CONTEXT AND OBJECTIVE:Mild autonomous cortisol secretion (MACS) is associated with increased mortality, mainly because of cardiovascular disease. Here we investigated the effects of cortisol-lowering medical treatment on blood pressure regulation, cardiac fat depots, heart function and morphology, and other cardiovascular risk factors. DESIGN, SETTING AND INTERVENTION:In this secondary analysis of our prospective, open-label, single-center study at the Medical University of Vienna, we investigated 15 patients with MACS (12 females; age 59 [53-64] years) before and after 12 weeks of treatment with evening doses of metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). OUTCOME MEASURES AND METHODS:Cardiac fat stores, morphology and myocardial function were evaluated using cardiac magnetic resonance imaging and spectroscopy. Orthostatic blood pressure regulation was measured by standardized protocols. Lipidomics, renin-angiotensin-aldosterone-system activity and branched-chain amino acid (BCAA) concentrations were assessed. RESULTS:Mean supine systolic (137[121-139] vs 122[115-129] mmHg; p=0.041) and diastolic (89[80-93] vs 75[71-86] mmHg; p=0.045) blood pressure decreased after treatment in patients without changes in concomitant antihypertensive medication. Epicardial fat was lower at follow up compared to baseline (1032.70[894.23-1482.90] vs 929.37[736.12-1317.15]mm2; p=0.022). No changes in paracardial- and intramyocardial fat, as well as in cardiac function and morphology were observed. The aldosterone-to-angiotensin II ratio was lower at follow up (1.56[0.87-2.82] vs 1.21[0.98-1.92]; p=0.042) and alterations in lipid profiles, but not in BCAA levels were identified. CONCLUSIONS:Treatment with evening doses of metyrapone improved blood pressure and reduced epicardial adipose tissue.

BACKGROUND:Little is known about the clinical characteristics, diagnostic delay and treatment survival in patients with palmoplantar pustulosis (PPP). OBJECTIVES:To analyse the survival rates of patients with PPP in Austria treated with phototherapy, conventional systemic therapies and biologics. METHODS:This was a retrospective study using data from the Psoriasis Registry Austria (PsoRA). The analysis included data collected between 16 May 1997 and 11 April 2024 from patients with PPP. RESULTS:We included data from 190 patients who underwent 397 treatments. Fifty-four per cent of patients (n = 37/69) were initially misdiagnosed as having eczema with a mean (SD) diagnostic delay of 2.8 (4.8) years. Patients were predominantly women (n = 141/190; 74.2%) and smoked (n = 76/98; 78%). Patients were treated with biologics (n = 198/397; 49.9%), phototherapy (n = 100/397; 25.2%) and conventional systemic therapies (n = 99/397; 24.9%). Median survival time for all treatments was 0.6 years [95% confidence interval (CI) 0.5-0.8], with patients on ustekinumab having the longest median survival time of 2.7 years (95% CI 2.3-upper limit not reached), surpassing all other therapies. This superiority disappeared after interleukin (IL)-23p19 inhibitors were introduced in Austria. Compared with biologics, conventional systemic treatments [hazard ratio (HR) 2.17; P < 0.001] and phototherapy (HR 4.43; P < 0.001) were associated with a significantly higher risk of treatment discontinuation. In the overall cohort, disease durations of ≥ 2 to < 10 years (HR 0.66; P = 0.05) and ≥ 10 years (HR 0.59; P = 0.004) significantly reduced the risk of treatment discontinuation, while concomitant plaque psoriasis significantly increased the risk of treatment discontinuation (HR 1.43; P = 0.05). In the biologic cohort, concomitant arthritis (HR 2.11; P = 0.002) and the presence of one comorbid disease (HR 2.34; P = 0.03) increased the risk of treatment discontinuation. Furthermore, sex, age at disease onset and smoking did not influence the risk of treatment discontinuation. CONCLUSIONS:Our findings suggest that more than half of patients with PPP experience a diagnostic delay of several years due to an initial misdiagnosis. Patients on ustekinumab (IL-12/23p40 inhibitor) had the longest treatment survival, although its superiority diminished with the introduction of IL-23p19 inhibitors. Finally, shorter disease duration and concomitant plaque psoriasis is a general risk factor for treatment discontinuation, while the presence of a comorbidity and concomitant psoriatic arthritis are risk factors for discontinuing biologics.

