Classification of atopic hand eczema and the filaggrin ... - copsac

Contact Dermatitis 2008: 59: 257–260Printed in Singapore. All rights reserved# 2008 The AuthorsJournal compilation # 2008 Blackwell MunksgaardCONTACT DERMATITISReview ArticleClassification of atopic hand eczema andthe filaggrin mutationsCHARLOTTE GIWERCMAN 1 ,ANNE LERBAEK 1 ,HANS BISGAARD 2 AND TORKIL MENNE´11 Department of Dermatology, and 2 Danish Pediatric Asthma Centre, Copenhagen UniversityHospital Gentofte, DK-2900 Hellerup, DenmarkHand eczema is a common disease with various risk factors of which atopic dermatitis is known to beone of the most important. Recently, two mutations in the gene coding for filaggrin, a proteinimportant for the skin barrier, have repeatedly been shown to be associated with atopic dermatitis.Moreover, one study point towards an association between the filaggrin null alleles and the subgroupof patients having both hand eczema and atopic dermatitis. For the remainder of hand eczemapatients, still unknown genetic risk factors exist. We propose that in future, classification of atopichand eczema should distinguish between patients with and without the filaggrin null alleles and tofurther differentiate between associations with type I allergy, type IV allergy and exposure to irritants,respectively. Furthermore, we suggest future studies of atopic hand eczema to analyse for thefilaggrin mutations. We believe this will increase the possibility of subgrouping this otherwise heterogenicdisease and thereby enable a better phenotype–genotype characterization of hand eczema.This could improve the preventive initiatives, secure better information of patients about the prognosisfor their disease, and possibly enable targeted treatment.Key words: atopic dermatitis; classification; contact allergy; filaggrin mutation; hand eczema.# Blackwell Munksgaard, 2008.Accepted for publication 23 May 2008Filaggrin is a protein essential for aggregating keratinfilaments, which lead to keratinocyte compactionand formation of the stratum corneum.Profilaggrin, the precursor of filaggrin, is locatedin the keratohyalin granules in the granular layer ofthe epidermis. The formation of the cornified cellenvelope is crucial for the skin barrier function as itprevents epidermal water loss and penetration ofinfectious agents, toxic chemicals, and allergens (1).Two polymorphisms in the filaggrin gene,R501X and 2282del4, both result in a loss of functionof the filaggrin protein. Homozygotes orcompound heterozygotes for the genetic variantshave a total loss of filaggrin products and thereforea dry, scaly skin (ichthyosis vulgaris), whereasheterozygotes present with a milder form or withoutsymptoms at all (2). The two loss-of-functiongenetic variants in the filaggrin gene were recentlyidentified as major predisposing factors for atopiceczema (3), an association confirmed by severalstudies (4–6). No genetic markers for hand eczemahave yet been identified and only a few studiespublished so far have investigated a possible relationshipbetween the filaggrin loss-of-functionmutations and the development of hand eczemaand/or contact allergy (7–9).Hand eczema is a common disease often knownto have a chronic relapsing course. Risk factorsinclude atopic dermatitis and exposure to allergensand irritants (10, 11). A twin study has shownthat genetic factors influence the risk of developinghand eczema (12).There is no universally accepted classification ofhand eczema. Traditionally classification is basedon aetiological factors (irritant, allergic, andatopic disease), the localization of the eczema(dorsum, palmar, fingers, and wrist), or morphologicalfeatures (vesicular, hyperkeratotic, lichenification,and recurrent vesicular hand dermatitis).It is generally believed that this classification systemis insufficient, which makes comparison ofstudies and therapeutic strategies difficult, andhampers the possibilities for better understandingand treating the disease (13, 14). It seems likelythat hand eczema is a common phenotype expressinga variety of underlying diseases.

