PSORIASIS AND VITAMIN D

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Slide 1 : PSORIASIS AND VITAMIN D COMPILED BY: Ashok Kumar Sharma
Slide 2 : INTRODUCTION Vitamin D- discovered in 1922 by Edward Mellanby while researching a disease called rickets
Slide 3 : OVERVIEW Vitamin D - Physiology - Vitamin D Receptor - Biochemical Effects - Vitamin D Deficiency Psoriasis and Vitamin D Therapeutic Utility of Vitamin D for Psoriasis Vitamin D and Metabolic Syndrome Future concerns
Slide 4 : VITAMIN D PHYSIOLOGY Fat-soluble vitamin. Some prefer to call it a ‘hormone’ When human skin is exposed to UV irradiation (290–315 nm), 7-dehydrocholesterol, stored in the basal and suprabasal layers of skin, is photolyzed to form pre-vitamin D3, which is then thermoisomerized to vitamin D3 Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. Calcitriol Ergocalciferol
Slide 5 : VITAMIN D PHYSIOLOGY -Vitamin D, The ‘Hormone’ Calcitriol From Kidneys Target Cells (having vitamin D receptor) Circulation (Bound to Vitamin D Binding Protein)
Slide 6 : VITAMIN D PHYSIOLOGY -Vitamin D Receptor First indication of a Vitamin D Receptor (VDR)- 40 years ago (Haussler, M.; Norman, A.W. Chromosomal receptor for a vitamin D metabolite. Proc. Natl. Acad. Sci., 1969, 62, 155-162.) Took nearly further 20 years to clone the gene for the VDR and to characterize it as a nuclear receptor for Calcitriol (McDonnell, D.P.; Mangelsdorf, D.J.; Pike, J.W.; Haussler, M.R.; O´Malley, B.W. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science, 1987, 235, 1214-1217.)
Slide 7 : VITAMIN D PHYSIOLOGY -Vitamin D Receptor VDR is composed of a DBD (DNA-Binding Domain) and a LBD (Ligand Binding Domain), which are linked by a hinge region 1,25 D3 (Ligand) Binds Here Binds to DNA
Slide 8 : VITAMIN D PHYSIOLOGY -Vitamin D Receptor VDR – Nuclear Receptor Superfamily (48 Members) All physiological actions of calcitriol mediated via the gene regulatory actions of the VDR Conformational structure of VDR
Slide 9 : VITAMIN D PHYSIOLOGY -Gene Transcription in Nuclei of Target Cells VDR 1,25 D VDR 1,25 D RXR mRNA Protein Synthesis CELLULAR EFFECTS
Slide 10 : VITAMIN D PHYSIOLOGY -Gene Transcription in Nuclei of Target Cells Activated VDR Increased CYP27B Gene Expression Protein Production Immune inputs from Toll-like Receptors Protean Actions of Vitamin D Toll-like receptors are a type of surface and secretory molecules produced by keratinocytes
Slide 11 : VITAMIN D PHYSIOLOGY -Biochemical Effects Promotes Calcium absorption Proven to be much more than a simple “calcium hormone.” Vitamin D receptor has been found in cells not related to mineral metabolism
Slide 12 : VITAMIN D PHYSIOLOGY -Biochemical Effects Role in: Cellular proliferation Differentiation, Apoptosis, and Angiogenesis Neuromuscular and immune function, and Reduction of inflammation Immune regulatory hormone with beneficial effects on inflammatory diseases, mediated by helper T- lymphocytes type 1 (Th1) cells, such as diabetes, psoriasis, Crohn’s disease, and multiple sclerosis
Slide 13 : VITAMIN D Serum concentration of 25(OH)D is the best indicator of vitamin D status; practically all people are sufficient at levels =50 nmol/L (=20 ng/mL) Sources of Vitamin D (1) Sun Exposure (2)Foods: Natural and Fortified (3) Supplements
Slide 14 : VITAMIN D DEFICIENCY Deficiency- Epidemic proportions Reasons: -Lack of exposure to sunlight -Obesity (fat sequesters vitamin D) -Distance from equator -Increasing age Contributary Factors -Skin pigmentation
Slide 15 : VITAMIN D DEFICIENCY Deficiency related to: - Increased incidence of cancer - Autoimmune diseases - Infections (including TB) - Allergic diseases - Type 2 diabetes - Cardiovascular disease Vitamin D regulates cell growth Vitamin D modulates immune response by regulating activities of: T and B cells, Macrophages, Thymus gland Vitamin D deficiency has inflammatory effects
