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Psorilax:Dove acquistare online |creme per psoriasi sulle gambe dermovitamine

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Psorilax:Dove acquistare online |creme per psoriasi sulle gambe dermovitamine

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Psorilax: prezzo, funziona, recensioni, opinioni, quanto costa

The Vitamin D Endocrine System (VDES) in Normal and Psoriatic Human Skin

In humans, vitamin D can be absorbed from the diet or synthesized in the skin from 7-dehydrocholesterol (7-DHC) after exposure to natural (solar) or artificial ultraviolet B (UVB) radiation.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) At least nine enzymatic reactions are involved in the photochemical cutaneous synthesis of vitamin D, hereunder four photoreversible reactions and one non reversible phototransformation.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),2 Lehmann B, Genehr T, Knuschke P, Pietsch J, Meurer M. UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J Invest Dermatol 2001; 117:11791185 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) 1,25-Dihydroxyvitamin D (1,25(OH)2D, calcitriol), a seco-steroidal hormone and the biologically active vitamin D metabolite, is synthesized from vitamin D by a well characterized biochemical reaction cascade. In a first step, vitamin D is hydroxylated in the liver in C-25 position by a cytochrome P450 enzyme, the vitamin D-25-hydroxylase (CYP27A1), before it gets hydroxylated a second time in the kidney in C-1 position by another cytochrome P450 enzyme, the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) to generate the biologically active vitamin D metabolite 1,25(OH)2D.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

The synthesis of 1,25-dihydroxyvitamin D3 in the kidney is regulated by a feedback-mechanism of the hormone itself, as well as by parathyroid hormone, calcium and cytokines like Interferon γ (IFNγ) or tumor necrosis factor α (TNFα).1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In the 1970s it was generally accepted in the scientific community that the kidney was the only source of 1,25(OH)2D3 production. However, during the last decades, in vitro and in vivo investigations (including studies on anephric humans) showed that various cell types including cultured human keratinocytes, monocytes, macrophages osteoblasts, prostate and colon cells, express the enzymatic machinery for the synthesis of 1,25(OH)2D3, i.e., the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), and are thus able to synthesize 1,25-dihydroxyvitamin D3.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In keratinocytes, studies could even prove the presence of both 1α-hydroxylase (CYP27B1) and 25-hydroxylase (CYP27A1).1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),3 Bikle DD, Neumanic MK, Gee E, Elias P. 1,25-Dihydroxyvitamin D3 production by human keratinocytes. J Clinical Invest 1886; 78:557566 (Crossref), (Web of Science ®) , (Google Scholar),4 Lehmann B, Tiebel O, Meurer M. Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents-a preliminary study. Arch Dermatol Res 1999; 291:507510 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) According to these findings,2 Lehmann B, Genehr T, Knuschke P, Pietsch J, Meurer M. UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J Invest Dermatol 2001; 117:11791185 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),4 Lehmann B, Tiebel O, Meurer M. Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents-a preliminary study. Arch Dermatol Res 1999; 291:507510 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) the keratinocyte is the only cell type known until today, that has the capacity to synthesize 1,25(OH)2D3 from 7-dehydrocholesterol.

During the last decades, it has been shown that the skin itself is an important target tissue for 1,25(OH)2D3,5 Gniadecki R. Stimulation versus inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 1996; 106:510516 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar) that exerts genomic and non-genomic effects.9 Haussler MR, Mangelsdorf DJ, Komm BS, Terpening CM, Yamaoka K, Allegretto EA, et al. Molecular biology of the vitamin D hormone. Recent Prog Horm Res 1988; 44:263305 (PubMed) , (Google Scholar) Non-genomic effects of calcitriol and analogs are mediated by effects on intracellular calcium.10 Bittiner B, Bleehen SS, Mac Neil S. 1α-25-(OH)2 Vitamin D3 increases intracellular calcium in human keratinocytes. Br J Dermatol 1991; 124:1223012235 (Crossref), (Web of Science ®) , (Google Scholar),11 MacLaughlin JA, Cantley LC, Holick MF. 1,25(OH)2D3 increases calcium and phosphatidylinositol metabolism in differentiating cultured human keratinocytes. J Nutr Biochem 1990; 1:8187 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In keratinocytes and various other cell types, calcitriol rapidly increases free cytosolic calcium levels.10 Bittiner B, Bleehen SS, Mac Neil S. 1α-25-(OH)2 Vitamin D3 increases intracellular calcium in human keratinocytes. Br J Dermatol 1991; 124:1223012235 (Crossref), (Web of Science ®) , (Google Scholar),11 MacLaughlin JA, Cantley LC, Holick MF. 1,25(OH)2D3 increases calcium and phosphatidylinositol metabolism in differentiating cultured human keratinocytes. J Nutr Biochem 1990; 1:8187 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Genomic effects of 1,25(OH)2D3 are mediated via binding to a nuclear receptor protein, the vitamin D receptor (VDR).9 Haussler MR, Mangelsdorf DJ, Komm BS, Terpening CM, Yamaoka K, Allegretto EA, et al. Molecular biology of the vitamin D hormone. Recent Prog Horm Res 1988; 44:263305 (PubMed) , (Google Scholar),12 Haussler MR. Vitamin D receptors: nature and function. Annu Rev Nutr 1986; 6:527562 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),13 Baker AR, Mc Donnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988; 85:32943298 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In the skin, VDR is expressed in keratinocytes, fibroblasts, Langerhans cells, sebaceous gland cells, endothelial cells and most cell types related to the skin immune system.14 Milde P, Hauser U, Simon R, Mall G, Ernst V, Haussler MR, et al. Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol 1991; 97:230239 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

