Uncommon Variants in FLG2 and NOD2 Are Associated with Atopic Dermatitis in the Ethiopian Population.

Loss-of-function variants in the FLG gene have been identified as the strongest cause of susceptibility to atopic dermatitis (AD) in Europeans and Asians. However, very little is known about the genetic etiology behind AD in African populations, where the prevalence of AD is notably high. We sought to investigate the genetic origins of AD by performing whole-genome sequencing in an Ethiopian family with 12 individuals and several affected in different generations. We identified 2 variants within FLG2 (p.D13Y) and NOD2 (p.A918S) genes cosegregating with AD in the affected individuals. Further genotyping analyses in both Ethiopian and Swedish AD cases and controls revealed a significant association with the FLG2 variant (p.D13Y, P < .0013) only in the Ethiopian cohort. However, the NOD2 variant (p.A918S) did not show any association in our Ethiopian cohort. Instead, 2 previously recognized NOD2 variants (p.A849V, P < .0085 and p.G908R, P < .0036) were significantly associated with AD in our Ethiopian cohort. Our study indicates that the FLG2 and NOD2 genes might be important in the etiology of AD in Ethiopians. Additional genetic and functional studies are needed to confirm the role of these genes and the associated variants into the development of AD.

Establishment and Utility of SwedAD: A Nationwide Swedish Registry for Patients with Atopic Dermatitis Receiving Systemic Pharmacotherapy.

SwedAD, a Swedish nationwide registry for patients with atopic dermatitis receiving systemic pharmacotherapy, was launched on 1 September 2019. We describe here the establishment of a user-friendly registry to the benefit of patients with atopic dermatitis. By 5 November 2022, 38 clinics had recorded 931 treatment episodes in 850 patients with an approximate national coverage rate of 40%. Characteristics at enrolment included median Eczema Area and Severity Index (EASI) 10.2 (interquartile range 4.0, 19.4), Patient-Oriented Eczema Measure (POEM) 18.0 (10.0, 24.0), Dermatology Life Quality Index (DLQI) 11.0 (5.0, 19.0) and Peak Itch Numerical Rating Scale-11 (NRS-11) 6.0 (3.0, 8.0). At 3 months, median EASI was 3.2 (1.0, 7.3) and POEM, DLQI, and NRS-11 were improved. Regional coverage varied, reflecting the distribution of dermatologists, the ratio of public to private healthcare, and difficulties in recruiting certain clinics. This study highlights the importance of a nationwide registry when managing systemic pharmacotherapy of atopic dermatitis.

The Impact of Systemic Treatment of Atopic Dermatitis on Depressive Symptoms: A Prospective Clinical Cohort Study

Information on depressive symptoms among patients with atopic dermatitis (AD) undergoing systemic treatment in a real-world setting is scarce. This prospective real-world clinical cohort study analysed data from SwedAD, a Swedish national register comprising patients with AD undergoing systemic treatment. Data were collected at baseline (n = 120) and at follow-up at 6 months (range 3-9 months, n = 59), and 12 months (10 months or later, n = 36). Depression was assessed with the Montgomery-Åsberg Depression Rating Scale-Self-report (MADRS-S) and AD with the Eczema Area Severity Index, the Patient-Oriented Eczema Measure, the Dermatology Life Quality Index and evaluation of pruritus. More than half of patients with moderate-to-severe AD had depressive symptoms at baseline, 24% presented with moderate-to-severe depression and 3% had pronounced suicidal ideation. Systemic treatment of AD significantly reduced both depression and AD symptoms at 6 months, and this positive effect remained at 12 months. In conclusion, depressive symptoms are common among adults with moderate-to-severe AD. Systemic treatment of AD significantly reduced depressive symptoms in parallel with AD symptoms.

Living with Atopic Dermatitis as a Young Adult in Relation to Health-related Quality of Life and Healthcare Contacts: A Population-based Study.

