ARTICLE
Auteur(s) : Donatella Schena,
Francesca Fantuzzi, Giampiero Girolomoni
Sezione di Dermatologia e Venereologia, Dipartimento di Scienze
Biomediche e Chirurgiche, Università di Verona, Piazzale A. Stefani
1, 37126 Verona, Italy
accepté le 4 Juin 2008
Cheilitis refers to an inflammatory process that affects the
lips, including the cutaneous side, the vermilion border and/or the
lip mucosa. The majority of cases of cheilitis affect the skin and
vermilion border, as the oral mucosa is less affected by
inflammatory and allergic reactions [1, 2]. Indeed, it is possible
that substances contacting the mucosa more easily induce tolerance
rather than immunogenic responses [2]. Chronic eczematous reactions
account for most cases of chronic cheilitis, but it is sometimes
difficult to establish the nature and cause of the reaction. Apart
from single case reports or small case series, only a few studies
on larger patient populations have been performed to define the
origins of chronic eczematous cheilitis [3-6]. In many cases,
chronic cheilitis is the result of an allergic reaction to small
molecular weight chemicals known as haptens, or more rarely to
protein allergens (allergic contact cheilitis, ACC) [7]. In other
cases, it derives from the direct toxic action of contacting
substances (irritant contact cheilitis, ICC), or from an intrinsic
propensity to develop inflammatory responses to minimal stimuli,
such as in atopic cheilitis. The diagnostic work up of chronic
eczematous cheilitis encompasses allergy testing with standard and,
frequently, extended patch test series to confirm or exclude the
involvement of an allergic component.
The objective of this study was to define the frequency of
contact allergy and atopy in relation to age and the site involved
in a cohort of patients with chronic eczematous cheilitis. The
results show that ACC to cosmetics and dental material is the most
common form in adult patients. Children suffer from both atopic
cheilitis and ACC to haptens and food proteins. Elderly patients
have ACC to cosmetics, dental material and topically applied
drugs.
Patients and methods
This was a retrospective study carried out from January 2001 to
December 2006. It involved the examination of 129 Caucasian
patients referring to our Contact and Occupational Dermatoses
Clinic who presented with eczematous lesions on the vermilion
border, the nearby skin or the lip mucosa. Inclusion criteria were
the presence of eczematous lesions for at least 3 months and the
execution of standard patch tests. Patients with lichenoid
reactions of the lips or the oral mucosa, orofacial granulomatosis,
swelling, burning or soreness of the lips but no lesions, were not
included. Demographic data, disease history, patients’ work
details, cosmetics and medications applied on the lips, dental
hygiene habits, co-morbid diseases, systemic medications and
physical findings were registered. Personal and family history of
atopic disease (asthma, atopic dermatitis and allergic
rhino-conjunctivitis) and past skin reactivity or serum specific
IgE to common allergens were noted. All the patients were patch
tested with the standard series (Firma, Florence, Italy) elaborated
by the Italian Society of Allergological, Occupational and
Environmental Dermatology (SIDAPA series)1. Forty-two patients were also investigated
with a patch test cheilitis series elaborated by us (table 1), which was used whenever the standard
patch test was negative or gave irrelevant positivity. This test
series was created utilizing the specific cheilitis battery
proposed by Firma, integrated with the most frequent haptens
responsible for ACC reported in the literature. Finally, 10
patients were tested directly with the suspected products, such as
toothpastes, lip-balms and lipsticks. To do this, the product was
applied directly on the skin using Haye’s test chambers and left in
place for 2 days, as previously reported [12]. Positive reactions
observed by testing patients’ own products have been validated by
executing stop-restart tests with the same product. Children
(≤ 14 years) were also investigated with the atopy patch tests
for house dust mite, latex, pollens and foods
(Alk-Abelló®, Hørsholm, Denmark) [8]. Patch tests were
carried out with Haye’s test chambers applied on the back and left
in place for 2 days. Readings were taken after 48 and 96 hours, and
scored according to the recommendation of the International Contact
Dermatitis Research Group [9, 10]. Positive reactions were defined
as relevant whenever the patient was exposed to an allergen during
episodes of cheilitis and cheilitis improved or disappeared when
the exposure ceased.
Table 1 Patch test with cheilitis series used
|
Benzoic acid 5% pet.
|
Oleyl alcohol 30% pet.
|
|
Cinnamic aldehyde 2% pet.
