Glatiramer acetate for treatment of relapsing-remitting multiple sclerosis

Expert Review of Neurotherapeutics

Volumn 12, Issue 4, 2012, Pages 371-384

  Johnson, Kenneth P ^a  

^a UNIVERSITY OF MARYLAND   (United States)

Author keywords

altered peptide ligand; clinically isolated syndrome; disease modifying therapy; glatiramer acetate; glatiramoids; immunomodulator; neuroprotection; protein and peptide therapeutics; relapsing remitting multiple sclerosis

Indexed keywords

BETA INTERFERON; BETA1A INTERFERON; CETIRIZINE; GLATIRAMER; INTERFERON BETA SERINE; MITOXANTRONE; NATALIZUMAB; NEUTRALIZING ANTIBODY; PLACEBO; PROTIRAMER; SALBUTAMOL; TERIFLUNOMIDE; UNCLASSIFIED DRUG;

ALLERGIC ENCEPHALOMYELITIS; AMYOTROPHIC LATERAL SCLEROSIS; ANTIINFLAMMATORY ACTIVITY; ANXIETY; ARTICLE; DISEASE COURSE; DRUG BINDING; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG FORMULATION; DRUG SAFETY; DRUG TOLERABILITY; DYSPNEA; FATIGUE; FEVER; FLUSHING; GLAUCOMA; GRAFT REJECTION; HEADACHE; HEART PALPITATION; HUMAN; IMMUNOMODULATION; INFLUENZA; INJECTION SITE INDURATION; INJECTION SITE PAIN; INJECTION SITE PRURITUS; INJECTION SITE REACTION; INJECTION SITE SWELLING; IRRITABLE COLON; LIPOATROPHY; MONOTHERAPY; MULTIPLE SCLEROSIS; MYALGIA; NEUROPROTECTION; NONHUMAN; OPTIC NERVE DISEASE; PARKINSON DISEASE; RETT SYNDROME; RISK BENEFIT ANALYSIS; SIDE EFFECT; SKIN REDNESS; THORAX PAIN; URTICARIA;

CLINICAL TRIALS AS TOPIC; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; PEPTIDES;

EID: 84860305280     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.12.25     Document Type: Article

References (131)

