Egyptian Journal of Dermatology and Venerology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 40  |  Issue : 1  |  Page : 1--8

The relationship between the levels of interleukin-17 and 25-hydroxyvitamin D in vitiligo outcome


Mohamed I Metwalli1, Fathia M Khattab1, Manal M El Amin2, Menna Allah H Abdel Aziz1,  
1 Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence Address:
MD Fathia M Khattab
Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Zagazig University, Egypt
Egypt

Abstract

Background The active form of vitamin D (1,25 hydroxyvitamin D) mediates the interaction between vitamin D and immune diseases including vitiligo, which was found to be associated with lower 25(OH)D levels. Objective To evaluate the role of vitamin D and interleukin (IL)-17 in vitiligo and its relationship with autoimmune diseases and to assess the therapeutic effect of vitamin D in patients with vitiligo. Patients and methods A total of 44 patients with vitiligo were measured for vitamin D and IL-17. Those with a low level of vitamin D took vitamin D droplet for 3 months and were then re-evaluated with Vitiligo European Task Force score before and after treatment. Results A significant negative correlation was found between vitamin D and IL-17 levels. A statistically significant increase in vitamin D level and decrease in IL-17 level was seen after treatment when compared with before treatment, accompanied by improvement of Vitiligo European Task Force scoring values after treatment. Conclusion The use of systemic vitamin D as a treatment modality for vitiligo can achieve reasonable improvement comparable to traditional modalities.



How to cite this article:
Metwalli MI, Khattab FM, El Amin MM, Abdel Aziz MH. The relationship between the levels of interleukin-17 and 25-hydroxyvitamin D in vitiligo outcome.Egypt J Dermatol Venerol 2020;40:1-8


How to cite this URL:
Metwalli MI, Khattab FM, El Amin MM, Abdel Aziz MH. The relationship between the levels of interleukin-17 and 25-hydroxyvitamin D in vitiligo outcome. Egypt J Dermatol Venerol [serial online] 2020 [cited 2020 Jun 5 ];40:1-8
Available from: http://www.ejdv.eg.net/text.asp?2020/40/1/1/275181


Full Text



 Introduction



Vitiligo is an autoimmune skin pigmentary disorder, with loss of the melanocytes in the epidermis [1].

Multiple theories have been proffered for melanocyte destruction, including genetic, autoimmune, biochemical, viral, and melanocyte detachment mechanisms. These research data suggest that autoimmune aberrations and oxidative stress are the key pathways mediating the destruction of melanocytes in vitiligo [2].

Theoretically, vitamin D plays a role in vitiligo pathogenesis through the following mechanisms: (a) proliferation and differentiation of the immune cells and modulation of immune activities; (b) association of its decreased serum levels with increased risk of autoimmune diseases; and (c) increasing size of melanocytes, number and length of their dendrites, levels of tyrosinase, and melanin synthesis [1].

It has been demonstrated that elevated expression of the proinflammatory cytokine interleukin (IL)-17, either in peripheral blood or tissues, contributes to the pathogenesis of vitiligo. IL-17-secreting T cells (Th17 cells) are greatly influenced by vitamin D. It has been suggested that vitamin D could cause immunomodulatory effects by inhibiting IL-17 formation through direct transcriptional inhibition of IL-17 gene expression [3].

In many studies, it was observed that vitamin D supplementation was therapeutically effective in different diseases, such as type 1 diabetes mellitus autoimmune thyroiditis and systemic lupus erythematosus. Therefore, the supplementation of vitamin D can be used as a treatment in autoimmune diseases such as vitiligo [4].

This study aimed to evaluate the role of vitamin D and IL-17 in vitiligo and its relationship with autoimmune diseases and to assess the therapeutic effect of vitamin D in patients with vitiligo.

 Patients and methods



This study was conducted in Dermatology, Venereology and Andrology Department, Faculty of Medicine, Zagazig University, from June 2018 to December 2018. The study included 44 patients with clinically proved vitiligo. They were recruited from the Outpatient Clinics of the Department of Dermatology, Venereology, and Andrology, Zagazig University Hospitals. There were 27 females and 17 males, and their age ranged from 6 to 55 years, with mean of 27.39 years. The diagnosis in each patient was made based on history, clinical presentation, and Wood’s lamp examination.