In vitro studies have revealed that 1,25(OH)2D3 is highly effective in inducing terminal differentiation and in inhibiting proliferation of cultured human keratinocytes in a dose-dependent manner (Table 1).5 Gniadecki R. Stimulation versus inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 1996; 106:510516 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),15 Smith EL, Walworth NC, Holick MF. Effect of 1α-25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown under serum-free conditions. J Invest Dermatol 1986; 86:709714 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),16 Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1-alpha,25-dihydroxyvitamin D3. Endocrinol 1983; 113:19501957 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Additionally, it acts on many cell types involved in immunologic reactions, including lymphocytes, macrophages and Langerhans cells (Table 1).1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),17 Griffin M, Kumar R. Effects of 1α,25-dihydroxyvitamin D3 and its analogs on dendritic cell function. J Cell Biochem 2003; 88:323326 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)21 Edfeldt K, Liu PT, Chun R, Fabri M, Schenk M, Wheelwright M, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA 2010; 107:2259322598 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Physiological and Pharmacological Actions of Vitamin D Analogs in Normal and Psoriatic Human Skin

Modulation of proliferation and differentiation in keratinocytes.

Many in vitro and in vivo studies demonstrate dose-dependent effects of vitamin D analogs on cell proliferation and differentiation. At lower concentrations (<10−8 M), 1,25(OH)2D3 promotes proliferation of keratinocytes in vitro, at higher pharmacological doses (≥10−8 M) keratinocyte proliferation is inhibited.5 Gniadecki R. Stimulation versus inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 1996; 106:510516 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),15 Smith EL, Walworth NC, Holick MF. Effect of 1α-25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown under serum-free conditions. J Invest Dermatol 1986; 86:709714 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),16 Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1-alpha,25-dihydroxyvitamin D3. Endocrinol 1983; 113:19501957 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In psoriatic skin, immunohistochemical and biochemical analyses have demonstrated antiproliferative and pro-differentiating effects in epidermal keratinocytes along with treatment with 1,25(OH)2D3 or analogs in vivo.7 Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 1997; 36:1928 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar) It has been shown that the immunohistochemical staining pattern for various markers of epidermal proliferation (e.g., proliferating cell nuclear antigen (PCNA), Ki-67-antigen) and differentiation (e.g., involucrin, transglutaminase K, filaggrin, cytokeratin 10) changes in lesional psoriatic skin along with topical treatment with 1,25(OH)2D3 or analogs almost completely to the staining pattern characteristic for nonlesional psoriatic or normal skin.7 Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 1997; 36:1928 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar) Although the mechanisms that mediate the antiproliferative and pro-differentiating effects of vitamin D analogs on keratinocytes are not completely understood, it is well known that these effects are at least in part genomic and mediated via VDR. It has been demonstrated that keratinocytes from vitamin D receptor-deficient mice do not respond in vitro to the antiproliferative effects of vitamin D analogs.22 Sakai Y, Demay MB. Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice. Endocrinology 2000; 141:20432049 (PubMed), (Web of Science ®) , (Google Scholar) It has been reported that 1,25(OH)2D3 (10−8 m) suppresses the proliferation rate of wild-type keratinocytes maintained in low calcium (68 ± 3.6% of control), while in contrast, no modulation of proliferation is observed in keratinocytes from VDR null mice.22 Sakai Y, Demay MB. Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice. Endocrinology 2000; 141:20432049 (PubMed), (Web of Science ®) , (Google Scholar)

At present, the molecular mechanisms by which vitamin D analogs regulate epidermal proliferation and differentiation are not completely understood. Major candidates for calcitriol target genes that may mediate 1,25(OH)2D3-induced terminal differentiation in keratinocytes are components of the hedgehog signalling pathway and distinct cell cycle associated proteins (i.e., INK4 family), including p21/WAF-1.23 Tang JY, Xiao TZ, Oda Y, Chang KS, Shpall E, Wu A, et al. Vitamin D3 inhibits hedgehog signalling and proliferation in murine basal cell carcinomas. Cancer Prev Res 2011; 4:744751 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),24 Holick MF, Reichrath J. Holick MF. Clinical Utility of 1,25-Dihydroxyvitamin D3 and its Analogues for the Treatment of Psoriasis. Vitamin D: Physiology, Molecular Biologic and Clinical Aspects 1999; Totowa, New York The Humana Press Inc. 357373 (Crossref) , (Google Scholar)

Immunomodulatory effects of 1,25(OH)2D3 and analogs in human skin.

