Molecular biomarkers in multiple sclerosis
Abstract
Multiple sclerosis (MS) is a highly heterogenous disease regarding radiological, pathological, and clinical characteristics and therapeutic response, including both the efficacy and safety profile of treatments. Accordingly, there is a high demand for biomarkers that sensitively and specifically apprehend the distinctive aspects of the MS heterogeneity, and that can aid in better understanding of the disease diagnosis, prognosis, prediction of the treatment response, and, finally, in the development of new treatments. Currently, clinical characteristics (e.g., relapse rate and disease progression) and magnetic resonance imaging play the most important role in the clinical classification of MS and assessment of its course. Molecular biomarkers (e.g., immunoglobulin G (IgG) oligoclonal bands, IgG index, anti-aquaporin-4 antibodies, neutralizing antibodies against interferon-beta and natalizumab, anti-varicella zoster virus and anti-John Cunningham (JC) virus antibodies) complement these markers excellently. This review provides an overview of exploratory, validated and clinically useful molecular biomarkers in MS which are used for prediction, diagnosis, disease activity and treatment response.
References
Van Den Hoogen WJ, Laman JD,T Hart BA. Modulation of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis by food and gut microbiota. Front Immunol. 2017;8:1081.
Grigoriadis N, Pesch V. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015;22(S2):3-13.
Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol. 2014;13(1):113-126.
Group BDW, Atkinson Jr AJ, Colburn WA, Degruttola VG, Demets DL, Downing GJet al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharm Therap. 2001;69(3):89-95.
Ziemssen T, Akgün K,Brück W. Molecular biomarkers in multiple sclerosis. J Neuroinflammation. 2019;16(1):1-11.
Paul A, Comabella M,Gandhi R. Biomarkers in multiple sclerosis. Cold Spring Harbor perspectives in medicine. 2019;9(3):a029058.
Ottervald J, Franzén B, Nilsson K, Andersson LI, Khademi M, Eriksson Bet al. Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers. J Proteom. 2010;73(6):1117-1132.
Guerau-De-Arellano M, Alder H, Ozer HG, Lovett-Racke A,Racke MK. miRNA profiling for biomarker discovery in multiple sclerosis: from microarray to deep sequencing. J Neuroimmunol. 2012;248(1-2):32-39.
Del Boccio P, Pieragostino D, Lugaresi A, Di Ioia M, Pavone B, Travaglini Det al. Cleavage of cystatin C is not associated with multiple sclerosis. Ann Neurol. 2007;62(2):201-204.
Lindsey JW, Crawford MP,Hatfield LM. Soluble Nogo-A in CSF is not a useful biomarker for multiple sclerosis. Neurology. 2008;71(1):35-37.
Waschbisch A, Sandbrink R, Hartung H-P, Kappos L, Schwab S, Pohl Cet al. Evaluation of soluble HLA-G as a biomarker for multiple sclerosis. Neurology. 2011;77(6):596-598.
Bushnell S, Zhao Z, Stebbins C, Cadavid D, Buko A, Whalley Eet al. Serum IL-17F does not predict poor response to IM IFNβ-1a in relapsing-remitting MS. Neurology. 2012;79(6):531-537.
Whitaker JN, Williams PH, Layton BA, Mcfarland HF, Stone LA, Smith Met al. Correlation of clinical features and findings on cranial magnetic resonance imaging with urinary myelin basic protein‐like material in patients with multiple sclerosis. Ann Neurol. 1994;35(5):577-585.
Lund SA, Giachelli CM,Scatena M. The role of osteopontin in inflammatory processes. J Cell Commun Signal. 2009;3(3):311-322.
Ram M, Sherer Y,Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol. 2006;26(4):299-307.
Disanto G, Adiutori R, Dobson R, Martinelli V, Dalla Costa G, Runia Tet al. Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome. J Neurol Neurosurg Psychiatry. 2016;87(2):126-129.
Martínez MaM, Olsson B, Bau L, Matas E, Calvo ÁC, Andreasson Uet al. Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis. Mult Scler J. 2015;21(5):550-561.
