Atopic Dermatitis (AD) is a chronic recurrent inflammatory disease of the skin characterised by pruritus and inflamed lesions, involving specific areas of the body and causing generalised xerotic skin. As the disease progresses from acute to subacute, to chronic stages, excoriation from scratching and a propensity to secondary infections leads to oozing lesions and further pruritus. Severity of pruritis is associated with quality of life. Scores on the PO-SCORAD (patient oriented SCORAD) questionnaire, which includes a visual analogue scale for pruritis severity, are associated with measures of quality of life [1
Eighty-five percent of AD is seen in children, of which 30% continue to suffer in their adult years [3
]. There are an estimated 15 million suffers in the United Kingdom (UK) [4
] and in the United States (US); 25% of children and 7% of adults have AD [3
]. The incidence of AD is growing world-wide, especially in urbanised countries, with a higher rate in northern latitudes during the winter months [5
]. The financial strain of AD at the level of individual, family and the public healthcare system cannot be underestimated. A 4.2 billion USD per year cost was estimated for the US alone with individual healthcare costs for AD patients higher by between 28.3% and 67.9% compared to non-AD patients [6
AD pathology involves a complex interplay of barrier issues of skin and various dysfunctions in host innate and adaptive immune systems. These include high IgE, eosinophil and distinct T-helper cell populations as well as cytokine dysmodulation [8
]. Bacterial and viral infestation from Staphylococcus Aureus and Herpes Simplex infections exacerbate pre-existing AD. However, factors contributing to long-term remission of AD are currently unknown [11
]. Presently, due to no identified clinical biomarkers, quantitative and qualitative clinical tools are used to gauge severity of clinical presentation, with the Scoring Atopic Dermatitis index (SCORAD) being the most validated and commonly used in clinical research. The severity scale for SCORAD is pegged at Mild AD <25 points, Moderate AD >25 points and Severe AD >50 points [13
There is much interest in the potential role of vitamin D deficiency in the development of AD, from multiple lines of research evidence. First, research has documented the aggravation of AD in winter, especially in higher latitude countries where serum 25(OH)D tends to be particularly low in this season [5
]. Second, improvement in AD symptoms in patients has been observed in research studies on VitD supplementation [15
]. Third, genetic polymorphisms including those of the Vitamin D Receptor (VDR) and a filaggrin gene mutation (up to 50% of the AD population, depending on specific mutation) have been identified as contributors to the development of AD [17
Of note, Vitamin D3
) is known to play a role in the skin barrier function, as it modulates structural proteins of the cornified dermis layer, regulating the glycoseramides essential for the hydrating protective lipid barrier which keeps the skin moisturized [19
]. It modulates innate immunity via the production of the anti-microbial peptides (AMPs) cathelicidin and defensin which can help reduce skin infection risk [20
]. In addition, Amon et al. (2018) discussed how vitamin D has inhibitory effects on monocyte production (via Toll-like receptors) and well as inhibiting dendritic cell activity and increasing mast cell release of IL10 [21
]. They also discussed how vitamin D reduces the release of proinflammatory cytokines from Th1 cells and inhibits the release of IgE by reducing B cell function [21
]. These mechanisms would theoretically aid the reduction of chronic inflammation in the skin.
The optimum 25(OH)D level for the prevention of, or rehabilitation of, inflammatory skin diseases is yet unknown. At present, for bone health, the US Endocrine Society recommends that serum 25(OH)D levels <50 nmol/L (20 ng/mL) are classified as deficient and 53–73 nmol/L (21–29 ng/mL) as insufficient. The UK Scientific Advisory Committee on Nutrition recommendations are more conservative, suggesting 25 nmol/L or higher as a population protective level for bone health [22
]. These are population estimates and the physiological need for vitamin D may be higher in some clinical conditions. More research is now required to assess the optimum serum 25(OH)D concentration specifically required for those with AD, as well as assessing the current 25(OH)D status in AD patients.