Many cell types involved in immunologic reactions (e.g., monocytes, T-and B-lymphocytes, Langerhans cells) do not only express VDR, but moreover possess the enzymatic machinery (25-hydroxyvitamin D-1α-hydroxylase (CYP27B1)) for the local synthesis of 1,25(OH)2D3.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) This local synthesis of 1,25(OH)2D3 in immune cells is considered to be of high importance for regulation and control of various immune responses. Today, it is known that 1,25(OH)2D3 inhibits activation of T-cells and induces the generation of CD25+/CD4+ regulatory T-cells.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),25 van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, van der Kleij HP, Opstelten DJ, et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T-cells. J Allergy Clin Immunol 2011; 127:15321540 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In dendritic cells, 1,25(OH)2D3 inhibits maturation and induces a phenotype that promotes tolerance and inhibits immunity after stimulation with antigens (Table 1).1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),17 Griffin M, Kumar R. Effects of 1α,25-dihydroxyvitamin D3 and its analogs on dendritic cell function. J Cell Biochem 2003; 88:323326 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),20 Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8:285293 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),25 van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, van der Kleij HP, Opstelten DJ, et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T-cells. J Allergy Clin Immunol 2011; 127:15321540 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) It also suppresses the expression of MHC II molecules and of costimulatory molecules including CD40, CD80 and CD86 in dentritic cells.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),17 Griffin M, Kumar R. Effects of 1α,25-dihydroxyvitamin D3 and its analogs on dendritic cell function. J Cell Biochem 2003; 88:323326 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),20 Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8:285293 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),25 van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, van der Kleij HP, Opstelten DJ, et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T-cells. J Allergy Clin Immunol 2011; 127:15321540 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In these cells, production of IL-10 is stimulated and production of IL-12 inhibited, leading to suppression of T-cell activation.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),17 Griffin M, Kumar R. Effects of 1α,25-dihydroxyvitamin D3 and its analogs on dendritic cell function. J Cell Biochem 2003; 88:323326 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),20 Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8:285293 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),25 van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, van der Kleij HP, Opstelten DJ, et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T-cells. J Allergy Clin Immunol 2011; 127:15321540 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Impressive effects of vitamin D compounds were reported in animal models of and in diseases that are related with the function of T-cells or dendritic cells (experimentally induced allergic encephalomyelitis, collagen-induced arthritis, autoimmune thyreoiditis, diabetes mellitus type I, graft-versus-host reaction).1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Furthermore, recent studies show that vitamin D deficiency may promote the pathogenesis of many autoimmune diseases like diabetes mellitus type I and that a sufficient vitamin D serum concentration may reduce the incidence of those diseases.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) At present, a connection between vitamin D and pathogenesis of atopic dermatitis (AD) is discussed. Epidemiologic studies have indicated that patients with atopic dermatitis have a lower vitamin D intake as compared to controls.26 Solvoll K, Soyland E, Sandstad B, Drevon CA. Dietary habits among patients with atopic dermatitis. Eur J Clin Nutr 2000; 54:9397 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) More recently, a correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children was reported.27 Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children. Br J Dermatol 2011; 164:10781082 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In that study, mean serum levels of 25-hydroxyvitamin D were significantly higher (p < 0.05) in patients with mild disease.27 Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children. Br J Dermatol 2011; 164:10781082 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) The authors concluded that vitamin D deficiency may be related to the severity of AD and advocate the need for studies evaluating the use of vitamin D as a potential treatment in patients with this disease.27 Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children. Br J Dermatol 2011; 164:10781082 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In line with these findings, it has been previously demonstrated that vitamin D analogs suppress in vitro IgE-production and IgE-mediated cutaneous reactions (Table 1).28 Katayama I, Minatohara K, Yokozeki H, Nishioka K. Topical vitamin D3 downregulates IgE-mediated murine biphasic cutaneous reactions. Int Arch Allergy Immunol 1996; 111:7176 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) These immunomodulatory effects identify vitamin D analogs, most likely new vitamin D analogs with more selective immunomodulatory activity, as promising new drugs for the prevention and therapy of inflammatory skin diseases including psoriasis, atopic dermatitis and allergic contact dermatitis.

New insights from the last years demonstrate that calcitriol induces the expression of the CCR-10 receptor on the surface of T-cells, which leads to a migration of these T-cells towards CCL-27-expressing epidermal keratinocytes (Table 1).20 Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8:285293 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) This UVB-induced and vitamin D mediated T-cell mobilization from the blood vessels of the dermis into the epidermis characterizes another immunomodulatory effect of vitamin D compounds: an on-demand rising of the T-cell answer in the epidermis.20 Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to “program” T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8:285293 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) The clinical relevance of this function of vitamin D compounds is not totally clarified until now and remains subject of further studies.

In recent years, it was also shown that the vitamin D endocrine system is a potent regulator of the innate immune response.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),18 Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjö A, Törmä H, Ståhle M. Vitamin D Induces the Antimicrobial Protein hCAP18 in Human Skin. J Invest Dermatol 2005; 124:10801082 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),19 Gombard HF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly upregulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005; 19:10671077 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Constant exposure to a wide variety of different microbial pathogens represents a major challenge for human skin.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Antimicrobial peptides (AMPs) are important mediators of cutaneous innate immunity, they protect primarily against microbial infections.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Cathelicidins were among the first AMPs identified in human skin and recent evidence indicates that they exert a dual role in innate immune defense:29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) At first, they are able to kill pathogens directly due to their antimicrobial activity.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Second, these pep-tides initiate a potent host response to infection causing cytokine release, inflammation and a cellular response.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Disturbed cathelicidin expression and function has been reported in several common inflammatory skin diseases, including psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In atopic dermatitis reduced levels of cathelicidin facilitating microbial superinfections have been discussed.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Additionally, abnormally processed cathelicidin peptides were shown to promote inflammation and a vascular response in rosacea.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Until recently, the precise molecular mechanisms underlying cathelicidin regulation were unknown.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression in human skin and other tissues.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) It was demonstrated that the human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly upregulated in myeloid cells by 1,25-dihydroxyvitamin D3.1 Holick MF. Vitamin D deficiency. NEJM 2007; 357:266281 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),18 Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjö A, Törmä H, Ståhle M. Vitamin D Induces the Antimicrobial Protein hCAP18 in Human Skin. J Invest Dermatol 2005; 124:10801082 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),19 Gombard HF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly upregulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005; 19:10671077 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) These mechanisms are of high importance for the defense against infectious diseases, including tuberculosis. More recently, it was also shown that T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism.21 Edfeldt K, Liu PT, Chun R, Fabri M, Schenk M, Wheelwright M, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA 2010; 107:2259322598 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Consequently, therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by modulating both innate and adaptive immune functions.29 Dombrowski Y, Peric M, Koglin S, Ruzicka T, Schauber J. Control of cutaneous antimicrobial peptides by vitamin D3. Arch Dermatol Res 2010; 302:401408 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Regulation of apoptosis.

