Fumaric acid ester

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Definition
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Antipsoriatic with immunomodulating and proliferation normalizing effect.

Pharmacodynamics (Effect)
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The pharmacological effects of fumaric acid esters have not yet been fully clarified. Probable is an antiproliferative effect on lymphocytes as well as a selective immunomodulatory antipsoriatic effect on activated T-lymphocytes. In co-cultures of keratinocytes and T-lymphocytes an inhibition of INF-gamma as well as an increased secretion of IL-10 could be detected. Thus FAE cause a reduction of lesional and global T-lymphocytes.

It is assumed that dimethylfumarate (DMF) interacts with the intracellular thiol system, which influences the cellular stability of the redox balance. Therefore, in the long run, an increase of reduced glutathione is observed. This increase inhibits redox-sensitive kinases, which consecutively inhibits phosphorylation and ubiquitination of the nuclear factor inhibitor kappa B ( NF-kappaB).

NF-kappaB itself has numerous target genes and mediates various effects. NF-kappaB is of great importance for the regulation of the immune response, cell proliferation and apoptosis. It inhibits the transcription of genes coding for pro-inflammatory mediators such as tumor necrosis factor, interleukin 8 and adhesion molecules. This results in a strong anti-inflammatory effect.

Indication
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Severe, therapy-resistant forms of psoriasis vulgaris.

Limited indication
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Hematological diseases. Renal failure

Dosage and method of use
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  • The oral application is carried out in increasing dosage, e.g. Fumaderm initial 1 tablet/day in week 1 up to a maximum of 6 tablets/day of Fumaderm in week 6.
  • The weekly increase from initially 1 tablet per day Fumaderm initial to 4-5 tablets has proven to be effective. If the patient tolerates Fumaderm well, it can then be switched to Fumaderm, whereby it should be noted that 1 tablet of Fumaderm initially corresponds to 4 tablets of Fumaderm.
  • However, in many cases it is not necessary to administer the maximum TD of 6 tablets/day (= 1.29 g/day) of Fumaderm p.o. After the skin symptoms have subsided (4-6 weeks after the start of therapy) it is recommended to reduce the daily intake to the individually required maintenance dose.
  • If necessary, discontinuation attempts are indicated to check the acuteity of the psoriasis and thus the need for further treatment.

Remember! Before the beginning and during the course of therapy (at first every 2 weeks, later every 4 weeks) check the diff.-BB, liver and kidney values!

Undesirable effects
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  • Gastrointestinal disorders, diarrhoea, flush, eosinophilia, leukopenia, in rare cases creatinine increase, proteinuria. The side effects such as flushed sensations and sensations of heat as well as gastrointestinal complaints usually decrease significantly with the duration of therapy.
  • Mild leukopenia, moderate to distinct lymphopenia are regular side effects of the therapy, rarely eosinophilia.
  • Although animal experiments have not shown any evidence of a teratogenic effect, fumarates must not be given during pregnancy.
  • A dose adjustment should be made in case of leukopenia, decrease in lymphocyte count < 500/μl, persistent eosinophilia > 25%, increase in creatinine > 30% or massive tubular proteinuria.
  • Malignoma induction: Based on clinical studies and spontaneous reports since the early 1990s, no evidence of an increased risk of malignancy was found in 110,000 patient-years. An antiproliferative and proaptotic effect was demonstrated in several studies. Recently, the development of Kaposi's sarcoma and malignant melanomahas been reported under therapy.

Contraindication
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Pregnancy, lactation, adolescents < 18 years, gastrointestinal ulcers, severe liver and kidney diseases.

Preparations
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Fumaderm, Fumaderm initial

Note(s)
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Remarkably, dimethyl fumarates have at times been used as antimicrobial (fungicidal) substances in the Chinese furniture industry (e.g. sofa cushions) and shoe industry. This can lead to contact allergic reactions among the production workers involved.

Literature
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  1. Altmeyer P et al (1996) Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients] Dermatologist 47: 190-196
  2. Altmeyer PJ et al (1996) Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 30: 977-981
  3. Altmeyer P et al (1996) Systemic treatment of psoriasis by fumaric acid derivatives. Ann Dermatol Venereol 123: 838-841
  4. Barth D et al (2011) Malignant melanomas under systemic therapy with fumaric acid ester coincidence or therapy success? cJDDG 9: 223-225
  5. Gesser B et al (2007) Dimethylfumarate specifically inhibits the mitogenic and stress-activated kinases 1 and 2 (MSK1/2): possible role for its anti-psoriatic effect. J Invest Dermatol 127: 2129-2137
  6. Gollnick H, Altmeyer P et al (2002) Topical calcipotriol plus oral fumaric acid is more effective and faster acting than oral fumaric acid monotherapy in the treatment of severe chronic plaque psoriasis vulgaris. Dermatology 205: 46-53
  7. Gutzmer R et al (2002) Successful therapy of annular elastolytic giant cell granuloma with fumaric acid esters. Dermatology 205: 421-424
  8. Hoefnagel JJ et al (2003) Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol 149: 363-369
  9. Höxtermann S, Nuchel C, Altmeyer P (1998) Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology 196: 223-230
  10. Stander H et al (2003) Efficacy of fumaric acid ester monotherapy in psoriasis pustulosa palmoplantaris. Br J Dermatol 149: 220-222
  11. Kreuter A et al (2002) Treatment of disseminated granuloma annulare with fumaric acid esters. BMC Dermatol 19: 5
  12. Lehmann M et al (2003) Asadullah K. Fumaric acid esters are potent immunosuppressants: inhibition of acute and chronic rejection in rat kidney transplantation models by methyl hydrogen fumarate. Arch Dermatol Res 294: 399-404
  13. Loewe R et al (2002) Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. J Immunol 168: 4781-4787
  14. Nowack U et al (2003) Successful treatment of recalcitrant cutaneous sarcoidosis with fumaric acid esters. BMC Dermatol 24: 15
  15. Ortiz-Urda S, Rappersberger K (2003) New immunosuppressive agents for treating psoriasis. dermatologist 54: 230-236
  16. Schad K et al (2010) Sofadermatitis. SDDG8: 897-899
  17. Sebok B et al (1998) The antipsoriatic dimethyl-fumarate suppresses interferon-gamma -induced ICAM-1 and HLA-DR expression on hyperproliferative keratinocytes. Quantification by a culture plate-directed APAAP-ELISA technique. Eur J Dermatol 8: 29-32

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Last updated on: 29.10.2020