Atopic dermatitis (AD) is the most frequent chronic relapsing, pruritic, inflammatory skin disease of childhood, with onset mainly in the first years of life 1. AD is the first manifestation of atopy in many patients who later have allergic rhinitis, asthma, or both, a pattern that has been referred to epidemiologically as the atopic march 2.
AD can be categorized into two forms: extrinsic and intrinsic. Extrinsic or (atopic type) shows high total serum immunoglobulin E (IgE) levels and the presence of specific IgE for environmental and food allergens, a positive skin-prick test, and is commonly associated with respiratory allergies, whereas intrinsic or the nonatopic type shows normal total IgE values and the absence of specific IgE, a negative skin-prick test, and there is no associated allergy such as bronchial asthma or allergic rhinitis 3.
The pathophysiology of AD remains poorly defined. It is a multifactorial disease that has a complex pathogenesis including genetic, immunologic, and environmental factors that lead to a dysfunctional skin barrier and dysregulation of the immune system 4.
Vitamin D is a steroid hormone that is responsible for intestinal absorption of calcium and phosphate; thus, a diet deficient in vitamin D causes rickets in children and osteomalacia in adults and can be ingested from the diet and/or supplements. The body can also synthesize vitamin D (from cholesterol) when sun exposure is adequate 5,6.
Vitamin D has been found to have immune-regulatory effects. 1,25-dihydroxyvitamin D3, which is the major form of vitamin D, is a modulator of immune functions, including activities of T-lymphocytes and B-lymphocytes, and modulates both innate and adaptive immune responses 7.
Vitamin D inhibits the formation of dendritic cells, which in turn reduces the activation of T-cells and the T-cells-mediated immune response. Vitamin D also acts on T-cells themselves, regulating the differentiation and activation of TH1 and TH2. It inhibits Th1 cells, which produce interferon and interleukin (IL)-2 and activate macrophages, and TH17 cells, which produce IL17 and IL22; these events (mentioned before) dominate the chronic and acute phases of AD 8. Vitamin D has also been shown to increase the production of regulatory T-cells, which play a very important role in self-tolerance and therefore in the prevention of autoimmunity and allergy 9.
Vitamin D also has an effect on the action of B cells by stimulating the production of IL10, which inhibits antigen presentation by dendritic cells and prevents T-cell activation. Also, vitamin D inhibits the production of IgE antibodies, the primary antibody associated with the allergic response 10.
Vitamin D has also been shown to induce cathelicidin expression in keratinocytes, which enhances antimicrobial activity against Staphylococcus aureus and selectively reduces cutaneous lymphocyte-associated antigen expression 11.
Vitamin D is also important for stratum corneum barrier formation by means of protein synthesis (such as filaggrin) and regulation of keratinocyte proliferation and differentiation. Vitamin D stimulates the production and the regulation of skin antimicrobial peptides, such as cathelicidins and β defensins 12,13. These antimicrobial peptides show both a direct antimicrobial activity and an induced host cellular response leading to cytokine release, inflammation, and angiogenesis. Therefore, vitamin D deficiency might predispose patients with AD to skin superinfection by S. aureus or its superantigens 14.
The current study aimed at confirming the relation between vitamin D levels in AD patients and the severity of the disease. In addition, this study aimed to evaluate the effect and the therapeutic role of vitamin D supplementation in Egyptian patients with AD.
Patients and methods
This work was designed as prospective case–control study and was approved by the Ethical Committee of the Faculty of Medicine, Mansoura University. The study included 50 participants younger than 12 years old. They were divided into two groups: group I included 30 patients with a complaint of AD and group II included 20 healthy volunteers of matched for age and sex, and served as controls. The patients and the control groups were selected from the outpatient clinic of Dermatology, Andrology, and STDs Department in Mansoura University Hospital from March 2014 to April 2015.
An informed consent was obtained from the patient’s relatives and relatives of the controls.
All patients who fulfilled the criteria for the diagnosis of AD including pruritus and three or more of the following were included in the study 15:
- History of itching in skin creases.
- History of asthma or hay fever.
- Generalized dry skin in the past year.
- Visible flexural eczema.
- Onset in the first 2 years of life.
In this study, we included patients younger than 12 years of age (from March 2014 to April 2015).
- Any patient who was taking vitamin D supplementation for the last 6 months.
