Topical anti‐inflammatory treatments for eczema: network meta‐analysis

Abstract

Background

Eczema (atopic dermatitis) is the most burdensome skin condition worldwide and cannot currently be prevented or cured. Topical anti‐inflammatory treatments are used to control eczema symptoms, but there is uncertainty about the relative effectiveness and safety of different topical anti‐inflammatory treatments.

Objectives

To compare and rank the efficacy and safety of topical anti‐inflammatory treatments for people with eczema using a network meta‐analysis.

Search methods

We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries on 29 June 2023, and checked the reference lists of included studies.

Selection criteria

We included within‐participant or between‐participant randomised controlled trials (RCTs) in people of any age with eczema of any severity, but excluded trials in clinically infected eczema, seborrhoeic eczema, contact eczema, or hand eczema. We included topical anti‐inflammatory treatments used for at least one week, compared with another anti‐inflammatory treatment, no treatment, or vehicle/placebo. Vehicle is a 'carrier system' for an active pharmaceutical substance, which may also be used on its own as an emollient for dry skin. We excluded trials of topical antibiotics used alone, complementary therapies, emollients used alone, phototherapy, wet wraps, and systemic treatments.

Data collection and analysis

We used standard Cochrane methods. Primary outcomes were patient‐reported eczema symptoms, clinician‐reported eczema signs and investigator global assessment. Secondary outcomes were health‐related quality of life, long‐term control of eczema, withdrawal from treatment/study, and local adverse effects (application‐site reactions, pigmentation changes and skin thinning/atrophy were identified as important concerns through patient and public involvement). We used CINeMA to quantify our confidence in the evidence for each outcome.

Main results

We included 291 studies involving 45,846 participants with the full spectrum of eczema severity, mainly conducted in high‐income countries in secondary care settings. Most studies included adults, with only 31 studies limited to children aged < 12 years. Studies usually included male and female participants, multiple ethnic groups but predominantly white populations. Most studies were industry‐funded (68%) or did not report their funding sources/details. Treatment duration and trial participation were a median of 21 and 28 days (ranging from 7 days to 5 years), respectively. Interventions used were topical corticosteroids (TCS) (172), topical calcineurin inhibitors (TCI) (134), phosphodiesterase‐4 (PDE‐4) inhibitors (55), janus kinase (JAK) inhibitors (30), aryl hydrocarbon receptor activators (10), or other topical agents (21). Comparators included vehicle (170) or other anti‐inflammatory treatments. The risk of bias was high in 242 of the 272 (89.0%) trials contributing to data analyses, most commonly due to concerns about selective reporting. Network meta‐analysis (NMA) was only possible for short‐term outcomes.

Patient‐reported symptoms

NMA of 40 trials (6482 participants) reporting patient‐reported symptoms as a binary outcome ranked tacrolimus 0.1% (OR 6.27, 95% CI 1.19 to 32.98), potent TCS (OR 5.99, 95% CI 2.83 to 12.69), and ruxolitinib 1.5% (OR 5.64, 95% CI 1.26 to 25.25) as the most effective, all with low confidence. Mild TCS, roflumilast 0.15%, and crisaborole 2% were the least effective. Class‐level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and was more effective than mild TCI and PDE‐4 inhibitors.

NMA of 29 trials (3839 participants) reporting patient‐reported symptoms as a continuous outcome ranked very potent TCS (SMD ‐1.99, 95% CI ‐3.25 to ‐0.73; low confidence) and tacrolimus 0.03% (SMD ‐1.57, 95% CI –2.42 to ‐0.72; moderate confidence) the highest. Direct information for tacrolimus 0.03% was based on one trial of 60 participants at high risk of bias. Roflumilast 0.15%, delgocitinib 0.25% or 0.5%, and tapinarof 1% were the least effective. Class‐level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and mild/moderate TCS was less effective than mild TCI.

A further 50 trials (9636 participants) reported patient‐reported symptoms as a continuous outcome but could not be included in NMA.

