**3. The effects of phototherapy on vitamin D status in patients with psoriasis**

A similar wavelength spectrum of UVB is responsible for vitamin D synthesis (280-315 nm), which has been successfully used for years to treat psoriasis and other chronic inflammatory skin disorders.

Phototherapy (broadband UVB, narrowband UVB and heliotherapy - treatment with natural sunlight) is an effective treatment, commonly used for widespread psoriasis. Therefore, phototherapy is an excellent option for patients with generalized psoriasis because of its superior systemic safety profile in comparison to systemic and biologic agents (51).

In addition to standard broadband ultraviolet radiation B (BUVB), (280-315 nm), narrowband phototherapy (NBUVB) (monochromatic UV between 311-312 nm) and heliotherapy (treatment with natural sunlight) have become important treatment modalities for psoriasis. Research suggests that NBUVB is more effective than broadband UVB for reducing PASI scores, as well as being a safer and better tolerated option for patients in comparison to PUVA when taken at suberythemogenic doses (52). Furthermore, these advantages along with the handling ease of the NBUVB lamp led to a reduction in the usage of broadband UVB. However, one drawback of the new lamp is that the radiation times have almost doubled (54). Additionally, several studies indicate that combination therapy using both calcipotriol and UVB radiation illustrate more rapid healing of psoriasis when compared to monotherapy of either treatment (50,55).

Serum levels of 25(OH)D increased during treatment with artificial UV (BUVB and NBUVB) and during heliotherapy(56-59). The increase in 25(OH)D was higher in the BUVB treated patients when compared to the NBUVB (p=0.008) and heliotherapy (p=0.017) treated groups. Low-dose NBUVB treatment significantly increased vitamin D status in

UVB and Vitamin D in Psoriasis 127

Patients with lower 25(OH)D levels at baseline responded better to sunlight and phototherapy which is consistent with other studies(3, 6, 57). All patients reached serum levels of 30 ng/ml (75 nmol/l) after two weeks of sun exposure(62). A circulating level of 25(OH)D of >30 ng/ml, or >75 nmol/L, appears to be necessary to maximize the health

Sun exposure is the major source of vitamin D for most humans(6). During the winter months vitamin D production is insufficient to meet the optimal requirements in both younger and older adults at Northern latitudes(74). Psoriasis lesions usually worsen during winter, and many patients are therefore given repeated UVB treatment during this season. In addition to healing psoriatic lesions, UVB therapy also provides these patients with vitamin D during the winter months, when levels of 25(OH)D in Northern countries are generally low. UVB therapy even increased serum 25(OH)D levels in patients taking vitamin D supplements. This is in line with previous studies, which reported that UV-induced vitamin D synthesis had a greater influence on the serum levels of circulating calcidiol than

Skin pigment, sunscreen use, aging, time of day, season, and latitude all affect previtamin D3 synthesis(18). There was no difference in the increase of 25(OH)D between the different skin types in the present studies(59). This was most likely due to subjects being exposed to individually adjusted doses of UVB depending on skin phototype and erythemal response to therapy. All patients had previously experienced UVB therapy for their psoriasis disease. As expected, fair-skinned patients required lower doses of UVB (broadband and narrowband) than patients with skin type III and IV. This finding is consistent with other studies examining the effect of skin pigmentation on vitamin D synthesis(77). Melanin pigment in human skin competes with, and absorbs UVB photons responsible for the

The increase in 25(OH)D during the first two weeks of heliotherapy was very similar to the increase in 25(OH)D during treatment with BUVB and NBUVB for two to three months. The correlation between sunlight measures and serum 25(OH)D is evidently weak(78). Patients reached their plateau of daily sun exposure after the first week. It is likely that vitamin D production was most prominent during the first week, when the patients experienced

The increase in 25(OH)D during 15 days of climate therapy was significant even though patients used sunscreen on body sites susceptible to sunburn, and though the skin was affected by psoriasis lesions(56, 62). This indicates that short-term therapeutic UVB exposures are sufficient to increase vitamin D synthesis in psoriasis patients. SPF-8 sunscreen has been observed to reduce the skin's production of vitamin D3 by 95%(79). Clothing also completely blocks all solar UVB radiation and thereby prevents vitamin D3

