Oral fumaric acid esters for psoriasis
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.
Data collection and analysis
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.
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.
Ausama Atwan, John R Ingram, Rachel Abbott, Mark J Kelson, Timothy Pickles, Andrea Bauer, Vincent Piguet
Plain language summary
Oral fumaric acid esters for the treatment of psoriasis
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.
What is the available evidence for the benefits and risks of using FAE for treating psoriasis?
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.
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.
Ausama Atwan, John R Ingram, Rachel Abbott, Mark J Kelson, Timothy Pickles, Andrea Bauer, Vincent Piguet
Implications for practice
The results of this review should be interpreted with caution because of the relatively small number of participants treated in the qualifying randomised controlled trials (RCTs) and lack of meta‐analyses due to outcome measure heterogeneity in the pre‐Psoriasis Area and Severity Index (PASI) era when some studies were conducted. The limited data obtained from this review provide evidence that oral fumaric acid esters (FAE) are superior to placebo and may be similar in efficacy to methotrexate (MTX). Because of the different ways of reporting changes in PASI scores in studies comparing FAE with placebo, we could only establish the magnitude of benefit for PASI 50. This was 4.5 times more likely to be achieved with FAE after 12 to 16 weeks, with a number needed to treat to benefit of 2. The single study comparing FAE with MTX demonstrated a similar reduction in mean PASI scores from baseline after 12 weeks, with a 7.6‐point reduction for the FAE group compared with a 7.8‐point reduction for those given MTX. Data from only one relatively small study, in which all participants had psoriatic arthritis, suggest that FAE are not associated with a higher rate of treatment discontinuation compared with placebo. However, this is at odds with clinical experience and the results of the prospective observational study by Walker 2014. The concomitant psoriatic arthritis may have affected this finding, so larger studies of participants selected primarily with cutaneous psoriasis are needed to provide a definitive answer. Commonly reported adverse effects associated with FAE include gastrointestinal symptoms (58% of participants in 1 study), flushing (42%, 48%, and 95% in 3 studies), eosinophilia (18.5% and 38.5% in 2 studies), and reversible proteinuria (29.6% in 1 study). However, the RCTs examined did not report long‐term follow‐up data, so the review cannot comment on long‐term safety of FAE for psoriasis, which is important because FAE may be taken for several years in routine clinical practice.
Implications for research
This review has highlighted several important gaps in the evidence base for the treatment of psoriasis with FAE. One of the main issues is outcome measure heterogeneity as some included RCTs were conducted prior to PASI and quality of life becoming the accepted efficacy measures for psoriasis. This will permit meta‐analysis of efficacy data. Comparison with active controls, such as methotrexate, is to be encouraged because these are well established as effective, licensed systemic therapies. The relative efficacy of FAE compared with other systemic psoriasis therapies is also important to establish in the context of the relatively high cost of FAE in most countries. This may be addressed by the ongoing trials, which aim to compare FAE with different active comparators, such as acitretin and biologic therapies (etanercept, adalimumab, and secukinumab). It is worth noting that the status of some of these ongoing trials is unknown (see Ongoing studies), so it is unclear whether they were ever completed or whether there might be any issue of publications bias.
The current RCTs available have not fully established the timescale in which FAE produce benefit in psoriasis. There is now consensus regarding gradual dose increments for FAE (Pathirana 2009) following treatment initiation, which should allow RCTs to compare speed of FAE action with other systemic therapies. Hence, an important future clinical trial would be a comparison of FAE with MTX both dosed using standardised increments and ensuring 12 weeks of treatment at the maximum dose prior to measuring the primary efficacy outcomes of PASI 75 and quality of life, as well as clear reporting of treatment discontinuation due to adverse effects.
This review also highlighted problems in the reporting of AE data, with much of this data either absent or not reported to Consolidated Standards of Reporting Trials (CONSORT) (www.consort‐statement.org). Following these clinical trial standards and ensuring consistency in reported outcomes based on the Core Outcome Measures in Effectiveness Trials (COMET) initiative are necessary to enhance the quality and robustness of evidence. Following the schedule of dose increments according to the European S3 guidelines will allow an accurate measure of adverse effects associated with FAE and the rate of treatment discontinuation because of these adverse effects. There is still a need to establish long‐term safety of FAE with a large enough patient cohort to detect rare adverse effects; this evidence should be available in the relatively near future from registers of biologic interventions for psoriasis that contain a systemic medications arm, such as the UK British Association of Dermatologists Biologic Interventions Register (BADBIR) database (Burden 2012).