It has been demonstrated that physiological concentrations of 1,25-dihydroxyvitamin D3 in keratinocyte cultures do not induce apoptosis but generate an apoptosis-resistance against ceramides, ultraviolet radiation and tumor necrosis factor α (TNFα) (Table 1).30 Geilen CC, Bektas M, Wieder T, Orfanos CR. 1α,25-Dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor α. J Biol Chem 1997; 272:89979001 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),31 Manggau M, Kim DS, Ruwisch L, Vogler R, Korting HC. 1α,25-Dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate. J Invest Dermatol 2001; 117:12411249 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Those antiapoptotic/cytoprotective effects of 1,25(OH)2D3 are obviously linked to the production of sphingosine-1-phosphate. This hypothesis has been proven by the fact that the antiapoptotic effect of 1,25-dihydroxyvitamin D3 can be completely suppressed by addition of the sphingosine kinase-inhibitor N,N-dimethylsphingosine.30 Geilen CC, Bektas M, Wieder T, Orfanos CR. 1α,25-Dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor α. J Biol Chem 1997; 272:89979001 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),31 Manggau M, Kim DS, Ruwisch L, Vogler R, Korting HC. 1α,25-Dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate. J Invest Dermatol 2001; 117:12411249 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In contrast, pharmacological concentrations of 1,25-dihydroxyvitamin D3 (≥10−6 M) do induce apoptosis. Dose-dependent differential effects have been also observed in the regulation of keratinocyte growth, where, as mentioned above, relatively low concentrations of 1,25-dihydroxyvitamin D3 (around 10−11 M) stimulate cell proliferation, whereas higher concentrations of 1,25-dihydroxyvitamin D3 have a dose-dependent antiproliferative effect.5 Gniadecki R. Stimulation versus inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D3: dependence on cell culture conditions. J Invest Dermatol 1996; 106:510516 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),15 Smith EL, Walworth NC, Holick MF. Effect of 1α-25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown under serum-free conditions. J Invest Dermatol 1986; 86:709714 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),16 Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1-alpha,25-dihydroxyvitamin D3. Endocrinol 1983; 113:19501957 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Biological effects of 1,25(OH)2D and analogs in psoriatic skin.

The precise mechanisms underlying the therapeutic effectiveness of vitamin D analogs in psoriasis are still not completely understood. Modulation of various markers of epidermal proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67 antigen) and differentiation (involucrin, transglutaminase K, filaggrin, cytokeratins 10, 16) was shown in situ in lesional psoriatic skin after topical application of vitamin D analogs (Table 1).7 Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 1997; 36:1928 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar) Interestingly, the effects of topical treatment with vitamin D analogs on dermal inflammation are less pronounced (CD-antigens, cytokines, HLA-DR etc.,) as compared to effects on epidermal proliferation or differentiation.7 Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 1997; 36:1928 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar) This could possibly be explained by the fact that the bioavailability of topically applied vitamin D compounds in the dermal compartment may be markedly reduced as compared to the epidermal compartment.7 Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA. Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 1997; 36:1928 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),8 Reichrath J, Perez A, Chen TC, Kerber A, Bahmer FA, Holick MF. The effectiveness of topical 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) application in the treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997; 77:268272 (PubMed), (Web of Science ®) , (Google Scholar)

In lesional psoriatic skin, the clinical improvement correlates with an increase of VDR mRNA in 1,25(OH)2D3 treated skin.32 Chen ML, Perez A, Sanan DK, Heinrich G, Chen TC, Holick MF. Induction of vitamin D receptor mRNA expression in psoriatic plaques correlates with clinical response to 1,25-dihydroxyvitamin D3. J Invest Dermatol 1996; 106:637641 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) However, not all patients with psoriasis respond to treatment with vitamin D analogs: “responders” can be discriminated from “non-responders” by an increase in VDR mRNA in treated skin areas.32 Chen ML, Perez A, Sanan DK, Heinrich G, Chen TC, Holick MF. Induction of vitamin D receptor mRNA expression in psoriatic plaques correlates with clinical response to 1,25-dihydroxyvitamin D3. J Invest Dermatol 1996; 106:637641 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

From studies analyzing VDR expression and genotype in psoriasis,33 Dayangac-Erden D, Karaduman A, Erdem-Yurter H. Polymorphisms of vitamin D receptor gene in Turkish familial psoriasis patients. Arch Dermatol Res 2007; 299:487491 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)40 Colin EM, Weel AEAM, Uitterlinden AG, Buurman CJ, Birkenhäger JC, Pols HAP, et al. Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mono-nuclear cells by 1,25-dihydroxyvitamin D3. Clin Endocrinol 2000; 52:211216 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) some report a correlation between VDR expression or individual VDR genotypes and the skin eruptions of psoriasis, as well as with responsiveness to treatment with vitamin D analogs.35 Park BS, Park JS, Lee DY, Youn JI, Kim IG. Vitamin D receptor polymorphism is associated with psoriasis. J Invest Dermatol 1999; 112:113116 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) While no differences in VDR genotype between controls and psoriasis patients were reported at the BsmI site, some analyses reported significant difference in terms of ApaI SNP35 Park BS, Park JS, Lee DY, Youn JI, Kim IG. Vitamin D receptor polymorphism is associated with psoriasis. J Invest Dermatol 1999; 112:113116 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) and FokI SNP.36 Saeki H, Asano N, Tsunemi Y, Takekoshi T, Kishimoto M, Mitsui H, et al. Polymorphisms of vitamin D receptor gene in Japanese patients with psoriasis vulgaris. J Dermatol Sci 2002; 30:167171 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) According to Colin et al. the FokI polymorphism is associated with the response to calcipotriol. Under conditions of vitamin D deficiency/insufficiency, this finding might have clinical implications. Other studies have shown that distinct vitamin D receptor genotypes are not associated with clinical response to calcipotriol.37 Lee DY, Park BS, Choi KH, Jeon JH, Cho KH, Song KY, et al. Vitamin D receptor genotypes are not associated with clinical response to calcipotriol in Korean psoriasis patients. Arch Dermatol Res 2002; 294:15 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Data concerning serum levels of 1,25(OH)2D or 25(OH) D in psoriatic patients are also conflicting. Some studies report reduced levels of 1,25(OH)2D in patients with manifest psoriasis.41 Staberg B, Oxholm A, Klemp P, Christiansen C. Abnormal vitamin D metabolism in patients with psoriasis. Acta Derm Venereol 1987; 67:6568 (PubMed), (Web of Science ®) , (Google Scholar) Additionally, the coincidence of pustular psoriasis with hypocalcemia42 Stewart AF, Battaglini-Sabetta J, Millstone L. Hypocalcemia-induced pustular psoriasis of von Zumbusch. New experience with an old syndrome. Ann Intern Med 1984; 100:677680 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) and the exacerbation of psoriasis along with chloroquin therapy (thereby reducing 1,25(OH)2D levels via inhibition of 1α-(OH)ase (CYP27B1)) are well known.43 Stone OJ. Chloroquine, ground substance, aggravation of psoriasis. Int J Dermatol 1985; 24:539 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Clinical Use of Calcitriol and Analogs in Psoriasis

