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Fingolimod as a first- or second-line treatment in a mini-series of young Hellenic patients with adolescent-onset multiple sclerosis: focus on immunological data

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Abstract

Background

Pediatric onset multiple sclerosis(POMS) is characterized by a highly active profile, often warranting treatment with high efficacy disease-modulating therapies (DMTs). Fingolimod, an oral sphingosine-1-phosphate receptor modulator, is the first Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved DMT for the treatment of POMS.

Object

Our aim is to present real-world data of seven fingolimod-treated POMS-patients, recruited in a single MS center in Greece.

Methods

Clinical and imaging/laboratory data from 7 Hellenic patients fulfilling the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for POMS diagnosis, who have received fingolimod treatment, were selected. Human leukocyte antigen (HLA) genoty** was performed with standard low-resolution sequence-specific oligonucleotide techniques.

Results

Three patients were treatment-naïve adolescents who received fingolimod as first-line treatment. Two experienced ongoing clinical and radiological disease activity and have been switched to natalizumab. The remaining cases were post-adolescent adults with POMS, where the vast majority experienced total/near-total disease remission. Fingolimod was generally well-tolerated. Two patients with high disease activity carried the HLA-DRB1*03 allele, while five patients were carriers of at least one of the HLA-DRB1*04, HLA-DRB1*13, and HLA-DRB1*14 alleles, which when not combined with HLA-DRB1*03 showed a trend towards a more favorable clinical course. Fingolimod responders showed a trend towards increased CD(16–56)+NK cell counts in immunophenoty** assays.

Conclusions

Our preliminary results support that response of POMS patients to fingolimod may be partially dependent on age and previous DMT, with younger and treatment-naïve patients presenting worse outcomes. The role of immunogenetics and immunophenoty** in personalized treatment warrants investigation in larger and more diverse populations.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Chitnis T, Glanz B, Jaffin S, Healy B (2009) Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler 15(5):627–631. https://doi.org/10.1177/1352458508101933

    Article  CAS  PubMed  Google Scholar 

  2. Harding KE, Liang K, Cossburn MD et al (2013) Long-term outcome of paediatric onset multiple sclerosis: a population based study. Neurol Neurosurg Psychiatry 84(2):141–147. https://doi.org/10.1136/jnnp-2012-303996

    Article  Google Scholar 

  3. Otallah S, Banwell B (2018) Pediatric multiple sclerosis: an update. Curr Neurol Neurosci Rep 18(11):76. https://doi.org/10.1007/s11910-018-0886-7

    Article  PubMed  Google Scholar 

  4. Chitnis T, Aaen G, Belman A et al (2020) Improved relapse recovery in paediatric compared to adult multiple sclerosis. Brain 143(9):2733–2741. https://doi.org/10.1093/brain/awaa199

    Article  PubMed  Google Scholar 

  5. Chitnis T, Arnold DL, Banwell B et al (2018) Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med 379(11):1017–1027. https://doi.org/10.1056/NEJMoa1800149

    Article  CAS  PubMed  Google Scholar 

  6. Arnold DL, Banwell B, Bar-Or A et al (2020) Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIG MS study. Neurol Neurosurg Psychiatry 91(5):483–492. https://doi.org/10.1136/jnnp-2019-322138

    Article  Google Scholar 

  7. Deiva K, Huppke P, Banwell B et al (2020) Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIG MS. J Neurol Neurosurg Psychiatry 91(1):58–66. https://doi.org/10.1136/jnnp-2019-321124

    Article  PubMed  Google Scholar 

  8. Chitnis T, Tenembaum S, Banwell B et al (2012) Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 18(1):116–127. https://doi.org/10.1177/1352458511430704

    Article  CAS  PubMed  Google Scholar 

  9. Ghezzi A, Moiola L, Pozzilli C et al (2015) Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol 25(15):174. https://doi.org/10.1186/s12883-015-0433-y

    Article  CAS  Google Scholar 

  10. Huppke P, Huppke B, Ellenberger D et al (2019) Therapy of highly active pediatric multiple sclerosis. Mult Scler 25(1):72–80. https://doi.org/10.1177/1352458517732843

    Article  PubMed  Google Scholar 

  11. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–9. https://doi.org/10.1038/nature10251

    Article  CAS  Google Scholar 

  12. Gontika M, Skarlis C, Artemiadis A et al (2020) HLA-DRB1 allele impact on pediatric multiple sclerosis in a Hellenic cohort. Mult Scler J Exp Transl Clin 6(1):2055217320908046. https://doi.org/10.1177/2055217320908046

    Article  PubMed  PubMed Central  Google Scholar 

  13. Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC et al (2013) International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 19(10):1261–1267. https://doi.org/10.1177/1352458513484547

    Article  PubMed  Google Scholar 

  14. Ziemssen T, Albrecht H, Haas J et al (2021) Descriptive analysis of real-world data on fingolimod long-term treatment of young adult RRMS patients. Front Neurol 3(12):637107. https://doi.org/10.3389/fneur.2021.637107

