Questions of management of patients with hard-to-treat remitting multiple sclerosis

82 patients diagnosed with remitting multiple sclerosis, (MS) undergoing treatment with fingolimod were followed up for minimum 12 months at the Moscow Multiple Sclerosis Centre. The purpose of the follow-up was to evaluate the effects of fingolimod. 9 of 12 patients were subject to a comprehensive immunological examination to identify subpopulations of circulating T-cells. All patients were in clinical remission at the time of recruitment. All patients showed a significant decrease in the frequency of exacerbations during therapy with fingolimod. The disability status on the EDSS scale did not progress during the whole year of the follow-up. The therapy showed significant decrease in the production of IL-17 and the amount of TH17 cells in comparison with the control group, thus demonstrating a relevant decrease in the the autoimmune process activity. Withdrawal of fingolimod in 6-8 weeks was associated with normalization of the lymphocyte level in the peripheral blood due to drug elimination and wash-out of S1P receptors. However, given that wash-out of S1P receptors results in increased production of IL-17 and, consequently, higher BBB permeability, it is appropriate to name the disease reactivation as "rebound syndrome" which is primarily associated with a sharp increase in IL-17. This raises questions about management of patients who for various reasons need withdrawal of fingolimod therapy.

рассеянный склероз, инвалидизация обострения, финголимод, интерлейкин-17, препараты, изменяющие течение рассеянного склероза, multiple sclerosis, fingolimod, interleukin-17, multiple sclerosis disease modifying drugs, disability, exacerbation

1. Brinkmann V, Davis M, Heise C et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem., 2002. 277: 21453-21457.

2. Hla T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol. Res., 2003. 47 (5): 401-407.

3. Alvarez ST, Milstien S, Spiegel S. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab, 2007. 18: 300-7.

4. Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther, 2007. 115: 84-105.

5. Wheeler D, Bandaru VV, Calabresi PA, et al. A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain, 2008. 131: 3092-3102.

6. Kulakowska A, Zendzian-Piotrowska M, Baranowski M et al. Intrathecal increase of sphingosine 1-phosphate at early stage multiple sclerosis. Neurosci Lett., 2010. 477: 149-152.

7. Van Doorn R, Van Horssen J, Verzijl D et al. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia, 2010. 58: 1465-1476.

8. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol., 2004. 22: 745-63.

9. Miron VE, Schubart A, Antel JP. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci., 2008. 274: 13-17.

10. Бойко А.Н. Рекомендации по использованию препарата финголимод (Гилениа). Медицинский совет, 2012. 4: 3-10.

11. Kappos L, O'Connor P, Radue EW et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology, 2015; 84(15): 1582-1591.