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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.


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


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).


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.


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


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.


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.


CPT Codes:


Unlisted chemistry procedure



  1. Amorini AM, Nociti V, Petzold A, et al. Serum lactate as a novel potential biomarker in multiple sclerosis. Biochim Biophys Acta. Jul 2014;1842(7):1137-1143.
  2. Aydin O, Ellidag HY, Eren E, et al. Ischemia modified albumin is an indicator of oxidative stress in multiple sclerosis. Biochem Med (Zagreb). 2014; 24(3):383-389.
  3. Berger T, Rubner P, Schautzer F et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003; 349(2):139-45.
  4. Brettschneider J, Jaskowski TD, Tumani H et al. Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases. J Neuroimmunol 2009; 217(1-2):95-101.
  5. Brill L, Goldberg L, Karni A, et al. Increased anti-KIR4.1 antibodies in multiple sclerosis: Could it be a marker of disease relapse? Mult Scler. Apr 2015; 21(5):572-579.
  6. Colomba P, Fontana S, Salemi G, et al. Identification of biomarkers in cerebrospinal fluid and serum of multiple sclerosis patients by immunoproteomics approach. Int J Mol Sci. 2014; 15(12):23269-23282.
  7. Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol 2014; 13(1):113-26.
  8. Dickens AM, Larkin JR, Griffin JL, et al. A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology. Oct 21 2014;83(17):1492-1499.
  9. Dimisianos N, Rodi M, Kalavrizioti D, et al. Cytokines as Biomarkers of Treatment Response to IFN beta in Relapsing-Remitting Multiple Sclerosis. Mult Scler Int. 2014; 2014:436764.
  10. Evans C, Beland SG, Kulaga S et al. Incidence and prevalence of multiple sclerosis in the Americas: a systematic review. Neuroepidemiology 2013; 40(3):195-2
  11. Findling O, Durot I, Weck A, et al. Antimyelin antibodies as predictors of disability after clinically isolated syndrome. Int J Neurosci. Aug 2014; 124(8):567-572.
  12. Fissolo N, Canto E, Vidal-Jordana A, et al. Levels of soluble TNF-RII are increased in serum of patients with primary progressive multiple sclerosis. J Neuroimmunol. Jun 15 2014; 271(1-2):56-59.
  13. Freedman MS, Laks J, Dotan N et al. Anti-alpha-glucose-based glycan IgM antibodies predict relapse activity in multiple sclerosis after the first neurological event. Mult Scler 2009; 15(4):422-30.
  14. Freedman MS, Metzig C, Kappos L et al. Predictive nature of IgM anti-alpha-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis. Mult Scler 2012; 18(7):966-73.
  15. Gironi M, Solaro C, Meazza C et al. Growth hormone and disease severity in early stage of multiple sclerosis. Mult Scler Int 2013; 2013:836486.
  16. Hadjigeorgiou GM, Doxani C, Miligkos M et al. A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis. J Clin Pharm Ther 2013; 38(6):433-9.
  17. Hartung HP, Reiners K, Archelos JJ et al. Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging. Ann Neurol 1995; 38(2):186-93.
  18. Holmoy T, Loken-Amsrud KI, Bakke SJ et al. Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity. PLoS One 2013; 8(9):e75021.
  19. Ingram G, Hakobyan S, Hirst CL et al. Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain 2010; 133(Pt 6):1602-11.
  20. Jafarzadeh A, Ebrahimi HA, Bagherzadeh S, et al. Lower serum levels of Th2-related chemokine CCL22 in women patients with multiple sclerosis: a comparison between patients and healthy women. Inflammation. Apr 2014; 37(2):604-610.
  21. Kacperska MJ, Jastrzebski K, Tomasik B, et al. Selected Extracellular microRNA as Potential Biomarkers of Multiple Sclerosis Activity-Preliminary Study. J Mol Neurosci. Dec 10 2014.
  22. Kappos L, Freedman MS, Polman CH et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007; 370(9585):389-97.
  23. Kappos L, Freedman MS, Polman CH et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009; 8(11):987-97.
  24. Keegan BM. Therapeutic decision making in a new drug era in multiple sclerosis. Semin Neurol 2013; 33(1):5-12.
  25. Kivisakk P, Healy BC, Francois K et al. Evaluation of circulating osteopontin levels in an unselected cohort of patients with multiple sclerosis: relevance for biomarker development. Mult Scler 2013.
  26. Koch MW, George S, Wall W, et al. Serum NSE level and disability progression in multiple sclerosis. J Neurol Sci. Mar 15 2015; 350(1-2):46-50.
