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Serum Biomarker Tests for Multiple Sclerosis

Policy Number: MP-563

Latest Review Date: October 2019

Category: Laboratory

Policy Grade: Active Policy but no longer scheduled for regular literature reviews and updates.

POLICY:

Serum biomarker tests for multiple sclerosis are considered not medically necessary and investigational in ALL situations.

DESCRIPTION OF PROCEDURE OR SERVICE:

Serum antibodies to polysaccharide-containing molecules, called glycans, and other potential serum biomarkers are in development for the diagnosis of multiple sclerosis (MS). These tests include gMS® Dx, for patients with a first episode or clinically isolated syndrome (CIS), and the multimarker prognostic test, gMS® Pro EDSS, for predicting deterioration in patients diagnosed with MS.

Estimated prevalence of MS in North America varies regionally and ranges from 240 of 100,000 in Canada to 191 of 100,000 in Minnesota and 40 of 100,000 in Texas. Women are affected twice as often as men, and median age of onset is 24 years. Most patients (85%) have the relapsing remitting form of MS (RRMS), and of these, 60% to 70% will progress to secondary progressive MS, usually 10 to 30 years after disease onset. Rarer forms are primary progressive MS and progressive relapsing MS.

MS is characterized by destruction of myelin in the central nervous system. Progressive focal demyelination eventually leads to axonal degeneration and cumulative physical and cognitive disabilities. Because any area of the brain, optic nerve, or spinal cord can be affected, symptoms are diverse and may include cognitive, speech, or vision deficits; numbness; pain; weakness or dyscoordination; and bowel or bladder dysfunction. Diagnosis is made by clinical symptoms, typical magnetic resonance imaging (MRI) findings, and oligoclonal antibodies in the cerebrospinal fluid according to current McDonald criteria. Diagnosis requires two clinical episodes occurring at two discreet points in time, or one clinical episode with MRI lesions indicating development at two discreet points in time (i.e., simultaneous appearance of old and new lesions). Disability progression is quantified in practice and in clinical trials by the Kurtzke Expanded Disability Status Scale. Patients with scores less than five are fully ambulatory; scores of 5 to 10 are defined by incrementally decreasing ability to walk.

MS is a complex disease with heterogeneous clinical presentation and disease course. Because prognosis is so hard to predict there has been interest in identifying biomarkers that are associated with disease progression.

The gMS®Dx test, a new blood based test for MS biomarkers, was developed by Glycominds to help physicians identify patients with a high probability of developing MS. The biomarker used in the gMS®Dx test is based on IgM antibodies against the a-glucose antigen (GAGA4). The test is designed to be used in patients as a part of the MS diagnostic work-up and is recommended for use in suspected MS patients for which the diagnosis of MS has not yet been confirmed. The results of the test are reported as negative (patient may still have MS or other neurological disease, continue with routine testing), positive (patient has a high likelihood of having MS), high positive (patient has a very high likelihood of having MS) per Glycominds. One advantage of the gMS®Dx test is that blood samples are relatively easy to obtain and are minimally invasive. A limitation of using biomarkers for diagnosing MS is that they may be affected by other systematic events such as viral infections. An additional limitation of the gMS®Dx test is that the biologic basis for the MS biomarker is unclear (Freeman 2009).

Glycominds has developed the gMS®Pro EDSS test, a blood based test that uses biomarkers to identify patients at high risk for severe disease progression. The biomarkers used in the gMS®Pro EDSS test are based on IgM antibodies against the a-glucose antigen (GAGA2, GAGA3, GAGA4, GAGA6).The aim of this test is to help clinicians choose the most appropriate disease treatment. The test is designed for use in patients at their first episode and for patients with relapse-remitting multiple sclerosis during their first decade of the disease. The results of the test are reported as negative (patient has a low risk to fast disability progression as measured by EDSS) or positive (patient has a high risk to fast disability progression as measured by EDSS) (Glycominds 2012). One advantage of the gMS®Pro EDSS test is that blood samples are relatively easy to obtain and are minimally invasive. A limitation of using biomarkers for diagnosing MS is that biomarkers may be affected by other systematic events such as viral infections (Harris 2009). An additional limitation of the gMS®Pro EDSS test is that the biologic basis for the MS biomarkers is unclear (Freeman 2009).

KEY POINTS:

This policy is based on a review of literature most recently performed on October 3, 2019.