Arrambide G, Espejo C, Eixarch H, Villar LM, Alvarez-Cermeño JC, Picón Cet al. Neurofilament light chain level is a weak risk factor for the development of MS. Neurology. 2016;87(11):1076-1084.
Barro C, Benkert P, Disanto G, Tsagkas C, Amann M, Naegelin Yet al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018;141(8):2382-2391.
Kuhle J, Nourbakhsh B, Grant D, Morant S, Barro C, Yaldizli Öet al. Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology. 2017;88(9):826-831.
Harris VK, Tuddenham JF,Sadiq SA. Biomarkers of multiple sclerosis: current findings. Degenerative neurological and neuromuscular disease. 2017;7:19.
Gafson AR,Giovannoni G. Towards the incorporation of lumbar puncture into clinical trials for multiple sclerosis. Mult Scler J. 2012;18(10):1509-1511.
Ziegler A, Koch A, Krockenberger K,Großhennig A. Personalized medicine using DNA biomarkers: a review. Hum Genet. 2012;131(10):1627-1638.
Sundström P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nyström Let al. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology. 2004;62(12):2277-2282.
De Jager P, Simon K, Munger K, Rioux J, Hafler D,Ascherio A. Integrating risk factors: HLA-DRB1* 1501 and Epstein–Barr virus in multiple sclerosis. Neurology. 2008;70(13 Part 2):1113-1118.
Hedström AK, Huang J, Michel A, Butt J, Brenner N, Hillert Jet al. High levels of Epstein–Barr virus nuclear antigen-1-specific antibodies and infectious mononucleosis act both independently and synergistically to increase multiple sclerosis risk. Front Neurol. 2020;10:1368.
Monson NL, Brezinschek H-P, Brezinschek RI, Mobley A, Vaughan GK, Frohman EMet al. Receptor revision and atypical mutational characteristics in clonally expanded B cells from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients. J Neuroimmunol. 2005;158(1):170-181.
Lefvert AK,Link H. IgG production within the central nervous system: a critical review of proposed formulae. Ann Neurol. 1985;17(1):13-20.
Ziemssen T, Akgün K,Brück W. Molecular biomarkers in multiple sclerosis. J Neuroinflammation. 2019;16(1):272-272.
Holmøy T. The Discovery of Oligoclonal Bands: A 50-Year Anniversary. Eur Neurol. 2009;62(5):311-315.
Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir Get al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62(6):865-70.
Keir G, Luxton RW,Thompson EJ. Isoelectric focusing of cerebrospinal fluid immunoglobulin G: an annotated update. Ann Clin Biochem. 1990;27 ( Pt 5):436-43.
Ohman S, Ernerudh J, Forsberg P, Henriksson A, Von Schenck H,Vrethem M. Comparison of seven formulae and isoelectrofocusing for determination of intrathecally produced IgG in neurological diseases. Ann Clin Biochem. 1992;29 ( Pt 4):405-10.
Petzold A. Intrathecal oligoclonal IgG synthesis in multiple sclerosis. J Neuroimmunol. 2013;262(1):1-10.
Poser CM, Paty DW, Scheinberg L, Mcdonald WI, Davis FA, Ebers GCet al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann Neurol. 1983;13(3):227-231.
Mcdonald WI, Compston A, Edan G, Goodkin D, Hartung H-P, Lublin FDet al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-127.
Polman CH, Reingold SC, Edan G, Filippi M, Hartung H-P, Kappos Let al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58(6):840-846.
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi Get al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi Met al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
Link H,Huang Y-M. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol. 2006;180(1-2):17-28.
Makhani N, Lebrun C, Siva A, Narula S, Wassmer E, Brassat Det al. Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome. Mult Scler J Exp Transl Clin. 2019;5(1):2055217319836664-2055217319836664.
Ziemssen T,Ziemssen F. The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Autoimmun Rev. 2005;4(7):460-467.
Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ,Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.
Flanagan EP, Cabre P, Weinshenker BG, Sauver JS, Jacobson DJ, Majed Met al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.
