Interferon beta was the first specific disease-modifying therapy licensed for multiple sclerosis (MS) and in its many forms remains the most commonly prescribed agent worldwide. It, however, has a modest effect in reducing relapse rates, magnetic resonance imaging activity, and disability, and many patients are unable to tolerate it because of the associated side effects or mode of administration. With the licensing of glatiramer acetate, natalizumab and mitoxantrone as disease-modifying therapies for MS alternative options are available to people with MS. Many exciting new therapies are also in the pipeline, namely, the monoclonal antibodies alemtuzumab, rituximab, and daclizumab and the promising oral agents BG00012, cladribine, fingolimod, laquinimod, and teriflunomide. In this article we review the immunopathology of MS and the proposed mechanisms of action of currently available and anticipated treatments. We also review the efficacy of each drug, use of combination therapy strategies, and the potential role of the interferon beta preparations in the future.
Get full access to this article
View all access options for this article.
References
1.
AharoniR, KayhanB, EilamR, SelaM, ArnonR. 2003. 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 U S A, 100:14157–14162.
2.
AktasO, KieseierB, HartungHP. 2010. Neuroprotection, regeneration and immunomodulation: broadening the therapeutic repertoire in multiple sclerosis. Trends Neurosci, 33:140–152.
3.
AlbertM, AntelJ, BruckW, StadelmannC. 2007. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol, 17:129–138.
4.
AllenIV, McKeownSR. 1979. A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci, 41:81–91.
5.
AndersenO, LyckeJ, TollessonPOothers.1996. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology, 47:895–900.
6.
Bar-OrA, CalabresiPA, ArnoldDothers.2008. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol, 63:395–400.
7.
Bartosik-PsujekH, BelniakE, Mitosek-SzewczykK, DoboszB, StelmasiakZ. 2004. Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine. Acta Neurol Scand, 109:390–392.
8.
BertolottoA, GilliF, SalaAothers.2003. Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients. Neurology, 60:634–639.
9.
BeutlerE, SipeJ, RomineJ, McMillanR, ZyroffJ, KoziolJ. 1996. Treatment of multiple sclerosis and other autoimmune diseases with cladribine. Semin Hematol, 33:45–52.
10.
BielekovaB, CatalfamoM, Reichert-ScrivnerSothers.2006. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A, 103:5941–5946.
11.
BordenEC, SenGC, UzeGothers.2007. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov, 6:975–990.
12.
BowmanEP, ChackerianAA, CuaDJ. 2006. Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy. Curr Opin Infect Dis, 19:245–252.
13.
BrassatD, RecherC, WaubantEothers.2002. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology, 59:954–955.
14.
BrinkmannV. 2009. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol, 158:1173–1182.
15.
BrownellB, HughesJT. 1962. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry, 25:315–320.
16.
BrunmarkC, RunstromA, OhlssonLothers.2002. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol, 130:163–172.
17.
CalabreseV, RavagnaA, ColombritaCothers.2005. Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2. J Neurosci Res, 79:509–521.
18.
CalabresiPA, GiovannoniG, ConfavreuxCothers.2007. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology, 69:1391–1403.
19.
CarsonDA, WassonDB, TaetleR, YuA. 1983. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood, 62:737–743.
20.
CharcotM. 1868. Histologie de la sclerose en plaque. Gazette Hôpitaux (Paris), 41554,557–558, 566.
21.
ChenXL, DoddG, ThomasSothers.2006. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol, 290:H1862–H1870.
22.
ClericoM, FaggianoF, PalaceJ, RiceG, TintoreM, DurelliL. 2008. Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis. Cochrane Database Syst Rev, 2:CD005278.
23.
CliffordDB, DeLA, SimpsonDM, ArendtG, GiovannoniG, NathA. 2010. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol, 9:438–446.
24.
CohenJA, BarkhofF, ComiGothers.2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med, 362:402–415.
25.
CohenJA, ImreyPB, CalabresiPAothers.2009. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology, 72:535–541.
26.
ColesAJ, CompstonDA, SelmajKWothers.2008. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med, 359:1786–1801.
27.
ColesAJ, CoxA, LePEothers.2006. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol, 253:98–108.
28.
ComiG, FilippiM, BarkhofFothers.2001a. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet, 357:1576–1582.
29.
ComiG, FilippiM, WolinskyJS. 2001b. 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.
30.
ComiG, PulizziA, RovarisMothers.2008. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet, 371:2085–2092.
31.
CookSD, QuinlessJR, JotkowitzA, BeatonP. 2001. Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients. Neurology, 57:1080–1084.
32.
