Content validity of the EQ-5D-5L with skin irritation and self-confidence bolt-ons in patients with atopic dermatitis: a qualitative think-aloud study.

OBJECTIVES: Two bolt-on dimensions (skin irritation, self-confidence) have been developed for the EQ-5D-5L to improve its content validity and responsiveness in psoriasis. However, the two bolt-ons are not strictly psoriasis-specific and are potentially relevant in other skin conditions. This study aims to explore the content validity of the EQ-5D-5L with two bolt-ons in patients with atopic dermatitis (AD). METHODS: In 2021-2022, qualitative, semi-structured interviews were conducted with 20 adult AD patients at a university dermatology clinic in Hungary. We aimed for a heterogeneous sample in terms of age, gender, education and disease severity. Patients completed the EQ-5D-5L with two bolt-ons using a think-aloud protocol. Probing questions were posed to investigate item relevance, potential conceptual overlaps, missing concepts and the appropriateness of the recall period. Interview transcripts were subjected to thematic analysis. RESULTS: The EQ-5D-5L with the two bolt-ons covered the most important aspects of health-related quality of life in AD patients. Most patients found both the skin irritation and self-confidence bolt-ons relevant. Fifteen potential missing concepts were identified, but only two (social relationships, judgement by others) were identified by more than one patient. A smaller conceptual overlap was found between the skin irritation and pain/discomfort dimensions in 7 patients (35%). Half the patients expressed a preference for a recall period of 1 week rather than of 'today'. CONCLUSIONS: The EQ-5D-5L with skin irritation and self-confidence bolt-ons showed good relevance, comprehensiveness and comprehensibility in patients with AD. However, in terms of comprehensiveness, social relationships and judgement by others (stigma) may be missing from the questionnaire.

Significant improvement in melanoma survival over the last decade: A Hungarian nationwide study between 2011 and 2019.

BACKGROUND: Recent real-world studies have reported significant improvements in the survival of malignant melanoma in the past few years, mainly as a result of modern therapies. However, long-term survival data from Central Eastern European countries such as Hungary are currently lacking. METHODS: This nationwide, retrospective study examined melanoma survival in Hungary between 2011-2019 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Crude overall survival and age-standardized 5-year net survival as well as the association between age, sex and survival were calculated. RESULTS: Between 2011 and 2019, 22,948 newly diagnosed malignant melanoma cases were recorded in the NHIF database (47.89% male, mean age: 60.75 years (SD: ±16.39)). Five-year overall survival was 75.40% (women: 80.78%; men: 69.52%). Patients diagnosed between 2017-2019 had a 20% lower risk of mortality compared to patients diagnosed between 2011-2012 (HR 0.80, 95% CI 0.73-0.89; p < 0.0001). Age-standardized 5-year net survival rates in 2011-2014 and 2015-2019 were 90.6% and 95.8%, respectively (women: 93.1% and 98.4%, men: 87.8% and 92.7%, respectively). The highest age-standardized 5-year net survival rates were found in the 0-39 age cohort (94.6% in the 2015-2019 period). CONCLUSION: Hungary has similar melanoma survival rates to Western European countries. Based on net survival, the risk of dying of melanoma within 5 years was cut by more than half (55%) during the study period, which coincides with the successful implementation of awareness campaigns and the wide availability of modern therapies.

Drug Delivery through the Psoriatic Epidermal Barrier-A "Skin-On-A-Chip" Permeability Study and Ex Vivo Optical Imaging.

Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the current study, imiquimod-induced psoriasiform dermatitis was used for monitoring the changes in skin thickness, transepidermal water loss, body weight, blood perfusion and drug permeability for a topical cream formulation of caffeine, both in wild type and in knock out mice. Morphological characterization of control and diseased tissues was performed by scanning electron microscopy and two-photon microscopy. The chemically induced psoriatic group showed increased skin permeability for the model drug during disease progression. In wild type and TRPA1 KO mice, however, enhanced skin thickness and hyperkeratosis blocked further increase of drug penetration at the late phase (96 h). These results indicate that topical drug therapy can be more effective in early phases of plaque development, when skin thickness is lower. Although paracellular connections (tight junctions) are looser in the advanced phase, hyperkeratosis blocks drug delivery through the transappendageal routes. Novel drug formulations may have the potency for effective drug delivery across the epidermal barrier even in the advanced phase. For development of more effective topical drugs, further research is proposed to explore drug penetration both in healthy and diseased conditions.

