*These authors have equally contributed to the article.
Atopic dermatitis (AD) is related to a deficiency of delta-6-desaturase, an enzyme responsible for converting linoleic acid to gamma-linolenic acid (GLA). Evening primrose oil (EPO) as a source of GLA has been of interest in the management of AD.
The aim of this randomized, double-blinded, placebo-controlled clinical study is to evaluate the efficacy and safety of EPO in Korean patients with AD.
Fifty mild AD patients with an Eczema Area Severity Index (EASI) score of 10 or less were enrolled and randomly divided into two groups. The first group received an oval unmarked capsule containing 450 mg of EPO (40 mg of GLA) per capsule, while placebo capsules identical in appearance and containing 450 mg of soybean oil were given to the other group. Treatment continued for a period of four months. EASI scores, transepidermal water loss (TEWL), and skin hydration were evaluated in all the AD patients at the baseline, and in months 1, 2, 3, and 4 of the study.
At the end of month 4, the patients of the EPO group showed a significant improvement in the EASI score (
We suggest that EPO is a safe and effective medicine for Korean patients with mild AD.
Atopic dermatitis (AD) is a chronic, recurrent, and inflammatory skin disease characterized by dry skin, itch, and erythema as well as increase in the transepidermal water loss (TEWL)
Some researchers have suggested that AD may be related to the abnormal metabolism of essential fatty acid, especially the abnormality in the production of gamma-linolenic acid (GLA)
Evening primrose oil (EPO) is a natural source of LA and GLA. The intake of GLA contained in EPO is presumed to cause an anti-inflammatory response as the blood concentrations of GLA and DGLA increase
This study was conducted for four months as a randomized, double-blinded, placebo-controlled clinical study. Among the outpatients who visited the Department of Dermatology at the Hallym University Medical Center for two years from August 2014 to July 2016, male and female patients who were diagnosed with mild AD according to the Diagnostic Criteria of Hanifin and Rajka
The patients were allocated to two groups using a computerized randomization scheme that were not disclosed to the observers. (1) The first group received unmarked oval 735 mg capsules containing 450 mg of EPO (40 mg of GLA) per capsule (Dalim, Seoul, Korea). (2) The placebo control group received placebo capsules that were identical in appearance, but contained 450 mg of soybean oil per capsule. For the randomization of the study drug group and the placebo group, randomization codes were given to the study products so that the clinical investigators and the subjects were unaware of the products in the double-blind study. The dose was four capsules per day for the patients between the ages of 2 and 12, and eight capsules per day for the others. The maximum allowable dose was provided to all the patients to avoid the effect of various doses on the response. During the study period, the patients were prohibited from taking phototherapy, a topocal immunosuppressant, a systemic immunosuppressant, a topical steroid, a systemic corticosteroid, or any other drugs. A washout period of one week was given before the treatment with regard to a topical steroid, a topical immunosuppressant, and a systemic antihistamine, and four weeks with regard to a systemic immunosuppressant, a systemic corticosteroid, and phototherapy. The patients of both the experimental group and the control group were recommended to use a moisturizer. We had patients use Atobarrier® lotion (Amorepacific Corp., Seoul, Korea) as the moisturizer. This lotion contains ceramide, cholesterol, and free fatty acids. We educated the patients to apply the amount of two fingers tip unit to one palm-sized lesion twice a day.
The drug administration and adverse effect evaluations were performed for all the patients. The EASI score, TEWL, skin hydration, and visual analogue scale (VAS) for pruritus were also evaluated in months 0, 1, 2, 3, and 4. Blood sampling for measuring blood immunoglobulin E (IgE) was performed in months 0 and 4. The severity of AD was evaluated by two dermatologists by using the EASI score
All the data were expressed as “mean±standard deviation.” Student's t-test was performed to compare the demographical and clinical characteristics between the two groups. The changes in the EASI score, TEWL, skin hydration, VAS for pruritus, and IgE was tested by performing Student's t-test and by using repeated-measures ANOVA. A
A total of 69 mild AD patients were enrolled and randomized into either the control group (14 males and 17 females) or the EPO group (20 males and 18 females). Six patients in the control group and 13 patients in the EPO group dropped out due to follow up loss. No patient dropped out because the disease worsened. Finally, a total of 50 mild AD patients from the ages of 2 to 24 (26 males and 24 females) completed the present clinical study. Twenty-five patients (13 males and 12 females) were randomly allocated to the EPO group, and 25 patients (11 males and 14 females) to the control group. The mean age of the patients was 9.2±7.4 years, and the mean EASI score at the beginning of the study was 4.60±1.22.
