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Treating relapsing–remitting multiple sclerosis: therapy effects on brain atrophy

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Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with a complex and heterogeneous pathology that may ultimately lead to neurodegeneration and brain atrophy. Brain volume loss in MS is known to occur early in the disease course and to be clinically relevant, as it has been related to disability progression. Nowadays, brain volume loss is relatively easy to measure with different automated, reproducible and accurate software tools. Therefore, most of (if not all) the newest clinical trials have incorporated brain volume outcomes as a measure of treatment effect. With this review, we aimed to update and summarize all existing data regarding brain volume and RRMS treatment in clinical trials as well as in open-label observational studies of drugs with positive results in its primary outcome in at least one phase III trial as of March 2014.

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References

  1. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354:942–955. doi:10.1056/NEJMra052130

    Article  CAS  PubMed  Google Scholar 

  2. Miller DH, Barkhof F, Frank JA et al (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain J Neurol 125:1676–1695

    Article  Google Scholar 

  3. Bermel RA, Bakshi R (2006) The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 5:158–170

    Article  PubMed  Google Scholar 

  4. Smith SM, Zhang Y, Jenkinson M et al (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17:479–489

    Article  PubMed  Google Scholar 

  5. Zivadinov R, Reder AT, Filippi M et al (2008) Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71:136–144

    Article  CAS  PubMed  Google Scholar 

  6. Filippi M, Rovaris M, Inglese M et al (2004) Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 364:1489–1496

    Article  CAS  PubMed  Google Scholar 

  7. De Stefano N, Comi G, Kappos L et al (2013) Efficacy of subcutaneous interferon -1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry 85:647–653. doi:10.1136/jnnp-2013-306289

    Article  PubMed Central  PubMed  Google Scholar 

  8. Kappos L, Freedman MS, Polman CH et al (2007) Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 370:389–397

    Article  CAS  PubMed  Google Scholar 

  9. Kappos L, Freedman MS, Polman CH et al (2009) Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 8:987–997

    Article  CAS  PubMed  Google Scholar 

  10. Rudick RA, Fisher E, Lee J-C et al (2000) Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon -1a. Mult Scler 6:365–372. doi:10.1177/135245850000600601

    CAS  PubMed  Google Scholar 

  11. Hardmeier M, Wagenpfeil S, Freitag P et al (2005) Rate of brain atrophy in relapsing MS decreases during treatment with IFN -1a. Neurology 64:236–240. doi:10.1212/01.WNL.0000149516.30155.B8

    Article  CAS  PubMed  Google Scholar 

  12. Kappos L, Traboulsee A, Constantinescu C et al (2006) Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 67:944–953. doi:10.1212/01.wnl.0000237994.95410.ce

    Article  CAS  PubMed  Google Scholar 

  13. Comi G, Martinelli V, Rodegher M et al (2009) 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 374:1503–1511

    Article  CAS  PubMed  Google Scholar 

  14. Comi G, Martinelli V, Rodegher M et al (2012) Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler J 19:1074–1083. doi:10.1177/1352458512469695

    Article  Google Scholar 

  15. Ge Y, Grossman RI, Udupa JK et al (2000) Glatiramer acetate (Copaxone) treatment in relapsing-remitting MS: quantitative MR assessment. Neurology 54:813–817

    Article  CAS  PubMed  Google Scholar 

  16. Rovaris M, Comi G, Rocca MA et al (2001) Short-term brain volume change in relapsing-remitting multiple sclerosis: effect of glatiramer acetate and implications. Brain J Neurol 124:1803–1812

    Article  CAS  Google Scholar 

  17. Sormani MP, Rovaris M, Valsasina P et al (2004) Measurement error of two different techniques for brain atrophy assessment in multiple sclerosis. Neurology 62:1432–1434. doi:10.1212/01.WNL.0000120663.85143.B3

    Article  CAS  PubMed  Google Scholar 

  18. Rovaris M, Comi G, Rocca MA et al (2007) Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial. Mult Scler 13:502–508. doi:10.1177/1352458506070704

