Concentration of filaggrin monomers, its metabolites and corneocyte surface texture in individuals with a history of atopic dermatitis and controls.

BACKGROUND: Atopic dermatitis (AD) is characterized by skin barrier dysfunction. Notably, a high number of nano-scale protrusions on the surface of corneocytes, which can be expressed by the Dermal Texture Index (DTI), were recently associated with paediatric AD, loss-of-function mutations in filaggrin gene (FLG) and reduced levels of natural moisturizing factors (NMF). No study has so far examined the association between these parameters and monomeric filaggrin levels in adults. OBJECTIVE: To determine DTI, monomeric filaggrin and NMF in healthy controls and a group of patients with controlled dermatitis. METHODS: A total of 67 adults (20 healthy controls and 47 dermatitis patients) were included. In the patient population, a personal history of AD was diagnosed by the U.K. Working Party's Diagnostic Criteria. All participants were tested for FLG mutations (R501X, 2282del4, R2447X). Transepidermal water loss, monomeric filaggrin, DTI and NMF were measured. RESULTS: In the patient population, 78.7% (37/47) had a history of AD and 59.5% (28/47) had FLG mutations. Patients had significantly higher levels of DTI and significantly lower levels of monomeric filaggrin and NMF compared to the 20 healthy controls. Among patients, reduced level of monomeric filaggrin and NMF correlated with the presence of FLG mutations and clinical phenotypes such as xerosis, palmar hyperlinearity and AD. Among healthy controls, DTI was significantly higher in the oldest age group compared to the two younger age groups. CONCLUSION: A significant difference in DTI, monomeric filaggrin and NMF levels was found when comparing dermatitis patients with healthy controls. These findings suggest that even mild dermatitis or non-visible inflammation has a significant and negative effect on the skin barrier as inflammation is known to reduce filaggrin levels. DTI was significantly increased in aged individuals in the healthy control group, suggesting a gradual change in corneocyte morphology with age.

Skin reaction and regeneration after single sodium lauryl sulfate exposure stratified by filaggrin genotype and atopic dermatitis phenotype.

BACKGROUND: Filaggrin is key for the integrity of the stratum corneum. Mutations in the filaggrin gene (FLGnull) play a prominent role in atopic dermatitis (AD) pathogenesis. People with AD have increased susceptibility to irritants. However, little is known about the effect of filaggrin genotype and AD phenotype on irritant response and skin regeneration. OBJECTIVES: To investigate the role of FLGnull and AD groups for skin reaction and recovery after sodium lauryl sulfate (SLS) irritation. METHODS: This is a case-control study comprising 67 subjects, including healthy controls and patients with and without FLGnull and AD. Reactivity to different doses of SLS at 24, 48, 72 and 145 h after SLS application was measured by transepidermal water loss (TEWL) and laser Doppler flowmetry (LDF). Reactivity was assessed univariately and by pattern analysis. RESULTS: All patient groups showed a higher degree of skin-barrier disruption and inflammation than did controls in response to SLS. Assessing reactivity by the delta value of the area under the curve for both TEWL and LDF showed significant differences between healthy controls and those with the AD phenotype, irrespective of filaggrin mutation. The poorest regeneration was among those with the AD phenotype. The two AD phenotype groups were separated by multivariate technique, due to earlier inflammatory reactivity among subjects with FLGnullplus AD compared with the AD phenotype alone. CONCLUSIONS: Both skin reaction and regeneration were significantly different between the patient population and the healthy controls. Additionally, response severity and regeneration depended more on AD phenotype than on filaggrin genotype, whereas the response was more rapid among the FLGnullplus AD individuals.

Skin prick test reactivity to aeroallergens by filaggrin mutation status.

BACKGROUND: Studies have shown that filaggrin gene (FLG) mutations are positively associated with sensitization to aero allergens. We hypothesized that FLG mutations would also have an effect on the mean size of positive skin prick test (SPT) reactions as well as the number of positive reactions. OBJECTIVE: To investigate the effect of FLG mutations on the mean size and the number of positive SPT reactions, as well as the association with positive specific IgE. METHODS: A random sample of 3335 adults from the general population in Denmark was genotyped for the R501X and 2282del4 mutations in the FLG. SPT and specific IgE measurements to common aeroallergens were also performed. RESULTS: FLG mutations did not influence the mean size and number of positive SPT reactions. Also, no association was found between FLG mutations and specific IgE measurements. CONCLUSION: Our findings suggest that FLG mutations alone are insufficient to cause secondary sensitization to allergens. The positive association seen in patients must be explained by a combination of further barrier abnormality caused by dermatitis as well as increased allergen exposure.

