Interaction between filaggrin null mutations and tobacco smoking in relation to asthma.

BACKGROUND: The mechanisms underlying the association between filaggrin (FLG) deficiency and asthma are not known. It has been hypothesized that FLG deficiency leads to enhanced percutaneous exposure to environmental substances that might trigger immune responses. We hypothesized that interactions between FLG deficiency and environmental exposures play a role in asthma development. OBJECTIVE: We sought to investigate possible interactions between FLG null mutations and tobacco smoking in relation to asthma. METHODS: A total of 3471 adults from a general population sample participated in a health examination. Lung function and serum specific IgE levels to inhalant allergens were measured, and information on asthma and smoking was obtained by means of questionnaire. Participants were genotyped for the 2 most common FLG null mutations in white subjects: R501X and 2282del4. Another Danish population was used for replication. RESULTS: The FLG null mutation genotype was significantly associated with a higher prevalence of asthma and decreased FEV(1)/forced vital capacity ratio. In logistic regression analyses with asthma as the outcome, a significant interaction was found between FLG null mutations and smoking status (P = .02). This interaction was confirmed, although it was not statistically significant, in another Danish population study. Interactions between FLG genotype and cumulated smoking exposure were found in relation to asthma (P = .03) and decreased FEV(1)/forced vital capacity ratio (P = .03). A 3-way interaction was found among FLG genotype, smoking, and asthma, suggesting that the FLG-smoking interaction mainly played a role in nonatopic subjects. CONCLUSION: FLG null mutations modified the effects of smoking on the risk of asthma. This finding might have implications for risk stratification of the population.

Prevalence of and factors influencing sensitization to corticosteroids in a Danish patch test population.

BACKGROUND: Corticosteroids are used to treat dermatoses, including allergic contact dermatitis, but can also cause contact allergy. The frequency of corticosteroid allergy varies between studies and is influenced by treatment traditions and availability. AIM: To estimate the prevalence of tixocortol-21-pivalate, budesonide and hydrocortisone-17-butyrate allergy in a Danish patch test population and characterize individuals with corticosteroid allergy. MATERIALS/METHODS: Three thousand five hundred and ninety-four patients were patch tested with tixocortol-21-pivalate, budesonide, and hydrocortisone-17-butyrate. Characterization was performed according to the MOAHLFA index and duration of disease. RESULTS: Two per cent had a steroid allergy: 0.8% had a tixocortol-21-pivalate allergy, 1% a budesonide allergy, and 1% a hydrocortisone-17-butyrate allergy. Tixocortol-21-pivalate and budesonide allergy were associated with atopic dermatitis in crude analyses, but only tixocortol-21-pivalate allergy and atopic dermatitis remained associated in adjusted analyses. Leg dermatitis was uniquely associated with tixocortol-21-pivalate allergy. Hydrocortisone-17-butyrate allergy was associated with duration of disease in both crude and adjusted analyses. DISCUSSION/CONCLUSION: Chronic dermatoses (atopic dermatitis and leg dermatitis) were identified as risk factors for group A corticosteroid allergy, probably because of more pronounced exposure to group A steroids resulting from ease of access that is exploited by patients with a chronic dermatosis. The duration of disease rather than the dermatosis itself seemed to be important for group B and D2 corticosteroid allergy.

Filaggrin null mutations and association with contact allergy and allergic contact dermatitis: results from a tertiary dermatology clinic.

