Fumaric acid ester

Antipsoriatic with immunomodulating and proliferation-normalizing effect. The monopreparation dimethyl ester Skilarence® 30 mg and 120 mg, as well as Tecfidera® 120 mg and 240 mg and the mixture of monoethyl and dimethyl fumarate Fumaderm® initial (30 mg) and Fumaderm® (120 mg), which has long been known in dermatology, are used.

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.

Moderate and severe, therapy-resistant forms of psoriasis vulgaris, dimethyl fumarate also approved in multiple sclerosis.

Hematological diseases. Renal failure

• Oral application is done in increasing dosage, e.g. Fumaderm initial 1 tbl./day in week 1 up to a maximum of 6 tbl./day Fumaderm in week 6.
• The weekly increase from 1 tablet/day Fumaderm initial to 4-5 tablets has proven to be effective. If well tolerated, it is then possible to switch to Fumaderm, keeping in mind that 1 tablet of Fumaderm is equivalent to 4 tablets of Fumaderm initial.
• In many cases, however, administration of the max. TD of 6 tbl./day (= 1.29 g/day) Fumaderm p.o. is not necessary. 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 trials are indicated in order to check the acuity of the psoriasis and thus the need for further treatment.

The monopreparation with dimethyl fumarate (Skilarence®) is also slowly increased, starting with Skilarence® 30 mg 1 / day, increasing up to 3 tbl / day, depending on tolerability change to Skilarence® 120 mg or further up to 4 tbl Skilarence® 30 mg - note: 1 tablet Skilarence® 120 mg corresponds to 4 tbl Skilarence® 30 mg. If well tolerated, continue to increase individually depending on effect; the maximum dose of 6 tbl is rarely needed.

In multiple sclerosis, the dimethyl fumarate Tecfidera® is recommended at the beginning, in the first 7 days 2 x 1 Tbl a 120 mg / day, then daily 2 tablets Tecfidera® 240 mg / day.

Reminder. Before starting and during the course of therapy (initially every 2, later every 4 weeks) check the Diff.

Gastrointestinal disturbances, diarrhea, flush, eosinophilia, leukopenia, in rare cases creatinine increase, proteinuria. Side effects such as flush-like sensations and sensation of heat as well as gastrointestinal disorders usually decrease significantly with duration of therapy.

Mild leukopenia, moderate to marked lymphopenia are regular side effects of therapy, rarely eosinophilia.

Although animal studies have shown no evidence of teratogenic effects, fumarates should not be given during pregnancy.

Dose adjustment should be made in the presence of leukopenia, decrease in lymphocyte count < 500/μl, persistent eosinophilia > 25%, increase in creatinine > 30%, or massive tubular proteinuria.

Malignancy Induction: Based on clinical trials and spontaneous reports since the early 1990s, there was no evidence of an increased risk of malignancy in 110,000 patient-years. An antiproliferative and proaptotic effect could be demonstrated in several studies. Recently, the development of Kaposi's sarcoma and malignant melanomaunder the therapy has been reported.

Psoriasis: Skilarence 30 mg®, Skilarence 120 mg®, Fumaderm®, Fumaderm initial®.

Multiple sclerosis: Tecfidera® 120mg/-240 mg enteric-coated hard capsules

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.

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] Hautarzt 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 melanoma under systemic therapy with fumaric acid esters-incidence or treatment success? cJDDG 9: 223-225
5. Gesser B et al (2007) Dimethylfumarate specifically inhibits the mitogen 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. JDDG8: 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
18. https://www.multiplesklerose.ch/PDF/de/Infoblaetter/02_MS-Medikamente/MS-Info_Tecfidera.pdf
19. https://www.patienteninfo-service.de/a-z-liste/t/tecfideraR-120mg-240-mg-magensaftresistente-hartkapseln#3