F036-Controversies in Vitamin D VITAMIN D AND ATOPIC DERMATITIS. Tissa Hata M.D. Professor, UCSD Department of Dermatology

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1 F036-Controversies in Vitamin D VITAMIN D AND ATOPIC DERMATITIS Tissa Hata M.D. Professor, UCSD Department of Dermatology

2 DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Tissa Hata M.D. F036-Controversies in Vitamin D DISCLOSURES GlaxoSmithKline-Investigator-Grants Galderma-Investigator-Grants Janssen-Investigator-Grants Abbvie-Advisory Board-Honoraria Bristol Myers Squibb-Investigator-Grants

3 ABNORMAL BARRIER IN ATOPIC DERMATITIS Altered lipid composition with decreased ceramides Decreased hydration with increased TEWL Decreased fillaggrin Normal skin Atopic Skin Clinics in Dermatology (2017) 35,

4 HBD-2 (µm in epidermis) LL-37 (µm in epidermis) Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY. (2002) N Engl J Med 347: Decreased expression of antimicrobial peptides in Atopics 3000 b-defensin (HBD-2) 3000 Cath (LL-37) AD Psoriasis AD Psoriasis

5 Could Vitamin D be the answer to Atopic dermatitis?

6 Vitamin D polymorphisms and Atopic Dermatitis A rare variant in CYP27A1 and its association with atopic dermatitis with high serum total IgE. Suzuki H, Makino Y, Nagata M, Furuta J, Enomoto H, Hirota T, Tamari M, Noguchi E. Allergy Oct;71(10): Vitamin D Receptor Gene BSMI, FOKI, APAI, and TAQI Polymorphisms and the Risk of Atopic Dermatitis. Kılıç S, Sılan F, Hız MM, Işık S, Ögretmen Z, Özdemir Ö. J Investig Allergol Clin Immunol. 2016;26(2): A Promoter Polymorphism of the Vitamin D Metabolism Gene Cyp24a1 is Associated with Severe Atopic Dermatitis in Adults.Hallau J, Hamann L, Schumann RR, Worm M, Heine G. Acta Derm Venereol Feb;96(2): Association of vitamin D receptor gene polymorphisms with severe atopic dermatitis in adults. Heine G, Hoefer N, Franke A, Nöthling U, Schumann RR, Hamann L, Worm M. Br J Dermatol Apr;168(4):855-8

7 Vitamin D has many functions! Muehleisen B1, Gallo RL. Vitamin D in allergic disease: shedding light on a complex problem. J Allergy Clin Immunol Feb;131(2): doi: /j.jaci

8 Vitamin D Functions for the Barrier Functions in skin barrier Promotes keratinocyte differentiation Increases synthesis of barrier proteins involucrin,transglutaminase, loricrin and filaggrin Increases lipid content of barrier by processing of long chain glycosylceramides and transport into lamellar bodies Skin Pharmacol Physiol 2018;31:74 86

9 VDRE found in the promotor of cathelicidin gene (CAMP) Addition of 1,25(OH)2D3 to human keratinocytes induces cathelicidin production

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11 Vitamin D does possess many functions beneficial to our AD patients Are lower levels of vitamin D associated with AD or AD severity?

12 Study No. of subjects 25 OHD and AD 25 OHD and AD severity Peroni DG. Br J Dermatol May;164(5): children with AD, Verona Italy Yes Kanda N. Allergy Jun;67(6): patients with 12 AD and 27 age matched controls in Japan YES Akan A. Pediatr Dermatol May- Jun;30(3): children with AD +/- sensitization Ankara Turkey Yes with + sensitization No with - sensitization Samochoki Z. J. Am. Acad. Dermatol. 2013, 69, Adults age with AD, 58 control in Poland No No Chiu YE. J Am Acad Dermatol Jul;69(1): subjects with AD age 1-18 from Wisconsin Dermatology No El Taieb. Dermatitis Nov- Dec;24(6): patient with AD between 2-12 and 30 controls from Egypt Yes Yes Wang SS. Pediatr Allergy Immunol Feb;25(1): AD children and 328 non allergic controls from Hong Kong Yes Yes Cheng HM. J Allergy Clin Immunol Apr;133(4) 15,212 adults 19 years or older, 392 with AD Korea Yes DiFilippo P. Int Arch Allergy Immunol. 2015;166(2): children with AD and 20 controls in Chieti Italy No

