Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. METHODS: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). RESULTS: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. CONCLUSIONS: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.

Determinants of Depressive Symptoms, Quality of Life, Subjective Health Status and Physical Limitation in Patients with Systemic Sclerosis.

Systemic sclerosis is a progressive connective tissue disease for which there is limited knowledge about physical limitations, quality of life and depression. The aim of this study was to assess these parameters during the disease process of systemic sclerosis, in a cross- sectional study of 79 patients and a longitudinal study of 33 patients over 10 years. Medical data were collected by physicians' questionnaires and sociodemographic data, pain, physical limitation, quality of life, subjective health status, risk of depressive symptoms by patients' questionnaires. Data analysis was descriptive and exploratory. Cross-tabulations, χ2 test and Student's t-test were used for calculations, Pearson's correlation to measure dependencies, and logistic regression analyses for categorized parameters. The cross-sectional analysis of 79 patients with systemic sclerosis (81% female, mean ± standard deviation age 61.5 ± 12.6 years) demonstrated a higher rate of patients with risk of depressive symptoms (42.3%) higher physical limitations, lower quality of life, and subjective health status than reference values for the general German population. Moderate to strong correlations between disease-related physical limitation, quality of life, subjective health status, risk of depressive symptoms and pain were detected (correlation according to Pearson -0.459 to -0.638, p < 0.001). Longitudinal analysis revealed a significant increase in disease activity, pain, physical limitation and risk of depressive symptoms (p < 0.001) during the disease process. This study demonstrates that nearly half of patients with systemic sclerosis probably experience depressive symptoms. The rate of patients with risk of depressive symptoms, pain and physical limitations increased during the systemic sclerosis disease process. Health-related quality of life and state of health declined, indicating the need for better interdisciplinary care for patients with systemic sclerosis.

Itching in Atopic Dermatitis: Patient- and Physician-reported Outcomes in the German Atopic Dermatitis Registry TREATgermany.

TREATgermany is an investigator-initiated prospective disease registry. It investigates physician- and patient-reported disease severity (Eczema Area and Severity Index (EASI), objective Scoring Atopic Dermatitis (oSCORAD), Investigator Global Assessment, Patient-Oriented Eczema Measure (POEM), Patient Global Assessment (PGA)), patient-reported symptoms (itch, sleep loss, depressive symptoms), therapy courses and dermatological quality of life (DLQI) in moderate-to-severe atopic dermatitis with SCORAD > 20. 1,134 atopic dermatitis patients (mean age 41.0 ± 14.7 years, 42.5% females) were enrolled by 40 German recruiting sites (dermatological clinics and practices) between June 2016 and April 2021. The current analysis focuses on itch scores obtained with a numerical rating scale (NRS)) documented for the previous 3 days prior to baseline visit. The results show that 97.2% (1,090 of 1,121) patients experienced itch. Itch severity correlated moderately with severity of atopic dermatitis oSCORAD (rho = 0.44 (0.39-0.48)) and EASI score (rho = 0.41 (0.36-0.46)). A strong correlation was found with self-reported disease severity as PGA (rho = 0.68 (0.65-0.71)), POEM sum score (rho = 0.66 (0.63-0.69)) and dermatological quality of life impairment DLQI (rho = 0.61 (0.57-0.65)). Itch as a subjective complaint is more closely correlated with patient-reported outcomes than with objective assessments by the physician.

Mapping exercise and status update of eight established registries within the TREatment of ATopic eczema Registry Taskforce.

BACKGROUND: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection. OBJECTIVES: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data. METHODS: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset). RESULTS AND CONCLUSIONS: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses.

The effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis: Results from the global SECURE-AD registry.