Two previous systematic reviews and meta-analysis in 2016 on vitamin D and AD [12
] have found a lower serum 25(OH)D in AD patients compared with non-AD patients [12
] as well as a reduced severity of disease in AD patients after vitamin D supplementation [12
]. However, new research has been conducted since the publication of these reviews and so there is a clear need for this systematic review and meta-analysis to be updated. A recent systematic review reviewed the area [24
] but did not include a meta-analysis so there was no updated effect size using data from recent trials. The aim of this work therefore was to provide an updated review of observational and intervention trial data on the role of VitD in AD, including all published studies up to February 2018. First, we assessed the mean difference, in observational studies, between 25(OH)D concentration in AD patients and HC, with a sub-analysis of adult and paediatric populations separately. This was to gauge differences in 25(OH)D from normal which may be of clinical importance. Second, we assessed the impact of VitD supplementation on AD severity (change in SCORAD index), quantifying the role of VitD dosage and trial duration, to both support further research and advise clinical guidelines.
Our findings show a lower serum 25(OH)D concentration by 14 nmol/L in the overall adult and paediatric AD population than in HC, with lower serum 25(OH)D also in the AD paediatric population by 16 nmol/L. There was no difference in the adult population alone, the effect size for which did not reach statistical significance. Therefore, our study shows that the AD population have lower 25(OH)D concentration than their healthy peers, particularly for children. Our results suggest that the AD paediatric population may be an “at-risk group” for VitD insufficiency. As per US Endocrine Society guidelines, all individuals at risk of vitD insufficiency must be assessed routinely for 25(OH)D status [37
]. This should be considered as best practice during the diagnosis and treatment of the AD paediatric population. VitD supplementation may be considered by the clinician taking into account baseline 25(OH)D status and possible contraindications (e.g., endocrine dysfunction).
Pooling results from repeated measures clinical trials in AD patients, post-supplementation we found a highly statistically significant difference between supplement and placebo groups in SCORAD of −21 points, using dosages of 1000–2000 IU daily for three months. Similarly, pooling results from VitD randomised control trials in AD patients, post-supplementation we found a highly statistically significant difference between supplement and placebo groups in SCORAD of −11 points, using dosages of 1000–2000 IU daily for one to two months.
In intervention trials, the minimal difference or improvement set as a measure of effectivity of the intervention is called the Minimal Clinical Important Difference or MCID. For the treatment of atopic dermatitis, the MCID of the SCORAD score which translates to clinical relevance is a reduction of 9 points [42
]. Our effect size of −11 to 21 points exceeds this threshold, suggesting clinical relevance. Therefore, we have found clear evidence for a clinically meaningful reduction in AD disease severity after VitD supplementation. Of note, the baseline average (mean or median) 25(OH)D for all intervention trials in the meta-analysis was <50 nmol/L, which would be classified as deficient [33
]. This shows that the trials included individuals who were truly deficient in 25(OH)D at baseline, so were not (on average) supplementing individuals who already had sufficient 25(OH)D status. After supplementation, this average 25(OH)D was >50 nmol/L in all trials except one [33
Bearing in mind the clinical background of the each patient, including individual 25(OH)D concentration and any existing endocrine issues, this research supports the empirical supplementation of daily VitD doses of approximately 1500–1600 IU/daily to AD patients, taking into account the baseline vitamin D levels and eventual endocrine issues or other concomitant diseases that contraindicate vitamin D supplementation.
This weighted mean of 1500–1600 IU (38–40 micrograms) daily dosage falls well below the European Food Standards Agency (EFSA) Tolerable Upper Intake Levels (UL) of 100 micrograms per day for all adults as well as children aged 11–17 years [43
]. It also falls below the UL for 1–10 year old children (50 micrograms per day) [43
] but is higher than the UL for infants (25 micrograms per day) [43
]. Clinical biochemical monitoring should be undertaken of children receiving 1500–1600 IU (38–40 micrograms per day) due to it being closer to their UL (50 micrograms per day) and infants should definitely not be given 1500–1600 IU/daily. Indeed, the UL is not a target, and is based on population (not individual) safety. Clinicians should make their own judgements about safe intakes for their individual patients, bearing in mind the effective dose suggested by this study (1500–1600 IU/daily).