Written informed consent was obtained from all patients, and the study was approved by the Research Ethical Committee of Faculty of Medicine, Zagazig University. The work has been carried out according to the Code of Ethics of the World Medical Association (Declaration of Helsinki) for studies involving a human.

Patients of any age, of both sex, who did not receive any other modalities of treatment for the past 3 months and had newly discovered vitiligo were included.

Exclusion criteria were patients on other treatment modalities of vitiligo for 3-month duration before the study, patients with renal and hepatic diseases, and pregnant and lactating women.

All patients were subjected to complete history taking, including, name, age, sex, occupation, and marital status residence; history of present dermatological disease, including onset, course, duration, site, and history of previous treatment for the disease; and history of associated other dermatological diseases, history of systemic diseases, history of drug intake, history of surgical operations, and family history. General examination of body systems was performed to discover associated medical conditions.

Vitiligo European Task Force (VETF) assesses the three dimensions of the disease (extent, staging, and spreading/progression) and therefore provides three different values. The body is divided into five different sites, specifically the head/neck, trunk, arms, legs and hands/feet. Extent is based on the rule of nines. For the calculation of the extent of vitiligo, hands and feet are included in the evaluation of the extent in arms and legs.

Staging is based on cutaneous and hair pigmentation in each body region except hands and feet, which are assessed separately and is assessed using grades from 0 to 4 on the largest macule. A proposal was made for simplifying the staging scale: stage 0: normal pigmentation (no depigmentation in area graded), stage 1: incomplete depigmentation (including spotty depigmentation, trichrome, and homogeneous lighter pigmentation), stage 2: complete depigmentation (may include hair whitening in a minority of hairs, <30%), and stage 3: complete depigmentation plus significant hair whitening (>30%).

Spreading was introduced in this system to include a dynamic dimension as rapidly progressive vitiligo needs urgent intervention to stabilize the disease. To assess spreading, a simple scale is used (+1: progressive; 0: stable; and −1: regressive).

It is recommended to look at the patch limits first using natural light and to compare this with Wood’s lamp limits. Finally, each site is clinically evaluated for the extent of vitiligo involvement, the staging, and the spreading of vitiligo. Assessment on spreading and staging is based on examination of the largest macule in each body area.

Laboratory investigations include the following

Routine laboratory investigations, including complete blood picture, liver function test, renal function test, and random blood glucose level.Specific laboratory investigations: Serum vitamin D by Cobas 8000 (Roche, Roche Diagnostics, Mannheim, Germany) (principle: electrochemoluminescence).

Serum level of interleukin-17 by enzyme-linked immunosorbent assay kits (Sun Red company, Shanghai Sunred Biological Technology Co., Ltd, Baoshan, Shanghai, China)

Principle: The kit uses a double-antibody sandwich enzyme-linked immunosorbent assay to assess the level of human IL-17 in samples. IL-17 is added to the monoclonal antibody enzyme well, which is pre-coated with human IL-17 monoclonal antibody, and then incubation is done. Then, IL-17 antibodies labeled with biotin are added, which are combined with streptavidin-HRP to form immune complex, and then incubation is carried out, and washing again is done to remove the uncombined enzyme. Then chromogen solutions A and B are added, and the color of the liquid changes to blue. With the effect of acid, the color finally becomes yellow. The chroma of color and the concentration of the human substance IL-17 of the sample were positively correlated.

All patients underwent a clinical assessment of their state, besides serum vitamin D and IL-17 measurements. According to vitamin D level, they had been divided into the following groups: optimal 30–80 ng/ml, insufficient 20–30 ng/ml, deficient 10–20 ng/ml, and severely deficient less than 10 ng/ml [5]. Patients with level below optimal concentration received oral supplementation of vitamin D at a dose of 1000 IU/day.

For 3–6 successive months, both vitamin D and IL-17 levels were evaluated besides clinical state evaluation. Photographs before, during, and after treatment photographs were taken by digital camera. The type of digital camera used is Samsung (Samsung company daegu, South Korea), with magnification power 14.2 megapixels, 27 mm wide, five-folds Optical Zoom Lens, and 2.7 inch LCD.

The patient had been assessed after 0, 12, and 24 weeks. Assessment was done by VETF scores and photographs.

