Effects of Serum Vitamin D levels and Vitamin D Supplementation on Urticaria: A Systematic Review and Meta-Analysis
Int. J. Environ. Res. Public Health 2021, 18,4911. https://doi.org/10.3390/ ijerph18094911
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Backgrounds: Several studies have shown that the level of 25-hydroxyvitamin D (25(OH)D) could affect urticaria. The association of Vitamin D (VitD) with urticaria has not been well established.
Methods: The up-to-date meta-analysis was performed to synthesize the new findings. We performed a systematic search in PubMed, EMBASE, Web of Science, and Cochrane Database. We included the observational studies with the comparisons of 25(OH)D between urticarial populations and controls and clinical studies with the clinical severity of urticaria records.
Results: A meta-analysis of seventeen studies of urticaria group vs. controls revealed a mean difference of -9.35 ng/mL (95% CI -12.27 to -6.44). There was also an association of urticaria with VitD deficiency. In the subgroup analysis of age and disease type, significant effects of 25(OH)D were found among adult and chronic urticarial populations. Six VitD supplementation trials showed a significant reduction in clinical urticarial score on intervention with VitD with the standard mean difference of -3.63 and -1.54 among randomized control studies and repeated measure trials, respectively.
Conclusions: The urticarial population, especially the adult chronic urticarial patients, may be associated with a high risk for lower serum 25(OH)D. VitD supplementations could result in a reduction of urticarial clinical symptoms.
The findings of our comprehensive meta-analysis showed lower serum 25(OH)D concentrations by 9.35 ng/mL in the overall urticarial population compared with healthy individuals. Moreover, serum 25(OH)D deficiency was associated with an increased prevalence of urticaria compared to the general population. Many previous studies pointed out the positive relationship between low VitD serum levels and urticaria. Compared to the most recent meta-analyses in this field, our study concurs with the results by Tsai et al. (2018)  and Wang (2018)  that lower VitD serum levels occur in urticarial patients. We also verified that VitD deficiency rather than insufficiency has a positive relationship with urticaria. Furthermore, the higher prevalence of VitD deficiency and lower serum VitD levels were only found in patients with CU but not in those with AU. There lacked association of serum Vit D levels with AU and children urticaria compared to CU and adults (Supplemental Figure S6). Neither can we ignore the impact of geographical location, where subgroup analysis indicated populations in lower latitudes with VitD deficiency were associated with a higher urticarial risk compared to those in high latitudes. According to previous studies, sun exposure is an important source of the human needs for cutaneous production of VitD. Ultraviolet B (UVB) could be absorbed and transformed to pre-vitamin D3 in the skin by the function of 7-dehydrocholesterol, which could be influenced by many factors such as season, latitude, time of day, etc. . For the effects of latitude or sun exposure on serum VitD level, notably, people who were below 37° and closer to the equator could synthesize more VitD3 in their skin within a year. In the early morning or evening, the apex angle of the day was so inclined that there was almost no VitD3 produced in the skin, even in summer. Therefore, studies have shown that safe exposure to the sun between 1000 and 1500 h in spring, summer, and autumn is considered to be critical for VitD generation because this is the only time that sufficient solar UVB reaches the earth's surface to produce VitD3 in the skin [48-50]. However, In addition to latitude, other critical determinants of VitD status may not have been adequately captured in our analysis, including seasonal and personal factors.
As noted above, our meta-analysis was different from prior studies since we also focused on the effects of VitD supplementation on urticaria. Pooled results from the repeated measures study indicated there were highly significant improvements after supplementation with reductions in urticarial severity scores of -1.54, using dosages of 7000-20,000 IU daily for 6-12 weeks. Similarly, pooling results from RCTs showed highly significant improvements after VitD supplementation with changes of severity by -3.63, using dosages around 4000 IU daily for 12 weeks. For all interventional studies used, the baseline average serum 25(OH)D was below 30 ng/mL and therefore below sufficient levels. Thus, we were not able to reveal the effects of supplementation in populations with sufficient serum 25(OH)D status. Nonetheless, we found that after supplementation, the mean 25(OH)D levels were >30 ng/mL in all trials except one with a mean concentration of 29 ng/mL. The weighted mean dose of 4000-12,000 IU/day (100-300 micrograms) was high in comparison with existing treatments, although no complications were reported .
Except for one study that did not describe the formulation of VitD supplementation used, only Boonpiyathad et al.  reported the use of VitD2, which can be metabolized more rapidly, which might explain why VitD2 is less effective than VitD3 in increasing 25(OH)D concentrations . However, it was assumed that large amounts of VitD2 might have fewer toxic effects than VitD3 . The optimum dose for effectiveness and safety of VitD supplements may be required in future studies.
In terms of the biological mechanisms involved, Ariaee et al. found that VitD treatment was associated with downregulation of IL-10, TGF-beta, FOXP3, and IL-17 in which type of cells . Although these were not statistically significant, there was evidence revealing that a Th17/Treg cell subsets imbalance was reported to be involved in the pathogenesis of CSU and have a functional role in relieving diseases. Skin inflammation could be relieved by the balance of Th17/Treg cell populations [54,55]. VitD also could inhibit migration of DCs and decrease IL-6, IL-12, IL-23, C-reactive protein, TNF-a, and IgE production [56-59]. Besides, the active form of VitD could downregulate Th1 gene expression as well as up- regulate Th2 gene expression, leading to a Th2 response and increased production of IL-4, IL-5, and IL-10 [17,60]. All these actions could plausibly contribute to the role of VitD in urticaria. However, few studies have been published, and more research is needed to better define the mechanisms.
Our study currently represents the most up-to-date meta-analysis concerning the role of VitD in urticaria in the broader global population, with most included studies scored as high quality. Our study is also the first for assessing clinical changes in urticarial disease severity and life quality after VitD supplementation. However, even considering publication bias, several limitations must be acknowledged concerning our study. First, the interventional studies used different urticaria severity scores, and some studies used self-control or non-placebo controls. Second, all studies involved high-dose VitD treatments, and we were unable to evaluate dosage effects. Third, the measurement tools for severity and life quality were different amongst interventional studies. Last, among both observational and interventional studies, the meta-analysis, especially for subgroups, was in limitations because there were small populations that were appropriate for inclusion. For example, Only a few studies about AU were included and may cause bias in the results.
Besides, there some evidence showing that substantial seasonal variations could be found in the 25(OH)D concentrations. Hansen et al. showed that among the general Danish population, most people have relatively sufficient VitD in the summer or fall, but they are more prone to VitD deficiency in the winter or early spring. Individualized and bi- seasonal measurements seemed necessary when assessing serum VitD status. The seasonal variations in 25-hydroxyvitamin D concentration varied in different regions in the world and could be affected by complex factors. With the lacked seasonal information on serum collection in most studies, it is difficult to compare VitD level and conditions among urticaria patients and healthy controls subgrouped by different seasons. The problem in all studies of linking vitamin D status to a disease process, that there is considerable seasonal variation in vitamin D status and that the season when blood samples are collected is often not stated. More related studies with descriptions about the season for blood sample collection are warranted.
In summary, our findings support that the urticaria population, especially the adult chronic urticaria patients, may be at high risk associated with lower serum 25(OH)D. VitD, as an immunomodulatory and anti-inflammatory agent, can benefit chronic urticaria. VitD supplementation appears to both reduce urticaria severity and improve life quality. Regardless, large multi-center, long-duration clinical studies are still required to investigate the clinical benefits and to understand the mechanisms of function of VitD in urticaria.
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