Abstract

Introduction: There has been a lot of talk lately about the importance of reduced serum vitamin D levels and their supplementation for patients with inflammatory skin diseases such as atopic dermatitis (AD) and other allergic diseases. Serum vitamin D values are associated with a number of factors such as limited sunlight exposure (modern lifestyle, extended indoor stay, enhanced sun protection, etc.) which can affect different diseases.

Aim: To evaluate serum vitamin D values in patients with inflammatory skin diseases, comparing them on the basis of other parameters (age, gender/sex, residential areas, total serum IgE), and establishing whether vitamin D supplementation would affect the improvement of the clinical picture of the disease.

Patients and methods: A total of 157 patients participated in this prospective study: 51 patients with AD, 55 with chronic urticaria (CU) and 51 with contact dermatitis (CD): 38 with irritant CD (ICD) and 13 with allergic CD (ACD). In all patients, the values of serum vitamin D were determined by chemiluminescence microparticle immunoassay (CMIA) and compared by diagnosis, age, sex, living environment, values of total IgE. In patients with reduced values of vitamin D, its supplementation for 3 months was recommended, after which the second evaluation of D vitamin values and disease status were determined and compared with an untreated/unsupplemented group with normal vitamin D values.

Results: Vitamin D deficiency was often observed in patients with AD, CU and CD, most frequently in the ICD group, and least frequently in the ACD group. No significant differences were found in terms of age, gender or living environment, nor was any correlation with total IgE found. In the subjects supplemented with vitamin D, their levels increased significantly and, after its supplementation, improvement of the clinical condition was more common than in the untreated group; however, the differences were not statistically significant (69.8 vs. 58.1, p=0.428).

Conclusions: Although serum vitamin D levels of the groups did not differ significantly, the supplementation of vitamin D in patients with prominent vitamin D deficiency may be useful and crucial for improving the prognosis of the disease.

allergic diseases, cholecalciferol, eczema, vitamin D deficiency, skin inflammatory diseases

In the past years, many studies and ample research have addressed the importance of vitamin D deficiency in certain diseases and their treatment, including inflammatory skin diseases such as atopic dermatitis (AD) and vulgar psoriasis.^[1,2] As we know, people obtain vitamin D predominantly by its synthesis in the skin under the influence of sunlight and by means of food. The reduction of the serum vitamin D values is associated with a number of factors such as limited exposure to sunlight (modern lifestyle, increased indoor staying, enhanced sun protection, etc.).^[1]

The impact of vitamin D status on health problems/outcomes is discussed in many branches of medicine and in many diseases, including allergic skin diseases.^[3–6] The higher incidence of allergic diseases observed on higher latitudes (with more frequent vitamin D deficiency) suggested that there may be a connection between the development of allergic diseases and vitamin D deficiency (“the vitamin D hypothesis”).^[1] Other factors, such as the bone health/condition of the patient, are also important and potentially related to it, especially given the frequent use of corticosteroids (topical and systemic), the existence of chronic inflammation and the like.

Concerning AD, the occurrence of eczema within AD is often the first manifestation of allergic disease in early childhood, usually followed by allergic rhinitis and asthma.^[1] An increased incidence of eczema has been observed in persons with lower serum vitamin D levels, especially in children, which is even more pronounced in adults. Various findings have been observed regarding the correlation between vitamin D levels and eczema severity. While some studies established that lower levels of vitamin D were associated with increased disease severity, others did not find any correlation with disease severity. A negative association between eczema severity and vitamin D levels (which was not observed in the patients without allergic sensitization) was also observed in the patients with proved allergic sensitization.^[7,8] To understand this correlation, it is important to know that eczema phenotypes are also associated with multiple vitamin D gene pathways, which suggests that vitamin D deficiency predisposes to eczema. As an endogenously produced hormone, vitamin D has effect on the regulation of more than 200 genes in different cell types. Aside the skin as the source of vitamin D for the body, it is incapable of responding to active metabolite of vitamin D [1,25(OH)₂D] and also express receptor for D vitamin and metabolizes it to a hormonally active form. Vitamin D regulates epidermal differentiation and hair follicle cycling (thus promoting barrier function, wound healing, hair growth, etc.). In addition, vitamin D participates in cellular and humoral immunity and in the formation and maintenance of the epithelial and endothelial barriers; it also participates in the metabolic pathways. In this respect, another important matter is the correlation between the beneficial effects of vitamin D and several biological pathways of the disease. In eczema, for example, the regulation of the immune system and the skin barrier are disturbed under the influence of vitamin D.^[1] Also, a lower vitamin D value can, for example, increase the skin’s sensitivity to bacterial and viral infections (inadequate antimicrobial defense), and it changes and modulates the outcomes of allergic conditions by its multiple effects on altered epidermal barrier function, impaired immune regulation, and others.^[1,9]