In 1985, MacLaughlin et al. reported that psoriatic fibroblasts were partially resistant to the antiproliferative effects of 1,25(OH)2D3.44 MacLaughlin JA, Gange W, Taylor D, Smith E, Holick MF. Cultured psoriatic fibroblasts from involved and uninvolved sites have partial but not absolute resistance to the proliferation-inhibition activity of 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1985; 82:54095412 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) This laboratory finding prompted them to speculate that calcitriol may be effective in the treatment of the hyperproliferative skin disease psoriasis.

Another line of investigation was the result of a clinical observation. In 1985, Morimoto and Kumahara reported that an osteoporosis patient, who was treated orally with 1α-(OH)D3, had a remission of psoriatic skin lesions.45 Morimoto S, Kumahara Y. A patient with psoriasis cured by 1α-hydroxyvitamin D3. Med J Osaka Univ 1985; 35:34 (Google Scholar) They demonstrated in a follow up study that almost 80% of 17 patients with psoriasis who were treated orally with 1α-(OH)D3 at a dose of 1.0 µg/day for up to 6 months showed clinically significant improvement.46 Morimoto S, Yochikawa K, Kozuka T, Kitano Y, Imawaka S, Fukuo K, et al. An open study of vitamin D3 treatment in psoriasis vulgaris. Br J Dermatol 1986; 115:421429 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

In the last years, numerous studies have reported that various vitamin D analogs, including calcitriol, calcipotriol, tacalcitol, hexafluoro-1,25-dihydroxyvitamin D3 and maxacalcitol are effective and safe in the topical treatment of psoriasis (Table 2).47 Holick MF, Chen ML, Kong XF, Sanan DK. Clinical uses for calciotropic hormones 1,25-dihydroxyvitamin D3 and parathyroid hormone related peptide in dermatology: a new perspective. J Invest Dermatol (Symp Proc) 1996; 1:19 (PubMed) , (Google Scholar)55 Kragballe K, Gjertsen BT, de Hoop D, Karlsmark T, van de Kerhof PCM, Larko O, et al. Double-blind right/left comparison of calcipotriol and betametasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337:193196 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Calcipotriol/calcitriol.

Applied twice daily in amounts of up to 100 grams of ointment (50 µg calcipotriol/g ointment) per week, calcipotriol was shown to be slightly more effective in the topical treatment of psoriasis than betamethasone 17-valerate.55 Kragballe K, Gjertsen BT, de Hoop D, Karlsmark T, van de Kerhof PCM, Larko O, et al. Double-blind right/left comparison of calcipotriol and betametasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337:193196 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) A mild dermatitis on the face has been reported as side effect in about 10% of patients treated with calcipotriol (50 µg/g) and was not reported after topical treatment with calcitriol.

Maxacalcitol.

In one study, maxacalcitol 25 µg/g has been reported as more effective than once-daily calcipotriol (50 µg/g) (Table 2).51 Barker JN, Ashton RE, Marks R, Harris RI, Berth-Jones J. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br J Dermatol 1999; 141:274278 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Allergic contact dermatitis to vitamin D analogs is very rare.57 Fisher DA. Allergic contact dermatitis to propylene glycol in calcipotriene ointment. Cutis 1997; 60:4344 (PubMed), (Web of Science ®) , (Google Scholar)59 Park YK, Lee JH, Chung WG. Allergic contact dermatitis from calcipotriol. Acta Derm Venereol 2002; 82:7172 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) The most common adverse event observed in psoriasis patients treated with maxacalcitol (6–50 µg/g maxacalcitol ointment), was a burning sensation in treated skin lesions.51 Barker JN, Ashton RE, Marks R, Harris RI, Berth-Jones J. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br J Dermatol 1999; 141:274278 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In three out of four patients developing this side effect in one study, symptoms were severe enough to recommend discontinuation of the treatment.51 Barker JN, Ashton RE, Marks R, Harris RI, Berth-Jones J. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br J Dermatol 1999; 141:274278 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Tacalcitol.

