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

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

VIT D RECEPTORS ROLE IN MAINTAINING NORMAL FOLLICULAR AND KERATINOCYTE FUNCTION

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)

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

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

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

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

VITILIGO

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

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

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

ASSOCIATIONS Thyroid dysfunction Other autoimmune disease Vitamin D deficiency

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

VITILIGO Study of 30 subjects (20 females, 10 males) between 18-45 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

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

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

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

ALOPECIA AREATA

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

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

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

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

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 16.6 +/-5.9ng/ml vs 40.5+/-5.7 in controls Calcium levels lower-decrease vit D leads to decreased calcium absorption from the GI

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

VITAMIN D AND PSORIASIS

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

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

TOPICAL VITAMIN D

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

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

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

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

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

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

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

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

SUNSCREEN AND VITAMIN D

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

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 1994-2014 Using sunscreen of SPF 30 daily reduces risk of SCC by 40%

INCIDENCE BCC 1976-1984 Rise of 145%

INCIDENCE OF SCC 2000-2010 Rise of 263%

INCIDENCE OF MM 1994-2014 Increased by 77%

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:10.1111/ijd.13857. 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 493213 http://dx.doi.org/10.1155/2014/493212 AlGhamdi K et al The Role of Vitamin D in Melanogensis with an Emphasis on Vitiligo Indian J Dermatol Venereol Leprol. 2013 Nov- Dex;79(6):750-8

REFERENCES Bhat YJ et al Vitamin D Level in Alopecia Areata Indian J Dermatol. 2017 Jul-Aug;62(4):407-410. 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):195-205 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):945-953. Searing DA et al Vitamin D in Atopic Dermatitis, Asthma and Allergic Disease Immunol Allergy Clin North Am. 2010 Aug; Aug(30): 397-409