    Article  Google Scholar 

  15. Gärtner J, Chitnis T, Ghezzi A et al (2018) Relapse rate and MRI activity in young adult patients with multiple sclerosis: a post hoc analysis of phase 3 fingolimod trials. Mult Scler J Exp Transl Clin 4(2):2055217318778610. https://doi.org/10.1177/2055217318778610

    Article  PubMed  PubMed Central  Google Scholar 

  16. Amidei A, Siciliano G, Pasquali L (2021) Efficacy of fingolimod after switching from interferon β-1a in an adolescent with multiple sclerosis: case report. Neurol Sci 42(Suppl 1):5–7. https://doi.org/10.1007/s10072-021-05170-w

    Article  PubMed  Google Scholar 

  17. Ferilli MAN, Papetti L, Valeriani M (2021) Fingolimod in pediatric multiple sclerosis: three case reports. Neurol Sci 42(Suppl 1):19–23. https://doi.org/10.1007/s10072-021-05076-7

    Article  PubMed  Google Scholar 

  18. Immovilli P, Rota E, Morelli N, Guidetti D (2021) Two-year follow-up during fingolimod treatment in a pediatric multiple sclerosis patient still active on first-line treatment. Neurol Sci 42(Suppl 1):15–18. https://doi.org/10.1007/s10072-021-05058-9

    Article  PubMed  Google Scholar 

  19. Zanetta C, Filippi M, Moiola L (2021) Fingolimod as an effective therapeutic strategy for pediatric relapsing-remitting multiple sclerosis: two case reports. Neurol Sci 42(Suppl 1):9–13. https://doi.org/10.1007/s10072-021-05270-7

    Article  PubMed  Google Scholar 

  20. Capobianco M, Bertolotto A, Malucchi S (2021) Fingolimod as first-line treatment in pediatric-onset multiple sclerosis: a case report. Neurol Sci 42(Suppl 1):25–28. https://doi.org/10.1007/s10072-020-05027-8

    Article  PubMed  Google Scholar 

  21. Chitnis T, Banwell B, Krupp L et al (2020) Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: results from the PARADIG MS study. Mult Scler 7:1352458520936934. https://doi.org/10.1177/1352458520936934

    Article  CAS  Google Scholar 

  22. Mehling M, Brinkmann V, Antel J et al (2008) FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71(16):1261–7. https://doi.org/10.1212/01.wnl.0000327609.57688.ea

    Article  CAS  PubMed  Google Scholar 

  23. Wu X, Xue T, Wang Z et al (2021) Different doses of fingolimod in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 17(12):621856. https://doi.org/10.3389/fphar.2021.621856

    Article  CAS  Google Scholar 

  24. Cree BAC, Goldman MD, Corboy JR et al (2020) Efficacy and safety of 2 fingolimod doses vs glatiramer acetate for the treatment of patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA Neurol 78(1):1–13. https://doi.org/10.1001/jamaneurol.2020.2950

    Article  PubMed Central  Google Scholar 

  25. Longbrake EE, Kantor D, Pawate S et al (2018) Effectiveness of alternative dose fingolimod for multiple sclerosis. Neurol Clin Pract 8(2):102–107. https://doi.org/10.1212/CPJ.0000000000000434

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fragoso YD, Spelman T, Boz C et al (2018) Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod. Mult Scler Relat Disord 19:105–108. https://doi.org/10.1016/j.msard.2017.11.018

    Article  PubMed  Google Scholar 

  27. Boffa G, Bruschi N, Cellerino M et al (2020) Fingolimod and dimethyl-fumarate-derived lymphopenia is not associated with short-term treatment response and risk of infections in a real-life MS population. CNS Drugs 34(4):425–432. https://doi.org/10.1007/s40263-020-00714-8

    Article  CAS  PubMed  Google Scholar 

  28. Paolicelli D, Manni A, D’Onghia M et al (2017) Lymphocyte subsets as biomarkers of therapeutic response in fingolimod treated relapsing multiple sclerosis patients. J Neuroimmunol 15(303):75–80. https://doi.org/10.1016/j.jneuroim.2016.12.012

    Article  CAS  Google Scholar 

  29. Ghadiri M, Rezk A, Li R et al (2020) Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis. Sci Rep 10(1):356. https://doi.org/10.1038/s41598-019-57114-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mimpen M, Smolders J, Hupperts R, Damoiseaux J (2020) Natural killer cells in multiple sclerosis: a review. Immunol Lett 222:1–11. https://doi.org/10.1016/j.imlet.2020.02.012

    Article  CAS  PubMed  Google Scholar 

  31. Moreno-Torres I, González-García C, Marconi M et al (2018) Immunophenotype and transcriptome profile of patients with multiple sclerosis treated with fingolimod: setting up a model for prediction of response in a 2-year translational study. Front Immunol 25(9):1693. https://doi.org/10.3389/fimmu.2018.01693

