Relevance of Coding Variation in FLG And DOCK8 in Finnish Pediatric Patients with Early-Onset Moderate-To-Severe Atopic Dermatitis.

Early-onset, persistent atopic dermatitis (AD) is proposed as a distinct subgroup that may have specific genotypic features. FLG gene loss-of-function variants are the best known genetic factors contributing to epidermal barrier impairment and eczema severity. In a cohort of 140 Finnish children with early-onset moderate-to-severe AD, we investigated the effect of coding variation in FLG and 13 other genes with epidermal barrier or immune function through the use of targeted amplicon sequencing and genotyping. A FLG loss-of-function variant (Arg501Ter, Ser761fs, Arg2447Ter, or Ser3247Ter) was identified in 20 of 140 patients showing higher transepidermal water loss values than patients without these variants. Total FLG loss-of-function variant frequency (7.14%) was significantly higher than in the general Finnish population (2.34%). When tested separately, only Arg2447Ter showed a significant association with AD (P = 0.003104). In addition, a modest association with moderate-to-severe pediatric AD was seen for rs12730241 and rs6587667 (FLG2:Gly137Glu). Loss-of-function variants, previously reported pathogenic variants, or statistically significant enrichment of nonsynonymous coding region variants were not found in the 13 candidate genes studied by amplicon sequencing. However, higher IgE and eosinophil counts were found in carriers of potentially pathogenic DOCK8 missense variants, suggesting that the role of DOCK8 variation in AD should be further investigated in larger cohorts.

Economic Burden and Quality of Life of Patients With Moderate to Severe Atopic Dermatitis in a Tertiary Care Hospital in Helsinki, Finland: A Survey-Based Study.

We investigated medical costs and quality of life (QOL) in 167 patients with moderate to severe atopic dermatitis (AD) at a tertiary health care hospital in Helsinki, Finland. In the studied cohort, AD caused a substantial economic burden to the patients and health care system. Most patients with AD in Finland can achieve disease control with topical treatments, but it is important to efficiently manage the patients who require additional supportive measures and specialist consultations, which may be challenging in the primary health care system due to the relapsing and remitting nature of the disease.

A Comparison of Topical Corticosteroids and Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis.

Topical corticosteroids (TCS) are a mainstay of treatment for atopic dermatitis (AD). There are shared physician and patient concerns that TCS use can result in skin atrophy and systemic absorption. The clinical use of topical calcineurin inhibitors (TCI) for AD is relatively limited despite evidence that TCI are safe and effective. Understanding the differences in efficacy and adverse effects between TCS and TCI can help shape prescription practices to the benefit of patients. The objective of this review is to characterize the difference in efficacy and adverse effects between TCS and TCI. A review of the literature between 2002 and 2022 was performed using the PubMed, EMBASE, and Cochrane Library databases. Ten studies comparing TCS of varying potencies with TCI approved for AD treatment were included in the review. Outcome measures were qualified using percent reductions on the modified Eczema Area and Severity Index score and decreases in physician's global evaluation of AD severity. Tacrolimus had statistically significant (P < .05) improvement in disease severity compared with TCS in 4 of the 5 studies that compared tacrolimus with weak TCS. The data suggest greater treatment efficacy of tacrolimus over weak TCS, and inferior efficacy of pimecrolimus (TCI) compared with both tacrolimus and weak TCS. It is difficult to draw conclusions between moderate, potent, and very potent TCS and TCI due to the small number of available studies. TCI can improve disease severity, especially on thin or intertriginous skin regions most vulnerable to adverse events with TCS treatment, and their use may help overcome adherence issues due to patient bias against TCS.

Topical tacrolimus versus corticosteroids in childhood moderate-to-severe atopic dermatitis and the impact on airway inflammation: a long-term randomized open-label study.