- Patients using systemic steroids or any anti-inflammatory systemic treatment in the previous 6 months.
- Patients known to have a state of vitamin D deficiency (to avoid selection bias).
- Patients with any associated skin or systemic disease.
All participants in this study were subjected to the following:
- Full assessment of history.
- General and dermatological examinations.
- Clinical assessment of the degree of AD in the patient group, that is, SCORing Atopic Dermatitis (SCORAD assessment) 16.
- Classifications of the patients were as follows:
- According to associated atopic disorders: intrinsic and extrinsic.
- According to treatment: a group treated with vitamin D and a group treated with placebo.
- Photographs were taken before and after the study.
Classifications of patients
Patients were classified according to the presence or absence of other allergic condition (such as bronchial asthma and allergic rhinitis) and total serum IgE level as follows 3:
- Extrinsic AD: associated with another allergic condition (such as bronchial asthma and allergic rhinitis) and a high level of total serum IgE.
- Intrinsic AD: not associated with other allergic conditions and normal levels of total serum IgE.
Out of 30 patients, 16 atopic dermatitis patients matched for age, sex, and SCORing Atopic Dermatitis were randomly selected, divided into two groups, and treated for 1 month.
The two groups were as follows: a vitamin D-treated group (n=8) and a group without vitamin D supplementation (n=8). The vitamin D-treated group received cholecalciferol (vitamin D) in the form of Vidrop [Medical Union Pharmaceutical (MUP), Ismailia, Egypt] at a dose of five drops (500 IU) daily (which is equal to the daily requirement of vitamin D) 17 and an emollient; the second group without vitamin D supplementation received the same emollient only. The severity of AD was evaluated on the basis of the SCORAD value before and after the trial.
A sample of 5 ml blood was withdrawn from each patient and control. Sera were separated and divided into two aliquots and stored at −20°C until analysis:
- One aliquot was used for the 25(OH)D assay.
- The second aliquot was used for the total IgE assay.
25 hydroxy vitamin D
An ELISA kit was used for the assessment of 25 hydroxy vitamin D [25(OH)D]. The kits were obtained from Sun Redbio (Shanghai, China).
Total immunoglobulin E
The IgE assay was performed using a microplate enzyme immunoassay kit supplied by Monobind Inc. (Lake Forest, California, USA).
Data were fed to the computer and analyzed using IBM SPSS software package, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Qualitative data were described using number and percent. Quantitative data were described using (minimum and maximum), mean, SD, and median.
χ2 of Fisher’s exact test was used to compare qualitative variables between the two groups. For quantitative variables, the Mann–Whitney U-test was used for the comparison between the two groups and the Wilcoxon signed rank test was used for paired (pre–post) comparisons. Spearman’s rank correlation coefficient (r) was used to determine the correlation between two variables in the same group. P value of less than 0.05 was considered statistically significant.
The present study included 30 patients with AD and 20 age-matched and sex-matched controls. The patient group included 19 (63.3%) males and 11 (36.7%) females. The ages of the patients ranged from 9 months to 11 years, with a median age of 4.5 years. There was no statistically significant difference in age and sex among AD patients compared with the controls. The disease duration ranged from 2 months to 9 years, with a median of 2 years.
A positive family history of atopy among first-degree relatives was found in 10 patients, representing 33.33% of the total number of patients (30 patients). Patients had aggravating factors and more than one factor may have been present in the same patient. Food allergy was suggested as a predisposing factor in 30% of patients. Moreover, other substances such as inhalants (33.3%), insect bites (23.3%), contact allergens (23.3%), infection (20%), and seasonal factors (20%) were suggested as predisposing factors in some patients.
The levels of serum vitamin D were significantly lower in the patient group compared with the control group, with P value of less than 0.001 (Table 1 and Fig. 1).
There was a significant increase in serum IgE levels in the patient group compared with the control group, with P value of less than 0.001 (Table 1 and Fig. 2).
There was no significant difference between intrinsic and extrinsic types in sex distribution, but there was a significant difference between these two types in age distribution, with a P value of less than 0.05. There was no significant difference between intrinsic and extrinsic types in serum vitamin D levels, with P-value more than 0.05 (Table 2); however, there was a significantly higher level of IgE in the extrinsic type than in the intrinsic type, with P value of less than 0.001 (Table 2). There was no significant difference between intrinsic and extrinsic types in the score index, with P-value more than 0.05 (Table 2).