As for chronic urticaria (CU), it is characterized by hives that can persist for more than 6 weeks, often associated with angioedema; according to etiology, the urticaria can be either induced or spontaneous (chronic spontaneous urticaria, CSU).^[10,11] As for the vitamin D levels in patients with urticaria, numerous studies in CSU patients have shown significantly lower serum levels of 25-(OH)-D than in the control group.^[12] However, there are differences between studies concerning the importance of vitamin D for CU. Some authors showed a negative association between the severity of CU and the serum 25-(OH)-D levels.^[13,14] Other authors did not report a significant correlation between CU duration/severity and correlation between CU duration/severity and vitamin D levels.^[15,16]

Contact dermatitis (CD) is an inflammation of the skin that occurs after skin contact with specific substances and has two main subtypes – allergic CD (ACD) and irritant CD (ICD).^[10] Studies on animals with ACD (mice) that examined the importance of vitamin D showed that the male mice with normal vitamin D levels had a better response in repairing ACD than the mice that lacked such levels, which was not observed in female mice (the mechanisms of different responses remain unknown).^[10] Although studies on the levels of vitamin D and the effects of its supplementation in CD patients are scarce, this animal study suggests that vitamin D supplementation may be beneficial to patients with ACD.

Due to insufficient scientific and clinical knowledge about this topic, we decided to examine the values of serum vitamin D in patients with AD, CU and CD (ICD, ACD) and the effects of its supplementation in the patients with low vitamin D levels.

In this study, we determined the values of serum vitamin D in patients with AD, CU and CD (ICD, ACD) and compared them within each disease; we also compared the vitamin D values among different patients grouped by such variables as age, gender, living environment, and total serum IgE levels (normal/elevated). In patients with established low vitamin D plasma concentration, its supplementation was recommended and, after compensation, a second evaluation of D vitamin blood concentration was done in the patients who were able to undergo such evaluation. In the patients who received supplementation, the disease status was also determined on the basis of the clinical disease condition established during visits after the vitamin D therapy (improvement, worsening, stable/unchanged manifestations). Finally, we aimed to determine whether vitamin D supplementation affected the improvement of clinical picture of the disease in comparison with patients with normal vitamin D levels who were not supplemented.

According to the results for vitamin D values in our patients with AD, CU, and CD, their levels did not differ significantly by age, sex, or residential area. Also, vitamin D levels did not differ significantly between AD, CU and CD with regard to the presence and type of allergy either. According to additional statistical analysis of the sample, vitamin deficiency was most common in ICD patients and least common in ACD, although these differences between diagnoses were not statistically significant. So, although our results did not confirm significance of vitamin D for examined diseases, the results by other authors could be taken into account. Thus, looking at the relationship between the occurrence and condition of AD/eczema and the values of vitamin D, the data from previous research (including in utero studies) provided inconsistent findings. While some observational studies support the protective effect of vitamin D (in utero) on the risk of developing eczema, according to other studies, its high level may even be a risk factor for eczema.^[1] As for skin diseases, vitamin D has so far been primarily investigated in patients with AD. In adults with AD, different study results (several randomized, placebo-controlled, double-blind studies) were found that examined its values and the significance of vitamin D supplementation for AD patients. Regarding the status of vitamin D in relation to the proven hypersensitivity of patients to allergens and the possible effects of vitamin D on hypersensitivity, heterogeneous results have been observed across observational studies.^[1] Based on the determination of vitamin D, it was observed in newborns that their mothers’ higher intake of vitamin D through food during pregnancy or newborns’ higher vitamin D levels are associated with reduced sensitivity to allergens in childhood. On the other hand, by monitoring pregnant women, Weisse et al. found that higher levels of 25(OH)D during the third trimester of pregnancy (with an average of 55 nmol/L) were associated with an increased risk of the child being allergic to food allergens.^[1,19]

