cutaneous lupus (including but not limited to lupus malar rash)

  • Chronic cutaneous lupus (including but not limited to discoid rash)

  • Oral ulcers

  • Nonscarring alopecia in the absence of other causes

  • Synovitis involving ≥ 2 joints, characterized by swelling or effusion or and ≥ 30 min of morning stiffness

  • Serositis

  • Renal: excessive protein in the urine or cellular casts in the urine

  • Neurologic disorder: seizures, psychosis, mononeuritis complex, or peripheral, or cranial neuropathy

  • Seizures

  • Hemolytic anemia

  • Leukopenia or lymphopenia

  • Thrombocytopenia

Immunologic Criteria 
  • Antinuclear antibody above laboratory reference range
  • Antibodies to double-stranded DNA above laboratory reference range
  • Antibodies to Smith nuclear antigen
  • Antiphospholipid antibody
  • Low complement (low C3, low C4, or low CH150)
  • Direct Coombs tests in the absence of hemolytic anemia

As previously noted, the SLICC classification system includes a wider range of laboratory tests than the ACR criteria. To date, the most common laboratory tests performed in the diagnosis of SLE are serum ANA, and, if positive, tests for anti-dsDNA and anti-Sm.

 

Currently, differential diagnosis depends on a combination of clinical signs and symptoms and individual laboratory tests. More accurate laboratory tests for SLE and other CTDs could facilitate diagnosis of the disease. Recently, laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE and other autoimmune CTDs have become commercially available.

 

In addition to exploration of individual biomarkers with higher accuracy than accepted markers (eg, ANA, anti-dsDNA), there is interest in identifying a panel of tests with high sensitivity and specificity for SLE diagnosis. At least 1 multibiomarker test to aid the diagnosis of SLE and other CTDs is commercially available. This panel contains two separate panels (the 10-marker Avise Lupus test and the Avise CTD test for a total of 22 different tests). Avise CTD includes nuclear antigen antibodies markers to help distinguish specific CTDs, a rheumatoid arthritis panel to rule-in or rule-out rheumatoid arthritis, an antiphospholipid syndrome panel to assess risk for thrombosis and cardiovascular events, and a thyroid panel to help rule-in or rule-out Graves disease and Hashimoto disease.

 

The index score, calculated using a proprietary algorithm, rates how suggestive test results are of SLE. Although there is information on cutoffs used to indicate positivity for individual markers, information is not available on how precisely the index score is calculated. The score can range from -5 (highly nonsuggestive of SLE) to 5 (highly suggestive of SLE) and a score of -0.1 to 0.1 is considered indeterminate.

 

Exagen also offers the Avise SLE Prognostic test, a 10-marker panel that can be ordered with the Avise SLE 2.0/Avise SLE + Connective Tissue 2.0 panels. The prognostic test focuses on patients’ risk of lupus nephritis, neuropsychiatric SLE, thrombosis, and cardiovascular events. The test includes anti-C1q, anti-ribosomal P, anti-phosphatidylserine/prothrombin immunoglobulin (Ig) M and IgG, anti-cardiolipin IgM, IgG, and IgA and anti-β2-glycoprotein 1 IgM, IgG, and IgA. Four of the ten markers are included in both panel tests.

 

Prior Approval:

 

Not applicable

 

Policy:

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

 

There is limited evidence that treatment decisions can be influenced by the Vectra DA score. There are no RCTs comparing the use of the Vectra DA score with an alternative method of measuring disease activity; as a result, there is no direct evidence that the Vectra DA test improves outcomes.

 

Serum biomarker panel testing with proprietary algorithms and/or index scores for the diagnosis of systemic lupus erythematosus and other connective tissue diseases (eg. Avise CDT assay, Avsie PG, Avise SLE, and Avise SLE+) is considered investigational.

 

There is uncertainty about how the use of a serum biomarker panel test for SLE would change patient management. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81490 Autoimmune (rheumatoid arthritis), analysis of 12 biomarkers using immunoassays, utilizing serum, prognostic algorithm reported as a disease activity score
  • 81599 Unlisted multianalyte assay with algorithmic analysis
  • 84999 Unlisted chemistry procedure.

 

Selected References:

  • Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology (Oxford). Dec 2012;51 Suppl 6:vi28-36. PMID 23221584

  • Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. Apr 2010;69(4):638-643. PMID 20237123

  • 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). May 2012;64(5):640-647. PMID 22473918

  • 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. Mar 2012;79(2):149-155. PMID 21680221

  • 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. Nov-Dec 2012;30(6):912-921. PMID 22935335

  • 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). Dec 2012;64(12):1794-1803. PMID 22736476

  • Crescendo Bioscience Inc. Vectra DA Patient Guide. 2017 Accessed May 24, 2017.

  • Eastman PS, Manning WC, Qureshi F, et al. Characterization of a multiplex, 12-biomarker test for rheumatoid arthritis. J Pharm Biomed Anal. Nov 2012;70:415-424. PMID 22749821

  • 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. PMID 23585841

  • Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford). Jul 2013;52(7):1202-1207. PMID 23392591

  • 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. PMID 25128518

  • Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritisdisease activity in the CAMERA tight control study. Ann Rheum Dis. Oct 2012;71(10):1692-1697. PMID 22596166

  • 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. PMID 24812287

  • 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. PMID 26958364

  • Fleischmann R, Connolly SE, Maldonado MA, et al. Brief Report: Estimating disease activity using Multi-Biomarker Disease Activity Scores in rheumatoid arthritis patients treated with abatacept or adalimumab. Arthritis Rheumatol. Sep 2016;68(9):2083-2089. PMID 27111089

  • 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. PMID 27111349

  • 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. PMID 27813312

  • Fleischmann R, Connolly SE, Maldonado MA, et al. Reply. Arthritis Rheumatol. Apr 2017;69(4):867-868. PMID 27992708

  • 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. Sep 2016;75(9):1637-1644. PMID 26483255

  • 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. PMID 26545940

  • 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. Jan 2013;29(1):85-92. PMID 23176063

  • Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012;64:640–7.

  • American College of Rheumatology (ACR). The 1982 Revised Criteria for Classification of Systemic Lupus Erythematosus.

  • Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997;40(9):1725. PMID 9324032

  • Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. Sep 1999;42(9):1785-1796. PMID 10513791

  • Dervieux T, Conklin J, Ligayon JA, et al. Validation of a multi-analyte panel with cell-bound complement activation products for systemic lupus erythematosus. J Immunol Methods. Jul 2017;446:54-59. PMID 28389175

 

Policy History:

  • September 2017 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.