Clinical features of gingival lesions in patients with
dystrophic epidermolysis bullosa: a cross-sectional study
G Fortuna,* † M Aria,‡ R Cepeda-Valdes,† A Pollio,§ MG Moreno-Trevino,¶ JC Salas-Alanıs† ¶
*Department of Oral Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA.
†DebRA Mexico Foundation, Guadalupe, Nuevo Leon, Mexico.
‡Department of Economics and Statistics, Federico II University of Naples, Monte Sant’Angelo, Naples, Italy.
§Department of Neuroscience, University of Padua, Padua, Italy.
¶Department of Basic Science, Universidad de Monterrey, Nuevo Leon, Mexico.
ABSTRACT
Background: Gingival lesions in patients with dystrophic epidermolysis bullosa (DEB) are a common manifestation.
However, their clinical features, frequency and severity are currently unknown.
Methods: Forty-five DEB patients were assessed by an oral medicine specialist, who analysed the presence/absence of four clinical signs (erythema, erosion/ulcer, atrophy, blister) on free and attached gingiva, using the Epidermolysis Bull- osa Oropharyngeal Severity score.
Results: Twenty-eight (62.2%) out of 45 DEB patients showed different types of gingival lesions, whose presence/absence and total frequency/distribution were not significantly different between males and females (p = 0.087 and p = 0.091, respectively). Erythema was the most prevalent lesion (66.2%) and the recessive DEB severe generalized (RDEB-sev gen) reached the highest median disease activity score. A significant correlation was observed between the DEB subtypes and the disease activity median score (p< 0.001), but not between age and total disease activity score in each group of DEB (p> 0.05). Lastly, logistic regression showed that only gender (p = 0.031) and RDEB-sev gen (p = 0.001) were risks fac- tors for the presence of gingival lesions.
Conclusions: Gingival lesions in DEB patients are a relatively common entity and may have multiple clinical aspects, emphasizing the need for thorough attention and awareness among dentists.
Keywords: EB, epidermolysis bullosa, disease activity, oral hygiene, treatment.
Abbreviations and acronyms: DEB = dystrophic epidermolysis bullosa; EBOS score = Epidermolysis Bullosa Oropharyngeal Severity score; RDEB-sev gen = recessive DEB severe generalized.
(Accepted for publication 22 April 2014.)
INTRODUCTION
Epidermolysis bullosa (EB) is considered an inherited mucocutaneous disorder characterized by a fragility of the skin and mucous membranes following mild mechanical trauma, resulting into development of con- tinuous blisters.1 Four major types of EB have been recently described based on the level of skin cleavage:
intraepidermal (EB simplex [EBS]); intralamina lucida (junctional EB [JEB]); sublamina densa (dystrophic EB [DEB]); and mixed (Kindler syndrome). For each of these, there exist several distinct subtypes.2
EB patients may display a wide variety of clinical manifestations, involving not only skin and mucous membranes, but internal organs as well. Oral-pharyn- geal manifestations in EB vary markedly in both character and severity depending largely on the EB
type.3Such features include repeated occurrence of blis- ters and erosions, accompanied by erythema, atrophy and ultimately scars, which lead to ankyloglossia, mi- crostomia, and the disappearance of gingival fornices.4
In human patients with EB simplex, the oral- pharyngeal involvement appears to be limited but with a high variability; erosions occur in about 25%
of EBS localized patients during infancy, and more common lesions within patients with generalized intermediate and generalized severe EBS. Conversely, the enamel seems to be normal with an occurrence of dental caries similar to unaffected populations.2
In the junctional type, EB patients usually show normal soft tissue mobility and architecture, except for the Herlitz EB subtype that is characterized by exuberant perioral granulation tissue. Subsequently, EB patients may experience microstomia and some
Australian Dental Journal 2015; 60: 18–23 doi: 10.1111/adj.12264
Australian Dental Journal
The official journal of the Australian Dental Association
loss of tissue mobility in the lips and perioral tissues.3 As some of the genes involved in the pathogenesis of the junctional EB subtypes (i.e. beta chain of laminin- 3325 and type 17 collagen6) also play a pivotal role in the formation of normal teeth, the enamel may pres- ent with different degrees of abnormalities, from gen- eralized pitting to a generalized hypoplasia.3
Dystrophic epidermolysis bullosa (DEB) (OMIM
#120120) is one of the four major types of EB, which can be inherited in a dominant (DDEB) or recessive (RDEB) fashion, exhibiting a wide variety of mucocu- taneous manifestations, ranging from very mild to very debilitating and severe phenotypes.1 In such patients, oral-pharyngeal manifestations may involve both the hard and soft tissues, displaying variability in clinical features and degree of severity.7,8 Indeed, the milder forms including localized EB simplex are usu- ally characterized by sporadic and small lesions that heal rapidly without scarring, whereas the more severe forms such as severe generalized RDEB, are characterized by oral-pharyngeal lesions that may affect the entire oral cavity and are variable in size, quality and quantity.4,9 In some cases, such lesions may lead to a scarring phenotype (i.e. microstomia, ankyloglossia and loss of vestibule), with severe impairment of the patient’s quality of life and oral health.4,9
