The Efficacy of Moisturisers Containing Ceramide Compared with Other Moisturisers in the Management of Atopic Dermatitis: A Systematic Literature Review and Meta-Analysis

Abstract

Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition that recurs frequently and has diverse clinical features. The main mechanism of AD is the dysfunction of the skin-epidermal barrier. One of the causes of stratum corneum (SC) structural integrity disruption is the decreased production of ceramide, an important lipid component in SC. The latest generation of moisturisers contain ceramide to help replace this lipid deficit. This study aimed to compare the efficacy of moisturisers containing ceramide with other moisturisers for AD management. Searches were conducted systematically on PubMed, the Cochrane Library, ScienceDirect, Clinicaltrials.gov, and Google Scholar for studies published from January 2012 to July 2022. Interventions and outcomes were compared in this study. Statistical analysis was performed with ReviewManager 5.4 software. Five articles met the eligibility and inclusion criteria. Three articles were meta-analyses on trans-epidermal water loss (TEWL) outcomes and two articles were meta-analyses on SCORing Atopic Dermatitis (SCORAD) outcomes. A meta-analysis of TEWL results found that TEWL values were not significantly different in subjects treated with ceramide-containing moisturisers (mean difference: −3.56, 95% CI [−8.63, 1.52], P = 0.17) with high heterogeneity (I² = 92%) compared to other treatments. The change in SCORAD was significantly higher in moisturisers containing ceramide (mean difference: −0.98, 95% CI [−1.63, −0.33], P = 0.003) with low heterogeneity (I² = 0%). Moisturisers containing ceramide improve SCORAD and TEWL; however only the changes in SCORAD in moisturisers containing ceramide is superior to other moisturisers.

Introduction

Atopic dermatitis (AD), also known as atopic eczema, is a chronic, recurrent, inflammatory skin condition that has a variable clinical manifestation. Atopic dermatitis has become a global health problem because it causes high healthcare costs worldwide and is associated with significant morbidity and decreased quality of life (QoL).[1]

The main mechanism of AD is the dysfunction of the skin's epidermal barrier. Filaggrin deficiency impacts various key pathways of the skin barrier function. Filaggrin is also an important source of natural moisturising factor (NMF); hence its deficiency leads to a decrease in NMF level. A decrease in NMF level also increases the pH of the stratum corneum (SC), which is normally acidic but becomes alkaline.[2] Production of ceramide, the most important class of lipid found in SC intercellular lipid matrix, is a pH-dependent process. Lipid imbalance and inadequate ceramide levels contribute to corneocyte lipid envelope formation and lipid mortar defects, which correlate with skin barrier damage. Damage to the skin barrier also causes an increase in trans-epidermal water loss (TEWL).[3,4]

One of the main components of AD management is skin barrier repair. Skin hydration through skin lubrication is important through the use of moisturiser. The newest generation of moisturiser contain ceramide to help replace lipid deficits in AD.[5,6] A study by Hon et al. in 2013 investigated patient preferences and the efficacy of an emollient containing ceramide and NMF precursor lipids in AD patients for two months. The results showed that after its use, the objective SCORing Atopic Dermatitis (SCORAD) score (P = 0.039) and skin hydration (P = 0.021) improved in the very good/good adherence to moisturiser group compared to the group with moderate/poor adherence to moisturiser.[7]

There is little evidence regarding the comparative efficacy of moisturisers containing ceramide over other moisturisers for AD treatment. This study compared the efficacy of a moisturiser containing ceramide with other moisturisers in AD treatment.

Materials and Methods

Study design

This is a meta-analysis study using randomised control trial (RCT) journals. The population in this study were articles containing studies that compared the efficacy of moisturisers containing ceramide in AD patients diagnosed with the Hanifin and Rajka or UK Working Party criteria with other moisturisers of all ages and genders. The intervention was moisturisers that contained ceramide. The comparison in this study was treatment with other moisturisers or a placebo. The outcome of this study was the degree of AD severity as measured by SCORAD or TEWL.