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples.

Psoriasis is a systemic inflammatory skin disorder that can be associated with sleep disturbance and negatively influence the daily rhythm. The link between the pathomechanism of psoriasis and the circadian rhythm has been suggested by several previous studies. However, there are insufficient data on altered clock mechanisms in psoriasis to prove these theories. Therefore, we investigated the expression of the core clock genes in human psoriatic lesional and non-lesional skin and in human adult low calcium temperature (HaCaT) keratinocytes after stimulation with pro-inflammatory cytokines. Furthermore, we examined the clock proteins in skin biopsies from psoriatic patients by immunohistochemistry. We found that the clock gene transcripts were elevated in psoriatic lesions, especially in non-lesional psoriatic areas, except for rev-erbα, which was consistently downregulated in the psoriatic samples. In addition, the REV-ERBα protein showed a different epidermal distribution in non-lesional skin than in healthy skin. In cytokine-treated HaCaT cells, changes in the amplitude of the bmal1, cry1, rev-erbα and per1 mRNA oscillation were observed, especially after TNFα stimulation. In conclusion, in our study a perturbation of clock gene transcripts was observed in uninvolved and lesional psoriatic areas compared to healthy skin. These alterations may serve as therapeutic targets and facilitate the development of chronotherapeutic strategies in the future.

The association of HLA-C and ERAP1 polymorphisms in early and late onset psoriasis and psoriatic arthritis patients of Hungary.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) of the HLA-C and ERAP1 genes were recently determined to contribute to psoriasis susceptibility. However, data regarding the association of these genes with specific subgroups of psoriasis are scarce. AIM: To examine the possible association of the HLA-C and ERAP-1 polymorphisms with early and late onset psoriasis and psoriatic arthritis. MATERIAL AND METHODS: Five ERAP1 SNPs and two HLA-C SNPs were genotyped in 105 psoriatic arthritis patients, 214 cutaneous psoriasis patients and 200 healthy individuals. Haplotypes were constructed for three ERAP1 SNPs (rs17482078, rs10050860, rs30187), and interaction between HLA-Cw*0602 and ERAP1 was also analysed. RESULTS: The HLA-Cw*0602 rs10484554 SNP was found to be a strong susceptibility factor for early onset cutaneous psoriasis and early onset psoriatic arthritis. ERAP1 SNPs (rs10050860, rs17482078, rs27525) appear to have a protective function for early onset psoriatic arthritis. The haplotype B was identified as a susceptibility factor for late onset psoriatic arthritis. In HLA-C positive individuals the rs27524 ERAP1 SNP was associated with a significantly increased risk of psoriatic arthritis development, whereas the rs27525 ERAP1 SNP had the opposite effect. CONCLUSIONS: These results suggest that the HLA-C and ERAP1 genes contribute to the pathogenesis of psoriasis and psoriatic arthritis in an age-dependent manner.

Efficacy of Biologics Targeting Tumour Necrosis Factor-alpha, Interleukin-17 -12/23, -23 and Small Molecules Targeting JAK and PDE4 in the Treatment of Nail Psoriasis: A Network Meta-analysis.

The comparative efficacy of registered anti-psoriatic biologics and small molecules in treating nail symptoms has not been systematically evaluated. The aim of this study was to perform a network meta-analysis to determine the efficacy of biologics and small mole-cules in nail psoriasis. A Bayesian network meta- analysis of 17 randomized clinical trials (a total of 6,053 nail psoriatic patients) was performed, comparing the short-term (week 10-16) efficacy of biologics and small molecules in the treatment of nail psoriasis. All active treatments were found to be superior to place-bo. Ixekizumab 80 mg every 4 weeks (Nail Psoriasis Severity Index (NAPSI) % improvement, Surface Under the Cumulative Ranking (SUCRA)=0.92) and etanercept 50 mg twice weekly (probability of achiev-ing NAPSI 50, SUCRA=0.82) proved the best short-term treatment options. However, efficacy end-points in psoriasis trials were not optimized for nail assessment, and outcome parameters were highly heterogeneous, limiting comparability. In conclusion, outcome parameters and efficacy endpoints of nail psoriasis trials should be standardized.