BACKGROUND: Filaggrin null (FLG) mutations lead to skin barrier disruption with a reduced resistance towards exogenous agents and also influence the course of disease in atopic dermatitis. OBJECTIVES: To examine the association between FLG mutations and contact allergy, polysensitization, hand eczema at first appearance of disease, occurrence, and course of dermatitis. METHODS: A venous blood sample from 430 individuals was genotyped for FLG mutations R501X and 2282del4 with polymerase chain reaction followed by typing through hybridization to paramagnetic polystyrene beads and analysis on a BioPlex 200. All individuals had a minimum of one positive patch test reaction. RESULTS: In all, 3.5% were 2282del4 heterozygote and 5.1% were R501X heterozygote. An odds ratio (OR) of 1.49 [95% confidence interval (CI) 0.74-3.00] was found for nickel allergy, OR 0.84 (95% CI 0.41-1.74) for polysensitization, OR 0.78 (95% CI 0.25-2.43) for dermatitis, OR 0.96 (95% CI 0.48-1.92) for hand eczema at debut, OR 1.25 (95% CI 0.99-1.57) for duration of disease, and OR 0.76 (95% CI 0.59-0.97) for age at onset. CONCLUSIONS: No association between nickel allergy, polysensitization, hand eczema at first appearance or occurrence of dermatitis, and FLG mutations was found. However, patients with FLG mutations had an earlier age of onset compared with the wild-type genotype and a trend towards longer duration of disease.

Prevalence of nickel and cobalt allergy among female patients with dermatitis before and after Danish government regulation: a 23-year retrospective study.

BACKGROUND: An increased prevalence of nickel allergy prompted the Danish government to prohibit excessive nickel release (ie, >0.5 microg nickel/cm(2)/wk) from consumer products in 1990. Concomitant allergy to nickel and cobalt is often observed among patients with dermatitis, probably as a result of cosensitization. OBJECTIVES: The study investigated the development of nickel and cobalt allergy among Danish female patients with dermatitis tested between 1985 and 2007. This was done to examine whether Danish nickel regulation has reduced the prevalence of nickel allergy and to examine whether the prevalence of cobalt allergy has increased as a result of the nickel regulation. METHODS: A retrospective analysis of all patch test data from our database was performed (n = 10,335). Comparisons were made using a chi-square test for trend. Logistic regression analyses were used to test for associations. RESULTS: The prevalence of nickel allergy decreased significantly among those aged 5 to 30 years from 27.6% in 1985 to 16.8% in 2007 (P(trend) < .002) but increased among those aged 31 to 49 years from 21.3% to 33.8% in the same period (P(trend) < .001). The median age was significantly higher among patients with isolated cobalt allergy than among patients with nickel allergy (P < .001). LIMITATIONS: No information on causative exposures was available. CONCLUSIONS: Nickel allergy decreased among young female patients with dermatitis between 1985 and 2007 whereas it increased among older patients, probably as a result of a cohort effect. The prevalence of cobalt allergy remained relatively unchanged.

Characterization of the polysensitized patient: a matched case-control study.

BACKGROUND: Polysensitization ( >or= 3 contact allergies) may be regarded as a special entity in patients with contact allergies. However, this group of polysensitized patients is poorly characterized. Filaggrin mutations are associated with atopic eczema and lead to impaired skin barrier which may predispose to contact allergy. Therefore, it is of interest to consider atopic eczema and contact allergies, especially in patients with multiple allergies. OBJECTIVE: To characterize polysensitized patients regarding occurrence, duration and course of dermatitis, and examine potential risk factors for polysensitization, including atopic eczema. METHODS: A questionnaire case-control study of 562 polysensitized and 1124 single/double-sensitized individuals was performed. RESULTS: The results show that 45% of polysensitized and 31% of single/double-sensitized patients had or had had atopic eczema, and atopic eczema was identified as a risk factor for polysensitization. Patients with leg ulcer constituted only a minor part of the polysensitized group and leg ulcers were not identified as a risk factor for polysensitization in this study. The influence of contact allergies on duration and course of disease diverged between the group of patients with atopic eczema and the group without atopic eczema. CONCLUSION: Patients with atopic eczema were overrepresented in the group of polysensitized patients and polysensitized patients should be viewed in the light of occurrence or lack of atopic eczema.

Associations between baseline allergens and polysensitization.

