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Multiple sclerosis therapy: An update on recently finished trials

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Abstract

Six pharmacological agents are currently approved for the treatment of multiple sclerosis (MS).However, all established substances are only partially effective in reducing disease progression or relapse rates. In addition, they have potentially serious side effects. Thus, significant efforts are being made to develop new agents or to optimize current therapies. The latter includes modifications of dose, route of administration or the time point of treatment initiation. In this review, we provide an update on the most important clinical phase II/III trials on approved and novel immunotherapeutic strategies in MS reported during the last two years. Pharmacotherapies include agents that target chemoattraction, cell migration, chemotherapies, and antigen-based therapies.

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References

  1. Achiron A, Gabbay U, Gilad R, Hassin- Baer S, Barak Y, Gornish M, Elizur A, Goldhammer Y, Sarova-Pinhas I (1998) Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 50:398–402

    PubMed  CAS  Google Scholar 

  2. Achiron A, Kishner I, Sarova-Pinhas I, Raz H, Faibel M, Stern Y, Lavie M, Gurevich M, Dolev M, Magalashvili D, Barak Y (2004) Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, doubleblind, placebo-controlled trial. Arch Neurol 61:1515–1520

    Article  PubMed  Google Scholar 

  3. Achiron A, Lavie G, Kishner I, Stern Y, Sarova-Pinhas I, Ben-Aharon T, Barak Y, Raz H, Lavie M, Barliya T, Faibel M, Cohen IR, Mandel M (2004) T cell vaccination in multiple sclerosis relapsing- remitting nonresponders patients. Clin Immunol 113:155–160

    Article  PubMed  CAS  Google Scholar 

  4. Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T, Sallach S, Endres M, Brocke S, Nitsch R, Zipp F (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197:725–733

    Article  PubMed  CAS  Google Scholar 

  5. Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392:565–568

    Article  PubMed  CAS  Google Scholar 

  6. Bar-Or A, Antel J, Bodner CA (2006) Antigen-specific immunomodulation in multiple sclerosis patients treated with MBP encoding DNA plasmid (BHT-3009) alone or combined with atorvastatin. Neurology 66 (5) (Suppl):A62–A62

    Google Scholar 

  7. Barbero P, Bergui M, Versino E, Ricci A, Zhong JJ, Ferrero B, Clerico M, Pipieri A, Verdun E, Giordano L, Durelli L (2006) Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis (INCOMIN Trial) II: analysis of MRI responses to treatment and correlation with Nab. Mult Scler 12:72–76

    Article  PubMed  CAS  Google Scholar 

  8. Baumhackl U, Fodermair S (1990) Enzymtherapie bei Multipler Sklerose. Allgemeinmedizin 19:169–172

    Google Scholar 

  9. Baumhackl U, Kappos L, Radue EW, Freitag P, Guseo A, Daumer M, Mertin J (2005) A randomized, double-blind, placebo-controlled study of oral hydrolytic enzymes in relapsing multiple sclerosis. Mult Scler 11:166–168

    Article  PubMed  CAS  Google Scholar 

  10. Ben-Nun A, Cohen IR (1981) Vaccination against autoimmune encephalomyelitis (EAE): attenuated autoimmune T lymphocytes confer resistance to induction of active EAE but not to EAE mediated by the intact T lymphocyte line. Eur J Immunol 11:949–952

    Article  PubMed  CAS  Google Scholar 

  11. Bielekova B, Goodwin B, Richert N, Cortese I, Takayuki K, Afshar G, Gran B, Antel J, Franck JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175

    Article  PubMed  CAS  Google Scholar 

  12. Birnbaum G, Altafullah I (2005) Neurology Volume 64 (6) (Suppl. 1):A385, P306. 158

    Google Scholar 

  13. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123 (Pt 6):1174–1183

    Article  PubMed  Google Scholar 

  14. Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164

    Article  PubMed  Google Scholar 

  15. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457

    Article  PubMed  CAS  Google Scholar 

  16. Budde K, Schmouder RL, Brunkhorst R, Nashan B, Lucker PW, Mayer T, Choudhury S, Skerjanec A, Kraus G, Neumayer HH (2002) First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 13:1073–1083

