Full details of the process of study selection are provided in Fig. 1. Four studies which examined a total of 296 adult patients were included (Table 1). Two studies [20, 23] were assessed as at unclear risk of bias, and two studies [21, 22] as at high risk of bias. Lack of blinding of the patients was the principal reason that the studies were judged as high risk of bias (Fig. 2).

Table 1 Characteristics of the included studies and results Full size table

Fig. 2 Risk of bias summary Full size image

In the study of Gehring and Gloor, EUL containing 4% urea twice daily was compared to hydrocortisone acetate 1% in EUL in 69 participants over a period of 1 week [20]. Disease severity was assessed by the participants as roughness of the skin on a visual analogue scale (VAS) from 1 to 10, with higher being better. VAS scores increased from baseline after 1 week by 2.19 [1.31 standard deviation (SD)] in the 31 patients treated with EUL and 2.60 (0.98 SD) in the 32 patients that applied hydrocortisone acetate 1% in EUL with a MD of −0.41 (95% CI −0.98 to 0.16; P = 0.16). Our primary outcomes participant satisfaction and adverse events were not evaluated. Investigators assessed redness on a 1–4 scale (lower score being less red). The changes in redness after 1 week were −0.84 (0.66 SD) in the EUL group and −1.00 (0.52 SD) in the hydrocortisone acetate 1% in EUL group (MD 0.16, 95% CI −0.13 to 0.45; P = 0.29). Roughness was also assessed on a scale from 1 to 4 and showed changes of −0.97 (0.59 SD) and −1.06 (0.45 SD), respectively, with a MD of 0.09 (95% CI −0.18 to 0.36; P = 0.52). The other secondary outcomes were not assessed. The quality of the evidence was low to moderate for the addressed outcomes (see Table 2).

Table 2 Summary of findings table study of Gehring and Gloor [20] Full size table

A study by Simpson et al. had a within participant design in which CRM twice daily was compared to ‘no moisturizer’ on the contralateral leg of 20 patients over a period of 27 days [23]. Two of our primary outcomes, disease severity as assessed by the participants and their satisfaction with the moisturizer, were not evaluated. Adverse events were evaluated and there were none reported to the treatment. In this study, the investigators used a dryness scale (0–4, higher score being worse) to assess disease severity. The reductions reported at the end of 27 days were 1.15 (0.41 SD) on the legs of the 20 patients treated with CRM and 0.91 (0.58 SD) on the non-treated contralateral legs with a mean of the paired differences of −0.24 (95% CI −0.42 to −0.06). In addition, both TEWL (measured with an evaporimeter) and skin hydration (measured with a corneometer) were used to investigate changes in skin barrier function. The reduction in TEWL was 1.59 g/m2/h (0.97 SD) on the CRM treated legs and 0.42 g/m2/h (1.13 SD) on the contralateral legs with a mean of the paired differences of −1.17 g/m2/h (95% CI −1.52 to −0.82). However, both of these reductions can be regarded as relatively minimal. Skin hydration improved by 16.91 units (6.31 SD) on the CRM treated legs and by 3.3 (3.86 SD) on the non-treated contralateral legs (mean of the paired differences 13.61, 95% CI 11.60–15.60). There was a statistically significant difference in favor of CRM for all of these specific investigator-assessed outcomes. None of the other secondary outcomes (prevention of flares, change in active topical treatment and quality of life) were assessed in this study. The quality of the evidence was rated low to very low for the prespecified outcomes that were addressed (see Table 3).

Table 3 Summary of findings table study of Simpson [23] Full size table

The two studies at high risk of bias (due to lack of blinding of the participants) evaluated topical corticosteroids plus moisturizer versus topical corticosteroid alone [21, 22].

In Hanifin et al. desonide 0.05% lotion twice daily in combination with the use of moisturizing cream three times daily (CMC) was compared over a period of 3 weeks to desonide 0.05% lotion twice daily, in 80 participants in a within-participant study design [21]. In the within-participant design study of Simpson et al., routine use of topical corticosteroids combined with twice daily CRM was compared to routine use of topical corticosteroids alone without the use of any moisturizer [22]. This study examined these comparisons in 123 patients over a 4-week period [22]. Participant-assessed disease severity was not assessed in either of the two studies. However, although participant satisfaction was measured in both, it did not involve the more direct measurement of our outcome of ‘satisfaction’. Thus, in Hanifin et al. [21], it was measured as ‘preference’, and in Simpson et al. [22] as ‘perception of the product’. In Hanifin et al. [21], the combined therapy of desonide 0.05% lotion plus moisturizing cream was preferred by 96% of the 78 participants and the remaining 4% preferred the desonide 0.05% lotion without the use of any moisturizer. In the other study [22], between 84.3% and 96.7% of the 123 participants reported that adding CRM to topical corticosteroids “reduces inflammation, relieves dry and itchy skin, provides long-lasting hydration, leaves skin protected and maintains healthy skin” [22]. Adverse events were only reported in one of the two studies [21]. After the 1st week of the study, 10 of the 80 participants reported burning and stinging on the side treated with desonide 0.05% and moisturizer, compared to 11 reports on the side treated with desonide 0.05% lotion alone. However, after 3 weeks, no adverse events were reported for the combined treatment, but two participants still reported burning and stinging on the side treated with desonide 0.05% lotion alone [21].

The investigators in Hanifin et al. assessed disease severity as ‘global assessment of improvement’ [21]. Based on a per-protocol analysis of 78 participants and their assessments, 70% of the participants were markedly improved to ‘clear’ on the body side treated with desonide 0.05% lotion with moisturizer used three times a day, versus 55% on the side that was treated with only desonide 0.05% lotion (investigators reported a P value of <0.01).

The investigators in Simpson et al. used the Eczema Area and Severity Index (EASI; score 0–72, higher is worse) [22]. The reductions in EASI were small on both sides and did not meet the minimal important difference (MID) of 6.6 [27]. On the side treated with desonide 0.05% lotion and moisturizer the reduction was 1.28 (1.94 SD) and on the desonide 0.05% lotion ‘only’ treated side 1.0 (1.50 SD), with a mean of the paired differences of −0.27 (95% CI −0.52 to −0.02), which although statistically significant is not clinically important.

Only Simpson et al. investigated skin barrier function using corneometry [22]. On the side treated with topical corticosteroids combined with moisturizer, skin hydration increased by 5.4 arbitrary units compared to 3 arbitrary units on the side treated with topical corticosteroids alone, both of which were considered small improvements. The other secondary outcomes (prevention of flares, change in topical active treatments and quality of life) were not assessed in these two studies. The quality of evidence was rated low to moderate for the addressed outcomes (see Table 4).