Waters PJ, Pittock SJ, Bennett JL, Jarius S, Weinshenker BG,Wingerchuk DM. Evaluation of aquaporin-4 antibody assays. Clin Exp Neuroimmunol. 2014;5(3):290-303.
Thangarajh M, Gomez-Rial J, Hedstrom AK, Hillert J, Alvarez-Cermeno JC, Masterman Tet al. Lipid-specific immunoglobulin M in CSF predicts adverse long-term outcome in multiple sclerosis. Mult Scler. 2008;14(9):1208-13.
De Biasi S, Simone AM, Bianchini E, Lo Tartaro D, Pecorini S, Nasi Met al. Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients. Eur J Immunol. 2019;49(12):2204-2221.
Sadaba MC, Tzartos J, Paino C, Garcia-Villanueva M, Alvarez-Cermeno JC, Villar LMet al. Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions. J Neuroimmunol. 2012;247(1-2):86-94.
Hinsinger G, Galeotti N, Nabholz N, Urbach S, Rigau V, Demattei Cet al. Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler. 2015;21(10):1251-61.
Borras E, Canto E, Choi M, Maria Villar L, Alvarez-Cermeno JC, Chiva Cet al. Protein-Based Classifier to Predict Conversion from Clinically Isolated Syndrome to Multiple Sclerosis. Mol Cell Proteomics. 2016;15(1):318-28.
Burman J, Raininko R, Blennow K, Zetterberg H, Axelsson M,Malmeström C. YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis. J Neuroimmunol. 2016;292:52-57.
Canto E, Tintore M, Villar LM, Costa C, Nurtdinov R, Alvarez-Cermeno JCet al. Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes. Brain. 2015;138(4):918-931.
Correale J,Fiol M. Chitinase effects on immune cell response in neuromyelitis optica and multiple sclerosis. Mult Scler J. 2011;17(5):521-531.
Modvig S, Degn M, Horwitz H, Cramer SP, Larsson HB, Wanscher Bet al. Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis. PloS one. 2013;8(10):e77163.
Hinsinger G, Galéotti N, Nabholz N, Urbach S, Rigau V, Demattei Cet al. Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler J. 2015;21(10):1251-1261.
Ingram G, Hakobyan S, Robertson N, Morgan BP. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009;155(2):128-139.
Abarca-Zabalía J, García MI, Lozano Ros A, Marín-Jiménez I, Martínez-Ginés ML, López-Cauce B et al. Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn's Disease. Int J Mol Sci. 2020;21(2):1-14.
Tatomir A, Talpos-Caia A, Anselmo F, Kruszewski AM, Boodhoo D, Rus Vet al. The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis. Immunol Res. 2017;65(6):1103-1109.
Ingram G, Hakobyan S, Hirst CL, Harris CL, Loveless S, Mitchell JPet al. Systemic complement profiling in multiple sclerosis as a biomarker of disease state. Mult Scler. 2012;18(10):1401-11.
Ingram G, Hakobyan S, Hirst CL, Harris CL, Pickersgill TP, Cossburn MDet al. Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain. 2010;133(6):1602-1611.
Hakobyan S, Luppe S, Evans DR, Harding K, Loveless S, Robertson NPet al. Plasma complement biomarkers distinguish multiple sclerosis and neuromyelitis optica spectrum disorder. Mult Scler. 2017;23(7):946-955.
Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick Met al. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol. 2017;264(3):453-466.
Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek Vet al. IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One. 2009;4(11):e7638.
Órpez-Zafra T, Pavía J, Hurtado-Guerrero I, Pinto-Medel MJ, Rodriguez Bada JL, Urbaneja Pet al. Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Mult Scler. 2017;23(7):937-945.
Shi Y, Ding Y, Li G, Wang L, Osman RA, Sun Jet al. Discovery of Novel Biomarkers for Diagnosing and Predicting the Progression of Multiple Sclerosis Using TMT-Based Quantitative Proteomics. Front Immunol. 2021;12:700031.
Islas-Hernandez A, Aguilar-Talamantes HS, Bertado-Cortes B, Mejia-Delcastillo GJ, Carrera-Pineda R, Cuevas-Garcia CFet al. BDNF and Tau as biomarkers of severity in multiple sclerosis. Biomark Med. 2018;12(7):717-726.
Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg Fet al. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler. 2011;17(3):335-43.
Amor S,Giovannoni G. Antibodies to myelin oligodendrocyte glycoprotein as a biomarker in multiple sclerosis — are we there yet? Multiple Sclerosis Journal. 2007;13(9):1083-1085.
Lalive PH, Menge T, Delarasse C, Della Gaspera B, Pham-Dinh D, Villoslada Pet al. Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis. Proc Natl Acad Sci U S A. 2006;103(7):2280-5.
Deisenhammer F, Zetterberg H, Fitzner B,Zettl UK. The Cerebrospinal Fluid in Multiple Sclerosis. Front Immunol. 2019;10:726-726.
Jarius S, Paul F, Aktas O, Asgari N, Dale RC, De Seze Jet al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation. 2018;15(1):134.
Spadaro M, Gerdes LA, Krumbholz M, Ertl-Wagner B, Thaler FS, Schuh Eet al. Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol.: Neuroimmunol. NeuroInflammation. 2016;3(5).
Höftberger R,Lassmann H, Chapter 19 - Inflammatory demyelinating diseases of the central nervous system, in Handbook of Clinical Neurology, G.G. Kovacs and I. Alafuzoff, Editors. 2018, Elsevier. p. 263-283.
Papp V, Langkilde AR, Blinkenberg M, Schreiber K, Jensen PEH,Sellebjerg F. Clinical utility of anti-MOG antibody testing in a Danish cohort. Mult Scler Relat Disord. 2018;26:61-67.
Tomassini V, De Giglio L, Reindl M, Russo P, Pestalozza I, Pantano Pet al. Anti-myelin antibodies predict the clinical outcome after a first episode suggestive of MS. Mult Scler. 2007;13(9):1086-94.
Abzalimov RR, Kaplan DA, Easterling ML,Kaltashov IA. Protein conformations can be probed in top-down HDX MS experiments utilizing electron transfer dissociation of protein ions without hydrogen scrambling. J Am Soc Mass Spectrom. 2009;20(8):1514-1517.
Massaro AR, De Pascalis D, Carnevale A,Carbone G. The neural cell adhesion molecule (NCAM) present in the cerebrospinal fluid of multiple sclerosis patients is unsialylated. Eur Rev Med Pharmacol Sci. 2009;13(5):397-9.
Massaro AR. The role of NCAM in remyelination. Neurological Sciences. 2002;22(6):429-435.
Gnanapavan S, Grant D, Illes-Toth E, Lakdawala N, Keir G,Giovannoni G. Neural cell adhesion molecule--description of a CSF ELISA method and evidence of reduced levels in selected neurological disorders. J Neuroimmunol. 2010;225(1-2):118-22.
Strekalova H, Buhmann C, Kleene R, Eggers C, Saffell J, Hemperly J et al. Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes. Neurobiol Aging. 2006;27(1):1-9.
Yuan A, Rao MV,Nixon RA. Neurofilaments at a glance. J Cell Sci. 2012;125(14):3257-3263.
Karlsson Je RL, Haglid Kg. Quantitative and qualitative alterations of neuronal and glial intermediate filaments in rat nervous system after exposure to 2,5-hexanedione. J Neurochem. 1991;5(Oct):1437-1444.
Novakova L ZH, Sundström P, Axelsson M, Khademi M, Gunnarsson M, Malmeström C, Svenningsson a, Olsson T, Piehl F, Blennow K, Lycke J. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017;Nov 28(89(22)):2230-2237.
Amor S VDSB, Bosca I, Raffel J, Gnanapavan S, Watchorn J, Kuhle J, Giovannoni G, Baker D, Malaspina a, Puentes F. Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis. Mult Scler. 2014;Sept(20(10)):1355-1362.
Akgün K KN, Haase R, Proschmann U, Kitzler Hh, Reichmann H, Ziemssen T. Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS. Neurol Neuroimmunol Neuroinflamm. 2019;May(6(3)):e555.