Most studies of health-related quality of life (HRQoL) and atopic dermatitis are based on data from dermatology clinics. The aim of this study was to determine whether atopic dermatitis affects HRQoL in adolescence and young adulthood, based on data from the population-based cohort BAMSE (Children, Allergy, Environmental, Stockholm, Epidemiology). A further aim was to determine if the use of topical corticosteroids and healthcare contacts affect HRQoL. Participants with data from birth to young adulthood (n=3,064) were included. Two generic instruments were used to measure HRQoL:General Health at age 12, 16 and 24 years and EQ-5D-3L, including EQ-visual analogue scale (EQ-VAS) at age 24 years. In addition, the disease-specific Dermatology Quality Life Index (DLQI) was used at 24 years. Healthcare consultations for atopic dermatitis were obtained from Stockholm Regional Healthcare Data Warehouse (n = 1,944). Participants with atopic dermatitis had an increased odds ratio (OR) of not feeling completely healthy (adjusted OR 1.50; 95% confidence interval (95% CI): 1.30-1.73). Participants with persistent atopic dermatitis, fulfilling atopic dermatitis criteria in the 12- and/or 16- and 24-year follow-ups reported worse EQ-VAS value 70.0 (95% CI 67.3-72.7) in the 25th percentile, than peers without atopic dermatitis. Over an 8-year period, contact with healthcare was limited (mean number 0.96). In conclusion, atopic dermatitis had a negative impact on HRQoL in young adults from adolescence to adulthood and healthcare consultations were few.

Young adults' perceptions of living with atopic dermatitis in relation to the concept of self-management: a qualitative study.

OBJECTIVES: Learning to take control of one's health is an important part of the transition from adolescence to adulthood. This study aimed to explore young adults' perceptions of living with atopic dermatitis (AD) in relation to the concept of self-management. DESIGN: A qualitative study with an inductive approach was performed through semistructured interviews (n=15). The interviews were recorded, transcribed verbatim and analysed with systematic text condensation. PARTICIPANTS: Young adults (mean age 23,4 years) with persistent AD in a longitudinal population-based birth cohort. To capture experience of living with persistent AD (preschool/school-age onset) of different severity (mild to severe/very severe), a purposive selection was performed. In total, 15 young adults were included. Persistent AD (preschool/school-age onset) was defined as dry skin in combination with itchy rash of typical localisation in the 12 months preceding the 16-year and the 24-year follow-ups. Severity was self-assessed using the Patient Oriented Eczema Measure. RESULTS: Despite having experience of AD since childhood, the respondents expressed uncertainty about treatment and how it affected their bodies. Their uncertainties and feelings affected how they used topical corticosteroids. The respondents emphasised that they perceived availability of healthcare and knowledge about treatment of AD among healthcare providers to be limited. The participants did not state any experiences of support to self-management from healthcare, which affect young adults' possibilities to take full control of their AD care. CONCLUSIONS: Young adults with preschool/school-age onset of AD are unsure how to treat and manage the disease. One explanation may be insufficient transition process.

Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis- and psoriasis-associated genes.

BACKGROUND: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. OBJECTIVE: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. METHODS: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. RESULTS: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. CONCLUSIONS: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.

Clinical Management of Atopic Dermatitis in Adults: Mapping of Expert Opinion in 4 Nordic Countries using a Modified Delphi Process.

Similarities and differences in the everyday clinical management of moderate-to-severe atopic dermatitis in Nordic countries are unknown. Using a modified Delphi approach, 15 dermatologists from Denmark, Finland, Norway and Sweden completed face-to-face and online questionnaires and participated in summary discussions to map expert opinion on the clinical management of moderate-to-severe atopic dermatitis in these Nordic countries. Through discussions, 6 adult patient profiles, reflecting common disease presentations of atopic dermatitis, were identified. Using these case profiles, diagnostic work-up, treatment goals, patient education and treatment approaches were discussed. Patient education was identified as essential for effective management. A treatment sequence of moderate-to-potent topical glucocorticosteroids and emollients, followed by systemic treatment, was recommended, allowing 3 months to ascertain systemic treatment response before switching, if necessary. Consensus was not reached on systemic treatment choice, reflecting differences in clinical practice and reimbursement between countries. Practical, case-based clinical recommendations were developed for optimal patient care.