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Aluminium chloride 2% aq.sol.
|
|
Anethole 5% pet.
|
Azulene 1%
|
|
Benzalkonium chloride 0.1% aq.
|
Benzoin 10% alc.
|
|
Carvone 5%
|
Beeswax 30% pet.
|
|
Chloroacetamide 0.2% aq.sol.
|
Dichlorophene 1% aq.sol.
|
|
D&C red 21 (Eosin)
|
Hexylresorcinol 1% pet.
|
|
Eugenol 5% pet.
|
Phenyl salicylate 1% pet.
|
|
Ethylene glicol 5% alc.
|
Isoeugenol 5% pet.
|
|
Limonene R 2% pet.
|
Limonene S 2% pet.
|
|
Menthol 1% pet.
|
Octylmethoxycinnamate 7.5% pet.
|
|
Benzophenone 3 5% pet.
|
Eucalyptus oil 1% alc.
|
|
Laurel oil 2% pet.
|
Cinammon oil 2% pet.
|
|
Peppermint oil 1% pet.
|
Rosemary oil 5% alc.
|
|
Spearmint oil 2% pet.
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Propyl gallate 1% pet.
|
|
Propolis As is
|
Quaternium-15 2% pet.
|
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Sodium benzoate 5% aq.sol.
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Sodium lauryl sulfate 1% aq.sol.
|
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Thymol 1% pet.
|
Vanillin 10% pet.
|
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Castor oil As is
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Ricinoleic acid 30%
|
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D1-alpha-Tocopherol 20%
|
Chlorhexidine digluconate 0.5% aq.
|
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Platinum chloride 1% aq.sol.
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Manganese chloride 2% pet.
|
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Palladium chloride 1% pet.
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Zinc chloride 2% aq.sol.
|
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Sorbitan monooleate 5% o.o.
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Butylhydroxyanisol 1% pet.
|
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butylhydroxytoluene 1% pet.
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D&C orange 17 (C.I. 12075) 2% pet.
|
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D&C Orange 4 (CI 15510) 2% pet.
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D&C red 11 (C.I. 15630) 2% pet.
|
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D&C Red 17 (C.I. 26100) 2% pet.
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D&C red 36 (C.I. 12085) 2% pet.
|
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D&C Red 22 50% pet.
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Yellow orange S yellow 6 pet.
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D&C Yellow chinoline 2% pet.
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Yellow tartrazine – yellow 5 pet.
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Results
A total of 129 patients referring with chronic eczematous cheilitis
were included in the study. They were 106 females and 23 males,
aged from 4 to 81 years (mean age, 42; median age, 41). Lesions
exclusively affected the vermilion border in 58% of cases or the
lip skin in 33%, both these locations in 7%, and the vermilion
border and the lip mucosa in only 2% of patients. Cheilitis lasted
from 3 to 72 months, with a mean and a median duration of 35.2 and
12 months, respectively. There were no substantial differences in
disease duration between the different classes of age. Most
patients referred subjective symptoms such as pruritus, burning or
pain.
Positive patch test reactions were considered of possible or
probable relevance in 84 patients (65.1%; 72 females and 12 males;
median age 40), but the use of the extended series was necessary to
reveal relevant hypersensitivity in 42 patients. Fifty-four
patients developed relevant reactivity to a single hapten, whereas
28 patients had multiple sensitivities; two subjects had negative
patch testing but developed positive reactions to products tested
as such (lipsticks and toothpastes). Table
2 lists the number of patients reactive to each hapten.
Among the relevant reactivities, the most commonly involved were
metals, fragrances and preservatives, present primarily in
cosmetics, but also in dental materials and oral hygiene products.
Among patients with positive patch tests, 40 (49%) also had a
history of atopic diseases (atopic eczema, asthma and/or
rhino-conjunctivitis). They were mostly adults aged from 20 to
60.
