Skip to main content

Dimethyl Fumarate for Treatment of Multiple Sclerosis: Mechanism of Action, Effectiveness, and Side Effects

Current Neurology and Neuroscience Reports volume 13, Article number: 394 (2013) Cite this article

Abstract

Dimethyl fumarate is an orally available treatment option for relapsing–remitting multiple sclerosis (MS) in a new formulation with improved gastroenteric coating. The mode of action comprises immunomodulatory effects and an activation of nuclear (erythroid-derived 2) related factor mediated antioxidative response pathways leading to additional cytoprotective effects. In two pivotal phase III trials, dimethyl fumarate, 240 mg twice daily, reduced relapse rates by about 50 % as compared with placebo. In the DEFINE trial, progression of disability was also significantly reduced. Both trials demonstrated a significant reduction of gadolinium-enhanced lesions as well as T2 lesions on cranial MRI. The studies revealed a beneficial safety profile of dimethyl fumarate. The most prevalent side effects were transient flushing and gastrointestinal tract irritation. Dimethyl fumarate has recently been approved in the USA for the treatment of relapsing–remitting MS. The compound is a welcome addition to the immunomodulatory treatment armamentarium for MS patients and physicians alike.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

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

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938–52.

    PubMed  Article  CAS  Google Scholar 

  2. van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta. 1812;2011:141–50.

    Google Scholar 

  3. Rieckmann P, Toyka KV. Escalating immunotherapy of multiple sclerosis. Austrian-German-Swiss Multiple Sclerosis Therapy Consensus Group [MSTCG]. Eur Neurol. 1999;42:121–7.

    PubMed  Article  CAS  Google Scholar 

  4. 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. 1998;352:1498–1504.

    Google Scholar 

  5. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285–94.

    PubMed  Article  CAS  Google Scholar 

  6. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology. 2001;57:S16–24.

    PubMed  CAS  Google Scholar 

  7. Gold R, Linker RA, Stangel M. Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action. Clin Immunol. 2012;142:44–8.

    PubMed  Article  CAS  Google Scholar 

  8. Litjens NHR, Burggraaf J, van Strijen E, van Gulpen C, Mattie H, Schoemaker RC, et al. Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004;58:429–32.

    PubMed  Article  CAS  Google Scholar 

  9. Werdenberg D, Joshi R, Wolffram S, Merkle HP, Langguth P. Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters. Biopharm Drug Dispos. 2003;24:259–73.

    PubMed  Article  CAS  Google Scholar 

  10. Hoxtermann S, Nuchel C, Altmeyer P. Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology. 1998;196:223–30.

    PubMed  Article  CAS  Google Scholar 

  11. Treumer F, Zhu K, Glaser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol. 2003;121:1383–8.

    PubMed  Article  CAS  Google Scholar 

  12. de Jong R, Bezemer AC, Zomerdijk TP, van de Pouw-Kraan T, Ottenhoff TH, Nibbering PH. Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. Eur J Immunol. 1996;26:2067–74.

    PubMed  Article  Google Scholar 

  13. Ockenfels HM, Schultewolter T, Ockenfels G, Funk R, Goos M. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br J Dermatol. 1998;139:390–5.

    PubMed  Article  CAS  Google Scholar 

  14. Asadullah K, Schmid H, Friedrich M, Randow F, Volk HD, Sterry W, et al. Influence of monomethylfumarate on monocytic cytokine formation—explanation for adverse and therapeutic effects in psoriasis? Arch Dermatol Res. 1997;289:623–30.

    PubMed  Article  CAS  Google Scholar 

  15. • Ghoreschi K, Bruck J, Kellerer C, Deng C, Peng H, Rothfuss O, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011;208:2291–303. This describes recent work on immunomodulatory actions of dimethyl fumarate.

    PubMed  Article  CAS  Google Scholar 

  16. Litjens NH, Rademaker M, Ravensbergen B, Rea D, van der Plas MJ, Thio B, et al. Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol. 2004;34:565–75.

    PubMed  Article  CAS  Google Scholar 

  17. Zhu K, Mrowietz U. Inhibition of dendritic cell differentiation by fumaric acid esters. J Invest Dermatol. 2001;116:203–8.

    PubMed  Article  CAS  Google Scholar 

  18. Lin SX, Lisi L, Dello RC, Polak PE, Sharp A, Weinberg G, et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro. 2011;3(2):e00055.

    PubMed  Article  Google Scholar 

  19. Wierinckx A, Breve J, Mercier D, Schultzberg M, Drukarch B, Van Dam AM. Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol. 2005;166:132–43.

    PubMed  Article  CAS  Google Scholar 

  20. Loewe R, Holnthoner W, Groger M, Pillinger M, Gruber F, Mechtcheriakova D, et al. Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kB/p65 in human endothelial cells. J Immunol. 2002;168:4781–7.

    PubMed  CAS  Google Scholar 

  21. Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM. The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol. 2001;144:1114–20.

    PubMed  Article  CAS  Google Scholar 

  22. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun. 1997;234:19–23.

    PubMed  Article  CAS  Google Scholar 

  23. Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain. 2006;129:1953–71.

    PubMed  Article  Google Scholar 

  24. Herrero-Herranz E, Pardo LA, Gold R, Linker RA. Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol Dis. 2008;30:162–73.

    PubMed  Article  CAS  Google Scholar 

  25. Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol. 2006;145:101–7.

    PubMed  Article  CAS  Google Scholar 

  26. •• Linker RA, Lee DH, Ryan S, Van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134:678–92. This is a preclinical study revealing that dimethyl fumarate activates the Nrf2 antioxidant pathway.