A significant inverse correlation was found between serum vitamin D levels and SCORAD, with r=−0.976, P value of less than 0.001 (Fig. 3).
A significant positive correlation was found between serum IgE levels and SCORAD, with r=0.535, P=0.002 (Fig. 4).
A significant negative correlation was found between serum vitamin D and serum IgE levels, with r=−0.488, P=0.006 (Fig. 5).
There was no significant difference between the two groups (a group treated with vitamin D and a group treated with an emollient) in terms of age and sex distributions, serum vitamin D levels, and SCORAD value, with P-value of more than 0.05 (Table 3).
Comparison of SCORAD before and after intake of oral vitamin D supplementation; revealed a significant decrease in SCORAD after therapy, with P=0.05, whereas in the group without vitamin D supplementation (who received emollients only), there was no significant difference between SCORAD at the beginning of the study and at the end of the study in this group, with P=0.357 (Table 3 and Fig. 6).
The present study comprised 30 patients with AD and 20 age-matched and sex-matched controls. AD patients showed a significant decrease in serum vitamin D level compared with the control group, thus confirming that a relationship exists between vitamin D deficiency and AD. These results are in agreement with those of Velsen et al.18, who carried out a study aiming to investigate changes in bone density in children with moderate to severe AD. They supported the fact that deficiency and insufficiency of vitamin D were found, respectively, in five and 25 of the 60 patients. Vitamin D levels were therefore insufficient in 50% of the patients.
Furthermore, Searing and Leung 19 investigated the relation of vitamin D with the pathogenesis of AD, asthma, and allergy, and proved that vitamin D has considerable effects on the skin and the immune system together with the fact that AD is mainly the result of a defective skin barrier and dysfunction of the immune system. In a previous study carried out by Litonjua 20, he confirmed the presence of a relation between vitamin D deficiency and an increased risk of developing allergies and asthma, but the appropriate dose necessary to reduce this risk still remains unclear.
Also, in the present study, there was a highly significant increase in the serum IgE levels in the patient group compared with the control group.
There was no significant difference between intrinsic AD and extrinsic AD in serum vitamin D levels. This is in agreement with Akan et al.21, who reported that there was no significant difference between sensitized (extrinsic) and nonsensitized (intrinsic) AD groups in serum vitamin D levels. In contrast to this, Cheon et al.22 compared the serum 25(OH)D level between two AD groups and found that children with sensitized (extrinsic) AD had lower 25(OH)D levels than children with nonsensitized (intrinsic) AD.
There was a significant inverse correlation between serum vitamin D levels and SCORAD, confirming that as the level of vitamin D decreases, the severity of AD increases.
The results of the present study were in agreement with those obtained by Peroni et al.23, who determined serum 25 (OH)D levels and SCORAD index levels in 37 Italian children and found an inverse correlation between serum concentrations of 25(OH)D and the clinical severity of AD; also, the mean serum levels of 25 (OH)D were significantly higher in patients with mild disease compared with those with moderate or severe AD. Also, Oren et al.24 reported that vitamin D deficiency contributes toward the development of AD. They found that there was an increased risk of AD among those who were vitamin D deficient, although there was no significant difference in the risk of asthma or allergic rhinitis. Brehm et al.25 reported that children with low vitamin D levels had increased markers of allergy and asthma severity. Also, Wang et al.26 reported that vitamin D deficiency was associated with AD in Hong Kong Chinese Children. Vitamin D levels showed an inverse correlation with both long-term and short-term AD severity. Baïz et al.27 observed a significant inverse association between cord serum 25(OH)D levels and the risk of transient early wheezing and AD by the ages of 1, 2, 3, and 5 years.
In contrast, Back et al.28 reported that higher intake of vitamin D3 in infancy was associated with more prevalent atopic manifestations. Gale et al.29 reported that high vitamin D values during pregnancy might also be harmful with respect to the development of allergic disease. Children whose mothers had a 25(OH)D concentration higher than 30 ng/ml during pregnancy had an increased risk of atopic eczema on examination at 9 months compared with children whose mothers had a concentration lower than 12 ng/ml.