13 Study No. of subjects 25OHD and AD 25OHD and AD severity Baek J. J Pediatr Oct;165(4): infants with atopic dermatitis, Korea Yes Noh S. J Allergy Clin Immunol Jun;133(6): e6. 82 subjects with AD, 49 control in Korea No Cheon BR. Korean J Pediatr Mar;58(3): children with AD and 32 control in Korea Yes Yes Barman M. Acta Paediatr Apr;104(4): year olds, 55 with AD and 55 healthy in Sweden No Han TY, Ann Dermatol Feb;27(1):10-4 Thuesen BH, Allergy Nov;70(11): (39 adults and 33 children)with AD and 140 healthy in Korea 2308 adult participants, mean age 49, 230 with AD in Denmark Yes in children No in adults No Robl, Pediatr Dermatol 2016 May;33(3): children younger than 14 years with AD in Brazil No Berents TL Br J Dermatol Jul;175(1): children with AD in Norway, mean age 5.1 months, 240 healthy in Norway Byun EJ BMJ Open Jul 10;7(7):e between years, 250 with AD in Korea No No

14 7 observational studies (906 AD patients vs 657 controls)

15 Kim MJ1, Kim SN2, Lee YW3,4, Choe YB5,6, Ahn KJ. Vitamin D Status and Efficacy of Vitamin D Supplementation in Atopic Dermatitis: A Systematic Review and Meta-Analysis. Nutrients Dec 3;8(12).

16 Kim MJ1, Kim SN2, Lee YW3,4, Choe YB5,6, Ahn KJ. Vitamin D Status and Efficacy of Vitamin D Supplementation in Atopic Dermatitis: A Systematic Review and Meta-Analysis. Nutrients Dec 3;8(12).

17 Kim MJ1, Kim SN2, Lee YW3,4, Choe YB5,6, Ahn KJ. Vitamin D Status and Efficacy of Vitamin D Supplementation in Atopic Dermatitis: A Systematic Review and Meta-Analysis. Nutrients Dec 3;8(12).

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19 Database from for Randomized Controlled Trials

20 Study Study design Amestejani 2012[3] RCT Di Filippo, 2015[13] CT Byremo 2006[9] RCT Camargo 2014[20] RCT Hata 2014[21] RCT Javanbakht, 2011[22] RCT Norizoe, 2014[23] RCT No. of subjects vs. control Mean age of subjects (±SD) 30 vs ± vs ± vs (range 3 13) 58 vs ± 5 30 vs ± vs ± vs ± 5.13 Intervention type duration source Main outcome 1600 IU Cholecalciferol 8 wk, Oral SCORAD Mean change[experimental, control] [ 9.5 ± 3.7, 1.8 ± 4.8] P value 1000 IU cholecalciferol 2 wkoral SCORAD ± 15.48, NR <0.001 Sun exposure in Canary Islands [ 16.0 ± 18.5, verses Norway SCORAD 6.2 ± 17.4] < IUCholecalciferol 4 wk Oral EASI 4000 IU Cholecalciferol 3 wk Oral 25(OH)D IUCholecalciferol 8 wk Oral SCORAD 0.01 [ 6.5 ± ± 7.6] 0.04 [9.4 ± 11.23, 9.4 ± 12.43] < ± ± 10.9 NR 800 IU Cholecalciferol 6 wkoral SCORAD 4.75 ± 7.49, 3.95 ± Sidbury, 2008[08] RCT Hata 2008[12] CT 5 vs IU median 7 (range 2 13) Ergocalciferol 4 wk, Oral EASI [ 4.6 ± NR, 2.2 ± NR] vs. 14 NR 4000 IUCholecalciferol 3 wk, Oral Cathelicidin [20.38 RCU, 0.78 RCU] <0.01

21 Supplementation shows a statistically significant decrease in severity of AD symptoms

22 Supplementation with vitamin D may improve AD, but numbers very small from the meta-analysis

23 Serum vitamin D status in adult patients with atopic dermatitis: Recommendations for daily practice Study from University Medical Center Utrecht between 3/13-3/14 of adult atopic patients Divided as difficult to treat on immunosuppressives, or on topical steroids 210 total subjects JAAD Volume 75, Issue 6, Pages (December 2016) DOI: /j.jaad

24 JAAD Volume 75, Issue 6, Pages (December 2016) DOI: /j.jaad

25 Fig 1 Distribution of vitamin D status different by treatment status Patients with difficult to treat AD had increased proportion of vitamin D deficiency Check vitamin D status in our difficult to treat patients JAAD Volume 75, Issue 6, Pages (December 2016) DOI: /j.jaad Journal of the American Academy of Dermatology , DOI: ( /j.jaad )

26 Mendelian randomization uses genetic associations to assess disease risks UK Biobank resource and from the SUNLIGHT(vitamin D), GABRIEL(asthma) and EAGLE (eczema) consortia. Identified 33,996 individuals strongly associated with 25-hydroxyvitamin D (25OHD) polymorphisms MR studies estimated the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses PLoS Med May 9;14(5):e

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28 Conclusions for vitamin D and Atopic Dermatitis The controversy continues! Further studies still need to be performed to see if vitamin D can improve the manifestations of AD