Clinician‐reported signs

NMA of 32 trials (4121 participants) reported clinician signs as a binary outcome and ranked potent TCS (OR 8.15, 95% CI 4.99, 13.57), tacrolimus 0.1% (OR 8.06, 95% CI 3.30, 19.67), ruxolitinib 1.5% (OR 7.72, 95% CI 4.92, 12.10), and delgocitinib 0.5% (OR 7.61, 95% CI 3.72, 15.58) as most effective, all with moderate confidence. Mild TCS, roflumilast 0.15%, crisaborole 2%, and tapinarof 1% were the least effective. Class‐level sensitivity analysis found potent/very potent TCS more effective than potent TCI, mild TCI, JAK inhibitors, PDE‐4 inhibitors; and mild TCS and PDE‐4 inhibitors had similar effectiveness.

NMA of 49 trials (5261 participants) reported clinician signs as a continuous outcome and ranked tacrolimus 0.03% (SMD ‐2.69, 95% CI ‐3.36, ‐2.02) and very potent TCS (SMD ‐1.87, 95% CI ‐2.69, ‐1.05) as most effective, both with moderate confidence; roflumilast 0.15%, difamilast 0.3% and tapinarof 1% were ranked as least effective. Direct information for tacrolimus 0.03% was based on one trial in 60 participants with a high risk of bias. For some sensitivity analyses, potent TCS, tacrolimus 0.1%, ruxolitinib 1.5%, delgocitinib 0.5% and delgocitinib 0.25% became some of the most effective treatments. Class‐level analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors, and moderate/mild TCS was more effective than mild TCI.

A further 100 trials (22,814 participants) reported clinician signs as a continuous outcome but could not be included in NMA.

Investigator Global Assessment

NMA of 140 trials (23,383 participants) reported IGA as a binary outcome and ranked ruxolitinib 1.5% (OR 9.34, 95% CI 4.8, 18.18), delgocitinib 0.5% (OR 10.08, 95% CI 2.65, 38.37), delgocitinib 0.25% (OR 6.87, 95% CI 1.79, 26.33), very potent TCS (OR 8.34, 95% CI 4.73, 14.67), potent TCS (OR 5.00, 95% CI 3.80, 6.58), and tacrolimus 0.1% (OR 5.06, 95% CI 3.59, 7.13) as most effective, all with moderate confidence. Mild TCS, crisaborole 2%, pimecrolimus 1%, roflumilast 0.15%, difamilast 0.3% and 1%, and tacrolimus 0.03% were the least effective. In a sensitivity analysis of low risk of bias information (12 trials, 1639 participants), potent TCS, delgocitinib 0.5% and delgocitinib 0.25% were most effective, and pimecrolimus 1%, roflumilast 0.15%, difamilast 1% and difamilast 0.3% least effective. Class‐level sensitivity analysis found potent/very potent TCS had similar effectiveness to potent TCI and JAK inhibitors and were more effective than PDE‐4 inhibitors; mild/moderate TCS were less effective than potent TCI and had similar effectiveness to mild TCI.

Longer‐term outcomes over 6 to 12 months showed a possible increase in effectiveness for pimecrolimus 1% versus vehicle (4 trials, 2218 participants) in a pairwise meta‐analysis, and greater treatment success with mild/moderate TCS than pimecrolimus 1% (based on 1 trial of 2045 participants).

Local adverse effects

NMA of 83 trials (18,992 participants, 2424 events) reporting application‐site reactions ranked tacrolimus 0.1% (OR 2.2, 95% CI 1.53, 3.17; moderate confidence), crisaborole 2% (OR 2.12, 95% CI 1.18, 3.81; high confidence), tacrolimus 0.03% (OR 1.51, 95%CI 1.10, 2.09; low confidence), and pimecrolimus 1% (OR 1.44, 95% CI 1.01, 2.04; low confidence) as most likely to cause site reactions. Very potent, potent, moderate, and mild TCS were least likely to cause site reactions.

NMA of eight trials (1786 participants, 3 events) reporting pigmentation changes found no evidence for increased pigmentation changes with TCS and crisaborole 2%, with low confidence for mild, moderate or potent TCS and moderate confidence for crisaborole 2%.