258 GIWERCMAN ET AL. Contact Dermatitis 2008: 59: 257–260We propose a revised classification for the subgroupof patients having atopic hand eczemabased on concurrent atopic dermatitis and filaggrinloss-of-function mutations.Risk Factors for Hand EczemaDuring the last three decades, research has, asmentioned above, shown atopic dermatitis, contactallergy, and irritants, e.g. wet work, to be themost important risk factors for the developmentof hand eczema.Atopic dermatitisMost studies agree that the frequency of atopicdermatitis is increased in patients with handeczema (10, 15–18). The explanation is an atopicskin diathesis, an endogenous risk factor not wellunderstood. The risk of developing hand eczemacan be predicted by means of a scoring system ofatopic dermatitis (19, 20).Contact allergyThe development of contact allergy requiresa combination of genetic susceptibility and environmentalexposure (21). Contact allergy is anindependent risk factor for developing handeczema as the hands are the prime site for exposureto allergens, occupational as well as domestic(17, 18, 22).Wet workSeveral studies have verified wet work as a majorexternal risk factor for the development of handeczema, probably because water decreases theprotectiveness of the skin and occlusion increasesits irritant effect (23, 24). Bryld et al. (17) did notfind wet work to be an independent risk factor intheir twin study. Instead, the authors suggest thatwet work is a risk factor only for a subgroup of thepopulation, in accordance with the general observationthat only some people develop handeczema although many more are heavily exposed.Genetic StudiesBased on a twin study, Bryld et al. (17) found thatgenetics influence the risk of acquiring handeczema. Furthermore, they concluded that anunknown genetic risk factor independent of atopicdermatitis and contact allergy is important fordeveloping hand eczema. In a follow-up studyon the same twin population, Lerbaek et al. (25)found that genetic risk factors explain 41% of thevariance in liability to develop hand eczema andmonozygotic twins to have a doubled risk fordeveloping hand eczema if their co-twin havehad hand eczema compared with a dizygotic twinindividual having a co-twin with hand eczema,and further document this risk factor to be independentof atopic dermatitis.Filaggrin Mutations and Atopic DermatitisIn 2006, Palmer et al. (3) documented for the firsttime the two filaggrin mutations, R501X and2282del4, to be associated with the developmentof atopic dermatitis. Several studies have confirmedthis finding, and the mutations are currentlythe most strongly associated genetic factorsknown to confer susceptibility to atopic dermatitisin European populations (6, 26). Odds ratios varybetween 3.73 and 7.1 (4, 27). No negative or equivocalstudies have been reported.The two mutations, R501X and 2282del4, arecarried by 16.7–56 % of all individuals with atopicdermatitis (6) and are inherited in a semidominantmode (2). The high frequencies of filaggrin mutationsare seen in studies investigating adults withboth persisting and early onset of atopic dermatitis.The mutations are associated with asthma andallergy as well as early onset of atopic dermatitisand persistence into adulthood as well as certainphenotypic characteristics, e.g. hyperlinearity ofthe hands (3, 4, 28). Other mutations in or nearbythe filaggrin gene have been documented. In onepopulation, a third mutation, R2447X, was asstrongly and independently associated with atopicdermatitis as the mutations R501X and 2282del4(29). Besides R2447X, two other mutations,S3247X and 3702delG as well as other lesser frequentmutations, have recently been shown to beassociated with atopic dermatitis. These mutationsare qualitatively different from the previouslyreported mutations with some residualfunction, as demonstrated by a significantly lowerpenetrance of eczema. Generally, these new mutationsreported are neither as prevalent nor asstrongly associated with atopic dermatitis (29, 30).Filaggrin Mutations and Hand EczemaLerbaek et al. investigated a possible associationbetween the filaggrin mutations and atopic handeczema (7). They found a borderline statistical significancepointing towards an association betweenthe subgroup of patients with hand eczema, atopicdermatitis, and the filaggrin mutations. All individualshaving hand eczema and atopic dermatitisalso had the filaggrin mutations, but the grouponly included 26 individuals and there was nocomparable control group with atopic dermatitis,