    PubMed  CAS  Google Scholar 

  17. Caon C, Din M, Ching W, Tselis A, Lisak R, Khan O (2006) Clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis. Eur J Neurol 13:471–474

    Article  PubMed  CAS  Google Scholar 

  18. Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621

    Article  PubMed  CAS  Google Scholar 

  19. Chiba K (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 108:308–319

    Article  PubMed  CAS  Google Scholar 

  20. Chunduru SK, Sutherland RM, Stewart GA, Doms RW, Paterson Y (1996) Exploitation of the Vbeta8. 2 T cell receptor in protection against experimental autoimmune encephalomyelitis using a live vaccinia virus vector. J Immunol 156:4940–4945

    PubMed  CAS  Google Scholar 

  21. Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN (2002) Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 59:679–687

    PubMed  CAS  Google Scholar 

  22. Cohen JA, Rovaris M, Goodman AD, Ladkani D, Wynn D, Filippi M (2007) Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS. Neurology 68:939–944

    Article  PubMed  CAS  Google Scholar 

  23. Coles A, Group TCS (2007) Efficacy of Alemtuzumab in Treatment-Naive Relapsing- Remitting Multiple Sclerosis: Analysis after Two Years of Study CAMMS223 Neurology 68(Suppl 1):A100

    Google Scholar 

  24. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA (2006) The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 253:98–108

    Article  PubMed  Google Scholar 

  25. Comi G, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M (2007) The Effekt of Two Doses of Laquinimod on MRI-Monitored Disease Activity in Patients with Relaspsing-Remitting Multiple Sclerosis: A Multi-Center, Randomized, Double-Blind, Placebo- Controlled Study. Neurology 68 (Suppl 1):A84

    Google Scholar 

  26. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582

    Article  PubMed  CAS  Google Scholar 

  27. Comi G, Filippi M, Wolinsky JS (2001) European/Canadian multicenter, double- blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 49:290–297

    Article  PubMed  CAS  Google Scholar 

  28. Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64:1270–1272

    PubMed  CAS  Google Scholar 

  29. Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180:63–70

    Article  PubMed  CAS  Google Scholar 

  30. Durelli L (2003) Dose and frequency of interferon treatment matter–INCOMIN and OPTIMS. J Neurol 250 (Suppl 4):IV9–IV14

    Article  PubMed  CAS  Google Scholar 

  31. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Montanari E, Zaffaroni M (2002) Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 359:1453–1460

    Article  PubMed  CAS  Google Scholar 

  32. Ebers GC (2004) Natural history of primary progressive multiple sclerosis. Mult Scler 10 Suppl 1:S8–13; discussion S13–15

    Article  PubMed  Google Scholar 

  33. Elices MJ (2002) BX-471 Berlex. Curr Opin Investig Drugs 3:865–869

    PubMed  CAS  Google Scholar 

  34. Faria AM, Weiner HL (2005) Oral tolerance. Immunol Rev 206:232–259

    Article  PubMed  CAS  Google Scholar 

  35. Fazekas F, Barkhof F, Filippi M, Grossman RI, Li DKB, McDonald WI, McFarland HF, Paty DW, Simon JH, Wolinsky JS, Miller DH (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53:448–456

    PubMed  CAS  Google Scholar 

  36. Fazekas F, Deisenhammer F, Strasser- Fuchs S, Nahler G, Mamoli B (1997) Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 349:589–593

    Article  PubMed  CAS  Google Scholar 

  37. Fazekas F, Freedman M, Hartung HP, Li D, Lublin F, Rieckmann P, Soelberg- Sorensen P, Maas-Enriquez M, Sommerauer B, Anderesi M (2006) Prevention of relapse with intravenous immunoglobulin study: initial results of a dose-finding trial in relapsing-remitting multiple sclerosis. J Neurol 253:101

    Google Scholar 

  38. Fazekas F, Sorensen PS, Filippi M, Ropele S, Lin X, Koelmel HW, Fernandez O, Pozzilli C, O’Connor P, Enriquez MM, Hommes OR (2005) MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 11:433–440

    Article  PubMed  CAS  Google Scholar 

  39. Fergusson D, Hutton B, Sharma M, Tinmouth A, Wilson K, Cameron DW, Hebert PC (2005) Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review. Transfusion 45:1640–1657