Psoriasis improved in all patients, with a reduction in the PASI score of about 75% on all regimens(59, 73). Improvement in psoriasis correlated positively with the increase in 25(OH)D3 levels in one (58) (p=0.047; the group of patients treated with BUVB and NBUVB) but not in the other studies (57, 61, 62, 73). There was no correlation between change in serum 25(OH)D levels and change in PASI or change in DLQI in the study of psoriasis patients treated with NBUVB in Ireland(73). No relationship was found between

benefits of vitamin D(6).

vitamin D synthesis(77).

production(79).

the per oral intake of supplements(75, 76).

redness and some of them even got sunburned(56).

patients with psoriasis, atopic eczema and other skin disorders with low initial levels of 25(OH)D(60, 61). Within the following intervention studies, age showed no correlation with the observed increase in 25(OH)D levels (57, 58, 62). This indicates the skin's capacity to produce vitamin D3 during phototherapy of psoriasis is independent of the patient's age or psoriasis severity. Phototherapy of psoriasis is the time-consuming procedure long enough to provide adequate cutaneous production of vitamin D even in elderly patients. The ability of the skin to produce vitamin D declines with age (63) due to insufficient sunlight exposure (11, 64) and a reduction in the functional production capacity of the skin(63, 65, 66). The increase in 25(OH)D3 was enhanced in patients with low baseline levels of vitamin D.

Vitamin D production in patients with psoriasis increased less with NBUVB than with BUVB phototherapy(58). One explanation might be that the optimal wavelength for initiation of the vitamin D3 pathway was 300±5 nm in vitro and in vivo(67, 68) which is in the BUVB range (280-315 nm). The synthesis of vitamin D was stimulated by wavelengths between 290-315 nm, but not for wavelengths longer than 315 nm. One study (58) reported that a wavelength of 311 nm effectively induced vitamin D synthesis, but not to the same extent as wavelengths in the BUVB range. UVB treatment including NBUVB treatment of psoriasis was a sufficiently time-consuming procedure to increase vitamin D. The time required for NBUVB to have an effect can reduce the difference in the potential of vitamin D production between the two lamps. The treatment time correlated strongly with the type of lamp (patients treated with NBUVB required 4 times the exposure patients treated with BUVB needed). This is consistent with other studies demonstrating that the dose response of the erythemal spectra of NBUVB should be about 4.2 times that of BUVB(69). The dose of UVB also correlated with the type of lamp, but no correlation between the dose of UVB and the increase of 25(OH)D3 levels was found (58). This might be due to the fact that serum concentrations of 25(OH)D3 were measured at different time points and a plateau level was reached after three weeks, which was also seen in a previous study(70). An *in vitro* study demonstrated that the dose-response relationship of UV exposure and cholecalciferol synthesis was nonlinear. It was hypothesized that exposure to additional UV did not result in a proportional increase in vitamin D levels(71). This might be explained by autoregulation of the skin synthesis, storage, and slow, steady release of vitamin D3 from the skin into the circulation(3). Non-linear vitamin D synthesis is easily explained by the photo equilibrium that is set up as a result of continued exposure to ultraviolet radiation as reported by Holick et al(72). Vitamin D production is a unique, autoregulated mechanism which occurs at two levels. Excessive sun exposure does not lead to overdosing of vitamin D3 due to conversion of previtamin D3 to inactive photoproducts (lumisterol 3 and tachisterol 3) as well as conversion of vitamin D3 to its isomers in the skin (5,6-trans vitamin D3, suprasterol I, suprasterol II) which are thought to have a low calcemic effect at physiological concentrations. The synthesis of previtamin D3 reached a plateau at about 10 to 15 percent of the original 7-dehydrocholesterol content(72). Vitamin D3 is synthesized in the skin and released steadily and slowly from the skin into the circulation(3).

