Oral isotretinoin (13-cis-retinoic acid) was first approved as a treatment for severe acne by the US Food and Drug Administration in 1982. However, its off-label uses for cases of less severe acne have increased over time1. Isotretinoin exerts its therapeutic effects on acne by reducing sebum excretion and follicular keratinization, as well as reducing colonies of Propionibacterium acnes. Its effectiveness is dependent on the accumulated dose, and any treatment must be continued long enough to reach the standard accumulated dose of 120 to 150 mg/kg2. Although the safety profile of isotretinoin is favorable, this treatment is associated with certain reversible, dose-related adverse effects. The most common adverse effect is mucocutaneous dryness in the lips, eyes, and other epidermal surfaces. Skin dryness together with an increase in transepidermal water loss (TEWL) and erythema during treatment with isotretinoin seem to be the key factors causing patient discomfort, and these adverse effects can compromise patient compliance3,4,5. Therefore, managing these adverse effects and their influence on patient compliance is the key to treatment success. Evening primrose oil (EPO) contain gamma-linolenic acid (GLA, 18:3ω6), a carboxylic acid with an 18-carbon chain and three cis double bonds.6 It is a fatty acid found primarily in vegetable oils; it improves skin hydration in healthy adults and atopic patients7,8, and is indicated for relieving xerosis in patients undergoing therapy with oral isotretinoin. It could be hypothesized that acne patients had better compliance with isotretinoin treatment with EPO because it causes fewer mucocutaneous adverse effects such as xerotic cheilitis. In this study, we investigated the efficacy and tolerability of EPO in preventing xerotic cheilitis in acne patients being treated with oral isotretinoin.

This was a prospective, randomized, and single-blind study to compare the effectiveness of EPO containing GLA as an adjuvant treatment in patients with moderate acne who are being treated with oral isotretinoin.

Forty patients were included in this study, 20 in the experimental group and 20 in the control group, ranging in age from 18 to 31 years (Table 1). The degree of acne was decreased significantly in both groups (p<0.001) after 2 months of treatment. In both groups, the mean number of comedones, pustules, and papules were decreased significantly at 2 months; however, the groups did not differ significantly in terms of the number of comedones and pustules (Table 2).

The clinical evaluation of the other cutaneous symptoms except xerotic cheilitis did not differ significantly between groups, although the experimental group tended to have a lower score than the control group for dryness of the skin (Fig. 1, Table 3, 4). The proportion of patients presenting with xerotic cheilitis after 2 months of therapy was significantly lower in the experimental group. On the lower lip, the experimental group tended to have a lower score than the control group for TEWL, and there was a significant difference between the two groups after 8 weeks of treatment (Fig. 2A, Table 5). Corneometry showed no significant differences between the two groups (Fig. 2B, Table 6).

On the quartile grading scale, the mean clinical improvement for xerotic cheilitis at 8 weeks after the final treatment was 2.20±0.52 in the control group and 3.15±0.81 in the experimental group (Fig. 3, Table 7). There were significant differences between the control and experimental groups (p<0.05). Concerning patient satisfaction, most of the final ratings were moderate or good in both groups, although the experimental group was significantly satisfied at week 4 (Fig. 4).

Isotretinoin is a type of retinoid that has been widely used in the topical and systemic treatment of various dermatoses: psoriasis, keratinization disorders, keratotic genodermatosis, and severe acne. It is also used in the treatment and/or chemoprevention of skin cancer and other neoplasms. Isotretinoin inhibits sebaceous gland function and keratinization; however, its exact mechanism of action is not well understood9. Moreover, this drug has immunomodulator and anti-inflammatory properties10. Oral isotretinoin is the treatment of choice for severe inflammatory acne and is considered an alternative treatment for patients with moderate and long-term mild inflammatory acne with poor response to other treatments11,12.

The recommended dose of oral isotretinoin for acne treatment is 0.5 to 1.0 mg/kg daily for 16 to 32 weeks, reaching 120 to 150 mg/kg2. This regimen is well known to produce good results; however, it causes several dose-dependent adverse effects such as xerotic cheilitis, mild xerosis, and epistaxis13. Because of these adverse effects, some patients have difficulty in complying with the recommended dose. These mucocutaneous adverse effects mainly reflect decreased sebum production, reduced stratum corneum thickness, and altered skin barrier function9. Cheilitis is the most common manifestation and occurs in virtually all patients who receive isotretinoin therapy14. In fact, the absence of cheilitis in an apparent "treatment failure" that should raise the suspicion of noncompliance15. In an effort to overcome this concern, the use of hydrating and emollient products is often recommended to control the most frequent mucocutaneous adverse effects. In this study, we investigated the efficacy of oral EPO instead of a topical emollient for relieving xerotic cheilitis in patients undergoing therapy with oral isotretinoin.