    Article  PubMed  Google Scholar 

  40. Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G (2001) Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 57:731–733

    PubMed  CAS  Google Scholar 

  41. Filippi M, Wolinsky JS, Comi G (2006) Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, doubleblind, randomised, placebo-controlled study. Lancet Neurol 5:213–220

    Article  PubMed  CAS  Google Scholar 

  42. Fox RJ, Ransohoff RM (2004) New directions in MS therapeutics: vehicles of hope. Trends Immunol 25:632–636

    Article  PubMed  CAS  Google Scholar 

  43. Francis G, Evans A, Panitch H (1997) MRI results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis [abstract]. Ann Neurol 42:467

    Google Scholar 

  44. Freedman M, Polman C, Kappos L, Edan G, Hartung HP, Miller D, Montalban X, Barkhof F, Bauer L, Dahms S, Pohl C, Sandbrink R (2007) Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Effects of Immediate vs. Early Onset of Interferon Beta-1b Treatment. Neurology 68 (Suppl 1):A85

    Article  Google Scholar 

  45. Freedman MS, Francis GS, Sanders EA, Rice GP, O’Connor P, Comi G, Duquette P, Metz L, Murray TJ, Bouchard JP, Abramsky O, Pelletier J, O’Brien F (2005) Randomized study of onceweekly interferon beta-1a therapy in relapsing multiple sclerosis: three-year data from the OWIMS study. Mult Scler 11:41–45

    Article  PubMed  CAS  Google Scholar 

  46. Frohman EM, Havrdova E, Lublin F, Barkhof F, Achiron A, Sharief MK, Stuve O, Racke MK, Steinman L, Weiner H, Olek M, Zivadinov R, Corboy J, Raine C, Cutter G, Richert J, Filippi M (2006) Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 63:614–619

    Article  PubMed  CAS  Google Scholar 

  47. Fujino M, Funeshima N, Kitazawa Y, Kimura H, Amemiya H, Suzuki S, Li XK (2003) Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 305:70–77

    Article  PubMed  CAS  Google Scholar 

  48. Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS (2003) Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains. Am J Pathol 162:139–150

    PubMed  Google Scholar 

  49. Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170–175

    Article  PubMed  CAS  Google Scholar 

  50. Gold R, Havrdova E, Kappos L, Limmroth V, Miller D, Polman C, Yang M, Eraksoy M, Meluzinova E, Rektor I, O’Neill GN (2006) Safety of a novel oral single-agent fumarate, BG00012, in patients with relapsing-remitting mutiple sclerosis: results of a phase 2 study. J Neurol 253:144

    Article  Google Scholar 

  51. Goodkin DE, Group NASS (2000) The North American Study of interferon beta-1b in secondary progressive multiple sclerosis. 52nd Annual Meeting of the American Academy of Neurology, San Diego, CA, 2000 Abstract #LBN 0. 002

  52. Gray O, McDonnell GV, Forbes RB (2003) Intravenous immunoglobulins for multiple sclerosis. Cochrane Database Syst Rev:CD002936

    Google Scholar 

  53. Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6:358–370

    Article  PubMed  CAS  Google Scholar 

  54. Haas J (2000) High dose IVIg in the post partum period for prevention of exacerbations in MS. Multiple Sclerosis 6:18–20

    Google Scholar 

  55. Hafler DA, Weiner HL (1995) Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev 144:75–107

    Article  PubMed  CAS  Google Scholar 

  56. Hartung HP (2005) Early treatment and dose optimisation BENEFIT and BEYOND. J Neurol 252 (Suppl 3):iii44–iii50

    Article  PubMed  CAS  Google Scholar 

  57. Hass J, Firzlaff M (2005) Twenty-fourmonth comparison of immunomodulatory treatments–a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone). Eur J Neurol 12:425–431

    Article  Google Scholar 

  58. Hauser SL, Waubant E, Douglas A, Vollmer T, Antel J, Fox R, Bar-Or A, Sarkar N, Langer-Gould A, Panzara M, Smith C (2007) A Phase II Randomized, Placebo-Controlled, Multicenter Trial of Rituximab in Adults with Relapsing Remitting Multiple Sclerosis (RRMS). Neurology 68(Suppl 1):A99