  27. Koudriavtseva T, D'Agosto G, Mandoj C, et al. High frequency of antiphospholipid antibodies in relapse of multiple sclerosis: a possible indicator of inflammatory-thrombotic processes. Neurol Sci. Nov 2014; 35(11):1737-1741.
  28. Kuhle J, Pohl C, Mehling M et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 2007; 356(4):371-8.
  29. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33(11):1444-52.
  30. Kvistad S, Myhr KM, Holmoy T, et al. Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Mult Scler. Dec 2014; 20(14):1833-1840.
  31. Lopez-Gomez C, Oliver-Martos B, Pinto-Medel MJ, et al. TRAIL and TRAIL receptors splice variants during long-term interferon β treatment of patients with multiple sclerosis: Evaluation as biomarkers for therapeutic response. J Neurol Neurosurg Psychiatry. 2016;87(2):130-137.
  32. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. Jul 15 2014; 83(3):278-286.
  33. Moccia M, Lanzillo R, Palladino R, et al. Uric acid: a potential biomarker of multiple sclerosis and of its disability. Clin Chem Lab Med. Sep 20 2014.
  34. Moreno C, Prieto P, Macias A et al. Modulation of voltage-dependent and inward rectifier potassium channels by 15-epi-lipoxin-A4 in activated murine macrophages: implications in innate immunity. J Immunol 2013; 191(12):6136-46.
  35. National Multiple Sclerosis Society. Primary progressive MS (PPMS). Types of MS. New York, NY: National Multiple Sclerosis Society; 2018. Available at: Accessed February 12, 2018.
  36. National Multiple Sclerosis Society. Progressive-relapsing MS (PRMS). Types of MS. New York, NY: National Multiple Sclerosis Society; 2018. Available at: Accessed February 12, 2018.
  37. Ortega-Madueno I, Garcia-Montojo M, Dominguez-Mozo MI, et al. Anti-human herpesvirus 6A/B IgG correlates with relapses and progression in multiple sclerosis. PLoS One. 2014; 9(8):e104836.
  38. Ouallet JC, Bodiguel E, Bensa C et al. Recommendations for useful serum testing with suspected multiple sclerosis. Rev Neurol (Paris) 2013; 169(1):37-46.
  39. Polachini CR, Spanevello RM, Casali EA, et al. Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis. Neuroscience. Apr 25 2014; 266:266-274.
  40. Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2):292-302.
  41. Polman CH, Reingold SC, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005; 58(6):840-6.
  42. Schwarz M, Spector L, Gortler M et al. Serum anti-Glc(alpha1,4)Glc(alpha) antibodies as a biomarker for relapsing-remitting multiple sclerosis. J Neurol Sci 2006; 244(1-2):59-68.
  43. Shimizu Y, Ota K, Ikeguchi R et al. Plasma osteopontin levels are associated with disease activity in the patients with multiple sclerosis and neuromyelitis optica. J Neuroimmunol 2013; 263(1-2):148-51.
  44. Siroos B, Balood M, Zahednasab H et al. Secretory phospholipase A2 activity in serum and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 2013; 262(1-2):125-7.
  45. Skundric D. Basic approaches in therapy of multiple sclerosis (MS) and related diseases: Current achievements and prospective. Cent Nerv Syst Agents Med Chem. 2018;18(1):21-31.
  46. Sternberg Z, Sternberg D, Drake A, et al. Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis. J Neuroimmunol. Sep 15 2014; 274(1-2):197-201.
  47. Stilund M, Reuschlein AK, Christensen T, et al. Soluble CD163 as a marker of macrophage activity in newly diagnosed patients with multiple sclerosis. PLoS One. 2014; 9(6):e98588.
  48. Trenova AG, Slavov GS, Manova MG, et al. Cytokines and disability in interferon-beta-1b treated and untreated women with multiple sclerosis. Arch Med Res. Aug 2014; 45(6):495-500.
  49. Trentini A, Manfrinato MC, Castellazzi M, et al. TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis. Mult Scler. Feb 6 2015.
  50. Trojano M, Avolio C, Simone IL et al. Soluble intercellular adhesion molecule-1 in serum and cerebrospinal fluid of clinically active relapsing-remitting multiple sclerosis: correlation with Gd-DTPA magnetic resonance imaging-enhancement and cerebrospinal fluid findings. Neurology 1996; 47(6):1535-41.
  51. Uysal S, Meric Yilmaz F, Bogdaycioglu N, et al. Increased serum levels of some inflammatory markers in patients with multiple sclerosis. Minerva Med. Jun 2014; 105(3):229-235.
  52. Waubant E, Goodkin DE, Gee L et al. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999; 53(7):1397-401.
  53. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014; 89(2):225-40.


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.