[How to choose the optimal therapy? New issues in the treatment of metastatic melanoma]. / Hogyan válasszunk megfelelõ szert? Új kérdések az áttétes melanoma kezelésében.

The last few years brought about a complete paradigm-shift in the field of melanoma therapy: eight new drugs, including three immunooncologic, four targeted and one oncolytic virus, became available in the daily practice. These new treatments provide a significantly increased overall survival potential for patients with metastatic melanoma. Choosing the optimal treatment for the individual patient, however, requires the careful evaluation of several patient- and drug-related factors, and poses a great challenge for the oncologists. This review summarizes the practical aspects of the selection of the optimal melanoma treatment.

Interleukin-1 receptors are differentially expressed in normal and psoriatic T cells.

This study was carried out to examine the possible role of interleukin-1 (IL-1) in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4(+)CD25(-) effector and CD4(+)CD25(+)CD127(low) regulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2) was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1) mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2) upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis.

Do not forget the stool examination!-cutaneous and gastrointestinal manifestations of Blastocystis sp. infection.

Blastocystis sp. is one of the most common parasites in the human intestinal tract. This infection commonly is accompanied by diarrhoea and abdominal pain, but extraintestinal symptoms, such as skin lesions, may also accompany the disease. In this study, our aim was to assess the frequency, clinical symptoms and skin manifestations of confirmed positive Blastocystis sp. infections. Data of 80 patients with confirmed positive Blastocystis sp. infections were assessed retrospectively. The average age of the patients was 46.3 years of age (with a range between 13 and 85 years of age). The number of female patients was higher than the number of males (48 vs. 32; 60 vs. 40%). Gastrointestinal and dermatological symptoms and the results of routine biochemical and haematological blood tests of enrolled patients were collected and analyzed. The skin manifestations were analyzed using the data available (including descriptions, photos and histologies). We discovered that 11.25% of our enrolled patients exhibited skin manifestations associated to Blastocystis sp., mainly on the females. The occurrence of Blastocystis sp. was 6% in symptomatic patients who required medical attendance in the time period between 2005 and 2013. Of the 80 patients, 73.75% indicated that they had gastrointestinal symptoms: 40 patients complained of abdominal pain and 17 with blood in their stool, while other symptoms, such as meteorism (15 subjects), weigh loss (8 subjects), perianal pain or itching (6 subjects), passing stool with mucus (5 subjects), vomiting (2 subjects) and fever (2 subjects) were less frequent. The prevalence of abdominal pain in the cohort without skin lesions was higher compared to those patients with skin problems (p = 0.007). The mean value of C-reactive protein showed elevated levels, but eosinophils were within a normal range. In addition, we did not find significant difference in eosinophilia between patients with vs. without skin manifestations. Thus, we suggest that eosinophilia is not an obligatory laboratory finding in protozoon infections, such as Blastocystis sp. In the light of our results, we suggest a stool parasite examination for patients with skin lesions of unknown origin.

Tumour regression predicts better response to interferon therapy in melanoma patients: a retrospective single centre study.

We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan-Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1-T4) of the primary tumour. Regression was significantly positively related to PFS ( P  = 0.0018, HR = 0.352) and OS ( P  = 0.0112, HR = 0.380), while ulceration showed a negative effect (PFS: P  = 0.0001, HR = 2.629; OS: P  = 0.0003, HR = 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.

Higher levels of autoantibodies targeting mutated citrullinated vimentin in patients with psoriatic arthritis than in patients with psoriasis vulgaris.