    Article  CAS  Google Scholar 

  59. Hemmer B, Vergelli M, Tranquill L, Conlon P, Ling N, McFarland HF, Martin R (1997) Human T-cell response to myelin basic protein peptide (83–99): extensive heterogeneity in antigen recognition, function, and phenotype. Neurology 49:1116–1126

    PubMed  CAS  Google Scholar 

  60. Hohlfeld R, Wekerle H (2004) Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci U S A 101 Suppl 2:14599–14606

    Article  PubMed  CAS  Google Scholar 

  61. Hohlfeld R, Wiendl H (2001) The ups and downs of multiple sclerosis therapeutics. Ann Neurol 49:281–284

    Article  PubMed  CAS  Google Scholar 

  62. Hommes OR, Sorensen PS, Fazekas F, Enriquez MM, Koelmel HW, Fernandez O, Pozzilli C, O’Connor P (2004) Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 364:1149–1156

    Article  PubMed  CAS  Google Scholar 

  63. Imitola J, Chitnis T, Khoury SJ (2006) Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies. Arch Neurol 63:25–33

    Article  PubMed  Google Scholar 

  64. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta- 1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898–904

    Article  PubMed  CAS  Google Scholar 

  65. Jiang H, Kashleva H, Xu LX, Forman J, Flaherty L, Pernis B, Braunstein NS, Chess L (1998) T cell vaccination induces T cell receptor Vbeta-specific Qa-1-restricted regulatory CD8(+) T cells. Proc Natl Acad Sci USA 95:4533–4537

    Article  PubMed  CAS  Google Scholar 

  66. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: results of a phase III multicenter, doubleblind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268–1276

    PubMed  CAS  Google Scholar 

  67. Kappos L, Barkhof F, Desmet A (2005) The effect of oral temsirolimus on new magnetic resonance imaging scan lesions, brain atrophy, and the number of relapses in multiple sclerosis: results from a randomised, controlled clinical trial. J Neurol 252 (Suppl 42):46–46

    Article  Google Scholar 

  68. Kappos L, Miller DH, MacManus DG, Gold R, Havrdova E, Limmroth V, Polman C, Schmierer K, Yousry T, Yang M, Eraksoy M, Meluzinova E, Rektor I, O’Neill G (2006) Efficacy of a novel oral single-agent fumarate, BG00012, in patients with relapsing-remitting multiple sclerosis: results of a phase 2 study. J Neurol 253:27

    Google Scholar 

  69. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R (2006) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 7:1242–1249

    Article  CAS  Google Scholar 

  70. Kappos L, Radu EW, Antel J (2005) Promising results with a novel oral immunomodulator– FTY720–in relapsing multiple sclerosis. Mult Scler 11(Suppl):S13-S13

    Google Scholar 

  71. Keegan M, Konig F, McClelland R, Bruck W, Morales Y, Bitsch A, Panitch H, Lassmann H, Weinshenker B, Rodriguez M, Parisi J, Lucchinetti CF (2005) Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366:579–582

    Article  PubMed  Google Scholar 

  72. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG (2002) Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 58:143–146

    Article  PubMed  CAS  Google Scholar 

  73. Kieburtz K, McDermott M (2002) Needed in MS: evidence, not EVIDENCE. Neurology 59:1482–1483

    PubMed  Google Scholar 

  74. Kim KS, Jacob N, Stohl W (2003) In vitro and in vivo T cell oligoclonality following chronic stimulation with staphylococcal superantigens. Clin Immunol 108:182–189

    Article  PubMed  CAS  Google Scholar 

  75. Kinkel RP, Kollman C, O’Connor P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman M, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M (2006) IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 66:678–684

    Article  PubMed  CAS  Google Scholar 

  76. Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta- 1a for multiple sclerosis. N Engl J Med 353:369–374

    Article  PubMed  CAS  Google Scholar 

  77. Kleinschnitz C, Meuth SG, Kieseier BC, Wiendl H (2006) Immunotherapeutic Approaches in MS: Update on Pathophysiology and Emerging Agents or Strategies 2006. EMID DT 7:35–63