    CAS  PubMed  Google Scholar 

  19. Comi G, Cohen JA, Arnold DL et al (2011) Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol 69:75–82. doi:10.1002/ana.22316

    Article  CAS  PubMed  Google Scholar 

  20. Mikol DD, Barkhof F, Chang P et al (2008) Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 7:903–914. doi:10.1016/S1474-4422(08)70200-X

    Article  CAS  PubMed  Google Scholar 

  21. O’Connor P, Filippi M, Arnason B et al (2009) 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 8:889–897. doi:10.1016/S1474-4422(09)70226-1

    Article  PubMed  Google Scholar 

  22. Lublin FD, Cofield SS, Cutter GR et al (2013) Randomized study combining interferon and glatiramer acetate in multiple sclerosis: the CombiRx Study. Ann Neurol 73:327–340. doi:10.1002/ana.23863

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Miller DH, Soon D, Fernando KT et al (2007) MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68:1390–1401

    Article  CAS  PubMed  Google Scholar 

  24. Radue E-W, Stuart WH, Calabresi PA et al (2010) Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. J Neurol Sci 292:28–35. doi:10.1016/j.jns.2010.02.012

    Article  CAS  PubMed  Google Scholar 

  25. Kappos L, Radue E-W, O’Connor P et al (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401

    Article  CAS  PubMed  Google Scholar 

  26. Cohen JA, Barkhof F, Comi G et al (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362:402–415

    Article  CAS  PubMed  Google Scholar 

  27. Calabresi PA, Radue E-W, Goodin D et al (2014) 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 13:545–556. doi:10.1016/S1474-4422(14)70049-3

    Article  CAS  PubMed  Google Scholar 

  28. Radue E-W (2012) Impact of Fingolimod Therapy on Magnetic Resonance Imaging Outcomes in Patients With Multiple Sclerosis. Arch Neurol 69:1259. doi:10.1001/archneurol.2012.1051

    Article  PubMed  Google Scholar 

  29. Cohen JA, Barkhof F, Comi G et al (2013) Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol 260:2023–2032. doi:10.1007/s00415-013-6932-0

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Khatri B, Barkhof F, Comi G et al (2011) Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 10:520–529

    Article  CAS  PubMed  Google Scholar 

  31. Arnold DL, Gold R, Kappos L et al (2014) Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 DEFINE study. J Neurol. doi:10.1007/s00415-014-7412-x

    Google Scholar 

  32. Miller DH, Fox RJ, Phillips JT et al (2015) Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study. Neurology 84:1145–1152. doi:10.1212/WNL.0000000000001360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. O’Connor P, Wolinsky JS, Confavreux C et al (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 365:1293–1303

    Article  PubMed  Google Scholar 

  34. Wolinsky JS, Narayana PA, Nelson F et al (2013) Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler J 19:1310–1319. doi:10.1177/1352458513475723

    Article  CAS  Google Scholar 

  35. Comi G, Jeffery D, Kappos L et al (2012) Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 366:1000–1009

    Article  CAS  PubMed  Google Scholar 

  36. On behalf of the BRAVO Study Group, Vollmer TL, Sorensen PS et al (2014) A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 261:773–783. doi:10.1007/s00415-014-7264-4

    Article  Google Scholar 

  37. CAMMS223 Trial Investigators, Coles AJ, Compston DAS et al (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359:1786–1801. doi:10.1056/NEJMoa0802670

    Article  Google Scholar 

  38. Cohen JA, Coles AJ, Arnold DL et al (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–1828

    Article  CAS  PubMed  Google Scholar 

  39. Coles AJ, Twyman CL, Arnold DL et al (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380:1829–1839

    Article  CAS  PubMed  Google Scholar 

  40. Paolillo A, Pozzilli C, Giugni E et al (2002) A 6-year clinical and MRI follow-up study of patients with relapsing–remitting multiple sclerosis treated with Interferon-beta. Eur J Neurol 9:645–655