CoxLB, FantlP, FitzpatrickM. 1949. The treatment of disseminated sclerosis by prolonged lowering of the blood prothrombin level. Med J Aust, 1:577–579.
33.
DawsonJW. 1916. The histology of disseminated sclerosis. Trans Roy Soc Edinb, 50:517.
34.
DragoF, BrusatiC, MancardiG, MurialdoA, ReboraA. 1999. Localized lipoatrophy after glatiramer acetate injection in patients with remitting-relapsing multiple sclerosis. Arch Dermatol, 135:1277–1278.
EdanG, MillerD, ClanetMothers.1997. 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, 62:112–118.
37.
EdanG, MorrisseySP, HartungHP. 2003. Use of mitoxantrone to treat MS. Multiple Sclerosis Therapeutics, 2ndCohenJA, RudickRA. London (UK): Martin Dunitz, 403–427.
38.
FarrellRA, GiovannoniG. 2007. Measuring and management of anti-interferon beta antibodies in subjects with multiple sclerosis. Mult Scler, 13:567–577.
39.
FidlerJM, DeJoySQ, GibbonsJJJr. 1986. Selective immunomodulation by the antineoplastic agent mitoxantrone. I. Suppression of B lymphocyte function. J Immunol, 137:727–732.
40.
FilippiM, RovarisM, RoccaMA, SormaniMP, WolinskyJS, ComiG. 2001. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes.”Neurology, 57:731–733.
41.
FooteAK, BlakemoreWF. 2005. Inflammation stimulates remyelination in areas of chronic demyelination. Brain, 128:528–539.
42.
FosterCA, MechtcheriakovaD, StorchMK, BalatoniB, HowardLM, BornancinF, WlachosA, SobanovJ, KinnunenA, BaumrukerT. 2009. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol, 19:254–266.
43.
FrancisGS, RiceGP, AlsopJC. 2005. Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology, 65:48–55.
44.
FranklinRJ, Ffrench-ConstantC. 2008. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci, 9:839–855.
FrenettePS, WagnerDD. 1996b. Adhesion molecules—part II: blood vessels and blood cells. N Engl J Med, 335:43–45.
47.
FrischerJM, BramowS, Dal-BiancoAothers.2009. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain, 132:1175–1189.
GhalieRG, EdanG, LaurentMothers.2002a. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS. Neurology, 59:909–913.
50.
GhalieRG, MauchE, EdanGothers.2002b. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler, 8:441–445.
GiovannoniG, ComiG, CookSothers.2010. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med, 362:416–426.
53.
GoodinDS, FrohmanEM, HurwitzBothers.2007. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 68:977–984.
54.
GranucciF, FeauS, AngeliV, TrotteinF, Ricciardi-CastagnoliP. 2003. Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming. J Immunol, 170:5075–5081.
55.
HartungHP, AktasO. 2009. Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann Neurol, 66:429–432.
56.
HartungHP, GonsetteR, KonigNothers.2002. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet, 360:2018–2025.
57.
HartungHP, MunschauerFEIII. 2004. Assessment and management of neutralizing antibodies in patients with multiple sclerosis. J Neurol, 251,Suppl. 2:II40–II42.
58.
HauserSL, WaubantE, ArnoldDLothers.2008. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med, 358:676–688.
59.
HavrdovaE, ZivadinovR, KrasenskyJothers.2009. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler, 15:965–976.
60.
HawkerK, O'ConnorP, FreedmanMSothers.2009. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol, 66:460–471.
61.
HemmerB, CepokS, NesslerS, SommerN. 2002. Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol, 15:227–231.
62.
HohlfeldR, KerschensteinerM, MeinlE. 2007. Dual role of inflammation in CNS disease. Neurology, 68:S58–S63.
63.
HohlfeldR, WekerleH. 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.
64.
HubbsAF, BenkovicSA, MillerDBothers.2007. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am J Pathol, 170:2068–2076.
65.
HussienY, SannaA, SoderstromM, LinkH, HuangYM. 2001. Glatiramer acetate and IFN-beta act on dendritic cells in multiple sclerosis. J Neuroimmunol, 121:102–110.
66.
Interferon Beta Study Group. 1996. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology, 47:889–894.
67.
ItohK, ChibaT, TakahashiSothers.1997. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun, 236:313–322.
68.
JacobsLD, BeckRW, SimonJHothers.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.
69.
JacobsLD, CookfairDL, RudickRAothers.1996. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)Ann Neurol, 39:285–294.
70.
JacobsenM, CepokS, QuakEothers.2002. Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain, 125:538–550.
71.
JohnsonKP, BrooksBR, CohenJAothers.1995. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology, 45:1268–1276.
72.
JungCG, KimHJ, MironVEothers.2007. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia, 55:1656–1667.