The treatment groups were well matched at baseline concerning demographic data and individual isotretinoin dose; there were no significant differences between the experimental and control groups. The comparison between groups did not show significant differences in terms of the number of comedones and pustules after 8 weeks of treatment. This means that isotretinoin had an about the same curative effect for acne vulgaris in both groups. Oral EPO did not influence the efficacy of oral isotretinoin treatment. GLA inhibits inflammatory responses by regulating nuclear factor-kappaB and activator protein-1 activation, and prostaglandin E1 and 15-hydroxyeicosatrienoic acid converted from GLA have anti-inflammatory properties. For these reasons, the acne lesions were expected to improve somewhat better in the experimental group; however, the results did not show this effect.16,17,18

The results also showed that the group with oral EPO showed lower TEWL and higher corneometry readings than the control group. These suggest that GLA might improve skin properties and protect the skin barrier. This difference can be attributed to the higher concentration of GLA in EPO that is necessary to maintain hydration19. Deficiencies in n-6 essential fatty acids (EFA) correlated with the severity of skin barrier dysfunction and cutaneous inflammation20. GLA efficiently reverses epidermal hyperproliferation owing to its metabolites such as anti-inflammatory eicosanoids that exert antiproliferative properties, and these actions are associated with an increase in ceramide synthesis and improvement of skin barrier function21.

The skin of the lip has many different properties compared with the hand dorsum skin. The lip does not contain hair or sweat glands and sebaceous glands. The lip skin epithelium is characterized by thin and nonkeratinized tissue and a poor water-holding capacity22. We detected a significantly high TEWL on the lip compared with that on the hand dorsum skin in patients treated with oral isotretinoin. The dryness and desquamation of the lip in patients treated with oral isotretinoin may be caused by the thin and low barrier function of the nonkeratinized epithelium22.

The human skin is rich in sebaceous glands, and the sebum excreted by these glands is primarily composed of tryglycerides, wax esters, and squalene23. Sebum analysis demonstrates that the major components of sebum differ from those of EFA24. Human skin is not able to biosynthesize GLA from the precursor linoleic acid (LA, 18:2ω6), or arachidonic acid (20:4ω6) from dihomogamma-linolenic acid (20:3ω6), because of the absence of the enzymes delta 6- and delta 5-desaturase19,25. Therefore, EFA metabolites have to be synthesized in the liver and transported to the skin through the bloodstream. Because EFAs come strictly from the diet24, dietary supplementation with GLA-containing EPO skips the metabolic step of 6-desaturation of LA to form GLA26. Such a supplementation should compensate for the lack of EFA in patients treated with isotretinoin27.

GLA and its synthetic derivatives serve important and diverse roles in the structural maintenance and immunologic balance of the epidermis28,29,30. Therefore, GLA might aid in the prevention of cheilitis by the following mechanisms: (i) maintenance of the stratum corneum permeability barrier and (ii) maturation and differentiation of the stratum corneum.

According to the patients' satisfaction level, the difference in clinical efficacy against xerosis between the experimental and control groups was a peak at 4 weeks after treatment, which gradually decreased. This means that the most uncomfortable period of cheilitis is at about 4 weeks after taking isotretinoin. Thereafter, the patients adapted themselves to the xerotic change. We observed that the use of oral EPO did not influence the efficacy of oral isotretinoin treatment and improved xerotic cheilitis and the sensation of dryness. It seemed that acne patients had better compliance with the treatment with EPO because of its fewer mucocutaneous adverse effects.

EPO was found to induce an improvement in the cutaneous barrier function of the lips in acne patients taking isotretinoin, as reflected in their TEWL. The addition of EPO prevented retinoid-induced adverse effects without any complications. The statistical correlation between EPO and xerotic cheilitis is relatively weak. On the basis of these results, additional studies are required before we can have a complete understanding of the role of EPO on xerotic cheilitis in acne patients being treated with oral isotretinoin.