Assessment of response [5] was done, as patients are good responders with at least 50% repigmentation, moderate responders with 25–50% repigmentation, and mild responders, with less than 25% repigmentation ([Figure 1] and [Figure 2]).{Figure 1}{Figure 2}

Statistical analysis

After data collection, the data were tabled and analyzed using SPSS-19, (IBM Corp, Armonk, NY, USA). The following tests were used: a chi - square (v2), Student t-test, Spearman’s correlation coefficient (r), and one-way ANOVA. Differences were considered statistically significant (S) when P < 0.05, highly significant (HS) when P < 0.001 and non-significant (NS) when P > 0.05. A receiver operating characteristic (ROC) curve analysis was conducted to evaluate the performance of the IL38 assay for the prediction of active atopic disease. The sensitivity (true positive rate) and the specificity (true negative rate) were determined, and 95% confidence interval (CI) was obtained for each study and subsequently combined. The statistical analysis was based on the intention-to-treat population. Data were represented as mean±SD, range, numbers, or percentages.

 Results



The study included 44 patients with vitiligo, and their age ranged from 6 to 55 years, with mean of 27.39 years. Demographic data of patients are listed in [Table 1].{Table 1}

There was a statistically significant increase in vitamin D level and decrease in IL-17 and VETF after treatment in comparison with before treatment reading ([Table 2]). Regarding response to treatment among the studied group, 45.5% had a moderate response and 54.5% had a mild response ([Table 3]). A negative significant correlation between vitamin D and IL-17 level was found ([Table 4]), and there was a statistically significant increase in vitamin D level and decrease in IL-17 level among mild responded cases ([Table 5]).{Table 2}{Table 3}{Table 4}{Table 5}

There was a statistically significant decrease in VETF among mild responder cases (P=0.03). Moreover, there was a statistically significant relationship between vitamin D level and autoimmune diseases before treatment among positive cases ([Table 6]).{Table 6}

 Discussion



This study included 44 patients with vitiligo, aged from 6 to 55 years old, with a mean age of 27.39 years. Of them, 27 (61.4%) patients were females. This is in agreement with Zhang et al. [6] who investigated vitamin D level in 114 patients with vitiligo and 100 controls among Chinese children. The patient group consisted of 50 boys and 64 girls, with an overall mean age of 7.37±3.78 years, whereas the control group consisted of 47 boys and 53 girls, with an overall mean age of 6.95±3.63. There was no significant difference in sex and age between the patient and the control groups (P>0.05).

Regarding skin phototype of our studied group, 56% were type IV, 25% were type III, and 18.2% were type II. In other words, low vitamin D level was associated with higher skin phototype. This was in agreement with Silverberg et al. [7], who had 20% of the investigated patients with type IV, with lower percentages with other skin phototypes.

Regarding the family history of autoimmune diseases of our studied cases, it was found that 52.3% of cases had a positive family history of autoimmune diseases. This was in concordance with Silverberg et al. [7], where 51.1% of their studied group patients were positive for family history of autoimmune diseases. This study also demonstrated that 47.8% of patients with positive family history were most frequent to have vitiligo. This was in concordance with Zhang et al. [6], who found 3.5% of their studied cases had a positive family history of vitiligo.

The results of this study show a statistically significant increase in vitamin D level after treatment (0.04) and a highly statistically significant decrease in both IL-17 level (0.001) and VETF score values (0.001).

Regarding vitamin D level, which was found to be decreased in patients with vitiligo, Aly et al. [8] recorded significantly lower serum levels of vitamin D among patients with vitiligo (13.81±3.55 ng/ml) versus controls (23.76±10.31 ng/ml) (P<0.001).

Takci et al. [9] demonstrated significantly lower vitamin D serum levels in patients with vitiligo than controls. They also detected a universal lack of vitamin D in the Turkish population.

Moreover, Zhang et al. [6] found that serum vitamin D concentrations in patients with vitiligo were lower and highly statistically significant (P<0.001) than controls, when a total of 114 children with vitiligo, consisting of 50 boys and 64 girls, with an overall mean age of 7.37±3.78 years, were included in the study.

In contrast to this study, Khurrum and AlGhamdi [10] demonstrated that there is no difference between the vitamin D levels of the patients with vitiligo and the control participants. In this study, 150 patients with vitiligo, comprising 90 (60%) males, with a mean age of 30.6±11.4 years, were recruited. The study also had 150 age-matched and sex-matched vitiligo-free control participants. There was no significant difference in median serum vitamin D levels between the cases and the controls (P=0.25). They found that the serum levels of vitamin D of the patients with vitiligo were found to be lower in males (P=0.01) and the younger age group (P=0.01). This may be owing to a larger sample size (150 patients) playing a role in such difference.

