Prevalence and causative allergens of contact cheilitis in Thailand

Cheilitis is an inflammatory condition of the lips. Its causes can be exogenous (irritants, allergens), endogenous (atopic dermatitis, systemic disorders) or unknown.


| INTRODUCTION
Cheilitis refers to inflammation of the lips.[3][4][5][6] There are various causes of cheilitis, including infections, allergies, toxins, medications, injuries and deficiencies in vitamins or minerals such as iron or vitamin B. Among the different types of cheilitis, contact cheilitis is frequently reported and typically presents with symptoms such as erythema, edema and scaling.Contact cheilitis is primarily caused by irritating or allergic substances.The diagnosis of contact cheilitis is mainly based on the patient's clinical history and examination.
Patch testing, which is a valuable diagnostic tool, can help identify the specific allergen responsible for allergic contact cheilitis (ACC). 7mmon causative allergens for ACC have been reported to include fragrances and the patient's own products, 1,8,9 such as oral hygiene products such as toothpastes and mouthwashes, 5,[10][11][12][13] lipsticks, 5,12,13 facial moisturizers, 12 sunscreens, 5 foods, 12,14 nail products 5 and dental materials. 12However, studies on ACC in Asian populations are limited and outdated, with most of them conducted over a decade ago. 13,15,16It is important to consider that cultural differences and local ingredient usage in different geographic regions may influence patterns of contact sensitization.Additionally, Asian countries often incorporate various local herbs as ingredients in food and cosmetic products.Therefore, the objectives of this study were to determine the prevalence of ACC, identify the common causative allergens and establish the associated factors in patients attending a contact dermatitis clinic.

| Study population
A retrospective chart review was conducted on the medical records of patients with cheilitis referred for patch testing at the contact dermatitis clinic of Siriraj Hospital, Mahidol University, Thailand.The study period covered January 2007 to December 2021.The clinical characteristics of the patients and their patch test results were collected.
The study protocol was authorized by the Siriraj Institutional Review Board (approval no.Si 615/2022).

| Patch testing
Patch testing was conducted in accordance with the guidelines of the International Contact Dermatitis Research Group. 17The Siriraj baseline series, which was adapted from international standards and European baseline series, 18 as well as a locally developed cheilitis series (Tables S1 and S2), were applied.Additional allergens and series were selected based on individual patients' histories. 18,19Patients' personal products and food were also tested, either dilution of 2% aqueous for toothpastes and wash-off products or as is for leave-on products. 20e allergens (Chemotechnique Diagnostics, Vellinge, Sweden) were applied using aluminium Finn Chambers (SmartPractice, Phoenix, Arizona) on the patients' upper back for 48 h.The results were read on days 2, 4 and 7, and the reactions were scored according to guidelines.

| Statistical analysis
Descriptive analysis was employed to present data as frequencies and percentages for categorical variables.The mean and standard deviation were used for data with a normal distribution, and the median and interquartile range were used for data with a nonnormal distribution.
Pearson's chi-square test was utilized for analysing categorical data, while independent sample t-tests were employed for comparing continuous data of the ACC and non-ACC groups.A p-value of less than 0.05 was considered statistically significant.The statistical analyses were conducted using PASW Statistics, version 18 (SPSS Inc., Chicago, IL).
Unspecified cheilitis, which includes cheilitis of unknown aetiology, was found in 135 patients (32.9%).The prevalence of ACC was 2.4% (131 out of 5366 cases) among the population undergoing patch testing and 32.0% (131 out of 410 cases) among cheilitis patients.
Table 1 provides demographic data for cheilitis patients.Compared to non-ACC patients, ACC patients were significantly more likely to be female, younger in age, have a disease duration of less than 3 months, have no underlying disease and be engaged in white-collar jobs.
Regarding patch testing results in ACC patients, 87 out of 131 patients (66.4%) had a positive reaction in the Siriraj baseline series, while 71 out of 131 cheilitis cases (54.2%) showed positive reactions in the additional cheilitis series.The most common positive reactions were observed for nickel sulfate (n = 39, 29.8%), potassium dichromate (n = 19, 14.5%), castor oil (n = 4, 14.3%), benzalkonium chloride (n = 17, 13%) and cinnamic alcohol (n = 14, 12.8%; Table 2).Contact allergy to patients' personal products was found in 96 out of 131 patients (73.3%), and among these cases, A total of 2887 personal products used by 402 patients with cheilitis were employed for patch testing.The three most commonly tested items were lip cosmetics (lipsticks and lip balms), toothpastes and facial moisturizers (Table 3).There were positive reactions to approximately 6% of the personal products (173/2887), with lipsticks being the most common source of positive reactions (100/173, 57.8%).Two patients showed a reaction to a natural herbal Thai lip balm (Si-Phueng).Toothpaste was the second most common source of positive reactions (26/173, 15%).
In terms of the proportion of positive reactions by product category, food and flavourings showed the highest positivity (18%, 11/61 products tested, Table 3).Six patients showed a total of 11 reactions to food and flavourings.There was one reaction each to herbal mouth freshener, freshener spray, pomelo peel, black galingale extract in aqueous, black galingale, basil leaf, white turmeric, yellow turmeric, turmeric powder, curry powder and curry powder (another brand).

