VITAMIN D AND THE SKIN JOYCE FARAH MD MS FAAD FARAH DERMATOLOGY AND COSMETICS, LLC ASSISTANT PROFESSOR OF MEDICINE AND ENT UPSTATE MEDICAL UNIVERSITY

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1 VITAMIN D AND THE SKIN JOYCE FARAH MD MS FAAD FARAH DERMATOLOGY AND COSMETICS, LLC ASSISTANT PROFESSOR OF MEDICINE AND ENT UPSTATE MEDICAL UNIVERSITY

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3 VIT D RECEPTORS ROLE IN MAINTAINING NORMAL FOLLICULAR AND KERATINOCYTE FUNCTION

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6 Precursor 7- dehydrocholesterol in membranes of keratinocyes in basal and spinous layers UVB photochemical reaction forms pre cursor to vitamin D3 cholecalciferol Converted to 1,25- hydroxyvitamin D by CYP271A1 and CYP2R1 (Vit D alpha hydroxulase)

7 VITAMIN D 3 Has innate and adaptive immune response modulatory effects Influences inflammatory processes Effectiveness of vitamin D supplementation in several skin diseases-more evidence emerging Most studies are observational and case controlled

8 VITAMIN D AND THE SKIN Regulates keratinocyte Proliferation Differentiation Apoptosis Regulates cutaneous immune system Down regulates pro-inflammatory cytokines in the skin Stimulates anti-microbial peptides (innate immunity) Regulates skin barrier integrity and permeability

9 IMMUNE MODULATION Inhibits dendritic cell formation Reduces T cell activation Also regulated differentiation of T cells into TH1 and TH2 Inhibits Th1-interferon, IL-2 (activates macrophages) IL-17 and IL-22 Increases regulatory T cells-cd25+/cd4+ These T cells promote tolerance and inhibit immunity after antigen activation Modulates the expression of approx 200 genes

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13 SKIN MICROBIOME Directly affects the maturation of immune system Protects against pathogens Keeps balance between inflammation and homeostasis

14 VITILIGO

15 Destruction of melanocytes Depigmented macules or patches Can vary in size Symmetric distribution: face, upper chest, hands, ankles groin, around orifices Localized-segmental or focal Segmental Generalized or universal VITILIGO

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17 Destruction of normal melanocytes Intrinsic melanocyte defects Defective free radical scavenging Genetic predisposition Trauma Exposure to depigmenting chemicals In response to BRAF or PD- 1 inhibitors in setting of metastatic melanoma treatment ETIOLOGY

18 Flat lesions Usually no to minimal erythema No scaling No textural changes Affects up to 2% of population worldwide

19 ASSOCIATIONS Thyroid dysfunction Other autoimmune disease Vitamin D deficiency

20 VITAMIN D AND VITILIGO Immuno-suppressive effects Increases levels of tyrosinase in cultured melanocytes

21 VITILIGO Study of 30 subjects (20 females, 10 males) between years with >5% BSA Equal number of age and sex matches subjects recruited for vitamin D level controls Baseline levels measured in both groups and at 6 and 12 weeks in study group Subjects treated with NBUVB x3 days per week for 12 weeks

22 VITILIGO No study or control subject had normal vit D3 levels Vitiligo patients had significantly lower levels across the board At weeks 6 and 12-significant re-pigmentation and increase in vitamin D3 levels Non responders, despite NBUVB, had unchanged vit D3 levels

23 VITAMIN D Nuclear vitamin D receptor Topical application of vitamin D increased L-3,4- dihydroxyphenyalanine-positive melanocytes Topical application with NBUVB shows improved repigmentation Vit D also decreased various cytokines thought to be involved in vitiligo

24 COMPLIMENTARY AND ALTERNATIVE THERAPIES Supplementation with vitamins and antioxidants Alpha lipoic acid-bid dosing with vitamin E, cysteine plus NBUVB Ginko balboa Polypodium leucotomos-extract of a tropical fern combined with NBUVB

25 ALOPECIA AREATA

26 AA Autoimmune disease T cell infiltrates around anagen hairs CD4+ and CD8+ T cells cytokines Vitamin D modulates its action via CD4+ and CD8+ T cells-effector cells Defect in regulatory cells Immunologic, environmental, psychological and generic factors

27 AA Associations: RA DM Vitiligo SLE Thyroiditis Pemphigus vulgaris Pernicious anemia Celiac disease

28 Vit D receptor (VDR) expressed in papillary dermal mesenchymal cells Preservation of hair cycle Defects in VDR associated with reduce hair follicle growth VDR knock out mice have AT AA

