Established corticosteroid creams should be applied only once daily in patients with atopic eczema

The clinical problem

Atopic eczema affects many adults and up to 20% of children,¹ with health costs comparable to diabetes² and asthma.³ One community survey of 1760 young children in the United Kingdom found that 84% had mild eczema, 14% moderate, and 2% severe eczema.⁴ Topical corticosteroids are a mainstay of treatment for inflammatory episodes.⁵ Most long established topical corticosteroids such as betamethasone valerate or hydrocortisone are applied at least twice daily, but three newer preparations (mometasone, fluticasone, and methylprednisolone) have been developed for once daily application. Here, I propose that established preparations need be applied only once daily.

The evidence for change

Ten randomised controlled trials compared once daily versus more frequent application of topical corticosteroids within the same potency group (table). The findings are summarised in a UK Health Technology Assessment report and guidance from the National Institute for Health and Clinical Excellence (NICE).^{6 7} Another short term study has been published more recently.⁸ One trial compared once versus twice daily moderately potent topical preparations; eight studies evaluated once versus twice daily potent preparations; one study compared once versus three times daily application of a super potent topical corticosteroid; and one study compared once versus twice daily super potent topical corticosteroids.^{6 8} Quality of reporting of the studies was generally poor except in three cases. Although some statistically significant outcomes favouring twice daily applications were identified, these were not consistent for the type of outcome selected or between doctors and patients. More importantly, none of the studies found clear evidence that applying topical corticosteroids more than once a day produced better overall clinical outcomes in eczema, such as the number of people with a good response. Clear evidence of a faster response with more frequent use or a better response in subgroups such as children was lacking. No data were given on relapse rates.

Randomised controlled trials comparing once daily application of topical corticosteroids with more frequent use in eczema

Date and country	Severity of eczema	Participants and setting	Corticosteroids tested	Main outcome measures	Results	Comment
1981, USA; unclear if company sponsored	Unclear; probably moderate to severe	149 people with bilateral eczema; pair wise comparisons were made; setting not reported	Superpotent; halcinonide 0.1% cream once daily plus placebo twice daily versus halcinonide 0.1% cream three times daily for 3 weeks	Compared response between arms (much better, slightly better, or equal response); improvement in lesions categorised as excellent (75-100%), good (50-74%), fair (25-49%), and poor (<25%)	31.5% responded better in three times daily group compared with 21.5% in once daily group; 47% showed no difference; 83.9% in three times daily group and 81.9% in once daily group had good or excellent response	Unusual study as once daily application was compared with three times daily; sides of the body were randomised; blinding was attempted; 33 dropped out by week 3 and it is unclear why; participants were inadequately described
1990, Italy; funding source unclear	Probably mild to moderate but no recognised severity scale	30 children; setting not reported	Moderate potency; clobetasone butyrate once daily versus twice daily at 8 am and 3 pm versus twice daily at 3 pm and 8 pm for 1 week	Mean scores of clinical severity in terms of symptoms and signs; serum cortisol and adrenocorticotrophin also measured	Reduction in symptoms and signs of eczema similar in all three groups but could be estimated only from graphs (see HTA systematic review)6	Poorly reported study; small numbers with low power to rule out small differences
1991, Denmark (3 centres); company sponsored	Probably moderate to severe	96 people aged 18-70 with typical atopic eczema seen at a dermatology clinic	Potent; mometasone furoate cream once daily versus hydrocortisone butyrate cream twice daily for 3 weeks	Doctor's global assessment of severity of eczema, patient's global assessment, serum cortisol values, and skin atrophy	88% in mometasone arm and 78% in hydrocortisone arm had clear or marked improvement (assessed by doctor) at 3 weeks (P=0.28); cortisol responses similar and no skin atrophy noted	Hydrocortisone butyrate usually considered less potent in the UK, so may not have been comparing like with like; poorly reported study
1993, Norway and Denmark; company sponsored	Mild to moderate and stable	116 people over 16 years old attending dermatology clinics	Potent; mometasone furoate 0.1% cream once daily versus betamethasone valerate 0.1% cream twice daily for 3 weeks	Improvement in global severity of eczema as assessed by doctor	Global improvement was 98% for mometasone and 86% for betamethasone (P<0.01)	Poorly reported study; could not tell if once or twice daily treatment was best as different corticosteroids were used in the two groups; once daily use of the newer compound seemed to be better than the older one used twice daily
1994, Italy; company sponsored	Probably moderate to severe; most had worsening disease at study entry	60 adults with stable or worsening disease attending 1 centre	Potent; mometasone furoate 0.1% ointment once daily versus betametasone dipropionate 0.05% ointment twice daily for 3 weeks	Individual skin signs, skin atrophy, and global scores	Similar numbers with skin clearance and good or moderate improvement in each group; changes in skin sign scores similar; 4 patients in the once daily and 5 in the twice daily group had mild telangiectasia	Poorly reported smaller study that compared a newer corticosteroid preparation once daily with an older compound twice daily
1995, UK (36 centres); company sponsored	At least moderate severity	270 people aged 1-65 referred to a dermatologist	Potent; fluticasone propionate 0.05% cream once daily plus vehicle once daily versus fluticasone propionate 0.05% cream twice daily	Doctor's global rating of target area, severity of six skin signs, adverse effects	Target area success was 80% and 85% for once daily and twice daily groups (P=0.35); sign scores were lower than baseline in 96% and 97%, respectively (P=0.72)	Quality of reporting good with an intention to treat analysis; subgroup analysis of 126 children under 12 years also reported in HTA report—results were similar to main study6
1995, 4 Nordic countries; company sponsored	Difficult to judge but probably moderate	150 people with atopic eczema aged 14-81	Probably potent; hydrocortisone butyrate 0.01% in lipocream once daily plus vehicle once daily versus hydrocortisone butyrate 0.01% in lipocream twice daily for 4 weeks	Individual skin signs graded on a 5 point scale and overall global improvement graded on a 6 point scale	Improvement in signs similar between the two groups; 96% of the once daily and 100% of the twice daily group showed at least definite improvement as assessed by a doctor (96% and 99% as assessed by the patient)	Poorly reported study; groups well balanced; unclear if hydrocortisone butyrate should be regarded as potent or less potent
1996, USA (9 centres); company sponsored	Probably moderate to severe although difficult to assess	238 patients with established eczema, aged ≥12 years	Potent; fluticasone propionate 0.05% once daily plus vehicle once daily, fluticasone propionate 0.05% twice daily, and vehicle only twice daily for 4 weeks	Doctor rated response of target lesion, signs and symptoms, and total severity score	69%, 78%, and 33% of patients in the once daily, twice daily active, and twice daily placebo groups had good or excellent clearance of target lesions. Mean change in total severity score was 79.5%, 81.8%, and 46.0% in the three groups	Quality of reporting was poor in parts; outcome measures not validated; large numbers of patients; none of the differences between once and twice daily fluticasone was clinically or statistically significant
1999, UK (35 centres); company sponsored	At least moderate	248 people aged 1-65 seen in secondary care	Potent: fluticasone propionate 0.005% cream once daily versus fluticasone propionate 0.005% cream twice daily for 4 weeks	Doctor's global rating of target area, various signs and symptoms, and adverse effects	72% and 84% of the once and twice daily groups had clear, good, or moderate improvement of target lesion (P=0.03); patient's assessment of target lesions not different; adverse events and dropout rates similar	Good comparison of the same topical steroid licensed for once daily use; full data were obtained from GlaxoSmithKline and published in full in the HTA report6; well reported study; subgroup analysis of those under 12 years showed similar results
2003, Northern Europe (39 centres)	Moderate to severe	376 people aged 12-56 attending dermatology outpatient clinics	Potent; fluticasone propionate 0.05% cream once daily versus twice daily versus ointment version of the same once and twice daily for four weeks (four groups in total)	Time to relapse and proportion with control of disease at end of stabilisation phase	80% and 84% of patients in the once daily and twice daily cream groups and 77% and 71% in the ointment groups had controlled eczema at end of stabilisation; no differences in adverse events	Good quality of reporting and a clean comparison of the same corticosteroid used once versus twice daily in a large number of people
2006, USA; company sponsored8	Moderate to severe (>20% of body surface involved)	121 children from various ethnic backgrounds in four sequential age cohorts (12-18 years, 6-12, 2-6, and <2) from several US centres	Superpotent; 0.1% fluocinonide cream applied once daily or twice daily for 2 weeks	HPA axis suppression and investigator rated efficacy measured in four categories: clear/almost clear, improved, not improved, and worse	Three children had biochemical evidence of HPA suppression—all in the twice daily groups; efficacy was similar in both groups (all had >90% improvement)	Study published since HTA report; short term study suggesting increased risk of HPA suppression with twice daily superpotent cream, although numbers were small; no efficacy data provided, so unable to calculate confidence intervals

