Vitamin D (Vit-D) has pivotal involvements from bone structure to brain function and is also vital for healthy skin.1 Besides, it plays an important role in the immune system. Hypovitaminosis D has been known to be associated with the disorders of calcium and carbohydrate metabolism, cancer, cardiovascular, and several autoimmune diseases.2 Vitiligo is a skin disease known to have metabolic, cytotoxic, inflammatory, and autoimmune etiologies among several other factors.3,4 The active form of Vit-D; 1.25-dihydroxyvitamin D3 (1.25(OH)D) has been reported to be associated with the pathogenesis of Vitiligo.1–3 As epidermis is affected in vitiligo, changes in the circulatory Vit-D levels could be evidenced.2–4

The available studies in the literature are inconsistent on Vit-D levels and Hypovitaminosis D is still controversial in vitiligo.5–34 In this updated systematic review and meta-analysis on vitiligo and Vit-D levels (ViViD Study), the serum Vit-D levels and their association with variables like age, disease duration, affected Body Surface Area (BSA), and Vitiligo Activity and Severity Index (VASI) were studied in vitiligo patients as compared to controls. A subgroup meta-analysis was conducted to study Vit-D levels in relation to gender, skin type, Vitiligo type, disease activity, vitiligo history, autoimmune comorbidities, and indoor-outdoor job status of vitiligo patients.

The criteria of Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) were followed in the conduction and reporting of this study. The study protocol has been registered with PROSPERO having registration number: CRD42019142156 (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=142156).

A total of 167 papers were identified for Vit-D levels in vitiligo, of which 63 were retrieved for abstract and full-text review. Of these, a total of 31 articles did not deal with the circulatory Vit-D levels in vitiligo, therefore are excluded. In one more paper, no data has been reported and therefore is not included.36 In one study, though there is no control group, the study has been included for sub-group analysis of male-female differences in Vit-D levels in vitiligo.37 One study by Xu et al. has been considered twice as Vit-D levels were reported in two separate vitiligo and control groups studied at different time periods.33 Finally, a total of 31 articles were included in this meta-analysis.5–34 The PRISMA flow diagram for this meta-analysis has been shown in Fig. 1. The detailed characteristics of the included studies and the NOS quality scores are presented in Table 1. With the obtained score range from 4 to 8, the overall quality of studies was medium to high. Of these included studies, 15 studies measured Vit-D by ELISA, 6 studies by chemiluminescence, 2 studies by RIA, one study by LCMS, and are not clear in 7 studies. While all the studies reported calcidiol levels, one study reported calcitriol concentrations.5 Except for two studies using plasma, all the studies used a serum for Vit-D measurement.13,30 While most of the studies excluded previous treatment for vitiligo, oral vitamin D supplementation, and any topical or systemic treatment that affects vitamin D levels, it is unclear in some studies.8,12,18,28 Studies where Narrowband Ultraviolet B (NB-UVB) treatment and/or vitamin D intervention were studied, only baseline vitamin D levels in vitiligo patients in comparison to controls were considered for meta-analysis.14,16,20,27,32

Figure 1.

The PRISMA flow diagram of this meta-analysis.

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Circulatory Vit-D level in vitiligo compared with controls

As shown in Fig. 2, vitiligo patients had decreased Vit-D levels compared with controls. With a significant between-study heterogeneity (I2 = 95%; p < 0.00001), the pooled SMD (95% CI) obtained with random-effects model was −1.03 (−1.35 to −0.71). This result suggests a significant difference in mean concentrations of Vit-D between vitiligo patients and controls, and the overall effect size for the obtained mean difference corrected for standard deviations and sample bias was statistically significant (Z = 6.22, p = 0.00001).

Figure 2.

The forest plot and cumulative meta-analysis of included studies.

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Publication bias and sensitivity analysis

The funnel plot analysis with Begg’s correlation (p < 0.001) and Egger’s regression tests (p < 0.001) indicate there might be a publication bias among the included studies (Fig. 3). However, it is unlikely that publication bias posed a significant effect on this meta-analysis as correcting that bias with the ‘trim-and-fill method’ substantiated our original results. With seven studies to be trimmed, the corrected values (SMD = −1.41, 95% CI: −1.81 to −1.00) still indicated significantly lower Vit-D levels in vitiligo as compared to controls. Further, a one-study-leave-out sensitivity analysis showed that no single study had significantly influenced the combined effect size. The combined SMD obtained was stable and remained statistically significant after leaving-out any particular study in the sensitivity analysis (Fig. 4).

Figure 3.

The funnel plot of publication bias.

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Figure 4.

A one study leave-out sensitivity analysis.

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Available literature shows contrasting results with regard to Vit-D levels in vitiligo.5–34 To our best knowledge, the two systematic reviews available on the topic are not updated and are limited with respect to the number of included studies, sub-group, and meta-regression analyses.2,3 Further, in one of these two studies, the data extraction with regard to an included study was wrong.2,33 And, in the other study, both the adult and child vitiligo were included in the meta-analysis.3 In this updated study, we performed a meta-analysis including 1840 vitiligo patients and 1539 controls from 31 reports. The result of our meta-analysis shows that circulatory Vit-D concentration is significantly lower among vitiligo patients as compared to controls (SMD = −1.03, p < 0.00001).