Though the main oral-pharyngeal mucosal lesions of EB are represented by vesiculo-bullous lesions, other types of lesions such as erythema, erosion and atrophy, may involve one of more of the 13 oral- pharyngeal mucosal sites (upper and lower lip, right and left buccal mucosa, upper and lower gingiva, upper and lower vestibule, hard palate, soft palate, oropharynx, floor of the mouth and tongue) with a variable frequency and severity.4
To date, there is no information regarding the fre- quency and severity of gingival lesions in patients with DEB, most likely due to the rare occurrence of this disorder in the human population, rendering an assessment of gingival lesions an arduous task. The purpose of this clinical study was to analyse the clini- cal features of gingival lesions in DEB patients from Northern Mexico, assessing their prevalence, localiza- tion and disease activity.
METHODS
Study design and patient assessment
This was a cross-sectional clinical study involving 45 patients diagnosed with DEB between June 2012 and November 2012, ascertained from Universidad de Monterrey, Mexico and DebRA Mexico, Monterrey, Mexico. All patients provided written informed con- sent for the management of personal data before par-
ticipating in the study. The study was approved by the ethical committee of the Universidad de Monter- rey, Mexico and was conducted in adherence with the Declaration of Helsinki Principles Guidelines.
All DEB patients recruited for this study met the following inclusion criteria: (1) patients of both gen- ders, all ages and races, with the presence of typical mucocutaneous lesions of DEB, as previously reported;2 (2) diagnosis of DEB based on analysis of a skin biopsy including histology, immunofluores- cence antigen mapping and, if available, electron microscopy and DNA analysis; and (3) patients able to give consent if older than 18 years. For younger patients, consent was obtained from their parents or a legal guardian. Patients were excluded from the study if they had used topical corticosteroids, topical or systemic antifungal therapy three weeks prior to the study as such medications might significantly affect their clinical appearance. Patients with present or past medical history of oral-pharyngeal malignancy and/or potentially malignant disorders on free and/or attached gingival mucosa, or who were pregnant or breastfeeding, were also excluded from this study.
DEB patients were divided into three groups based on the most recent International Consensus classifica- tion:213 with DDEB, 8 with RDEB-intermediate gen- eralized (RDEB-int gen) and 24 with RDEB-severe generalized (RDEB-sev gen). The assessor consisted of one board-certified oral medicine specialist (GF) who had extensive experience diagnosing, treating and managing patients with EB. A complete clinical intra- oral examination was performed for all 45 patients.
Free and attached gingiva of maxilla and mandible were analysed in order to detect the presence or absence of four clinical signs: erythema, erosion/ulcer, atrophy, blister, as defined elsewhere.10 These signs represented the disease activity, which has been evalu- ated in all affected patients through the Epidermolysis Bullosa Oropharyngeal Severity (EBOS) score.4 The disease activity score was evaluated on upper and/or lower gingiva affected by one or more clinical signs.
We decided to assign one point to each clinical sign present on one or both jaws.
Statistical analysis
Descriptive statistics of demographic characteristics and EB type/subtype distribution was calculated as mean standard deviation. A McNemar’s test was employed to compare the presence of any type of gin- gival lesions and a Fisher’s exact test was used to detect any possible difference in the distribution of dentition between males and females. The chi-square test was used to compare the frequency of lesions between the two genders. Medians, interquartile ranges (IQR), and range of disease activity scores
were calculated for each DEB group. A non- parametric Kruskal–Wallis analysis of variance (K–W ANOVA) was used to assess the difference of disease activity median score among the three groups of DEB, whereas a Spearman’s correlation coefficient was employed to assess the relationship between age and disease activity total score calculated in each DEB group. Lastly, backward logistic regression analysis was carried out using the presence of gingival lesions as a dependent variable, and age, gender and type of DEB as the independent variables.
P-values of less than 0.05 were considered signifi- cant. Statistical analyses were performed using the SPSS software (IBM SPSS for Windows, version 20.0;
IBM, USA).