73.
KapposL, ClanetM, Sandberg-WollheimMothers.2005. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study. Neurology, 65:40–47.
74.
KapposL, FreedmanMS, PolmanCHothers.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.
75.
KapposL, GoldR, MillerDHothers.2008. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet, 372:1463–1472.
76.
KapposL, RadueEW, O'ConnorPothers.2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med, 362:387–401.
77.
KarussisDM, MeinerZ, LehmannDothers.1996. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology, 47:341–346.
78.
KimHJ, IferganI, AntelJPothers.2004. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol, 172:7144–7153.
79.
KochMW, MostertJP, de VriesJJ, DeKJ. 2007. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology, 68:1163–1164.
80.
KolattukudySJ, KattanMW, MillerD, FoxR. 2007. Risk tolerance in multiple sclerosis patients. AAN AbstractP04.084.
81.
KornT, MagnusT, ToykaK, JungS. 2004. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide—mechanisms independent of pyrimidine depletion. J Leukoc Biol, 76:950–960.
82.
KornT, ToykaK, HartungHP, JungS. 2001. Suppression of experimental autoimmune neuritis by leflunomide. Brain, 124:1791–1802.
83.
KutzelniggA, Faber-RodJC, BauerJothers.2007. Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol, 17:38–44.
84.
KutzelniggA, LucchinettiCF, StadelmannCothers.2005. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain, 128:2705–2712.
85.
LassmannH, WekerleH. 2006. The pathology of multiple sclerosis. CompstonA, ConfavreuxC, LassmanH, McDonaldIet al.McAlpine's Multiple Sclerosis. London: Churchill Livingstone, 557–600.
86.
LearySM, MillerDH, StevensonVL, BrexPA, ChardDT, ThompsonAJ. 2003. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology, 60:44–51.
87.
Le PageE, LerayE, TaurinGothers.2008. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry, 79:52–56.
88.
LeppertD, WaubantE, BurkMR, OksenbergJR, HauserSL. 1996. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol, 40:846–852.
89.
LiJ, JohnsonD, CalkinsM, WrightL, SvendsenC, JohnsonJ. 2005. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci, 83:313–328.
90.
LiliemarkJ. 1997. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet, 32:120–131.
91.
LindsayKL, TrepoC, HeintgesTothers.2001. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology, 34:395–403.
92.
LublinFD, LavasaM, VitiC, KnoblerRL. 1987. Suppression of acute and relapsing experimental allergic encephalomyelitis with mitoxantrone. Clin Immunol Immunopathol, 45:122–128.
93.
MalucchiS, SalaA, GilliFothers.2004. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology, 62:2031–2037.
94.
MillerA, ShapiroS, GershteinRothers.1998. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J Neuroimmunol, 92:113–121.
95.
MillerDH, SoonD, FernandoKTothers.2007. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology, 68:1390–1401.
96.
MillerDH, ThompsonAJ, FilippiM. 2003. Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol, 250:1407–1419.
97.
MixE, Meyer-RieneckerH, ZettlUK. 2008. Animal models of multiple sclerosis for the development and validation of novel therapies—potential and limitations. J Neurol, 255,Suppl. 6:7–14.
98.
MontalbanX. 2004. Overview of European pilot study of interferon beta-Ib in primary progressive multiple sclerosis. Mult Scler, 10,Suppl. 1:S62–S64.
99.
MS Study Group. 1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology, 43:655–661.
100.
MunschauerFEIII, KinkelRP. 1997. Managing side effects of interferon-beta in patients with relapsing-remitting multiple sclerosis. Clin Ther, 19:883–893.
101.
O'ConnorP. 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.
102.
O'ConnorPW, LiD, FreedmanMSothers.2006. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology, 66:894–900.
103.
PanitchH, GoodinDS, FrancisGothers.2002. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology, 59:1496–1506.
PetersonJW, BoL, MorkS, ChangA, TrappBD. 2001. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol, 50:389–400.
106.
PolmanC, BarkhofF, Sandberg-WollheimM, LindeA, NordleO, NedermanT. 2005. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology, 64:987–991.
107.
PolmanCH, O'ConnorPW, HavrdovaEothers.2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med, 354:899–910.
108.
PRISMS. 1998. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet, 352:1498–1504.
109.
PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. 2001. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology, 56:1628–1636.
110.
PutnamTJ, ChiavacciLV. 1947. Results of treatment of multiple sclerosis with dicoumarin. Arch Neurol Psychiatry, 57:1–13.
111.
RamtahalJ, JacobA, DasK, BoggildM. 2006. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. J Neurol, 253:1160–1164.