1. Koutsouraki E, Costa V, Baloyannis S. Epidemiology of multiple sclerosis in Europe: A review. Int. Rev. Psychiatry 22(1), 2-13 (2010).
2. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 9(6), 599-612 (2010).
3. Ascherio A, Munger KL. Epstein-Barr virus infection and multiple sclerosis: A review. J. Neuroimmune Pharmacol. 5(3), 271-277 (2010).
4. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part 2: Noninfectious factors. Ann. Neurol. 61(6), 504-513 (2007). (Pubitemid 47068132)
5. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part 1: The role of infection. Ann. Neurol. 61(4), 288-299 (2007). (Pubitemid 46676728)
6. Di Pauli F, Reindl M, Ehling R et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult. Scler. 14(8), 1026-1030 (2008).
7. Munger KL, Delorenze GN, Levin LI et al. A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts. Neurology 62(10), 1799-1803 (2004). (Pubitemid 38661738)
8. Simon KC, Munger KL, Kraft P, Hunter DJ, De Jager PL, Ascherio A. Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis. J. Neurol. 258(9), 1676-1682 (2011).
9. Simon KC, Munger KL, Xing Y, Ascherio A. Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult. Scler. 16(2), 133-138 (2010).
10. Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: Lessons from 28 cases. Lancet Neurol. 9(4), 438-446 (2010).
11. Le Page E, Leray E, Edan G. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: A 5-year prospective study. Mult. Scler. 17(7), 867-875 (2011).
12. Brassat D, Recher C, Waubant E et al. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology 59(6), 954-955 (2002).
13. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: A randomised multicentre study of active disease using MRI and clinical criteria. J. Neurol. Neurosurg. Psychiatry 62(2), 112-118 (1997). (Pubitemid 27090928)
14. Johnson KP, Brooks BR, Cohen JA et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a Phase 3 multicenter, double-blind placebo-controlled trial. The Copolymer 1 multiple sclerosis study group. Neurology 45(7), 1268-1276 (1995).
15. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann. Neurol. 39(3), 285-294 (1996). (Pubitemid 26100751)
16. Kappos L, Radue EW, O'Connor P et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362(5), 387-401 (2010).
17. Gold R, Rieckmann P, Chang P, Abdalla J. The long-term safety and tolerability of high-dose interferon β-1a in relapsing- remitting multiple sclerosis: 4-year data from the PRISMS study. Eur. J. Neurol. 12(8), 649-656 (2005). (Pubitemid 41117291)
18. Coyle PK. The role of natalizumab in the treatment of multiple sclerosis. Am. J. Manag. Care 16(Suppl. 6), S164-S170 (2010).
19. The IFNβ Multiple Sclerosis Study Group. Interferon β-1b is effective in relapsing- remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43(4), 655-661 (1993).
20. Conway D, Cohen JA. Emerging oral therapies in multiple sclerosis. Curr. Neurol. Neurosci. Rep. 10(5), 381-388 (2010).
21. Buttmann M. Treating multiple sclerosis with monoclonal antibodies: A 2010 update. Expert Rev. Neurother. 10(5), 791-809 (2010).
22. Sela M. Poly(a-amino acids) - from a better understanding of immune phenomena to a drug against multiple sclerosis. Acta Polym. 49, 523-525 (1998). (Pubitemid 128728685)
23. Teitelbaum D, Webb C, Bree M, Meshorer A, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis in rhesus monkeys by a synthetic copolymer. Clin. Immunol. Immunopathol. 3, 256-262 (1974).
24. Bornstein MB, Miller A, Slagle S et al. A pilot trial of Cop 1 in exacerbating- remitting multiple sclerosis. N. Engl. J. Med. 317(7), 408-414 (1987). (Pubitemid 17131177)
25. Bornstein MB, Miller AI, Teitelbaum D, Arnon R, Sela M. Multiple sclerosis: Trial of a synthetic polypeptide. Ann. Neurol. 11(3), 317-319 (1982). (Pubitemid 12183665)
26. Bornstein MB, Miller AE, Teitelbaum D, Arnon R, Sela M. Treatment of multiple sclerosis with a synthetic polypeptide: Preliminary results. Trans. Am. Neurol. Assoc. 105, 348-350 (1980).
27. Varkony H, Weinstein V, Klinger E et al. The glatiramoid class of immunomodulator drugs. Expert Opin. Pharmacother. 10(4), 657-668 (2009). Seminal paper describing the pharmacology, preclinical and clinical efficacy, immunogenicity and safety of members of the glatiramoid class of compounds.
28. Johnson KP. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: An update. Expert Opin. Drug Metab. Toxicol. 6(5), 643-660 (2010).
29. Copaxone®, prescribing information. Teva Pharmaceuticals Inc., PA, USA (2009).
30. Kala M, Rhodes SN, Piao WH, Shi FD, Campagnolo DI, Vollmer TL. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Expert Neurol. 221(1), 136-145 (2010). Adoptive transfer of B cells from glatiramer acetate (GA)-treated mice decreased proliferation of autoreactive T cells, inhibited secretion of Th1 cytokines and suppressed experimental autoimmune encephalomyelitis in recipient mice, demonstrating the importance of GA activity on B cells.
31. Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc. Natl Acad. Sci. USA 100(24), 14157-14162 (2003). (Pubitemid 37499207)
32. Aharoni R, Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc. Natl Acad. Sci. USA 97(21), 11472-11477 (2000).
33. Aharoni R, Teitelbaum D, Sela M, Arnon R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 94(20), 10821-10826 (1997). (Pubitemid 27430819)
34. Brenner T, Arnon R, Sela M et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J. Neuroimmunol. 115(1-2), 152-160 (2001). Evaluation of the immunogenicity of GA and the effects of anti-GA antibodies on clinical safety and efficacy (see also [39]). (Pubitemid 32245663)
35. Ragheb S, Abramczyk S, Lisak D, Lisak R. Long-term therapy with glatiramer acetate in multiple sclerosis: Effect on T-cells. Mult. Scler. 7(1), 43-47 (2001). (Pubitemid 32396578)
36. Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2- polarized immune responses in patients with multiple sclerosis. J. Clin. Invest. 105(7), 967-976 (2000). (Pubitemid 30203069)
37. Teitelbaum D, Brenner T, Abramsky O, Aharoni R, Sela M, Arnon R. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult. Scler. 9(6), 592-599 (2003). (Pubitemid 37479408)
38. Farina C, Vargas V, Heydari N, Kumpfel T, Meinl E, Hohlfeld R. Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients. J. Neuroimmunol. 123(1-2), 188-192 (2002). (Pubitemid 34195620)
39. Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc. Natl Acad. Sci. USA 101(Suppl. 2), 14593-14598 (2004). (Pubitemid 39346729)
40. Blanchette F, Neuhaus O. Glatiramer acetate: Evidence for a dual mechanism of action. J. Neurol. 255(Suppl. 1), 26-36 (2008). (Pubitemid 351341870)
41. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56(6), 702-708 (2001). (Pubitemid 32240087)
42. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology 74(Suppl. 1), S25-S30 (2010).
43. Weber MS, Hohlfeld R, Zamvil SS. Mechanism of action of glatiramer acetate in treatment of multiple sclerosis. Neurotherapeutics 4(4), 647-653 (2007). (Pubitemid 47499292)
44. Ziemssen T, Schrempf W. Glatiramer acetate: Mechanisms of action in multiple sclerosis. Int. Rev. Neurobiol. 79, 537-570 (2007).
45. Fridkis-Hareli M, Teitelbaum D, Gurevich E et al. Direct binding of myelin basic protein and synthetic copolymer 1 to Class 2 major histocompatibility complex molecules on living antigen-presenting cells - specificity and promiscuity. Proc. Natl Acad. Sci. USA 91(11), 4872-4876 (1994).
46. Wolinsky JS. Glatiramer acetate for the treatment of multiple sclerosis. Expert Opin. Pharmacother. 5(4), 875-891 (2004). (Pubitemid 38489510)
47. Aharoni R, Teitelbaum D, Arnon R, Sela M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc. Natl Acad. Sci. USA 96(2), 634-639 (1999). (Pubitemid 29061260)
48. Jee Y, Liu R, Bai XF, Campagnolo DI, Shi FD, Vollmer TL. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol. 18(4), 537-544 (2006).
49. Gran B, Tranquill LR, Chen M et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology 55(11), 1704-1714 (2000).
50. Aharoni R, Teitelbaum D, Sela M, Arnon R. Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J. Neuroimmunol. 91(1-2), 135-146 (1998). (Pubitemid 28545254)
51. Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jalbut S. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Mult. Scler. 7(4), 209-219 (2001). (Pubitemid 32780690)
52. Miller A, Shapiro S, Gershtein R et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): Implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J. Neuroimmunol. 92(1-2), 113-121 (1998). (Pubitemid 29015996)
53. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc. Natl Acad. Sci. USA 102(52), 19045-19050 (2005). (Pubitemid 43049563)
54. Azoulay D, Vachapova V, Shihman B, Miler A, Karni A. Lower brain-derived neurotrophic factor in serum of relapsing remitting MS: Reversal by glatiramer acetate. J. Neuroimmunol. 167(1-2), 215-218 (2005). (Pubitemid 41242305)
55. Chen M, Valenzuela RM, Dhib-Jalbut S. Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor. J. Neurol. Sci. 215(1-2), 37-44 (2003). (Pubitemid 37279143)
56. Liu J, Johnson TV, Lin J et al. T cell independent mechanism for copolymer-1- induced neuroprotection. Eur. J. Immunol. 37(11), 3143-3154 (2007). (Pubitemid 350131293)
57. Aharoni R, Herschkovitz A, Eilam R et al. Demyelination arrest and remyelination induced by glatiramer acetate treatment of experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105(32), 11358-11363 (2008). GA increased proliferation, differentiation and survival of oligodendrocyte precursor cells and promoted their recruitment to the site of injury, enhancing myelin repair in situ.
