Fumaric Acid Esters
Information about the use of Fumaric Acid Esters in the treatment of psoriasis.
Sometime around 1969, Schweckendiek first developed a “fumaric acid” protocol for psoriasis, which was then “standardized” by a person named Schafer. Schafer’s therapy used FAEs both orally and topically (an ointment or bath), along with a diet. He claimed great success, but German dermatologists got results that contradicted each other, and found some serious side effects.[1] After going nowhere for over ten years, research began picking up again in the mid-1980s, with some preliminary reports of success, low(ish) toxicity, and long-term usefulness.[1,2]
The most work, however, has been done only in the last ten years, in which we’ve seen an rather-dramatic increase in clinical trials of FAEs[32-36], and also many attempts to figure out the mechanisms through which FAEs might act on psoriasis.[14-31, 36]
That FAEs can treat psoriasis is no longer a question. They can, but their use is mainly restricted to people with severe psoriasis who’ve tried and failed at other treatments. Potential side effects are often considered to be too great a risk for people with mild or moderate psoriasis, or for people who haven’t yet tried any of the other “first attempt” therapies.
The late 1980s saw the start of a number of case reports and other articles about the side effects of FAEs.[3-13] These side effects usually include gastrointestinal distress (nausea, stomach aches, diarrhea) and flushing. Up to 69% of patients attempting FAE therapy can experience these problems (even when the pills are specially coated), and a lot of people (relatively) have dropped out of clinical trials of FAEs because of them. Often, these gut-related troubles will diminish over time, but it’s best to be prepared for them at the start.
Less-common side effects include more-serious problems, like kidney disturbances. Kidney function will often return to normal after FAE therapy is discontinued. Other effects include abnormalities in white blood cells counts (also reversible), and, very rarely, cases of osteoporosis have been linked to the long-term use of FAEs. For these reasons, it is vital to be regularly monitored by a physician while using these drugs (blood counts and kidney function).
How well do FAEs work? Reports vary, but it seems safe to say that, on average, people in clinical trials have experienced drops in PASI scores of between 70 and 80 percent. Similar to other psoriasis therapies, which, considering the high risk of side effects, is one of the reasons why FAEs aren’t generally used unless other treatments have failed.
Therapy with FAEs begins at low dosages, and is increased over months, or until beneficial effects are noticed. This is done in order to keep the dosage as low as possible, since the risk of side effects increases with the amount of the drug that is used.
FAEs have been approved for use in Germany since 1994, and, as of 1999, approval was pending in other European countries.[36] I have never heard of any plans to get them approved for use in psoriasis (or any other disease) here in the U.S.A., and given the similar risk-to-benefit profile to methotrexate, I would be surprised if such approval was sought in the near future.
The sole approved manufacturer of an FAE product right now is a company called Fumedica GmbH in Germany. They make Fumaderm® and Fumaderm® Initial (which is taken for the first three weeks of therapy). It is possible that arrangements can be made between Fumedica and dermatologists so that patients outside of Germany can use these products on an “experimental” basis, but I don’t know all the details. Contact Fumedica directly, or have your doctor do so.
Complicating the whole FAE ‘picture’ is the fact that many people, including those who should know better, are confused by the phrase “fumaric acid therapy.” This phrase properly refers only to treatment with fumaric acid esters, the drugs described above.
Unfortunately, naturopaths and other “alternative medicine” proponents often suggest that people with psoriasis take fumaric acid supplements, but these are, in fact, worthless for the treatment of this disease.[37,38] Fumaric acid is a common food additive (it helps give Gummi Bears a sour taste, for example). According to Fumedica, fumaric acid isn’t even absorbed by the intestines, and so taking it in pill form is literally flushing your money down the toilet.
It was thought, at one time, that the Krebs Cycle in psoriasis was disturbed, and a lack of fumaric acid led to a build-up of “half products” from the cycle, which lead to psoriasis. This is not discussed in the medical literature any more, and (as written above) several other mechanisms have been proposed through which FAEs would have an effect, so it’s probably safe to assume the Krebs Cycle idea was simply wrong.
A protocol that is still discussed (or at least available on web sites) is one published by Dr. Helmut Christ. This protocol included an elimination diet and exercise. Along with the FAE pills (today’s standard), Dr. Christ’s regimen included FAE ointments and baths (which can induce different side effects in the skin itself). The formulations included everyday fumaric acid, which is ineffective.