Our results were in agreement with those of Finamor et al. [11] who treated 16 patients with 35 000 IU vitamin D daily for 6 months. At baseline, 100% of patients had serum vitamin D 30 ng/ml. After 6 months of supplementation, levels increased from18.4±8.9 to 132.5±37.0 ng/ml (P<0.0005).

Karagüzel et al. [12] also found that levels of 25(OH)D were increased significantly after 6 months of treatment in 30 patients of newly diagnosed focal vitiligo aged from 6 to 17 years with vitamin D deficiency from 11.1±4.0 to 29.5±12.8 (<0.001). A dose of 1500 IU/day vitamin D was given if the serum 25(OH)D levels were less than 20 ng/ml and 3000 IU/day were given if the levels were less than 10 ng/ml.

Regarding serum level of IL-17, it was found to be increased in the serum of patients with vitiligo. Zhou et al. [13] detected significantly higher serum IL-17 levels in 45 patients with active nonsegmental vitiligo versus 45 controls using enzyme-linked immunosorbent assay (P=0.0145).

Our results were in agreement with those of Malerba et al. [14] which noted downregulation of serum IL-17 level (from 200 to 150 pg/ml) in a patient with vitiligo and psoriasis after NB-UVB therapy with the improvement of lesions of both diseases (follicular repigmentation of the patches of vitiligo).

Regarding VETF scoring, VETF values were noted to be decreased with treatment, which was in agreement with Szczurko et al. [15], who noted improvement of VETF spreading score after 2-month duration of using Ginkgo biloba in patients with vitiligo.

Regarding the clinical response to treatment, our results showed that ∼45.5% of patients had moderate response (25–50% repigmentation) and ∼54.5% had poor response (<25% repigmentation). This is in agreement with Finamor et al. [11], who treated 16 patients with 35 000 IU vitamin D daily for 6 months and noted that 14 of 16 patients with vitiligo achieved 25–75% repigmentation.

Our study demonstrated a negative significant correlation between serum levels of both vitamin D and IL-17. This is in agreement with Aly et al. [8], who recorded significantly higher serum levels of IL-17 among patients with vitiligo (17.48±8.7 ng/ml) versus controls (12.48±3.33 ng/ml) (P=0.001) and noted significantly lower serum levels of vitamin D among patients with vitiligo (13.81±3.55 ng/ml) versus controls (23.76±10.31 ng/ml) (P<0.001). They concluded that vitamin D represents a potential player in the complex pathogenesis of vitiligo. Its possible regulatory relation with IL-17 as a proinflammatory cytokine is involved in such disease.

According to our study, 20.5% of patients had autoimmune disease association. In our study, thyroid disorders and rheumatoid arthritis were the most common autoimmune disease associations. Moreover, there was a statistically significant relationship between low vitamin D level and associated autoimmune diseases (<0.001). Our results were in agreement with Silverberg et al. [7], who reported that very low 25-hydroxyvitamin D levels were associated with comorbid autoimmune illness (odds ratio: 10.00; 95% confidence interval: 1.06–94.7).

Regarding association with rheumatoid arthritis, our results were in agreement with Kostoglou-Athanassiou et al. [16]. In the cohort of 44 patients with RA. 25(OH)D3 levels were found to be low compared with the control group. The levels of 25(OH)D3 were 15.26±1.07 and 25.8±1.6 ng/ml in the patient and control groups, respectively (P<0.001). Moreover, Meena et al. [17], found in 84% patients of RA were vitamin D-deficient versus only 34% of controls. The serum vitamin D levels were also significantly lower in patients with RA (mean value of 21.05±10.02 ng/ml), as compared with the controls (mean value of 32.87±14.16 ng/ml). There was a significant inverse correlation between serum vitamin D levels and RA disease activity.

Regarding our study, 9.1% of patients had systemic disease association in the form of disc prolapse disease. Moreover, there was nonsignificant relationship between low vitamin D level and disc diseases as an association. This is unlike Sedighi and Haghnegahdar [18], who hypothesized that vitamin D3 plays a role in reducing the severity of discogenic pain and that vitamin D3 can improve discogenic-related sensory deficits in vitamin D-deficient patients.

