Xerosis is Associated with Atopic Dermatitis, Hand Eczema and Contact Sensitization Independent of Filaggrin Gene Mutations

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1 Act Derm Venereol 2013; 93: INVESTIGATIVE REPORT Xerosis is Associted with Atopic Dermtitis, Hnd Eczem nd Contct Sensitiztion Independent of Filggrin Gene Muttions Jcob P. Thyssen 1, Jenne D. Johnsen 1, Clus Zchrie 2, Torkil Menné 2 nd Alln Linneberg 3 1 Ntionl Allergy Reserch Centre, 2 Deprtment of Dermto-Allergology, Copenhgen University Hospitl Gentofte, Hellerup, nd 3 Reserch Centre for Prevention nd Helth, Copenhgen University Hospitl Glostrup, Glostrup, Denmrk Atopic dermtitis, hnd eczem nd contct sensitiztion re prevlent disorders, nd my, in mny cses, be secondry to skin brrier bnormlity. The im of this study ws to investigte the ssocition between selfreported generlized xerosis, topic dermtitis, hnd eczem nd contct sensitiztion, tking filggrin gene muttions into ccount. Questionnire dt were collected from cross-sectionl study performed in generl popultion in Copenhgen. A totl of 3, yerolds were ptch-tested nd 3,335 were genotyped for the 2282del4 nd R501X muttions in the filggrin gene. nd hnd eczem were significntly ssocited with generlized xerosis, wheres contct sensitiztion (not nickel showed only borderline significnt ssocition. These results suggest tht generlized xerosis my increse the risk of common skin disorders. Key words: xerosis; topic dermtitis; hnd eczem; contct sensitiztion; generl popultion; epidemiology. Accepted Oct 18, 2012; Epub hed of print Feb 18, 2013 Act Derm Venereol 2013; 93: Jcob Pontoppidn Thyssen, Ntionl Allergy Reserch Centre, Deprtment of Dermto-Allergology, Copenhgen University Hospitl Gentofte, University of Copenhgen, Niels Andersens Vej 65, DK-2900 Hellerup, Denmrk. E-mil: jcob.p.thyssen@regionh.dk Xerosis is chrcterized by skin tht is dehydrted, displys slight-to-severe flking nd scling, hs fine lines nd crcks, nd which my show redness. The prevlence of self-reported xerosis ws 6.2% in yer-old Norwegins (1. In mixed popultion of Chinese controls (n = 312 nd ptients with coronry hert disese (n =224, men ges 56 nd 69 yers, respectively, xerosis ws observed in 46 47%. Futhermore, generlized xerosis ws found in 19.2% nd 7.6%, respectively, with men of 14% (2. Cuses of xerosis include environmentl exposures (e.g. ultrviolet (UV light, cold climte, indoor heting, excessive bthing, nd use of sops, non-cutneous disese (e.g. thyroid nd hemtologicl disorders, drug use (e.g. cimetidine nd hypocholesterol gents, skin inflmmtion nd genetic predisposition (e.g. common filggrin gene (FLG muttions (3, 4. In elderly ptients, risk fctors include incresing ge, femle gender, tretments tht cn potentilly cuse xerosis, sweting, nd history of topic dermtitis (AD (5. AD, hnd eczem nd contct sensitiztion re chr c - terized by complexity nd multi-fctoril pthogenesis. A strong ssocition ws recently identified between AD nd muttions in the FLG (6, 7, wheres moderte ssocition ws found with genetic vritions in the cludin 1 gene (encoding epiderml tight junctions in minly Africn Americns (8, supporting the notion tht skin inflmmtion is often secondry to skin brrier bnormlity (9. Although genetic risk fctors for hnd eczem nd contct sensitiztion re not yet well-chrcterized, nd re expected to ply more modest role for the pthogenesis, they include FLG muttions nd polymorphisms in detoxifiction systems nd immunologicl pthwys (4, Whether xerotic skin increses the risk of hnd eczem nd contct sensitiztion hs been little-investigted, wheres the ssocition between AD nd xerosis is wellestblished. We hypothesize tht generlized xerosis, whether