D as in Delta: The Changing Views on Vitamin D in Dermatology

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The COVID-19 global pandemic has had innumerable ramifications, mostly for ill. However, one silver lining was the coming together of the scientific community to wage war against this invisible enemy. As part of the understanding of disease risk factors, the importance of adequate vitamin D levels has returned to the forefront.

It appears that however implausible, there has been another global pandemic smoldering for years: hypovitaminosis D. This unrecognized pandemic affects upwards of 40 percent of the population, according to the National Health and Nutrition Examination Survey (NHANES) from 2011-2012.¹ More recently, the NHANES data looking at children found that 61 percent of subjects aged 1-21 years were vitamin D insufficient.²

VITAMIN D: IMMUNE REGULATION

Vitamin D is a hormone, and its value goes far beyond calcium regulation and bone metabolism. While the immune system is tremendously complex, a number of recent studies indicate that vitamin D can regulate the adaptive and innate immune response in various inflammatory and autoimmune diseases.^3,4 The active metabolite of vitamin D exerts an anti-inflammatory effect on human monocytes and macrophages by down-regulating the expression and production of several pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8.⁵ It also has shown immune-modulation including attenuation and stimulation of Th1 and Th2 cell proliferation and has been demonstrated to play a major role in the maintenance of immune tolerance by mediating other cytokines.⁶ Vitamin D reduces the release of proinflammatory cytokines from Th1 cells and inhibits the release of IgE by reducing B cell function.⁷ Current research suggests that vitamin D has the ability to alter the expression of more than 200 genes, including those in the gut microbiome, where vitamin D receptors are abundant.⁸

ROLE OF THE MICROBIOME

Over the last decade, emerging data have shown promise in the relationship between the gut microbiome and systemic disease. The importance of immune modulation at the gastrointestinal level is easily reconciled, considering that approximately 70 percent of the entire immune system is found in this site.⁹ Adaptive and innate immune responses include mucosal macrophages and dendritic cells capable of synthesizing biologically active vitamin D, modulating host-microbial interactions, cellular differentiation, and proliferation, as well as susceptibility to pathogenic infections, all of which are crucial for maintaining a healthy microbiome.¹⁰ It is becoming more evident that the immune system and microbiome are interconnected and that vitamin D is a critical intermediary player in this dynamic.⁸

PATHOPHYSIOLOGY OF ATOPIC DERMATITIS

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, affects 11.3–12.7 percent and 6.9–7.6 percent of children and adults, respectively.¹¹ Although the pathophysiology has yet to be fully elucidated, it is characterized by skin barrier disruption and transepidermal water loss, which allows for penetration of allergens, irritants, and pathogens, leading to inflammation.⁶ Previous studies have shown that type 2 immune cytokines play important roles in chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides, and allergic inflammation.¹¹ Vitamin D has been shown to have a regulatory influence on both the immune system and skin barrier function.¹² Indeed, modulating T cell profiles and the production of antimicrobial peptides in the skin could potentially improve cutaneous inflammatory and vascular response as well as reduce secondary skin infections.¹³ In combination with these diverse factors, the gut microbiome contributes to the development and natural course of AD, and previous studies have found that in early life the gut microbiome is associated with age of onset, severity, remission, flares, and even phenotype of AD.¹⁴ This alters focus from a disease limited to the skin to one of a systemic nature. Current standard treatment modalities focus on topical steroids, emollients, and systemic and topical immunosuppressives. However, evidence suggests supplementation of vitamin D may downregulate the immune system and improve disease severity in some patients.

OBSERVATIONAL STUDIES

Numerous studies^15-17 have found a significant inverse relationship between serum vitamin D levels and AD severity. Interestingly, infants born to mothers with low vitamin D intake during pregnancy have an increased prevalence of AD, as do infants born in fall or winter, compared to those born in spring or summer.¹⁶ Vitamin D deficiency in AD has been correlated with increased bacterial infections, winter exacerbations, and the presence of more active lesions in sun-protected areas.¹⁸ Historically, winter-related AD has been attributed to local factors, such as ambient humidity, and the potential role of vitamin D status has largely been ignored.¹⁹ However, the benefit from ultraviolet B therapy for AD may be in part suppression of Langerhans cells and inflammation but also an elevation of serum vitamin D levels.¹⁸

CLINICAL TRIALS

A 2008 double-blinded pilot conducted by Sidbury et al¹⁹ studied 11 children with AD who reported worsening in the winter months. While no serum vitamin D levels were measured, one month of 1000IU of vitamin D showed benefit over the placebo group. Investigator Global Assessment for the supplemental group showed an 80 percent improvement compared to 17 percent for placebo.