112.
RavnborgM, BendtzenK, ChristensenOothers.2009. Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis. Mult Scler, 15:323–328.
113.
RiceGP, FilippiM, ComiG. 2000. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology, 54:1145–1155.
114.
RoseAS, KuzmaJW, KurtzkeJF, NamerowNS, SibleyWA, TourtellotteWW. 1970. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo–final report. Neurology, 20:1–59.
115.
RoseAS, KuzmaJW, KurtzkeJF, SibleyWA, TourtellotteWW. 1968. Cooperative study in the evaluation of therapy in multiple sclerosis; ACTH vs placebo in acute exacerbations. Preliminary report. Neurology, 18,Suppl-10.
116.
RoseAS, KuzmaJW, KurtzkeJF, SibleyWA, TourtellotteWW. 1969. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbation. Trans Am Neurol Assoc, 94:126–133.
117.
RudickRA, StuartWH, CalabresiPAothers.2006. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med, 354:911–923.
118.
SavitskyN, KarlinerW. 1951. Electroshock therapy and multiple sclerosis. N Y State J Med, 51:788.
119.
SayreLM, PerryG, SmithMA. 2008. Oxidative stress and neurotoxicity. Chem Res Toxicol, 21:172–188.
120.
SchillingS, GoelzS, LinkerR, LuehderF, GoldR. 2006. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol, 145:101–107.
121.
ShariefMK, SemraYK, SeidiOA, ZoukosY. 2001. Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis. J Neuroimmunol, 120:199–207.
122.
Simarro-PuigJ, LlorCJ. 1951. Treatment of multiple sclerosis with nitrogen mustards. Rev Clin Esp, 40:393–395.
123.
SmolenJS, EmeryP, KaldenJRothers.2004. The efficacy of leflunomide monotherapy in rheumatoid arthritis: towards the goals of disease modifying antirheumatic drug therapy. J Rheumatol Suppl, 71:13–20.
124.
SorensenPS, DeisenhammerF, DudaPothers.2005. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol, 12:817–827.
125.
SorensenPS, MellgrenSI, SvenningssonAothers.2009. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol, 8:519–529.
126.
SospedraM, MartinR. 2005. Immunology of multiple sclerosis. Annu Rev Immunol, 23:683–747.
127.
StadelmannC, KerschensteinerM, MisgeldT, BruckW, HohlfeldR, LassmannH. 2002. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells?Brain, 125:75–85.
128.
TeitelbaumD, AharoniR, KlingerEothers.2004. Oral glatiramer acetate in experimental autoimmune encephalomyelitis: clinical and immunological studies. Ann N Y Acad Sci, 1029:239–249.
129.
TrappBD, PetersonJ, RansohoffRM, RudickR, MorkS, BoL. 1998. Axonal transection in the lesions of multiple sclerosis. N Engl J Med, 338:278–285.
130.
van SechelAC, BajramovicJJ, van StipdonkMJ, Persoon-DeenC, GeutskensSB, van NoortJM. 1999. EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol, 162:129–135.
131.
WaxmanSG. 2006a. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci, 7:932–941.
132.
WaxmanSG. 2006b. Ions, energy and axonal injury: towards a molecular neurology of multiple sclerosis. Trends Mol Med, 12:192–195.
133.
WierinckxA, BreveJ, MercierD, SchultzbergM, DrukarchB, Van DamAM. 2005. Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol, 166:132–143.
134.
WolinskyJS. 2004. The PROMiSe trial: baseline data review and progress report. Mult Scler, 10,Suppl. 1:S65–S71.
135.
WolinskyJS, NarayanaPA, NoseworthyJHothers.2000. Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators. Neurology, 54:1734–1741.
136.
WynnD, KaufmanM, MontalbanXothers.2010. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol, 9:381–390.
137.
XuX, BlinderL, ShenJothers.1997. In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-lpr/lpr mice. J Immunol, 159:167–174.
138.
YangJS, XuLY, XiaoBG, HedlundG, LinkH. 2004. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol, 156:3–9.
139.
YongVW. 2002. Differential mechanisms of action of interferon-beta and glatiramer aetate in MS. Neurology, 59:802–808.
140.
YongVW, ChabotS, StuveO, WilliamsG. 1998. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology, 51:682–689.
141.
ZeisT, GraumannU, ReynoldsR, Schaeren-WiemersN. 2008. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain, 131:288–303.
142.
ZhaoJ, MooreAN, RedellJB, DashPK. 2007. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci, 27:10240–10248.
143.
ZiemssenT, KumpfelT, KlinkertWE, NeuhausO, HohlfeldR. 2002. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain, 125:2381–2391.