RESULTS
Patients’ characteristics and frequency/distribution of gingival lesions
Forty-five patients with DEB were enrolled in the study; their ages ranged from 6 months to 63 years (mean: 18.9 years for males and 21.4 for females).
Fourteen men (31.1%) and 31 women (68.9%) were evaluated to determine the presence/absence of ery- thema, erosion/ulcer, blister and atrophy on the upper and lower gingiva (Table 1).
Of the 45 DEB patients, 28 [11 males (24.4%) and 17 females (37.7%)] exhibited gingival involvement with a variable distribution among the three different DEB groups. Neither the presence/absence of the four types of gingival lesions (p = 0.087) nor the distribu- tion of the dentition (p = 0.0512) were significantly different between males and females (Table 1).
Similarly, the frequency and distribution of gingival analysis demonstrated the presence of 74 lesions in 28 out of 45 (62.2%) DEB patients, where erythema was the most common gingival lesion (66.2%), followed by erosions/ulcers (31.1%), and atrophic lesions were completely absent (Fig. 1). All gingival lesions were equally distributed with no statistically significant dif- ference between males and females either on the max- illa (p= 0.246) or mandible (p = 0.223) (Table 2).
Correlation of disease activity score with DEB types and age
A significant correlation was observed between the three DEB types and the median disease activity score calculated either on both jaws or separately (K–W ANOVA; p < 0.001) (Table 3), but not between age and the disease activity total score. For example, there was an increased score in all DEB groups that corre- lated with age (DDEB:q = 0.372, p = 0.21; RDEB–int gen: q = 0.362, p = 0.22; RDEB-sev gen: q = 0.132,
p= 0.53), calculated on both jaws, but none were sta- tistically significant (Table 4).
Multivariate logistic regression analysis
Logistic regression analysis showed that, after control- ling for various potential confounders, the only signifi- cant predictors for the development of gingival lesions were gender (males carry a higher risk; p = 0.031) and the type of DEB (recessive forms carry a higher risk; p = 0.001), whereas age was not a significant risk factor (p = 0.826) (Table 5).
DISCUSSION
We describe the results of a cross-sectional study on 45 patients with DEB. To the best of our knowledge, this is the first study to report on the frequency and severity of gingival lesions in a population affected by DEB.
The study sample mainly comprised patients with RDEB-sev gen (53.3%) and was quite homogenous in terms of age between males and females, but not in terms of gender distribution and prevalence of gingi- val lesions. Indeed, the number of females significantly exceeded the number of males (31 vs 14) and the total Table 1. Characteristics of patients with DEB
No. of patients (%)
Total 45 (100)
Male 14 (31.1)
Female 31 (68.9)
Mean age (range) M: 18.9 yrs (0.5–59)
F: 21.4 yrs (1.5–63)
Dominant form 13 (28.9)
Recessive form 32 (71.1)
EB type/
subtype
Total number of males (%)
Total number of females (%)
Total number of DEB patients
DDEB 5 (11.1) 8 (17.8) 13 (28.9)
RDEB-int gen 0 (0) 8 (17.8) 8 (17.8)
REDEB-sev gen 9 (20) 15 (33.3) 24 (53.3)
Total 14 (31.1) 31 (68.9) 45 (100)
Gingival lesions Male patients (%)
Female patients (%)
P-value
Presence 11 (78.6) 17 (54.8) 0.087
Absence 3 (21.4) 14 (45.2)
Total 14 (100.0) 31 (100.0)
Dentition Primary Mixed Permanent P-value
Male patients with lesions (%)
1 (9) 4 (36.4) 6 (54.6) 0.512 Female patients with
lesions (%)
0 5 (29.4) 12 (70.6)
RDEB-int gen= recessive dystrophic epidermolysis bullosa, interme- diate generalized; RDEB-sev gen= recessive dystrophic epidermoly- sis bullosa, severe generalized; DDEB = dominant dystrophic epidermolysis bullosa.
number of gingival lesions was higher in females than in males (44 vs 30). However, the probability of pre- senting with gingival lesions was higher in males than in females (OR: 7.52; p= 0.031) (Table 5). The influ- ence of gender on the course and type of gingival involvement is unknown. Our logistic regression
analysis demonstrated that the recessive form repre- sents a higher risk factor for the onset of gingival lesions than the dominant form, mostly in the severe generalized form (OR: 45.29; p= 0.001) (Table 5).