58. Ford C, Goodman AD, Johnson K et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: Results from the 15 year analysis of the US prospective open-label study of glatiramer acetate. Mult. Scler. 16(3), 342-350 (2010). The longest prospective trial of a single immunomodulatory agent in relapsing- remitting multiple scleroris (RRMS). Patients receiving continuous GA for up to 15 years experience low rates of sustained progression of neurologic disability and conversion to secondary progressive mutliple sclerosis (MS).
59. Awasthi A, Murugaiyan G, Kuchroo VK. Interplay between effector Th17 and regulatory T cells. J. Clin. Immunol. 28(6), 660-670 (2008).
60. Aharoni R, Eilam R, Stock A et al. Glatiramer acetate reduces Th-17 inflammation and induces regulatory T-cells in the CNS of mice with relapsing- remitting or chronic EAE. J. Neuroimmunol. 225(1-2), 100-111 (2010).
61. Begum-Haque S, Sharma A, Kasper IR et al. Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 204(1-2), 58-65 (2008).
62. Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc. Natl Acad. Sci. USA 102(18), 6449-6454 (2005). (Pubitemid 40617463)
63. Jee Y, Piao WH, Liu R et al. CD4(+) CD25(+) regulatory T cells contribute to the therapeutic effects of glatiramer acetate in experimental autoimmune encephalomyelitis. Clin. Immunol. 125(1), 34-42 (2007). (Pubitemid 47374537)
64. Saresella M, Marventano I, Longhi R et al. CD4+CD25+FoxP3+PD1- regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy. FASEB J. 22(10), 3500-3508 (2008).
65. Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+) FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J. Neuroimmunol. 216(1-2), 113-117 (2009). Inhibitory function and homeostasis of regulatory T cells (Tregs) are impaired in patients with RRMS. This small study (n = 15) showed GA use for up to 6 months increased the frequency and function of Tregs in RRMS patients.
66. Putheti P, Soderstrom M, Link H, Huang YM. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J. Neuroimmunol. 144(1-2), 125-131 (2003). (Pubitemid 37329937)
67. Karandikar NJ, Crawford MP, Yan X et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J. Clin. Invest. 109(5), 641-649 (2002). (Pubitemid 34204843)
68. Tennakoon DK, Mehta RS, Ortega SB, Bhoj V, Racke MK, Karandikar NJ. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J. Immunol. 176(11), 7119-7129 (2006). (Pubitemid 43787894)
69. Kim HJ, Ifergan I, Antel JP et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J. Immunol. 172(11), 7144-7153 (2004). (Pubitemid 38669158)
70. Weber MS, Prod'homme T, Youssef S et al. Type 2 monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 13(8), 935-943 (2007). GA stimulates anti-inflammatory cytokine responses by antigen-presenting cells, suggesting that a primary target of GA activity may be antigen-presenting cells. (Pubitemid 47222047)
71. Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple sclerosis: Glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127(Pt 6), 1370-1378 (2004). (Pubitemid 38745515)
72. Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J. Immunol. 170(9), 4483-4488 (2003). (Pubitemid 36519953)
73. Begum-Haque S, Sharma A, Christy M et al. Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis. J. Neuroimmunol. 219(1-2), 47-53 (2010).
74. Schori H, Kipnis J, Yoles E et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma. Proc. Natl Acad. Sci. USA 98(6), 3398-3403 (2001). (Pubitemid 32220857)
75. Kipnis J, Yoles E, Porat Z et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: Possible therapy for optic neuropathies. Proc. Natl Acad. Sci. USA 97(13), 7446-7451 (2000). (Pubitemid 30431483)
76. Benner EJ, Mosley RL, Destache CJ et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc. Natl Acad. Sci. USA 101(25), 9435-9440 (2004). (Pubitemid 38812892)
77. Angelov DN, Waibel S, Guntinas-Lichius O et al. Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 100(8), 4790-4795 (2003). (Pubitemid 36457807)
78. Ben-Zeev B, Aharoni R, Nissenkorn A, Arnon R. Glatiramer acetate (GA, Copolymer-1) an hypothetical treatment option for Rett syndrome. Med. Hypotheses 76(2), 190-193 (2010).
79. Aharoni R, Yussim A, Sela M, Arnon R. Combined treatment of glatiramer acetate and low doses of immunosuppressive drugs is effective in the prevention of graft rejection. Int. Immunopharmacol. 5(1), 23-32 (2005). (Pubitemid 39626680)
80. Aharoni R, Teitelbaum D, Arnon R, Sela M. Copolymer 1 inhibits manifestations of graft rejection. Transplantation 72(4), 598-605 (2001). (Pubitemid 32802739)
