Background: Glatiramer acetate (GA) is an effective treatment for the earliest stages of multiple sclerosis (MS)-clinically isolated syndrome (CIS) or clinically definite MS (CDMS). Objective: This study aims to determine the differences in the lymphocyte population (at baseline and the course of five years) between confirmed sustained progression (CSP) and non-CSP groups and to identify potential biomarkers among these parameters that can predict a positive response to the treatment. Methods: Twelve male and 60 female patients were included in the study. Peripheral blood samples were collected before and five years after treatment with GA. The authors compared lymphocyte parameters between the CSP and non-CSP groups by statistical analyses. Univariate and penalized logistic regression models were fitted to identify the best lymphocyte parameters at baseline and their combination for potential biomarkers. Subsequently, the ROC analysis was used to identify cut-offs for selected parameters. Results: The parameter CD4+/CD45RO+ was identified as the best single potential biomarker, demonstrating the ability to identify patients with CSP. Moreover, a combination of four lymphocyte parameters at baseline, relative lymphocyte counts, CD3+/CD69+, CD4+/CD45RO+, and CD4+/CD45RA+ab, was identified as a potential composite biomarker. This combination explains 23% of the variability in CSP, which is better than the best univariate parameter when compared to CD4+/CD45RO+ at baseline. Conclusions: The results suggest that other biomarkers can help monitor the conditions of patients and predict a favourable outcome.

Department of Clinical Immunology and Allergology University Hospital Hradec Králové Sokolská 581 500 05 Hradec Králové Czech Republic

Department of Neurology Faculty of Medicine and University Hospital Hradec Králové Charles University Prague Sokolská 581 500 05 Hradec Králové Czech Republic

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Boneschi F.M., Rovaris M., Johnson K.P., Miller A., Wolinsky J.S., Ladkani D., Shifroni G., Comi G., Filippi M. Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: Meta-analysis of three double-blind, randomized, placebo-controlled clinical trials. Mult. Scler. J. 2003;9:349–355. doi: 10.1191/1352458503ms932oa. PubMed DOI

Comi G., Martinelli V., Rodegher M., Moiola L., Bajenaru O., Carra A., Elovaara I., Fazekas F., Hartung H.P., Hillert J., et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): A randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1503–1511. doi: 10.1016/S0140-6736(09)61259-9. PubMed DOI

Khan O., Rieckmann P., Boyko A., Selmaj K., Zivadinov R., GALA Study Group Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann. Neurol. 2013;73:705–713. doi: 10.1002/ana.23938. PubMed DOI

Khan O., Rieckmann P., Boyko A., Selmaj K., Ashtamker N., Davis M.D., Kolodny S., Zivadinov R. Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study. Mult. Scler. 2017;23:818–829. doi: 10.1177/1352458516664033. PubMed DOI

Schrempf W., Ziemssen T. Glatiramer acetate: Mechanisms of action in multiple sclerosis. Autoimmun. Rev. 2007;6:469–475. doi: 10.1016/j.autrev.2007.02.003. PubMed DOI

Veugelers P., Fisk J., Brown M., Stadnyk K., Sketris I., Murray T., Bhan V., Sketris I. Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: A longitudinal population-based evaluation. Mult. Scler. J. 2009;15:1286–1294. doi: 10.1177/1352458509350307. PubMed DOI

Ford C., Goodman A.D., Johnson K., Kachuck N., Lindsey J.W., Lisak R., Luzzio C., Myers L., Panitch H., Preiningerova J., et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: Results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult. Scler. 2010;16:342–350. doi: 10.1177/1352458509358088. PubMed DOI PMC

Munari L., Lovati R., Boiko A. Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst. Rev. 2004:CD004678. doi: 10.1002/14651858.CD004678. PubMed DOI

Polman C.H., Reingold S.C., Edan G., Filippi M., Hartung H.-P., Kappos L., Lublin F.D., Metz L.M., McFarland H.F., O’Connor P.W., et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 2005;58:840–846. doi: 10.1002/ana.20703. PubMed DOI

Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M., Fujihara K., Havrdova E.K., Hutchinson M., Kappos L., et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann. Neurol. 2011;69:292–302. doi: 10.1002/ana.22366. PubMed DOI PMC

Vališ M., Vyšata O., Sobíšek L., Klímová B., Andrýs C., Vokurková D., Pavelek Z. Monitoring of Lymphocyte Populations During Treatment with Interferon-β-1b to Predict Multiple Sclerosis Disability Progression. J. Interferon Cytokine Res. 2018;39:164–173. doi: 10.1089/jir.2018.0100. PubMed DOI

R Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; Vienna, Austria: 2017.