BACKGROUND: Limited data are available on the effects of systemic immunomodulatory treatments on COVID-19 outcomes in patients with atopic dermatitis (AD). OBJECTIVE: To investigate COVID-19 outcomes in patients with AD treated with or without systemic immunomodulatory treatments, using a global registry platform. METHODS: Clinicians were encouraged to report cases of COVID-19 in their patients with AD in the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Atopic Dermatitis (SECURE-AD) registry. Data entered from 1 April 2020 to 31 October 2021 were analysed using multivariable logistic regression. The primary outcome was hospitalization from COVID-19, according to AD treatment groups. RESULTS: 442 AD patients (mean age 35.9 years, 51.8% male) from 27 countries with strongly suspected or confirmed COVID-19 were included in analyses. 428 (96.8%) patients were treated with a single systemic therapy (n = 297 [67.2%]) or topical therapy only (n = 131 [29.6%]). Most patients treated with systemic therapies received dupilumab (n = 216). Fourteen patients (3.2%) received a combination of systemic therapies. Twenty-six patients (5.9%) were hospitalized. No deaths were reported. Patients treated with topical treatments had significantly higher odds of hospitalization, compared with those treated with dupilumab monotherapy (odds ratio (OR) 4.65 [95%CI 1.71-14.78]), including after adjustment for confounding variables (adjusted OR (aOR) 4.99 [95%CI 1.4-20.84]). Combination systemic therapy which did not include systemic corticosteroids was associated with increased odds of hospitalization, compared with single agent non-steroidal immunosuppressive systemic treatment (OR 8.09 [95%CI 0.4-59.96], aOR 37.57 [95%CI 1.05-871.11]). Hospitalization was most likely in patients treated with combination systemic therapy which included systemic corticosteroids (OR 40.43 [95%CI 8.16-207.49], aOR 45.75 [95%CI 4.54-616.22]). CONCLUSIONS: Overall, the risk of COVID-19 complications appears low in patients with AD, even when treated with systemic immunomodulatory agents. Dupilumab monotherapy was associated with lower hospitalization than other therapies. Combination systemic treatment, particularly combinations including systemic corticosteroids, was associated with the highest risk of severe COVID-19.

Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis.

BACKGROUND: Few studies have analyzed the blood transcriptome in atopic dermatitis (AD). OBJECTIVE: We explored blood transcriptomic features of moderate to severe AD. METHODS: Blood messenger RNA sequencing on 60 adults from the TREATgermany registry including 49 patients before and after dupilumab treatment, as well as from an independent cohort of 31 patients and 43 controls was performed. Patient clustering, differential expression, correlation and coexpression network analysis, and unsupervised learning were conducted. RESULTS: AD patients showed pronounced inflammatory expression signatures with increased myeloid and IL-5-related patterns, and clearly segregated into 2 distinct clusters, with striking differences in particular for transcripts involved in eosinophil signaling. The eosinophil-high endotype showed a more pronounced global dysregulation, a positive correlation between disease activity and signatures related to IL-5 signaling, and strong correlations with several target proteins of antibodies or small molecules under development for AD. In contrast, the eosinophil-low endotype showed little transcriptomic dysregulation and no association between disease activity and gene expression. Clinical improvement with receipt of dupilumab was accompanied by a decrease of innate immune responses and an increase of lymphocyte signatures including B-cell activation and natural killer cell composition and/or function. The proportion of super responders was higher in the eosinophil-low endotype (32% vs 11%). Continued downregulation of IL18RAP, IFNG, and granzyme A in the eosinophil-high endotype suggests a residual disturbance of natural killer cell function despite clinical improvement. CONCLUSION: AD can be stratified into eosinophilic and noneosinophilic endotypes; such stratification may be useful when assessing stratified trial designs and treatment strategies.

High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis.

BACKGROUND: Eczema herpeticum (EH) is a disseminated skin infection caused by herpes simplex virus in atopic dermatitis (AD) patients. The frequency of EH and the clinical features of EH patients have not yet been investigated in a larger cohort. METHODS: We sought to investigate the TREATgermany cohort, a multicenter, non-interventional clinical registry of moderately to severely affected AD patients in Germany. Baseline characteristics of patients included between December 2017 and April 2021 were compared between patients without, single, and multiple EH. RESULTS: Of the 893 patients, 195 (21.8%) had at least one EH. Of the 195 patients with EH, 107 had multiple EH (54.9%), representing 12.0% of the total study population. While there were no differences in demographic characteristics, previous treatment, and disease scores at enrollment (itch, IGA, oSCORAD, EASI), patients with EH had more frequent atopic comorbidities and sensitizations to house dust mite, food, and mold. DISCUSSION: TREATgermany registry data suggest a high prevalence and recurrence rate of EH, while there appears to be no specific clinical phenotype, besides an increase in allergies, to identify EH patients in the daily routine.

