Atopic dermatitis (AD), caused by a complex interplay of genetic and environmental factors, is a relapsing and chronic inflammatory disease of the skin. Worldwide, AD is a common health problem that affects 10–20% of children and 1–3% of adults. The exact cause of AD is not well understood, nevertheless, defective epidermal barrier function, impaired antimicrobial defence mechanisms and increased cutaneous inflammation are reported to be the major culprits.1 Defective epidermal barrier function is thought to be related to the downregulation of the filament-aggregating protein, filaggrin, reduced ceramide, loricrin, involucrin levels, increased levels of endogenous proteolytic enzymes, and enhanced trans-epidermal water loss.2

Humans obtain their vitamin D either through the skin via cutaneous conversion of 7-dehydrocholestrol into previtamin D3 by exposure to solar ultraviolet B radiation or through the gut, via food and/or supplement ingestion. Vitamin D also plays an important role in skin functions beyond acting as a hormone on calcium metabolism. It promotes cornified envelope formation and synthesis of the lipid permeability barrier.3 Antimicrobial peptides (AMPs) have a pivotal role on antimicrobial defence and are secreted at the surface of the skin as a first-line defence against infection. Liu et al.4 demonstrated that the release of AMPs (such as cathelicidin), antimicrobial response, triggered by the toll-like receptor and vitamin D-mediated immunity. The results of studies investigating the levels of vitamin D in patients with AD are contradictory. In some studies, it has been shown that there is a relationship between vitamin D levels and disease severity in patients with AD.5–9 On the contrary, there are studies showing that there is no relationship.10–12 The effect of vitamin D levels on survival of the disease has not been evaluated in children with AD.

The aims of this study were to compare the vitamin D levels of children with AD and healthy children, to investigate the relationship between the severity of AD and vitamin D levels, and to investigate the effect of vitamin D on survival of AD.

A total of 69 children enrolled to the study. The study was approved by the local ethics committee of the same institute and adhered to the principles of Helsinki Declaration. Consent was obtained from all subjects and/or their parents.

In the patient group, forty patients (58%) were male and the mean age was 5.6±2.7 years. In the control group, thirty-five children (50%) were male and the mean age was 5.4±2.3 years. These two parameters did not differ significantly between groups (Table 1). Mean 25OHD3 level was lower in the patient group compared to the control group; 19.86±6.7ng/mL (min–max: 6.8–40) vs. 24.07±9.08ng/mL, respectively, (p=0.002). Thirty-seven children (53.6%) had 25OHD3 deficiency, 26 children (37.7%) had 25OHD3 insufficiency and six children (8.7%) had normal 25OHD3 levels in the patient group, whereas 22 children (31.4%) had 25OHD3 deficiency, 41 children (58.6%) had 25OHD3 insufficiency and seven (10%) had normal 25OHD3 levels in the control group (p=0.027) (Table 1).

The patients were grouped into three subgroups according to their SCORAD scores, namely mild AD group, moderate AD group and severe AD group. Gender, age, the presence of familial atopy, the duration of disease, the percentage of eosinophils, IgE level, the presence of sensitivity in skin prick test, sensitivity to house dust mite, pollens, dander, A. alternata, cockroach and food did not different significantly between subgroups of patients (p>0.05) (Table 2). However, mean 25OHD3 levels, and vitamin D status were significantly different between groups (p<0.05) (Table 2). In terms of vitamin D status in the pairwise comparison of the groups, vitamin D deficiency was greater in children with severe and moderate AD groups (respectively, p=0.005, p=0.018). In Tukey's post hoc analysis for 25OHD3 level, the 25OHD3 levels of severe AD are significantly lower than mild or moderate AD (respectively, p=0.001, p=0.026). There was a negative correlation between 25OHD3 levels and severity of AD (r=−0.480; p=0.001).

Follow-up visits were planned between 3 and 12 months. After/at least four years following the first examination, patients were reassessed as to whether atopic dermatitis continued or not. Fifteen patients continued on follow-up. 29 patients’ parents were interviewed by telephone. A total of 44 patients were re-evaluated. The remaining 25 patients could not be evaluated because they did not interview for various reasons, such as incorrect phone numbers, unrecorded phone number, and poor parental understanding. Atopic dermatitis persisted in 30 (68.2%) of these 44 patients. Patients were divided into two groups as those with persistent atopic dermatitis and those with complete remission. There was no significant difference in terms of gender, familial atopy, presence of asthma or allergic rhinitis, sensitivity in skin prick tests, sensitivity to allergens and vitamin D insufficiency between these groups (p>0.05) (data not shown). However, while age, the age of AD onset, vitamin D deficiency, SCORAD level and severe AD were higher in the persistent group compared to the remission group, 25OHD3 levels were higher in the remission group compared to the persistent group (p<0.05) (Table 3).