Efficacy and safety of treatment with tacalcitol (4 µg/g and 20 µg/g) has been shown as well.53 Miyachi Y, Ohkawara A, Ohkido M, Harada S, Tamaki K, Nakagawa H, et al. Long-term safety and efficacy of high-concentration (20 microg/g) tacalcitol ointment in psoriasis vulgaris. Eur J Dermatol 2002; 12:463468 (PubMed), (Web of Science ®) , (Google Scholar),54 van de Kerkhof PC, Berth-Jones J, Griffiths CE, Harrison PV, Honigsmann H, Marks R, et al. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis. Br J Dermatol 2002; 146:414422 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),60 Katayama I, Ohkawara A, Ohkido M, Harada S, Tamaki K, Nakagawa H, et al. High-concentration (20 µg/g) tacalcitol ointment therapy on refractory psoriasis vulgaris with low response to topical corticosteroids. Eur J Dermatol 2002; 12:553557 (PubMed), (Web of Science ®) , (Google Scholar) In one study, topical treatment with tacalcitol was generally well tolerated and there were no serious or unexpected adverse events reported. However, discontinuation of the treatment as a result of skin irritation was seen in 5.9% of the patients.54 van de Kerkhof PC, Berth-Jones J, Griffiths CE, Harrison PV, Honigsmann H, Marks R, et al. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis. Br J Dermatol 2002; 146:414422 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) The greatest incidence of cutaneous side-effects occurred during initial treatment and decreased markedly as the treatment was well-tolerated with continued use.54 van de Kerkhof PC, Berth-Jones J, Griffiths CE, Harrison PV, Honigsmann H, Marks R, et al. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis. Br J Dermatol 2002; 146:414422 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Concerning specific local-safety parameters of various vitamin D analogs including cumulative irritancy, cutaneous contact sensitization, photoallergic contact sensitization and phototoxicity the results of four separate studies were analyzed.61 Queille-Roussel C, Duteil L, Parneix-Spake A, Arsonnaud S, Rizova E. The safety of calcitriol 3 microg/g ointment. Evaluation of cutaneous contact sensitization, cumulative irritancy, photoallergic contact sensitization and phototoxicity. Eur J Dermatol 2001; 11:219224 (PubMed), (Web of Science ®) , (Google Scholar) In that study, calcitriol (3 µg/g) ointment was classified as non-irritant compared to calcipotriol, tacalcitol and white petrolatum (control), petrolatum and tacalcitol were slightly irritant and calcipotriol was moderately irritant.61 Queille-Roussel C, Duteil L, Parneix-Spake A, Arsonnaud S, Rizova E. The safety of calcitriol 3 microg/g ointment. Evaluation of cutaneous contact sensitization, cumulative irritancy, photoallergic contact sensitization and phototoxicity. Eur J Dermatol 2001; 11:219224 (PubMed), (Web of Science ®) , (Google Scholar) Using standard photoallergenicity testing methodology, no skin reactions of photoallergic nature were found.61 Queille-Roussel C, Duteil L, Parneix-Spake A, Arsonnaud S, Rizova E. The safety of calcitriol 3 microg/g ointment. Evaluation of cutaneous contact sensitization, cumulative irritancy, photoallergic contact sensitization and phototoxicity. Eur J Dermatol 2001; 11:219224 (PubMed), (Web of Science ®) , (Google Scholar)

Combined topical treatment with calcipotriol ointment (50 µg/g) and betamethasone ointment was shown to cause less skin irritation and to be slightly more effective than calcipotriol used twice daily.62 Ortonne JP. Calcipotriol in combination with betametasone diproprionate. Nouv Dermatol 1994; 13:736751 (Google Scholar)

It is a fact that patients with psoriasis may need intermittent treatment for their whole lives. It is now acepted that vitamin D analogs are effective and safe for the topical treatment of skin areas that are usually difficult to treat and that respond slowly.63 Ortonne JP, Humbert P, Nicolas JF, Tsankov N, Tonev SD, Janin A, et al. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg/g ointment and calcipotriol 50 microg/g ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol 2003; 148:326333 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) They do not exhibit tachyphylaxis and topical treatment can be continued indefinitely. Additionally, they are effective in the treatment of psoriatic skin lesions in children and in HIV-patients.64 Saggese G, Federico G, Battini R. Topical application of 1,25-dihydroxyvitamin D3 (calcitriol) is an effective and reliable therapy to cure skin lesions in psoriatic children. Eur J Pediatr 1993; 152:389392 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)66 Travis LB, Silverberg NB. Psoriasis in infancy: therapy with calcipotriene ointment. Cutis 2001; 68:341344 (PubMed), (Web of Science ®) , (Google Scholar)

Treatment of face and flexures.

In general, the use of calcipotriol ointment on face and flexures is not recommended due to irritancy. Nevertheless, most patients tolerate calcitriol or analogs on these sites. Calcitriol ointment (3 µg of calcitriol per gram of petrolatum) was found to be better tolerated and more effective than calcipotriol ointment (50 µg of calcipotriol per gram of petrolatum) in the treatment of psoriasis in sensitive areas.63 Ortonne JP, Humbert P, Nicolas JF, Tsankov N, Tonev SD, Janin A, et al. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg/g ointment and calcipotriol 50 microg/g ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol 2003; 148:326333 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Treatment of scalp psoriasis.

Calcipotriol solution has been shown to be effective in the topical treatment of scalp psoriasis (Table 2, reviewed in refs. 67 Green C, Ganpule M, Harris D, Kavanagh G, Kennedy C, Mallett R, et al. Comparative effects of calcipotriol (MC 903) solution and placebo (vehicle of MC 903) in the treatment of psoriasis of the scalp. Br J Dermatol 1994; 130:483487 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)69 Koo J. Vitamin D and scalp psoriasis. Cutis 2002; 70:2124 (PubMed), (Web of Science ®) , (Google Scholar)), including a double-blind, randomized multicenter study.67 Green C, Ganpule M, Harris D, Kavanagh G, Kennedy C, Mallett R, et al. Comparative effects of calcipotriol (MC 903) solution and placebo (vehicle of MC 903) in the treatment of psoriasis of the scalp. Br J Dermatol 1994; 130:483487 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) 49 patients were treated twice a day over four weeks.67 Green C, Ganpule M, Harris D, Kavanagh G, Kennedy C, Mallett R, et al. Comparative effects of calcipotriol (MC 903) solution and placebo (vehicle of MC 903) in the treatment of psoriasis of the scalp. Br J Dermatol 1994; 130:483487 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) 60% of patients on calcipotriol showed clearance or marked improvement vs. 17% in the placebo group. No side effects were reported.

Treatment of nail psoriasis.

Nails in general respond slowly and are very difficult to treat. Although it has been reported that calcipotriol ointment is effective in the treatment of nail psoriasis, there has been no consistently effective treatment for psoriatic nails up to now.70 Petrow W. Treatment of a nail psoriasis with calcipotriol. Akt Dermatol 1995; 21:396400 (Google Scholar)

Oral treatment with vitamin D and analogs.