    Google Scholar 

  78. Koch-Henriksen N, Sorensen PS, Christensen T, Frederiksen J, Ravnborg M, Jensen K, Heltberg A, Kristensen O, Stenager E, Petersen T, Hansen T (2006) A randomized study of two interferon- beta treatments in relapsingremitting multiple sclerosis. Neurology 66:1056–1060

    Article  PubMed  CAS  Google Scholar 

  79. Koralnik IJ (2006) Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 60:162–173

    Article  PubMed  Google Scholar 

  80. Kozik M (1973) Activity of hydrolytic enzymes in a case of subacute multiple sclerosis. Pathol Eur 8:143–147

    PubMed  CAS  Google Scholar 

  81. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212

    Article  PubMed  Google Scholar 

  82. Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6:1399–1402

    Article  PubMed  CAS  Google Scholar 

  83. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353:375–381

    Article  PubMed  CAS  Google Scholar 

  84. Leary SM, Thompson AJ (2005) Primary progressive multiple sclerosis: current and future treatment options. CNS Drugs 19:369–376

    Article  PubMed  CAS  Google Scholar 

  85. Lehmann HC, Hartung HP, Hetzel GR, Stuve O, Kieseier BC (2006) Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders. Arch Neurol 63:930–935

    Article  PubMed  Google Scholar 

  86. Lehmann HC, Hartung HP, Hetzel GR, Stuve O, Kieseier BC (2006) Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders. Arch Neurol 63:1066–1071

    Article  PubMed  Google Scholar 

  87. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477

    Article  PubMed  CAS  Google Scholar 

  88. Lewanska M, Siger-Zajdel M, Selmaj K (2002) No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 9:565–572

    Article  PubMed  CAS  Google Scholar 

  89. Lublin FD (2002) When marketing and science intersect: do patients with MS benefit? Neurology 59:1480–1481

    Article  PubMed  Google Scholar 

  90. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717

    Article  PubMed  CAS  Google Scholar 

  91. Mao-Draayer Y, Braff S, Pendlebury W, Panitch H (2002) Treatment of steroid-unresponsive tumefactive demyelinating disease with plasma exchange. Neurology 59:1074–1077

    Article  PubMed  Google Scholar 

  92. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360

    Article  PubMed  CAS  Google Scholar 

  93. Meden H, Mielke S, Marx D, Wuttke W, Kuhn W (1997) Hormonal treatment with sex steroids in women is associated with lower p105 serum concentrations. Anticancer Res 17:3075–3077

    PubMed  CAS  Google Scholar 

  94. Menge T, Hartung HP, Stuve O (2005) Statins–a cure-all for the brain? Nat Rev Neurosci 6:325–331

    Article  PubMed  CAS  Google Scholar 

  95. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23

    Article  PubMed  CAS  Google Scholar 

  96. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62:258–264

    Article  PubMed  Google Scholar 

  97. Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, Hartung HP, Archelos JJ (2002) Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 59:990–997

    Article  PubMed  CAS  Google Scholar 

  98. Niino M, Bodner C, Simard ML, Alatab S, Gano D, Kim HJ, Trigueiro M, Racicot D, Guerette C, Antel JP, Fournier A, Grand’Maison F, Bar-Or A (2006) Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 59:748–754

    Article  PubMed  CAS  Google Scholar 

  99. Noseworthy JH, Vandervoort MK, Penman M, Ebers G, Shumak K, Seland TP, Roberts R, Yetisir E, Gent M, Taylor DW (1991) Cyclophosphamide and plasma exchange in multiple sclerosis. Lancet 337:1540–1541

    Article  PubMed  CAS  Google Scholar 

  100. O'Connor P (2003) The effects of intramuscular interferon beta-Ia in patients at high risk for development of multiple sclerosis: a post hoc analysis of data from CHAMPS. Clin Ther 25:2865–2874

    Article  PubMed  Google Scholar 

  101. O'Connor P, Antel J, Comi G (2006) Oral FTY720 in relapsing MS: Results of the dose-blinded, active drug extension phase of a phase II study. Neurology 66 (5)(Suppl):A123–A123