29 AA Have lower levels of 25(OH)D and 1,25 (OH)D Mean higher values of parathyroid hormone

30 AA Hospital based cross sectional study 50 patients and 35 healthy age and sex matched controls Vit D 25(OH), parathyroid hormone, random BS and calcium measured in summer Deficiency defined as serum Vit D 25(OH) less than 30 ng/ml Mean serum 25(OH)D levels in AA /-5.9ng/ml vs 40.5+/-5.7 in controls Calcium levels lower-decrease vit D leads to decreased calcium absorption from the GI

31 CONCLUSION Negative correlation between severity of AA and vitamin D level Role for vitamin D in pathogenesis and therefore role for supplementation in treatment Further work on oral supplementation as well as topical therapy

32 VITAMIN D AND PSORIASIS

33 Chronic immune modulated inflammatory skin disease Hyper-proliferation of epidermis Mediated by inflammatory infiltrates 2-3% of population PSORIASIS

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37 PSORIASIS 1,25(OH)D shown to have anti-proliferative effects on keratinocytes IL-17 and IL-22 upregulate S100A7 levels (high in psoriasis)-vit D decreases these levels Association between VDR polymorphism and risk of psoriasis Decreased VDR expression decreases effectiveness of tight junctions-keratinocyte differentiation and proliferation recent studies demonstrate lower 1,25(OH)D levels in psoriatic patients vs controls

38 TOPICAL VITAMIN D

39 VITAMIN D SUPPLEMENTATION Accelarated loss from hyperproliferative epidermis Adjunctive therapy Modulation of psoriasis related co-morbidities

40 ATOPIC DERMATITIS AFFECTS APPROX 18 MILLION AMERICANS DISEASE OF BARRIER AND IMMUNOLOGIC DYSFUNCTION

41 VIT D AND ATOPIC DERMATITIS Helps regulate synthesis of glycosylceramides Needed in barrier and function and permeability of stratum corneum Increases synthesis of involucrin, transglutaminase, loricrin, and filaggrin in the stratum spinosum AMPs-cathelicidin and beta defensin have VDR Atopics vs psoriatics, dysfunction of above causes increased infections in atopics

42 ATOPIC DERMATITIS Acute phase is a Th2 response (IL-4 and IL-13) Chronic phase see a shift to Th1 (interferon gamma)

43 STUDIES Peroni et al found correlation between 25(OH)D levels and severity of atopic dermatitis

44 Oren et al found that there is a 5-fold increase in AD in vitamin D deficient patients

45 STUDIES 14 moderate to severe atopics- 4,000 IU/day for 21 days Biopsied skin lesionsincrease in cathelicidin expression

46 Double blind randomized control trial in children in winter Vit D 1000 IU/day for one month Basline global assessment in skin vs controls showed significant improvement STUDIES

47 SUNSCREEN AND VITAMIN D

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50 Clinical studies have not found that sunscreen use leads to deficiency In fact, in winter vitamin D levels are lower than in summer in same individual People who use sunscreen daily can maintain vitamin D levels Most people do not use sunscreen adequately All you need is 15 mintues of exposure

51 NMSC Screening for keratinocyte cancers at least once a year More patients diagnosed with skin cancer each year than all other cancers combined NMSC diagnosis increased by 77% between Using sunscreen of SPF 30 daily reduces risk of SCC by 40%

52 INCIDENCE BCC Rise of 145%

53 INCIDENCE OF SCC Rise of 263%

54 INCIDENCE OF MM Increased by 77%

55 REFERENCES Cho JM et al Association between atopic dermatitis and squamous call carcinoma: a case-controlled study [published online December 15, 2017]. Int J Dermatol. doi: /ijd Baum C et al Guideline of care for the management of basal cell carcinoma [published online January 2018] J Am Acad Dermatol Alam M et al Guideline for the management of cutaneous squamous cell caricnoma [published online January 10, 2018] J Am Acad Dermatol Sherawat M et al Correlation of Vitamin D Levles with Pigmentation in Vitiligo Patients Treated with NBUVB Therapy ISRN Dermatol Vol 2014, Article ID AlGhamdi K et al The Role of Vitamin D in Melanogensis with an Emphasis on Vitiligo Indian J Dermatol Venereol Leprol Nov- Dex;79(6):750-8

56 REFERENCES Bhat YJ et al Vitamin D Level in Alopecia Areata Indian J Dermatol Jul-Aug;62(4): Darwish, NMM et al. Serum Level of Vitamin D with alopecia areata. Egyp J of Basic Applies Sciences. March 2017;4(1):9-14 Barnea L et al. Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist Rev Endocr Metabl Disord. 2017; 18(2): Skin Cancer Foundation. Skin Cancer Facts and Statistics SkinCancer.org. decarvalho Mesquita K et al. Atopic dermatitis and vitamin D: Facts and controversies An Bras Dermatol 2013 Nov-Dec; 88(6): Searing DA et al Vitamin D in Atopic Dermatitis, Asthma and Allergic Disease Immunol Allergy Clin North Am Aug; Aug(30):