Atopic dermatitis (AD) is a common and recurring chronic inflammatory disease characterized by pruritus and eczema. It is commonly associated with hypersensitivity to allergens, more frequently with allergic diseases such as allergic rhinitis and asthma [1
]. It reportedly affects 5%–20% of children and 1%–3% adults worldwide, and its prevalence is increasing in industrialized countries [2
]. The pathophysiology of AD is mainly the result of epidermal barrier defectiveness and immune dysregulation [1
]. The traditional therapeutic options for AD are antihistamine and immune modulatory agents, including topical/oral corticosteroids and topical/oral calcineurin inhibitors. These classic treatments are focused on reducing skin inflammation [4
], but their potential side effects and poor patient adherence indicate the importance of finding new therapeutic options. Recent studies have suggested that vitamin D supplementation may be a safe and effective alternative treatment for AD. A Cochrane review provided evidence for the efficacy of dietary vitamin D supplements as a treatment for AD in 2012 [5
]. However, only two studies were reviewed, and owing to their low quality, the review could not produce conclusive evidence for the efficacy of vitamin D supplements in AD treatment.
The present study performed a systematic review and meta-analysis to determine the serum 25-hydroxyvitamin D (25(OH)D) levels in AD patients compared with those in healthy controls. In addition, we reviewed double-blind randomized controlled trials to assess the efficacy of vitamin D supplementation as a treatment for AD by using the Scoring Atopic Dermatitis (SCORAD) index and the Eczema Area and Severity Index (EASI) score.
In the present study, we reviewed and comprehensively summarized case–control studies and randomized controlled studies, providing potentially important information. First, serum 25(OH)D level was lower in the AD patients—particularly in the pediatric patients. In addition, this meta-analysis showed that SCORAD index and EASI score were decreased after vitamin D supplementation as a treatment for AD.
Accumulating studies have identified the pathogenesis of AD, including epidermal barrier disruption, immunologic dysfunction, and personal susceptibility. Based on genetic susceptibility (such as loss of filaggrin gene), the AD patients were found to have a defective skin barrier and dysregulation of the innate immune system, which results in failure of immunologic responses to allergens and microbial pathogens [23
]. The association between vitamin D deficiency and AD is not clear, but several studies have suggested possible roles of vitamin D in AD. A previous study demonstrated that antimicrobial peptides such as cathelicidin and β-defensin increased after vitamin D supplementation in vitro [25
]. Liu et al. [26
] also found antimicrobial response triggered by the Toll-like receptor and vitamin D-mediated immunity. Clinical trials also showed that vitamin D supplementation promotes cathelicidin production and induces LL-37 expression. Thus, vitamin D promotes antimicrobial activity, with a lower vitamin D level thereby reducing antimicrobial activity and external tolerability to pathogens, making it key in the pathogenesis of AD [27
Serum 25(OH)D level was lower in the AD patients than in the healthy controls across all ages (standardized mean difference = −2.03 ng/mL). Several studies were performed to investigate the association between vitamin D deficiency and AD. However, the association between 25(OH)D and AD is controversial, particularly in adult patients. A large-scale cohort study involving Korean adult patients found that lower serum 25(OH)D levels were associated with AD [28
]. On the contrary, a recent Danish cohort study found that serum 25(OH)D level was not associated with AD and other allergic diseases in adults [29
]. The above-described results prompted us to perform a sub-group analysis after dividing AD patients into an adult group and a pediatric group. We found that serum 25(OH)D level was markedly lower in the pediatric patients. Pediatric AD patients may have an increased risk of allergen penetration through the skin, and most allergies are initiated in childhood. Therefore, we believe that a low vitamin D level could worsen AD, especially in pediatric patients. In adult AD patients, the serum 25(OH)D level was lower than the control group, but this difference was not statistically significant. Our results should be interpreted with caution, because the total number of adult AD patients enrolled in our study was small. Further larger and well-controlled observational studies are required in the future to consolidate the association between serum 25(OH)D and AD.
