Leukotriene receptor antagonists for eczema
Eczema is a common, chronic, inflammatory skin condition that is frequently associated with atopic conditions, including asthma. Leukotriene receptor antagonists (LTRAs) have a corticosteroid‐sparing role in asthma, but their role in eczema remains controversial. Currently available topical therapies for eczema are often poorly tolerated, and use of systemic agents is restricted by their adverse effect profile. A review of alternative treatments was therefore warranted.
To assess the possible benefits and harms of leukotriene receptor antagonists for eczema.
We searched the following databases to September 2017: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database. We also searched five trial registries, and handsearched the bibliographies of all extracted studies for further relevant trials.
Randomised controlled trials of LTRAs alone or in combination with other (topical or systemic) treatments compared with other treatments alone such as topical corticosteroids or placebo for eczema in the acute or chronic (maintenance) phase of eczema in adults and children.
Data collection and analysis
We used the standard methodological procedures expected by Cochrane. The primary outcome measures were change in disease severity, long‐term symptom control, and adverse effects of treatment. Secondary outcomes were change in corticosteroid requirement, reduction of pruritis, quality of life, and emollient requirement. We used GRADE to assess the quality of the evidence for each outcome.
Only five studies (including a total of 202 participants) met the inclusion criteria, all of which assessed oral montelukast; hence, we found no studies assessing other LTRAs. Treatment ranged from four to eight weeks, and outcomes were assessed at the end of treatment; therefore, we could only report short‐term measurements (defined as less than three months follow‐up from baseline). Montelukast dosing was 10 mg for adults (age 14 years and above) and 5 mg for children (age 6 years to 14 years). One study included children (aged 6 years and above) among their participants, while the remaining studies only included adults (participant age ranged from 16 to 70 years). The participants were diagnosed with moderate‐to‐severe eczema in four studies and moderate eczema in one study. The study setting was unclear in two studies, multicentre in two studies, and single centre in one study; the studies were conducted in Europe and Bangladesh. Two studies were industry funded. The comparator was placebo in three studies and conventional treatment in two studies. The conventional treatment comparator was a combination of antihistamines and topical corticosteroids (plus oral antibiotics in one study).
Four of the studies did not adequately describe their randomisation or allocation concealment method and were considered as at unclear risk of selection bias. Only one study was at low risk of performance and detection bias. However, we judged all studies to be at low risk of attrition and reporting bias.
We found no evidence of a difference in disease severity of moderate‐to‐severe eczema after short‐term use of montelukast (10 mg) when compared with placebo. The outcome was assessed using the modified EASI (Eczema Area and Severity Index) score and SASSAD (Six Area, Six Sign Atopic Dermatitis) severity score (standardised mean difference 0.29, with a positive score showing montelukast is favoured, 95% confidence interval (CI) ‐0.23 to 0.81; 3 studies; n = 131; low‐quality evidence).
When short‐term montelukast (10 mg) treatment was compared with conventional treatment in one study, the mean improvement in severity of moderate‐to‐severe eczema was greater in the intervention group (measured using SCORAD (SCORing of Atopic Dermatitis) severity index) (mean difference 10.57, 95% CI 4.58 to 16.56; n = 31); however, another study of 32 participants found no significant difference between groups using the same measure (mean improvement was 25.2 points with montelukast versus 23.9 points with conventional treatment; no further numerical data provided). We judged the quality of the evidence as very low for this outcome, meaning the results are uncertain.
All studies reported their adverse event rate during treatment. Four studies (136 participants) reported no adverse events. In one study of 58 participants with moderate eczema who received montelukast 10 mg (compared with placebo), there was one case of septicaemia and one case of dizziness reported in the intervention group, both resulting in study withdrawal, although whether these effects were related to the medication is unclear. Mild side effects (e.g. headache and mild gastrointestinal disturbances) were also noted, but these were fairly evenly distributed between the montelukast and placebo groups. The quality of evidence for this outcome was low.
No studies specifically evaluated emollient requirement or quality of life. One study that administered treatment for eight weeks specifically evaluated pruritus improvement at the end treatment and topical corticosteroid use during treatment. We found no evidence of a difference between montelukast (10 mg) and placebo for both outcomes (low‐quality evidence, n = 58). No other study assessed these outcomes.
The findings of this review are limited to montelukast. There was a lack of evidence addressing the review question, and the quality of the available evidence for most of the measured outcomes was low. Some primary and secondary outcomes were not addressed at all, including long‐term control.