Filaggrin gene mutations in relation to contact allergy and hand eczema in adolescence.

BACKGROUND: Filaggrin is an important protein for structure and function of the skin barrier. Filaggrin gene (FLG) mutations are known to result in dry skin, impaired skin barrier, and increased risk for atopic dermatitis. However, it is not clear whether these mutations are associated with contact allergy or hand eczema in adolescence. OBJECTIVES: The purpose of this study was to investigate whether FLG mutations are associated with contact allergy, self-reported hand eczema, or dry skin in adolescence. METHODS: We used data from the 16-year follow-up in the BAMSE cohort, information obtained from a Web-based questionnaire including questions on hand eczema and dry skin, from FLG mutation analysis (R501X, R2447X, 2282del4), and patch testing (n = 1822). RESULTS: Logistic regression analyses showed no statistically significant associations between FLG mutations and contact allergy (any contact allergy, nickel allergy, or fragrance allergy) according to patch test, or self-reported hand eczema at 16 years, or hand eczema ever. However, FLG mutations were associated with self-reported dry skin at 16 years. CONCLUSIONS: FLG mutations are associated with self-reported dry skin at 16 years. However, in this study no consistent associations were found between FLG mutations and contact allergy or hand eczema at 16.

Future reduction of cutaneous malignant melanoma due to improved sun protection habits and decreased common melanocytic nevi density among Swedish children?: A follow-up from 2002 to 2012.

We have previously demonstrated significant improvements in sun protection regimens and significantly fewer common melanocytic nevi (CMN) among 7-year-old children in southern Sweden when comparing year 2007 with 2002. The aim of this study was to investigate whether the observed decreasing trend also can be observed at age 10 and, in addition, to compare the CMN density change between 7 and 10 years of age during two periods of time. Two open cohorts were used, cohort I with schoolchildren investigated in 2002 at age 7 and in 2005 at age 10 and cohort II with schoolchildren investigated in 2009 at age 7 and in 2012 at age 10. A significant decrease in CMN density (number/m2 BSA) at age 10 from 2005 to 2012 was observed: 15.9 (14.7-17.2) and 11.4 (10.1-12.7), respectively. The density growth rate from 7 to 10 years was 2.8 (2.1-3.5) between 2002 and 2005 and decreased significantly to 0.9 (0.2-1.5) between 2009 and 2012. Significant increases were observed for 'often use of sunscreen', 'often staying in shade' and 'often staying indoors' from cohort I to cohort II: 65 vs 80%, 7.6 vs 13% and 7.3 vs 19%, respectively. The decrease in number of CMN among 10-year-old children confirms a current trend in Sweden. If this persists, a future reduction of cutaneous malignant melanoma incidence in Sweden might be anticipated. The results also indicate that CMN count could be used as an indicator of ultraviolet exposure.

Association Between Atopic Dermatitis and Cardiovascular Disease: A Nationwide Register-based Case-control Study from Sweden.

The associations between atopic dermatitis (AD) and cardiovascular disease (CVD) are debated. The aim of this study was to investigate the association between AD and coronary artery disease or ischaemic stroke in a nationwide, register-based, case-control study (104,832 AD cases, 1,022,435 controls) based on linkage of Swedish national register data between 1968 and 2016. Patients were classified as having severe AD if they had received systemic pharmacotherapy for AD or had been treated in a dermatological ward with AD as the main diagnosis. Other AD was classified as non-severe. After multivariable adjustments for comorbidities and socioeconomic status, overall AD was associated with angina pectoris (adjusted odds ratio (aOR) 1.13, 95% confidence interval (CI) 1.08-1.19), but among males with severe AD this association was not found, compared with the general population. Male non-severe AD was associated with myocardial infarction (OR 1.15, 95% CI 1.07-1.23). Severe AD was associated with ischaemic stroke, with similar estimates in men and women (aOR 1.19, 95% CI 1.07-1.33). Subgroup analyses among women indicated smoking as an important risk factor among severe cases. Dia-betes mellitus, hyperlipidaemia, and hypertension were more prevalent in severe AD than in controls, and hyper-lipidaemia and hypertension were also more prevalent in non-severe AD than in controls. In conclusion, in this study, AD was associated with CVD, and this should be kept in mind, especially when managing patients with severe AD.

Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis.

Dupilumab, the first biologic approved for treatment of atopic dermatitis, has demonstrated significant clinical effect and quality of life-enhancing capacity in clinical trials. In these, dupilumab-associated conjunctivitis where reported in a minority of patients. The present case series describe 10 patients treated with dupilumab where eye complications were very common. We have described patient characteristics, including FLG mutations, atopic history and clinical effect of dupilumab. Nine of 10 developed eye-complications, most commonly conjunctivitis (in 7/10). Other adverse events were herpes simplex virus uveitis and varicella-zoster virus meningitis. Although our case series is small, we conclude that dupilumab is an effective treatment option in severe atopic dermatitis, but that the risk of adverse events from the eyes and recurrence of herpes virus infections should be kept in mind. Close collaboration with an ophthalmologist is recommended, especially among patients with severe, long-lasting atopic dermatitis and/or previous eye disease.

Prognosis of Preschool Eczema and Factors of Importance for Remission.

Information on factors of importance for remission of eczema is scarce. This study explored factors related to the remission and course of preschool eczema (PSE) (eczema at 1, 2 and/or 4 years of age) to 16 years of age (n = 889) in a Swedish cohort. Half of the children were in complete remission by school age (at age 8, 12, and 16 years). In multivariate prognostic models, persistent PSE (eczema at 1, 2 and 4 years of age) (odds ratio 0.27 (95% confidence interval 0.18-0.41)), PSE with sleep disturbance (due to itch at least once a week at 1, 2 and/or 4 years of age) (0.59 (0.43-0.81)), parental allergy (0.73 (0.55-0.96)), parental smoking at child's birth (0.70 (0.50-0.99)) and filaggrin mutation (R501X, R2447X, 2282del4) (0.47 (0.26-0.85)) were inversely associated with complete remission by school age. Male sex (1.37 (1.03-1.82)) and exclusive breastfeeding ≥4 months (1.44 (1.01-2.05)) were positively associated with complete remission by school age. In conclusion, half of the children with PSE were in complete remission by school age. The most important prognostic factors were persistent PSE and PSE with sleep disturbance due to itch.

Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden.

BACKGROUND: Health-related quality of life (HR-QoL) is impaired in patients with hereditary angioedema (HAE) but has not yet been satisfactorily described. OBJECTIVE: To study HR-QoL in patients with HAE by combining different HR-QoL instruments with disease activity assessment. METHODS: All adults in the Swedish HAE registry were invited to take part in this questionnaire study, which used the generic HR-QoL instruments, EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the RAND Corporation Short Form 36 (RAND-36), the disease-specific Angioedema Quality of Life instrument (AE-QoL), the recently introduced Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication. RESULTS: Sixty-four of 133 adults (26 men, 38 women) between 18 and 91 years old responded. The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood. Women had lower HR-QoL in the RAND-36 for general health and energy/fatigue (p < 0.05). Patients who reported any AAS of >0 had significantly impaired HR-QoL. There were significant associations (p < 0.05) between the AAS and EQ-5D-5L, between the AAS and all dimensions of the RAND-36 except physical function, and between the AAS and AE-QoL in all dimensions. Nine of 36 patients who reported sick leave during the previous 4 weeks had significantly impaired HR-QoL in all the instruments (p < 0.05). There was no significant difference in HR-QoL in the patients with and the patients without prophylactic medication, except for the nutrition dimension of the AE-QoL (p < 0.05). CONCLUSION: Comprehensive information is obtained by combining different HR-QoL instruments. Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis. Increased disease activity was associated with impaired HR-QoL, which justifies more active disease management.