In a study by Ryan, the number of exposures to NBUVB was the sole predictor of an increase in serum 25(OH)D level, whereas prior phototherapy was the only predictor of baseline serum 25(OH)D levels in the group of psoriasis patients treated with phototherapy(73).

patients with psoriasis, atopic eczema and other skin disorders with low initial levels of 25(OH)D(60, 61). Within the following intervention studies, age showed no correlation with the observed increase in 25(OH)D levels (57, 58, 62). This indicates the skin's capacity to produce vitamin D3 during phototherapy of psoriasis is independent of the patient's age or psoriasis severity. Phototherapy of psoriasis is the time-consuming procedure long enough to provide adequate cutaneous production of vitamin D even in elderly patients. The ability of the skin to produce vitamin D declines with age (63) due to insufficient sunlight exposure (11, 64) and a reduction in the functional production capacity of the skin(63, 65, 66). The increase in 25(OH)D3 was enhanced in patients with low baseline levels of vitamin D.

Vitamin D production in patients with psoriasis increased less with NBUVB than with BUVB phototherapy(58). One explanation might be that the optimal wavelength for initiation of the vitamin D3 pathway was 300±5 nm in vitro and in vivo(67, 68) which is in the BUVB range (280-315 nm). The synthesis of vitamin D was stimulated by wavelengths between 290-315 nm, but not for wavelengths longer than 315 nm. One study (58) reported that a wavelength of 311 nm effectively induced vitamin D synthesis, but not to the same extent as wavelengths in the BUVB range. UVB treatment including NBUVB treatment of psoriasis was a sufficiently time-consuming procedure to increase vitamin D. The time required for NBUVB to have an effect can reduce the difference in the potential of vitamin D production between the two lamps. The treatment time correlated strongly with the type of lamp (patients treated with NBUVB required 4 times the exposure patients treated with BUVB needed). This is consistent with other studies demonstrating that the dose response of the erythemal spectra of NBUVB should be about 4.2 times that of BUVB(69). The dose of UVB also correlated with the type of lamp, but no correlation between the dose of UVB and the increase of 25(OH)D3 levels was found (58). This might be due to the fact that serum concentrations of 25(OH)D3 were measured at different time points and a plateau level was reached after three weeks, which was also seen in a previous study(70). An *in vitro* study demonstrated that the dose-response relationship of UV exposure and cholecalciferol synthesis was nonlinear. It was hypothesized that exposure to additional UV did not result in a proportional increase in vitamin D levels(71). This might be explained by autoregulation of the skin synthesis, storage, and slow, steady release of vitamin D3 from the skin into the circulation(3). Non-linear vitamin D synthesis is easily explained by the photo equilibrium that is set up as a result of continued exposure to ultraviolet radiation as reported by Holick et al(72). Vitamin D production is a unique, autoregulated mechanism which occurs at two levels. Excessive sun exposure does not lead to overdosing of vitamin D3 due to conversion of previtamin D3 to inactive photoproducts (lumisterol 3 and tachisterol 3) as well as conversion of vitamin D3 to its isomers in the skin (5,6-trans vitamin D3, suprasterol I, suprasterol II) which are thought to have a low calcemic effect at physiological concentrations. The synthesis of previtamin D3 reached a plateau at about 10 to 15 percent of the original 7-dehydrocholesterol content(72). Vitamin D3 is synthesized in

the skin and released steadily and slowly from the skin into the circulation(3).

phototherapy(73).

In a study by Ryan, the number of exposures to NBUVB was the sole predictor of an increase in serum 25(OH)D level, whereas prior phototherapy was the only predictor of baseline serum 25(OH)D levels in the group of psoriasis patients treated with Patients with lower 25(OH)D levels at baseline responded better to sunlight and phototherapy which is consistent with other studies(3, 6, 57). All patients reached serum levels of 30 ng/ml (75 nmol/l) after two weeks of sun exposure(62). A circulating level of 25(OH)D of >30 ng/ml, or >75 nmol/L, appears to be necessary to maximize the health benefits of vitamin D(6).