Dr. Christ reported 100% success in a book, but also is quoted as saying, “If the skin does not clear up, the patient is either not taking his medication correctly (that is too little medication), or he/she is not sticking to the diet, or the diagnosis is incorrect.” In other words, he blamed the patients or the diagnosis for failures. Since no medication or therapy works 100% of the time, this is a horrible attitude for a doctor to have.
Psoriatics sometimes stumble across this old (12 years, as of this writing) protocol, since it is still available at places like Gary Null’s web site
, and wonder why their dermatologist hasn’t told them about it. The above discussion should make it clear that the protocol described has been largely discredited for quite some time, as it was developed in the early days of fumaric acid therapies, when much “trial and error” guesswork was going on as to the cause of psoriasis and the reasons why FAEs worked the way they appeared to.Dr. Christ published a paper in 1999 claiming to have better than 80% success with FAEs while also dosing patients with a thymus extract and selenium intravenously.[39] He concludes that internal systemtic therapies like FAEs (or his combination) should be used in preference to the typical external therapies, but he needs to take into account the severity of the disease and other factors which might make systemic treatment unacceptable or unrealistic.
Lastly, and unfortunately, FAEs have been sold in the U.S. “over-the-counter” by some people who believe the treatment to be “natural” and “safe.” Again, FAEs are not approved by the FDA for the treatment of any disease, and they are serious drugs requiring professional medical oversight during treatment.
Unreviewed Treatments and Information
Gary Null’s reprint of the Arthritis Trust of America article
The Hall of Pshame
Mihopharm
The National Psoriasis Foundation
Fumedica
Medline Abstracts
Unreviewed Product Sales
Psoractin (monoethylfumarate, by Ecological Formulas/Cardio Research)
Psorex (monoethylfumarate, by )
Bayho
Gaines Nutrition says Psorex contains “A special ester of 120 mg Fumaric Acid,” doesn’t actually say what’s special about it, and there’s also a warning that only monoethylfumarate is “effective.”
Natural Eye Care
Gaines Nutrition
says Psorex contains “A special ester of 120 mg Fumaric Acid,” doesn’t actually say what’s special about it, and there’s also a warning that only monoethylfumarate is “effective.”Natural Eye Care
Footnotes
Note: I reference these papers for the information contained in their abstracts only. I am aware that the full-text articles may provide valuable additional information, but I am not able to access the full text for most of these as of this writing.
1. “Systemic therapy with fumaric acid derivates: new possibilities in the treatment of psoriasis.” Nieboer et al, Journal of the American Academy of Dermatology 1989 Apr;20(4):601-8
2. “[Peroral long-term treatment of psoriasis using fumaric acid derivatives.]” Bayard et al, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 1987 May;38(5):279-85
3. “Fumaric acid therapy in psoriasis: a double-blind comparison between fumaric acid compound therapy and monotherapy with dimethylfumaric acid ester.” Nieboer et al, Dermatologica 1990;181(1):33-7
4. “[Acute kidney insufficiency in the treatment of psoriasis using fumaric esters.]” Roodnat et al, Schweizerische Medizinische Wochenschrift 1989 Jun 10;119(23):826-30
5. “[Acute kidney insufficiency in patients treated with fumaric acid esters for psoriasis.]” Roodnat et al, Nederlands Tijdschrift Voor Geneeskunde 1989 Dec 30;133(52):2623-6
6. “[Acute kidney failure during psoriasis therapy with fumaric acid derivatives.]” Dalhoff et al, Deutsche Medizinische Wochenschrift 1990 Jun 29;115(26):1014-7
7. “[Two cases of side effects of a fumaric acid ester — local therapy.]” Dücker and Pfeiff, Zeitschrift fur Hautkrankheiten 1990 Aug;65(8):734-6
8. “[The nephrotoxic effect of therapy with fumaric acid esters in psoriasis.]” Stuhlinger et al, Deutsche Medizinische Wochenschrift 1990 Nov 9;115(45):1712-5
9. “[Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study.]” Nugteren-Huying et al, Nederlands Tijdschrift Voor Geneeskunde 1990 Dec 8;134(49):2387-91
10. “[Osteomalacia as an apparently rare side effect of oral fumaric acid therapy. Secondary DeToni-Debré Fanconi syndrome in the adult.]” Fliegner and Spiegel, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 1992 Sep;43(9):554-60
11. “The risk of sensibilization and contact urticaria upon topical application of fumaric acid derivatives.” de Haan et al, Dermatology (Basel, Switzerland) 1994;188(2):126-30