cquired or inherited, my increse the risk of common skin disorders, including AD, hnd eczem nd contct sensitiztion. We present here, for the first time, ssocition estimtes between generlized xerosis nd common skin disorders djusted for common FLG muttions. MATERIALS AND METHODS Study popultion During , cross-sectionl study ws performed in the generl popultion in Copenhgen. Of 7,931 rndomly invited dult Dnes born in Denmrk nd ged yers, 3,471 (43.7% prticipted in generl helth exmintion, nd 3,335 (96.1% were successfully FLG genotyped for R501X nd 2282del4. For study detils, plese refer to previous publictions (13. The ethics committee of Copenhgen County pproved the study (KA A written informed consent form ws obtined from ll prticipnts prior to the beginning of the study. Questionnire Prticipnts were sked bout generl helth, lifestyle, nd socioeconomic fctors. Before the questions on eczem, description ws provided: Eczem is n itching skin disorder showing redness, dryness, nd possibly vesicles nd exudtion. Eczem is present t the sme re for some time. Prticipnts were sked: Hve you 2013 The Authors. doi: / Journl Compiltion 2013 Act Dermto-Venereologic. ISSN

2 Xerosis nd common skin diseses 407 ever hd hnd eczem?. Prticipnts who gve n ffirmtive nswer were further sked: Hve you hd hnd eczem within the pst 12 months?, At wht ge did you hve hnd eczem on the first occurrence? (< 6, 6 14, 15 18, nd > 18 yers, How often hve you suffered from hnd eczem? (only 1 time (< 2 weeks, only 1 time (> 2 weeks, severl times, nerly ll the time. Prticipnts were lso sked: Hs your doctor ever told you tht you suffered from AD?, Hve you ever hd dry skin ll over your body? nd Hve you ever hd dry skin ll over your body within the pst 12 months?. An ffirmtive nswer ws used to crete the vrible generlized xerosis ever nd generlized xerosis within pst 12 months. Filggrin genotyping Regions covering the muttions R501X nd 2282del4 of the FLG were mplified from genomic DNA by PCR, nd the DNA frgments obtined were hybridized to both muttion-specific nd wild-type-specific DNA-probes ttched to microbeds. Hybridiztion ws detected in Bio-Plex 200 device nd genotypes derived from detection dt. The genotyping method ws recently described in detil (14. Ptch-tests Ptch-testing ws performed by using the pnel 1 nd 2 of the stndrdized redy to pply TRUE-test (Mekos Lbortories, Hillerød, Denmrk. Ptch-test redings were crried out on dy 2. For detils plese refer to our previous publiction (15. Since nickel exposure is often ssocited with skin penetrtion, e.g. er nd body-piercing, we used contct sensitiztion vrible without nickel llergy to prevent potentil confounding by exposures where the skin comprtments hd been by-pssed (16. Mesurement of immunoglobulin E ntibodies Venous blood ws tken on the dy of exmintion. Serum ws collected fter centrifugtion t 3,000 r.p.m. for 10 min nd stored frozen until nlysis for IgE specific to birch, grss (timothy, ct, nd mite (Dermtophgoides pteronyssinus with the ADVIA Centur IgE ntibody ssy system (Siemens, Deerfield, IL, USA (17. The nlysis ws judged to be positive if the mesurement exceeded 0.35 ku/l for t lest one of the 4 llergens tested. Sttisticl nlysis Chrcteristics of prticipnts were compred using the χ 2 test. Logistic regression models were used for ssocition testing. In these models, tests for interctions were performed by using log-likelihood rtio test. FLG muttion sttus ws defined s subjects who were heterozygote, compound heterozygote or homozygote for the muttions R501X or 2282del4. Dt nlyses were performed using the Sttisticl Products nd Service Solutions pckge (SPSS Inc., Chicgo, IL, USA for Windows (relese Odds