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The Transition From First-Line to Second-Line Therapy in Multiple Sclerosis

  • Multiple Sclerosis and Related Disorders (P Villoslada, Section Editor)
  • Published:
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Opinion statement

Sufficient control of disease activity in multiple sclerosis (MS) patients, particularly in the early phase of the disease, is crucial for the prevention of an unfavorable outcome. While currently available disease modifying drugs are generally clearly assigned as first-line or second-line treatment, no universal guidelines exist that help in the real world setting to decide when and how exactly a transition from first-line to second-line therapy should be initiated. Furthermore, the concept of first and second-line therapies is constantly evolving. In order to facilitate evidence-based decision making in this common situation, we here summarize existing data on the optimization of treatment when the first-line drug needs to be switched. Obviously, a switch of treatment starts with an exploration of the motivation to switch, which usually may be ascribed to either inadequate treatment response or tolerability, safety, or adherence issues. In the latter situation, intra class switching, e.g., from interferon (IFN) beta to glatiramer acetate (GA) or, in case of aversion against injectables, from GA/IFN beta to one of the new orals dimethylfumarate or teriflunomide can be a reasonable option. If treatment failure is the reason for a switch, existing data suggest that escalation to a more powerful drug such as natalizumab, fingolimod or even alemtuzumab is more appropriate. Of note, in some drugs, different formal approvals apply in different countries. For example, while fingolimod is approved as second-line therapy in the European Union, it can be used as first-line drug in the United States and in Switzerland. The flip side of these more powerful drugs might be a less favorable risk-benefit ratio. As long as data are not yet sufficient to allow a direct comparison of efficacy among second-line drugs, the treatment decision should be primarily based on the individual situation and risk profile of the patient.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis—a quiet revolution. Nat Rev Neurol. 2015;11:134–42. Comprehensive review on the achievements of drug therapy in MS over the last two decades.

  2. Sinnecker T, Mittelstaedt P, Dörr J, Pfueller CF, Harms L, Niendorf T, et al. Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol. 2012;69:739–45.

    Article  PubMed  Google Scholar 

  3. Oberwahrenbrock T, Ringelstein M, Jentschke S, Deuschle K, Klumbies K, Bellmann-Strobl J, et al. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler J. 2013;19:1887–95.

    Article  Google Scholar 

  4. Filippi M, van den Heuvel MP, Fornito A, He Y, Hulshoff Pol HE, Agosta F, et al. Assessment of system dysfunction in the brain through MRI-based connectomics. Lancet Neurol. 2013;12:1189–99.

    Article  PubMed  Google Scholar 

  5. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86. Important revision of the classification of MS disease courses.

  6. Kurtzke JF. On the evaluation of disability in multiple sclerosis. Neurology. 1961;11:686–94.

    Article  CAS  PubMed  Google Scholar 

  7. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343:1430–8.

    Article  CAS  PubMed  Google Scholar 

  8. Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain J Neurol. 2010;133:1900–13. Milestone publication for the perception of MS as a two-stage disease.

  9. Coyle PK. Current evaluation of alemtuzumab in multiple sclerosis. Expert Opin Biol Ther. 2014;14:127–35.

    Article  CAS  PubMed  Google Scholar 

  10. Paul F, Dörr J, Wurfel J, Vogel HP, Zipp F. Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2007;78:198–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Dörr J, Bitsch A, Schmailzl KJ, Chan A, von Ahsen N, Hummel M, et al. Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment. Neurology. 2009;73:991–3.

    Article  PubMed  Google Scholar 

  12. Stroet A, Hemmelmann C, Starck M, Zettl U, Dörr J, Paul F, et al. Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany. Ther Adv Neurol Disord. 2012;5:75–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Cocco E, Marrosu MG. The current role of mitoxantrone in the treatment of multiple sclerosis. Expert Rev Neurother. 2014;14:607–16.

    Article  CAS  PubMed  Google Scholar 

  14. Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    Article  CAS  PubMed  Google Scholar 

  15. Kappos L, Radue E-W, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

    Article  CAS  PubMed  Google Scholar 

  16. Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.

    Article  CAS  PubMed  Google Scholar 

  17. Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8:254–60.