BACKGROUND: Childhood atopic dermatitis (AD) is often followed by other atopic comorbidities such as asthma. AIM: To compare the effectiveness of topical tacrolimus (TAC) and topical corticosteroids (TCSs) and their impact on airway inflammation and bronchial hyperresponsiveness in patients with paediatric AD. METHODS: This was a 3-year randomized open-label comparative follow-up study of 152 1-3-year-old children with moderate-to-severe AD (trial registration: EudraCT2012-002412-95). Frequent study visits including clinical examinations, laboratory investigations (total IgE, specific IgEs, blood eosinophils), skin prick and respiratory function tests to assess airway inflammation and bronchial hyperresponsiveness (exhaled nitric oxide, airway responsiveness to exercise and methacholine) were performed. RESULTS: Changes in eczema parameters at 36 months were similar in the TCS and TAC groups for mean body surface area (BSA) difference 1.4 [95% confidence interval (CI) -1.48 to 4.19); P = 0.12], mean Eczema Area and Severity Index (EASI) difference 0.2 (95% CI -1.38 to 1.82; P = 0.2), mean Investigator's Global Assessment (IGA) difference, 0.3 (95% CI -0.12 to 0.67; P = 0.12) and mean transepidermal water loss (TEWL) difference at the eczema site, -0.3 (95% CI -4.93 to 4.30; P = 0.96) and at the control site, 1.4 (95% CI -0.96 to 3.60, P = 0.19). The control-site TEWL increased more towards the end of follow-up in the TCS vs. TAC group (mean change difference -4.2, 95% CI -8.14 to -0.29; P = 0.04). No significant impact on development of airway inflammation or bronchial hyperresponsiveness occurred in early effective eczema-treatment responders vs. others ('early' vs. 'other' response was defined as the difference in treatment response to airway outcomes in BSA, EASI or IGA at 3 months). CONCLUSION: Children with moderate-to-severe AD benefit from long-term treatment with TCS or TAC. There were no significant differences in treatment efficacy. No differences in the impact on airways occurred between early effective treatment responders vs. others.

Allergic conjunctivitis: a risk factor for recurrent herpes simplex virus infections in patients with atopic dermatitis

Background: Patients with atopic dermatitis have an increased risk of herpes simplex virus (HSV) infections. Objectives: We carried out a retrospective, cross-sectional study to investigate the association of disease severity, concomitant atopic diseases and filaggrin mutations with the risk of cutaneous HSV infections in 463 patients with atopic dermatitis. Materials & Methods: The correlation between predisposing factors and HSV infections was analysed using chi-square and Mann Whitney U-tests, and the relationship was further studied with binomial logistic regression to ascertain odds ratios. Results: Allergic conjunctivitis (aOR: 1.770; CI: 1.008-3.109; p = 0.047) and patient age (aOR: 1.022; CI: 1.007-1.036; p = 0.004) showed statistically significant associations with recurrent HSV infections and eczema herpeticum. HSV infections were not linked to severity of atopic dermatitis (p = 0.435) or filaggrin mutation status (p = 0.886). Conclusion: The results highlight the importance for attentiveness of HSV infections in atopic dermatitis patients with concomitant allergic conjunctivitis.

Keratosis pilaris and filaggrin loss-of-function mutations in patients with atopic dermatitis - Results of a Finnish cross-sectional study.

Keratosis pilaris (KP) associates with epidermal barrier defects in atopic dermatitis (AD) but its role in disease severity and concomitant atopic diseases seems to vary between populations. We performed a cross-sectional observational study with 502 randomly selected AD patients of a Finnish tertiary health care center. At a single clinical examination, disease severity (Rajka Langeland severity score and EASI), clinical signs and patient history were evaluated and total IgE levels and frequent filaggrin (FLG) loss-of-function mutations were investigated. There was no link with disease severity (p = 0.649, 95% CI 0.569-0.654), asthma (p = 0.230, 95% CI 0.206-0.281) or atopic sensitization (p = 0.351, 95% CI 0.309-0.392). Keratosis pilaris was significantly associated with palmar hyperlinearity (p < 0.000, 95% CI 0.000-0.006, OR 4.664, 95% CI 2.072-10.496) and the filaggrin loss-of-function mutation 2282del4 (p < 0.000, 95% CI 0.000-0.009, OR 4.917, 95%CI 1.961-12.330). The prevalence of KP in the cohort was generally low and KP seems to be infrequent in Finnish AD patients. This may be explained by the fact that the tested FLG loss-of-function mutations are rarer in the Finnish population compared for example, with central Europe or Asia. Mutations in other locations of the FLG gene or other genes of the epidermal barrier may play a more important role.

Atopic dermatitis in adults: a population-based study in Finland.