We found no evidence of a difference between montelukast (10 mg) and placebo on disease severity, pruritus improvement, and topical corticosteroid use. Very low‐quality evidence means we are uncertain of the effect of montelukast (10 mg) compared with conventional treatment on disease severity. Participants in only one study reported adverse events, which were mainly mild (low‐quality evidence).
There is no evidence that LTRA is an effective treatment for eczema. Serious limitations were that all studies focused on montelukast and only included people with moderate‐to‐severe eczema, who were mainly adults; and that each outcome was evaluated with a small sample size, if at all.
Further large randomised controlled trials, with a longer treatment duration, of adults and children who have eczema of all severities may help to evaluate the effect of all types of LTRA, especially on eczema maintenance.
Leila Ferguson, Masaki Futamura, Efstratios Vakirlis, Reiji Kojima, Hatoko Sasaki, Amanda Roberts, Rintaro Mori
Plain language summary
Are non‐steroidal anti‐inflammatory medicines known as leukotriene receptor antagonists helpful and safe for eczema?
We wanted to see if anti‐inflammatory leukotriene receptor antagonists (LTRAs) reduced symptoms or improved quality of life in adults and children with established eczema; if they are safe; and whether they could be recommended as an effective alternative eczema treatment. We included studies that compared LTRAs with other treatments alone, such as topical corticosteroids (anti‐inflammatory steroid (synthetic hormone) medications), or with placebo (an identical but inactive treatment).
Eczema, also called 'atopic eczema' and 'dermatitis', is a common dry skin condition. Eczema can be mild, moderate, or severe depending on how itchy or red the skin is, how much skin is affected, and its impact on daily life. Eczema is sometimes linked to a group of conditions, including asthma. Corticosteroids are a commonly used treatment, but long‐term treatment can produce unwanted side effects, such as skin thinning. LTRAs have been shown to improve asthma symptoms, and their use in eczema would reduce the amount of steroids used. LTRAs are not currently given for eczema, and whether they are effective for this condition is uncertain.
This evidence is current to September 2017. We found five studies with a total of 202 participants (both genders). All included participants had moderate‐to‐severe eczema diagnosed by a specialist doctor. The studies lasted four to eight weeks. The study setting was unclear in two studies, multicentre in two studies, and single centre in one study; the studies were conducted in Europe and Bangladesh. All studies used the LTRA montelukast, at a dose of either 5 mg or 10 mg. Only one study included children (31 participants, age 6 years and older). The age range for the other four studies was 16 to 70 years. LTRA treatment was compared with placebo or conventional treatment, which includes currently used eczema treatments, such as steroid creams. Varied scoring systems were used to calculate the effect of the treatments on participants' eczema. Two included studies were funded by the company that produces montelukast.
Limited available data meant we were unable to draw firm conclusions on the effectiveness of LTRA in eczema. Like other reviews on this topic, this review is unlikely to change how eczema is treated because there is no convincing evidence that montelukast, the only LTRA that could be assessed, is helpful for eczema.
We found no evidence of a difference between montelukast and placebo in terms of improving eczema disease severity (low‐quality evidence). When montelukast was compared with conventional treatment, participants using montelukast in one study saw an improvement in disease severity, but no difference was observed in another study. We are uncertain about these results because the quality of the evidence was very low.
None of the studies looked at long‐term eczema control, moisturiser (emollients) use, or quality of life.
We found no evidence that montelukast lessened itching or reduced the need for steroid creams during treatment when compared to placebo (low‐quality evidence). The studies comparing montelukast with conventional treatments did not assess these outcomes.
Participants in four studies did not experience side effects. In one study comparing montelukast with placebo, there were two reported incidents in the montelukast group that resulted in participant withdrawal: one episode of septicaemia (blood poisoning) and one episode of dizziness. However, it was not clear whether these were related to the montelukast treatment. Other mild side effects were reported (e.g. headache, stomach‐related disturbances), but by participants in both groups. We therefore found no evidence of a difference between montelukast and placebo or conventional treatments, but this is assessment is based on low‐quality evidence.
Quality of the evidence
The quality of evidence was low for all but one key result, that is montelukast’s effect on ‘change (improvement) in disease severity’ when compared with conventional treatment, the evidence for which was considered to be very low quality. Overall, very few studies addressed our review question.