These results are consistent with previous observa- tions2,3 that confirmed that the RDEB-sev gen form
(a) (b)
(c) (d)
Fig. 1 (a) Diffuse and marked erythema of the upper gingiva in a patient with RDEB-int gen showing accumulation of dental plaque on upper right and left central incisors; (b) localized and mild erythema in a patient with DDEB without any sign of dental plaque; (c) diffuse and marked erythema and ero- sions of the lower right gingiva in a patient with RDEB-sev gen without any sign of dental plaque; (d) generalized erythematous and erosive lesions
involving all upper and lower gingiva in a patient with RDEB-sev gen showing localized plaque accumulation.
Table 3. Disease activity score on gingival mucosa per type of DEB
Gingiva EB type Median IQR Range
(min–max) K–W ANOVA
Both jaws DDEB 0.0 [0–0] [0–2] p< 0.001
RDEB-int gen 0.5 [0–2] [0–2]
RDEB-sev gen 2.0 [2–4] [0–4]
Maxilla DDEB 0.0 [0–0] [0–1] p< 0.001
RDEB-int gen 0.0 [0–1] [0–1]
RDEB-sev gen 1.0 [1–2] [0–2]
Mandible DDEB 0.0 [0–0] [0–2] p< 0.001
RDEB-int gen 0.5 [0–1] [0–1]
RDEB-sev gen 1.0 [1–2] [0–2]
IQR= interquartile range; RDEB-int gen = recessive dystrophic epidermolysis bullosa, intermediate generalized; RDEB-sev gen = recessive dys- trophic epidermolysis bullosa, severe generalized; DDEB= dominant dystrophic epidermolysis bullosa.
Table 2. Frequency and distribution of four types of lesions in DEB patients with gingival involvement
No. of lesions maxilla (%) No. of lesions mandible (%) Total no. of lesions (%)
Type of lesion Male Female Male Female Male Female
Erythema 10 (62.5) 15 (68.18) 9 (64.3) 15 (68.18) 19 (63.3) 30 (68.1)
Erosion/ulcer 5 (31.2) 7 (31.82) 4 (28.6) 7 (31.82) 9 (30) 14 (31.9)
Blister 1 (6.3) 0 (0) 1 (7.1) 0 (0) 2 (6.7) 0 (0)
Atrophy 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
P-value 0.246 0.223 0.091
represents the most disabling and disfiguring EB form in terms of oral-pharyngeal manifestations. This includes the presence of the four active lesions wide- spread on the entire oral cavity as well as a remark- able scarring phenotype, with subsequent impairment of phonatory and masticatory functions.
Our results showed a greater frequency of erythem- atous lesions on both jaws equally distributed between the groups of males and females. It seems reasonable to believe that the predominance of such lesions in the study group may indicate an active status of inflammation (high disease activity score), mainly related to the fragility of epithelium that can easily form blisters, erosions/ulcerations, and to a lesser extent, an accumulation of local irritating factors (i.e.
dental plaque, aggravation of the symptomatology, gingival inflammation), such as dental plaque, with a subsequent aggravation of the symptomatology and increased levels of gingival inflammation. As gingival lesions are usually persistent and painful, such dis- comfort could predispose patients to visit their den- tists less frequently and not efficiently perform domiciliary oral hygiene practices.
Notably, only 8 DEB patients (28.5%) reported ery- thematous lesions associated with dental plaque: 2 females and 2 males in the mixed dentition and 2 females and 2 males in the permanent dentition (Table 1). In all 8 patients, gingival lesions were extensive and involved all upper and/or lower mucosa gingiva, while dental plaque was site-specific. There- fore, it is very unlikely that dental plaque could be the primary cause of erythema as it is more likely to be just an aggravating factor.
Therefore, due to a wide variety and quite common presence of oral-pharyngeal lesions, mostly located on gingival mucosa, oral management of DEB patients represents a big challenge. It must include topical medications to reduce inflammation as well as the chance of developing new blisters/erosions, and peri- odic sessions of professional oral hygiene and daily domiciliary oral hygiene in order to remove local irri- tating factors that may aggravate gingival lesions.
Several studies11–13 have already demonstrated the usefulness of topical corticosteroids (i.e. clobetasol or flucinonide 0.05% ointment in adhesive paste), or topical calcineurine inhibitors (i.e. tacrolimus 0.1% in the treatment of lichen planus, mucous membrane pemphigoid and pemphigus vulgaris). These encourag- ing results might lead clinicians to perform clinical tri- als for EB patients presenting with gingival lesions.
However, this rare disease is inherited and the therapy would be a palliative treatment rather than a cure.