Antibodies against citrullinated proteins/peptides (ACPAs), and especially antibodies targeting mutated citrullinated vimentin (anti-MCVs), are novel biomarkers of rheumatoid arthritis (RA). Whereas ACPAs are specific and sensitive markers for RA, there have hardly been any reports relating to ACPAs in psoriatic arthritis (PsA) or in psoriasis without joint symptoms (PsO). The aim of the present study was to investigate the prevalence of anti-MCVs in PsA and PsO. Serum anti-MCV titers were measured in 46 PsA and 42 PsO patients and in 40 healthy controls by means of a commercial enzyme-linked immunosorbent assay. The potential correlations of the serum autoantibody levels with several clinical and laboratory parameters were examined. The anti-MCV levels in the PsA patients were significantly higher than those in the PsO group. Among the clinical variables, the presence of tender knee joints and nail psoriasis was significantly associated with anti-MCV positivity in the PsA patients. Higher anti-MCV titers in the PsO patients were associated with a more severe disease course and with the early onset of psoriatic skin symptoms. Our results suggest that anti-MCVs can be used as novel markers in the diagnosis of PsA and in a subset of PsO patients.

[Surgery for malignant melanoma - Expected standards]. / A melanoma malignum sebészeti ellátása ­ Elvárható standardok.

Melanoma surgery has changed significantly in recent years. The highly radical operations with many complications, in addition to which the complete and disease-free survival remained low, were gradually replaced by less radical operations. With the introduction of new systemic treatments (targeted and immuno-oncological) in adjuvant indications, certain surgeries, such as elective block dissections, have now been displaced from surgical treatments and the role of surgery has also been re-evaluated. The surgery for primary tumor removal, reexcision, sentinel lymph node biopsy and lymph region surgery, and surgical treatment of skin and distant metastases have changed. In this summary communication, the authors provide an overview of the currently accepted surgical therapy of melanoma malignum based on the international literature and their own practice.

[Dermoscopy of inflammatory skin diseases]. / Dermatoskopie entzündlicher Hauterkrankungen.

The dermoscope was initially used in dermatology to distinguish between pigmented and nonpigmented tumors, both benign and malignant. Over the last two decades, however, the spectrum of dermoscopy has broadened and its role in the diagnosis of nonneoplastic diseases, in particular inflammatory skin diseases, has become increasingly important. In the diagnosis of general and inflammatory skin diseases, it is recommended that dermoscopic evaluation should be performed after clinical examination. In the following summary, the dermoscopic features of the most common inflammatory skin diseases are described. Among the detailed parameters are the vascular structures, color, scaling, follicular findings, and specific signs associated with each disease.

Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome is a rare multisystemic disease, characterized by numerous basal cell carcinomas. The ideal approach for patients with the syndrome would be a treatment with a high cure rate, minimal scarring, short healing time and mild side-effects. Electrochemo-therapy is a novel therapeutic option that ablates tumours with electrical current and simultaneously administered anticancer drugs. Three patients with Gorlin-Goltz syndrome were treated with electrochemotherapy using intravenous bleomycin. Clinical response was obtained in 98 (99%) of the lesions, 86 (87%) of them showed complete response. In 2 tumours, regression was confirmed with histological examination. Long-term cosmetic results were excellent. We consider electrochemotherapy to be an additional tool in the therapeutic armamentarium for Gorlin-Goltz syndrome, and suggest using it as early as possible in selected patients to avoid disfiguring scarring.

[Fluorescence diagnosis of non-melanoma skin cancer]. / Hámeredetu bordaganatok fluoreszcens diagnosztikája.

Photodynamic therapy involves - in dermatological practice usually exogenous - application of a photosensitizer then activation of accumulated protoporphyrin IX by light with an appropriate wavelength after a short incubation period. It is an evidence based method to treat certain non-melanoma skin cancers. During treatment when the excited protoporphyrin IX returns to base state, reactive oxygen species are formed leading to cell death in rapidly proliferating cells. Fluorescence of excited protoporphyrin IX can be used in diagnostics as well. In ultraviolet light, the photodamaged or neoplastic areas show coral red fluorescence which can clearly be distinguished from the much lower fluorescence of adjacent normal tissue. This process is suitable for exact determination of tumor margins so it can be used for planning surgical procedures or after photodynamic therapy at a follow up visit for the visualization of the therapeutic result. The present article reviews the literature of photodynamic diagnosis that is also used by the authors.

Comparison of the Objective Severity and the Esthetic Perception of Nail Symptoms in Psoriasis.