Slide 16 : PSORIASIS Psoriasis - common Th1-mediated inflammatory disease characterized by scaly plaques on the skin Also associated with: psoriatic arthritis, Crohn’s disease, diabetes mellitus (type 2), metabolic syndrome, depression, and cancer
Slide 17 : HOW LINK BETWEEN PSORIASIS AND VITAMIN D WAS DISCOVERED A chance observation: severe psoriasis in a patient improved after receiving Vit D for osteoporosis (A patient with psoriasis cured by 1 alpha-hydroxyvitamin D3. Med J Osaka Univ. 1985 Mar;35(3-4):51-4) Calcitriol inhibits proliferation and promotes differentiation of keratinocytes (Calcipotriol (MC 903), a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes. Arch Dermatol Res. 1990;282(3):164-7)
Slide 18 : PSORIASIS AND VITAMIN D How Vitamin D benefits Psoriasis? Mechanisms: 1)Mainly through Vitamin D Receptor (VDR) to regulate keratinocyte growth and differentiation (The main anti-proliferative effect of vitamin D on cells is a cell cycle block at the G1 phase) 2)Influence on immune functions of dendritic cells and Type 1 helper T lymphocytes: -inhibits production of interleukin (IL)-2 and IL-6, -blocks transcription of interferon-c and -granulocyte macrophage colony-stimulating factor mRNA -inhibits cytotoxic T cells and natural killer cell activity -downregulating Cutaneous Lymphocyte-associated antigen (CLA) responsible for skin T cell infiltration
Slide 19 : PSORIASIS AND VITAMIN D How Vitamin D benefits Psoriasis? Recent novel concept: By Controlling Antimicrobial Peptide/‘‘Alarmin’’Expression in Psoriasis A dysregulated interplay between keratinocytes and infiltrating immune cells underlies cutaneous inflammation in psoriasis (Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445: 866–873.) Resident/ Infiltrating Cells Keratinocytes Cytokines/ Soluble Antimicrobial Peptides (AMPs)
Slide 20 : PSORIASIS AND VITAMIN D AMPs-activators of adaptive immune responses and inflammation (Called ‘Alarmins’) AMPs- 2 families: the defensins , the cathelicidins Dysregulated expression of AMPs in psoriasis Psoriatic Plaques: IL-17A, IL-17F and IL-8 HBD2 and HBD3 cathelicidin Vit D Analogs As AMPs are directly involved in psoriasis pathogenesis, targeting AMP expression or function might be a promising approach in the treatment of cutaneous inflammation in psoriasis.
Slide 21 : PSORIASIS AND VITAMIN D How vitamin D might benefit psoriasis? - Another novel concept (Sci Transl Med. 2011 May 11;3(82):82ra38. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.) Increased Cytosolic DNA Increased DNA Sensor Associated With Inflammasomes Increased Proinflammatory Cytokines Cathelicidin Vitamin D Psoriatic Keratinocyte Inflammasomes are protein molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines
Slide 22 : PSORIASIS AND VITAMIN D Indirect evidence of the role of vitamin D in psoriasis: 1) coincidence of pustular psoriasis with hypocalcemia 2)exacerbation of psoriasis with chloroquin therapy [thereby reducing 1,25(OH)2D levels via inhibition of 1a-(OH)ase] 3)therapeutic efficacy of UV-B in psoriasis may be at least in part due to an increased cutaneous vitamin D synthesis (Arch Dermatol. 2010 Aug;146(8):836-42. The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland.)
Slide 23 : PSORIASIS AND VITAMIN D Is Vitamin D Deficiency more common in psoriasis patients (compared to healthy people)? A landmark study gives answer in the affirmative. Also vitamin D deficiency was associated with psoriasis independently of age, sex, body mass index, calcium, PTH levels and season of blood sampling. This deficiency increased in winter. (Vitamin D status in patients with chronic plaque psoriasis. Br J Dermatol.2012 Mar;166(3):505-10) Up to 75% of Irish patients with psoriasis were shown to have vitamin D insufficiency during wintertime. (Arch Dermatol. 2010 Aug;146(8):836-42. The effect of narrowband UV-B treatment for psoriasis on vitamin D status during wintertime in Ireland.)