12. “Longterm treatment of psoriasis using fumaric acid preparations can be associated with severe proximal tubular damage.” Raschka and Koch, Human and Experimental Toxicology 1999 Dec;18(12):738-9
13. “[Multiple pathological fractures within the scope of DeToni-Debre-Fanconi syndrome after fumarate therapy in psoriasis.]” Warzecha et al, Der Unfallchirurg 2001 May;104(5):448-51
14. “A defective purine nucleotide synthesis pathway in psoriatic patients.” Kiehl and Ionescu, Acta Dermato-Venereologica 1992 Aug;72(4):253-5
15. “Effects of monomethylfumarate on human granulocytes.” Nibbering et al, The Journal of Investigative Dermatology 1993 Jul;101(1):37-42
16. “Fumaric acid esters (FAEs) suppress CD 15- and ODP 4-positive cells in psoriasis.” Bacharach-Buhles et al, Acta Dermato-Venereologica Supplementum 1994;186:79-82
17. “Antiproliferative and cytotoxic profiles of antipsoriatic fumaric acid derivatives in keratinocyte cultures.” Sebök et al, European Journal of Pharmacology 1994 Jan 3;270(1):79-87
18. “IL-1 alpha-induced expression of ICAM-1 on cultured hyperproliferative keratinocytes: suppression by antipsoriatic dimethyl-fumarate.” Sebök et al, International Journal of Dermatology 1994 May;33(5):367-70
19. “The effect of fumaric acid esters and dithranol on acanthosis and hyperproliferation in psoriasis vulgaris.” Bacharach-Buhles et al, Acta Dermato-Venereologica 1996 May;76(3):190-3
20. “Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate.” de Jong et al, European Journal of Immunology 1996 Sep;26(9):2067-74
21. “Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells.” Vandermeeren et al, Biochemical and Biophysical Research Communications 1997 May 8;234(1):19-23
22. “Intracellular signalling by binding sites for the antipsoriatic agent monomethylfumarate on human granulocytes.” Nibbering et al, The British Journal of Dermatology 1997 Jul;137(1):65-75
23. “Influence of monomethylfumarate on monocytic cytokine formation — explanation for adverse and therapeutic effects in psoriasis?” Asadullah et al, Archives for Dermatological Research 1997 Oct;289(11):623-30 (also here)
24. “Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis.” Höxtermann et al, Dermatology (Basel, Switzerland) 1998;196(2):223-30
25. “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.” Sebok et al, European Journal of Dermatology 1998 Jan-Feb;8(1):29-32
26. “The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network.” Ockenfels et al, The British Journal of Dermatology 1998 Sep;139(3):390-5
27. “Inhibition of dendritic cell differentiation by fumaric acid esters.” Zhu and Mrowietz, The Journal of Investigative Dermatology 2001 Feb;116(2):203-8
28. “The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells.” Stoof et al, The British Journal of Dermatology 2001 Jun;144(6):1114-20
29. “Dithranol and dimethylfumarate suppress the interferon-gamma-induced up-regulation of cytokeratin 17 as a putative psoriasis autoantigen in vitro.” Bonnekoh et al, Skin Pharmacology and Applied Skin Physiology 2001 Jul-Aug;14(4):217-25
30. “Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.” Loewe et al, The Journal of Investigative Dermatology 2001 Dec;117(6):1363-8
31. “Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells.” Loewe et al, Journal of Immunology 2002 May 1;168(9):4781-7
32. “Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients.” Altmeyer et al, Journal of the American Academy of Dermatology 1994 Jun;30(6):977-81
33. “[Efficacy and safety profile of fumaric acid esters in oral long-term therapy with severe treatment refractory psoriasis vulgaris. A study of 83 patients.]” Altmeyer et al, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 1996 Mar;47(3):190-6
34. “Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study.” Mrowietz et al, The British Journal of Dermatology 1998 Mar;138(3):456-60
35. “Fumaric acid esters: an alternative systemic treatment for psoriasis.” Ameen and Russell-Jones, Clinical and Experimental Dermatology 1999 Sep;24(5):361-4
36. “Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference.” Mrowietz et al, The British Journal of Dermatology 1999 Sep;141(3):424-9
37. “[Psoriasis therapy with fumaric acid and fumaric acid esters.]” Raab, Zeitschrift fur Hautkrankheiten 1984 May 15;59(10):671-9
38. “Effect of fumaric acid, its dimethylester, and topical antipsoriatic drugs on epidermal differentiation in the mouse tail model.” Sebök et al, Skin Pharmacology 1996;9(2):99-103
39. “[Immunomodulating therapy of psoriasis vulgaris.]” Christ, Medizinische Klinik 1999 Oct 15;94 Suppl 3:90-2