British Journal of Dermatology 2004; 150: 630–632.
`
`DOI: 10.1111/j.0007-0963.2004.05903.x
`
`TOPICAL REVIEW
`
`Fumaric acid esters, their place in the treatment of psoriasis
`
`A . D . O R M E R O D A N D U . M R O W I E T Z *
`Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB15 8SG, U.K.
`*Department of Dermatology, University of Schleswig-Holstein, Campus Kiel, Schittenhemstrasse 7, 24105 Kiel, Germany
`
`Accepted for publication 18 November 2003
`
`Fumaric acid esters (FAE) have evolved as a therapy for
`psoriasis through an unusual route, beginning with
`self-experimentation by the German chemist Schweck-
`endiek whose premise was that psoriasis might be due
`to an aberration of the citric acid cycle. While this is
`not the case, our understanding of the active moiety, its
`mode of action and place in psoriasis therapy are still
`developing. However, there is cumulating evidence
`that dimethylfumarate (DMF), the main ingredient of
`the marketed mixture, is the active compound.
`Hoefnagel et al. recently reported on the long-term
`effects and safety of FAE1 and Mrowietz et al. published
`a consensus statement regarding the appropriate use of
`this therapy in psoriasis in 1998.2 An article in this
`issue of the journal3 is among the first to explore the
`possibilities of combination therapy, adding FAE to
`other second line drugs to treat patients with more
`difficult and severe psoriasis that is unresponsive to
`conventional modalities.
`The clinical development has been partly in the
`Netherlands but mainly in Germany where the German
`psoriasis patient organization promoted licensing of
`the product FumadermÒ (Fumapharm AG, Lucerne,
`Switzerland) which constitutes a mixture of dimethyl-
`fumarate and calcium, magnesium, and zinc salts of
`monoethyl hydrogen fumarate.
`A large number of patient-years’ experience of
`therapy have been established in the German experi-
`ence after inauguration of treatment in 1959 and
`registration of FumadermÒ in 1994. Nugteren-Huying
`et al.4 showed that lesional area was reduced by 68%
`with the combination of DMF and monoethylfumarate.
`The long-term safety and efficacy of the commercial
`product were demonstrated in an open study of 196
`patients treated with FumadermÒ or DMF alone for up
`to 2 years.5 In a first double-blind, placebo-controlled
`
`Correspondence: A.D.Ormerod.
`E-mail: a.d.ormerod@btinternet.com
`
`630
`
`study the efficacy of FumadermÒ in the treatment of
`severe psoriasis vulgaris was established.6 Another
`prospective study of 101 patients showed a 75%
`reduction in psoriasis area and severity index (PASI)
`in 4 months observed in the per protocol population of
`70 patients.7 However, all studies have a high dropout
`rate because of gastrointestinal complaints which
`occur in up to 60% of patients, and flushing in 30%
`of patients which is worse at the onset of therapy.
`There is
`some evidence that pentoxifylline helps
`prevent flushing8 and that flushing declines with
`ongoing therapy.
`Recently, Hoefnagel et al.1 reported a useful series of
`long-term follow-up studies of 41 patients treated for a
`year and 12 treated for 10–14 years with FAE. Of these
`patients, 73% had adverse events, usually mild, con-
`sisting of flushing, diarrhoea, nausea, tiredness and
`stomach pains while, in the blood, transient eosino-
`philia was observed in 14–25% and lymphocytopenia
`(less than 20% of white cells) was observed in 76%
`leading to withdrawal of treatment in four patients.
`The median lymphopenia was a 5Æ5% reduction and
`reached a plateau without progressive lymphopenia
`between 1 year and 12 years of therapy. Raised liver
`enzymes, usually c-glutamyl
`transpeptidase, are a
`common finding found in 25% of patients; this is
`usually reversed on stopping therapy. Raised creatinine
`was found in one patient who was subsequently
`retreated without this problem. Overall there are no
`reports of severe long-term toxicity or development of
`neoplasias or a higher susceptibility for bacterial
`infections, thus making FAE a safe regimen compared
`with other agents. Published guidelines for therapy2
`recommend a schedule of gradual incremental intro-
`duction and reduction if
`lymphocytes
`fall below
`)1 or
`0Æ5 · 109 L
`counts below 3Æ0 ·
`leucocyte
`)1.
`109 L
`However, the guidelines do not allow for combin-
`ation therapy with drugs other than topical treatments
`
`Ó 2004 British Association of Dermatologists
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`Sawai (IPR2019-00789), Ex. 1027, p. 001
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`

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`as explored by Balasubramaniam et al. in this issue.3
`Balasubramaniam et al.3 have pioneered the combina-
`tion of FAE in combination with second line drugs—
`ciclosporin, methotrexate, hydroxyurea and acitretin
`for additional benefit or to facilitate dose reduction in
`second line therapeutic agents. Inevitably the numbers
`of patients so treated are small and it is too early to
`conclude the safety of these combinations; nevertheless
`a new potential avenue for combination therapy is
`presented and once more FAE appear less toxic than
`other drugs, potentially making the combinations ideal.