81. Aharoni R, Sonego H, Brenner O, Eilam R, Arnon R. The therapeutic effect of glatiramer acetate in a murine model of inflammatory bowel disease is mediated by anti-inflammatory T-cells. Immunol. Lett. 112(2), 110-119 (2007). (Pubitemid 47379855)
82. Aharoni R, Kayhan B, Brenner O, Domev H, Labunskay G, Arnon R. Immunomodulatory therapeutic effect of glatiramer acetate on several murine models of inflammatory bowel disease. J. Pharmacol. Exp. Ther. 318(1), 68-78 (2006).
83. Aharoni R, Kayhan B, Arnon R. Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acid-induced experimental colitis. Inflamm. Bowel Dis. 11(2), 106-115 (2005). (Pubitemid 40711214)
84. Comi G, Filippi M, Wolinsky JS. 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(3), 290-297 (2001). (Pubitemid 32202781)
85. Mikol DD, Barkhof F, Chang P et al. Comparison of subcutaneous interferon β-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(10), 903-914 (2008). GA and high-dose IFN-b1b have comparable efficacy in RRMS patients. Notably, effects on relapse rate in these studies are much higher than those reported in pivotal studies conducted 20 years ago, perhaps reflecting improvements in MS diagnosis and trend toward earlier treatment (see also [88]).
86. O'Connor P, Filippi M, Arnason B et al. 250 microg or 500 microg interferon β-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: A prospective, randomised, multicentre study. Lancet Neurol. 8(10), 889-897 (2009).
87. Poser CM, Paty DW, Scheinberg L et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann. Neurol. 13(3), 227-231 (1983). (Pubitemid 13158528)
88. Polman CH, Reingold SC, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann. Neurol. 58(6), 840-846 (2005). (Pubitemid 41746873)
89. Kieseier BC, Stuve O. A critical appraisal of treatment decisions in multiple sclerosis - old versus new. Nat. Rev. Neurol. 7, 255-262 (2011).
90. Rovaris M, Comi G, Rocca MA et al. 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(4), 502-508 (2007). (Pubitemid 46796510)
91. Johnson KP, Brooks BR, Ford CC et al. Glatiramer acetate (Copaxone): Comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial. Mult. Scler. 9(6), 585-591 (2003). (Pubitemid 37479407)
92. Johnson KP, Ford CC, Lisak RP, Wolinsky JS. Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data. Acta Neurol. Scand. 111(1), 42-47 (2005).
93. Ford CC, Johnson KP, Lisak RP, Panitch HS, Shifronis G, Wolinsky JS. A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients. Mult. Scler. 12(3), 309-320 (2006). (Pubitemid 43827186)
94. Wolinsky JS, Comi G, Filippi M, Ladkani D, Kadosh S, Shifroni G. Copaxone's effect on MRI-monitored disease in relapsing MS is reproducible and sustained. Neurology 59(8), 1284-1286 (2002). (Pubitemid 35192412)
95. Cadavid D, Wolansky LJ, Skurnick J et al. Efficacy of treatment of MS with IFNb-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 72(23), 1976-1983 (2009).
96. Lublin F, Baier M, Cutter G et al. A trial to assess the safety of combining therapy with interferon-1a and glatiramer acetate in patients with relapsing MS. Neurology 56, Abstract A148 (2001).
97. Ytterberg C, Johansson S, Andersson M et al. Combination therapy with interferon-b and glatiramer acetate in multiple sclerosis. Acta Neurol. Scand. 116(2), 96-99 (2007). (Pubitemid 47174182)
98. Goodman AD, Rossman H, Bar-Or A et al. GLANCE: Results of a Phase 2, randomized, double-blind, placebo-controlled study. Neurology 72(9), 806-812 (2009).
99. Vollmer T, Panitch H, Bar-Or A et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult. Scler. 14(5), 663-670 (2008). (Pubitemid 351954409)
100. Arnold DL, Campagnolo D, Panitch H et al. Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS. J. Neurol. 255(10), 1473-1478 (2008).
101. Khoury SJ, Healy BC, Kivisakk P et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Arch. Neurol. 67(9), 1055-1061 (2010).
102. Freedman M, Wolinsky JS, Frangin G et al. Oral teriflunomide or placebo added to glatiramer acetate for 6 months in patients with relapsing multiple sclerosis: Safety and efficacy results. Neurology 74 (2010) (Abstract A293).
103. Comi G, Martinelli V, Rodegher M et al. 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(9700), 1503-1511 (2009). Results of the placebo-controlled, randomized PreCISe study showed that GA delays conversion to clinically definite MS in patients with clinically isolated syndromes.