Samochocki et al¹⁸ studied 95 patients and revealed that 80 percent of participants had a vitamin D level less than 30ng/mL. Supplementation of 2,000IU per day for three months resulted in a statistically significant decreased SCORAD index and objective SCORAD as well as no observed bacterial infections.

Camargo et al²⁰ conducted a larger study out of Boston and Ulaanbaatar, Mongolia, examining 107 children who reported phenotypic worsening of AD during winter months. Supplementation of cholecalciferol 1000IU was completed daily for one month. All children were allowed the same petrolatum-based emollient as needed during the study. Compared with placebo, vitamin D supplementation produced a clinically and statistically significant improvement in EASI scoring.

Mansour et al²¹ conducted a double-blind randomized placebo-controlled trial in Egypt that included 86 patients. Patients received 1600IU daily or placebo over a 12-week period. Mean change in EASI scoring was significantly greater in the supplementation group (56.44 percent) vs placebo (42.09 percent), and 38.6 percent of supplemented patients had a >75 percent improvement in EASI score.

While mounting evidence seems to show a positive association with vitamin D supplementation and improvement in disease severity, a number of studies show that supplementation lacks benefit. Back et al²² showed that the increased intake of vitamin D during childhood correlates with an increased risk of AD at six years of age. A large, cross-sectional study in Germany showed lower levels of vitamin D was associated with reduced odds of AD in both children and adolecents.²³ Despite conflicting results, the majority of studies suggest that vitamin D is protective against AD,¹⁷ and meta-analyses have shown that vitamin D supplementation results in an improvement in AD severity in both SCORAD and EASI grading.^24-28 While optimal serum levels of vitamin D have yet to be determined, supplementation of vitamin D can be considered a safe and tolerable therapy²⁴ and should be considered from both a disease prevention and existing therapy perspective.^28,29

More work needs to be done to further elucidate the parameters of this somewhat intermittent relationship, and it seems plausible that some subtypes of AD may respond better to supplementation than others. Until we achieve a precision-medicine level of understanding of AD, it may be difficult to untangle the evidence fully. Given the complexity amongst the genes implicated in the pathogenesis of AD, it is unlikely that individual gene polymorphisms contribute significantly to the development of AD; rather the disease may result from a synergistic effect of multiple genes.³⁰ These wide gene variations may pose some evolutionary advantages as well as explain why some therapeutics work in some but not all patients. The ability to further classify AD into various endotypes based on filaggrin mutations, IgE levels, age, ethnicities, and various cytokine activation will allow for a much more precise selection of therapeutic options.³¹

LIMITATIONS

While a large portion of the population is deemed vitamin D deficient or insufficient, it is essential to establish an optimal range for supplementation. Optimal levels for bone health have been well established with serum 25(OH)D levels of >50nmol/L and toxicity not occurring until >250nmol/L.³² The primary source of vitamin D for humans is ultraviolet B light. Variations in ultraviolet B radiation occur with season, latitude, and air pollution, which can significantly impact vitamin D levels.³³ This may explain why some AD patients flare during winter months, whereas previous hypotheses believed it was a relation to humidity. The aforementioned studies have investigated amounts of daily supplementation, which ranged from 800-2000IU daily, whereas other studies failed to measure serum concentrations. An optimal level for AD, or other inflammatory skin diseases, has yet to be established, and further clinical studies should investigate optimal levels.

CONCLUSION

The understanding of the relationship between vitamin D and AD has fluctuated over time, not unlike understanding of the disease itself. However, it seems that there is an effect of vitamin D supplementation for at least a group of patients. Given its relative safety, low expense, and the possibility of benefit, it seems reasonable to consider vitamin D supplementation, particularly in patients who report worsening of AD in the winter. While the data may be conflicting, there are significantly more publications supporting the use of vitamin D in AD. This article stresses the importance that clinicians be aware of the changing landscape of this pandemic. While every patient is unique, perhaps it is time to rethink the clinical approach to addressing this chronic inflammatory disease. Adjuvant supplementation of this hormone may provide clinical improvement for some of our patients.

The authors have no relevant disclosures.

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