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Serum Biomarker Tests for Multiple Sclerosis

Policy Number: MP-563

Latest Review Date: August 2021

Category: Laboratory

Policy Grade: Effective August 2016: Active Policy but no longer scheduled for regular literature reviews and updates.

POLICY:

Serum biomarker tests for multiple sclerosis are considered investigational in ALL situations.

DESCRIPTION OF PROCEDURE OR SERVICE:

Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system defined by multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring. The most common presenting symptoms are sensory disturbances, followed by weakness and visual disturbances, but the disease has a highly variable pace and many atypical forms. MS is primarily diagnosed clinically. The core requirement for the diagnosis is the demonstration of central nervous system lesion dissemination in time and space, based upon either clinical findings alone or a combination of clinical and MRI findings. The history and physical examination are most important for diagnostic purposes. MRI is the test of choice to support the clinical diagnosis of MS. Prognosis is hard to predict, which has prompted interest in identifying biomarkers that are associated with disease progression.

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), and the multimarker prognostic test, gMS® Pro EDSS (for predicting deterioration in patients diagnosed with MS).

KEY POINTS:

This policy has been updated with most recent review of literature on August 31, 2021.

Summary of Evidence

There is an unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response, and predict potential adverse effects in MS. Currently, no biomarkers of MS have been validated. An observational study with several limitations and a retrospective exploratory analysis of a prospective cohort study have been identified. Further prospective studies are necessary to assess the utility of this technology for decision-making in individual patients. There is insufficient evidence to determine whether this technology will impact diagnosis and/or patient management.

Practice Guidelines and Position Statements

International Advisory Committee on Clinical Trials in Multiple Sclerosis

In 2014, the International Advisory Committee on Clinical Trials in Multiple Sclerosis, jointly sponsored by the U.S. National Multiple Sclerosis Society, the European Committee for Treatment and Research in Multiple Sclerosis and the MS Phenotype Group, re -examined MS phenotypes, exploring clinical, imaging, and biomarker advances through working groups and literature searches. The committee concluded that “To date, there are no clear clinical, imaging, immunologic or pathologic criteria to determine the transition point when RRMS [relapse remitting MS] 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.

The International Panel on Diagnosis of Multiple Sclerosis

The Panel reviewed the 2010 McDonald criteria and recommended: “In a patient with a typical clinically isolated syndrome and fulfilment of clinical or MRI criteria for dissemination in space and no better explanation for the clinical presentation, demonstration of CSF-specific oligoclonal bands in the absence of other CSF findings atypical of multiple sclerosis allows a diagnosis of this disease to be made.” The Panel goes on to state that “CSF oligoclonal bands are an independent predictor of the risk of a second attack when controlling for demographic, clinical, treatment, and MRI variables” and that in the absence of atypical CSF findings, demonstration of these CSF oligoclonal bands can allow for a diagnosis of MS to be made. The Panel remarks that inclusion of this CSF criterion can substitute for the traditional “dissemination in time” criterion, but that no laboratory test in isolation can confirm an MS diagnosis.

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.

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 Amendments. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

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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  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. 3Brettschneider 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.
  4. 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.
  5. Cantó, E., Barro, C., Zhao, C., Caillier, S. J., Michalak, Z., Bove, R., Kuhle, J. (2019). Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years. JAMA Neurol, 76(11), 1359 - 1366.
  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.
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  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.
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  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. Filippi, M., & Rocca, M. A. (2011). MR imaging of multiple sclerosis. Radiology, 259(3), 659- 681.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  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. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. Keegan BM. Therapeutic decision making in a new drug era in multiple sclerosis. Semin Neurol 2013; 33(1):5-12.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  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: https: //www.nationalmssociety.org/What-is-MS/Types-of-MS/Primary-progressive-MS. 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: https: //www.nationalmssociety.org/What-is-MS/Types-of-MS/Progressive-relapsing-MS. Accessed February 12, 2018.
  37. Olek M, Howard J. Clinical course and classification of multiple sclerosis - UpToDate. In J. Dashe (Ed.), UpToDate. Available at: https://www.uptodate.com/contents/clinical-presentation-course-and-prognosis-of-multiple-sclerosis-in-adults. Retrieved August 31, 2021.
  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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.
  49. Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Comi, G., Cohen, J. A. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol, 17(2), 162-173.
  50. 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.
  51. 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.
  52. 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.
  53. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014; 89(2):225-40.

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.

Medical Policy Group, August 2021 (9): Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.


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.