BACKGROUND: The prevalence of atopic dermatitis (AD) has increased, but studies in adult or elderly populations are sparse. METHODS: We investigated 12-month and lifetime prevalences of AD in the Finnish adult population ≥30 years of age and analyzed living environment factors, socioeconomic factors, lifestyle-related factors, and serum vitamin D levels for their associations with AD in a national health examination survey. RESULTS: The lifetime prevalence was 21.9% and 12-month prevalence 10.1%. The highest prevalence (lifetime 28.6%, 12-month 15.4%) was seen in subjects 30-39 years of age. Prevalence decreased with age. Subjects with highly educated parents were more likely to have active AD, though there was no effect of higher education in subjects themselves. Younger age and being an ex-smoker were associated with active AD. Female sex and daily smoking increased the risk in subjects 30-49 years of age. There was no dose-response relationship to serum vitamin D levels and no association with the living environment. CONCLUSIONS: Our data show that the number of adult patients with atopic dermatitis has grown and prevalence numbers of AD in Finnish adults are among the highest reported. Together with the aging of the society, the burden of AD is not limited to childhood.

Effective treatment of atopic dermatitis in small children significantly improves the quality of life of patients and their families.

BACKGROUND: Atopic dermatitis (AD) has a severe impact on quality of life (QoL). OBJECTIVES: To analyze the impact of AD on QoL of small children with moderate-to-severe AD in a tertiary health care hospital in Helsinki, Finland. MATERIALS & METHODS: Based on interim analysis of this longitudinal follow-up study, we investigated treatment response (topical corticosteroids vs. tacrolimus) and QoL of 152 small children with moderate-to-severe AD. RESULTS: The tacrolimus group had a significantly better treatment response at 12 months visit, but thereafter no differences were observed (p = 0.029; Mann-Whitney U test). The odds ratio for group comparisons was 2.258 (CI: 1.151-4.431). There was a significant improvement in QoL during follow-up in both treatment groups. Our study showed substantial improvements in disease severity and QoL based on active management and effective treatments in small children with AD. The main improvement was seen during the first year in both treatment groups with a lasting response. CONCLUSION: Effective treatment has a significant positive impact on the QoL of small children with AD and their families.

Management of Ocular Manifestations of Atopic Dermatitis: A Consensus Meeting Using a Modified Delphi Process.

There is a need for unified guidance on the management of ocular manifestations of atopic dermatitis and ocular manifestations associated with dupilumab in the Nordic region (Denmark, Finland, Norway and Sweden). This initiative gathered Nordic dermatologists and ophthalmologists to identify consensus in this area using a modified Delphi process. The initiative was led by a Nordic expert panel who developed a questionnaire that was circulated to a wider group. The results informed an agenda consisting of 24 statements to be voted on using a 5-point Likert scale at a meeting in Copenhagen on 24 April 2019. A facilitator moderated discussion and revised statements according to expert feedback for a second vote when required to reach consensus. Consensus was reached for 23 statements regarding the diagnosis, treatment and referral of these patients, which we hope will improve patient management in the Nordic region.

Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2.

Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized.Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL.Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness.Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001).Limitations: Cultural differences of translated PROs.Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.

Young children with moderate-to-severe atopic dermatitis can be treated safely and effectively with either topical tacrolimus or mild corticosteroids.

AIM: We collected evidence and safety data for topical tacrolimus in small children with atopic dermatitis (AD) and compared the usage with topical corticosteroid. METHODS: This was an interim analysis of 75 patients (55% female) at 1 year of an ongoing 3-year randomised open-label comparative follow-up study of topical tacrolimus vs corticosteroid treatment. One- to three-year-old children with moderate-to-severe eczema referred to the Skin and Allergy Hospital in Helsinki, Finland, were enrolled. RESULTS: Efficacy parameters, the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), transepidermal water loss (TEWL), eczema area, serum total immunoglobulin E (IgE) and the blood eosinophil count, showed improvement in both groups during the study. However, patients with signs of early sensitisation at baseline (elevated serum total IgE, elevated eosinophil count, positive prick tests or specific IgEs to aero or food allergens) had statistically significantly lower TEWL at the eczema site and a smaller eczema area at 12 months in the tacrolimus group. No severe adverse effects were seen during the treatment. CONCLUSION: Children with AD and signs of early sensitisation appeared to benefit more from early tacrolimus than corticosteroid treatment. Small children may need stronger but nevertheless safe ointment options when treating moderate-to-severe AD.

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.

The Value of FLG Null Mutations in Predicting Treatment Response in Atopic Dermatitis: An Observational Study in Finnish Patients.

The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response.

High serum total IgE predicts poor long-term outcome in atopic dermatitis.

Most patients with severe atopic dermatitis have elevated serum IgE levels, but there has been little research into IgE as a predictive biomarker in long-term disease outcome. The aim of this study was to evaluate the predictive value of IgE and other factors in patients with atopic dermatitis in a university clinic setting. There were 169 eligible patients (14-78 years) with a mean follow-up of 4.15 years. High baseline IgE (≥ 10,000 IU/ml) was the most important patient-related factor for a poor long-term outcome, being negatively associated with good treatment response (odds ratio (OR) 0.062, p = 0.002). Only 14.3% of patients with this high baseline IgE achieved a good treatment response in follow-up, compared with 79.7% in patients with lower (< 1,000) IgE values (p < 0.001). Serum total IgE may provide an easily measurable way to predict long-term outcome, and to help to select those patients in need of closer follow-up.

An update on current pharmacotherapy options in atopic dermatitis.

INTRODUCTION: New knowledge on the pathogenesis of atopic dermatitis (AD) gives us new treatment options. This review emphasizes long-term treatment results. AREAS COVERED: This study includes basic pathogenic factors in AD and presents present and future treatment options. Topical corticosteroids treat the inflammation effectively short term. Topical calcineurin inhibitors (TCIs) show better benefit/risk ratio in long-term treatment. For topical treatment, an effective maintenance treatment results in optimal control of the AD. Of systemic immunosuppressive treatments, efficacy has been shown with azathioprine, ciclosporin, methotrexate and mycophenolate-free sodium. With these compounds, the treatment outcome was ~ 50% improvement in clinical signs compared with baseline. New treatments under study include systemic compounds, which suppress the T helper type 2 cells. The importance of adherence to treatment is often overlooked, although it has a major impact on treatment outcome. For the present review, PubMed was used as a primary source. EXPERT OPINION: Combination of future T(H)2-specific systemic treatment with optimal topical treatment with TCI, especially tacrolimus ointment, could help to completely control the skin inflammation in AD. The ultimate goal is to control AD completely, which should help to control the atopic airway disease as well.

Long-term efficacy and tolerability of tacrolimus 0.03% ointment in infants:* a two-year open-label study.

BACKGROUND: Tacrolimus ointment is effective for treatment of moderate to severe atopic dermatitis (AD) in children aged ≥2 years (Br J Dermatol, 2004; 150: 554). Here, efficacy and tolerability of tacrolimus 0.03% ointment were evaluated in 50 infants aged <2 years at start of treatment. METHODS: Infants with AD previously enrolled in a tacrolimus ointment pharmacokinetics trial were eligible for a 24-month open-label phase II study. Tacrolimus 0.03% ointment was applied to affected areas until clearance. In cases of exacerbation or clinical worsening, patients restarted treatment. RESULTS: Mean ± SD Eczema Area and Severity Index (EASI) score improved, from 11.2 ± 10.5 baseline to 2.6 ± 4.1 at endpoint (24 months); mean affected body surface area decreased from 25.2 ± 21.1% to 5.1 ± 9.0%, with improvement on all items of the Physicians' Assessment of Individual Signs. The Physicians' Global Evaluation of Clinical Response showed a result of "cleared"/"excellent" for 63.3% of patients; 85.7% of parents/guardians assessed symptoms as "much better." Treatment was well tolerated, with common, nonserious respiratory infections and gastroenteritis the most frequently reported adverse events. The most common application-site events were infections and pruritus. Over 98% of blood samples showed tacrolimus concentrations <1.0 ng/ml; >40% showed concentrations below the lower limit of quantification (0.0250 ng/ml). CONCLUSIONS: Over a period of two years, tacrolimus 0.03% ointment was associated with substantial clinical improvement of AD in infants aged <2 years. Treatment tolerability was similar to that seen in older children.