    Article  CAS  PubMed  Google Scholar 

  41. Frank JA, Richert N, Bash C et al (2004) Interferon-β-1b slows progression of atrophy in RRMS: three-year follow-up in NAb− and NAb+ patients. Neurology 62:719–725. doi:10.1212/01.WNL.0000113765.75855.19

    Article  CAS  PubMed  Google Scholar 

  42. Zivadinov R, Locatelli L, Cookfair D et al (2007) Interferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy. Mult Scler 13:490–501. doi:10.1177/1352458506070446

    CAS  PubMed  Google Scholar 

  43. Calabrese M, Bernardi V, Atzori M et al (2011) Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Mult Scler J 18:418–424. doi:10.1177/1352458510394702

    Article  Google Scholar 

  44. Khan O, Bao F, Shah M et al (2012) Effect of disease-modifying therapies on brain volume in relapsing–remitting multiple sclerosis: results of a five-year brain MRI study. J Neurol Sci 312:7–12. doi:10.1016/j.jns.2011.08.034

    Article  PubMed  Google Scholar 

  45. Rojas JI, Patrucco L, Miguez J et al (2013) Brain atrophy as a non-response predictor to interferon-beta in relapsing-remitting multiple sclerosis. Neurol Res 36:615–618. doi:10.1179/1743132813Y.0000000304

    Article  PubMed  Google Scholar 

  46. Magraner M, Coret F, Casanova B (2012) The relationship between inflammatory activity and brain atrophy in natalizumab treated patients. Eur J Radiol 81:3485–3490. doi:10.1016/j.ejrad.2012.01.028

    Article  CAS  PubMed  Google Scholar 

  47. Vidal-Jordana A, Sastre-Garriga J, Pérez-Miralles F et al (2013) Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler J 19:1175–1181

    Article  CAS  Google Scholar 

  48. Sastre-Garriga J, Tur C, Pareto D et al (2014) Brain atrophy in natalizumab-treated patients: a 3-year follow-up. Mult Scler Houndmills Basingstoke Engl. doi:10.1177/1352458514556300

    Google Scholar 

  49. Rinaldi F, Calabrese M, Seppi D et al (2012) Natalizumab strongly suppresses cortical pathology in relapsing-remitting multiple sclerosis. Mult Scler J 18:1760–1767. doi:10.1177/1352458512447704

    Article  CAS  Google Scholar 

  50. Portaccio E, Stromillo ML, Goretti B et al (2013) Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study. Eur J Neurol 20:986–990. doi:10.1111/j.1468-1331.2012.03882.x

    Article  CAS  PubMed  Google Scholar 

  51. Zivadinov R (2005) Reproducibility and accuracy of quantitative magnetic resonance imaging techniques of whole-brain atrophy measurement in multiple sclerosis. J Neuroimaging 15:27–36. doi:10.1177/1051228404271010

    Article  PubMed  Google Scholar 

  52. Huppertz H-J, Kröll-Seger J, Klöppel S et al (2010) Intra- and interscanner variability of automated voxel-based volumetry based on a 3D probabilistic atlas of human cerebral structures. Neuroimage 49:2216–2224. doi:10.1016/j.neuroimage.2009.10.066

    Article  PubMed  Google Scholar 

  53. Dalton CM, Chard DT, Davies GR et al (2004) Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 127:1101–1107. doi:10.1093/brain/awh126

    Article  PubMed  Google Scholar 

  54. Perez-Miralles F, Sastre-Garriga J, Tintore M et al (2013) Clinical impact of early brain atrophy in clinically isolated syndromes. Mult Scler J 19:1878–1886. doi:10.1177/1352458513488231

    Article  CAS  Google Scholar 

  55. Racke MK, Lovett-Racke AE, Karandikar NJ (2010) The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology 74:S25–S30

    Article  CAS  PubMed  Google Scholar 

  56. Thöne J, Ellrichmann G, Seubert S et al (2012) Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol 180:267–274. doi:10.1016/j.ajpath.2011.09.037

    Article  PubMed  Google Scholar 

  57. Freedman MS, Kaplan JM, Markovic-Plese S (2013) Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis. J Clin Cell Immunol 4:152. doi:10.4172/2155-9899.1000152