Looking at the effect of vitamin D supplementation recorded among our patients with low vitamin D values, improvement in their clinical status was observed somewhat more often than in the untreated/non-supplemented group (although the differences were not statistically significant). Clinical improvement was observed in most patients and none of them experienced any deterioration (in those treated with vitamin D supplementation vitamin D levels increased significantly). When looking at other literature data, particularly significant are the results of monitoring the effect of vitamin D supplementation on the disease in patients with AD. Using oral supplementation with vitamin D (1600 IU daily for 60 days), Amestejani et al. and Javanbakht et al. found a significant reduction in AD severity (compared to the placebo group), while according to Hata et al., a shorter use of a higher dose (4000 IU daily for only 21 days) did not lower the severity of eczema.^[1,20-22] According to a wide meta-analysis by Kim et al.^[23], AD patients have lower serum 25(OH)D levels than the control group, with significantly lower levels in children. Generally, vitamin D supplementation decreased AD severity and improved AD condition, although specific mechanisms are unclear/unknown.^[23] Due to the lack of appropriate/high-quality randomized controlled trials on the effects of vitamin D (from food, dietary supplements and/or exposure to sunlight) on eczema development, as well as conflicting evidence, further research is needed, for instance, on the effects of sunlight on eczema incidence and severity (at different points in early life).^[1] Exposure to UV rays (UVB) is also important and it needs to be investigated, for example, by measuring UV radiation by UV dosimeters. Therefore, the use of oral vitamin D supplementation as an adjunct treatment for AD in children and adults requires further studies to determine the appropriate dose and duration of treatment, especially in different populations (e.g., different races, latitudes and seasons).

While existing analyses of the role of vitamin D in AD have yielded conflicting results, studies on CU clearly indicate the benefit of assessing vitamin D status in them, although far fewer studies have investigated vitamin D in CU than in AD.^[10] Thus, vitamin D supplementation has been shown to be beneficial for some CU patients. There are also scientific observations that vitamin D deficiency may be an additional indicator of autoimmune urticaria. According to the retrospective study by Woo et al. comparing four different disease groups (72 patients with CU, 26 patients with acute urticaria, 26 patients with AD and 72 healthy controls), serum levels of 25(OH)D were significantly reduced in CU patients compared to other groups.^[14] It has also been observed that vitamin D deficiency may increase the likelihood of acute urticaria transitioning to CU (based on monitoring of 10 patients with acute urticaria with extremely low vitamin D <10 ng/ml, where 5 of these patients became chronic).^[10] Cases of perennial CU have also been reported in which severe vitamin D deficiency (serum level 25(OH)D 4.7 ng/ml) was identified, and these cases of perennial urticaria were cured after vitamin D supplementation (at a dose of 2000 IU daily). Similarly, in a retrospective study involving 28 patients with urticaria and angioedema (with vitamin D levels <32 ng/ml), a positive response and complete resolution of symptoms was observed in 61% of them after vitamin D supplementation.

Although the connection between vitamin D and total IgE is also mentioned in the literature, according to our results, vitamin D values did not correlate linearly with total IgE, nor did they differ significantly between patients with normal and elevated IgE, so they were not significant for follow-up. However, earlier research on the relationship between the values of total IgE and vitamin D gave useful data. One earlier study found that vitamin D has an effect on IgE production in patients with CU (total IgE values are usually increased in CU patients). Thus, after vitamin D supplementation (in vitro), IgE production (from stimulated B lymphocytes) was significantly reduced, so vitamin D could act by immunomodulation of IgE-mediated pathways in urticaria, although other immunological and non-immunological factors should be considered as well.^[10] Various prospective studies have shown that high-dose vitamin D3 supplementation in CU patients is safe and beneficial. Particularly significant is the study randomizing 42 CU patients to those with high (4000 IU/d) or low (600 IU/d) vitamin D3 supplementation over 12 weeks, with triple-drug therapy (cetirizine, ranitidine, and montelukast), which reduced the total severity of urticaria. The triple therapy in the first week reduced the Urticaria Severity Score (USS) by 33%, and in subjects supplemented with high doses of vitamin D3, a further reduction in USS by 40% was observed by 12 weeks. Patients on high doses of vitamin D3 had less frequent occurrence of urticaria (fewer days with it) and a smaller body surface area affected by it. In one prospective study (58 patients with CSU and 45 controls), significantly lower levels of vitamin D were found in CSU patients than in controls.^[10] After CSU patients whose levels of 25(OH)D were less than 30 ng/ml received 300,000 IU of vitamin D per month, a significant improvement in urticaria activity (UAS4) and quality of life (CU-Q2oL) was observed after 12 weeks. Furthermore, more extensive clinical trials would be needed to determine the most favourable dose of vitamin D supplementation for CU and possible mechanisms of vitamin D action.