104. Martinelli V, Comi G, Rodegher M et al. Results from the 5 year prospective follow-up of patients receiving glatiramer acetate in the precise study on delaying conversion to CDMS. Presented at: The 63rd Annual Meeting of the American Academy of Neurology. Honolulu, HI, USA, 9-16 April 2011 (Abstract PD6.006). Results of the active-treatment extension phase of the PreCISe trial are the first data to show a significant reduction in brain atrophy associated with early versus delayed use of immunomodulatory treatment in patients with clinically isolated syndromes at 5 years (treatment effect -28%; p = 0.0209). The results strongly support early treatment with GA in patients with a first demeylinating event suggestive of MS to prevent irreversible axonal damage.
105. De Stefano N, Narayanan S, Francis GS et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch. Neurol. 58(1), 65-70 (2001). (Pubitemid 32053209)
106. Wolinsky JS, Narayana PA, O'Connor P et al. Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann. Neurol. 61(1), 14-24 (2007). (Pubitemid 46214240)
107. Wolinsky JS, Shochat T, Weiss S, Ladkani D. Glatiramer acetate treatment in PPMS: Why males appear to respond favorably. J. Neurol. Sci. 286(1-2), 92-98 (2009).
108. Hauser SL, Johnston SC. Balancing risk and reward: The question of natalizumab. Ann. Neurol. 66(3), A7-A8 (2009).
109. Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann. Neurol. 65(4), 367-377 (2009).
110. Cohen JA, Barkhof F, Comi G et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362(5), 402-415 (2010).
111. Anderson G, Meyer D, Herrman CE et al. Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: An open-label, multicenter, randomized comparative study. J. Neurol. 257(11), 1917-1923 (2010).
112. Jolly H, Simpson K, Bishop B et al. Impact of warm compresses on local injection-site reactions with self-administered glatiramer acetate. J. Neurosci. Nurs. 40(4), 232-239 (2008).
113. Glenski S, Conner J. 29 gauge needles improve patient satisfaction over 27 gauge needles for daily glatiramer acetate injections. Drug Healthcare Patient Safety 1, 81-86 (2009).
114. Pardo G, Boutwell C, Conner J, Denney D, Oleen-Burkey M. Effect of oral antihistamine on local injection site reactions with self-administered glatiramer acetate. J. Neurosci. Nurs. 42(1), 40-46 (2010).
115. Mancardi GL, Murialdo A, Drago F et al. Localized lipoatrophy after prolonged treatment with copolymer 1. J. Neurol. 247(3), 220-221 (2000). (Pubitemid 30189407)
116. Edgar CM, Brunet DG, Fenton P, McBride EV, Green P. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can. J. Neurol. Sci. 31(1), 58-63 (2004). (Pubitemid 38325760)
117. Aharoni R, Brenner O, Cohen A, Arnon R. The therapeutic effect of TV-5010 in a murine model of inflammatory bowel disease - Dextran induced colitis. Int. Immunopharmacol. 8(11), 1578-1588 (2008).
118. De Stefano N, Filippi M, Confavreux C et al. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult. Scler. 15(2), 238-243 (2009).
119. Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M. Phase 3 dose-comparison study of glatiramer acetate for multiple sclerosis. Ann. Neurol. 69(1), 75-82 (2011).
120. Comi G, Abramsky O, Arbizu T et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36 week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult. Scler. 16(11), 1360-1366 (2010).
121. Comi G, Pulizzi A, Rovaris M et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing- remitting multiple sclerosis: A multicentre, randomised, double-blind, placebo-controlled Phase 2b study. Lancet 371(9630), 2085-2092 (2008). (Pubitemid 351842581)
122. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS - teriflunomide. Clin. Immunol. 142(1), 49-56 (2011).
123. Gold R. Oral therapies for multiple sclerosis: A review of agents in Phase 3 developmenet or recently approved. CNS Drugs 25(1), 37-52 (2011).
124. Coles AJ, Compston DA, Selmaj KW et al. Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N. Engl. J. Med. 359(17), 1786-1801 (2008).
125. Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis - A focus on alemtuzumab. Clin. Immunol. 142(1), 25-30 (2011).
126. Berger JR. Natalizumab and progressive multifocal leucoencephalopathy. Ann. Rheum. Dis. 65(Suppl. 3), iii48-iii53 (2006).
127. Correale J, Farez MF. The impact of parasite infections on the course of multiple sclerosis. J. Neuroimmunol. 233(1-2), 6-11 (2011).
128. Correale J, Farez M. Helminth antigens modulate immune responses in cells from multiple sclerosis patients through TLR2-dependent mechanisms. J. Immunol. 183(9), 5999-6012 (2009).
129. Correale J, Farez M, Razzitte G. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann. Neurol. 64(2), 187-199 (2008).
130. Polman CH, Bertolotto A, Deisenhammer F et al. Recommendations for clinical use of data on neutralising antibodies to interferon-b therapy in multiple sclerosis. Lancet Neurol. 9(7), 740-750 (2010).
131. Smith B, Carson S, Fu R et al. Drug Class Review on Disease-Modifying Drugs for Multiple Sclerosis. Final Update 1 Report. Oregon Health & Science University, OR, USA (2010).