Exploring the association between chorangioma and infantile haemangioma in singleton and multiple pregnancies: a case-control study in a Swedish tertiary centre.

OBJECTIVES: Placenta or placental chorangioma could be the origin site of infantile haemangioma since they share various histochemical and genetic characteristics with placental vascular tissue. The aim of the current study was to investigate the association between chorangiomas and infantile haemangiomas in singleton and multiple pregnancies. MATERIALS AND METHODS: An informative questionnaire enquiring about the presence or not of infantile haemangioma and including illustrative photos of haemangioma was sent to 469 (153 cases with chorangioma and 316 controls) mothers of 323 singleton (104 cases and 219 controls) and 146 multiple (49 cases and 97 controls) liveborn neonates registered in Sweden. Overall, 310 mothers (66.1%) from 216 singleton and 94 multiple pregnancies (96 cases and 214 controls) provided feedback and their consent to participate in the current case-control study. RESULTS: The incidence of infantile haemangioma showed no statistically significant differences between cases and controls (18.8% vs 18.2%) or between singleton and multiple pregnancies (18.9% vs 17.0%). The frequency of pre-eclampsia was significantly higher in cases with chorangioma compared with controls (41.7% vs 24.3%, OR=2.22, 95% CI 1.33 to 3.71, p=0.0022) and in singleton compared with multiple pregnancies (33.3% vs 21.3%, OR=1.85, 95% CI 1.04 to 3.26, p=0.034), whereas there were no significant differences in the incidence of infantile haemangioma in neonates of mothers with or without pre-eclampsia or in neonates of mothers with multiple compared with singleton pregnancies. CONCLUSION: There was no association between placental chorangiomas and infantile haemangiomas. Multiple pregnancies or pre-eclampsia were not significantly related to higher incidence of infantile haemangioma.

A population-based study of self-reported skin exposures and symptoms in relation to contact allergy in adolescents.

BACKGROUND: Knowledge about the relations between skin exposures, skin symptoms and contact allergy in adolescents is limited. OBJECTIVES: To explore self-reported skin exposures and skin symptoms in girls and boys, and to assess the associations between exposures, symptoms and contact allergy at age 16 years. PARTICIPANTS AND METHODS: In all, 3115 adolescents from the population-based BAMSE birth cohort answered a questionnaire at age 16 concerning various skin exposures and related skin symptoms. Of these, 2285 were patch tested. RESULTS: The prevalences of self-reported piercing (55.4%), hair dyeing (50.1%) and related skin symptoms were high, particularly in girls. Piercing and itchy rash after contact with metal items were associated with increased risks of nickel allergy [respectively: odds ratio (OR) 1.77, 95%CI: 1.04-3.03, and OR 2.25, 95%CI: 1.57-3.23]. An itchy rash resulting from the use of personal hygiene products or makeup was associated with a positive patch test reaction to fragrance mix I (OR 2.11, 95%CI: 1.02-4.35). CONCLUSIONS: Adolescents are exposed to skin-sensitizing substances, for example because of piercing, hair dyeing, and tattooing. Such early-life skin exposure may lead to lifelong contact allergy and future allergic contact dermatitis and hand eczema.

IgE sensitization in relation to preschool eczema and filaggrin mutation.