The efficacy and safety of oral calcitriol (Table 2) as a potential treatment of psoriasis was demonstrated in a long-term follow-up study.71 Perez A, Raab R, Chen TC, Turner A, Holick MF. Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br J Dermatol 1996; 134:10701078 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Of the 85 patients receiving oral calcitriol for 36 months, 88.0% had some improvement in their disease, while 26.5%, 26.3% and 25.3% had complete, moderate and slight improvement in their disease, respectively. To avoid its effects on enhancing dietary calcium absorption, it is very important to provide calcitriol at night time. Perez et al.71 Perez A, Raab R, Chen TC, Turner A, Holick MF. Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis. Br J Dermatol 1996; 134:10701078 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) showed that as a result of this dosing technique along with maintaining a calcium intake of no more than 1 g/day, calcitriol doses of 2 µg to 4 µg/night are nicely tolerated by psoriatic patients.

Combination of vitamin D analogs with other therapies.

Kragballe and coworkers reported that efficacy of topical calcipotriol treatment in psoriasis can be ameliorated by simultaneous ultraviolet-B phototherapy.72 Kragballe K. Combination of topical calcipotriol (MC 903) and UVB radiation for psoriasis vulgaris. Dermatologica 1990; 181:211214 (Crossref), (PubMed) , (Google Scholar) This therapeutic efficacy of UV-B in psoriasis may be at least in part due to an increased cutaneous vitamin D synthesis. Vitamin D analogs can be topically applied at any time up to two hours before or immediately after UV-radiation. The combination of topical treatment with vitamin D analogs and UV-radiation does not alter the tolerability or safety of therapy.72 Kragballe K. Combination of topical calcipotriol (MC 903) and UVB radiation for psoriasis vulgaris. Dermatologica 1990; 181:211214 (Crossref), (PubMed) , (Google Scholar),73 Kerscher M, Volkenandt M, Plewig G, Lehmann P. Combination phototherapy of psoriasis with calcipotriol and narrow band UVB. Lancet 1993; 342:923 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

Results of a controlled, right/left study have demonstrated that pretreatment of psoriasis with tacalcitol increases the responsiveness to 311-nm UV-B74 Messer G, Degitz K, Plewig G, Rocken M. Pretreatment of psoriasis with the vitamin D3 derivative tacalcitol increases the responsiveness to 311-nm ultraviolet B: results of a controlled, right/left study. Br J Dermatol 2001; 144:628629 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) and that tacalcitol ointment (4 µg/g) and 0.1% tazarotene gel are both comparably effective in improving the therapeutic result of PUVA (psoralen plus UV-A) therapy in patients with chronic plaque-type psoriasis.75 Tzaneva S, Honigsmann H, Tanew A, Seeber A. A comparison of psoralen plus ultraviolet A (PUVA) monotherapy, tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis. Br J Dermatol 2002; 147:748753 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),76 Mascaro JM. Vitamin D and psoralen plus UVA radiation. Cutis 2002; 70:1315 (PubMed), (Web of Science ®) , (Google Scholar) Adverse reactions occurred more often with 0.1% tazarotene than with tacalcitol but were generally mild and completely reversible upon using a lower concentration of 0.05% tazarotene.75 Tzaneva S, Honigsmann H, Tanew A, Seeber A. A comparison of psoralen plus ultraviolet A (PUVA) monotherapy, tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis. Br J Dermatol 2002; 147:748753 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) It has been concluded that both agents, besides accelerating the treatment response, might also help to reduce possible long-term hazards of PUVA treatment by virtue of their UV-A dose-sparing effect. A case report previously described two patients treated with a combination treatment of calcipotriol and bath psoralens and UV-A who developed hyperpigmentation at the lesional sites where calcipotriol ointment was applied.77 Glaser R, Rowert J, Mrowietz U. Hyperpigmentation due to topical calcipotriol and photochemotherapy in two psoriatic patients. Br J Dermatol 1998; 139:148151 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

The efficacy of topical treatment with vitamin D analogs in psoriasis can also be increased by combination with other therapies: tumor necrosis factor α (TNFα)-inhibitors, methotrexate (MTX), low dose oral cyclosporine (2 mg/kg/day), oral acitretin, topical dithranol, topical steroids.78 Grossman RM, Thivolet J, Claudy A, Souteyrand P, Guilhou JJ, Thomas P, et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: a result of a multicenter placebo-controlled study. J Am Acad Dermatol 1994; 31:6874 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)83 Campione E, Mazzotta A, Paternò EJ, Diluvio L, Prinz JC, Chimenti S. Effect of calcipotriol on etanercept partial responder psoriasis vulgaris and psoriasi arthritis patients. Acta Derm Venereol 2009; 89:288291 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) It has been shown for example that the combination of calcipotriol and MTX is safe and well tolerated and resulted in lower cumulative dosages of MTX compared with MTX and vehicle.81 de Jong EM, Mork NJ, Seijger MM, De La Brassine M, Lauharanta J, Jansen CT, et al. The combination of calcipotriol and methotrexate compared with methotrexate and vehicle in psoriasis: results of a multicentre placebo-controlled randomized trial. Br J Dermatol 2003; 148:318325 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

As an outlook in the future, it can be assumed that the number of different vitamin D compounds, that will be used for the topical treatment of psoriasis, will continue to increase. Moreover, these compounds will be available in different formulations and in combination with corticosteroids and other agents.

Perspectives for the Evaluation of New Vitamin D Analogs with Less Calcemic Activity

For supraphysiological doses may be needed to reach clinical improvement, the use of vitamin D analogs in dermatology was considered decades ago to be limited since serious side effects, mainly on calcium metabolism, might occur. Consequently, it has been in recent years a major goal to synthesize new vitamin D compounds with strong immunosuppressive, antiproliferative and/or differentiating effects but only marginal effects on calcium metabolism. Although this major goal has still not been reached, clinical and laboratory findings during the last decades have now resulted in promising concepts.