Patch tests were positive but of uncertain or not relevant
significance in 26 (20.1%) and negative in 19 (14.7%). Of these
patients, 24 (18.6% of total patients) were diagnosed as having
atopic dermatitis of the lips, since there was a personal history
of atopic dermatitis elsewhere (38%), asthma (10%) and/or
rhino-conjunctivitis (7%), and at least one determination
documenting skin or serum allergen specific IgE. However, only two
of these patients had concurrent atopic dermatitis lesions and
atopic cheilitis at the moment of the visit. Finally, the 21
patients (16.3%) with either negative (n. 19) or irrelevant
positive patch tests (n. 2), as well as no past or present history
of atopic diseases, were diagnosed as ICC. In the majority of
patients with ICC, the disease was associated with the use of
cosmetics or hygiene products. Separating patients according to age
range, four classes could be identified (table
3). ACC was more common in adult and aged patients, whereas
atopic cheilitis was the predominant form in children, but it was
also observed in adults. All the children were investigated with
atopy patch tests and all eight atopic children gave positive
reactions to food, but with uncertain significance in six. In
contrast, two atopic children had ACC to food allergens (egg and
shellfish respectively). Table 4 shows
that the sources of allergens vary in relation to the patients’
ages. Cosmetics were the most common cause in adults whereas dental
materials and oral hygiene products were common in all age groups.
In elderly patients topical medicines (neomycin) accounted for a
relevant proportion of positive reactions (21%).
Table 2 Number of patients with positive and relevant
patch test reactions
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Positive patch test
|
Relevant patch test
|
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Positive patch test
|
Relevant patch test
|
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Metals
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37
|
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Preservatives/antioxidants
|
22
|
|
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Nickel sulphate
|
20
|
10
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Kathon CG
|
4
|
2
|
|
Potassium dichromate
|
6
|
3
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Formaldehyde
|
3
|
0
|
|
Manganese chloride
|
4
|
3
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Thimerosal
|
3
|
0
|
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Cobalt chloride
|
4
|
0
|
Benzalkonium chloride
|
2
|
1
|
|
Gold sodium thiosulphate
|
2
|
2
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Euxyl K 400
|
2
|
2
|
|
Palladium
|
1
|
1
|
Hexylresorcinol
|
2
|
1
|
|
|
|
Propyl gallate
|
2
|
2
|
|
Fragrances/flavouring agents
|
25
|
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Tocopherol
|
2
|
0
|
|
Fragrance mix
|
10
|
9
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Imidazolidinylurea
|
1
|
0
|
|
Balsam Perù
|
8
|
8
|
Sodium lauryl sulphate
|
1
|
1
|
|
Limonene R e S
|
3
|
3
|
|
|
|
|
Benzoin
|
2
|
0
|
Drugs
|
5
|
|
|
Menthol
|
2
|
1
|
Neomycin sulphate
|
5
|
5
|
|
Pepper mint oil
|
2
|
2
|
|
|
|
|
Eucalyptus oil
|
1
|
1
|
Product as it is
|
3
|
|
|
|
|
Toothpaste Acquafresh
|
1
|
1
|
|
Miscellaneous
|
19
|
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Toothpaste AZ carie
|
1
|
1
|
|
Colophony
|
4
|
1
|
Neutrogena labbra
|
1
|
1
|
|
Lanolin
|
3
|
2
|
|
|
|
|
Beeswax
|
2
|
2
|
|
|
|
|
Propolis (resin)
|
2
|
1
|
|
|
|
|
Toluenesulfonamide formaldehyde resin
|
2
|
1
|
|
|
|
|
Castor oil
|
1
|
1
|
|
|
|
|
Propylene glycol
|
1
|
1
|
|
|
|
|
Red 17 (dye)
|
1
|
1
|
|
|
|
Table 3 Different age classes of patients with chronic
eczematous cheilitis
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|
|
|
|
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Allergic contact cheilitis
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4 (40%)
|
37 (72.5%)
|
24 (52.2%)
|
19 (86.4%)
|
|
Atopic cheilitis
|
6 (60%)
|
11 (21.6%)
|
5 (10.9%)
|
2 (9.1%)
|
|
Irritant contact cheilitis
|
-
|
3 (5.9%)
|
17 (36.9%)
|
1 (4.5%)
|
Table 4 Allergic contact cheilitis and sources of
allergens in different age classes of patients with chronic
eczematous cheilitis
|
|
|
|
|
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Cosmetics
|
-
|
23 (62%)
|
14 (58%)
|
5 (26%)
|
|
Dental materials
|
1 (25%)
|
6 (16%)
|
4 (17%)
|
6 (32%)
|
|
Oral hygiene products
|
1(25%)
|
8 (22%)
|
5 (21%)
|
4 (21%)
|
|
Medicines
|
-
|
-
|
1 (4%)
|
4 (21%)
|
|
Foods (egg, shellfish)
|
2 (50%)
|
-
|
-
|
-
|
*Number of patients with ACC on patients with chronic
eczematous cheilitis.
