The role of fumarates in the therapy of psoriasis
Current guidelines provide an overview of appropriate systemic therapy for moderate-to-severe plaque psoriasis with conventional and biological agents. Conventional oral systemic agents include acitretin, ciclosporin, methotrexate, and fumaric acid esters (FAEs; fumarates) [
33]. FAEs are ester derivatives of FA (Table
1). Major derivatives of interest for oral therapy are dimethyl fumarate (DMF) and monoethyl fumarate (MEF) and its salts.
Table 1
Chemical structure and basic properties of free FA and the FAEs: DMF, MEF and three salts of MEF
(Adapted from Brennan et al. [
10])
DMF | C6H8O4 | 144.13 | 102 | 1 | No ionizable protons | |
FA | C4H4O4 | 116.07 | | | | |
MEF | C6H8O4 | 144.13 | | | | |
MEF-Ca | C12H14CaO8 | 326.31 | 285 | 294 | 3.3 | |
MEF-Zn | C12H14O8Zn | 351.62 | 300 | 300 | 3.3 | |
MEF-Mg | C12H14MgO8 | 310.54 | 169 | 826 | 3.3 | |
Schweckendiek was the first to propose in 1959 that psoriasis was caused by a disturbance involving FA in the citric acid cycle [
5,
39]. Subsequently, Kiehl and Ionescu [
18] described a defective purine nucleotide synthesis pathway in patients with psoriasis. These authors noted a correlation between increased adenosine triphosphate (ATP) levels in blood cells after administration of FA and FAEs and clearance of skin lesions. Although FA deficiency is not known as a cause of disease in humans, a proprietary mixture of FAEs (Fumaderm®, Biogen Idec), with an empirically determined dosing schedule, became established as a first-line systemic therapy for moderate-to-severe psoriasis in Germany, with a reported efficacy comparable to other systemic agents, such as methotrexate [
41].
This particular FAE combination was first registered in Germany in 1994, and the current formulation is an enteric-coated tablet, available in two dosages (Fumaderm® initial and Fumaderm®), which contain DMF 30 mg or 120 mg and three salts of MEF, MEF-Ca (67 mg or 87 mg), MEF-Zn (both 3 mg) and MEF-Mg (both 5 mg), respectively [
8]. Psorinovo® is a pharmacy-compounded DMF-only formulation (enteric-coated tablets, GMP Apotheek Mierlo-Hout) that is used to treat psoriasis in the Netherlands [
35], where the local psoriasis treatment guidelines recommend FAEs as an induction treatment on moderate-to-severe disease [
42]. In addition to psoriasis, DMF is used as the first-line therapy for relapsing–remitting multiple sclerosis [
4,
22,
23,
25]. A delayed-release oral formulation of DMF, Tecfidera® (120 and 240 mg), has been approved for this indication in Europe [
15] and the US [
9].
The safety profile of fumarates has been established through decades of clinical use. Adverse events (AEs) may affect up to two-thirds of patients [
5,
38]. However, AEs are usually mild, and most commonly include gastrointestinal symptoms such as diarrhoea, stomach ache, cramps, increased frequency of stools, nausea, and vomiting [
5,
26,
38]. Formulation research to address this problem has led to the delayed-release formulation of the currently licensed FAE combination [
8]. Other common AEs include flush, leukocytopenia and lymphopenia [
2,
17], and reversible peripheral eosinophilia. In fact, all FAE-containing products approved for treatment of psoriasis require periodic blood monitoring and, depending on the severity of lymphopenia, incorporate their own treatment discontinuation guidelines as part of their prescribing information, to prevent opportunistic infections [
8]. A few cases of progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system characterized by progressive inflammation and damage to the brain, have been reported with the use of FAEs in patients with long-standing and pronounced lymphopenia. In all cases, patients had not been appropriately monitored. PML is indeed a clinically relevant risk; however, the risk is believed to be minimal, should appropriate and periodic blood monitoring be carried out in FAE-treated patients [
30].
In terms of their metabolism, FAEs are completely absorbed in the small intestine [
28]. DMF has a half-life of approximately 12 min and is hydrolyzed to monomethyl fumarate (MMF; also known as methyl hydrogen fumarate, MHF) which has a half-life of 36 h [
28]. MMF reaches peak plasma concentrations after 5–6 h, is metabolized via the citric acid cycle to fumaric acid, water and carbon dioxide, and is excreted mainly through the breath [
28]. DMF is considered to act as a prodrug of MMF. DMF has been the primary orally administered fumarate of interest in most preclinical studies.
Much of the available data regarding the mode of action of FAEs in psoriasis have been obtained using the licensed FAE combination; however, the relative contributions of each FAE component to the therapeutic activity remained unclear. Despite its widespread acceptance in Germany, as an empirical mixture of different FAEs, this FAE combination remains unapproved for psoriasis elsewhere [
26]. Current European S3 guidelines recommend FAEs for the short- and long-term treatment of moderate-to-severe plaque psoriasis [
33]. FAEs are also included in US guidelines, but with the caveat that they are not registered in that country [
24]. The Cochrane Collaboration stated that while FAEs are superior to placebo for the treatment of psoriasis, there was still a need for more robust clinical trials and long-term safety data [
5]. A recent phase III, double-blind, placebo-controlled study is a recent trial fulfilling such needs [
32].
Altogether, an improved understanding of the relative contribution of each individual FAE compound toward their overall therapeutic effect in psoriasis is desirable. As a general principle, single-compound preparations (i.e. medicines with just one active pharmaceutical ingredient) are preferable over ‘combination products’ containing different active agents. The presence of compounds in a product that is not necessary for the therapeutic effect should be critically discussed, because of possible side effects.
The aim of this review is to evaluate the available clinical data regarding the effects of individual FAEs, in particular DMF and MEF, to describe the relative contribution of these compounds to the effectiveness of the approved FA mixture in the management of psoriasis.