Atopic diseases by filaggrin mutations and birth year.

BACKGROUND: The prevalence of atopic disorders has increased in recent years. The pathogenesis is complex with genetic and environmental risk factors. Filaggrin loss-of-function mutations are common and associated with atopic disorders. We investigated whether the prevalence of filaggrin mutations increased in different birth cohorts in adults from the general population in Denmark. METHODS: Cross-sectional questionnaire and filaggrin gene mutation (R501X and 2282del4) data from 3335 18- to 69-year-old adults were available for analyses. RESULTS: The effect of filaggrin mutations on the prevalence of atopic diseases, albeit not statistically significant, depended mostly on birth year for atopic dermatitis (AD). A nonsignificant increase in the prevalence of filaggrin mutations was noted across birth year groups reporting AD, with 12.9% in adults born in 1936-1949 and 19.0% born in 1976-1988. CONCLUSIONS: If confirmed in other populations, the observed increase suggests that mutation carriers have been more susceptible to environmental changes accentuating the rise in AD prevalence.

Individuals who are homozygous for the 2282del4 and R501X filaggrin null mutations do not always develop dermatitis and complete long-term remission is possible.

BACKGROUND: About 8-10% of the general population in Europe carry a null mutation in the filaggrin gene which is associated with early onset of atopic dermatitis as well as persistence into adulthood. No studies have investigated whether individuals with the homozygous filaggrin null genotype always develop dermatitis. OBJECTIVES: The aim of this study was to describe the natural history of individuals with no filaggrin expression. MATERIALS: Three study populations were included: (i) a random sample of 3335 subjects aged 18-69 years from the general population in Copenhagen who underwent general health examination; (ii) a total of 499 patients seen in our dermatitis clinic since 2009 and who were filaggrin genotyped as a part of the routine diagnostic work up; and (iii) a prospective, longitudinal, birth cohort study of 411 children born to mothers with a history of asthma. Filaggrin genotyping was performed for the 2282del4 and R501X mutations. RESULTS: Filaggrin homozygous/compound heterozygous individuals accounted for 0.3% of adults, 3% of dermatitis patients and 0.7% of children. Respectively, one of nine adults and one of three children never experienced dermatitis until now. All hospital patients had atopic dermatitis with onset during (early) childhood. Year-long complete remission was observed in half of patients. CONCLUSIONS: The natural history of individuals with the filaggrin null genotype is fairly good in the sense that they may not develop dermatitis at all, and if they do, they may experience complete remission.

The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta-analysis.

BACKGROUND: Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient-based case-control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. OBJECTIVES: To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross-sectional general population questionnaire data. Also, to perform a meta-analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. METHODS: Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18-69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta-analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. RESULTS: The prevalence of self-reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74-1.89; P = 0.78). The meta-analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81-1.35). CONCLUSIONS: Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta-analysis on published studies.

Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.

BACKGROUND: Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling. OBJECTIVES: To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population. METHODS: Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested. RESULTS: In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis. CONCLUSIONS: Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.

Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy.

BACKGROUND: The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined. AIM: To assess FLG status in a subset of patients with AD and a minimum of one positive patch-test reaction. METHODS: In total, 430 people from a hospital population and 3335 people from the general population were tested for FLG mutations by DNA hybridization to paramagnetic polystyrene beads and analysis on a multiplex analysis system. All of the individuals in the hospital population had a minimum of one CA. AD was diagnosed according to the UK Working Party Criteria, (questions-only version). Individuals from the hospital population who had both AD and CA were considered as cases, and comparison of mutation carrier frequency was estimated (χ(2) test) against individuals without AD but with CA from the hospital population, individuals from the general population, and individuals with AD from the general population. RESULTS: The mutation frequency in patients with AD and CA in the hospital population was significantly less than that of people with AD from the general population (OR = 0.54; 95% CI 0.30-0.98). No difference in mutation frequency was found between individuals with and without AD in the hospital population (OR = 1.40; 95% CI 0.70-2.79), or between individuals with AD and CA in the hospital population and in the overall general population (OR = 1.29; 95% CI 0.76-2.20). CONCLUSIONS: The spectrum of observable traits characteristic for the FLG mutation genotype in patients with AD is at present not defined. Our results indicate that the subset of patients with both AD and CA represent a phenotype of AD that is not associated with FLG mutations.

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study.

BACKGROUND: Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. OBJECTIVES: To investigate the association between FLG null mutations and hand eczema. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. RESULTS: Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.27-7.01], but not in subjects without atopic dermatitis (OR 0.82; 95% CI 0.41-1.67). CONCLUSIONS: FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population.