    PubMed  Article  Google Scholar 

  27. van Muiswinkel FL, Kuiperij HB. The Nrf2-ARE signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. Curr Drug Targets CNS Neurol Disord. 2005;4:267–81.

    PubMed  Article  Google Scholar 

  28. Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, Luesch H. A genomic screen for activators of the antioxidant response element. Proc Natl Acad Sci U S A. 2007;104:5205–10.

    PubMed  Article  CAS  Google Scholar 

  29. Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH, Issberner A, et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012;9:163.

    PubMed  Article  CAS  Google Scholar 

  30. • Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012;341:274–84. This describes comprehensive in vitro work on the cytoprotective role of FAE.

    PubMed  Article  CAS  Google Scholar 

  31. van Horssen J, Drexhage JA, Flor T, Gerritsen W, van der Valk P, de Vries HE. Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med. 2010;49:1283–9.

    PubMed  Article  Google Scholar 

  32. Schweckendiek W. Treatment of psoriasis vulgaris. Med Monatsschr. 1959;13:103–4.

    PubMed  CAS  Google Scholar 

  33. Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German multicentre study. Br J Dermatol. 1998;138:456–60.

    PubMed  Article  CAS  Google Scholar 

  34. Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol. 1999;141:424–9.

    PubMed  Article  CAS  Google Scholar 

  35. Altmeyer P, Hartwig R, Matthes U. Das Wirkungs- und Sicherheitsprofil von Fumarsäureestern in der oralen Langzeittherapie bei schwerer therapieresistenter Psoriasis vulgaris. Eine Untersuchung an 83 Patienten. Hautarzt. 1996;47:190–6.

    PubMed  Article  CAS  Google Scholar 

  36. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368:1657–8.

    PubMed  Article  CAS  Google Scholar 

  37. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368:1658–9.

    PubMed  Article  Google Scholar 

  38. Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med. 2013;368:1659–61.

    PubMed  Article  CAS  Google Scholar 

  39. Schwab N, Ulzheimer JC, Fox RJ, Schneider-Hohendorf T, Kieseier BC, Monoranu CM, et al. Fatal PML associated with efalizumab therapy: insights into integrin aLb2 in JC virus control. Neurology. 2012;78:458–67.

    PubMed  Article  CAS  Google Scholar 

  40. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006;13:604–10.

    PubMed  Article  CAS  Google Scholar 

  41. Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–72.

    PubMed  Article  CAS  Google Scholar 

  42. Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, et al. Effect of BG-12 on contrast-enhanced lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler. 2012;18:314–21.

    PubMed  Article  CAS  Google Scholar 

  43. • MacManus DG, Miller DH, Kappos L, Gold R, Havrdova E, Limmroth V, et al. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol. 2011;258:449–56. This provides MRI evidence for a tissue-protective effect of the dimethyl fumarate preparation BG-12 in RRMS.

    PubMed  Article  CAS  Google Scholar 

  44. •• Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–107. This is a pivotal phase III study of the dimethyl fumarate preparation BG-12 in RRMS.

    PubMed  Article  CAS  Google Scholar 

  45. •• Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–97. This is a pivotal phase III study of the dimethyl fumarate preparation BG-12 in RRMS.

    PubMed  Article  CAS  Google Scholar 

  46. Bar-Or A, Gold R, Kappos L, Arnold DL, Giovannoni G, Selmaj K, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol. 2013. doi:10.1007/s00415-013-6954-7.

    PubMed  Google Scholar 

  47. Hutchinson M, Fox RJ, Miller DH, Phillips JT, Kita M, Havrdova E, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol. 2013. doi:10.1007/s00415-013-6968-1.

    PubMed  Google Scholar 

  48. Ellrichmann G, Petrasch-Parwez E, Lee DH, Reick C, Arning L, Saft C, et al. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease. PLoS One. 2011;6:e16172.

    PubMed  Article  CAS  Google Scholar 

  49. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR, et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci. 2008;1147:61–9.

    PubMed  Article  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Ralf A. Linker has been a consultant for Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis Pharma, and TEVA Pharma, has received grant support from Biogen Idec, Merck Serono, and Novartis Pharma, has received honoraria from Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, and TEVA Pharma, has patents (planned, pending, or issued) for Biogen Idec, has received payment for development of educational presentations including service on speakers bureaus from Novartis Pharma, and has received travel/accommodation expenses covered or reimbursed by Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis Pharma, and TEVA Pharma.

Ralf Gold has received grant support from Biogen Idec for investor-sponsored experimental trials, has received a consulting fee or honorarium for the board or speaker honoraria for Biogen Idec, and has received support for travel to meetings for study or otherwise for steering committee meetings for Biogen Idec.

Human and Animal Rights and Informed Consent

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

Author information

Affiliations

  1. Department of Neurology, Friedrich–Alexander University Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany

    Ralf A. Linker

  2. Department of Neurology, St. Josef-Hospital/Ruhr University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany

    Ralf Gold

Authors
  1. Ralf A. Linker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ralf Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ralf Gold.

Additional information

This article is part of the Topical Collection on Demyelinating Disorders

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Linker, R.A., Gold, R. Dimethyl Fumarate for Treatment of Multiple Sclerosis: Mechanism of Action, Effectiveness, and Side Effects. Curr Neurol Neurosci Rep 13, 394 (2013). https://doi.org/10.1007/s11910-013-0394-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-013-0394-8

Keywords

  • Multiple sclerosis
  • Neuroinflammation
  • Oral
  • Immunotherapy
  • Neuroprotection
  • Clinical trial
  • Dimethyl fumarate
  • Effectiveness
  • Side effects