Domiciliary oral hygiene should be practised with a manual toothbrush containing a small head and soft bristle soaked in lukewarm water prior to use, or alternatively, cotton buds (cotton swabs), disposable mini brushes, clean cotton cloth, or gauze, if the patients’s mouth is very sore. In addition, the use of alcohol-free chlorhexidine 0.12% and fluoride is strongly recommended as adjuvant therapy.14 Profes- sional hygiene should also be practised with an ultra- sonic scaler, used gently and carefully to reduce the possibility of bulla formation.14
In this study, we have focused our attention only on those lesions representing the disease activity of EB rather than any possible scarring phenotype, as the former might be modulated with an appropriate topi- cal therapy11–13 in association with several preventive measures,7,15 whereas the latter represents a stable condition that may aggravate over time. Indeed, a scarring phenotype may remarkably alter gingival fornices and lead to their partial or complete oblitera- tion with subsequent impairment of food clear- ance.14,16 Vestibule obliteration is an irreversible condition lacking medical treatment, but a promising therapy might come from periodontal plastic surgery to increase the width of attached gingival.17
The limitations of this study include the reduced sample size and the lack of inclusion of any Mexican Table 4. Correlation between age and disease activity
total score calculated in each DEB group
Gingiva EB type Spearmanq
correlation
P-value
Both jaws DDEB 0.372 0.210
RDEB-int gen 0.362 0.221
RDEB-sev gen 0.132 0.530
Maxilla DDEB (total) 0.537 0.058
RDEB-int gen 0.437 0.121
RDEB-sev gen 0.132 0.530
Mandible DDEB (total) 0.101 0.741
RDEB-int gen 0.159 0.653
RDEB-sev gen 0.161 0.441
RDEB-int gen= recessive dystrophic epidermolysis bullosa, interme- diate generalized; RDEB-sev gen= recessive dystrophic epidermoly- sis bullosa, severe generalized; DDEB = dominant dystrophic epidermolysis bullosa.
Table 5. Multivariate logistic regression analysis of risk factors associated with the presence of any type of gingival lesion
Independent variables
B SE P-value OR (95%CI)
Age (years) 0.005 0.024 0.826 1.01 (0.66–1.45) Male vs Female 2.018 1.238 0.031 7.52 (4.56–13.92) RDEB-int
gen vs DDEB
1.883 1.366 0.067 6.57 (2.62–15.22) RDEB-sev
gen vs DDEB
3.813 1.174 0.001 45.29 (30.17–70.73) Adjusted R2 0.514 <0.001
OR= adjusted odds ratio; RDEB-int gen = recessive dystrophic epi- dermolysis bullosa, intermediate generalized; RDEB-sev gen= reces- sive dystrophic epidermolysis bullosa, severe generalized; DDEB= dominant dystrophic epidermolysis bullosa.
patients with simplex and junctional EB. A better understanding of the population frequency and sever- ity of gingival lesions could be achieved through fur- ther multicentre investigations on larger cohorts representing all types/subtypes of EB. However, this appears an ongoing challenge as EB is a rare condi- tion with significant mortality and morbidity rates in addition to a high risk of participant fatigue. At the time of the study, we did not perform a complete periodontal examination as an additional exam would have been too burdensome for the EB patients. How- ever, we intend to follow-up with this in the near future to better address this aspect.
Our study is unique in demonstrating the preva- lence of erythema as a major manifestation of gingival lesions in DEB patients. The high frequency of all these different types of gingival lesions (mainly ery- thema/erosions) in DEB patients emphasizes the need for further investigations. This will be required to bet- ter ascertain whether and how such lesions may influ- ence periodontal status, considering that the accumulation of local irritating factors (i.e. dental pla- que) may only partly contribute to this. Nonetheless, we cannot exclude a potential relationship between gingival lesions and the plaque-related periodontal damage, concluding that DEB patients require a higher level of attention.
It is likely that other factors strictly related to path- ogenesis of such disorder may play a role in the for- mation of gingival lesions and subsequent periodontal involvement. For this reason, this study is also aimed at alerting not only oral medicine specialists but gen- eral dental practitioners to be highly careful in treat- ing DEB patients.
ACKNOWLEDGEMENTS
We would like to thank patients with EB for their courage, strength and love, all DebRA Mexico staff, especially Lic Erika Salas. We would like to thank Dr Gina DeStefano, Columbia University, for her kind assistance in editing the original manuscript.
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Address for correspondence:
Dr Giulio Fortuna Chief Resident Department of Oral Medicine Carolinas Medical Center 1000 Blythe Boulevarde Charlotte NC 28203 USA Email: giulio.fortuna@carolinashealthcare.org