BACKGROUND: It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins. OBJECTIVES: To investigate the association between FLG null mutations and (nickel) contact sensitization. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. RESULTS: The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. CONCLUSIONS: This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.

The prevalence of chromium allergy in Denmark is currently increasing as a result of leather exposure.

BACKGROUND: Chromium allergy has traditionally been caused by occupational skin contact with cement. In 1983, Danish legislation made the addition of ferrous sulphate compulsory in cement to reduce the water-soluble chromium content to not more than 2 ppm. An effect from this intervention has previously been demonstrated among Danish construction workers. OBJECTIVES: To investigate the development of chromium allergy among patients with dermatitis tested between 1985 and 2007 in Denmark. Furthermore, to determine causative exposures in patients with chromium allergy. PATIENTS AND METHODS: A retrospective analysis of patch test data was performed (n = 16,228) and charts from patients with chromium allergy were reviewed. Comparisons were made using a chi(2) test. Logistic regression analyses were used to test for associations. RESULTS: The prevalence of chromium allergy decreased significantly from 3.6% in 1985 to 1% in 1995 (P(trend) < 0.001) but increased to 3.3% in 2007 (P(trend) < 0.001). The frequency of clinically relevant cement exposure decreased significantly among patients with chromium allergy from 12.7% in 1989-1994 to 3.0% (P < 0.01) in 1995-2007, whereas the frequency of relevant leather exposure increased significantly from 24.1% during 1989-1994 to 45.5% during 1995-2007 (P < 0.02). CONCLUSIONS: Chromium allergy is currently increasing in Denmark due to leather exposure.

Sites of dermatitis in a patch test population: hand dermatitis is associated with polysensitization.

BACKGROUND: Sites of dermatitis in larger series of contact allergic patients are rarely reported. Increased risk of polysensitization has been linked only to stasis dermatitis and leg ulcers. However, a large proportion of polysensitized individuals may have dermatitis in other skin areas. OBJECTIVES: To examine the site of dermatitis at time of first appearance in contact allergic individuals with special focus on the distribution of dermatitis in polysensitized individuals and to examine if widespread dermatitis is more frequent in polysensitized than in single/double-sensitized patients. METHODS: A matched case-control study was carried out including 394 polysensitized and 726 single/double-sensitized patients who responded to a postal questionnaire. All subjects were recruited from a hospital patch test population. RESULTS: The hands were the most frequent and the anogenital region was the least frequent skin area affected with dermatitis. Dermatitis on the hands/wrists [odds ratio (OR) 1.58], in the armpits (OR 1.56) and on the back (OR 1.91) was positively associated with polysensitization. The hands were the only skin area with dermatitis which maintained the association to polysensitization in two subpopulations consisting of, respectively, individuals with and without atopic eczema. Dermatitis on the scalp was negatively associated with polysensitization (OR 0.66) primarily for individuals without atopic eczema. The dermatitis did not seem to be more widespread in polysensitized compared with single/double-sensitized patients. CONCLUSIONS: Special awareness in patients with hand dermatitis seems justified either to prevent development of multiple contact allergies or to document polysensitization as an aetiological factor.

Patch test dose-response study: polysensitized individuals do not express lower elicitation thresholds than single/double-sensitized individuals.

BACKGROUND: It is not known if reduced elicitation thresholds are evident among polysensitized individuals when using allergens to which the patients are already sensitized. Reduced elicitation thresholds may be an expression of increased reactivity in this patient group. OBJECTIVES: To examine and compare elicitation dose-response curves and elicitation thresholds in a polysensitized vs. a single/double-sensitized group for allergens to which the test subjects were already sensitized. PATIENTS/METHODS: Fifty-one patients (13 polysensitized and 38 single/double-sensitized) were patch tested with nickel sulphate, methyldibromo glutaronitrile (MDBGN) and p-phenylenediamine (PPD) in dilution series. The ratio between the doses eliciting a response in 50% of patients in the two groups was used as the measure for relative sensitivity. RESULTS: The dose-response curves of the polysensitized group for MDBGN and PPD were shifted to the right, and for nickel sulphate shifted to the left, compared with the single/double-sensitized group. The relative sensitivity for each of the three allergens and a combined relative sensitivity for all three allergens were not significantly different when comparing the polysensitized and single/double-sensitized groups. CONCLUSION: No increased sensitivity, in the form of distinct elicitation thresholds, could be demonstrated in polysensitized individuals compared with individuals with one or two contact allergies.