In our analysis, larger results were seen in trials of three month duration but from the limited data available we were not able to assess whether this was due to the 3 month duration itself, or if it was simply that all the three month studies were repeated measures studies, rather than full randomised placebo control trials. Nevertheless, it stands to logical reason that supplementing for three months, rather than one to two months, is likely to lead to a better clinical response.
In terms of previous systematic reviews and meta-analyses in the field, our work supports the findings of systematic reviews by Kim et al. (2016) [12
], Kim and Bae (2016) [23
], Huang et al. (2018) [24
] and Vaughn et al. (2019) [44
] in terms of finding a lower 25(OH)D status in AD patients than controls, and finding an effect of vitamin D supplementation on symptom severity.
Our textual systematic review indicated that most interventional trials have documented a reduction in skin infection after VitD supplementation. Some observational evidence also suggested an association between lower 25(OH)D concentration and increased cutaneous secondary-colonisation of S. aureus and herpes, suggesting that increasing 25(OH)D levels in the AD population may support the reduction of and prevention of secondary cutaneous infections, albeit this was based on a small number of studies and there was not enough data to perform a meta-analysis.
In terms of biological mechanisms, it is feasible that VitD could affect the severity of AD, including number of infections. VitD is known to modulate innate and adaptive immune responses [45
]. The physiological role of VitD in supporting healthy skin [20
], as well as the fact that lower 25(OH)D concentrations are known to correlate with increased allergic sensitisation [46
], higher IgE level [47
], and lower serum cathelicidin levels [48
], suggest a role of VitD in modulating AD severity. Moreover, studies involving the disruption of the VDR have showed lower levels of involucrin, profilaggrin and loricin barrier proteins [49
]. Improvement in 25(OH)D leads to upregulation of functional human cathelicidin (hCAP18) in keratinocytes from AD patients, as well as from those from patients with psoriasis and normal skin [50
]. In support of the above mechanisms, Albenali et al. (2016) [38
] showed that higher IgE levels, higher virulence and colonisation of S. aureus
were recorded when serum 25(OH)D levels were low. A significantly increased risk of having skin lesions with methicillin-resistant S. aureus
(MRSA) has been found in persons with VitD deficiency [51
]. Udompataikul et al. (2015) [36
] found a reduction in S. aureus
colonization in a paediatric population on VitD supplementation while Samochocki et al. (2013) [33
] found no incidence of infection in their adult supplemented population. Albenali et al. (2016) [38
] observed a 4-fold upregulation of LL-37 in the stratum corneum on VitD supplementation and a reduction in AD complicated by eczema herpeticum.
Secondary infections and re-infections in AD are notoriously challenging to treat, with excess use of topical and oral antibiotics increasing the risk of microbial antibiotic resistance. A recently published study [54
] analysed eleven-year nationally representative data and calculated the morbidity, mortality and cost of secondary infections in AD to be in excess of 11 to 228 million USD annually. Improving 25(OH)D levels in AD may support the war on antibiotic resistance by reducing the risk and severity of cutaneous infections. However, a lot more research is needed on this subject due to the small amount of currently published literature.
In terms of strengths, our systematic review and meta-analysis is the most up to date available on the role of VitD in AD in both adults and children. It calculated pooled effect sizes in terms of mean difference in serum 25(OH)D levels between the AD population and HC. Our effect size is also larger than the mean difference found in the other meta-analysis by Kim and Bae (2016) [23
]. Our review is the first to document clinically relevant changes in disease severity (as assessed by SCORAD) after VitD supplementation.
