Discussion
The present study findings
demonstrated that children with moderate-to-severe AD, but not mild AD,
to be more susceptible to ECC development, compared to those without the
disease. Although complex pathogenic mechanisms of AD are still
evolving, current concepts suggest that defective skin barrier may be a
potential driving factor in AD pathogenesis and not a consequence of the
disease 17. As skin/hair and dental enamel originate
from ectoderm, we proposed a sub-clinical structural hypothesis to
explain this link based on presence of hair keratin proteins in the
mature enamel organic matrix 18 and association of its
mutations with increased caries risk 19. This was
substantiated in a prospective twin study reporting children with
infantile eczema to be at 2 times higher risk of developmental enamel
defects 20, which is a well-established risk factor
for ECC susceptibility 21.
Degree/type of skin barrier dysfunction may be one of the major
differences between mild and severe forms of the disease, as evidenced
by, a) a two-fold increased risk of genetic defects in skin proteins
(filaggrin, FLG ) in severe AD individuals compared to mild AD22, and b) an increased skin permeability dysfunction
(transepidermal water loss, TEWL) in severe AD individuals, compared to
milder forms of the disease 23. Furthermore,
polymorphisms in genes regulating skin barrier function/homeostasis have
been linked with tooth developmental anomalies. First, defects in
desmosomal proteins such as desmoplakin have been associated with severe
AD 24 and enamel dysplasia 25,
respectively. Second, defects in genes encoding for laminin-332 and type
XVII collagen have not only been associated with AD26, but also play a critical role in differentiation
of enamel-forming (ameloblasts) cells 27. Hence, it
may be plausible that severity of AD (with corresponding skin barrier
defects) may parallel degree of enamel defects and hence risk of caries.
Further characterization of enamel proteins in exfoliated deciduous
teeth from children with moderate-to-severe AD and non-AD are ongoing
and may elucidate or even confirm the pathogenic pathway proposed in the
study.
It can be argued that children with exacerbated AD symptoms, especially
in moderate-to-severe AD, may exhibit compromised compliance and/or
attention towards oral hygiene 4 and thus lead to
increased caries susceptibility. Hence, the association between AD
severity and ECC was further tested controlling for post-natal dietary
(such as duration of breastfeeding, child’s daily frequency of sweet
snacks) and oral hygiene factors (such as child’s brushing frequency)
(Table 3). Consistently, similar findings were revealed, with
moderate-to-severe AD cases to be at 2-fold higher ECC risk compared to
those without AD, substantiating an underlying biological link
independent of the dietary-behavioural effect, between
moderate-to-severe AD and ECC.
Diagnosis of AD, especially in epidemiological studies, may be subject
to potential errors especially in in young children. Conventionally,
caregiver-reported history of doctor-diagnosed AD is employed in
epidemiological studies 9, with a reported sensitivity
of 70% and a positive predictive value (PPV) of 87% in
children/adolescents (<18 years) in a referral dermatological
care setting with high prevalence rates (∼29.5%) 10.
However, in the present study when the true disease outcome was low
(7.3%), our results showed lower sensitivity (51.9%) and PPV (24.8%)
in identifying true AD cases (Table 4). These findings indicate that
although caregiver-reported criteria may be useful in estimating AD
burden in populations with high prevalence rates, its utility in very
young children and/or cohorts with low prevalence rates may be
compromised. Furthermore, although more than two-thirds of
moderate-to-severe AD children in the first 2 years of life demonstrate
sensitization to food allergens 11, low PPV (22.6%)
and sensitivity (40.3%) of a positive skin prick test suggested that
allergic sensitization alone may not be sufficient for AD diagnosis in
early-life. In contrast, combining a positive SPT with a
caregiver-reported history of doctor-diagnosed AD, as employed in our
previous work 8, resulted in a ~2-fold
higher PPV (45.4%) compared to single use of SPT or caregiver-report
alone. However, since overall PPV values still remained low (inflated
Type I error), its utility in epidemiological studies needs to weighed
against the more established diagnostic systems such as Hanifin and
Rajka criteria and UK Working Party criteria 28.
The strengths of this study include the longitudinal study design, use
of physician diagnosis in AD estimation, and enumeration of caries at
the surface-level (number of surfaces affected), instead of
individual-level outcome (yes/no) reported previously8. Study limitations include few moderate (N=12) and
severe AD (N=2) cases available in the cohort. Second, missing data seen
due to multiple time-points of data collection reduced the sample size
(N=581). Nevertheless, post-imputation results using multiple imputation
by chained equation (creating 40 imputed datasets), demonstrated that
exclusion of few missing cases did not affect the results of the study
(Appendix Table 2). Third, it was logistically impossible to obtain
inter- and intra-examiner reliability among physicians for AD
assessment, although both Hanifin-Rajka criteria 29and SCORAD scores 30 have been shown to exhibit high
inter-rater agreement (ICC>0.80) among
physicians/dermatologists. Fourth, severity of AD cases may be
underestimated in the current study owing to possible regression of skin
lesions before the time of clinic visits and the logistic inability to
obtain SCORAD in the first year when the prevalence of the disease is at
its peak 1. Lastly, there may be potential residual
confounding as not all confounding factors could be accounted in the
analysis due to constraints of sample size.
In conclusion, children with moderate-to-severe atopic dermatitis
demonstrated a two-fold increased caries risk at 3 years compared to
those without the disease, and early dental referral may be beneficial.
Furthermore, diagnostic accuracy of caregiver-reported history of
doctor-diagnosed AD, skin prick test, and the combined criteria may be
compromised in identifying true AD cases in certain populations with low
AD prevalence rates.