Literature search

A literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [Figure 1]. It was conducted on five databases: Medline, EBSCOhost, the Cochrane Library, Scopus, and Clinicaltrials.gov. It was carried out using search terminology according to PICO (Patient, Intervention, Comparison, Outcome) [Table 1].

Figure 1.

PRISMA flow chart

Table 1.

Literature search based on research PICO

P	I	C	O
Atopic dermatitis	Ceramide	Another moisturiser	SCORAD
Atopic eczema			TEWL
Eczematous dermatitis

A boolean operator was used in the form of AND to search for literature containing all keywords and OR to search for literature containing alternative keywords. The search strategy was carried out using the following search keywords: (”Atopic dermatitis” OR “Atopic eczema” OR “Eczematous dermatitis”) AND (”Ceramide”) AND (”treatment” OR “therapeutic”) AND (”SCORAD” OR “TEWL”). Literature screening was carried out afterwards according to the PRISMA flowchart.

The inclusion criteria of this study were literature in the form of RCT for the last 10 years and literature with an AD diagnosis method that complied with the Hanifin-Rajka or UK Working Party criteria which were treated with moisturisers containing ceramide and compared with other moisturisers and SCORAD/TEWL was used to assess the severity degree. There were no restrictions on country and the patient's age, race, and gender. The exclusion criteria from this study were in vitro research or on non-human subjects, research with non-extractable data, publication in abstract form without full text, research with a case report research design, case series, reviewed systematic research, and studies using pseudoceramide moisturisers.

Data extraction and analysis

Data extraction was performed using the Microsoft Office Excel program (Microsoft Corp., Redmond, WA, USA). Study characteristics were recorded for all studies. Parameters taken included ceramide concentration and AD severity before and after therapy, as well as adverse events and length of follow-up.

Statistical analysis is presented in the form of mean and standard deviation. The final results are presented in the form of tables and forest plots. Statistical analysis was performed using ReviewManager 5.4 software. P < 0.05 was considered statistically significant.

Results

Article search results

There are a total of 6,026 articles in the initial search results [Figure 2]. Five articles were obtained after going through the exclusion processes, which in the end was subjected to qualitative analysis and meta-analysis [Table 2].

Figure 2.

Article screening with PRISMA flow

Table 2.

Data extraction table

Authors	Country	Study Type	Total Sample	Intervention	Comparison	Follow-Up Time	Outcome
Mustifah et al.,[17] 2018	Indonesia	Double- blind, RCT	15	Cream B (ceramide)	Cream A (Aloe vera)	Second week	TEWL
Tabri and Yuniati,[15] 2018	Indonesia	Double- blind, RCT	16 (ceramide 1%: 4, lanolin 10%: 4, urea 10%: 4, control: 4)	Ceramide 1%	Lanolin 10%	Day 14	TEWL
Somjorn et al.,[11] 2022	Thailand	Double- blind, RCT	38	Linoleic acid, 5% dexpanthenol and ceramide (LDC cream)	Urea 5% cream	Second and fourth week	SCORAD
Fischer et al.,[16] 2018	Germany	Double- blind, RCT	26	Placebo (replaced by water)	Glycerol (10%), evening primrose (6%) and grapeseed oil (6%), rich in omega-6 fatty acids, ceramide 3 and licochalcone A (<1%)	Baseline, first, second, fourth, eighth, and twelfth week	TEWL
Nurasrifah et al.,[12] 2019	Indonesia	Double-blind, RCT	30	Petrolatum	Ceramide, polidocanol, and menthol	Baseline, first, second, and fourth week	SCORAD

TEWL

Three studies were evaluated using TEWL as the main outcome [Table 3]. A study by Tabri and Yuniati[15] reported the highest mean TEWL in the treatment group (11.62 ± 3.58). A study by Fischer et al.[16] reported the highest mean TEWL in the comparison group (18.36 ± 1.75). A study by Mustifah et al.[17] reported the lowest mean TEWL in all groups (6.55 ± 3.25 in treatment group and 7.39 ± 3.17 in comparison group).