We demonstrated that serum 25 OHD levels were significantly lower in patients with AD compared to healthy controls. It is reported that vitamin D has a crucial role in skin functions and has vital importance in the maintenance of antimicrobial defence mechanisms and epidermal barrier function. For this reason, it is not implausible to expect an association between vitamin D deficiency and an increased AD incidence. Research investigating the relationship between vitamin D level and AD disease severity revealed controversial results. Studies demonstrating a correlation between serum vitamin D levels and disease severity in patients with AD (5–9) and studies documenting no correlation at all10–12 are both present in literature. In a new meta-analysis assessing vitamin D levels in AD, seven observational studies were evaluated. As a result, Vitamin D levels especially in childhood atopic dermatitis were found to be lower than controls.16 Our result is consistent with this meta-analysis.

In our study, we determined that 25OHD3 levels were lower in patients with severe AD compared to patients with mild and moderate AD. Vitamin D has been shown to have an important role in AMP function. AMPs are secreted by many different cells in the skin, including keratinocytes and mast cells. Human cathelicidin, a chemoattractant for neutrophils and monocytes, enhances microbial killing in phagocytic vacuoles and has a defined vitamin D-dependent mechanism.17 Peroni et al.7 reported an increased susceptibility to infections with Staphylococcus aureus and M. Furfur in AD patients with vitamin D insufficiency.7 Vitamin D deficiency leads to low levels of AMP and impairment of skin barrier functions thus rendering the individual prone to infections. As a result of them, recurrent infections increase the severity of AD by enhancing the inflammation of skin. Peroni et al.7 have reported that mean serum 25(OH)D levels were significantly higher in patients with mild AD (36.9±15.7ng/mL) compared to those with moderate (27.5±8.3ng/mL) or severe AD (20.5±5.9ng/mL) (p<0.05). Akan et al.5 reported a negative correlation between disease severity and serum vitamin D level in AD patients with allergen sensitivity. Lee et al.8 documented a correlation between vitamin D levels and AD disease severity only in patients with food allergy. In our study, we detected a negative correlation between vitamin D levels and AD disease severity in patients with AD. In contrast to these studies, Samochocki et al.10 conducted a study in an adult population and failed to document a connection between vitamin D level and SCORAD scores. Similarly, Chiu et al.11 could not demonstrate a link between serum vitamin D levels and AD disease severity. These inconsistent results may be attributed to cross-sectional nature of these studies and to clinical, demographic and seasonal discrepancies of the study populations.

Another important result of our study is that the current age, age at onset of disease, severity of atopic dermatitis and vitamin D deficiency were higher in the persistent group compared to the remission group. Factors which affect the persistence of atopic dermatitis are examined in a new meta-analysis. In this meta-analysis, the onset of atopic dermatitis after two years of age, the duration of illness, the severity of AD at baseline and female gender were found as factors affecting the persistence of atopic dermatitis.18 Consistent with the meta-analysis, we also found that the onset of the disease after two years and severe AD were more in the persistent group compared to remission group in our study. While the duration of disease was higher in the persistent group, this difference was not statistically significant. Similarly, we also found no difference in terms of gender. The inconsistency in our results may have occurred due to the small number of the sample.

Interestingly, we found that children with atopic dermatitis with vitamin D deficiency are more likely to have disease persistence. This relationship has not been investigated before in the literature. Comprehensive studies are needed in order to make a clearer decision on this issue.

A major limitation of our study is its small sample size. It is a single-centre study which only recruited children. Our cross-sectional study investigated vitamin D levels which were obtained once in autumn or winter period. More than one sample could have been obtained and mean vitamin D levels throughout the year could have been measured in order to minimise the seasonal differences. Despite these limitations, our study is important in terms of patients being followed-up by the same allergist at the same health centre and showing the relationship between vitamin D level and the natural history/progress of atopic dermatitis, which have not been evaluated previously in the literature.

As a result, we found that 25OHD3 levels in atopic dermatitis were lower than in controls. In addition, a negative correlation between severity of AD and vitamin D level was detected. After at least four years of follow-up, age, the onset of the disease after two years of age, severe AD and vitamin D deficiency in the persistent group were higher than in the remission group. Vitamin D levels must be measured in patients with severe AD and replacement therapy should be performed in case of deficiency. There is a need for more comprehensive studies on the effect of vitamin D levels on the natural course of AD.

The principal investigator, Mahmut Dogru, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The author declares that they have no conflict of interest.