After supplementing GLA, the clinical improvement was compared between the EPO group and the control group. The mean EASI score was significantly different between the experimental group and the control group in month 4 (
The changes in TEWL were compared on month 4 between the experimental group and the control group to the TEWL value at the beginning of the study (
With reference to the skin hydration value at the beginning of the study, the changes in the skin hydration in month 4 were compared between the experimental group and the control group (
The subjective itch feeling felt by patients, measured in VAS, was 4.3±1.1, 4.1±1.4, 4.2±1.5, 4.1±1.4, and 3.8±1.1 in months 0, 1, 2, 3, and 4, respectively, in the experimental group. This indicates that the score decreased by about 0.5 points in four months (
The blood IgE concentration decreased from 298.85±58.21 (IU/ml) at the beginning of the study to 264.65±40.86 (IU/ml) in month 4 in the experimental group (
An adverse effect was found in neither the experimental group nor the control group during the study period. The laboratory tests showed no abnormal findings.
Evening promise, a plant from the Onagraceae family, is called this because it only blooms at night, and the evening promise seed oil contains a large amount of LA as well as GLA, which is an unsaturated essential fatty acid
AD may be related to a mild genetic abnormality in the essential fatty acid metabolism. Studies conducted in the 1930s to 1950s revealed that a lack of omega-6 essential fatty acids can cause an inflammatory skin state in both animals and humans. Studies conducted in the 2000s verified that a lack of LA is not present in the blood of AD patients. Instead, the LA concentration was high in the blood, breast milk, and adipose tissue of the patients with AD, but the concentration of the LA metabolites was substantially low. This finding suggests that the conversion of LA to GLA decreased
GLA, a C18-three double bonds (18:3) omega-6 unsaturated fatty acid, is synthesized from LA by the action of delta-6-desaturase, the transforming enzyme
On the basis of the hypothesis, the clinical improving effect of EPO on the treatment of mild AD was verified in the present study. The EASI score of the experimental group administered with EPO was gradually decreased from month 1, showing a significantly difference decrease in the EASI score in comparison with the control group. Although not significantly different, TEWL showed a greater tendency to improvement in the experimental group than in the control group. The skin hydration value also improved in a similar pattern on the forearm, but not on the cheek. No significant difference was found in the VAS for pruritus and IgE in the EPO group and the control group. None of the two groups showed an adverse effect related to the drug.
Since it was found that deficiency of GLA may contribute to the factors of AD, many studies regarding the effect of GLA supplementation on AD patients have been conducted, but the results have been inconsistent. Recently, the Cochrane Review performed a systematic review of borage oil and EPO and concluded that the intake of these mixtures is not an effective therapy for AD
On the contrary, Bordoni et al.
Two studies were conducted to verify the effect of GLA on Korean AD patients. Yoon et al.
In the present study, a measure of improvement in the EASI score, TEWL, and skin hydration was also found in the placebo group. However, this observation was neither consistent nor gradual, but inconsistent. The irregular improvement found in the control group may have been because of the effect of a local moisturizer, an inherent placebo response, and the natural catamnesis of AD.
Despite the Cochrane Review
The present study was conducted as a randomized, double-blinded, placebo-controlled clinical study with 50 patients with mild AD to investigate the therapeutic effect and safety of EPO. The results of the present study showed that there was a significantly improved EASI score in the group supplemented with EPO than in the placebo group. The TEWL and the skin hydration value also showed a tendency of improvement after the administration of EPO. No adverse effect was found in relation to EPO. These results may support the basis of using EPO as an adjuvant therapeutic agent for Korean patients with mild AD.
This study was supported by grants of the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (NRF-2017 R1A2B4006252, 2018R1C1B6007998), Korea Healthcare technology R&D project, funded by Ministry of Health & Welfare, Republic of Korea (HI17C0597), and the Hallym University Research Fund (HURF-2017-35, HURF-2017-52, HURF-2017-83).
The authors have nothing to disclose.
Variable | Group | ||
---|---|---|---|
EPO | Placebo | ||
Patients | 25 | 25 | |
Sex (male/female) | 13/12 | 11/14 | |
Age (yr) | 9.7±8.4 (2.4~24) | 8.6±6.4 (2~23) | 0.509 |
Initial EASI score | 4.69±1.63 (0.8~10.0) | 4.50±0.86 (0.7~6.8) | 0.835 |
Initial TEWL (g/h/m2) | |||
Forearm | 23.53±13.81 (6.4~36.2) | 20.94±5.71 (15.3~31.0) | 0.510 |
Cheek | 13.30±10.42 (4.7~26.4) | 10.74±3.51 (3.5~17.9) | 0.226 |
Initial skin hydration (a.u.) | |||
Forearm | 54.62±18.97 (25.8~82.8) | 55.00±17.59 (30.7~84.3) | 0.955 |
Cheek | 37.26±14.19 (8.2~64.4) | 39.33±16.59 (5.8~58.6) | 0.716 |
IgE (IU/ml) | 294.65±58.21 | 305.80±40.86 | 0.530 |
Values are presented as number only or mean±standard deviation (range). EPO: evening primrose oil, EASI: Eczema Area Severity Index, TEWL: transepidermal water loss, a.u.: arbitrary unit, IgE: immunoglobulin E.