rtios (OR nd 95% confidence intervls (CI were given. Tble I. The prevlence of universl xerotic skin t some point in life strtified by popultion chrcteristics Totl Crude odds rtio (95% confidence intervl Sex Men 44.7 (1,491/3, (137/1,462 1 (ref Women 55.3 (1,844/3, (350/1, ( Age yers 18.7 (624/3, (99/612 1 (ref yers 48.4 (1,615/3, (234/1, ( yers 32.9 (1,096/3, (154/1, ( No 13.0 (392/3,018 1 (ref Yes 5.5 (178/3, (80/ ( Filggrin gene muttion (FLG No 13.0 (389/3,001 1 (ref Yes 8.1 (269/3, (98/ ( No 14.5 (452/3,114 1 (ref Yes 4.6 (154/3, (35/ ( No 11.8 (301/2,542 1 (ref Yes 21.5 (716/3, (184/ ( No 25.5 (96/377 1 (ref 0.67 Yes 9.9 (329/3, (87/ ( Age t first onset of hnd eczem < 6 yers 1.2 (39/ (20/39 1 (ref yers 2.5 (82/ (29/ ( yers 2.6 (88/ (30/ ( > 18 yers 15.2 (506/ (103/ ( Hnd eczem persistence One time only (< 2 weeks durtion 1.9 (63/ (44/172 1 (ref One time only (> 2 weeks 11.8 (393/ (15/ ( Severl times 2.2 (72/ (105/ ( Nerly ll the time 5.2 (175/ (17/ ( An ffirmtive nswer to the question, Hs doctor ever informed you tht you suffered from topic dermtitis?. b An ffirmtive nswer to the question, Hve you ever hd hnd eczem?. p-vlue

3 408 J. P. Thyssen et l. RESULTS The overll prevlence of AD ws 5.5% (177/3,040. In individuls with positive or negtive specific IgE, the prevlence of AD ws 9.4% (70/678 nd 4.3% (107/2,362, respectively (p < 0.001, supporting the vlidity of self-reported AD in this cohort. We lso found tht AD nd hnd eczem ever were strongly ssocited. Hence, the prevlence of hnd eczem ws 53.4% (93/174 nd 19.8% (603/3,046 in individuls with nd without AD (p < 0.001, respectively. The overll prevlence of self-reported generlized xerosis t some point in life nd within the pst 12 months were 14.6% (487/3,265 nd 10.4% (338/3,265, respectively. Study popultion chrcteristics strtified by generlized xerosis re shown in Tble I. Crude dt nlysis showed tht xerosis ws significntly ssocited with femle gender, AD, FLG muttions, hnd eczem ever, nd contct sensitiztion. The R501X nd 2282del4 muttions were successfully genotyped for 99.4% nd 99.5% of the prticipnts. The observed genotype frequencies of the 2 FLG polymorphisms did not devite significntly from the expected frequencies under ssumption of Hrdy- Weinberg equilibrium in ny of the study popultions (p > 0.05.The prevlence of FLG muttions in different subgroups is presented in Tble II. The overll prevlence ws 8.1% (269/3,335. In crude dt nlysis, FLG muttions were strongly ssocited with AD nd xerosis ever nd modertely ssocited with hnd eczem nd contct sensitiztion. In individuls with generlized xerosis t some point, the strongest ssocition ws found with hnd eczem within the pst 12 months, wheres non-significnt ssocitions were found with AD nd contct sensitiztion. The ttributble risks (AR of reporting generlized xerosis for the dignosis of AD, hnd eczem nd contct sensitiztion (not nickel were 13%, 19% nd 3%, respectively. In djusted logistic regression nlyses, hnd eczem nd AD were significntly ssocited with generlized xerosis (Tble III. A regression nlysis restricted to individuls without AD, nd with hnd eczem ever s the dependent vrible nd the explntory vribles s described in Tble III, showed similr positive nd significnt ssocition with generlized xerosis (the OR ws 2.21; 95% CI Moreover, borderlinesignificnt ssocition with contct sensitiztion ws found, the OR being 1.46 (95% CI Subgroup nlysis restricted to individuls without self-reported AD did not chnge the ssocition estimte (the OR ws 1.41; 95% CI Further nlysis showed tht the ssocition with contct senstiztion ws driven minly by chemicls used in topicl products (dt not shown. Hnd eczem within the pst 12 months ws