Van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra C, Van Der Valk Pet al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med. 2008;45(12):1729-1737.
Graversen JH, Madsen M,Moestrup SK. CD163: a signal receptor scavenging haptoglobin–hemoglobin complexes from plasma. Int J Biochem Cell Biol. 2002;34(4):309-314.
Stilund M, Reuschlein AK, Christensen T, Moller HJ, Rasmussen PV,Petersen T. Soluble CD163 as a marker of macrophage activity in newly diagnosed patients with multiple sclerosis. PLoS One. 2014;9(6):e98588.
Chwojnicki K, Iwaszkiewicz-Grześ D, Jankowska A, Zieliński M, Łowiec P, Gliwiński M et al. Administration of CD4 + CD25 high CD127 - FoxP3 + Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study. BioDrugs. 2021;35(1):47-60.
Pette M, Fujita K, Kitze B, Whitaker JN, Albert E, Kappos Let al. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology. 1990;40(11):1770-6.
Gafson A, Craner MJ,Matthews PM. Personalised medicine for multiple sclerosis care. Mult Scler J. 2017;23(3):362-369.
Nikfar S RR, Abdollahi M. A meta-analysis of the efficacy and tolerability of interferon-β in multiple sclerosis, overall and by drug and disease type. Clin Ther. 2010;2010 Oct;32(11):1871-88.
Rudick RA, Lee JC, Simon J, Ransohoff RM,Fisher E. Defining interferon β response status in multiple sclerosis patients. Ann Neurol. 2004;56(4):548-555.
Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam Ret al. Occurrence of anti-drug antibodies against interferon-beta and natalizumab in multiple sclerosis: a collaborative cohort analysis. PloS one. 2016;11(11):e0162752.
Dunn N, Fogdell-Hahn A, Hillert J,Spelman T. Long-Term Consequences of High Titer Neutralizing Antibodies to Interferon-β in Multiple Sclerosis. Front Immunol. 2020;11.
Deisenhammer F, Schellekens, H. & Bertolotto. Measurement of neutralizing antibodies to interferon beta in patients with multiple sclerosis. J Neurol. 2004;251:ii31–ii39.
Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung H-P, Hemmer Bet al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010;9(7):740-750.
Bertolotto A, Gilli F, Sala A, Audano L, Castello A, Magliola Uet al. Evaluation of bioavailability of three types of IFNβ in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification. J Immunol Methods. 2001;256(1-2):141-152.
Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri Let al. Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology. 2008;70(13 Part 2):1119-1127.
Yednock T.A. CC, Fritz L.C., Sanchez-Madrid F., Steinmant L. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature. 1992;356:63-66.
Mattoscio M NR, Sormani Mp. Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis. Neurology. 2015;84(14):1473-1482.
Vennegoor A RT, Mrijbis E, Seewann a, Uitdehaag Bm, Balk Lj. Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis. Mult Scler J. 2012;19:593-600.
Sehr T, Proschmann U, Thomas K, Marggraf M, Straube E, Reichmann Het al. New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies. J Neuroinflammation. 2016;13(1):1-11.
Hegen H AM, Deisenhammer F. Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients. Drugs. 2016;76:1421-1445.
Sehr T PU, Thomas K, Marggraf M, Straube E, Reichmann H. New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies. J Neuroinflammation. 2016;13:164.
Kaufmann M HR, Proschmann U, Ziemssen T, AkgüN K. Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long- Term Follow Up. Front Neurol. 2018;9:1071.
Deisenhammer F JM, Lauren a, Sj Din a, Ryner M, Fogdell-Hahn A. Prediction of natalizumab anti-drug antibodies persistency. Multiple Scler Houndmills Basingstoke Engl. 2018;1352458517753721.
Link J RR, Auer M, Ryner M, H Ssler S, Bachelet D. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results. PLoS One. 2017;12:e0170395.
Calabresi P GG, Confavreux C, Galetta S, Havrdova E, Hutchinson,M. The incidence and significance of anti-natalizumab antibodies:
Results from AFFIRM and SENTINEL. Neurology. 2007;69(1):391-400.