BACKGROUND: Eczema (atopic dermatitis) is associated with an increased risk of having IgE antibodies. IgE sensitization can occur through an impaired skin barrier. Filaggrin gene (FLG) mutation is associated with eczema and possibly also with IgE sensitization. OBJECTIVE: We sought to explore the longitudinal relation between preschool eczema (PSE), FLG mutation, or both and IgE sensitization in childhood. METHODS: A total of 3201 children from the BAMSE (Children Allergy Milieu Stockholm Epidemiology) birth cohort recruited from the general population were included. Regular parental questionnaires identified children with eczema. Blood samples were collected at 4, 8, and 16 years of age for analysis of specific IgE. FLG mutation analysis was performed on 1890 of the children. RESULTS: PSE was associated with IgE sensitization to both food allergens and aeroallergens up to age 16 years (overall adjusted odds ratio, 2.30; 95% CI, 2.00-2.66). This association was even stronger among children with persistent PSE. FLG mutation was associated with IgE sensitization to peanut at age 4 years (adjusted odds ratio, 1.88; 95% CI, 1.03-3.44) but not to other allergens up to age 16 years. FLG mutation and PSE were not effect modifiers for the association between IgE sensitization and PSE or FLG mutation, respectively. Sensitized children with PSE were characterized by means of polysensitization, but no other specific IgE sensitization patterns were found. CONCLUSIONS: PSE is associated with IgE sensitization to both food allergens and aeroallergens up to 16 years of age. FLG mutation is associated with IgE sensitization to peanut but not to other allergens. Sensitized children with preceding PSE are more often polysensitized.

Intragenic Copy Number Variation in the Filaggrin Gene in Ethiopian Patients with Atopic Dermatitis.

Genetic variants in filaggrin (FLG) involving truncating mutations or intragenic copy number variation are strongly associated with the risk of developing atopic dermatitis (AD) in European and Asian populations. Few loss-of-function mutations have been identified in Africans, although an association between FLG copy number variation and AD severity in a small African American cohort has been proposed. We studied the association between FLG copy number and AD in 132 Ethiopians and found no association between AD severity and FLG copy number, suggesting that other, still unidentified genetic factors are of more importance in predisposing Ethiopians to AD.

Association between preschool eczema and medication for attention-deficit/hyperactivity disorder in school age.

BACKGROUND: Several studies show an association between eczema and attention-deficit/hyperactivity disorder (ADHD) in childhood, but the mechanisms and time sequence remain unclear. Information on the association between eczema and other disorders involving the central nervous system (CNS) is limited. The aim was to explore whether preschool eczema was associated with ADHD or other CNS-associated disorders requiring pharmacotherapy at school age and to analyze whether eczema at other ages of childhood was associated with medication for ADHD. METHODS: From a Swedish birth cohort, 3606 children were included in the analyses. At 1, 2, 4, 8, 12, and 16 years of age, their parents answered questionnaires regarding eczema the last year. Information on prescribed medications during school age (10-18 years of age) was derived by record linkage to the Swedish Prescribed Drug Register. RESULTS: A total of 1178 (32.7%) of the children had preschool eczema (eczema at 1, 2, and/or 4 years), and 162 (4.5%) of the children had dispensed ADHD medication at school age. Preschool eczema was not associated with ADHD medication at school age (crude odds ratio 1.16; 95% Confidence Intervals: 0.83-1.61). There was no significant association between preschool eczema and use of antidepressants, migraine drugs, or anti-epileptics at school age. Infantile eczema, school-age eczema, and eczema ever up to 16 years of age were not associated with ADHD medication at school age. CONCLUSIONS: In this large birth cohort, there were no significant associations between preschool eczema and medications for ADHD, depression/anxiety/phobia, migraine, or epilepsy at school age.

[New treatments for atopic dermatitis]. / Nya läkemedel mot atopiskt eksem väntar på godkännande - Bättre förståelse av den molekylära sjukdomsmekanismen kan ge fler och bättre verktyg för behandling.

New treatments for atopic dermatitis Atopic dermatitis is one of the most common skin disorders in Sweden. The pathogenesis is a complex counterplay between a defect skin barrier and an abnormal immune response that can be caused by genetic and/or environmental factors. Atopic dermatitis has a huge negative impact on quality of life. New and more specific treatments are under way and hopefully we will, in the near future, better treat even the more severe cases of atopic dermatitis.