In terms of limitations, it is important to note that the data from trials in our analysis included mainly mild and moderate AD with only a few severe cases. Also, no data from infants (<1 year of age) or pregnant women were included. The specific reduction in SCORAD seen, and difference in 25(OH)D between AD patients and HC may differ in these groups from that found in this review. Finally, our results are based on a mean weighted dose of around 1500–1600 IU per day and SCORAD reductions observed seen are likely to differ with higher or lower doses.
Three trials [35
] could not be included in the meta-analysis due to no reporting of the standard deviation for SCORAD. These happened to be the higher dose trials and so this limited our analysis to trials with dosage ranges of 1000 IU–2000 IU/daily. Six trials confirmed the form of VitD given as VitD3
, but two trials did not report the form of VitD used. The longest trials were only of three months duration hence the effect of longer-term supplementation could not be analysed. Our meta-analysis of 25(OH)D concentration in AD compared to HC was limited by the small sample size, especially for the adult population. Similarly, the meta-analysis of the interventional studies was limited by the small number of trials suitable for inclusion.
Quality analysis of the interventional studies showed four higher scoring randomised double blind clinical trials with mention of adequate randomisation and blinding [35
]. In terms of the other studies, one study was designed as a clinical evaluation study and so was not a randomised clinical trial, [38
] and Samochocki et al. (2013) [33
] did not mention randomisation but confirmed blinding of both participants and researchers. Di Filippo et al. (2015) [29
], Albenali et al. (2016) [38
] and Tsotra et al. (2017) [41
] did not mention randomisation or blinding of participants.
There was some potential evidence of publication bias in that there was asymmetry in the funnel plots, with very few studies having positive effect sizes (i.e., cases having higher serum 25(OH)D than controls). However, the funnel plots only contained a small number of studies (n = 11 or n = 12) so they must be interpreted with caution. The number of interventional studies were too few to judge publication bias so there may still be a possibility of unpublished studies with null findings, despite best efforts being made to locate unpublished data. In some trials, the limited information on form of VitD supplemented (D2 vs. D3) and the absence of information on ingredient type and source of the D2 or D3 prevented further analysis in this regard.
In terms of further research, there is an urgent need for longer term, well conducted trials in distinct age categories, at different severity levels and also for different histopathological disease stages. Intervention trials with VitD dosage titration based on the severity of the disease, concomitant cytokines, the cell landscape and dermal cathelicidin levels are also needed. Trials designed to understand the link between VitD supplementation, skin barrier function and innate immunity to reduce secondary cutaneous infections in AD would help provide evidence that may justify the need for VitD supplementation to modulate the prevalence of microbe colonisation and reduce the need for antibiotics in these patients. Studies assessing effects of VitD supplementation on topical steroid usage would also be useful as reduced usage of steroids would have cost benefits. If optimal serum 25(OH)D levels could indirectly support the reduction of antibiotic usage and curtail antibiotic resistance, further research in this area is clearly urgently required. Particularly, research investigating and quantifying the effect of VitD on gut and skin microbiota may support supplementation as a possible preventative and adjuvant treatment strategy.
Further trials with specifically vitamin D3
may provide data to support form dosage and time period of the supplementation for fastest recovery with least risk. Assessing the source and ingredients in vitamin D supplements used in trials may shed new light on a population known for sensitisation especially in the younger years. VitD3
forms of supplements are likely to support a more efficient increase in serum 25(OH) levels [55
] but are usually derived from lanolin (from sheep’s wool).
Finally, the textual systematic review suggested that studies of VitD supplementation in mild to moderate AD did not show changes in pruritus (based on SCORAD), skin xerosis, lichenification, skin conductance and moisture levels of skin [36
]. This suggests the need for investigating other possible treatment strategies including, possibly targeting specific cytokines, such as monoclonal antibodies against IL-31 to reduce pruritus, as well as the use of nutritional factors, to support AD therapy.