Khademi M KI, Andersson Ml, Iacobaeus E, Brundin L, Sellebjerg F, Hillert J, Piehl F, Olsson T. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler. 2011;17(3):335-343.
Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström Cet al. Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing‐remitting multiple sclerosis. J Neurochem. 2017;141(2):296-304.
Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström Cet al. Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis. Mult Scler J. 2017;23(1):62-71.
Uher T, Horakova D, Tyblova M, Zeman D, Krasulova E, Mrazova Ket al. Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later. Mult Scler. 2016;22(6):770-81.
Klesney-Tait J, Turnbull IR,Colonna M. The TREM receptor family and signal integration. Nat Immunol. 2006;7(12):1266-73.
Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia Fet al. Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci. 2004;20(10):2617-28.
Öhrfelt A, Axelsson M, Malmeström C, Novakova L, Heslegrave A, Blennow Ket al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult Scler J. 2016;22(12):1587-1595.
A. Bellizzi CN, E. Anzivino, D. Rodio, D. Fioriti, M. Mischitelli, F. Chiarini, V. Pietropaolo. Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies. J Neurovirol. 2012;18:1-11.
C.S. Tan YC, R.P. Viscidi, R.P. Kinkel, M.C. Stein, I.J. Koralnik. Discrepant findings in immune responses to JC virus in patients receiving natalizumab. Lancet Neurol. 2010;9:565-566.
Mcgavern DB,Kang SS. Illuminating viral infections in the nervous system. Nat Rev Immunol. 2011;11(5):318-329.
Gorelik L LM, Bixler S, Crossman M, Schlain B, Simon K, Pace a, Cheung a, Chen Ll, Berman M, Zein F, Wilson E, Yednock T, Sandrock a, Goelz Se, Subramanyam M. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68(3):295-303.
Antoniol C,Stankoff B. Immunological Markers for PML Prediction in MS Patients Treated with Natalizumab. Front Immunol. 2014;5:668.
Bozic C, Subramanyam M, Richman S, Plavina T, Zhang A,Ticho B. Anti‐JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol. 2014;21(2):299-304.
Matko S AK, Tonn T, Ziemssen T, Odendahl M. Antigen-shift in varicella-zoster virus-specific T-cell immunity over the course of Fingolimod-treatment in relapse-remitting multiple sclerosis patients. Mult Scler Relat Disord. 2020;Feb(38):101859.
Arvin Am WJ, Kappos L, Morris Mi, Reder at, Tornatore C, Gershon a, Gershon M, Levin Mj, Bezuidenhoudt M, Putzki N. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72(1)(Jan):31-39.
Ziemssen T TK. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10(10)(Oct):343-359.
Cook S LT, Comi G, Montalban X, Giovannoni G, Nolting a, Hicking C, Galazka a, Sylvester E. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis. Mult Scler Relat Disord. 2019;Apr(29):157-167.
Schwab N S-HT, Posevitz V, Breuer J, Göbel K, Windhagen S, Brochet B, Vermersch P, Lebrun-Frenay C, Posevitz-Fejfár a, Capra R, Imberti L, Straeten V, Haas J, Wildemann B, Havla J, Kümpfel T, Meinl I, Niessen K, Goelz S, Kleinschnitz C, Warnke C, Buck D, Gold R, Kieseier Bc, Meuth Sg, Foley J, Chan a, Brassat D, Wiendl H. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology. 2013;Sep 3(81(10)):865-871.
Schwab N S-HT, Pignolet B, Spadaro M, Görlich D, Meinl I, Windhagen S, Tackenberg B, Breuer J, Cantó E, Kümpfel T, Hohlfeld R, Siffrin V, Luessi F, Posevitz-Fejfár a, Montalban X, Meuth Sg, Zipp F, Gold R, Du Pasquier Ra, Kleinschnitz C, Jacobi a, Comabella M, Bertolotto a, Brassat D, Wiendl H. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler. 2016;July(22(8)):1048-1060.
Schwab N S-HT, Wiendl H. CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients. Schwab N, Schneider-Hohendorf T, Wiendl H. 2016;30(Aug):958-9.
