Eighteen RCTs (n=6,904) were included in the review. Eight (n=2,601), including three submitted on an in-confidence basis, evaluated pimecrolimus and ten (n=4,303) evaluated tacrolimus.
The studies were of varying quality. Four studies reported adequate methods of randomisation and five reported blinding of assessors and/or patients. All but one study stated potential conflicts of interest. Most of the studies used intention-to-treat analysis, had high rates of withdrawals, and were rated as having high generalisability. The studies were generally short term (6 weeks); one study in children lasted 12 months.
Children (3 RCTs).
One RCT reported a greater improvement in IGA scores with pimecrolimus compared with placebo, either by at least one point (59.9% versus 33.1%), or in indicating that the skin was clear or almost clear of eczema (26.9 versus 2.9 at 3 weeks, P<0.05; 27% versus 11.8% at 6 weeks, P<0.001). This RCT also reported that a significantly greater proportion of children on pimecrolimus had well or completely controlled eczema (60% versus 39%, P<0.05) and a greater median reduction in the EASI score (45% versus 1%, P<0.001), and more children had mild or absent pruritis compared with the control group (57% versus 34%).
A second RCT reported that more children treated with pimecrolimus had no flares at 6 and 12 months compared with those treated with topical corticosteroids (76% versus 52% and 71% versus 43%, respectively). This RCT also reported that a greater proportion of children using pimecrolimus were not using topical corticosteroids (64.7% versus 37.1%, P<0.05) or antihistamines (57.2% versus 92.9%), and used topical corticosteroids for fewer days (4.1 versus 9.1 days) compared with the use of emollients.
The third RCT was confidential.
Adults (5 RCTs).
One RCT reported an improvement in the IGA score of at least one point, indicating that the skin was clear or almost clear of eczema, in a higher proportion of those treated with pimecrolimus compared with placebo(68.6% versus 36.5%, P<0.001). This RCT also reported that more people had no flares at 24 weeks (44.8% versus 18.8%, P<0.001), had a longer time to first flare (144 versus 26 days), avoided the use of topical corticosteroids (14.2 versus 37.2 days usage, P<0.001), and had greater decreases in the quality of life index - atopic dermatitis (QoLIAD) (25.6% versus 7.4%) and Dermatology Life Quality Index (DLQI) scores (22% versus 6.7%) with pimecrolimus compared with placebo.
A second RCT reported that the proportion of patients whose eczema was clear or almost clear at 3 weeks was higher with pimecrolimus than with placebo (11.1% versus 0%, P=0.056), but lower than with topical corticosteroids (11.1% versus 50%, P<0.05). This RCT also reported a greater reduction in EASI scores (pimecrolimus 48.3%; corticosteroids 78%; placebo 0%) and that fewer people had mild to moderate pruritis at 12 months (pimecrolimus 46.7%; corticosteroids 81%; placebo 18.6%) with treatment compared with placebo.
A third RCT reported that topical corticosteroids significantly increased the proportion of patients with moderate or better improvements on the IGA scale compared with pimecrolimus (88.8% versus 52.3%, P<0.001). This RCT also reported a greater reduction in EASI scores (73.9% versus 50.7%, P=0.006) and that more people had mild to moderate pruritis at 12 months (52.4% versus 24.7%, P=0.069) with corticosteroids than with pimecrolimus.
A fourth RCT reported significantly more people had totally or partially cleared eczema (93.8% versus 12.5%, P<0.001) and a greater mean decrease in the Atopic Dermatitis Severity Index score (79.1% versus 10.3%, P<0.01) with pimecrolimus compared with placebo.
The fifth RCT was confidential.
Adverse effects were reported in 4 RCTs. Minor local adverse effects were common: in 3 RCTs, up to 49% of patients reported burning at the application site with pimecrolimus, compared with 3.1 to 35% with placebo and 10% with corticosteroids. The meta-analysis showed no significant difference between pimecrolimus and placebo for rates of bacterial infection or skin burning. Pimecrolimus significantly increased viral infections in comparison with placebo (relative risk 1.97, 95% confidence interval, CI: 1.21, 3.19).
The studies were of varying quality. Five studies reported methods of randomisation. Withdrawal rates were high in groups allocated to placebo. Most of the studies used a modified intention-to-treat analysis. The studies were generally short term (2 to 3 weeks, range: 2 weeks to 6 months). All studies in children and 3 of the 5 studies in adults were rated as having high generalisability.
Children (4 RCTs). Tacrolimus 0.03% was significantly more effective (at least 90% on PGE) than corticosteroids at 3 weeks in children with moderate to severe eczema (RR 2.56, 95% CI: 1.95, 3.36; 2 RCTs). Two further RCTs showed that, compared with placebo, 0.03% and 0.1% tacrolimus ointment significantly increased the proportion of patients cleared or markedly improved on the PGE scale (P<0.007 and P<0.001).
Three RCTs reported statistically significant mean improvements in the EASI score with 0.1% and 0.03% tacrolimus compared with placebo (77%, 72%, 26%, P<0.001; 82%, 75%, 37%, P<0.001; and 76.7%, 66.7%, 47.6%, P<0.001).
Two of 3 RCTs reported greater improvements in the pruritus visual analogue scale score with 0.1% and 0.03% tacrolimus compared with placebo (3.9, 3.2, 1.8, P=0.027; 3.9, 3.9, 0.8; and 3.0%, 2.6%, 3.1%).
Further results for the secondary outcomes were reported.
Adults (7 RCTs).
Six RCTs reported changes in the PGE scale. Three RCTs studied 0.03% tacrolimus and reported improvements in eczema compared with placebo (46.2% versus 13.8%, P<0.041; and 59% versus 10%), but not compared with topical corticosteroids (57.9% versus 70.9%). All 6 RCTs reported results for 0.1% tacrolimus, and reported greater efficacy compared with placebo (100% versus 0%; 57% versus 13.8%, P<0.001; and 81% versus 10%, P<0.001) and topical corticosteroids, but not significantly so (60.7% versus 56.5%; 62.9% versus 40.7%; and 76.9% versus 70.9%). A meta-analysis of 2 RCTs showed that tacrolimus 0.1% was not more effective (at least 75% on the PGE scale) than corticosteroids in adults with moderate to severe eczema (RR 1.08, 95% CI: 0.97, 1.21).
Two RCTs did not report the PGE scale. One reported greater improvements on the EASI scale with topical corticosteroids compared with 0.03% tacrolimus (P<0.05), but not 0.1% tacrolimus. The other reported a greater reduction in the DLQI score with 0.03% and 0.1% tacrolimus compared with placebo (21.1, 27.1 and 5.6, respectively).
Further results for the secondary outcomes were reported.
Withdrawal due to adverse effects occurred in 1.6 to 5.7% of participants on tacrolimus, compared with 4.5 to 12.3% on placebo and 1.6 to 3.3% on topical corticosteroids. The meta-analysis showed no significant difference in overall skin infections between 0.03% or 0.1% tacrolimus and topical corticosteroids. Skin burning was significantly more common with tacrolimus 0.03% (RR 3.49, 95% CI: 2.33, 5.52; 1 RCT) and tacrolimus 0.1% (RR 4.17, 95% CI: 3.36, 5.18; 3 RCTs) in comparison with topical corticosteroids.