Review question
Are H1 antihistamines (which inhibit the action of chemicals released as part of an allergic reaction; known as 'histamines'), taken as tablets or liquid, effective and safe in people of any age with diagnosed eczema, if given in addition to creams and ointments, compared to treatment with an inactive substance (placebo) or nothing added to creams and ointments?
Background
Eczema (also known as 'atopic eczema/dermatitis') is a skin disorder frequently affecting both children and adults. In developed countries, 10% to 20% of all people are affected by eczema during their lifetime. The main symptom is itch, which results in scratching and, together with skin inflammation, frequently produces reddening of the skin. The symptoms of eczema can lead to sleeplessness and fatigue, lowering quality of life. Antihistamines are frequently given for itch (specifically H1 antihistamines taken by mouth), and they may alleviate the symptoms of eczema when given in addition to conventional treatments directly applied to the skin (e.g. emollients, moisturisers, steroid creams), although they are not thought to cure it. Many antihistamines are available without prescription, for instance, cetirizine or loratadine. Although H1 antihistamines are frequently prescribed for treating eczema, we do not know whether they are effective and safe.
Study characteristics
We searched for relevant studies up to May 2018. We included 25 randomised controlled trials with 3285 participants of all ages with diagnosed eczema. Eight studies included children or adolescents, and 17 included adults. The gender of participants and the severity of symptoms often were not reported. All studies were conducted in secondary care settings, including hospital clinics, research clinics, dermatology centres, and surgery centres, meaning that participants were likely to have more severe eczema than if recruitment occurred from first point of contact settings (i.e. primary care). All but one study compared H1 antihistamine versus placebo. Researchers studied 13 different H1 antihistamines, most of which were less sedating H1 antihistamines (known as 'second-generation antihistamines'). Studies lasted between three days and 18 months. Seven trials received funding from pharmaceutical companies; they are the largest trials included in this review.
Key results
We found no convincing evidence that H1 antihistamines help patients with eczema.
One study compared cetirizine 0.5 mg/kg/d versus placebo (in children over a period of 18 months). No data were provided on patient-assessed itch symptoms of eczema. Cetirizine is probably associated with fewer (mainly mild) adverse events and the need for slightly less additional H1 antihistamine to prevent flares. Even though physician-assessed clinical signs were reduced in both groups, results show no differences between groups (all moderate-quality evidence).
When compared with placebo, we found no evidence that an increased dose of cetirizine 10 mg/d over four weeks makes a difference in terms of patient-assessed itch, number of side effects, physician-assessed signs, or number of eczema flares as measured by the amount of treatment used (all low-quality evidence). Side effects reported in both groups included drowsiness, skin-related problems, breathing issues, and headaches.
Compared with placebo, fexofenadine 120 mg/d given to adults for one week probably slightly improves patient-assessed itch, as well as producing a greater reduction in the area of itch, as assessed by a physician, and it probably makes little or no difference in the number of participants experiencing side effects (mostly drowsiness and headaches) or in the extent of treatment required as an indicator of the number of eczema flares (all moderate-quality evidence).
We found no evidence of a difference between placebo and loratadine 10 mg/d given to adults for four weeks in patient-assessed itch, occurrence of side effects, or physician-assessed signs of eczema (all low-quality evidence). This study did not measure the number of eczema flares. Study authors reported only one side effect (folliculitis), which occurred with placebo.
Only one study measured quality of life, but results could not be analysed.
Quality of the evidence
For all outcomes across key comparisons, evidence was of low to moderate certainty. Reasons for lowering the quality of evidence include concerns over how studies were carried out and inclusion of too few participants, leading to less accurate results.
Based on the main comparisons, we did not find consistent evidence that H1 AH treatments are effective as 'add-on' therapy for eczema when compared to placebo; evidence for this comparison was of low and moderate quality. However, fexofenadine probably leads to a small improvement in patient-assessed pruritus, with probably no significant difference in the amount of treatment used to prevent eczema flares. Cetirizine was no better than placebo in terms of physician-assessed clinical signs nor patient-assessed symptoms, and we found no evidence that loratadine was more beneficial than placebo, although all interventions seem safe.
The quality of evidence was limited because of poor study design and imprecise results. Future researchers should clearly define the condition (course and severity) and clearly report their methods, especially participant selection and randomisation; baseline characteristics; and outcomes (based on the Harmonising Outcome Measures in Eczema initiative).