BACKGROUND: Identification of patients at risk of developing polysensitization is not possible at present. An association between weak sensitizers and polysensitization has been hypothesized. OBJECTIVES: To examine associations of 21 allergens in the European baseline series to polysensitization. PATIENTS/METHODS: From a database-based study with 14 998 patients patch tested with the European baseline series between 1985 and 2005, a group of 759 (5.1%) patients were polysensitized. Odds ratios were calculated to determine the relative contribution of each allergen to polysensitization. RESULTS: Seven allergens--parabens mix, N-isopropyl-N-phenyl-p-phenylenediamine, sesquiterpene lactone mix, wool alcohols, potassium dichromate, Myroxylon pereirae, and cobalt chloride - showed statistically significant positive associations to polysensitization. Five allergens p-phenylenediamine, neomycin sulfate, epoxy resin, primin, and nickel sulfate showed statistically significant negative associations to polysensitization. For the allergens with the strongest associations, only every second individual with these particular allergies had two or more additional allergies. CONCLUSIONS: No common denominator for the association between the allergens and the polysensitization was apparent, and any association, whether positive or negative, was relatively low. Based on these results, sensitization to specific baseline allergens cannot be used as risk indicators for polysensitization.

Patients with multiple contact allergies: a review.

Patients with multiple contact allergies, also referred to as polysensitized, are more frequent than predicted from prevalence of single sensitivities. The understanding of why some people develop multiple contact allergies, and characterization of patients with multiple contact allergies is limited. This review presents the current knowledge on the topic and discusses the evidence and characteristics of an increased susceptibility factor, possible causes to and genetic markers for the increased susceptibility, composition of the patient group and identification of patients at risk of developing multiple contact allergies. Evidence of allergen clusters among polysensitized individuals is also reviewed. The literature supports the idea that patients with multiple contact allergies constitute a special entity within the field of contact allergy. There is no generally accepted definition of patients with multiple contact allergies. We suggest that contact allergy to 3 or more allergens are defined as multiple contact allergies.

Trends of contact allergy to fragrance mix I and Myroxylon pereirae among Danish eczema patients tested between 1985 and 2007.

BACKGROUND: Fragrance contact allergy has for long been recognized as an important health issue. In Denmark, the frequency of fragrance mix (FM) I contact allergy increased between 1985-1986 and 1997-1998 among male and female dermatitis patients. OBJECTIVES: To investigate the development of FM I and Myroxylon pereirae (MP) contact allergy between 1985 and 2007 with an emphasis on recent years. METHODS: A retrospective analysis of all patch test data from our database was performed. Comparison of sensitivity rates was made using a chi-squared test for trend. Logistic regression analyses were used to test for associations. RESULTS: Of 16,173 patients, 7.2% were sensitized to FM I and 4% to MP. FM I contact allergy was associated with female sex [odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.33-1.74] and age between 41 and 60 years (OR = 3.20; 95% CI = 1.98-5.21). Significant declines of FM I and MP reactions among women but not men were observed between 1999 and 2007. CONCLUSIONS: Although the frequency of FM I contact allergy has decreased in Denmark in recent years, it is still high. Furthermore, fragrance contact allergy is caused by other important allergens not included in this analysis. Allergic contact reactions to the ingredients of FM I remain a problem in European consumers.

Skin pH, atopic dermatitis, and filaggrin mutations.

BACKGROUND: The acidic pH of the skin plays a role in antimicrobial defense by regulating the bacterial skin flora and aspects of barrier. Filaggrin is a co-factor in maintaining a low skin pH because of its degradation into acidic amino acids. Accordingly, lack of filaggrin due to filaggrin mutations may influence skin pH. OBJECTIVE: We aimed to determine the epidermal pH in different groups stratified by filaggrin mutations and atopic dermatitis. Further, we investigated the changes in pH according to severity of mutational status among patients with dermatitis, irrespective of skin condition. METHODS: pH was measured with a multiprobe system pH probe (PH 905), and the study population was composed of 67 individuals, who had all been genotyped for 3 filaggrin mutations (R501X, 2282del4, R2447X). RESULTS: We found no clear pattern in relation to filaggrin mutation carrier status. Individuals with wild-type filaggrin displayed both the most acidic and most alkaline values independent of concomitant skin disease; however, no statistical differences between the groups were found. CONCLUSIONS: The lack of significant diversity in skin pH in relation to filaggrin mutation carrier status suggests that the effect of filaggrin mutations on skin pH is not pronounced.