    Article  PubMed  Google Scholar 

  18. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89:225–40.

    Article  PubMed  Google Scholar 

  19. Heesen C, Köpke S, Solari A, Geiger F, Kasper J. Patient autonomy in multiple sclerosis—possible goals and assessment strategies. J Neurol Sci. 2013;331:2–9.

    Article  CAS  PubMed  Google Scholar 

  20. Mäurer M, Dachsel R, Domke S, Ries S, Reifschneider G, Friedrich A, et al. Health care situation of patients with relapsing-remitting multiple sclerosis receiving immunomodulatory therapy: a retrospective survey of more than 9000 German patients with MS. Eur J Neurol Off J Eur Fed Neurol Soc. 2011;18:1036–45.

    Google Scholar 

  21. Cocco E, Sardu C, Spinicci G, Musu L, Massa R, Frau J, et al. Influence of treatments in multiple sclerosis disability: A cohort study. Mult. Scler. Houndmills Basingstoke Engl. 2014.

  22. Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85:67–75.

    Article  PubMed  Google Scholar 

  23. Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y. UBC Neurologists. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73:1616–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Bermel RA, You X, Foulds P, Hyde R, Simon JH, Fisher E, et al. Predictors of long-term outcome in multiple sclerosis patients treated with interferon β. Ann Neurol. 2013;73:95–103. Important report on the long-term impact of MRI activity in IFN beta treated MS patients.

  25. Prosperini L, Mancinelli CR, De Giglio L, De Angelis F, Barletta V, Pozzilli C. Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2014;20:566–76.

    Article  CAS  Google Scholar 

  26. Río J, Tintoré M, Sastre-Garriga J, Nos C, Castilló J, Tur C, et al. Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response. Eur J Neurol Off J Eur Fed Neurol Soc. 2012;19:899–904.

    Google Scholar 

  27. Sormani MP, Rio J, Tintorè M, Signori A, Li D, Cornelisse P, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2013;19:605–12.

    Article  CAS  Google Scholar 

  28. Río J, Rovira A, Tintoré M, Sastre-Garriga J, Castilló J, Auger C, et al. Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients. Mult Scler Houndmills Basingstoke Engl. 2014;20:1602–8.

    Article  Google Scholar 

  29. Havrdova E, Galetta S, Stefoski D, Comi G. Freedom from disease activity in multiple sclerosis. Neurology. 2010;74 Suppl 3:S3–7. Introduction of the NEDA concept.

  30. Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Dörr J, Bellmann-Strobl J, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2010;16:1134–40.

    Article  Google Scholar 

  31. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC. Towards the implementation of “no evidence of disease activity” in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord. 2015;8:3–13.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72:152–8.

    Article  PubMed  Google Scholar 

  33. Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27:239–47.

    Article  CAS  PubMed  Google Scholar 

  34. Gajofatto A, Bacchetti P, Grimes B, High A, Waubant E. Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2009;15:50–8.

    Article  CAS  Google Scholar 

  35. Carrá A, Onaha P, Luetic G, Burgos M, Crespo E, Deri N, et al. Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina. Eur J Neurol Off J Eur Fed Neurol Soc. 2008;15:386–93.

    Google Scholar 

  36. Capobianco M, Rizzo A, Malucchi S, Sperli F, Di Sapio A, Oggero A, et al. Glatiramer acetate is a treatment option in neutralising antibodies to interferon-beta-positive patients. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2008;29 Suppl 2:S227–9.

    Google Scholar 

  37. Caon C, Din M, Ching W, Tselis A, Lisak R, Khan O. Clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis. Eur J Neurol Off J Eur Fed Neurol Soc. 2006;13:471–4.

    CAS  Google Scholar 

  38. Prosperini L, Borriello G, De Giglio L, Leonardi L, Barletta V, Pozzilli C. Management of breakthrough disease in patients with multiple sclerosis: when an increasing of Interferon beta dose should be effective? BMC Neurol. 2011;11:26.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–97.

    Article  CAS  PubMed  Google Scholar 

  40. Vermersch P, Czlonkowska A, Grimaldi LME, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler Houndmills Basingstoke Engl. 2014;20:705–16.