NMA of 25 trials (3691 participants, 36 events) reporting skin thinning found no evidence for increased skin thinning with short‐term (median 3 weeks, range 1‐16 weeks) use of mild TCS (OR 0.72, 95% CI 0.12, 4.31), moderate TCS (OR 0.91, 95% CI 0.16, 5.33), potent TCS (OR 0.96, 95% CI 0.21, 4.43) or very potent TCS (OR 0.88, 95% CI 0.31, 2.49), all with low confidence. Longer‐term outcomes over 6 to 60 months showed increased skin thinning with mild to potent TCS versus TCI (3 trials, 4069 participants, 6 events with TCS).

Authors' conclusions

Potent TCS, JAK inhibitors and tacrolimus 0.1% were consistently ranked as amongst the most effective topical anti‐inflammatory treatments for eczema and PDE‐4 inhibitors as amongst the least effective. Mild TCS and tapinarof 1% were ranked amongst the least effective treatments in three of five efficacy networks. TCI and crisaborole 2% were ranked most likely to cause local application‐site reactions and TCS least likely. We found no evidence for increased skin thinning with short‐term TCS but an increase with longer‐term TCS.

Plain language summary

Comparing skin treatments for eczema

Key messages:

° Strong corticosteroids, JAK inhibitors and tacrolimus 0.1% (all drugs that suppress the immune system) are consistently effective at reducing signs and symptoms of eczema.

° Unwanted effects, such as burning and stinging, are more likely with tacrolimus, pimecrolimus and crisaborole and less likely with corticosteroids; other unwanted effects, such as skin thinning, are only likely when strong corticosteroids are used long term.

° Given uncertainty about long‐term effectiveness and safety, other factors such as availability, cost and priorities, should be considered.

What did we want to find out?

Eczema (atopic dermatitis) is a common inflammatory skin condition with no cure. We compared various skin‐applied (topical) anti‐inflammatory treatments used to reduce eczema symptoms. We wanted to find the most effective and also the safest topical anti‐inflammatory treatments for people with eczema.

What did we do?

We included randomised trials for people with eczema of all ages and severities. Topical treatments had to be used for at least a week and were compared with other anti‐inflammatory treatments or none. We excluded trials of contact dermatitis or hand eczema, and excluded trials of antibiotics, complementary therapies, moisturisers alone, phototherapy, wet wraps, or treatments which are taken as a tablet, syrup or injection.

We looked at different types of evidence of effectiveness: patient‐reported symptoms of eczema, clinician‐reported signs of eczema, and side effects. Our analysis followed standard Cochrane procedures, and we used a tool called CiNEMA to rate our confidence in the evidence.

What did we find?

We analysed 291 studies involving 45,846 people with eczema of different severities. Most of the studies took place in wealthier countries and focused on adults. Only 31 studies focused on children under 12 years. They assessed treatments like corticosteroid creams and calcineurin inhibitors. The studies lasted between seven days and five years and most studies were funded by companies who make anti‐inflammatory treatments for eczema.

Potent corticosteroids, Janus kinase inhibitors such as ruxolitinib 1.5%, and tacrolimus 0.1% were consistently effective at reducing signs and symptoms of eczema. Phosphodiesterase‐4 inhibitors such as crisaborole 2% were amongst the least effective. Side effects such as burning and stinging were more likely with tacrolimus, pimecrolimus and crisaborole and less likely with corticosteroids. There was no evidence of increased skin thinning with short‐term (16 weeks or fewer) use of any treatment, including once or twice daily potent corticosteroids. We found that longer‐term (over 16 weeks) use of corticosteroids may increase skin thinning. Skin thinning occurred in about 1 in 300 people who used mild, moderate or potent corticosteroids for six months to five years.

Our confidence in the evidence varied across the different types of measurements and different treatments. That depended on things like the size and number of trials of the different treatments, how different the results were between the trials, and whether we judged the results had been reported fairly.

What are the limitations of the evidence?

There was not enough information on the long‐term effectiveness and safety of topical anti‐inflammatory treatments. This review should be seen as a guide to the range of treatments that work best and are safest for short‐term control for most people with eczema. Product availability, cost and individual priorities vary, so there is no single treatment that is best for everyone.

How up to date is this evidence?

The evidence is up to date to June 2023.