Sun exposure is the major source of vitamin D for most humans(6). During the winter months vitamin D production is insufficient to meet the optimal requirements in both younger and older adults at Northern latitudes(74). Psoriasis lesions usually worsen during winter, and many patients are therefore given repeated UVB treatment during this season. In addition to healing psoriatic lesions, UVB therapy also provides these patients with vitamin D during the winter months, when levels of 25(OH)D in Northern countries are generally low. UVB therapy even increased serum 25(OH)D levels in patients taking vitamin D supplements. This is in line with previous studies, which reported that UV-induced vitamin D synthesis had a greater influence on the serum levels of circulating calcidiol than the per oral intake of supplements(75, 76).

Skin pigment, sunscreen use, aging, time of day, season, and latitude all affect previtamin D3 synthesis(18). There was no difference in the increase of 25(OH)D between the different skin types in the present studies(59). This was most likely due to subjects being exposed to individually adjusted doses of UVB depending on skin phototype and erythemal response to therapy. All patients had previously experienced UVB therapy for their psoriasis disease. As expected, fair-skinned patients required lower doses of UVB (broadband and narrowband) than patients with skin type III and IV. This finding is consistent with other studies examining the effect of skin pigmentation on vitamin D synthesis(77). Melanin pigment in human skin competes with, and absorbs UVB photons responsible for the vitamin D synthesis(77).

The increase in 25(OH)D during the first two weeks of heliotherapy was very similar to the increase in 25(OH)D during treatment with BUVB and NBUVB for two to three months. The correlation between sunlight measures and serum 25(OH)D is evidently weak(78). Patients reached their plateau of daily sun exposure after the first week. It is likely that vitamin D production was most prominent during the first week, when the patients experienced redness and some of them even got sunburned(56).

The increase in 25(OH)D during 15 days of climate therapy was significant even though patients used sunscreen on body sites susceptible to sunburn, and though the skin was affected by psoriasis lesions(56, 62). This indicates that short-term therapeutic UVB exposures are sufficient to increase vitamin D synthesis in psoriasis patients. SPF-8 sunscreen has been observed to reduce the skin's production of vitamin D3 by 95%(79). Clothing also completely blocks all solar UVB radiation and thereby prevents vitamin D3 production(79).

Psoriasis improved in all patients, with a reduction in the PASI score of about 75% on all regimens(59, 73). Improvement in psoriasis correlated positively with the increase in 25(OH)D3 levels in one (58) (p=0.047; the group of patients treated with BUVB and NBUVB) but not in the other studies (57, 61, 62, 73). There was no correlation between change in serum 25(OH)D levels and change in PASI or change in DLQI in the study of psoriasis patients treated with NBUVB in Ireland(73). No relationship was found between

UVB and Vitamin D in Psoriasis 129

epidermal cellular functions in an auto- and paracrine manner, but this should not be crucial for systemic vitamin D effects (5) and systemic vitamin D deficiency does not stimulate

Cutaneous production of 1,25(OH)2D3 may regulate growth, differentiation, apoptosis and other biological processes in the skin(87, 88). Therefore, topical vitamin D analogs have been used as a safe and effective treatment for psoriasis vulgaris(89, 90). The NBUVB has been shown to have less capacity to induce a local skin production of 1,25(OH)2D3 at 44% of the monochromatic irradiation at 300 ±2.5 nm(68). Nevertheless, the known therapeutic effect of UVB light therapy for the treatment of psoriasis may be mediated via UVB-induced production of 1,25(OH)2D(81). In vitro studies have shown that the substrate concentration of cholecalciferol in keratinocytes mainly determines the synthesis rate of 1,25(OH)2D in these cells(91). Thus, higher synthesis rates of cholecalciferol should result in a faster and more pronounced release of 1,25(OH)2D into the extracellular fluid. UVB-induced membrane damage to epidermal keratinocytes may also increase the outflow of newly

It is not clear if the serum 25(OH)D level is linked to the level of the active form of vitamin D3 present in the skin. It has been suggested that cutaneous conversion of 25(OH)D to 1,25(OH)2D does not play a role because the amount of free 25(OH)D3 that penetrates the cell membrane of epidermal keratinocytes is too small to produce sufficient amounts of 1,25(OH)2D(88). The main form of circulating 25(OH)D is presented in a complex with vitamin D-binding protein (DBP) with only a very small amount (0.03%) available as the free form. Furthermore, the deeper layers of the epidermis are not vascularized, which further impairs the passage of the 25(OH)D3-DBP complex from blood to epidermal