Table 3.

TEWL data

Article	Year	Intervention	TEWL
			Mean	SD	N
Mustifah et al.[17]	2018	Ceramide	6.55	3.25	15
		Aloe vera	7.39	3.17	15
Fischer et al.[16]	2018	Ceramide	11.32	1.47	26
		Placebo	18.36	1.75	26
Tabri and Yuniati[15]	2018	Ceramide	11.62	3.58	4
		Lanolin	13.62	5.68	4

From the three studies, with a total of 45 subjects who were given ceramide topically and 45 subjects who were given other treatments, there was no significant difference in post-treatment TEWL values. Trans-epidermal water loss values were found to be lower in subjects who were given ceramide (mean difference: −3.56, 95% CI [−8.63, 1.52], P = 0.17) with high heterogeneity (I² = 92%) [Figure 3].

Figure 3.

Forest plot for TEWL

SCORAD changes

There were two studies that evaluated SCORAD as the main outcome [Table 4]. A study by Somjorn et al.[11] reported the highest mean SCORAD reduction in all groups (−13.83 ± 1.83 in the treatment group and − 13.04 ± 3.22 in the comparison group). A study by Nurasrifah et al. reported the lowest mean SCORAD decrease in all groups (−13.97 ± 0.144 in the treatment group and − 12.91 ± 0.56 in the comparison group).[12]

Table 4.

SCORAD changes data

Article	Year	Intervention	SCORAD
			Mean	SD	N
Nurasrifah et al.[12]	2019	Ceramide	−13.97	1.44	15
		Petrolatum jelly	−12.91	0.56	15
Somjorn et al.[11]	2022	Ceramide	−13.83	1.83	38
		Urea	−13.04	3.22	38

From the two studies with a total of 53 subjects who were given ceramide topically and 53 subjects who were given other treatments, there was a significant difference in SCORAD changes. Changes in SCORAD was higher in the ceramide-treated subjects (mean difference: −0.98, 95% CI [−1.63, −0.33], P = 0.003) with low heterogeneity (I² = 0%) [Figure 4].

Figure 4.

Forest plot for SCORAD changes

Discussion

There was a significant difference between moisturisers containing ceramide and other moisturisers in terms of SCORAD changes in this study. Ceramide is central to barrier structure and its permeability function.[8] Ceramide consists of sphingoid bases (SB) linked via amide bonds to fatty acids.[9] The Th2 immune response, which frequently occurs in AD, characterises acute skin lesions. Tumour necrosis factor (TNF)-α and cytokine IF-γ induce IL-4 to suppress ceramide synthesis in human epidermis. Atopic dermatitis patients experience reduced ceramide levels and shorter ceramide chain lengths, resulting in increased skin barrier permeability.[10] Previous studies have reported that shorter ceramide chains and certain SB components such as sphinganine and sphingosine are related to AD severity. Moisturisers containing ceramides are also thought to have anti-inflammatory effects. Inflammation is an important component in determining SCORAD. Previous studies have demonstrated the effectiveness of ceramide-produced phytosphingosine on anti-inflammatory and antimicrobial activity.[9,10]

Previous studies have shown that moisturisers containing ceramide are effective in reducing AD severity, as measured by SCORAD. A study by Somjorn et al.[11] compared AD patients who received either linoleic cream, dexpanthenol 5%, and ceramide (LDC) cream, or urea 5% cream. The SCORAD reduction in the LDC group decreased more significantly compared to the urea group (P = 0.043). LDC cream contains dexpanthenol or pantothenic acid (vitamin B5), which acts as a humectant and has anti-inflammatory effects. This could explain the better efficacy of LDC creams for reducing SCORAD compared to moisturisers containing urea.[11]