The symptoms of eczema can lead to sleeplessness and fatigue and may have a substantial impact on quality of life. Use of oral H1 antihistamines (H1 AH) as adjuvant therapy alongside topical agents is based on the idea that combining the anti-inflammatory effects of topical treatments with the blocking action of histamine on its receptors in the skin by H1 AH (to reduce the principal symptom of itch) might magnify or intensify the effect of treatment. Also, it would be unethical to compare oral H1 AH alone versus no treatment, as topical treatment is the standard management for this condition.
To assess the effects of oral H1 antihistamines as 'add-on' therapy to topical treatment in adults and children with eczema.
We searched the following databases up to May 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database (Global Resource of EczemA Trials; from inception). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We also searched the abstracts of four conference proceedings held between 2000 and 2018.
We sought RCTs assessing oral H1 AH as 'add-on' therapy to topical treatment for people with eczema compared with topical treatment plus placebo or no additional treatment as add-on therapy.
We used standard Cochrane methodological procedures. Primary outcome measures were 'Mean change in patient-assessed symptoms of eczema' and 'Proportion of participants reporting adverse effects and serious adverse events'. Secondary outcomes were 'Mean change in physician-assessed clinical signs', 'Mean change in quality of life', and 'Number of eczema flares'.
We included 25 studies (3285 randomised participants). Seventeen studies included 1344 adults, and eight studies included 1941 children. Most studies failed to report eczema severity at baseline, but they were conducted in secondary care settings, so it is likely that they recruited patients with more severe cases of eczema. Trial duration was between three days and 18 months. Researchers studied 13 different H1 AH treatments. We could not undertake pooling because of the high level of diversity across studies in terms of duration and dose of intervention, concomitant topical therapy, and outcome assessment. Risk of bias was generally unclear, but five studies had high risk of bias in one domain (attrition, selection, or reporting bias). Only one study measured quality of life, but these results were insufficient for statistical analysis.
Although this review assessed 17 comparisons, we summarise here the results of three key comparisons in this review.
Cetirizine versus placebo
One study compared cetirizine 0.5 mg/kg/d against placebo over 18 months in 795 children. Study authors did not report patient-assessed symptoms of eczema separately for pruritus. Cetirizine is probably associated with fewer adverse events (mainly mild) (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.46 to 1.01) and the need for slightly less additional H1 AH use as an indication of eczema flare rate (P = 0.035; no further numerical data given). Physician-assessed clinical signs (SCORing Atopic Dermatitis index (SCORAD)) were reduced in both groups, but the difference between groups was reported as non-significant (no P value given). Evidence for this comparison was of moderate quality.
One study assessed cetirizine 10 mg/d against placebo over four weeks in 84 adults. Results show no evidence of differences between groups in patient-assessed symptoms of eczema (pruritus measured as part of SCORAD; no numerical data given), numbers of adverse events (RR 1.11, 95% CI 0.50 to 2.45; mainly sedation, other skin-related problems, respiratory symptoms, or headache), or physician-assessed changes in clinical signs, amount of local rescue therapy required, or number of applications as an indicator of eczema flares (no numerical data reported). Evidence for this comparison was of low quality.
Fexofenadine versus placebo
Compared with placebo, fexofenadine 120 mg/d taken in adults over one week (one study) probably leads to a small reduction in patient-assessed symptoms of pruritus on a scale of 0 to 8 (mean difference (MD) -0.25, 95% CI -0.43 to -0.07; n = 400) and a greater reduction in the ratio of physician-assessed pruritus area to whole body surface area (P = 0.007; no further numerical data given); however, these reductions may not be clinically meaningful. Results suggest probably little or no difference in adverse events (mostly somnolence and headache) (RR 1.05, 95% CI 0.74 to 1.50; n = 411) nor in the amount of 0.1% hydrocortisone butyrate used (co-intervention in both groups) as an indicator of eczema flare, but no numerical data were given. Evidence for this comparison was of moderate quality.
Loratadine versus placebo
A study of 28 adults compared loratadine 10 mg/d taken over 4 weeks versus placebo. Researchers found no evidence of differences between groups in patient-assessed pruritus, measured by a 100-point visual analogue scale (MD -2.30, 95% CI -20.27 to 15.67); reduction in physician-assessed clinical signs (SCORAD) (MD -4.10, 95% CI -13.22 to 5.02); or adverse events. Study authors reported only one side effect (folliculitis with placebo) (RR 0.25, 95% CI 0.01 to 5.76). Evidence for this comparison was of low quality. Number of eczema flares was not measured for this comparison.