Medical Policy: 02.04.68
Original Effective Date: September 2017
Reviewed: June 2021
Revised: June 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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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.
This medical policy addresses the use of the following biomarker and multiplex autoantigen microarray testing for autoimmune disease including the following:
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:
Fleischmann et. al. evaluated the ability of Vectra DA to measure disease activity in participants of the Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate (AMPLE) trial. In the AMPLE trial (Schiff, 2014), a total of 646 subjects naïve to biological agents were randomized to receive abatacept (n=318) or adalimumab (n=328). Multi-biomarker disease activity (MBDA) results were available for 259 and 265 subjects, respectively. No association was found between the MBDA score and disease activity as defined by American College of Rheumatology (ACR) recommended disease activity measures (CDAI, SDAI, DAS28-C-reactive protein, or Routine Assessment of Patient Index Data with 3 measures [RAPID-3]) in either treatment group. The authors concluded:
These findings indicated that the MBDA score should not be used to guide RA management decisions, particularly in patients treated with abatacept or adalimumab as a first biologic agent. Treatment decisions in RA should be based on clinical judgment, utilizing the disease activity measures recommended by the ACR for point-of-care clinical use.
For individuals who have rheumatoid arthritis (RA) who receive the Vectra DA test, the evidence includes post hoc analyses of archived serum samples from randomized controlled trials and prospective cohort studies. The published data is conflicting as to whether or not multi-biomarker disease activity (MBDA) blood tests, such as the Vectra DA, perform as well as other RA disease markers. There is insufficient published evidence indicating that treatment decisions can be influenced by MBDA test scores, and insufficient evidence demonstrating the effect of the MBDA testing on net health outcomes.
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. In 2019, new classification criteria endorsed by the European League Against Rheumatism (EULAR) and the ACR were developed and validated. The 2019 EULAR/ACR classification criteria requires, a positive ANA as an entry criterion. For those with a positive ANA, additive criteria are assessed in 7 clinical and 3 immunological domains. Weighted criteria (ranging from 2 to 10 points) are evaluated within each domain, with only the highest weighted criterion in a specific domain counting towards the total score. The weighted feature allows for criteria that are more tightly associated with SLE to contribute more heavily to the overall score. A classification of SLE requires a total score of ≥10 points.
The EULAR/ACR classification criteria are as follows:
To date, the most common laboratory tests performed in the diagnosis of SLE are serum ANA, and if this is positive, tests for anti-dsDNA and anti-Sm. ANA tests are highly sensitive (i.e., with a high negative predictive value) but have low specificity and relatively low positive predictive value, particularly when the ANA is positive at a low level. Specificity of testing can be increased by testing for specific antibodies against individual nuclear antigens (extractable nuclear antigens, or ENAs) to examine the “pattern” of ANA positivity. These include antigens against single and double-stranded DNA, histones, Sm, Ro, La, and RNP. The presence of anti-dsDNA or anti-Sm is highly specific for SLE because few patients without SLE test positive; however, neither of these tests have high sensitivity (Suresh, 2007). The presence of other antibody patterns may indicate the likelihood of alternate diagnoses. For example, the presence of Ro and La antibodies suggests Sjogren syndrome, while the presence of antihistone antibodies suggests drug-induced lupus.
More accurate laboratory tests for systemic lupus erythematosus (SLE) could facilitate diagnosis, prognosis and management. Recently, laboratory-developed, diagnostic panel tests with proprietary algorithms and/or index scores for the diagnosis of SLE have become commercially available. AVISE testing offers next-generation insight autoimmune lab tests to include the following:
Panel tests for systemic lupus erythematosus (SLE) include markers that are standard in the work-up of SLE, but also contain novel markers, most notably cell-bound complement activation products (CB-CAPs). The accuracy of CB-CAPs in establishing a diagnosis of SLE is not known, nor is the use of these novel biomarkers recommended in clinical practice guidelines. In addition to reporting the results of the panel of tests, an index score is reported that rates how suggestive the results of the panel are of a diagnosis of SLE. Information is not available on how this index score is calculated, nor is it known how this score performs in diagnosing SLE compared with currently accepted clinical and laboratory criteria. Finally, the utility of assessing multiple biomarkers simultaneously, rather than the more commonly performed sequential testing, is unknown. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Currently one test the SLE-key rule-out test (ImmunoArray) is designed to rule-out the likelihood of a systemic lupus erythematous (SLE) diagnosis.
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.
Two industry-funded studies evaluating the SLE-key test have been published. The available published literature on the SLE-key rule-out test is limited in that it includes samples only from individuals already diagnosed with SLE or healthy people, and not from the population most likely to be tested in clinical practice, individuals with suspected SLE. The initial development and validation study included an even more selected population, females between the ages of 18 and 60. Moreover, the impact of the test on patient management such as reducing the need for other tests or permitting an earlier diagnosis has not been studied. Furthermore, data are not available on the impact of SLE-key Rule-Out testing on health outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 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”
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 Act (CLIA). These tests are available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA Clinical for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
The use of multi-marker biomarker disease activity (MBDA) testing using Vectra DA for rheumatoid arthritis (RA) is considered investigational for all indications. The evidence is insufficient to determine the effects of the technology on net health outcomes.
Serum biomarker panel testing with proprietary algorithms and/or index scores for the diagnosis, prognosis or management of systemic lupus erythematosus (SLE), including, but not limited to the following, are considered investigational for all indications because the evidence is insufficient to determine the effects of the technology on net health outcomes:
Multiplex autoantigen microarray testing to screen for, diagnose or manage systemic lupus erythematous (SLE) using SLE-key rule-out test is considered investigational for all indications. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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