Contact Dermatitis 2008: 59: 257–260 HAND ECZEMA AND FILAGGRIN MUTATIONS 259but without hand eczema. No association betweenthe filaggrin mutations and hand eczema in generalor contact allergy was found, but this mightbe because of lack of statistical power and a possibleassociation could not be excluded. A recentstudy by de Jongh et al. has confirmed these findingsbut is hampered by the same problem of statisticalpower (9).A single study of the filaggrin mutations andnickel allergy has been published. Novak et al.(8) confirm earlier findings of an associationbetween the filaggrin mutations and atopic dermatitis.They observed an association between contactsensitization to nickel and contact sensitization tonickel combined with intolerance to fashion jewellery.The positive association between the filaggrinnull alleles and contact sensitization to nickelcould be explained in different ways. One possibilityis that because the mutations induce a skinbarrier dysfunction, nickel could act as an irritantinstead of an allergen and thus result in falsepositivepatch results, which in particular wouldapply to the atopic individuals. But, in the populationinvestigated by Novak et al. (8), nickelallergy occurs with the same frequency in bothatopic and non-atopic individuals. Another explanationcould be nickel accumulation in the skin offilaggrin mutation-positive individuals because ofincreased ability to bind to the filaggrin-mutatedepidermis.Further studies, including twin studies and populationstudies, are needed to investigate whethercontact sensitization to nickel itself is associatedwith the filaggrin mutations or the observed associationis biased because of the above-mentionedexplanations.DiscussionSo far, only two studies have been published concerningfilaggrin mutations and atopic handeczema. The tendency towards an associationbetween atopic hand eczema and the allele variantsis plausible because atopic dermatitis is themost frequent risk factor for developing handeczema, and previous work has suggested thatatopic dermatitis is the core phenotype associatedwith the filaggrin mutations. Further studies withmore statistical power are needed to better investigatethis topic.The gene for filaggrin is probably not the onlyresponsible carrier of barrier-deficiency. Accordingto Bryld et al. (12, 17) and Lerbaek et al. (7, 18,25), genetic risk factors independent of atopicdermatitis and contact allergy exists. Twin studiesdocument that genes account for up to 82% ofthe individual susceptibility to develop atopicdermatitis (31–33) but only 16.7–56% of individualswith atopic dermatitis carry the filaggrinmutations. Obviously other genes must be of relevance,which might be genes coding for otherimportant substances in the epidermal skin barrier,both proteins and lipids. Further studies areneeded, including extended genetic studies.The possible association between the atopichand eczema and the filaggrin mutations is interestingas it raises the possibility of subgroupingthis otherwise heterogenic disease and therebyenables a better phenotype–genotype characterizationof atopic hand eczema. This could improvethe preventive initiatives, secure better informationof patients about the prognosis for their disease,and possibly enable targeted treatment.Also, as it seems that the filaggrin mutations areassociated with both a prolonged course of atopicdermatitis and hand eczema, being able to screenfor the mutations could help to better inform thepatients about the prognosis for their diseaseincluding carrier guidance.In a future classification of hand eczema, wesuggest subgrouping patients having atopic handeczema. We propose a distinction betweenpatients with and without the filaggrin loss-offunctionpolymorphisms and a further differentiationbetween associations with type I allergy,type IV allergy and exposure to irritants, respectively.Furthermore, we suggest future studies ofhand eczema to analyse for inherited barrier deficienciessuch as the filaggrin mutations.References1. Candi E, Schmidt R, Melino G. The cornified envelope:a model of cell death in the skin. Nat Rev Mol Cell Biol2005: 6: 328–340.2. Smith F J, Irvine A D, Terron-Kwiatkowski A et al. Loss-offunctionmutations in the gene encoding filaggrin cause ichthyosisvulgaris. Nat Genet 2006: 38: 337–342.3. Palmer C N, Irvine A D, Terron-Kwiatkowski A et al. Commonloss-of-function variants of the epidermal barrier proteinfilaggrin are a major predisposing factor for atopicdermatitis. Nat Genet 2006: 38: 441–446.4. Marenholz I, Nickel R, Ruschendorf F et al. 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