    Article  CAS  Google Scholar 

  102. Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497

    Article  PubMed  CAS  Google Scholar 

  103. Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA (1990) Tcell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346:183–187

    Article  PubMed  CAS  Google Scholar 

  104. OWIMS (1999) Evidence of interferon beta-1a dose response in relapsingremitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group. Neurology 53:679–686

    Google Scholar 

  105. Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I (2005) HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. Faseb J 19:1407–1421

    Article  PubMed  CAS  Google Scholar 

  106. Panitch H, Francis G, and the Oral Myelin Study Group (1997) Clinical results of a phase III trial of oral myelin in relapsing-remitting multiple sclerosis. Ann Neurol 42:459

    Google Scholar 

  107. Panitch H, Goodin D, Francis G, Chang P, Coyle P, O'Connor P, Li D, Weinshenker B (2005) Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci 239:67–74

    Article  PubMed  CAS  Google Scholar 

  108. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P, Monaghan E, Li D, Weinshenker B (2002) Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59:1496–1506

    PubMed  CAS  Google Scholar 

  109. Patti F, Pappalardo A, Florio C, Politi G, Fiorilla T, Reggio E, Reggio A (2006) Effects of interferon beta-1a and –1b over time: 6-year results of an observational head-to-head study. Acta Neurol Scand 113:241–247

    Article  PubMed  CAS  Google Scholar 

  110. Pittock SJ, Weinshenker BG, Noseworthy JH, Lucchinetti CF, Keegan M, Wingerchuk DM, Carter J, Shuster E, Rodriguez M (2006) Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol 63:611–614

    Article  PubMed  Google Scholar 

  111. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T (2005) Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 64:987–991

    PubMed  CAS  Google Scholar 

  112. Polman CH, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Dahms S, Pohl C, Sandbrink R, group obotBs (2006) Betaferon in newly emerging multiple sclerosis for initial treatment (BENEFIT): subgroup analyses. Neurology Suppl. 2:103

    Google Scholar 

  113. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910

    Article  PubMed  CAS  Google Scholar 

  114. Poser CM, Brinar VV (2001) Diagnostic criteria for multiple sclerosis. Clin Neurol Neurosurg 103:1–11

    Article  Google Scholar 

  115. Ransohoff RM (2005) Natalizumab and PML. Nat Neurosci 8:1275

    Article  PubMed  CAS  Google Scholar 

  116. Rizvi SA, Bashir K (2004) Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology 63(12 Suppl 6):S47–54

    Article  PubMed  CAS  Google Scholar 

  117. Roach ES (2006) Early multiple sclerosis: to treat or not to treat? Arch Neurol 63:619

    Article  PubMed  CAS  Google Scholar 

  118. Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5:560–570

    Article  PubMed  CAS  Google Scholar 

  119. Rovaris M, Cohen J, Goodman A, Comi G, Filippi M (2006) Results of a randomised, double-blind, parallelgroup study assessing safety and efficacy of 40 mg vs. 20 mg of glatiramer acetate on MRI-measured disease activity in relapsing-remitting multiple sclerosis. J Neurol 253 (Suppl 2):144

    Google Scholar 

  120. Rudick RA, Cutter GR, Baier M, Weinstock- Guttman B, Mass MK, Fisher E, Miller DM, Sandrock AW (2005) Estimating long-term effects of diseasemodifying drug therapy in multiple sclerosis patients. Mult Scler 11:626–634

    Article  PubMed  CAS  Google Scholar 

  121. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354:911–923

    Article  PubMed  CAS  Google Scholar 

  122. Ruprecht K, Klinker E, Dintelmann T, Rieckmann P, Gold R (2004) Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology 63:1081–1083

    PubMed  CAS  Google Scholar 

  123. Sandberg-Wollheim M, Bever C, Carter J, Farkkila M, Hurwitz B, Lapierre Y, Chang P, Francis GS (2005) Comparative tolerance of IFN beta-1a regimens in patients with relapsing multiple sclerosis. The EVIDENCE study. J Neurol 252:8–13

    Article  PubMed  CAS  Google Scholar 

  124. Schilling S, Linker RA, Konig FB, Koziolek M, Bahr M, Muller GA, Paulus W, Gartner J, Bruck W, Chan A, Gold R (2006) [Plasma exchange therapy for steroid-unresponsive multiple sclerosis relapses: Clinical experience with 16 patients, ]. Nervenarzt 77:430–438