The active form of Vit-D and Vitamin D Receptor (VDR) mediates several important biological functions such as calcium and phosphate metabolism, bone formation, growth, and differentiation. Studies have indicated that VDR polymorphisms are associated with Vit-D levels and exhibit a genetic predisposition for vitiligo.3,36 Though the etiopathogenesis of vitiligo is not completely clear, Vit-D is known to mediate immune regulation and immune diseases in addition to diabetes and cardiovascular diseases among others.1–3 It is also known that vitiligo is associated with autoimmune comorbidities and therefore altered circulatory Vit-D levels may be associated with vitiligo patients. The several factors which can influence the circulatory Vit-D level include vitiligo type, skin type, disease activity, vitiligo history, autoimmune comorbidities, age, indoor-outdoor job status, sun exposure, seasonal variations, and Vit-D measurement methods. In one cohort study, low Vit-D levels were reported to be associated with autoimmune comorbidities (Odds Ratio = 10.00), but not with age, gender, race/ethnicity, family history of vitiligo or autoimmune disease, new-onset disease, or affected BSA.38

Our sub-group analysis produced interesting results. As there were ten studies from Egypt, maximum for any other country, we performed subgroup meta-analysis based on Egypt and non-Egypt studies (21 studies). In both cases, statistical significance was retained for a decreased Vit-D level in vitiligo. However, when non-Egypt countries were further stratified, the subgroup India (7 studies) showed a statistical significance, whereas the sub-groups of studies from China (3 studies) and Turkey (4 studies) did not produce a statistically significant difference in Vit-D levels between their respective vitiligo and control groups (Table 2). This is suggestive of a between-study heterogeneity due to the ‘country’ of the included studies and the circulatory Vit-D levels may vary among countries because of different latitudes, genetic and food factors.2,3 This is further substantiated by our meta-regression analysis indicating ‘country’ as a significant source of heterogeneity (Table 3). No significant differences were noted when Vit-D levels were compared between different types of non-segmental vitiligo, presence or absence of vitiligo history, and autoimmune comorbidities. Though the female and skin type IV vitiligo patients showed lower Vit-D levels, no statistical significance was achieved when compared to males and skin type III, respectively. The disease activity appears to have some effect with stable vitiligo showing lower Vit-D levels as compared to active vitiligo, no significant p-value was found (Table 2). Also, there was no significant influence from age, gender, sample size, year of publication, and disease duration was observed in the meta-regression analysis. Accordingly, the meta-analysis of correlation coefficients also yielded no statistically significant associations of Vit-D with age, disease duration, BSA, and VASI score (Table 4).

It is noteworthy that Vit-D levels were significantly lower in indoor/urban vitiligo patients when compared to their outdoor/rural counterparts (Table 2). This clearly suggests less outdoor activity is associated with decreased Vit-D levels in vitiligo. It indicates that the environment and hence the intensity of sun exposure may influence Vit-D levels. Although we could extract and summarize in Table 1, the different seasons/time frames during which the included studies were conducted and Vit-D measurements were made, data reported were insufficient to conduct a meta-analysis on the seasonal influence and associated Vit-D variations in vitiligo.

When a separate meta-analysis was performed based on ELISA (15 studies) and non-ELISA studies (9 studies), the statistical significance was only retained in a group of studies using ELISA, while the non-ELISA methodology (chemiluminescence in particular) is an important factor contributing to the heterogeneity among studies. However, in meta-regression (24 studies), the ‘method’ used as a covariate did not show a statistically significant value. Considering the PubMed/MEDLINE indexed papers are of good quality with credible information, we repeated a separate meta-analysis on PubMed (18 reports) and non-PubMed studies (13 reports), and results retained statistical significance in either case (Table 2).

Considering the increased risk of vitiligo and the risk of autoimmune comorbidities associated with decreased Vit-D status, our meta-analysis and previous studies point towards the need for maintaining sufficient Vit-D levels by phototherapy with NB-UVB and/or Vit-D supplementation.39–41 Further, antioxidant supplementation in combination with phototherapy has also been studied in vitiligo.42,43 One recent study provides a piece of novel evidence on a significant positive association of sufficient Vit-D levels with the stability of the disease and a satisfactory repigmentation process in adult vitiligo patients.41 This previous evidence and this meta-analysis also strengthen the need to assess vitamin D status in vitiligo. Considering the therapeutic effectiveness of Vit-D supplementation and a reported correlation between sufficient Vit-D levels and the vitiligo disease course is promising, more randomized controlled trials are further needed on the role of Vit-D supplementation.40,41 This also opens up the scope for a future meta-analysis of RCTs on the effectiveness of Vit-D supplementation in vitiligo.

Our study limitations include the between-study heterogeneity which could be attributable to heterogeneous study populations from different countries, different sample sizes, and differences in methodologies, varied environmental, genetic, dietary factors, and lifestyle habits, and other inherent limitations of case-control/observational study designs. However, as heterogeneity could not be completely eliminated in a meta-analysis, this has been addressed by applying the random-effects model for estimating the overall effect-size and by a cumulative and one-study leave out a sensitivity analysis to study whether any individual study would significantly affect the obtained overall effect-size. A one-study-removed sensitivity analysis revealed that no single study/observation had significantly influenced the pooled overall effect size. Therefore, our results could be considered robust. Further, all the included studies were matched for confounders like age and sex.

In conclusion, our meta-analysis indicates decreased Vit-D status in vitiligo patients as compared to controls. These results of our meta-analysis highlight the need to assess Vit-D status for improving its level in vitiligo. Further studies on the role of Vit-D with vitiligo pathogenesis and severity are needed in the future.

None declared.

Seshadri Reddy Varikasuvu: Designed the study; conducted literature search; performed analysis; wrote the manuscript; read and approved the final manuscript.

Sowjanya Aloori: Participated in literature search; selection criteria; data collection and revisions; read and approved the final manuscript.

Saurabh Varshney: Participated in literature search; selection criteria; data collection and revisions; read and approved the final manuscript.

Aparna Varma Bhongir: Assisted in literature search and revised the manuscript; read and approved the final manuscript.

None declared.