Friedman J.H., Hastie T., Tibshirani R. Regularization Paths for Generalized Linear Models via Coordinate Descent. J. Stat. Softw. 2010;33:1–22. doi: 10.18637/jss.v033.i01. PubMed DOI PMC

Barrau M.A., Montalban X., Sáez-Torres I., Brieva L., Barberà N., Martínez-Cáceres E.M. CD4(+)CD45RO(+)CD49d(high) cells are involved in the pathogenesis of relapsing-remitting multiple sclerosis. J. Neuroimmunol. 2000;111:215–223. doi: 10.1016/S0165-5728(00)00357-X. PubMed DOI

Beynon V., Quintana F.J., Weiner H.L. Activated human CD4+CD45RO+ memory T-cells indirectly inhibit NLRP3 inflammasome activation through downregulation of P2X7R signalling. PLoS ONE. 2012;7:e39576. doi: 10.1371/journal.pone.0039576. PubMed DOI PMC

Blanco Y., Moral E., Costa M., Gómez-Choco M., Torres-Peraza J., Alonso-Magdalena L., Alberch J., Jaraquemada D., Arbizu T., Graus F., et al. Effect of glatiramer acetate (Copaxone®) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: A longitudinal study. Neurosci. Lett. 2006;406:270–275. doi: 10.1016/j.neulet.2006.07.043. PubMed DOI

Pavelek Z., Vyšata O., Sobíšek L., Klímová B., Andrýs C., Vokurková D., Mazurová R., Štourač P., Vališ M. Lymphocyte populations and their change during five-year glatiramer acetate treatment. Neurol. Neurochir. Pol. 2018;52:587–592. doi: 10.1016/j.pjnns.2018.08.001. PubMed DOI

Valenzuela R.M., Kaufman M., Balashov K.E., Ito K., Buyske S., Dhib-Jalbut S. Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis. J. Neuroimmunol. 2016;15:59–65. doi: 10.1016/j.jneuroim.2016.06.005. PubMed DOI

Mindur J.E., Valenzuela R.M., Yadav S.K., Boppana S., Dhib-Jalbut S., Ito K. IL-27: A potential biomarker for responders to glatiramer acetate therapy. J. Neuroimmunol. 2017;15:21–28. doi: 10.1016/j.jneuroim.2016.07.004. PubMed DOI

Kruszewski A.M., Rao G., Tatomir A., Hewes D., Tegla C.A., Cudrici C.D., Nguyen V., Royal W., 3rd, Bever C.T., Jr., Rus V., et al. RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp. Mol. Pathol. 2015;99:498–505. doi: 10.1016/j.yexmp.2015.09.007. PubMed DOI PMC

Tatomir A., Talpos-Caia A., Anselmo F., Kruszewski A.M., Boodhoo D., Rus V., Rus H. The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis. Immunol. Res. 2017;65:1103–1109. doi: 10.1007/s12026-017-8961-8. PubMed DOI PMC

Hewes D., Tatomir A., Kruszewski A.M., Rao G., Tegla C.A., Ciriello J., Nguyen V., Royal W., 3rd, Bever C.T., Jr., Rus V., et al. SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis. Exp. Mol. Pathol. 2017;102:191–197. doi: 10.1016/j.yexmp.2017.01.014. PubMed DOI

Ciriello J., Tatomir A., Hewes D., Boodhoo D., Anselmo F., Rus V., Rus H. Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp. Mol. Pathol. 2018;105:175–180. doi: 10.1016/j.yexmp.2018.07.008. PubMed DOI

Tumani H., Kassubek J., Hijazi M., Lehmensiek V., Unrath A., Süssmuth S., Lauda F., Kapfer T., Fang L., Senel M., et al. Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate. Eur. Neurol. 2011;65 doi: 10.1159/000324035. PubMed DOI

Lublin F.D., Reingold S.C., Cohen J.A., Cutter G.R., Sørensen P.S., Thompson A.J., Wolinsky J.S., Balcer L.J., Banwell B., Barkhof F., et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83:278–286. doi: 10.1212/WNL.0000000000000560. PubMed DOI PMC

Zetterberg H., Teunissen C. Fluid biomarkers for disease activity in multiple sclerosis. Mult. Scler. J. 2017;23:1660–1661. doi: 10.1177/1352458517736151. PubMed DOI