Summary of Evidence

Results from a recent observational study with several limitations suggest that the gMS®Dx test has a sensitivity or 33.7% (95% CI, 30.2 to 37.3) and a specificity of 98.5% (95% CI, 91.7 to 100) for differentiating relapsing remitting multiple sclerosis (RRMS)/secondary progressive multiple sclerosis (SPMS) from other neurological disorders (Brettschneider, 2009). There is insufficient evidence to determine whether the gMS®Dx test will impact diagnosis. There is insufficient evidence to determine whether the gMS®Dx test will change patients management. Weak evidence suggest that the gMS®Dx test has a sensitivity or 33.7% and a specificity of 98.5% for differentiating RRMS/SPMS from other neurological disorders. There is insufficient evidence to determine whether the gMS®Dx test will impact diagnosis. There is insufficient evidence to determine whether the gMS®Dx test will change patients management.

A prospective cohort study that included 286 patients with clinically isolated syndrome (CIS) evaluated the prognostic value of the gMS®Pro EDSS test. Results from this study suggest that that the gMS®Pro EDSS test does not significantly predict prognosis, conversion to McDonald MS, or EDSS progression in patients with CIS. Results from a retrospective study of 100 RRMS patients taken at their first presentation of RRMS suggest that using a panel of four different antibodies had a sensitivity of 37.9% and a specificity of 83.3% for predicting early relapse in patients with RRMS following their first presentation. Results from this study should be interpreted with caution as this is a retrospective exploratory analysis (Freedman 2009). No studies were identified that address the impact of gMS®Pro EDSS on patients management. There is insufficient evidence to determine the accuracy of the gMS®Pro EDSS test. There is insufficient evidence to determine whether the gMS®Pro EDSS test will change patients management.

Antibodies to glycan molecules are thought to impair immune function. Commercial assays are available to measure serum antibody levels to one (glucose [α1,4]glucose[α], also called GAGA4) or several (GAGA2, -3, -4, and -6) glycan molecules. These tests, gMS Dx and gMS Pro EDSS, are marketed to aid diagnosis and prognosis in MS, respectively. However, further research is needed as the evidence is insufficient to prove clinical utility. Therefore, both are considered investigational for all uses.

Tests for serum levels of other MS biomarkers, including but not limited to apoptosis-related molecules, intercellular adhesion molecules, and myelin peptides, are considered investigational.

Practice Guidelines and Position Statements

Multiple Sclerosis Think Tank

In 2013, the Multiple Sclerosis Think Tank, a group of approximately 40 hospital neurologists in France, published consensus recommendations for serum tests useful to diagnose MS. Recommendations were developed by systematic review of the literature and a Delphi consensus process. Panelists concurred that “there is currently no useful biological blood test for the positive diagnosis of MS.”

Advisory Committee on Clinical Trials in MS

In 2014, the Advisory Committee on Clinical Trials in MS, jointly sponsored by the U.S. National Multiple Sclerosis Society and the European Committee for Treatment and Research in MS, and the MS Phenotype Group published results of its deliberations to re-examine current MS clinical course descriptions in light of current evidence for improved descriptive terminology (e.g., incorporating evidence for serum and other biomarkers). The Committee concluded, “To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the transition point when RRMS converts to SPMS [secondary progressive MS]; the transition is usually gradual. This has limited our ability to study the imaging and biomarker characteristics that may distinguish this course.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

gMS Dx, gMS Pro EDSS, multiple sclerosis, serum biomarkers

APPROVED BY GOVERNING BODIES:

FDA-approved tests for serum biomarkers in MS are currently unavailable. Glycominds Ltd offered gMS® Dx and gMS® Pro EDSS as laboratory-developed (in-house) tests at its Clinical Laboratory Improvement Act (CLIA)-certified laboratory in Simi Valley, California. However, current status of the tests is unknown because links to the company website are inactive, and ordering information is not readily available through the parent company, Coronis Partners. Although commercial versions of other biomarker assays were not identified, clinical laboratories may offer in-house assays to measure serum biomarkers in MS.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet general regulatory standards of CLIA and must be licensed by CLIA for high-complexity testing.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

84999             

Unlisted chemistry procedure

 

REFERENCES:

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POLICY HISTORY:

Medical Policy Panel, April 2014

Medical Policy Group, September 2014 (1) New policy, previously only listed on the Investigational Listing; remains investigational

Medical Policy Administration Committee, October 2014

Available for comment September 19 through November 2, 2014

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, July 2016

Medical Policy Group, August 2016 (3): Editing review only; no new literature to add to policy; no changes in policy statement; retiring policy. Policy placed in “retired” mode and removed from schedule.

Medical Policy Group, October 2019 (9): Updates to Description, Key Points, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.