The receptor for calcitriol and the production of 1,25(OH)2D vary with the differentiation in a manner suggesting feedback regulation, and both are reduced in the later stages of differentiation(93). 1,25(OH)2D increases involucrin, transglutaminase activity, and cornified envelope formation in preconfluent keratinocytes(94). NBUVB treatment increases cathelicidin and decreases HBD2 levels in healing skin lesions of psoriasis and atopic dermatitis(61). It has been shown that HBD2 and cathelicidin expression in psoriatic skin are higher in serum vitamin D sufficient patients than in serum vitamin D

The 1,25(OH)2D molecule and its analogs, as well as UVB phototherapy, exert antiproliferative, prodifferentiative, and immune-modulatory effects on keratinocytes that are of particular importance for the therapy of hyperproliferative skin diseases such as psoriasis vulgaris(5, 96). However, the full range of UVB and vitamin D3 effects is not

PTH decreased after the treatment with phototherapy(57). 25(OH)D concentrations below 30 ng/ml (75 nmol/l) resulted in secondary hyperparathyroidism and a decrease in BMD(97). PTH increases with increasing age, possibly due to less sunlight exposure and/or reduced calcium/vitamin D intake(98). The clear concomitant decrease in serum PTH after UVB exposure indicates that the skin's capacity to synthesize vitamin D is maintained even at

**4. Serum PTH in psoriasis patients during treatment with phototherapy** 

epidermal synthesis of 1,25(OH)2D(86).

synthesized calcitriol(92).

keratinocytes(88).

deficient psoriasis patients(95).

completely understood.

levels of 25(OH)D and psoriasis but a negative correlation was found between the severity of psoriasis and the basal serum level of 1,25(OH)2D(80).

The skin is the only tissue yet known in which the complete UVB-induced pathway from 7- DHC via intermediates (previtamin D3, vitamin D3, 25(OH)D) to the final product 1,25(OH)2D, takes place under physiological conditions(81), (Figure 1). Levels of 1,25(OH)2D tended to increase during phototherapy, but significant increases were noticed only during heliotherapy, and only in women with 25(OH)D3 below 30 ng/ml, and in ages ≥ 70 years. One explanation might be that these patients had lower serum concentrations of 25(OH)D at the start of the treatment.

Fig. 1. Schematic outline of vitamin D metabolism and mechanism of action in psoriasis.

It has been postulated that the synthesis of 1,25(OH)2D is tightly regulated, and that increases in 25(OH)D concentrations due to exposure to sunlight have no effect on serum 1,25(OH)2D levels(6, 82). The observation that both 25(OH)D and 1,25(OH)2D increased in vitamin D deficient subjects following UVB exposure(83) or after vitamin D supplementation(84) has been reported previously. The increase of 1,25(OH)2D levels between patients treated with heliotherapy and patients treated with NBUVB differed (p=0.02). This might be explained by lower values of 25(OH)D at baseline in patients treated with heliotherapy(59).

Keratinocytes are capable of producing a variety of vitamin D metabolites, including 1,25(OH)2D, 24,25(OH)2D, 1,24,25(OH)3D(85) from exogenous and endogenous sources of 25(OH)D. Thus, the local UVB-triggered production of calcitriol may primarily regulate

levels of 25(OH)D and psoriasis but a negative correlation was found between the severity

The skin is the only tissue yet known in which the complete UVB-induced pathway from 7- DHC via intermediates (previtamin D3, vitamin D3, 25(OH)D) to the final product 1,25(OH)2D, takes place under physiological conditions(81), (Figure 1). Levels of 1,25(OH)2D tended to increase during phototherapy, but significant increases were noticed only during heliotherapy, and only in women with 25(OH)D3 below 30 ng/ml, and in ages ≥ 70 years. One explanation might be that these patients had lower serum concentrations of

**UVB**

**7-Dehydrocholesterol**

**Liver**

**1,25(OH)2D Extra-renal cells 1α-OHase**

**Promoted differentiation and Inhibited proliferation of keratinocytes Immunomodulation**

**Psoriasis improvement** 

**Cholecalciferol (Vitamin D3)**

**25-hydroxyvitamin D3**

**Kidney**

Fig. 1. Schematic outline of vitamin D metabolism and mechanism of action in psoriasis.

