1. Can unresponsiveness to nickel be induced by repeated nickel patch tests through infancy? Elisabeth S Christiansen¹, ², Klaus E Andersen ¹, Carsten Bindslev-Jensen ¹, Susanne Halken², Henrik F Kjaer², Esben Eller¹, Arne Høst², Charlotte G Mortz¹ 1. Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, DK-5000 Odense C, Denmark 2. Hans Christian Andersen Children’s Hospital, Odense University Hospital, University of Southern Denmark, DK-5000 Odense C, Denmark

2. Disclosure  In relation to this presentation, I declare that there are no conflicts of interest. June 2015

3.  65 million Europeans may be allergic to nickel  Nickel allergy: still the most common contact allergy both among children and adults  But can unresponsiveness to nickel be induced in humans? June 2015 Spiewak et al, 2007 Gang S et al, 2013, Background

4. What do we know about unresponsiveness?  Peroral nickel exposure can induce tolerance  A study from 1968 exposed human volunteers to dinitrochlorobenzene (DNCB) epicutaneously and concluded that it is possible to manipulate the level of contact sensitivity in man by manipulating the circumstances under which sensitization is induced  A study among workers in a cashew nut shell oil processing factory also suggested hyposensitization to poison ivy after working in the factory for several months June 2015 Lowney E, 1968, Reginella et al, 1989

5. The DARC cohort  The Danish Allergy Research Center (DARC) cohort is a prospective non-intervention birth cohort comprising 562 children born in 1998/99  Clinical examination and questionnaire was preformed at 0, 3, 6, 9, 12, 18, 36, 72 and 180 month (14 years)  Patch tested: Nickel sulphate 200 µg/cm² and fragrance mix I at 0, 3, 6, 12, 18 and 36 month.  At the 14 years follow-up investigation in 2013-14 all participants (372) were offered re-patch tests with TRUE Test® panel 1, 2 and 3 June 2015

6. The TOACS cohort  The Odense Adolescence Cohort Study (TOACS) established in 1995-1996 is a cross sectional study among 1501 eight grade school children (mean age 14 years) and including a questionnaire, clinical examination  Patch tests were performed on 1146 participants with TRUE Test® panel 1 and 2 June 20156

7. Prevalence of sensitization to nickel sulphate and fragrance mix I in the DARC and TOACS cohorts DARC TOACS Total n=249 Women n= 149 Men n=100 Total n=1146 Women n=620 Men n=526 Positive patch test to nickel sulphate 200 µg/cm² 1.2% (3)* 95% CI 0.25-3.47 2.0% (3)0 8.6% (98)* 95% CI 6.98-10.22 13.7 % (85)2.5% (13) Positive patch test to fragrance mix I 0001.8% (21) 1.6% (10) 2.1% (11) June 2015 7 * P<0.05

8. Prevalence of ear piercing, atopic dermatitis and hand eczema in the DARC and the TOACS cohorts DARC TOACS ParticipantsWomenMenParticipantsWomenMen Ear pierced ever (%, proportions) 50.2 (187/372) 86.2 (168/195) 10.7 (19/177) 50.8 (731/1438) 81.5 (581/713) 20.7 (150/725) Atopic dermatitis one- year period prevalence (%, proportions) 7.3 (27/372) 8.7 (17/195) 5.7 (10/177) 6.7 (90/1340) 7.7 (53/684) 5.6 (37/656) Hand ezcema lifetime prevalence (%, proportions) 4.8 (18/372)* 6.2 (12/195) 3.4 (6/177) 9.2 (133/1438)* 12.2 (87/713) 6.3 (46/725) June 2015 * P<0,05

9. Test year 1985-1990 % (number tested = 2103) 1991-1996 % (number tested = 2649) 1997-2001 % (number tested = 2688) 2002-2007 % (number tested = 2895) P trend (chi- square) Nickel allergy All age groups 17.9 (377)17.5 (464)18.6 (500)20.2 (586).01 5-30 y25.1 (149)22.8 (143)20.2 (116)18.3 (110).002 31-49 y19.6 (131)21.8 (186)25.6 (236)29.0 (287).001 ≥50 y11.5 (97)11.6 (135)12.4 (148)14.5 (189).02 June 2015 Patch test reactivity to nickel among 10,335 female patients with dermatitis tested at Glostrup hospital between 1985 and 2007 Thyssen et al, 2009

10. Nickel allergy is still frequent in young German females – probably because of insufficient protection from nickel ‐ releasing objects Schnuch et al. Contact Dermatitis Volume 64, Issue 3, pages 142-150, 27 JAN 2011 DOI: 10.1111/j.1600-0536.2010.01841.x http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0536.2010.01841.x/full#f1 Volume 64, Issue 3, http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0536.2010.01841.x/full#f1 June 2015

11.  A factor 7 difference in nickel patch test reactivity in the two cohorts could that be explained by the nickel regulation on its own?  We suggest that nickel unresponsiveness can be induced by repeated nickel patch tests in infancy June 201511 Conclusion

12. Thank you for your attention June 2015