    Article  CAS  Google Scholar 

  41. Castillo-Trivino T, Mowry EM, Gajofatto A, Chabas D, Crabtree-Hartman E, Cree BA, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6, e16664.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Belachew S, Phan-Ba R, Bartholomé E, Delvaux V, Hansen I, Calay P, et al. Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis. Eur J Neurol Off J Eur Fed Neurol Soc. 2011;18:240–5.

    CAS  Google Scholar 

  43. Putzki N, Kollia K, Woods S, Igwe E, Diener HC, Limmroth V. Natalizumab is effective as second line therapy in the treatment of relapsing remitting multiple sclerosis. Eur J Neurol Off J Eur Fed Neurol Soc. 2009;16:424–6.

    CAS  Google Scholar 

  44. Bergvall N, Makin C, Lahoz R, Agashivala N, Pradhan A, Capkun G, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PLoS One. 2014;9, e88472.

    Article  PubMed Central  PubMed  Google Scholar 

  45. He A, Spelman T, Jokubaitis V, Havrdova E, Horakova D, Trojano M, et al. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis. JAMA Neurol. 2015;1–10. Important paper arguing for escalation of treatment insead of intra class switching.

  46. Prosperini L, Giannì C, Leonardi L, De Giglio L, Borriello G, Galgani S, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2012;18:64–71.

    Article  CAS  Google Scholar 

  47. CAMMS223 Trial Investigators, Coles AJ, Compston DAS, Selmaj KW, Lake SL, Moran S, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786–801.

    Article  Google Scholar 

  48. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819–28.

    Article  CAS  PubMed  Google Scholar 

  49. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829–39.

    Article  CAS  PubMed  Google Scholar 

  50. Kalincik T, Horakova D, Spelman T, Jokubaitis V, Trojano M, Lugaresi A, et al. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol. 2015;77:425–35.

    Article  CAS  PubMed  Google Scholar 

  51. Bergvall N, Lahoz R, Reynolds T, Korn JR. Healthcare resource use and relapses with fingolimod versus natalizumab for treating multiple sclerosis: a retrospective US claims database analysis. Curr Med Res Opin. 2014;30:1461–71.

    Article  CAS  PubMed  Google Scholar 

  52. Williamson EM, Berger JR. Infection risk in patients on multiple sclerosis therapeutics. CNS Drugs. 2015.

  53. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378:1779–87.

    Article  CAS  PubMed  Google Scholar 

  54. Pfender N, Martin R, Pt A. Daclizumab (anti-CD25) in multiple sclerosis. Exp Neurol. 2014;262:44–51.

    Article  CAS  PubMed  Google Scholar 

  55. Lublin FD, Cofield SS, Cutter GR, Conwit R, Narayana PA, Nelson F, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73:327–40. Crucial study evaluating the combination of IFN beta and GA treatment.

  56. Narula S, Hopkins SE, Banwell B. Treatment of pediatric multiple sclerosis. Curr Treat Options Neurol. 2015;17:336.

    Article  PubMed  Google Scholar 

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Conflict of Interest

Jan Dörr declares the receipt of research support from Novartis and Bayer Healthcare, speaker honoraria from Novartis, Teva and Bayer Healthcare, honoraria for advisory from Teva, Genzyme, and Bayer Healthcare, and travel support from Bayer Healthcare and Novartis.

Friedemann Paul declares the receipt of speaker honoraria, travel grants, and research grants from Teva, Sanofi Aventis, Bayer Healthcare, Merck Serono, Biogen Idec; MedImmune and Novartis; travel reimbursement and research support by the Guthy Jackson Charitable Foundation; support by the German Research Foundation (DFG Exc 257), the German Ministry of Education and Research (Competence Network Multiple Sclerosis), the Artur Arnstein Foundation and the Werth Foundation of the City of Cologne. Member of the steering committee of the OCTIMS study sponsored by Novartis.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    Jan Dörr MD & Friedemann Paul MD

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  1. Jan Dörr MD
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Correspondence to Jan Dörr MD.

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This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders

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Dörr, J., Paul, F. The Transition From First-Line to Second-Line Therapy in Multiple Sclerosis. Curr Treat Options Neurol 17, 25 (2015). https://doi.org/10.1007/s11940-015-0354-5

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