Many outcomes were not assessed, including long‐term control, and those that were assessed had relatively few participants, which were mainly adults. The studies focused solely on moderate‐severe eczema, and there were concerns with the participants or investigators knowing which treatment was received.
Leila Ferguson, Masaki Futamura, Efstratios Vakirlis, Reiji Kojima, Hatoko Sasaki, Amanda Roberts, Rintaro Mori
Implications for practice
The overall objectives of this review were not well met by the evidence found: our findings are limited to montelukast, as this was the only leukotriene receptor antagonist (LTRA) used in all five studies. It is possible that the two studies assessing montelukast versus placebo in Characteristics of studies awaiting classification might have altered the conclusions of the review had more data been available from them.
The majority of the participants in the included studies were adults, and all had either moderate or severe eczema. Furthermore, the trials were short term and did not measure some of our chosen outcomes. We were thus unable to draw conclusions on the effect of LTRA on children or those with mild or chronic eczema, as well as the following outcomes: need for emollient use, effect on long‐term control, or improvement in quality of life.
We found no evidence of a difference between montelukast (10 mg) and placebo on disease severity, reduction of pruritus, or topical corticosteroid use (low‐quality evidence).
Very‐low quality evidence means we are uncertain of the effect of montelukast (10 mg) compared with conventional treatment on disease severity.
Participants in only one study reported adverse events, which were mainly mild (low‐quality evidence).
Based on the evidence in this review, montelukast may add no benefit to current conventional eczema treatments more than placebo.
Implications for research
Given that the studies included in this review provided inconsistent results, we were unable to draw robust conclusions about the use of LTRA in eczema in the short term. Since most of the included studies focused on adults and lasted three months or less, further longer‐term research focusing on children may be worthwhile, as may further studies in adults. Future trials might include people with eczema of varying severity (including mild eczema). Encouragingly, a study awaiting classification that we identified is looking solely at the effect of LTRA in the paediatric population (Melamed 2010).
Future randomised controlled trials should be rigorously designed and conducted, including undertaking a sample size calculation and ensuring blinding. Furthermore, they should follow the CONSORT statement to ensure that they adequately report on methodological aspects as well as complete and transparent reporting (CONSORT 2010). This will improve critical appraisal and interpretation as well as assessment of the validity of the results.
Eczema should not be grouped together with other atopic conditions, such as asthma; otherwise, conclusions that are separate to the effects in asthma cannot be extracted. However, the subgroup of those with eczema and asthma would be worth evaluation, because this phenotype might represent a more responsive group than those with eczema only. One included study involved participants with both eczema and asthma (Capella 2001), but we could not conduct any sensitivity analyses. All the included studies used montelukast as the LTRA for intervention. The current evidence on adverse effects means that this continues to be the LTRA of choice, for the time being. Any future studies should specially report on adverse effects.
Since the evidence does not currently support LTRA as an effective treatment for eczema, further studies comparing LTRA to placebo may be warranted. Longer‐term randomised controlled trials comparing montelukast with conventional treatment (topical steroids and emollients) versus conventional treatment alone that look at the effectiveness of LTRA as a maintenance therapy would only be worthwhile if positive effects were seen in trials of LTRA versus placebo. All studies included in this review had a treatment duration of eight weeks or less. A longer study period would enable evaluation of alternative outcome measures, such as flare‐free remission periods. Future studies might also assess other available LTRAs such as zafirlukast (sold as Accolate).
Outcome measures currently in use include validated severity scores, and these are appropriate. Additional measures that would be beneficial include explicit recording of topical corticosteroid use to enable precise comparisons between groups, quality of life measures, emollient use, specific analysis of measures such as pruritus and sleep, as well as maintenance outcomes such as flare‐free periods. All measures reported should include measures of effect, such as standard deviation, to enable review authors to conduct meta‐analyses.
Many cross‐over studies are being conducted in this area, due to the capacity of individuals to act as their own control. However, particularly with short study durations, this style of study is more challenging to analyse, as the effect of an intervention may hangover into the washout period and beyond. Additionally, eczema is a very variable condition, and this study design is more suited to constant chronic conditions rather than relapsing remitting types. Any future trials should report adequately on methods of allocation and potential sources of bias, as many studies analysed here did not.
Conventional therapies in eczema involve laborious application of topical therapies and are often aimed at short‐term acute flare resolution. A longer‐term maintenance therapy that is more acceptable to patients is still needed. These recommendations for future research are valid to September 2017, the date of our last search.