    Article  PubMed  CAS  Google Scholar 

  125. Schwid SR, Thorpe J, Sharief M, Sandberg-Wollheim M, Rammohan K, Wendt J, Panitch H, Goodin D, Li D, Chang P, Francis G (2005) Enhanced benefit of increasing interferon beta- 1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study. Arch Neurol 62:785–792

    Article  PubMed  Google Scholar 

  126. Sehgal SN (2003) Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35:7S–14S

    Article  PubMed  CAS  Google Scholar 

  127. Sorensen PS, Fazekas F, Lee M (2002) Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 9:557–563

    Article  PubMed  CAS  Google Scholar 

  128. Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, Kirsmeier H, Larsen VA, Lee ML (1998) Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50:1273–1281

    PubMed  CAS  Google Scholar 

  129. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103:807–815

    Article  PubMed  CAS  Google Scholar 

  130. Sospedra M, Martin R (2005) Antigen- specific therapies in multiple sclerosis. Int Rev Immunol 24:393–413

    Article  PubMed  CAS  Google Scholar 

  131. SPECTRIMS SG (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results. Neurology 56:1496–1504

    Google Scholar 

  132. Steinman L (2005) Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 4:510–518

    Article  PubMed  CAS  Google Scholar 

  133. Steinman L (2006) The coming of age for antigen-specific therapy of multiple sclerosis. Eur J Neurol 13:793–794

    Article  PubMed  CAS  Google Scholar 

  134. Steinman L (2001) Immunotherapy of multiple sclerosis: the end of the beginning. Curr Opin Immunol 13:597–600

    Article  PubMed  CAS  Google Scholar 

  135. Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26:565–571

    Article  PubMed  CAS  Google Scholar 

  136. Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H (1998) Multiple sclerosis: in situ evidence for antibody- and complement- mediated demyelination. Ann Neurol 43:465–471

    Article  PubMed  CAS  Google Scholar 

  137. Stuve O, Cepok S, Elias B, Saleh A, Hartung HP, Hemmer B, Kieseier BC (2005) Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing- remitting multiple sclerosis. Arch Neurol 62:1620–1623

    Article  PubMed  Google Scholar 

  138. Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK (2006) Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 59:743–747

    Article  PubMed  CAS  Google Scholar 

  139. Stuve O, Youssef S, Weber MS, Nessler S, von Budingen HC, Hemmer B, Prod’homme T, Sobel RA, Steinman L, Zamvil SS (2006) Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest 116:1037–1044

    Article  PubMed  CAS  Google Scholar 

  140. Sun D, Qin Y, Chluba J, Epplen JT, Wekerle H (1988) Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T-T cell interactions. Nature 332:843–845

    Article  PubMed  CAS  Google Scholar 

  141. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 353:362–368

    Article  Google Scholar 

  142. Vandenbark AA (2005) TCR peptide vaccination in multiple sclerosis: boosting a deficient natural regulatory network that may involve TCRspecific CD4+ CD25+ Treg cells. Curr Drug Targets Inflamm Allergy 4:217–229

    Article  Google Scholar 

  143. Vartanian T (2003) An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther 25:105–118

    Article  PubMed  CAS  Google Scholar 

  144. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, Preiningerova J, Rizzo M, Singh I (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363:1607–1608

    Article  PubMed  CAS  Google Scholar 

  145. Waisman A, Ruiz PJ, Hirschberg DL, Gelman A, Oksenberg JR, Brocke S, Mor F, Cohen IR, Steinman L (1996) Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. Nat Med 2:899–905

    Article  PubMed  CAS  Google Scholar 

  146. Warren KG, Catz I, Ferenczi LZ, Krantz MJ (2006) Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class IIdefined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebocontrolled clinical trial and 5 years of follow-up treatment. Eur J Neurol 13:887–895

    Article  PubMed  CAS  Google Scholar 

  147. Warren KG, Catz I, Wucherpfennig KW (1997) Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis. J Neurol Sci 152:31–38