It has been postulated that the synthesis of 1,25(OH)2D is tightly regulated, and that increases in 25(OH)D concentrations due to exposure to sunlight have no effect on serum 1,25(OH)2D levels(6, 82). The observation that both 25(OH)D and 1,25(OH)2D increased in vitamin D deficient subjects following UVB exposure(83) or after vitamin D supplementation(84) has been reported previously. The increase of 1,25(OH)2D levels between patients treated with heliotherapy and patients treated with NBUVB differed (p=0.02). This might be explained by lower values of 25(OH)D at baseline in patients treated

Keratinocytes are capable of producing a variety of vitamin D metabolites, including 1,25(OH)2D, 24,25(OH)2D, 1,24,25(OH)3D(85) from exogenous and endogenous sources of 25(OH)D. Thus, the local UVB-triggered production of calcitriol may primarily regulate

of psoriasis and the basal serum level of 1,25(OH)2D(80).

**Skin**

25(OH)D at the start of the treatment.

**Vitamin D metabolism**

**1,25-dihydroxyvitamin D3**

**Maintains calcium balance in the body**

with heliotherapy(59).

**Vitamin D3 Vitamin D2**

**Dietary intake**

epidermal cellular functions in an auto- and paracrine manner, but this should not be crucial for systemic vitamin D effects (5) and systemic vitamin D deficiency does not stimulate epidermal synthesis of 1,25(OH)2D(86).

Cutaneous production of 1,25(OH)2D3 may regulate growth, differentiation, apoptosis and other biological processes in the skin(87, 88). Therefore, topical vitamin D analogs have been used as a safe and effective treatment for psoriasis vulgaris(89, 90). The NBUVB has been shown to have less capacity to induce a local skin production of 1,25(OH)2D3 at 44% of the monochromatic irradiation at 300 ±2.5 nm(68). Nevertheless, the known therapeutic effect of UVB light therapy for the treatment of psoriasis may be mediated via UVB-induced production of 1,25(OH)2D(81). In vitro studies have shown that the substrate concentration of cholecalciferol in keratinocytes mainly determines the synthesis rate of 1,25(OH)2D in these cells(91). Thus, higher synthesis rates of cholecalciferol should result in a faster and more pronounced release of 1,25(OH)2D into the extracellular fluid. UVB-induced membrane damage to epidermal keratinocytes may also increase the outflow of newly synthesized calcitriol(92).

It is not clear if the serum 25(OH)D level is linked to the level of the active form of vitamin D3 present in the skin. It has been suggested that cutaneous conversion of 25(OH)D to 1,25(OH)2D does not play a role because the amount of free 25(OH)D3 that penetrates the cell membrane of epidermal keratinocytes is too small to produce sufficient amounts of 1,25(OH)2D(88). The main form of circulating 25(OH)D is presented in a complex with vitamin D-binding protein (DBP) with only a very small amount (0.03%) available as the free form. Furthermore, the deeper layers of the epidermis are not vascularized, which further impairs the passage of the 25(OH)D3-DBP complex from blood to epidermal keratinocytes(88).

The receptor for calcitriol and the production of 1,25(OH)2D vary with the differentiation in a manner suggesting feedback regulation, and both are reduced in the later stages of differentiation(93). 1,25(OH)2D increases involucrin, transglutaminase activity, and cornified envelope formation in preconfluent keratinocytes(94). NBUVB treatment increases cathelicidin and decreases HBD2 levels in healing skin lesions of psoriasis and atopic dermatitis(61). It has been shown that HBD2 and cathelicidin expression in psoriatic skin are higher in serum vitamin D sufficient patients than in serum vitamin D deficient psoriasis patients(95).