A major break-through for the topical treatment with vitamin D analogs was the development of calcipotriol (calcipotriene, MC 903). Calcipotriol has similar VDR binding properties as compared to calcitriol, but has low affinity for the vitamin D binding protein (DBP). These properties result in strong effects in the target tissue skin and reduced unwanted systemic effects, when topically applied for the treatment of skin diseases. Consequently, calcipotriol is very effective and safe in the topical treatment of psoriasis.49 Kragballe K, Beck HI, Sogaard H. Improvement of psoriasis by topical vitamin D3 analogue (MC 903) in a double-blind study. Br J Dermatol 1988; 119:223230 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),62 Ortonne JP. Calcipotriol in combination with betametasone diproprionate. Nouv Dermatol 1994; 13:736751 (Google Scholar),63 Ortonne JP, Humbert P, Nicolas JF, Tsankov N, Tonev SD, Janin A, et al. Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg/g ointment and calcipotriol 50 microg/g ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas. Br J Dermatol 2003; 148:326333 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) In vivo studies in rats showed that effects of calcipotriol on calcium metabolism are 100–200x lower as compared to calcitriol, while in vitro effects on proliferation and differentiation on human keratinocytes are comparable.84 Reichrath J, Holick MF. Holick MF. Clinical Utility of 1,25-dihydroxyvitamin D3 and its analogs for the treatment of psoriasis and other skin diseases. Vitamin D. Physiology, Molecular Biology and Clinical Applications 2010; 2:New Jersey Humana Press Totowa 10431060 (Google Scholar),85 Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune response. Biochem Pharmacol 1991; 42:15691575 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) Serum half-life in rats was shown to be 4 min after treatment with calcipotriol in contrast to 15 min after treatment with calcitriol.84 Reichrath J, Holick MF. Holick MF. Clinical Utility of 1,25-dihydroxyvitamin D3 and its analogs for the treatment of psoriasis and other skin diseases. Vitamin D. Physiology, Molecular Biology and Clinical Applications 2010; 2:New Jersey Humana Press Totowa 10431060 (Google Scholar),85 Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune response. Biochem Pharmacol 1991; 42:15691575 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar) The rapid degradation of calcipotriol after systemic administration has limited its oral use but made it an ideal drug for topical use.

Other promising approaches are: (1) The creation of new synthetic compounds that are metabolized in the skin and therefore exert only little systemic side effects. Vitamin D analogs, obtained by a combination of the 20-methyl modification with biologically interesting artificial side chain subunits or 2β-substituted calcitriols are promising candidates.85 Binderup L, Latini S, Binderup E, Bretting C, Calverley M, Hansen K. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune response. Biochem Pharmacol 1991; 42:15691575 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)87 Schönecker B, Reichenbächer M, Gliesing S, Prousa R, Wittmann S, Breiter S, et al. Norman AW, Bouillon R, Thomasset M. 2β-substituted calcitriols and other A-ring substituted analogues—synthesis and biological results. Vitamin D. A pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications 1994; Berlin Walter de Gruyter 99100 (Google Scholar) (2) Enhancing the local concentration of calcitriol in the skin without generating systemic side effects via inhibiting the cutaneous activity of vitamin D metabolizing enzymes, i.e., various hydroxylases (catabolic D3-OHases, i.e., 24-hydroxylase (CYP24A1)) that are present in the skin and mediate the catabolism of calcitriol.88 Schuster I, Herzig G, Vorisek G. Norman AW, Bouillon R, Thomasset M. Steroidal hormones as modulators of vitamin D metabolism in human keratinocytes. Vitamin D. A pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications 1994; Berlin Walter de Gruyter 184185 (Google Scholar),89 Zhao J, Marcelis S, Tan BK, Verstuaf A, Boillon R. Norman AW, Bouillon R, Thomasset M. Potentialisation of vitamin D (analogues) by cytochrom P-450 enzyme inhibitors is analog- and cell-type sepcific. Vitamin D. A pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications 1994; Berlin Walter de Gruyter 9798 (Google Scholar) A well characterized inhibitor of CYP24A1 in the skin is ketoconazole.88 Schuster I, Herzig G, Vorisek G. Norman AW, Bouillon R, Thomasset M. Steroidal hormones as modulators of vitamin D metabolism in human keratinocytes. Vitamin D. A pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications 1994; Berlin Walter de Gruyter 184185 (Google Scholar),89 Zhao J, Marcelis S, Tan BK, Verstuaf A, Boillon R. Norman AW, Bouillon R, Thomasset M. Potentialisation of vitamin D (analogues) by cytochrom P-450 enzyme inhibitors is analog- and cell-type sepcific. Vitamin D. A pluripotent steroid hormone: structural studies, molecular endocrinology and clinical applications 1994; Berlin Walter de Gruyter 9798 (Google Scholar) It is a promising concept to enhance the concentration of endogeneous calcitriol locally in the skin by the topical application of these compounds without generating systemic side effects.

(3) The synthesis of new vitamin D analogs that activate different vitamin D signaling pathways and may induce strong effects on cell proliferation and differentiation in the target tissues skin or immune system, but only marginal effects on calcium metabolism via different affinities for the various homo- or heterodimers of VDR and nuclear cofactors including RXRα.90 Carlberg C, Bendik I, Wyss A, Meier E, Sturzenbecker LJ, Grippo JF, Hunziker W. Two nuclear signalling pathways for vitamin D. Nature 1993; 361:657660 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar),91 Schräder M, Müller KM, Becker-Andre M, Carlberg C. Response element selectivity for heterodimerization of vitamin D receptors with retinoic acid and retinoid X receptors. J Mol Endocrinol 1994; 12:327339 (Crossref), (PubMed), (Web of Science ®) , (Google Scholar)

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