Associations of filaggrin gene loss-of-function variants with urinary phthalate metabolites and testicular function in young Danish Men.

BACKGROUND: Filaggrin is an epidermal protein that is crucial for skin barrier function. Up to 10% of Europeans and 5% of Asians carry at least one null allele in the filaggrin gene (FLG). Reduced expression of filaggrin in carriers of the null allele is associated with facilitated transfer of allergens across the epidermis. We hypothesized that these individuals may have increased transdermal uptake of endocrine disruptors, including phthalates. OBJECTIVES: We investigated urinary excretion of phthalate metabolites and testicular function in young men with and without FLG loss-of-function variants in a cross-sectional study of 861 young men from the general Danish population. METHODS: All men were genotyped for FLG R501X, 2282del4, and R2447X loss-of-function variants. We measured urinary concentrations of 14 phthalate metabolites and serum levels of reproductive hormones. We also evaluated semen quality. RESULTS: Sixty-five men (7.5%) carried at least one FLG-null allele. FLG-null carriers had significantly higher urinary concentrations of several phthalate metabolites, including a 33% higher concentration of MnBP (mono-n-butyl phthalate; 95% CI: 16, 51%). FLG-null variants were not significantly associated with reproductive hormones or semen quality parameters. CONCLUSION: This study provides evidence that carriers of FLG loss-of-function alleles may have higher internal exposure to phthalates, possibly due to increased transepidermal absorption. FLG loss-of-function variants may indicate susceptible populations for which special attention to transepidermal absorption of chemicals and medication may be warranted.

Nickel sensitization, hand eczema, and loss-of-function mutations in the filaggrin gene.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease. Recently, it was demonstrated that a large proportion of individuals with AD have an epidermal expression deficiency of filaggrin (FLG). This unique finding may have great implications for our understanding of nickel sensitization because nickel is chelated in the epidermis and perhaps to FLG. This review aims to briefly present the current knowledge about nickel sensitization in relation to FLG deficiency and speculate on its possible implications. The new knowledge concerning loss-of-function mutations in the FLG gene (the lack of specific nickel-chelating power in the stratum corneum and a generally defective skin barrier) suggests that an additive effect from irritants and nickel may aggravate hand eczema in individuals with loss-of-function mutations in the FLG gene. This hypothesis calls for a reevaluation of the potential risk of nickel sensitization through the establishment of cohorts with and without such mutations.

20 Years of standard patch testing in an eczema population with focus on patients with multiple contact allergies.

Results of standard patch tests performed with the same methodology in one centre are rarely available over a large time span. This gives the unique opportunity to study not only prevalence but also persistency of contact allergy and characterize subpopulations. The objectives were to investigate sensitivity rates and persistencies of patch test results and characterize patients with multiple contact allergies. A 20-year retrospective database-based study of 14 998 patients patch tested with the European Standard Series was performed. 34.5% were sensitized, primarily women. Sensitivity to nickel was most frequent and least frequent to mercaptobenzothiazole, N-isopropyl-N-phenyl-p-phenylenediamine and benzocaine. Yearly proportion of negative, mono/double-allergic, and multiple-allergic cases remained stable. Persistency of positive reactions was high for para-phenylenediamine, Cl(Me)isothiazolinone, and primin and poor for paraben mix. 5.1% were multiple allergic, primarily women, and 90% got diagnosed by the first test. Frequency of multiple allergies increased with age. More multiple- than mono/double-allergic patients were tested multiple times. Persistency and sensitivity rates in a Danish eczema population are provided and are useful for decisions regarding the standard series. Patients with multiple contact allergies are typically elderly women who might have long-lasting and hard-to-treat eczema. Cumulative environmental exposure seems necessary to develop multiple allergies.