    Article  CAS  Google Scholar 

  32. Johnson TA, Evans BL, Durafourt BA et al (2011) Reduction of the peripheral blood CD56(bright) NK lymphocyte subset in FTY720-treated multiple sclerosis patients. J Immunol 187(1):570–9. https://doi.org/10.4049/jimmunol.1003823

    Article  CAS  PubMed  Google Scholar 

  33. Anagnostouli MC, Velonakis G, Dalakas MC (2021) Aggressive herpes zoster in young patients with multiple sclerosis under dimethyl fumarate: significance of CD8+ and natural killer cells. Neurol Neuroimmunol Neuroinflamm 8(4):e1017. https://doi.org/10.1212/NXI.0000000000001017

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gontika MP, Anagnostouli MC (2018) Anti-myelin oligodendrocyte glycoprotein and human leukocyte antigens as markers in pediatric and adolescent multiple sclerosis: on diagnosis, clinical phenotypes, and therapeutic responses. Mult Scler Int 22(2018):8487471. https://doi.org/10.1155/2018/8487471

    Article  CAS  Google Scholar 

  35. De Silvestri A, Capittini C, Mallucci G et al (2019) The involvement of HLA class II alleles in multiple sclerosis: a systematic review with meta-analysis. Dis Markers 6(2019):1409069. https://doi.org/10.1155/2019/1409069

    Article  CAS  Google Scholar 

  36. DeLuca GC, Ramagopalan SV, Herrera BM et al (2007) An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus. Proc Natl Acad Sci U S A 104(52):20896–901. https://doi.org/10.1073/pnas.0707731105

    Article  PubMed  PubMed Central  Google Scholar 

  37. Imrell K, Landtblom AM, Hillert J, Masterman T (2006) Multiple sclerosis with and without CSF bands: clinically indistinguishable but immunogenetically distinct. Neurology 67(6):1062–4. https://doi.org/10.1212/01.wnl.0000237343.93389.35

    Article  PubMed  Google Scholar 

  38. Kikuchi S, Fukazawa T, Niino M et al (2003) HLA-related subpopulations of MS in Japanese with and without oligoclonal IgG bands Human leukocyte antigen. Neurology 60(4):647–51. https://doi.org/10.1212/01.wnl.0000048202.09147.9e

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Immunogenetics Laboratory, 1st Department of Neurology, Medical School, Aeginition University Hospital, National and Kapodistrian University of Athens, Vas. Sophias, 74, 115 28, Athens, Greece

    Maria Gontika, Charalampos Skarlis, Nikolaos Markoglou & Maria Anagnostouli

  2. Multiple Sclerosis and Demyelinating Diseases Unit, 1st, Department of Neurology, Medical School, Aeginition University Hospital, National and Kapodistrian University of Athens, Vas. Sophias, 74, 115 28, Athens, Greece

    Maria-Eleftheria Evangelopoulos & Maria Anagnostouli

  3. Research Unit of Radiology, 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    George Velonakis

  4. University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair On Adolescent Health Care, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece

    George P. Chrousos

  5. Neuroimmunology Unit, Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece

    Marinos Dalakas

  6. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

    Marinos Dalakas

  7. 1st Department of Neurology, Medical School, Aeginition University Hospital, National and Kapodistrian University of Athens, NKUA, Vas. Sophias, 74, 115 28, Athens, Greece

    Leonidas Stefanis & Maria Anagnostouli

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  1. Maria Gontika
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  9. Maria Anagnostouli
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Contributions

MG: major contribution in patients’ evaluation, acquisition, analysis and interpretation of the data, and manuscript preparation. CS: analysis and interpretation of the data and HLA genoty**. NM: patients’ evaluation and analysis and interpretation of the data. ME-E: patients’ evaluation, analysis and interpretation of the data, and revision of the manuscript. GV: major role in the acquisition of data, drafting, and revision of the manuscript for intellectual content, mainly on MRIs. GH: revised critically the manuscript for intellectual content. MD, GPS, and LS: revised the manuscript for intellectual content. MA: substantial contributions to the conception or design of the work, patients’ evaluation, and revision of the manuscript for intellectual content

All authors accepted the version to be submitted.

Corresponding author

Correspondence to Maria Anagnostouli.

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The study received ethical approval from the Hospital Ethics Committee, consistent with the Declaration of Helsinki.

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Informed consent was obtained from all individual participants included in the study and their legal guardians.

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Informed consent was obtained from all individual participants included in the study and their legal guardians.

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The authors declare no competing interests.

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Gontika, M., Skarlis, C., Markoglou, N. et al. Fingolimod as a first- or second-line treatment in a mini-series of young Hellenic patients with adolescent-onset multiple sclerosis: focus on immunological data. Neurol Sci 43, 2641–2649 (2022). https://doi.org/10.1007/s10072-021-05623-2

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