The first 10 studies are cited and described in detail in the HTA report.⁶

HPA=hypothalamus-pituitary-adrenal; HTA=Health Technology Assessment.

KEY POINTS

• Established topical corticosteroids such as betamethasone valerate have typically been used twice daily or more frequently for treating inflammatory episodes of eczema

• Reducing the frequency of application to once daily does not seem to result in loss of efficacy and could lead to fewer local side effects

• Using topical corticosteroids just once a day may be more convenient for patients and may save costs if established preparations are used

The main adverse effect of topical corticosteroids is thinning of the skin.⁹ The studies included in the technology assessment were too short in duration (three to four weeks) to see if once daily application results in less skin thinning. However, as skin thinning is related to the amount and duration of topical corticosteroid, its strength, and its site of application,¹⁰ reducing the frequency of application could reduce local adverse effects.

It seems logical that applying topical corticosteroids once daily instead of twice daily would reduce costs by up to 50%. However, three newer potent topical corticosteroid preparations have been specifically manufactured and tested for once daily use (mometasone furoate, fluticasone propionate, and methylprednisolone aceponate^{7 11}). Newer once daily preparations may still cost more than twice daily use of older preparations such as betamethasone valerate. No trial has directly compared once daily betamethasone with once daily newer preparations. A blanket recommendation for a switch to once daily application of topical corticosteroids could paradoxically increase costs.⁶ This dilemma led to a mixed recommendation in the original NICE guidance to use topical corticosteroids once or twice daily and to use the cheapest alternative.⁷ Later papers have been more forthright in supporting once daily application of established corticosteroids.^{12 13}

The barriers to change

The case for changing to once daily application of established corticosteroids is strong. It is based on lack of evidence of superior efficacy in 11 randomised controlled trials; cost savings of up to 50% to the state or patient if an established preparation such as betamethasone valerate 0.1% is considered; the convenience to patients of applying preparations just once daily (important as a recent study suggested that mean adherence to twice daily topical corticosteroids was only 23%¹⁴); and the possibility that side effects such as skin thinning can be reduced. Conflicting written advice in package inserts can be overcome by counselling patients beforehand. A change to once daily topical corticosteroids was suggested 10 years ago.¹⁵ Perhaps the biggest barrier to change is habit.

How should we change our practice?

Patients using moderate, potent, or very potent topical corticosteroids more than once a day should switch to once daily use. However, the above evidence on short term use of mostly potent topical corticosteroids in people in secondary care may not be generalisable to those with very mild eczema using mild preparations, such as 1% hydrocortisone, for longer periods.