Background:Mild autonomous cortisol secretion (MACS) is associated with an increased morbidity and mortality. Treatment options range from adrenalectomy to conservative management of comorbidities, but evidence on the effects of medical treatment is scarce. We therefore aimed to investigate the metabolic effects of evening metyrapone treatment in patients with MACS. Methods:We did a prospective, open-label, proof-of-concept trial (EudraCT: 2022-000161-40). Patients with uni-or bilateral adrenal incidentaloma and MACS defined by cortisol >1·8 μg/dL after 1 mg-dexamethasone-suppression-testing without clinical signs of Cushing's syndrome were included. Participants were investigated at baseline and after 12 weeks of treatment with metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). Intrahepatic lipid content (IHL) and abdominal visceral/subcutaneous fat mass were measured by magnetic resonance spectroscopy and imaging. Resting blood pressure measurements and blood sampling before and during an oral glucose tolerance test were conducted. IHL was the primary outcome parameter. Wilcoxon-signed-rank-tests were used for statistical analysis. Findings:Between May 2023 and September 2024, 19 patients were enrolled. Fifteen patients were included in the final analysis (12 female, median age 59 years [IQR 53-64]; median BMI 28 kg/m2 [25-32]; median cortisol after 1 mg-dexamethasone-suppression-testing 2·9 μg/dL [2·4-4·6]). Metyrapone treatment significantly lowered median IHL at follow up compared with baseline (3·85% of water signal [IQR 1·52-6·58] vs 1·92% [1·12-5·91]; p = 0·010). Median fasting insulin (12·6 μlU/mL [IQR 10·5-19·5] vs 9·3 μlU/mL [7·2-14·4]; p = 0·041), median c-peptide concentrations (3·0 ng/mL [2·5-4·4] vs 2·8 ng/mL [2·2-3·4], p = 0·024) and inflammatory parameters (median leukocyte count 8·1 G/L [6·4-8·9] vs 7·4 G/L [6·0-8·8]; p = 0·018; median neutrophil-to-lymphocyte-ratio 2·39 [1·74-2·75] vs 2·04 [1·47-2·55]; p = 0·00020) improved. Median systolic (128 mmHg [IQR 122-139] vs 122 mmHg [119-126]; p = 0·075) and diastolic (83 mmHg [80-95] vs 78 mmHg [75-91]; p = 0·10) blood pressure was non-significantly lower at follow up. No patient reported adverse symptoms of adrenal insufficiency during the study period. Interpretation:Treatment of MACS with evening doses of metyrapone lowers hepatic lipid content and improves the metabolic risk profile and might offer a novel therapeutic approach. Funding:Esteve (formerly HRA pharma) to the Medical University of Vienna (PI:PW).

BACKGROUND:Skin barrier dysfunction is central to inflammation and susceptibility to infection in atopic dermatitis (AD). Cutaneous T-cell lymphoma (CTCL) shares clinical similarities with AD and is also associated with a high prevalence of Staphylococcus aureus (S. aureus) colonisation. However, the mechanisms driving skin barrier damage in CTCL and the contribution of bacteria remain poorly understood. METHODS:We investigate how the interplay between S. aureus (and staphylococcal enterotoxins (SEs)) and primary malignant- and non-malignant T cells affects keratinocyte expression of skin barrier proteins; in vitro, in an EL4 murine lymphoma model of bacteria-driven tumour progression, and in CTCL patient lesions colonised with SE-producing S. aureus before and after bacterial eradication by antibiotic treatment. RESULTS:S. aureus and SEs activate malignant and non-malignant T cells to release barrier-repressing cytokines, including IL-4, IL-13, IL-22, and OSM, and JAK-dependent downregulation of filaggrin and loricrin in keratinocytes. In the EL4 model, bacteria-colonised tumour-bearing mice show significant filaggrin loss in tumour-adjacent epidermis, whereas antibiotic-treated mice maintain near-normal expression. Clinically, antibiotic eradication of SE-producing S. aureus partially restores filaggrin and loricrin expression in three of four patients, paralleling reduced inflammatory signalling. CONCLUSIONS:SE-producing S. aureus promotes skin barrier impairment in CTCL through cytokine-driven, JAK-dependent repression of structural proteins in keratinocytes. These findings identify microbial-immune crosstalk as a contributor to CTCL skin pathology and provide mechanistic rationale for strategies targeting S. aureus colonisation as adjunctive therapy in CTCL.

BACKGROUND:Erythropoietic protoporphyria (EPP) is a rare genetic disorder characterized by severe phototoxic reactions that occur within minutes of light exposure. In clinical studies, afamelanotide has been shown to prolong pain-free sun exposure, improve quality of life, and reduce the frequency and severity of phototoxic reactions. OBJECTIVE:To present the real-world data of the Austrian EPP cohort treated with afamelanotide. PATIENTS AND METHODS:Data from all Austrian EPP patients treated with afamelanotide in 2023 (n = 20) were analyzed and compared to baseline data on quality of life, phototoxic burn tolerance time (PBTT), reported UV index on the day with the longest PBTT, and incidence and severity of phototoxic reactions. RESULTS:Before treatment, the EPP QoL score had a median of 11.11 (IQR 3.03-19.44) and increased to a median of 79.17 (IQR 75.00-97.22) under therapy. Phototoxic burn tolerance time (PBTT) increased from a median of 15 minutes (IQR 10-25) to a median of 250 minutes (IQR 120-300) under therapy. Before therapy 88% of patients had phototoxic reactions, while on therapy only 33% were affected. Treatment side effects were only mild and transient. CONCLUSIONS:The real-world data of the Austrian cohort confirm the effectiveness and safety of afamelanotide in EPP patients.