Introduction: Nail changes are frequent in psoriasis, and the negative impact of nail psoriasis on patients' quality of life is well known. No data are available however about the association of the objective severity of nail psoriasis and the subjective perception of these symptoms. The purpose of this study was to determine the correlation between the severity of psoriatic nail changes (as determined by the Nail Psoriasis Severity Index [NAPSI]) and the esthetic assessment of nail psoriasis. Methods: Participants (general population and psoriasis patients) were asked to rate 19 nail images (including psoriatic and healthy nails) on a 0-10 scale, based on how disturbing they considered them esthetically. Objective severity (NAPSI) scores of nails were compared to the subjective evaluation values. Results: Nail symptom severity correlated well with the subjective scores. However, while nails with low (0) and high (6-8) NAPSI values received consistent subjective scores, the esthetic perception of nails with moderate NAPSI scores was rather heterogeneous. The age of the respondents showed robust positive correlation with the subjective assessment of nail symptoms both within the psoriatic and the general population. Discussion: Gender, the presence of psoriasis, or medical education had no significant influence on the esthetic assessment of psoriatic nail changes.

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation.

Transient Receptor Potential Ankyrin 1 (TRPA1) has been reported to influence neuroinflammation and lymphocyte function. We analysed the immune phenotype and activation characteristics of TRPA1-deficient mice (knockout-KO) generated by targeted deletion of the pore-loop domain of the ion channel. We compared TRPA1 mRNA and protein expression in monocyte and lymphocyte subpopulations isolated from primary and secondary lymphatic organs of wild type (WT) and KO mice. qRT-PCR and flow cytometric studies indicated a higher level of TRPA1 in monocytes than in lymphocytes, but both were orders of magnitude lower than in sensory neurons. We found lower CD4+/CD8+ thymocyte ratios, diminished CD4/CD8 rates, and B cell numbers in the KO mice. Early activation marker CD69 was lower in CD4+ T cells of KO, while the level of CD8+/CD25+ cells was higher. In vitro TcR-mediated activation did not result in significant differences in CD69 level between WT and KO splenocytes, but lower cytokine (IL-1ß, IL-6, TNF-α, IL-17A, IL-22, and RANTES) secretion was observed in KO splenocytes. Basal intracellular Ca2+ level and TcR-induced Ca2+ signal in T lymphocytes did not differ significantly, but interestingly, imiquimod-induced Ca2+ level in KO thymocytes was higher. Our results support the role of TRPA1 in the regulation of activation, cytokine production, and T and B lymphocytes composition in mice.

Hemizygous nonsense variant in the moesin gene (MSN) leads to a new autoimmune phenotype of Immunodeficiency 50.

Here, we present the findings of an investigation involving two male siblings with juvenile total tooth loss, early-onset chronic leg ulcers, and autoimmune thyroiditis, as well as focal segmental glomerulosclerosis with associated pulmonary emphysema in one and diabetes mellitus in the other. The clinical picture and lupus anticoagulant, cryoglobulin, and cold agglutinin positivity suggested the diagnosis of antiphospholipid syndrome. Flow cytometry analysis showed immunophenotypes consistent with immune dysregulation: a low number of naive T cells, elevated CD4+ T cell counts, and decreased CD8+ T-cell counts were detected, and more than half of the T-helper population was activated. Considering the siblings' almost identical clinical phenotype, the genetic alteration was suspected in the background of the immunodeficiency. Whole exome sequencing identified a previously not described hemizygous nonsense variant (c.650G>A, p.W217X) within exon 6 of the moesin (MSN) gene localized on chromosome X, resulting in significantly decreased MSN mRNA expression compared to healthy controls. We present a putative new autoimmune phenotype of Immunodeficiency 50 (MIM300988) characterized by antiphospholipid syndrome, Hashimoto's thyroiditis, leg ulcers, and juvenile tooth loss, associated with W217X mutation of the MSN gene.

Influence of FLG loss-of-function mutations in host-microbe interactions during atopic skin inflammation.

BACKGROUND: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. OBJECTIVE: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. METHODS: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (ADMut) (n = 15), along with matched wild-type (ADWt) patients and healthy controls. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. RESULTS: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of ADWt demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional ADWt or ADMut skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. CONCLUSIONS: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont.