Serum vitamin D level - the effect on the clinical course of psoriasis.

INTRODUCTION: Psoriasis is a hyperproliferative disorder of the skin, and vitamin D analogs are widely used in its treatment. It is evident that ultraviolet radiation enables vitamin D3 (cholecalciferol) formation in the epidermis, and this product is further converted into the active metabolites 25-hydroxycholecalciferol and 1,25-hydroxycholecalciferol, which exert several important effects on the skin. The disruption in proper functioning of the skin which occurs in psoriasis leads to a loss of capacity for cutaneous synthesis of vitamin D3. In consequence, it activates a vicious circle that impairs homeostasis of the skin and results in a progressive decrease in the level of vitamin D in the whole human body. AIM: To estimate the prevalence of vitamin D serum deficiency in patients with psoriasis and analyse the association of vitamin D food intake with clinical features.
MATERIAL AND METHODS: Forty adults with psoriasis and 40 healthy subjects (control group) were recruited. Psoriasis plaques were diagnosed and evaluated by the PASI scale. Collected blood samples enabled measurement of serum vitamin D level by assessment with the immunoenzyme technique.
RESULTS: The analysis with the Mann-Whitney U test revealed a statistically significant difference in 25-hydroxycholecalciferol level between healthy individuals and patients with psoriasis (p = 0.048). In both groups (control and psoriatic) the level of 25-hydroxycholecalciferol was seriously deficient (< 50 nmol/l). There was also a negative correlation of 25-hydroxycholecalciferol serum level with both PASI (r = -0.43) and the duration of psoriasis (r = -0.53).
CONCLUSIONS: It is necessary to bear in mind that not only the ingestion of food rich in vitamin D is necessary, but also the production of vitamin D with sun exposure. The quantity of 25-hydroxycholecalciferol is very important both in the general population and in patients with psoriasis, because these groups have a distinct metabolism.

Introduction

Psoriasis is a hyperproliferative disorder of the skin, and vitamin D3 analogs are widely used in its treatment. There are several agents, such as tacalcitol, calcipotriol and the recently approved maxacalcitol, which are administered either as monotherapy or in combination with topical steroids, such as betamethasone dipropionate, in the treatment of psoriasis. These analogs exert prodifferentiating and antiproliferative effects on keratinocytes, and additionally they manifest important anti-inflammatory properties [1].

The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is well known for its influence on bones and control of calcium and phosphate homeostasis. It is now evident that 1,25(OH)2D3 exerts much more effects in various tissues which express the vitamin D receptor (VDR) or possess certain enzymes – those necessary for generation of 1,25(OH)2D3 by activating hydroxylation of vitamin D3 metabolites. It is believed that most tissues have the ability to convert vitamin D3 into its active form, 1,25(OH)2D3, which in turn binds to the VDR and forms the 1,25(OH)2D3/VDR complex, which subsequently regulates the expression of several genes. Among special properties of 1,25(OH)2D3 are both a prodifferentiating and an antiproliferative influence on normal and cancer cells, as well as some immunomodulatory effects. These aspects are very desirable; however, excessive doses of 1,25(OH)2D3 are known to result in hypercalcemia. It could potentially limit the use of 1,25(OH)2D3 analogs in any therapy, but synthetic analogs are administered topically, which reduces the risk of calcemic side effects and simultaneously preserves all beneficial effects of 1,25(OH)2D3 [1-4].

There has been a lot of speculation in evaluation of the optimal concentration of vitamin D and a threshold below which a vitamin D insufficiency is recognized. The reference concentration for vitamin D (25-hydroxycholecalciferol) is considered to be 30–50 ng/ml (75–125 nmol/l), while a serum level below 20 ng/ml (or 50 nmol/l) indicates vitamin D deficiency. The problem of vitamin D insufficiency seems to be very common in Europe and the USA, and some estimations suggest its prevalence in the general population to be as high as 50%. Undoubtedly, the low level of vitamin D leads to a pathological condition with muscle weakness, rickets or osteomalacia, which are complications of poor prognosis [5].