    Article  Google Scholar 

  58. Colombo E, Di Dario M, Capitolo E et al (2014) Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol 76:325–337. doi:10.1002/ana.24217

    Article  CAS  PubMed  Google Scholar 

  59. Groves A, Kihara Y, Chun J (2013) Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci 328:9–18. doi:10.1016/j.jns.2013.02.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Miron VE, Schubart A, Antel JP (2008) Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 274:13–17. doi:10.1016/j.jns.2008.06.031

    Article  CAS  PubMed  Google Scholar 

  61. Coelho RP, Payne SG, Bittman R et al (2007) The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 323:626–635. doi:10.1124/jpet.107.123927

    Article  CAS  PubMed  Google Scholar 

  62. Kelland EE, Gilmore W, Hayardeny L et al (2014) In vitro assessment of the direct effect of laquinimod on basic functions of human neural stem cells and oligodendrocyte progenitor cells. J Neurol Sci 346:66–74. doi:10.1016/j.jns.2014.07.058

    Article  CAS  PubMed  Google Scholar 

  63. Kerschensteiner M, Gallmeier E, Behrens L et al (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Dhib-Jalbut S, Marks S (2010) Interferon-β mechanisms of action in multiple sclerosis. Neurology 74:S17–S24

    Article  CAS  PubMed  Google Scholar 

  65. Ransohoff RM (2007) Natalizumab for multiple sclerosis. N Engl J Med 356:2622–2629

    Article  CAS  PubMed  Google Scholar 

  66. Linker RA, Lee D-H, Ryan S et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain J Neurol 134:678–692. doi:10.1093/brain/awq386

    Article  Google Scholar 

  67. Bar-Or A, Pachner A, Menguy-Vacheron F et al (2014) Teriflunomide and its mechanism of action in multiple sclerosis. Drugs 74:659–674. doi:10.1007/s40265-014-0212-x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. De Stefano N, Filippi M, Miller D et al (2007) Guidelines for using proton MR spectroscopy in multicenter clinical MS studies. Neurology 69:1942–1952. doi:10.1212/01.wnl.0000291557.62706.d3

    Article  PubMed  Google Scholar 

  69. Sormani MP, Arnold DL, De Stefano N (2014) Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 75:43–49. doi:10.1002/ana.24018

    Article  PubMed  Google Scholar 

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Conflicts of interest

Dr. Vidal-Jordana reports personal fees from Teva, Biogen-Idec, Novartis, and Genzyme, all outside the submitted work. Dr. Sastre-Garriga reports personal fees from Biogen-Idec, Novartis, Almirall, Teva, Roche, Merck-Serono and grants and personal fees from Genzyme, all outside the submitted work. Dr. Rovira serves on scientific advisory boards for Biogen Idec, Novartis, Genzyme, and OLEA Medical, and on the editorial board of the American Journal of Neuroradiology and Neuroradiology, has received speaker honoraria from Bayer, Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd., OLEA Medical, Stendhal, Novartis and Biogen Idec, receives research support from Bayer, and has research agreements with Siemens AG. Dr. Montalban has received speaking honoraria and travel expense reimbursement for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen Idec, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme, Teva and Trophos.

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Authors and Affiliations

  1. Department of Neurology-Neuroimmunology and Multiple Sclerosis Centre of Catalonia (Cemcat), Edifici Cemcat, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, P. Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Angela Vidal-Jordana, Jaume Sastre-Garriga & Xavier Montalban

  2. Magnetic Resonance Unit, Radiology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    Alex Rovira

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  1. Angela Vidal-Jordana
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  2. Jaume Sastre-Garriga
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  3. Alex Rovira
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  4. Xavier Montalban
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Correspondence to Jaume Sastre-Garriga.

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Vidal-Jordana, A., Sastre-Garriga, J., Rovira, A. et al. Treating relapsing–remitting multiple sclerosis: therapy effects on brain atrophy. J Neurol 262, 2617–2626 (2015). https://doi.org/10.1007/s00415-015-7798-0

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