Itch, sleep loss, depressive symptoms, fatigue, and productivity loss in patients with moderate-to-severe atopic dermatitis: Analyses of TREATgermany registry data.

BACKGROUND: TREATgermany is a multicenter registry including patients with moderate-to-severe atopic dermatitis (AD) from currently 74 study centers (university clinics, hospitals and practices) in Germany. As of August 31, 2021, 1,230 adult patients were enrolled. METHODS: In TREATgermany, patients and physicians fill in questionnaires pertaining to symptoms, disease severity, quality of life, depressiveness, and fatigue. In particular, limitations in work performance are assessed using the Work Limitations Questionnaire (WLQ). To assess associations between occupational performance/work limitations and symptoms, correlations and regression models were calculated. RESULTS: The examined sample of 228 employed patients reported an average of 6% at-work productivity loss within the past two weeks prior to enrolment in the registry. The WLQ productivity loss score was moderately associated with itch (r = 0.32) and sleep loss (r = 0.39) and strongly associated with depressive symptoms (r = 0.68) and fatigue (r = 0.60). CONCLUSIONS: The analyses of the registry data show that moderate-to-severe atopic dermatitis has a negative impact on the work productivity of the patients. The analyses further point out the relevant associations between work productivity, depressive symptoms, and fatigue highlighting the disease burden caused by the psychological components of AD.

Real-world data on the effectiveness, safety and drug survival of dupilumab: an analysis from the TREATgermany registry.

This interim analysis from the atopic dermatitis registry TREATgermany shows robust long-term efficacy, favourable safety and high persistence of dupilumab under real life conditions.

Atopic dermatitis displays stable and dynamic skin transcriptome signatures.

BACKGROUND: Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as "improvement" under therapy. These observations were mainly made in trials and based on microarray data. OBJECTIVES: Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry. METHODS: Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted. RESULTS: Both lesional and nonlesional skin showed a stable "core" signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, TH17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized TH17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab. CONCLUSION: The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of TH17 and natural killer cell signaling.

Elevated NK-cell transcriptional signature and dysbalance of resting and activated NK cells in atopic dermatitis.

BACKGROUND: Altered quantities, activity, and composition of natural killer (NK) cells in blood as well as expression changes of genes involved in NK-cell function in skin lesions of patients with atopic dermatitis (AD) were recently reported. OBJECTIVES: We sought to comprehensively analyze cutaneous NK-cell transcriptomic signatures in AD, and to examine changes under treatment. METHODS: We analyzed NK-cell signatures in skin transcriptome data from 57 patients with moderate to severe AD and 31 healthy controls. In addition, changes after 12 weeks of systemic treatment (dupilumab n = 21, cyclosporine n = 8) were analyzed. Deconvolution of leucocyte fractions was conducted. Immunofluorescence staining of NK cells was performed on paraffin-embedded skin sections. RESULTS: Immunofluorescence staining revealed a relatively high abundance of both NK cells and CD3+CD56+ cells in lesional as compared with nonlesional and healthy skin. Lesional and to a lesser extent nonlesional skin showed a strong upregulation of NK-cell markers together with a dysbalanced expression of inhibitory and activating receptors, which was not reverted under treatment. Digital cytometry showed a decrease in activated and an increase in resting NK cells in both lesional and nonlesional skin, which was reverted by both treatment with dupilumab and cyclosporine. The NK-cell transcriptomic signature remained upregulated after treatment, but there was a shift on the qualitative level, indicating a compositional change in NK-cell subsets toward CD56bright NK cells. CONCLUSIONS: Lesional AD skin shows a NK-cell dysregulation, which despite clinical improvement under systemic therapy was only partially reverted, and which may represent a yet underappreciated disease mechanism.