The role of vitamin D is considered to vary, and some evidence suggests vitamin D to be a modulatory factor of the activity in dendritic cells and keratinocytes, or the proliferation in T-cells. All metabolites of vitamin D act via the VDR, which is expressed in many tissues, including the skin. It is evident that ultraviolet radiation enables vitamin D3 (cholecalciferol) formation in the epidermis, and this product is further converted to the active metabolites 25-hydroxycholecalciferol and 1,25-hydroxycholecalciferol3, which have an influence on cutaneous functions. One of these metabolites, 25-hydroxycholecalciferol, manifests double activity in keratinocytes, by inhibition of their proliferation and enhancement of the maturity. Taking such influence on keratinocytes into consideration, a deficiency in 25-hydroxycholecalciferol could be a risk factor for the development of psoriasis with possible involvement of disturbances in the cellular immune system (T lymphocytes), as well as in angiogenesis [1, 5, 6]. It is believed that psoriasis could activate a vicious circle with severe impairment of cutaneous functions and, secondarily, a progressive decrease in the level of vitamin D3 derivatives in the whole human body, including the skin.

Aim

The aim of this study was to estimate the prevalence of vitamin D serum deficiency in patients with psoriasis and perform further analysis of the association of vitamin D food intake with clinical features.

Material and methods

Forty adults with psoriasis and 40 subjects (healthy control group) were recruited. All patients with psoriasis and all control group subjects agreed to participate in the study. Informed consent was obtained from all subjects. For publication of patient photos, consent to publish was obtained. All the participants were asked to complete the specific questionnaire. The obtained data included age, gender, duration of psoriasis, concomitant diseases and medications. In the group of patients psoriasis was moderate to severe. Psoriasis plaques were diagnosed and evaluated by a specialized medical team with assessment of the Psoriasis Area and Severity Index (PASI). All patients were seen by a dermatologist, who collected data considering the demographic, health status and any other relevant details. Cases were age- and gender-matched for comparison. Collected blood samples enabled measurement of the serum level of a vitamin D3 derivative (25-hydroxycholecalciferol) using an immunoenzyme assessment technique (25(OH)-Vitamin D Xpress ELISA kit Immundiagnostik AG, Germany). Sensitivity of the method is 6.2 nmol/l, in-series error 6%, inter-series error 7.4%.

All measurements were conducted during winter months to avoid the influence of sun exposure on synthesis of vitamin D3 and its derivative 25-hydroxycholecalciferol (Table 1).

Table 1

Reference intervals for 25(OH)-vitamin D3 (ng/ml), males and females

Age	N	2.5%	97.5%
0 to < 3 months	131	5	42
3 to < 6 months	135	9	60
6 months to < 1 year	147	18	58
1 to < 3 years	394	15	54
3 to < 10 years	619	14	46
10 to < 13 years	286	11	50
13 to < 15 years	275	10	44
15 to < 18 years	390	8	45
< 18 years	421	8	56

Conversion factor: 1 ng/ml = 2.5 nmol/l, 1 nmol/l = 0.4 ng/ml.

The results were referred to normal serum ranges of 25-hydroxycholecalciferol according to the American Society for Bone and Mineral Research 2011: deficiency (seriously deficient): < 50 nmol/l; insufficiency (deficient): 50–74 nmol/l; sufficiency (adequately supplied): > 75 nmol/l.

Statistical analysis

Initially, all results obtained from patients and healthy controls were compared using the Shapiro-Wilk test. Subsequently, the Mann-Whitney U test was used to compare the quantitative variables. Correlations were estimated by nonparametric Spearman’s rank test. In this study, a p-value of < 0.05 was considered to be statistically significant.

Results

Results was presented in Tables 2–4.