The effect of vitamin D supplementation should be considered from two aspects: AD incidence and modification of AD severity [21
]. We focused on AD severity, which is associated with disease modification. The present study included four randomized double-blind clinical trials and found that vitamin D supplementation decreased the SCORAD index and EASI score, and that vitamin D supplementation benefits AD patients. However, Norizoe et al. [30
] gave vitamin D supplements to mothers during lactation, which did not improve the AD status of the infants. These authors suggested that vitamin D supplementation in infants during breast feeding could increase the risk of food allergy later in life, and supplementation during lactation could have a negative effect on the development of the Th1 and Th2 immune balance [31
]. Therefore, vitamin D supplementation should be provided carefully whilst considering the age of the patient, and further studies will be needed.
Two of the included clinical trials (by Sidbury et al. [21
] and Camargo et al. [22
]) enrolled pediatric patients who had a history of AD worsening in the winter, and both studies showed that EASI score was decreased after vitamin D supplementation. These authors explained that the lower sun exposure in the winter leads to vitamin D deficiency, and lower vitamin D levels could worsen AD. Similarly, a recent study reported that birth in winter season may be associated with AD, which suggested that inadequate sunlight exposure (associated with lower vitamin D status) increased the risk of AD [32
]. Accumulating data have proven that phototherapy is the most efficacious, well-tolerated treatment option for AD. Ultraviolet B radiation suppresses the expressions of pro-inflammatory cytokines such as interleukin (IL)-12, IL-2, and interferon-γ, and stimulates IL-10 production via keratinocytes, thereby reducing expression levels of pro-inflammatory cytokines and suppressing the growth of natural killer cells [33
]. Thus, vitamin D supplementation can compensate for the reduced ultraviolet exposure and alleviate AD severity. From these data, we assume that vitamin D supplementation is effective in AD patients, and that the characteristics of their condition—including seasonal variation of severity—should be considered.
The results of this study should be interpreted with caution, because of the several limitations of our meta-analysis. First, information about basal 25(OH)D levels and changes in 25(OH)D level after vitamin D supplementation was lacking. Heaney et al. [35
] suggested a guideline for clinical studies of nutrient effects. The author emphasized the measurement of basal levels of nutrients, and that when performing meta-analysis, all the included studies should have similar basal nutrient levels. Owing to the inadequate information from the included articles, we could not provide the exact status of 25(OH)D level. Javanbakht et al. [19
] did not report basal 25(OH)D levels in detail, but they reported the prevalence of vitamin D deficiency, which was 72.7% in the placebo group and 81.8% in the vitamin D supplemented group. Amestejani et al. [20
] also measured 25(OH)D level and reported a mean 25(OH)D level of 9.8 ng/mL before vitamin D supplementation, which was categorized as vitamin D-deficient status. Studies performed by Camargo et al. [22
] and Sidbury et al. [21
] did not provide data on 25(OH)D levels. However, these studies included the AD patients who had a history of worsening in the winter season, and the authors assumed that the worsening in the winter season was associated with vitamin D deficiency. Thus, we assumed that the included AD patients in this meta-analysis probably had vitamin D deficiency and similar 25(OH)D levels. Second, we did not adjust for potential confounding factors of the serum 25(OH)D level in the selected populations, such as altitude, latitude, sun exposure, seasonal variation, level of outdoor activities, and dietary vitamin D intake [36
]. Third, significant interstudy heterogeneity was present, which can be partially attributed to the confounding factors. The study included uncontrollable factors of AD treatment, such as usage of topical steroid and confounding factors as mentioned earlier. Finally, this meta-analysis included a small number of randomized clinical trials in the assessments of the efficacy of vitamin D supplementation. However, we thought a meta-analysis would still be worthwhile to determine the overall association between serum 25(OH)D and SCORAD index. Further larger studies that include a subgroup analysis of infant, pediatric, and adult AD patients are required to clarify the benefits of vitamin D supplementation.
In conclusion, this meta-analysis summarized the evidence for the role of vitamin D in AD patients. Serum 25(OH)D level was lower in the AD patients than in the controls, and the subgroup analysis showed that the difference in serum 25(OH)D level was significant in the pediatric patients. In addition, in comparison with a placebo group, vitamin D supplementation decreased AD severity and improved the symptoms and clinical signs of AD. However, the specific mechanisms underlying the role of vitamin D in this relationship are still unclear. Further studies are required to clarify the molecular pathways and mechanisms underlying the effects of vitamin D, with large-scale clinical trials needed to assess the effect of vitamin D treatment on AD outcomes.