    Article  PubMed  CAS  Google Scholar 

  148. Webb M, Tham CS, Lin FF, Lariosa- Willingham K, Yu N, Hale J, Mandala S, Chun J, Rao TS (2004) Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153:108–121

    Article  PubMed  CAS  Google Scholar 

  149. Weber MS, Prod’homme T, Steinman L, Zamvil SS (2005) Drug Insight: using statins to treat neuroinflammatory disease. Nat Clin Pract Neurol 1:106–112

    Article  PubMed  CAS  Google Scholar 

  150. Weiner HL, Mackin GA, Matsui M, Orav EJ, Khoury SJ, Dawson DM, Hafler DA (1993) Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259:1321–1324

    Article  PubMed  CAS  Google Scholar 

  151. Weinshenker BG, O’Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW, Pineda AA, Stevens LN, Rodriguez M (1999) A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 46:878–886

    Article  PubMed  CAS  Google Scholar 

  152. Weissert R, Wiendl H, Pfrommer H, Storch MK, Schreiner B, Barth S, Seifert T, Melms A, Dichgans J, Weller M (2003) Action of treosulfan in myelin-oligodendrocyte-glycoprotein- induced experimental autoimmune encephalomyelitis and human lymphocytes. J Neuroimmunol 144:28–37

    Article  PubMed  CAS  Google Scholar 

  153. Wiendl H, Hohlfeld R (2002) Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 16:183–200

    Article  PubMed  CAS  Google Scholar 

  154. Wiendl H, Kieseier BC, Weissert R, Mylius HA, Pichlmeier U, Hartung HP, Melms A, Kuker W, Weller M (2007) Treatment of active secondary progressive multiple sclerosis with treosulfan. J Neurol 254(7):884–889

    Article  PubMed  CAS  Google Scholar 

  155. Wolinsky JS (2004) The PROMiSe trial: baseline data review and progress report. Mult Scler 10 (Suppl 1):S65–71; discussion S71–62

    Article  PubMed  CAS  Google Scholar 

  156. Wucherpfennig KW, Sette A, Southwood S, Oseroff C, Matsui M, Strominger JL, Hafler DA (1994) Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones. J Exp Med 179:279–290

    Article  PubMed  CAS  Google Scholar 

  157. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jager HR, Clifford DB (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354:924–933

    Article  PubMed  CAS  Google Scholar 

  158. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84

    Article  PubMed  CAS  Google Scholar 

  159. Zamvil SS, Steinman L (2003) Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 38:685–688

    Article  PubMed  CAS  Google Scholar 

  160. Zipp F, Hartung HP, Hillert J, Schimrigk S, Trebst C, Stangel M, Infante- Duarte C, Jakobs P, Wolf C, Sandbrink R, Pohl C, Filippi M (2006) Blockade of chemokine signaling in patients with multiple sclerosis. Neurology 67:1880–1883

    Article  PubMed  CAS  Google Scholar 

  161. Zipp F, Hartung HP, Hillert J, Schimrigk S, Trebst C, Stangel M, Pohl C, Filippi M (2005) Blockade of chemokine receptor in multiple sclerosis patients. Mult Scler 11(1):S13

    Article  Google Scholar 

  162. Zwibel HL (2006) Glatiramer acetate in treatment-naive and prior interferon- beta-1b-treated multiple sclerosis patients. Acta Neurol Scand 113: 378–386

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dept. of Neurology, Bayerische Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany

    C. Kleinschnitz MD, S. G. Meuth MD, PhD & H. Wiendl MD

  2. University of Düsseldorf, Dept. of Neurology, Düsseldorf, Germany

    B. Kieseier MD, PhD

  3. University of Texas, Dept. of Neurology, Southwestern Medical Center at Dallas, TX, U.S.A.

    O. Stüve MD

  4. Neurology Section, VA North Texas Health Care System, Medical Service, Dallas

    O. Stüve MD

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  1. C. Kleinschnitz MD
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  2. S. G. Meuth MD, PhD
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Kleinschnitz, C., Meuth, S.G., Stüve, O. et al. Multiple sclerosis therapy: An update on recently finished trials. J Neurol 254, 1473–1490 (2007). https://doi.org/10.1007/s00415-007-0684-7

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