Slide 24 : VITAMIN D IN THE TREATMENT OF PSORIASIS AND METABOLIC SYNDROME Psoriasis is a systemic immune-mediated inflammatory disease primarily involving Th1 cells. Metabolic Syndrome: metabolic abnormalities including -glucose intolerance, -insulin resistance, -central obesity, -dyslipidemia, and -Hypertension Metabolic syndrome is significantly increased in patients with psoriasis (about 30 % prevalence) Metabolic syndrome is accepted to be centered on insulin resistance and obesity
Slide 25 : VITAMIN D IN THE TREATMENT OF PSORIASIS AND METABOLIC SYNDROME Recent research suggests that vitamin D can improve metabolic syndrome -Obese patients show vitamin D deficiency; weight loss increases vitamin D levels -Hypovitaminosis patients have a higher risk of insulin resistance and metabolic syndrome -Serum triglycerides, waist circumference, and body mass index is inversely related to vitamin D levels -low vitamin D levels : increased incidence of cardiovascular events (Dermatol Res Pract.2011;2011:276079. Epub 2011 Jun 5. Systemic role for vitamin d in the treatment of psoriasis and metabolic syndrome)
Slide 26 : PSORIASIS AND VITAMIN D THERAPEUTIC USE (A) TOPICAL USE: Analogs reportedly effective: -Calcitriol- effective like calcipotriol but non irritant, -Calcipotriene (originally named Calcipotriol)- commonly used, mildly irritant -Tacalcitol- less effective, mildly irritant, and -Maxacalcitol- more effective than calcipotriol but induces severe burning sensation No Comparative Clinical Studies Between The Vitamin D Analogs
Slide 27 : PSORIASIS AND VITAMIN D ADVANTAGES OF TOPICAL VITAMIN D ANALOGS: Effective and safe for indefinite use Allow a ‘steroid-sparing’ effect Do not show tachyphylaxis Effective in the treatment of psoriatic skin lesions in children and in HIV-patients Efficacy of topical treatment with vitamin D analogs in psoriasis can also be increased by combination with other therapies: -Tumor necrosis factor a (TNFa)-inhibitors, -Methotrexate -Cyclosporine (low-dose oral- 2 mg/kg/day), -Acitretin (oral), -Dithranol (topical) -Steroids (topical) -Phototherapy
Slide 28 : PSORIASIS AND VITAMIN D THERAPEUTIC USE: (A) ORAL USE Very few studies have investigated the use of oral vitamin D in patients with psoriasis Oral Vitamin D effective (Safety and efficacy of oral calcitriol (1,25- dihydroxyvitamin D3) for the treatment of psoriasis. Br J Dermatol 1996; 134:1070–8. Treatment of psoriasis by oral calcitriol. Ann Dermatol Venereol 1994; 121:252.) 88% of 85 psoriasis patients treated with oral vitamin D had improvement in their psoriasis. Calcitriol given at night, along with limiting daily calcium intake. (“Safety and efficacy of oral calcitriol (1,25- dihydroxyvitamin D) for the treatment of psoriasis,” British Journal of Dermatology, vol. 134, no. 6, pp. 1070–1078, 1996.)
Slide 29 : PSORIASIS AND VITAMIN D Recent report- Resolution of adalimumab-induced psoriasis in a woman with RA after the use of high vitamin D doses for the treatment of vitamin D deficiency. (Resolution of adalimumab-induced psoriasis after vitamin D deficiency treatment. Rheumatol Int. 2011 Feb 3.)
Slide 30 : PSORIASIS AND VITAMIN D Why Oral/Parenteral preparations of Vitamin D are not used as much as the Topical preparations? Pharmacologic doses of oral Calcitriol produce substantial hypercalcemia and hypercalciuria thus limiting its use for dermatologic indications Main idea behind development of newer vitamin D coumpounds: Dissociation of beneficial cell- or immuneregulatory functions from undesired side effects on calcium metabolism. This goal was reached for very few compounds and some, such as calcipotriol , are on the market and others are in development Guiding Principle: Not those analogues are chosen that were the most potent in in vitro and in vivo assays, but those who showed in vivo the lowest calcemic potential. This selection is safe, but does not provide the most effective drug to the patient.
Slide 31 : PSORIASIS AND VITAMIN D Promising approaches towards discovering newer compounds: 1) Compounds metabolized in the skin only, exerting little systemic effects 2) Enhancing local concentration of compounds in the skin by inhibiting cutaneous activity of vitamin D metabolizing enzymes 3) Synthesis of compounds that differentially affect the skin or immune system, without affecting calcium metabolism
Slide 32 : PSORIASIS AND VITAMIN D More definitive evidence required to show that clinical benefit would be gained from vitamin D supplementation in patients with psoriasis in whom vitamin D is pathologically low Once detected, vitamin D deficiency could be corrected, although no evidence of the possible benefits of vitamin D supplementation in reducing inflammation and /or the risk of other incident autoimmune diseases has yet been proven (Does vitamin D affect risk of developing autoimmune disease?: a systematic review. Semin Arthritis Rheum 2011; 40:512–31)
Slide 33 : RECOMMENDATION TO MANAGE VITAMIN D DEFICIENCY Fanatic emphasis on sun avoidance in an effort to prevent skin cancer may risk increasing rates or severity of other diseases including other cancers: Colorectal, Breast, Ovarian and Prostate Given the above concerns, what is a responsible approach to balance the need for adequate vitamin D levels while minimizing the risk of skin cancer for the vast majority of our population? Recommendation: All people, especially individuals at high risk for vitamin D deficiency, get vitamin D safely through - a healthy diet that includes drinking milk, eating foods that are good sources of vitamin D (both natural and enriched), and -taking vitamin supplements if necessary. This recommendation is supported by the US Department of Health and Human Services and the US Department of Agriculture (Commentary: A responsible approach to maintaining adequate serum vitamin D levels. J Am Acad Dermatol. 2007 Oct;57(4):594-5)
Slide 34 : CONCLUSIONS The study of the role of vitamin D in overall health status has become, in the past few years, a very active area of investigation. Vitamin D effective in psoriasis It is one of the many agents available for psoriasis Vitamin D pathway is one of the many pathways behind pathogenesis of psoriasis A causal or temporal relationship between vitamin D deficiency and psoriasis yet to be established Whether correction of vitamin D level in a psoriasis patient showing low vitamin D level would lead to clinical improvement in psoriasis needs to be proven
Slide 35 : THANKS FOR A VERY PATIENT HEARING

 


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