Nurasrifah et al.[12] reported that moisturisers containing ceramide, menthol, and polidocanol significantly reduced SCORAD, although the results were not significantly different from petrolatum. Menthol is a monoterpene in an essential oil isolated from Menthe piperita and Mentha arvensis, which have been known for its antipruritic and analgesic effects since ancient times. The antipruritic properties of menthol also appear to be promoted from the selective activation of κ-opioid receptors which could reduce itching, whereas μ-opioid receptor agonists induce it. Serum β-endorphin, a μ-opioid receptor agonist, increased in AD patients compared to controls.[12,13]

There was no significant difference between moisturisers containing ceramide and other moisturisers in terms of TEWL in this study. The stratum corneum is composed of differentiated keratinocytes and extracellular lipids, mainly ceramides, cholesterol, and free fatty acids that form the lipid lamellae. Ceramide represents a major lipid class by mass (~50%) and has a diverse molecular structure that is classified into 12 subclasses in human SC. Typical ceramide subclasses detected in SC consist of non-hydroxide fatty acids [N], α-hydroxyl fatty acids [A], esterified α-hydroxy fatty acids [EO], dihydrosphingosine [DS], sphingosine [S], 6-hydroxy sphingosine [H], and phytosphingosine [P].[14] Lipid imbalance and inadequate ceramide levels contribute to deformed corneocyte lipid envelope and lipid mortar formations. This correlates with an increase in TEWL and an increase in skin barrier permeability.[3]

Tabri and Yuniati[15] evaluated 16 AD patients who were assigned to four groups: ceramide 1%, lanolin 10%, urea 10%, and control. A significant reduction in TEWL values was found in each group after the application of moisturiser from day 07 to day 14. There was a decrease in the TEWL value from 22.37 ± 6.94 to 11.62 ± 3.58 in the ceramide group and from 23.23 ± 8.23 to 13.62 ± 5.68 in the lanolin group.[15] Another study from Mustifah et al. compared the efficacy of ceramide cream with Aloe vera in 15 AD patients. They found that the lowest mean TEWL of the ceramide group occurred in the second week of observation (7.39 ± 3.17). The lowest mean TEWL of the A. vera group also occurred in the second week of observation (6.55 ± 3.25). The TEWL value of the A. vera group was lower than that of the ceramide group, although it was not statistically significant (P = 0.512).[16]

The insignificant difference in TEWL could be caused by several factors. Each study that assessed the TEWL comparison between groups had small samples (Mustifah et al.[17]: 15 samples, Tabri and Yuniati[15]: 16 samples, Fischer et al.:[16] 26 samples) and was heterogeneous (I² = 90%). Occlusive moisturisers such as petrolatum or lanolin coat the surface of the skin with a water-repellent lipid layer that blocks water in and out. These agents could transiently relieve xerosis, which is a characteristic of AD, by blocking skin water loss. Humectant moisturisers such as A. vera absorb water from the surrounding atmosphere. Emollient moisturisers (i.e., vegetable oils such as sunflower or corn oil) are enriched with essential fatty acids and could enhance barrier function. This moisturising emollient also reduces inflammation through activation of peroxisome proliferator-activated receptors (PPARs) and even provides nutritional benefits. Other effects exerted by them on the barrier function are eicosanoid production, membrane fluidity, cell signalling, increased skin repair and permeability.[18,19] Other studies that reported the efficacy of moisturisers containing ceramide in improving TEWL had a longer follow-up period (six weeks) than the currently selected studies (two weeks), which might influence the final outcome of this study.[20] Moisturisers containing ceramide are also thought to have anti-inflammatory effects, and inflammation is an important component in SCORAD but not in TEWL.[5]

Moisturisers containing ceramide are more effective at improving AD severity—as shown by SCORAD changes—but are not better at improving TEWL when compared to other moisturisers. More randomised clinical trial studies on moisturisers containing ceramide are needed in similar settings and populations. A meta-analysis with uniform comparison of variables needs to be conducted in order to compare the efficacy and safety of moisturisers containing ceramide with other types of moisturisers in AD patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.