lso positively ssocited with generlized xerosis Tble II. Prevlence of filggrin gene muttions in different sub groups FLG muttions Crude OR (95% CI p-vlue All 8.1 (269/3,335 No 7.4 (228/3, Yes 19.7 (35/ ( Contct sensitiztion No 7.8 (249/3, Yes 13.0 (20/ ( No 7.5 (193/2, Yes 9.9 (71/ ( No 8.1 (31/ Yes 12.2 (40/ ( No 6.0 (166/2, Yes 20.1 (98/ ( Generlized xerosis within pst 12 months No 12.7 (20/ Yes 22.5 (76/ ( All individuls with generlized xerosis No 17.6 (46/ Yes 23.6 (49/ ( Contct sensitiztion No 19.2 (87/ Yes 31.4 (11/ ( No 19.3 (58/ Yes 21.2 (39/ ( No 13.5 (13/96 1 Yes 29.9 (26/ ( Generlized xerosis within pst 12 months No 13.7 (18/131 1 Yes 22.8 (76/ ( An ffirmtive nswer to the question, Hs doctor ever informed you tht you suffered from topic dermtitis?. b An ffirmtive nswer to the question, Hve you ever hd hnd eczem?. OR: odds rtio; CI: confidence intervl. within the pst 12 months (djusted OR 1.66; 95% CI While the ssocition estimtes between xerosis nd hnd eczem nd contct sensitiztion, respectively, were similr in FLG muttion nd nonmuttion crriers, slightly stronger ssocition ws observed between xerosis pst 12 months nd hnd eczem within the pst 12 months mong FLG muttion crriers (OR 2.67; 95% CI vs. OR 1.47; 95% CI Also, slightly stronger ssocition ws observed between AD nd xerosis mong FLG muttion crriers (OR 7.27; 95% CI vs. OR 4.45; 95% CI ; however, the interction term ws non-significnt (p In similr djusted logistic regression nlysis with generlized xerosis s the dependent vrible, n ssocition with onset of hnd eczem before 6 yers (OR 2.23; 95% CI , t ge 6 14 yers (OR 1.78; 95% CI , nd t ge yers (OR 1.55; 95% CI ws shown. No significnt reltionship ws however shown between

4 Xerosis nd common skin diseses 409 Tble III. Logistic regression nlyses showing the ssocition between topic dermtitis, hnd eczem, nd contct sensitiztion, respectively, nd dry skin Explntory vribles n = 3,193 Adjusted OR (95% CI c n = 3,174 Adjusted OR (95% CI c n = 3,193 Adjusted OR (95% CI c No 1 (ref 1 (ref 1 (ref Yes 4.82 ( ( ( Sex Mle 1 (ref 1 (ref 1 (ref Femle 1.28 ( ( ( Age yers 1 (ref 1 (ref 1 (ref yers 0.75 ( ( ( yers 0.25 ( ( ( Filggrin muttions No 1 (ref 1 (ref 1 (ref Yes 1.91 ( ( ( No 1 (ref 1 (ref Yes 2.02 ( ( Atopic dermtitis No 1 (ref 1 (ref Yes 3.48 ( ( An ffirmtive nswer to the question, Hs doctor ever informed you tht you suffered from topic dermtitis?. b An ffirmtive nswer to the question, Hve you ever hd hnd eczem?. c Logistic regression nlysis mutully djusted for shown vribles. OR: odds rtio; CI: confidence intervl generlized xerosis nd hnd eczem persistence, lbeit the reltionship ws positive. Finlly, xerosis within the pst 12 months ws positively ssocited with these vribles (dt not shown. No differences were observed when strtifiction by sex ws performed. DISCUSSION Generlized xerosis ws positively ssocited with AD, hnd eczem nd contct sensitiztion in n dult generl popultion. While it is possible tht xerosis followed primry skin inflmmtion, we find it more likely tht xerosis cme first s, for exmple, xillry llergic contct dermtitis to frgrnces, mild AD in the elbow flexures, nd hnd eczem re loclized conditions nd therefore unlikely to cuse generlized xerosis. Also, previous studies hve suggested tht xerosis is risk fctor for hnd eczem, t lest in individuls with AD (18, 19. The ssocition with contct sensitiztion could be cused by frequent ppliction of topicl products contining contct llergens, e.g. to tret xerotic or inflmed skin s indicted by recent study (16. However, it should be cknowledged tht the ssocition with contct sensitiztion ws only borderline significnt in crude nd djusted nlyses nd tht it could be result of