Discussion
Lips can be affected by a large variety of inflammatory disorders,
including lichenoid reactions, lupus erythematosus, orofacial
granulomatosis, urticaria. Chronic eczematous cheilitis is the
commonest form, and manifests with erythema, dryness, scaliness,
fissuring and is often accompanied by angular lesions (figure 1). Females are
more frequently affected than males, as confirmed in our study,
where we observed a F:M ratio of 4.6:1, a predominance that can be
explained by the presumption that women use more cosmetics and lip
products than men and are also more likely to seek medical
attention for a process affecting physical appearance. The nature
and causes of chronic eczematous cheilitis can be diverse, but most
cases can be defined as of allergic, irritant or atopic origin. The
prevalence of ACC remains uncertain, and only a few studies of
sufficient size have investigated this issue. In these studies the
prevalence of ACC among patients attending a tertiary referral
center varied form 15% to 34%, whereas ICC and atopic cheilitis
represented 5-37% and 19-33%, respectively [3-6]. In our series,
ACC was diagnosed in 65% of patients, whereas ICC and atopic
cheilitis accounted for 16.3% and 18.6%, respectively. The higher
percentage of patients with ACC and lower percentage of ICC in our
study may be related to the higher selection of patients attending
our Clinic. Indeed there are no studies investigating the
prevalence of ACC and other eczematous cheilitis in the general
population. ACC was more common in adults and rarely observed in
children. The main causes of ACC were cosmetics, such as lipsticks
[3, 4, 6], oral hygiene products [4, 12], dental materials [13,
14], nail cosmetics, and, more rarely, foods [15], and these data
have been confirmed in our case series. Metals, fragrances, and
preservatives were the most relevant haptens contained in cosmetics
and oral hygiene products. Metals were most likely the relevant
haptens present in dental materials. Other than nickel, manganese
and cobalt reactivity was detected in some patients, in all cases
together with nickel. The relevance of dental material was
established by the disappearance or marked improvement of cheilitis
upon material withdrawal, but we did not address the role of each
individual metal [13, 14]. Also, we did not test for acrylates and
methacrylates, as these substances are very rarely involved in
cheilitis [13, 14]. Patch tests with extended series or with the
product as is was required to establish the cause of ACC in about
half and in three patients, respectively. These results confirm the
necessity to consider a wide range of possible substances before
excluding the allergic nature of the cheilitis, and thus the
importance of using extensive patch test series [16, 17]. Taking
into account different age groups, cosmetics were found to be the
most frequent cause of ACC in adults, whereas dental materials and
oral hygiene products were common in all age groups. Topical
medicines (neomycin) seemed to be a relevant cause of ACC only in
the elderly, where they accounted for a relevant proportion of
reactions (21%). Atopic cheilitis was diagnosed in less than 20% of
our patients, a percentage that is in the lower range of previous
studies [3-6], possibly because patients with atopic dermatitis in
typical areas were not included in the study. Indeed the lips are
commonly involved in patients with atopic dermatitis. Diagnosis may
be instead more difficult when the patient comes with eczematous
lesions limited to the lips. In such case a careful history, the
presence of specific IgE, and the absence of hapten patch test
reactivity help in the diagnosis. A number of reports analyzed
patch test reactions to protein allergens in patients with atopic
eczema, but no definitive conclusion about the relevance of this
tests can be drawn at the moment [8, 11, 18]. Only ten children
were included in our study, with eight showing a positive patch
test reaction to foods. However, the reaction was interpreted as
relevant only in two (shellfish and egg), where avoidance led to
disease resolution, and re-challenge to disease reappearance. At
any rate, the number of children included in our study was too low
to draw any conclusion on the importance of food allergy in
cheilitis. Two additional children had ACC to haptens. The
anatomical sites involved seemed not to be related to the type of
eczematous cheilitis and, in the case of ACC to the source of
hapten, in line with previous results [19].
Conclusion
Chronic eczematous cheilitis may be of disparate nature and
attributed to different factors. Patch testing is essential for
investigating a suspected contact cheilitis, and extended patch
test series and/or testing with the patient’s personal products is
very important to definitively establish the causative substance.
Atopy is very common in the population, including patients with
cheilitis, and thus the atopic nature of the symptoms should be
precisely defined.
Acknowledgements
Financial support: none. Conflict of interest: none.
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1 www.sidapa.com
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