| DISCUSSION
Cheilitis is a relatively common skin disease, with a prevalence of 7.6% among patients referred for patch testing in our study.2][3][4][5][6] The increased prevalence may be attributed to the growing use of various types of cosmetics.
1,22 Another one-third of patients had unspecified cheilitis.This could be attributed to either endogenous causes such as cheilitis simplex and atopic cheilitis, or exogenous factors such as irritants and hidden allergens that may not have been identified through history-taking and patch testing.
The predominance of young females in our ACC patient group can be attributed to their higher potential exposure to lip cosmetic products, which can lead to the development of ACC. 23Our ACC patients also tended to have a disease duration of less than 3 months before undergoing patch testing.This can be explained by the fact that ACC causes more noticeable symptoms, prompting patients to seek early medical attention, especially those who are otherwise healthy.Conversely, patients with longer disease durations are frequently advised to discontinue or change their cosmetic usage, which may lead to the resolution of ACC.As a result, these patients may not seek patch testing.
To our knowledge, this is the first study to explore contact allergies in Thai patients with cheilitis.We discovered that metals, oils, preservatives, fragrances and patients' personal products, including T A B L E 1 Baseline demographic data and clinical characteristics of patients with allergic contact cheilitis and nonallergic contact cheilitis.a "White-collar workers" are known as "suit-and-tie workers" who often avoid physical labor, which implies they belong to a higher social class.
b "Blue-collar workers" refers to workers who engage in hard manual labor, typically in agriculture, manufacturing, construction, mining or maintenance, or who undertake any physically exhausting task that implies belonging to a lower social class.
lipsticks and toothpastes, were the most common sensitizers.
Although the profile of contact allergies has varied among studies, our investigation revealed that nickel sulfate had the highest positive reaction, similar to a recent large study in North America. 6Nickel is a common cause of ACC.It can be found in dental devices, instrument mouthpieces, piercing jewellery, makeup containers, food, drinks and as a contaminant in low-quality cosmetic products. 9The second most common sensitizer was potassium dichromate.It exhibited a high proportion of contact allergies due to its strong correlation with positive reactions to nickel in patch testing. 24Despite metal showing the highest positivity in patch testing, it might not entirely account for the cause of ACC.
Castor oil, which is derived from the seed of the castor bean (Ricinus communis), is the third most common allergen causing ACC.It is a nonvolatile fatty oil, with ricinoleic acid constituting 90% of its content.Ricinoleic acid has been previously identified as the primary cause of ACC in Singapore. 13Interestingly, four out of twenty-eight patients (14.3%) tested positive for castor oil in our study.Castor oil is widely used in lip care products worldwide, with sporadic cases of allergy reported. 25,26In most previous studies, 2,6,21 the allergen was not patch tested, likely due to its limited commercial availability.However, castor oil or ricinoleic acid has emerged as an allergen for contact cheilitis and should be included in a standard cheilitis series if feasible.
Fragrances were also prominent among the most frequent contact allergens identified in our ACC cases.Fragrance mix I and Myroxylon pereirae (M.pereirae) have been recognized as the main allergens associated with ACC. 1,4,21Fragrance mix I is primarily found in cosmetic products, lip care products, toothpastes, oral hygiene preparations and mouthwash. 27Consequently, both cinnamic aldehyde and cinnamic alcohol, which are ingredients of fragrance mix I, exhibited significant positive reactions when tested individually in the current investigation.M. pereirae, a widely recognized sensitizer, shares similar sources of exposure with fragrance mix I, being commonly used in fragrances.The extensive utilization of fragrances is believed to contribute to the high prevalence of contact allergy observed in ACC cases worldwide. 1,3,22rrently, there is no standardized cheilitis series available worldwide.Our supplementary cheilitis patch test series was based on Fisher's contact dermatitis textbook. 28We also included the culprit allergens that were commonly present in personal care products used in our country, as well as those found in lip products brought by patients.Although we aimed to include all possible relevant allergens in the cheilitis series, we were only able to detect them in half of the ACC patients.This finding has prompted us to revise our cheilitis series to encompass a broader range of relevant allergens.International standardized cheilitis series should be developed.Interestingly, 26% of ACC patients could be identified through patch testing with patients' personal products, despite obtaining negative results from standard allergens.Therefore, we encourage patch testing with patients' own products in conjunction with standard allergens in all cheilitis patients to increase the diagnostic yield.