In the present study, a positive significant correlation was found between serum IgE levels and SCORAD, and a negative significant correlation was found between serum vitamin D and serum IgE levels. Our results are in agreement with those obtained by Cheon et al.22, who reported that the SCORAD index was positively correlated with total IgE levels. Serum 25(OH)D levels showed a significant inverse correlation with serum total IgE level. Also, Heine et al.10 reported that vitamin D inhibits the expression of IgE by B cells and enhances the expression of IL-10 by dendritic cells and T cells; thus, it can be used as a modulator of allergic immune responses.
In the present study, we evaluated SCORAD in eight patients before and after intake of oral vitamin D supplementation for 1 month at a dose of five drops of Vidrop (500 IU) daily, which equals the daily requirement of vitamin D per day and emollient. According to the SCORAD index, the group treated with vitamin D showed a significant improvement compared with the group without vitamin D supplementation.
Sidbury et al.30 carried out a randomized double-blind study for which they recruited children (n=11) aged 2–13 years and randomized them to 1000 IU of vitamin D or placebo for 1 month. At the end of the month, baseline changes in global assessments of skin indicated that the vitamin D treatment group showed a significant improvement in the baseline score compared with the group treated with placebo. Javanbakht et al.31 evaluated the efficacy of vitamin D (1600 IU/day) and E supplementation for 60 days in AD in a randomized-controlled study. Their AD patients showed a significant decrease in SCORAD, but the difference was not statistically significant compared with the decrease in patients receiving placebo. Amestejani et al.32 also reported a significant decrease in the severity of AD by vitamin D supplementation (1600 IU/day) for 60 days irrespective of the initial severity of AD. Similarly, Samochocki et al.33 observed an improvement in AD severity with a 3-month supplementation of vitamin D (2000 IU/day).
Vitamin D plays a role in the maintenance of epidermal barrier proteins through enhanced expression of filaggrin, involucrin, and AMP, and prevents the penetration of allergens and microbes, resulting in less activation of the inflammatory cascade, thereby explaining the greater prevalence of AD in those with vitamin D deficiency, and explains the improvement following vitamin D supplementation 34. This was confirmed by Hata et al.35, who correlated oral intake of vitamin D with the production of the AMP cathelicidin.
According to the present results, it can be concluded that serum levels of 25(OH)D were significantly lower in patients than in controls and vitamin D deficiency is related to the severity of AD, suggesting a therapeutic benefit from oral vitamin D supplementation in improvement of disease severity.
Conflicts of interest
There are no conflicts of interest.
1. Schultz-Larsen F, Hanifin J. Epidemiology of atopic dermatitis
. Immunol Allergy Clin North Am 2002; 22:1–24.
2. Fleischer DM, Bock SA, Spears GC, Wilson CG, Miyazawa NK, Gleason MC, et al. Oral food challenges in children with a diagnosis of food allergy. J Pediatr 2011; 158:578–583.e1.
3. Johansson S, Bieber T, Dahl R. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization. J Allergy Clin Immunol 2004; 113:832–836.
4. Kabashima K. New concept of the pathogenesis of atopic dermatitis
:interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci 2013; 70:3–11.
5. Holick MF. High prevalence of vitamin D
inadequacy and implications for health. Mayo Clin Proc 2006; 81:353–373.
6. Norman AW. From vitamin D
to hormone D: fundamentals of the vitamin D
endocrine system essential for good health. Am J Clin Nutr 2008; 88:491S–499S.
7. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D
: modulator of the immune system. Curr Opin Pharmacol 2010; 10:482–496.
8. Oyoshi MK, He R, Kumar L, Yoon J, Geha RS. Cellular and molecular mechanisms in atopic dermatitis
. Adv Immunol 2009; 102:135–226.
9. Hypponen E, Berry DJ, Wjst M, Power C. Serum 25-hydroxyvitamin D and IgE
– a significant but non-linear relationship. Allergy 2009; 64:613–620.
10. Heine G, Niesner U, Chang H, Steinmeyer A, Zugel U, Zuberbier T, et al. 1,25-Dihydroxyvitamin D promotes IL-10 production in human B-cells. Eur J Immunol 2008; 38:2210–2218.
11. Schauber J, Dorschner RA, Yamasaki K, Brouha B, Gallo RL. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology 2006; 118:509–519.
12. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros 2007; 6:403–410.
13. Schauber J, Gallo RL. The vitamin D
pathway: a new target for control of the skin’s immune response? Exp Dermatol 2008; 17:633–639.
14. Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D
dependent mechanism. J Clin Invest 2007; 117:803–811.
15. William H, Burney P, Pembroke A. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis
. III. Independent hospital validation. Br J Dermatol 1994; 131:406–416.
16. Oranjie AP. Practical issues on interpretation of scoring of atopic dermatitis
: SCORAD index, index, objective SCORAD, patient-oriented SCORAD and Three-Item Severity Score. Curr Probl Dermatol 2011; 41:149–155.
17. Abrams SA. Dietary guidelines for calcium and vitamin D
: a new era. Pediatrics 2011; 127:566–568.
18. Velsen SG, Knol MG, Eijk RL, Vroede MA, Wit TC, Lam MG, et al. Bone mineraldensity in children with moderate to severe atopic dermatitis
. J Am Acad Dermatol 2010; 63:824–831.
19. Searing D, Leung D. Vitamin D
in atopic dermatitis
, asthma and allergic disease. Immunol Allergy Clin North Am 2010; 30:397–409.
20. Litonjua AA. Vitamin D
deficiency as a risk factor for childhood allergic disease and asthma. Curr Opin Allergy Clin Immunol 2012; 12:179–185.
21. Akan A, Azkur D, Ginis T, Toyran M, Kaya A, Vezir E, et al. Vitamin D
level in children is correlated with severity of atopic dermatitis
but only in patients with allergic sensitizations. Pediatr Dermatol 2013; 30:359–363.
22. Cheon BR, Shin JE, Kim YJ, Shim JW, Kim DS, Jung HL, et al. Relationship between serum 25-hydroxyvitamin D and interleukin-31 levels, and the severity of atopic dermatitis
in children Korean. J Pediatr 2015; 58:96–101.
23. Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis
in children. Br J Dermatol 2011; 164:1078–1082.
24. Oren E, Banerji A, Camargo CA Jr. Vitamin D
and atopic disorders in an obese population screened for vitamin D
deficiency. J Allergy Clin Immunol 2008; 121:533–534.
25. Brehm J, Celedon J, Avla L, Hunninghake G, Forno E, Litonjua A, et al. Serum vitamin d
levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 2009; 179:765–771.
26. Wang SS, Hon KL, Kong AP, Pong HN, Wong GW, Leung TF. Vitamin D
deficiency is associated with diagnosis and severity of childhood atopic dermatitis
. Pediatr Allergy Immunol 2014; 25:30–35.
27. Baïz N, Dargent-Molina P, Wark JD, Souberbielle JC, Annesi-Maesano I. Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis
. J Allergy Clin Immunol 2014; 133:147–153.
28. Back O, Blomquist HK, Hernell O, Stenberg B. Does vitamin D
intake during infancy promote the development of atopic allergy? Acta Derm Venereol 2009; 89:28–32.
29. Gale CR, Robinson SM, Harvey NC, Javaid MK, Jiang B, Martyn CN, et al. Maternal vitamin D
status during pregnancy and child outcomes. Eur J Clin Nutr 2008; 62:68–77.
30. Sidbury R, Sullivan AF, Thadhani RI, Camargo CA Jr. Randomized controlled trial of vitamin D
supplementation for winter-related atopic dermatitis
in Boston: a pilot study. Br J Dermatol 2008; 159:245–247.
31. Javanbakht MH, Keshavarz SA, Djalali M, Siassi F, Eshraghian MR, Firooz A, et al. Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis
. J Dermatolog Treat 2011; 22:144–150.
32. Amestejani M, Salehi BS, Vasigh M, Sobhlchiz A, Karami M, Alinia H. Vitamin D
supplementation in the treatment of atopic dermatitis
: a clinical trial study. J Drugs Dermatol 2012; 11:327–330.
33. Samochocki Z, Bogaczewicz J, Jeziorkowska R, Sysa-Jędrzejowska A, Glińska O, Karczmarewicz E, et al. Vitamin D
effects in atopic dermatitis
. J Am Acad Dermatol 2013; 69:238–244.
34. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173:2909–2912.
35. Hata TR, Kotol P, Jackson M, Nguyen M, Paik A, Udall D, et al. Administration of oral vitamin D
induces cathelicidin production in atopic individuals. J Allergy Clin Immunol 2008; 122:829–831.
Keywords:© 2017 Egyptian Women's Dermatologic Society
atopic dermatitis; IgE; vitamin D