As for other skin diseases, the importance of vitamin D is mentioned only in some of them, e.g. in patients with ACD, which would help clarify its role in allergic and other inflammatory skin diseases.^[10] There have been only two studies assessing the serum values of vitamin D and evaluating the effects of its supplementation in ACD. A study conducted on mice found that mice with higher serum vitamin D levels may be more likely to experience improvement in ACD.^[10] Another important study is the one by Xavier et al.^[24] on patients with ACD following exposure to Parthenium. In this study, 72 patients were recruited and randomized to receive either cholecalciferol tablet (60,000 IU per week) or placebo (for 8 weeks) with standard background treatment. They measured IL-10 and serum 25-hydroxyvitamin D levels at baseline and at 8 weeks which showed a significant increase in both groups. So, cholecalciferol supplementation for 2 months did not reduce ACD severity. In addition, there are some other important observations concerning the role of vitamin D supplementation for skin barrier functions recorded by other studies.^[23,25-28] According to one previous in vitro study, after vitamin D supplementation, antimicrobial peptides such as cathelicidin and β-defensin increased, i.e. the supplementation promotes cathelicidin production and induces cathelicidin LL-37 expression. Since vitamin D promotes antimicrobial activity, its lower level reduces antimicrobial activity and external tolerability to pathogens, important for AD and CD.^[23] Also, 1,25(OH)₂D and its receptor regulate the processing of long-chain glycosylceramides, which are crucial for the skin barrier formation and skin defending, and they also induce Toll-like receptor 2 (TLR2) and its co-receptor CD14, which initiate the skin innate immune response.^[25] Activation of these receptors leads to the induction of CYP27B1 (the only enzyme capable of transferring the inactive form into the active vitamin D form), which in turn induces cathelicidin resulting in the killing of invasive organisms. In addition, according to literature, mice lacking the receptor for vitamin D (VDR) or the enzyme CYP27B1 show decreased lipid content of the lamellar bodies, leading to a defective permeability barrier and a defective response of the innate immune system to invading infections.^[25] However, as to date there have been no studies on the role of vitamin D in ICD in humans, our results on ICD could be useful for gaining more knowledge about vitamin D in these patients. However, for now, vitamin D supplementation has not been included in the recommendations for ACD either and requires clinical studies.^[10] Since UV radiation contributes to vitamin D stores, the added benefit of UV rays for patients with inflammatory skin diseases such as CD and AD should always be borne in mind.

Since our results did not show significance of vitamin D for our patients, probably due to small number of patients and a limited number of variables/parameters, further studies could take into account more patients and their data: season variations, sun exposure and sun protection, type and quality of conducted therapy (including the use of corticosteroids), patients’ lifestyle, their atopic condition (atopic or non-atopic), other diseases, the existence of chronic inflammation, disease duration, etc. Therefore, further research on vitamin D supplementation in patients with CD and related factors involved is needed.

Our results indicate that patients with AD, CU, CD treated with vitamin D supplementation are slightly more likely to experience an improvement in clinical condition than the untreated group, although the differences are not statistically significant. It is also significant that vitamin D supplementation led to improvement in most subjects and that none of them experienced any deterioration, indicating the possibility of a beneficial effect in some patients without adverse effects. There remains a lot of room to examine the role of possible nutrition and other lifestyle factors as potential approaches to the prevention of allergic and inflammatory skin diseases.

This research was funded by the authors.

Author contributions

L.L.M. contributed to conception and design of the article; L.L.M., N.M., M.D., N.P., I.P., and MK analysed the data; L.L.M., N.M., and M.K. wrote the manuscript; all authors contributed to manuscript revision, read and approved the submitted version.

Competing Interests

The authors have declared that no competing interests exist.