Medical Policy: 02.04.68
Original Effective Date: September 2017
Reviewed: June 2020
Revised: June 2020
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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.
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). Rheumatologists usually use four blood tests in the diagnosis of RA. These blood tests are the Sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor, and the anti-CCP. The ESR and the CRP, both inflammatory markers, are also used in the ongoing monitoring of RA to assess your level of inflammation.
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).
The Vectra DA test consists of 12 individual biomarkers:
The Vectra DA test scores range from 1 to 100. Categories of scores were constructed to correlate with the DAS28-CRP scale:
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.
To demonstrate clinical utility, there should be evidence that the multibiomarker disease activity score is at least as good a measure of disease activity as other available measures or that the multibiomarker disease activity score demonstrates an incremental benefit when used as an adjunct with other disease activity measures. To demonstrate equivalence with other measures directly, an RCT comparing health outcomes of 2 groups, 1 group managed using the Vectra DA test and the other group managed by another disease activity measure is needed. To directly demonstrate an incremental benefit when used as an adjunct, an RCT should compare health outcomes in patients receiving treatment guided by MBDA plus a disease activity measure with outcomes in patients receiving treatment guided only by the other disease activity measure.
More extensive biomarker testing is being offered by various laboratories. As an example, Myriad’s HumanMAP represents a comprehensive menu of quantitative, multiplexed immunoassays covering dozens of different pathways. The number of biomarkers tested can be set or personalized with frequently 80+ biomarkers being tested at one time. Biomarker panels are frequently marketed as disease specific and helpful in drug development.
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.
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 multi biomarker 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.
Some individual biomarkers, eg, ANA and anti-dsDNA, are considered standard of care in the diagnosis of connective tissue diseases, and, presumably, the technical accuracy of these tests has been established. The technical accuracy of tests for novel biomarkers in biomarker panel tests is not known.
No studies were identified that evaluated the diagnostic accuracy of any commercially available biomarker panel for systemic lupus erythematosus (SLE) or Rheumatoid arthritis (RA).
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.
The European League Against Rheumatism (2017) updated its guidelines on the management of early arthritis. The League recommended that arthritis activity be assessed at 1- to 3-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.
NICE recommends monthly monitoring of CRP and disease activity until remission or low disease activity. Remission is defined as a DAS28 score of under 2.6, and low is defined as a DAS28 score of under 3.2. NICE does not mention biomarkers in its recommendations for research (NICE, 2018).
In 1997 the American College of Rheumatology (ACR) updated criteria for the classification of SLE. The ACR classification criteria are as follows:
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 antiDNA 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.
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.
In the 2018 CRA guidelines and recommendations for assessing and monitoring SLE, they state, “Best clinical practice includes a complete history and physical examination at baseline, with laboratory monitoring possibly including but not limited to complete blood count (CBC), liver enzymes, creatine kinase, creatinine and estimated glomerular filtration rate (eGFR), urine routine/microscopic (urinalysis), urine protein-creatinine ratio, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complements (C3, C4), anti-dsDNA, antinuclear antibodies, antibodies to extractable nuclear antigens, antiphospholipid antibodies (aPL), lupus anticoagulant (LAC), anticardiolipin (aCL), anti-β2-glycoprotein I (anti-β2-GPI), and lipid profile. Follow-up (sic) laboratory monitoring will depend on the patient’s clinical status and may include CBC, eGFR, urinalysis, urine protein-creatinine ratio, CRP, and/or ESR, C3, C4, and anti-dsDNA antibodies.
The AAP released guidelines through Choosing Wisely. In it, they state “Do not order antinuclear antibody (ANA) and other autoantibody testing on a child unless there is strong suspicion or specific signs of autoimmune disease”
Specific biomarkers in the panel are as follows:
10 marker Avise SLE 2.0 test:
Auto-antibodies: ANA, Anti-dsDNA, Anti-mutated citrullinated vimentin (Anti-MCV), C4d erythrocyte-bound complement fragment (EC4d), C4d lymphocyte-bound complement (BC4d), Anti-Sm, Jo-1, Sci-70, CENP, SS-B/La,
12 marker Avise SLE + Connective Tissue 2.0 test:
Auto-antibodies: U1RNP, RNP70, SS-A/Ro.
Rheumatoid arthritis auto-antibodies: Rheumatoid factor IgM, Rheumatoid factor IgA, Anti-cyclic citrullinated peptide IgG.
Anti-phospholipid syndrome auto-antibodies: Cardiolipin IgM, Cardiolipin IgG, B2-glycoprotein 1 IgG, B2-glycoprotein 1 IgM.
Thyroid auto-antibodies: Thyroglobulin IgG, Thyroid perodixidase IgG.
In addition to reporting individual test results, an index score is reported that rates how suggestive results of tests are of SLE. Information is not available as to how this 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 to be in the indeterminate zone.
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. Veracis Inc. offers panel test SLE-key® Rule Out to assist with the diagnosis of SLE. The panel testing SLE-key® uses proprietary iCHIP® microarray combined with a classifier algorithm to analyze protein biomarkers and definitively exclude a diagnosis of systemic lupus erythematosus.
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. Additionally, there are no RCTs of Vectra DA as an adjunct to other disease activity measures compared with using the disease activity measures alone. 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, rheumatoid arthritis and miscellaneous connective tissue diseases including, but not limited to the following, are considered investigational.
There is uncertainty about how the use of a serum biomarker panel test would change patient management. The evidence is insufficient to determine the effects of the technology on health outcomes.
Large biomarker panels for various diseases (e.g. HumanMAP, Human InflammationMAP, Human ImmunoMAP) generally used in the scope of clinical trials are considered investigational.
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