Background
Psoriasis is a long-term inflammatory skin condition that can markedly reduce the quality of life of affected individuals. Treatments taken by mouth (oral treatments), such as methotrexate, ciclosporin, and acitretin, are commonly prescribed to people with moderate to severe psoriasis. Oral fumaric acid esters (FAE) are licensed for the treatment of psoriasis in Germany but remain unlicensed in most other countries. This means that there are different treatment options offered to people in different countries.
Review question
What is the available evidence for the benefits and risks of using FAE for treating psoriasis?
Study characteristics
Our review included six randomised control trials (RCTs) that involved 544 participants. Five RCTs compared FAE with placebo, and one compared FAE with methotrexate. The outcomes we were interested in measuring were the Psoriasis Area and Severity Index (PASI), which is a psoriasis severity score, and the proportion of participants who discontinued treatment because of adverse (side) effects that are common but sufficiently serious that the drug had to be stopped, such as severe diarrhoea, infections, or cutaneous malignancy.
Key results
It was difficult to pool and compare results because outcome measures differed between the studies. Three studies reported significant benefit with FAE when compared with placebo after 12 to 16 weeks of treatment, but we could not combine these results in a statistical analysis to show the overall difference. The included studies did not fully examine the chance of discontinuing FAE treatment because of adverse effects, which is uncertain. One study showed that individuals on FAE are nearly five times more likely to develop nuisance adverse effects; the most common were diarrhoea and abdominal cramps, flushing, reversible protein loss in the urine, and raised levels of eosinophil blood cells. Two RCTs were similar enough to allow the combination of their results and found that FAE were better than placebo when measured by the proportion of individuals who experienced at least a 50% improvement in their psoriasis severity score. One study reported improvement of individuals' quality of life with FAE in comparison with placebo, but the significance of this difference could not be calculated. The benefit of FAE was similar to methotrexate after 12 weeks when changes in disease severity from the start to the end of the trial were compared. The number of individuals experiencing nuisance adverse effects with these two treatments was not significantly different. The included studies, which were too small and of limited duration to provide evidence about rare or delayed effects, reported no serious adverse effects of FAE.
Quality of the evidence
The risk of study bias, which means any factors that may systematically deviate away from the true findings, was unclear in most studies. This may be because most of the studies were conducted decades ago or were incompletely reported. Several analyses comparing FAE with placebo and methotrexate were limited because the studies were small or did not provide enough information to establish how these treatments compare with each other. Therefore, the overall quality of the evidence was low when comparing FAE with placebo and very low when comparing FAE with methotrexate.
Future RCTs should use standard psoriasis outcome measures, including a validated quality of life scale, to enable the comparison and combination of results. They should be longer in duration or have longer follow-up phases to provide evidence about any delayed adverse effects.
Evidence suggests that FAE are superior to placebo and possibly similar in efficacy to MTX for psoriasis; however, the evidence provided in this review was limited, and it must be noted that four out of six included studies were abstracts or brief reports, restricting study reporting. FAE are associated with nuisance adverse effects, including flushing and gastrointestinal disturbance, but short-term studies reported no serious adverse effects.
Psoriasis is a chronic inflammatory skin condition that can markedly reduce life quality. Several systemic therapies exist for moderate to severe psoriasis, including oral fumaric acid esters (FAE). These contain dimethyl fumarate (DMF), the main active ingredient, and monoethyl fumarate. FAE are licensed for psoriasis in Germany but used off-licence in many countries.
To assess the effects and safety of oral fumaric acid esters for psoriasis.
We searched the following databases up to 7 May 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 4, 2015), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials. We handsearched six conference proceedings that were not already included in the Cochrane Skin Group Specialised Register.
Randomised controlled trials (RCTs) of FAE, including DMF monotherapy, in individuals of any age and sex with a clinical diagnosis of psoriasis.
Two review authors independently assessed trial quality and extracted data. Primary outcomes were improvement in Psoriasis Area and Severity Index (PASI) score and the proportion of participants discontinuing treatment due to adverse effects.
We included 6 studies (2 full reports, 2 abstracts, 1 brief communication, and 1 letter), with a total of 544 participants. Risk of bias was unclear in several studies because of insufficient reporting. Five studies compared FAE with placebo, and one study compared FAE with methotrexate. All studies reported data at 12 to 16 weeks, and we identified no longer-term studies. When FAE were compared with placebo, we could not perform meta-analysis for the primary outcome of PASI score because the three studies that assessed this outcome reported the data differently, although all studies reported a significant reduction in PASI scores with FAE. Only 1 small study designed for psoriatic arthritis reported on the other primary outcome of participants discontinuing treatment due to adverse effects (2 of 13 participants on FAE compared with none of the 14 participants on placebo; risk ratio (RR) 5.36, 95% confidence interval (CI) 0.28 to 102.1; 27 participants; very low-quality evidence). However, these findings are uncertain due to indirectness and a very wide confidence interval. Two studies, containing 247 participants and both only reported as abstracts, allowed meta-analysis for PASI 50, which showed superiority of FAE over placebo (RR 4.55, 95% CI 2.80 to 7.40; low-quality evidence), with a combined PASI 50 of 64% in those given FAE compared with a PASI 50 of 14% for those on placebo, representing a number needed to treat to benefit of 2. The same studies reported more participants achieving PASI 75 with FAE, but we did not pool the data because of significant heterogeneity; none of the studies measured PASI 90. One study reported significant improvement in participants' quality of life (QoL) with FAE, measured with Skindex-29. However, we could not compute the mean difference because of insufficient reporting in the abstract. More participants experienced adverse effects, mainly gastrointestinal disturbance and flushing, on FAE (RR 4.72, 95% CI 2.45 to 9.08; 1 study, 99 participants; moderate-quality evidence), affecting 76% of participants given FAE and 16% of the placebo group (representing a number needed to treat to harm of 2). The other studies reported similar findings or did not report adverse effects fully.
One study of 54 participants compared methotrexate (MTX) with FAE. PASI score at follow-up showed superiority of MTX (mean Difference (MD) 3.80, 95% CI 0.68 to 6.92; 51 participants; very low-quality evidence), but the difference was not significant after adjustment for baseline disease severity. The difference between groups for the proportion of participants who discontinued treatment due to adverse effects was uncertain because of imprecision (RR 0.19, 95% CI 0.02 to 1.53; 1 study, 51 participants; very low-quality evidence). Overall, the number of participants experiencing common nuisance adverse effects was not significantly different between the 2 groups, with 89% of the FAE group affected compared with 100% of the MTX group (RR 0.89, 95% CI 0.77 to 1.03; 54 participants; very low-quality evidence). Flushing was more frequent in those on FAE, with 13 out of 27 participants affected compared with 2 out of 27 given MTX. There was no significant difference in the number of participants who attained PASI 50, 75, and 90 in the 2 groups (very low-quality evidence) whereas this study did not measure the effect of treatments on QoL. The included studies reported no serious adverse effects of FAE and were too small and of limited duration to provide evidence about rare or delayed effects.