rndom error. Although FLG muttions re ssocited with xerosis (3, 4, AD, hnd eczem, nd contct sensitiztion (4, 11, 20, xerosis remined positively ssocited with these disorder despite djustment for FLG muttions. The FLG shows intrgenic copy number vrition with lleles encoding 10, 11 or 12 filggrin monomers (21. Since low copy number hs been ssocited with AD independently of FLG muttions nd is probbly due to lower levels of filggrin metbolites (the nturl moisturizing fctor (21, it is possible tht FLG copy number vrition lso my ffect the risk of developing hnd eczem nd contct sensitiztion. Tken together, our results support the hypothesis tht xerotic skin my be n independent risk fctor for common eczemtous skin disorders. Study weknesses include low prticiption rte, possibly resulting in selection bis. However, the study ws 2-hour generl helth exmintion with brod focus on helth where no skin exmintion ws provided besides ptch testing. Hence, we do not expect tht we selected individuls with skin diseses in prticulr for this study. The question on hnd eczem within the pst 12 months hs been vlidted, showing high specificity (22. While none of the remining questions hve been vlidted, the positive ssocition between AD nd specific IgE supports its use in this study. Since we only performed genotyping for the 2 most common muttions in the FLG covering bout 80% of known muttions (23, misclssifiction my hve ffected our results. Also, our study ws restricted to Dnes born in Denmrk nd the results cn therefore not be generlized. We re not wre of ny published studies tht hve investigted genetic risk fctors for xerosis besides the FLG muttions. Genetic discovery studies re wrrnted to identify muttions tht re ssocited with xerosis. Ultimtely, these my lso increse the risk of AD, hnd eczem nd contct sensitiztion. It is cknowledged tht proportion of the genetic contribution to these common skin diseses hs not yet been identified, mking such

5 410 J. P. Thyssen et l. n ttempt worthwhile. For hnd eczem, the genetic influence is moderte, nd it ws recently shown tht the heritbility ws not explined by co-morbidity with AD (24. For contct sensitiztion, the heritbility is suspected to be moderte to low (12, 25, lthough twin studies hve focused minly on nickel sensitiztion. For AD, the estimted heritbility is high, t 71 84% (26. Studies re currently investigting whether the use of moisturizers cn prevent the development of AD nd topic disorders. While we re witing the outcome of these studies, it should be emphsized tht low-llergenic formultions used to tret xerosis should be recommended to void contct sensitiztion. ACKNOWLEDGEMENTS Funding sources: The Leo Phrm Reserch Foundtion, The Else nd Mogens Wedell-Wedellsborgs Foundtion, the Jcob Mdsen og hustrus Olg Mdsens Foundtion, the Gerhrd Brøndsteds trvel grnt nd the Dnish physicins insurnce under Codn/SEB Pension re thnked for their unrestricted finncil support of Jcob Thyssens slry. The Dnish Bord of Helth, The Dnish Environmentl Protection Agency, The Copenhgen County Reserch Foundtion, The Velux Foundtion, Denmrk nd The Dnish Scientific Reserch Council re thnked for supporting the study. Furthermore, MEKOS Lbortories, Denmrk kindly donted some of the TRUE tests. Study sponsors hd no role in the design, collection or interprettion of dt. The uthors declre no conflicts of interest. REFERENCES 1. Dlgrd F, Svensson A, Holm JO, Sundby J. Self-reported skin morbidity in Oslo. Associtions with sociodemogrphic fctors mong dults in cross-sectionl study. Br J Dermtol 2004; 151: Guo J, Li LF. Prevlence of xerosis in ptients with coronry hert disese. 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