Table 2

Serum level of 25-hydroxycholecalciferol, PASI, age and duration of psoriasis in patient group and control group

Parameter	N	Mean	Median	Min.	Max.	SD
Study group	40	32.25	29.75	23.59	48.12	6.79
PASI	40	10.36	11.15	1.20	28.00	6.26
Age	40	41.55	41.50	18.00	76.00	14.42
Duration of psoriasis	40	12.89	11.50	0.50	40.00	9.01
D_control	40	56.13	55.34	49.65	86.57	6.82

Table 4

25-hydroxycholecalciferol serum level in female group

Group	N	Mean	Median	Min.	Max.	SD
Study	21	32.50	28.91	24.58	48.12	7.46
D_control	21	54.77	53.55	49.65	71.23	5.17

The analysis with the Mann-Whitney U test revealed a statistically significant difference in 25-hydroxycholecalciferol level between healthy individuals and patients with psoriasis (p = 0.048) (Figure 1). In both groups (control and psoriatic) the level of 25-hydroxycholecalciferol was seriously deficient (< 50 nmol/l). There was also a negative correlation of 25-hydroxycholecalciferol serum level with both PASI (r = –0.43) and the duration of psoriasis (r = –0.53) (Figure 2).

Figure 1

Significant difference between 25-hydroxycholecalciferol serum level in control group and in group of patients with psoriasis (p = 0.048)

Figure 2

Negative correlation between 25-hydroxycholecalciferol serum level and PASI (r = –0.43) and psoriasis duration (r = –0.53)

Discussion

Vitamin D3 and its analogs exhibit a strong antiproliferative and prodifferentiating influence on both normal and malignant cell types. Several vitamin D3 analogs have been approved for the treatment of psoriasis, osteoporosis or secondary hyperparathyroidism, and frequently they comprise the first or second-line treatment option.

The exact mechanism of action of vitamin D analogs still requires further elucidation. Undoubtedly, the reason why specific analogs manifest superagonistic activity in specific tissues remains unknown, although several studies have tried to clarify the mechanisms behind these tissue-specific effects. Moreover, since some cell types prefer specific catabolism pathways and enzymes above others, the degradation process may also contribute to the tissue-specific activity of vitamin D analogs. The affinity for the vitamin D binding protein (DBP) may also play a role in the activity of vitamin D analogs, because it regulates the bioavailability of vitamin D for tissues [1, 7, 8]. The relation between 25-hydroxycholecalciferol and psoriasis has been studied since the 1930s. A chance discovery was reported in 1985 by Morimoto et al., who noticed that the administration of vitamin D3 could improve psoriasis in some cases [8]. The new synthetic analogs of vitamin D, such as tacalcitol and calcipotriol, present lower hypercalcemic activity with simultaneously preservation of all biological effects considering the regulation of epidermal cell proliferation and differentiation, the inhibition of angiogenesis and the modulation of cytokine production [9-14].

In our study, the serum level of 25-hydroxycholecalciferol stayed below the normal serum range recommended by the American Society for Bone and Mineral Research, in both groups (controls and patients). The concentration of 25-hydroxycholecalciferol was significantly lower in patients with psoriasis than in healthy individuals, and the lowest measure was obtained from patients with severe psoriasis. These results correlate with similar observations of other authors. Both the studies of Ricceri et al. and Orgaz-Molina et al. revealed a high prevalence of insufficiency and deficiency in serum 25-hydroxycholecalciferol, which was greater in patients with psoriasis than in control subjects [15, 16]. Additionally, comparatively to our observations, significantly lower values of 25-hydroxycholecalciferol were reported by Ricceri et al., and these concentrations negatively correlated with PASI [15]. An interesting observation was made in the study of Orgaz-Molina et al., who reported a higher risk of 25-hydroxycholecalciferol insufficiency in psoriatic patients with a body mass index of 27 or more. A possible explanation for such a relationship was the lower physical activity level and therefore reduced sun exposure of heavier psoriatic patients. Another possible mechanism is the increased sequestration of vitamin D3 in fat, which could result in its reduced bioavailability in serum [16].