In our study, the most common sources of ACC were lip cosmetics (lipsticks and lip balms) and toothpastes.Lip cosmetics accounted for the majority (57.8%) of implicated products.In terms of product categories, lipsticks and toothpastes showed the highest rates of positive patch test results.Therefore, when evaluating suspected cases of ACC, it is important to include lipsticks and toothpastes in the patch testing panel.Our findings align with previous literature, which consistently identified patients' own lipsticks as the primary source of contact allergens in individuals with cheilitis. 3,4,13Lim et al. 13 identified cosmetics, including lipsticks, lip balms and other cosmetics, as the most common causes of ACC (58%), followed by toothpastes (29%) and medicaments (7%).Similarly, a study conducted in the United States 3 reported similar sources, such as lipsticks (25.9%), makeup (18.5%) and other cosmetics (18.5%).
We identified two patients who were allergic to Si-Phueng, a popular lip balm in Thailand made from beeswax, coconut oil, castor oil, creamed coconut, flavour and colour.Si-Phueng is believed to be a safe natural cosmetic source.The potential allergens present in Si-Phueng could be beeswax, castor oil, colourants or fragrance.
Unfortunately, these two patients did not exhibit relevant positive reactions to standard allergens, making it difficult to confirm the presence of hidden allergens in Si-Phueng.
Toothpaste ranked second among the patients' personal products in our study.Due to its complex formulation, which typically includes over 20 ingredients, the presence of potential allergens in toothpaste is inevitable. 29A multicenter study by Francalanci et al. 11 noted that the most common cause of toothpaste-induced ACC was flavouring agents.Mint flavours, such as menthol, peppermint oil, spearmint oil and L-carvone are commonly used in toothpastes.The literature has highlighted these substances as allergens responsible for cheilitis. 2,30recent study from Australia reported a high rate of relevant reactions to peppermint oil (5 out of 61) and spearmint (4 out of 61).However, we did not find positive reactions to menthol and peppermint oil in our study.We only observed two ACC patients with a reaction to L-carvone, which is the primary component in spearmint.The discrepancy in results may be due to differences in exposure between countries.While L-carvone is an uncommon and weak allergen, contact allergy to it has been increasing over the past 5 years according to a Swedish study, likely due to daily exposure.30 However, further studies are needed to confirm the association between this allergen and cheilitis.
While lipstick, toothpaste and facial moisturizer are the top three most commonly recognized sources of ACC due to their close application to the lesion site, the food and flavouring category yielded the highest test results.Our data revealed that certain herbs that are well known in Thailand can cause cheilitis, such as turmeric, basil and black galingale.Turmeric, widely used in Thai traditional medicine and as a flavouring in food, including curry powder, has been reported to cause immediate-type hypersensitivity reactions. 31Contact allergy to turmeric and curry powder is rare, 32 but we found a case of cheilitis with an allergic reaction to curry powder and turmeric.Basil (Ocimum basilicum), belonging to the Lamiaceae family found in tropical countries, is another herb that can cause cheilitis.There is only one documented case in the literature of occupational allergic contact dermatitis from basil, suggesting that eugenol present in basil may play a role in contact sensitization. 33Black galingale, also known as Thai ginseng, is used in Thai medicine due to its various biological activities. 34Although many compounds have been isolated from black galingale, this was the first case showing an allergic reaction to it.The unique pattern of contact allergy observed with these herbs reflects the differences in sensitization among different geographic areas.
Although food and flavourings are not common causes of cheilitis, patch testing with these substances should still be conducted in suspected patients due to the high rate of positive results.
There are several limitations worth mentioning in our study.The retrospective nature of the study resulted in some incomplete data; diagnosis, and other investigations.We were unable to obtain the relevance of patch testing results, which some allergen positivity may have been clinically relevant in the past or irrelevant.Additionally, as a referral center, we did not have follow-up data for some patients after patch testing.Our non-ACC group was also classified based on available patch testing results, which means we may have missed culprit allergens that were not included in the patch testing panels.Being a single-center tertiary referral study limits the generalizability of our findings.A relatively small sample size is another limitation, making it essential to conduct larger studies to validate our results.

| CONCLUSIONS
ACC should be considered in patients with cheilitis, particularly young women with short-duration symptoms.Metals, fragrances and castor oil are the most common allergens associated with ACC in Thailand.
Baseline patch testing series alone is insufficient for diagnosing ACC.
A standardized cheilitis series should be established as a commercially available panel.Patch testing remains an essential tool for the diagnosis of ACC.It is important to test appropriate standard allergens along with patients' own products, especially lipstick and toothpaste, to identify the causative agents of the eruption.
Positive patch test reactions in the Siriraj baseline series and cheilitis series among 131 patients with allergic contact cheilitis.
T A B L E 2 Contact allergens (screening series) Concentration tested (%) N tested (N = 131) N positive (%) T A B L E 3 Personal products used for patch testing in 402 patients with cheilitis.