`By way of caution patients were closely monitored and
`the dose escalation proceeded more slowly and cau-
`tiously than for FAE monotherapy.
`At the beginning of fumarate treatment rare cases of
`nephrotoxicity were reported; however,
`in all con-
`trolled trials this adverse event has never occurred. In a
`prospective study of kidney changes during fuma-
`rate treatment a reversible micromolecular tubular
`proteinuria has been seen, but the glomerular filtration
`rate was unaffected9 and it is therefore recommended
`to monitor also for proteinuria. There is experimental
`evidence in rats and mice that fumaric acid mono-
`ethylester may be responsible for this effect.10 Also very
`rare cases of secondary osteomalacia have been report-
`ed.11
`The mode of action of FAE is thought to be mainly
`an inhibition of T-cell activity partly due to the
`induction of preferential apoptosis in activated T
`cells,12 and there is some evidence for a shift from a
`T-helper (Th) 1-type response to a Th2-type pattern so
`that the production of interleukin (IL)-10 inhibits the
`key Th1 cytokines IL-2, IL-12 and interferon (IFN)-c.
`In vitro studies showed that in psoriatic keratinocyte
`and lymphocyte cocultures IFN-c was inhibited and
`IL-10 was increased.13 Activated lymphocytes in the
`presence of anti-CD3 ⁄ CD28 showed increased IL-4
`and IL-5 production;
`this
`is consistent with the
`eosinophilia observed in the early stages of therapy.14
`However, in vivo studies showed that in longer-term
`treatment, IL-4 and IL-10 levels diminish with IFN-c
`in response to phytohaemagglutinin stimulation of
`peripheral blood mononuclear cells.15 A very recent
`investigation showed that the major ingredient DMF is
`the most potent antiproliferative component. DMF and
`its main metabolite methyl hydrogen fumarate are
`inhibitors of dendritic cell differentiation.16
`potent
`DMF was also shown to induce apoptosis in higher
`concentrations.16 Many of the experimental results
`obtained with FAE may be related to the observation
`
`F U M A R I C A C I D E S T E R S I N P S O R I A S I S
`
`6 3 1
`
`that DMF is also a potent inhibitor of nuclear factor B
`translocation.17,18
`fumaric
`Particularly where the wider licensing of
`acid esters and its introduction as a combination
`treatment are concerned it would be desirable to study
`the cleaner profile of DMF alone, rather than the
`complex mixture of FumadermÒ.
`
`References
`
`1 Hoefnagel JJ, Thio HB, Willemze R et al. Long-term safety aspects
`of systemic therapy with fumaric acid esters in severe psoriasis.
`Br J Dermatol 2003; 149: 363–9.
`2 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
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`3 Balasubramaniam P, Stevenson O, Berth-Jones J. Fumaric acid
`esters in severe psoriasis including experience of use in combin-
`ation with other systemic modalities. Br J Dermatol doi: 10.1111/
`j.0007-0963.2004.05739.
`4 Nugteren-Huying WM, van der Schroeff JG, Hermans J et al.
`[Fumaric acid therapy in psoriasis; a double-blind, placebo-con-
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`6 Altmeyer PJ, Matthes U, Pawlak F et al. Antipsoriatic effect of
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`8 Friedrich M, Sterry W, Klein A et al. Addition of pentoxifylline
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`9 Boesken WH, Oser B, Roth J et al. Nephrotoxische Wirkungen
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`seltene
`11 Fliegner L, Spiegel P. Osteomalazie als offenbar
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`12 Treumer F, Zhu K, Gla¨ser R, Mrowietz U. Dimethylfumarate is a
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`13 Ockenfels HM, Schultewolter T, Ockenfels G et al. The antipsori-
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`Br J Dermatol 1998; 139: 390–5.
`14 de Jong R, Bezemer AC, Zomerdijk TP et al. Selective stimulation
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`monomethylfumarate. Eur J Immunol 1996; 26: 2067–74.
`15 Litjens NH, Nibbering PH, Barrois AJ et al. Beneficial effects of
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`Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 630–632
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`Sawai (IPR2019-00789), Ex. 1027, p. 002
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`6 3 2 A . D . O R M E R O D A N D U . M R O W I E T Z
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`16 Zhu K, Mrowietz U. Inhibition of dendritic cell differentiation by
`fumaric acid esters. J Invest Dermatol 2001; 116: 203–8.
`17 Loewe R, Holnthoner W, Groger M et al. Dimethylfumarate
`inhibits TNF-induced nuclear entry of NF-kappa B ⁄ p65 in
`human endothelial cells. J Immunol 2002; 168: 4781–7.
`
`18 Vandermeeren M, Janssens S, Wouters H et al. Dimethylfumarate
`is an inhibitor of cytokine-induced nuclear translocation of
`NF-kappa B1, but not RelA in normal human dermal fibroblast
`cells. J Invest Dermatol 2001; 116: 124–30.
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`Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 630–632
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`Sawai (IPR2019-00789), Ex. 1027, p. 003
`
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