The main source of vitamin D3 is its cutaneous synthesis, which is activated by UV radiation; however, the safe dose of exposure to UV radiation, which does not cause the development of skin cancer, has remained controversial. The current trends in lifestyle involve only minimal sun exposure through most of the year but with excessive sunbathing during the holiday period, which undoubtedly implies a risk for the development of cutaneous neoplasia, including melanoma [1, 2, 9, 17, 18].

The impact of light exposure on the synthesis of 25-hydroxycholecalciferol has been evaluated in several clinical studies. Ala-Houhala et al. analyzed the influence of narrow-band ultraviolet B (UVBnb) phototherapy on the serum level of 25-hydroxycholecalciferol and the severity of skin lesions in patients with psoriasis. In that study, the response to UVBnb was assessed in 12 patients who were concomitantly supplemented with oral cholecalciferol, 20 µg daily. At baseline, the serum level of 25-hydroxycholecalciferol was 74.14 nmol/l (much higher than in our study), and it increased by 49.4 nmol/l above baseline at the 18th exposure of UVBnb [11]. In another study, Feldmeyer et al. compared the differences in serum concentrations of 25-hydroxycholecalciferol which occurred after phototherapy with different light spectra. The group of 116 dermatologic patients included several disease entities (atopic dermatitis, psoriasis, morphea, and others), and all individuals underwent UVA1 (n = 38), UVBnb (n = 48) or combined UVA/UVBnb (n = 30) phototherapy with the frequency of 2 to 3 times a week for 53 to 90 days. It was observed that phototherapy with UVBnb and UVA/ UVBnb increased the 25-hydroxycholecalciferol serum level significantly, whereas UVA1 therapy alone induced a reduction in serum 25-hydroxycholecalciferol concentrations [19].

A considerable source of vitamin D3 that enables limitation of sun exposure seems to be its additional food intake, in the form of certain foods or dietary supplements. Unfortunately, most meals contain only a little vitamin D3, and those rich in vitamin D3 are eaten irregularly, which may be an important explanation of why both study groups do not consume adequate quantities of vitamin D3 [1, 2, 9, 20, 21]. In a pilot study, Finamor et al. observed that prolonged high-dose vitamin D3 administration could be very beneficial for patients with psoriasis. It was found that treatment with vitamin D3 (35,000 IU daily) resulted in a significant increase in serum level of 25-hydroxycholecalciferol, which correlated with a significant improvement in the PASI score of all patients. Essentially, all patients presented low vitamin D status (serum 25-hydroxycholecalciferol ≤ 30 ng/ml) at baseline, which is in agreement with our results [22].

The benefit/risk ratio should be taken into account, since the sun exposure is undoubtedly crucial in supporting an adequate level of vitamin D3. Overall, moderate sun exposure throughout the year and a balanced diet should be the recommended practice to support a sufficient amount of vitamin D3 metabolites with maintenance of the serum 25-hydroxycholecalciferol within reference limits. In addition, new studies that determine both the intake and blood levels of 25-hydroxycholecalciferol in psoriasis patients are required [1, 2, 23].

Conclusions

The considerably low serum content of vitamin D3 in both psoriasis patients and the control group indicate the need for more research to evaluate the vitamin D3 status of our population.

It is necessary to bear in mind that not only meals rich in vitamin D, but also sun exposure, are essential to maintain an adequate level of this vitamin.

Although the food intake of vitamin D3 is very important for both the general population and psoriasis patients, these groups manifest altered metabolism of vitamin D3 and, in consequence, different vitamin D3 requirements.

Table 3

25-hydroxycholecalciferol serum level in male group

Group	N	Mean	Median	Min.	Max.	SD
Study	19	31.97	29.77	23.59	44.81	6.16
D_control	19	57.62	56.18	50.33	86.57	8.16