Perception of the coronavirus pandemic by patients with atopic dermatitis - Results from the TREATgermany registry.

BACKGROUND: TREATgermany, a registry for patients with moderate to severe atopic dermatitis (AD), established an additional questionnaire in spring 2020 to investigate the effects of the coronavirus pandemic on the daily life of patients with AD. MATERIAL AND METHODS: A questionnaire was used to analyze general information regarding a patient's experience of the coronavirus pandemic and, using the Inventory of Life-Changing Events, the resulting personal burden. To analyze possible associations between disease severity (EASI score, oSCORAD, IGA, PGA, POEM), quality of life (DLQI) and personal burden, t-tests, analyses of variance and correlations were evaluated, controlled for sex and age. RESULTS: 58 % (n = 233) of the included 400 registry patients reported high burden scores caused by the coronavirus pandemic, regardless of an actual infection. Men showed significantly higher burden scores than women, and younger than older respondents (both P = 0.03). There were no differences in burden scores related to the physician's assessment of disease severity. However, patients with higher quality of life impairments and higher disease severity perceived the burden of the coronavirus pandemic as less severe (DLQI P = 0.019, PGA P = 0.044). CONCLUSIONS: Our data show that registry patients considered the coronavirus pandemic as a life-changing event and perceived the burden differently. This should be taken into account in the treatment of patients with moderate to severe AD as well as in further studies.

Health utilities for controlled and uncontrolled chronic hand eczema in healthcare employees.

BACKGROUND: Health utilities provide a universally applicable method for measuring the relative preferences or values of specific health states. Health economic studies use health utilities to estimate disease burden and the cost-effectiveness of interventions. Chronic hand eczema (CHE) affects many individuals and adversely affects work productivity. Health utilities for CHE from the perspective of healthcare professionals are lacking. OBJECTIVES: To assess health utilities for CHE from the perspectives of employees in the healthcare sector and affected patients. METHODS: A cross-sectional study with volunteers from the healthcare sector (n = 126) and patients (n = 32) was conducted to establish health utilities (ranging from 1 = perfect health to 0 = death) for mild and severe CHE. RESULTS: The median health utilities of the healthy volunteers derived with the time trade-off method were 0.97 (mean: 0.92) for mild CHE and 0.77 (mean: 0.75) for severe CHE. The median health utilities for mild and severe CHE from the perspective of affected patients were 0.98 (mean: 0.91) and 0.82 (mean: 0.77), respectively. Differences in health utilities between the two study groups were not significant. CONCLUSION: CHE constitutes a considerable burden from the perspective of healthcare employees. Effective control of CHE constitutes an important public health goal.

Association between aircraft, road and railway traffic noise and depression in a large case-control study based on secondary data.

BACKGROUND: Few studies have examined the relationship between traffic noise and depression providing inconclusive results. This large case-control study is the first to assess and directly compare depression risks by aircraft, road traffic and railway noise. METHODS: The study population included individuals aged ≥40 years that were insured by three large statutory health insurance funds and were living in the region of Frankfurt international airport. Address-specific exposure to aircraft, road and railway traffic noise in 2005 was estimated. Based on insurance claims and prescription data, 77,295 cases with a new clinical depression diagnosis between 2006 and 2010 were compared with 578,246 control subjects. RESULTS: For road traffic noise, a linear exposure-risk relationship was found with an odds ratio (OR) of 1.17 (95% CI=1.10-1.25) for 24-h continuous sound levels ≥70dB. For aircraft noise, the risk estimates reached a maximum OR of 1.23 (95% CI=1.19-1.28) at 50-55dB and decreased at higher exposure categories. For railway noise, risk estimates peaked at 60-65dB (OR=1.15, 95% CI=1.08-1.22). The highest OR of 1.42 (95% CI=1.33-1.52) was found for a combined exposure to noise above 50dB from all three sources. CONCLUSIONS: This study indicates that traffic noise exposure might lead to depression. As a potential explanation for the decreasing risks at high traffic noise levels, vulnerable people might actively cope with noise (e.g. insulate or move away).