However, there was a significant statistical relationship between the level of IL-17 level and disc prolapse. This is in agreement with Cheng et al. [19] who found an association of pain and increased Th17 lymphocyte and IL-17 levels in patients with herniated and non-herniated lumbar discs.

 Conclusion



There is a relationship between low vitamin D level and high IL-17 level as a proinflammatory cytokine. Both these measures were found to be associated with patients with vitiligo and showed improvement with treatment. Vitamin D plays an important role in the development of vitiligo and other autoimmune diseases. The use of systemic vitamin D as a treatment modality for vitiligo can achieve reasonable improvement comparable to traditional modalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Bagherani N, Smoller BR, Lotti T. Vitamin D supplementation for vitiligo. Dermatol Ther 2017; 30:58–61.
2Grimes P, Nashwati R. The role of diet and supplements in vitiligo management. Dermatol Clin 2017; 35:235–243.
3Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 2012; 76:315–325.
4Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1, 25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004; 80:1717S–1720S.
5Park OJ, Han JS, Lee SH, Park CS, Won CH, Lee MW et al. Expression of epidermal c-kit+ of vitiligo lesions is related to responses to excimer laser. Ann Dermatol 2016; 28:457–463.
6Zhang X, Wang W, Li Y, Wang H, Liu R, Zhu L. Serum 25-hydroxyvitamin D status in chinese children with vitiligo: a case–control study. Clin Pediatr (Phila) 2018; 57:802–805.
7Silverberg JI, Silverberg AI, Malka E, Silverberg NB. A pilot study assessing the role of 25 hydroxy vitamin D levels in patients with vitiligo vulgaris. J Am Acad Dermatol 2010; 62:937–941.
8Aly D, Mohammed F, Sayed K, Gawdat H, Mashaly H, Abdel Hay R et al. Is there a relation between vitamin D and interleukin-17 in vitiligo? A cross-sectional study. Dermatology 2017; 233:413–418.
9Takci Z, Tekin Ö, Ertuğrul DT, Karadağ AS, Akin KO. A case-control study: evaluation of vitamin D metabolism in patients with vitiligo. Turk J Med Sci 2015; 45:837–841.
10Khurrum H, AlGhamdi KM. The relationship between the serum level of vitamin D and vitiligo: a controlled study on 300 subjects. J Cutan Med Surg 2016; 20:139–145.
11Finamor DC, Sinigaglia-Coimbra R, Neves LC, Gutierrez M, Silva JJ, Torres LD et al. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol 2013; 5:222–234.
12Karagüzel G, Sakarya NP, Bahadır S, Yaman S, Ökten A. Vitamin D status and the effects of oral vitamin D treatment in children with vitiligo: a prospective study. Clin Nutr ESPEN 2016; 15:28–31.
13Zhou L, Shi YL, Li K, Hamzavi I, Gao TW, Huggins RH et al. Increased circulating Th17 cells and elevated serum levels of TGF‐beta and IL‐21 are correlated with human non-segmental vitiligo development. Pigment Cell Melanoma Res 2015; 28:324–329.
14Malerba M, Damiani G, Radaeli A, Ragnoli B, Olivini A, Calzavara-Pinton PG. Narrowband ultraviolet B phototherapy in psoriasis reduces proinflammatory cytokine levels and improves vitiligo and neutrophilic asthma. Br J Dermatol 2015; 173:1544–1545.
15Szczurko O, Shear N, Taddio A, Boon H. Ginkgo biloba for the treatment of vitilgo vulgaris: an open label pilot clinical trial. BMC Complement Altern Med 2011; 11:21.
16Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, Raftakis I, Antoniadis C. Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab 2012; 3:181–187.
17Meena N, Chawla SPS, Garg R, Batta A, Kaur S. Assessment of vitamin D in rheumatoid arthritis and its correlation with disease activity. J Nat Sci Biol Med 2018; 9:54.
18Sedighi M, Haghnegahdar A. Role of vitamin D3 in treatment of lumbar disc herniation − pain and sensory aspects: study protocol for a randomized controlled trial. Trials 2014; 15:373.
19Cheng L, Fan W, Liu B, Wang X, Nie L. Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity. Injury 2013; 44:1805–1810.