The 1,25(OH)2D molecule and its analogs, as well as UVB phototherapy, exert antiproliferative, prodifferentiative, and immune-modulatory effects on keratinocytes that are of particular importance for the therapy of hyperproliferative skin diseases such as psoriasis vulgaris(5, 96). However, the full range of UVB and vitamin D3 effects is not completely understood.

### **4. Serum PTH in psoriasis patients during treatment with phototherapy**

PTH decreased after the treatment with phototherapy(57). 25(OH)D concentrations below 30 ng/ml (75 nmol/l) resulted in secondary hyperparathyroidism and a decrease in BMD(97). PTH increases with increasing age, possibly due to less sunlight exposure and/or reduced calcium/vitamin D intake(98). The clear concomitant decrease in serum PTH after UVB exposure indicates that the skin's capacity to synthesize vitamin D is maintained even at

UVB and Vitamin D in Psoriasis 131

Vitamin D is important for bone metabolism(121). Vitamin D deficiency thus contributes to the pathogenesis of osteoporosis and hip fractures(122). Supplementation strategies involving calcium and vitamin D supplements are cost-effective for preventing osteoporotic

The same range of UVB (290–315 nm) that induces vitamin D synthesis also improves psoriasis. Treatment with UVB in patients with psoriasis is most common during winter months when UVB is lacking, and levels of vitamin D are low in Northern countries(123). Furthermore, UVB therapy heals psoriasis and supplies these patients with vitamin D at levels similar to those of the general population(123), which might have positive effects on

**6. Blood glucose and lipid status in psoriasis patients during treatment with** 

Psoriasis is considered a chronic and debilitating inflammatory disease associated with serious comorbidities (124, 125). Large epidemiological studies have shown that psoriasis and psoriatic arthritis are associated with metabolic diseases including obesity, dyslipidemia and diabetes(126). The chronic inflammation in psoriasis can predispose patients to other inflammatory conditions. The proinflammatory cytokines, such as tumor necrosis factor- (TNF-), and other factors that are overproduced in patients with psoriasis likely contribute

Inflammatory factors have also been associated with insulin resistance and β-cell failure, both of which are key features of type 2 diabetes mellitus (129). There is evidence that vitamin D may stimulate pancreatic insulin secretion directly through nuclear receptors that are found in a wide variety of tissues, including T and B lymphocytes, skeletal muscle, and the pancreatic islet β-cells(130). There is some evidence that suggests increased PTH activity is associated with, and possibly causes, reduced insulin sensitivity(130). The prevalence of impaired glucose tolerance and diabetes mellitus is increased in patients with primary

Vitamin D has a wide range of effects on the immune system: it promotes the differentiation of monocytes into macrophages thus increasing their cytotoxic activity; reduces the antigenpresenting activity of macrophages to lymphocytes; prevents dendritic cell maturation; inhibits T lymphocyte-mediated immunoglobulin synthesis in B cells and inhibits delayedtype hypersensitivity reactions(8, 133, 134). Furthermore vitamin D has been reported to down-regulate the production of several cytokines: IL-2, IL-6 and IL-12, interferon-γ, TNF-α, and TNF-β (134, 135). Alternations in vitamin D status and/or action may affect insulin sensitivity, β-cell function or both. Therefore, vitamin D may be involved in the pathogenesis of type 2 diabetes mellitus at both environmental and genetic levels(129). Psoriasis patients are more likely to be insulin resistant and to have impaired glucose tolerance, higher fasting

Heliotherapy improves lipid and carbohydrate status of psoriasis patients(56). Increases in high-density lipoprotein (HDL)-cholesterol and decreases in HbA1c during climate therapy could be explained by several factors. One possible mechanism could be a direct effect of vitamin D on insulin sensitivity(130). Another is that sun exposure usually implies greater outdoor physical activity, leading to beneficial effects on lipids and insulin sensitivity,

to the increased risk for the development of metabolic syndrome(127, 128).

insulin levels, and impaired β-cell function than non-psoriatic subjects(136).

fractures(123).

bone status as well.

hyperparathyroidism (131, 132).

**heliotherapy** 

older ages and with part of the skin covered by psoriatic lesions. Serum concentrations of calcium and creatinine were unaltered after phototherapy(58).