BACKGROUND:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS:To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS:Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS:Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Far-UVC exhibits potent antimicrobial activity while limiting penetration into viable epidermis. Unlike conventional 254 nm UV-C, far-UVC induces DNA photodamage only in superficial keratinocytes, with no evidence of basal cell involvement or photocarcinogenesis in preclinical and pilot human studies. These features have established far-UVC as a promising tool for infection control in occupied environments. Beyond disinfection, far-UVC may also represent a novel therapeutic modality in dermatology. Several dermatoses, including atopic dermatitis, cutaneous T-cell lymphoma, and polymorphic light eruption, are characterized by cutaneous dysbiosis that drive inflammation. Far-UVC’s selective action on surface-associated pathogens could modulate microbial imbalance while sparing deeper commensals and host tissue. Early data suggest potential for ecological rebalancing and immune modulation. Translational studies are now needed to test whether controlled far-UVC exposures can reshape microbial communities and improve disease outcomes in dysbiosis-driven dermatoses.

BACKGROUND:Bullous pemphigoid (BP) is the most common autoimmune blistering disease and primarily affects the elderly. Systemic corticosteroids and immunosuppressive drugs are the standard treatment, but side effects often restrict their use. Doxycycline has been proposed as an alternative, but there is limited long-term, real-world data on its efficacy and tolerability. We aimed to evaluate the effectiveness and length of doxycycline treatment in BP patients. PATIENTS AND METHODS:This retrospective, single-center study analyzed data from patients with a confirmed BP diagnosis treated with doxycycline. The comprehensive dataset included information on disease severity, concomitant therapies, and treatment response. Treatment duration was analyzed using the Kaplan-Meier method. RESULTS:The cohort comprised 102 patients with a mean age of 79 (range 51-95) years. A clinical response (an improvement of 1 or 2 on the PGA score, which ranges from 2 to -2) was observed in 85 patients (83.3 %), many of whom received combination therapy with other drugs (67.7 %). The median length of doxycycline treatment was 122.7 weeks. Adverse events, mainly of gastrointestinal origin, were rare, non-serious and manageable. CONCLUSIONS:Doxycycline proved to be an effective and well-tolerated long-term treatment for elderly patients with BP, when used either as monotherapy or in combination.

Background Psoriasis is a systemic inflammatory skin disease for which new topical treatments are needed. Psoriatic inflammation is associated with overexpression of eukaryotic translation initiation factors (eIFs), which regulate gene expression in processes such as proliferation, apoptosis, and differentiation. However, their role in psoriasis remains unclear. Objective To investigate the contribution of eIF1A and eIF3B to psoriasis pathogenesis and evaluate the therapeutic potential of their inhibition via small interfering RNA (siRNA). Methods We used two mouse models reflecting different mechanisms of psoriasis: (i) topical application of imiquimod (IMQ) and (ii) K5.TGFβ transgenic mice promoting keratinocyte proliferation. eIF1A and eIF3B were inhibited by either topical or systemic siRNA administration. A 3D human psoriasis model was also used for validation. Results Inhibition of eIF1A and eIF3B reduced inflammation in both mouse models and the 3D human model. Downregulation of these factors normalized keratinocyte proliferation, epidermal thickness, and cytokine expression (e.g., TNFα, IL-1β, IL-17, IL-22). Differentiation markers such as KRT16 and FLG were restored. These findings suggest that eIF1A and eIF3B play a key role in maintaining the psoriatic inflammatory phenotype. Conclusion Our findings reveal a translational imbalance in psoriasis and identify eIF1A and eIF3B as crucial regulators of disease pathophysiology. Targeting these factors represents a promising new therapeutic strategy for psoriasis treatment.

Antimicrobial peptides (AMPs) are key components of barrier immunity and are traditionally attributed to epithelial cells and granulocytes. Here, we report human β-defensin 124 (DEFB124) as a previously uncharacterized AMP predominantly produced by dermal stromal cells. Transcriptomic analyses across independent therapeutic cohorts showed consistent induction of DEFB124 during the restoration of skin homeostasis in atopic dermatitis (AD). Spatial transcriptomics, qPCR, and protein analyses localized DEFB124 expression to dermal fibroblasts and adipocytes. The murine ortholog β-defensin 25 (Defb25) showed a similar stromal expression pattern, was induced following intradermal Staphylococcus aureus (S. aureus) challenge, and was suppressed by type 2 cytokines through IL-4 receptor signaling. Recombinant DEFB124 showed dose-dependent antimicrobial activity in vitro and reduced bacterial burden in vivo, whereas Defb25 mRNA knockdown impaired fibroblast antimicrobial capacity and exacerbated S. aureus infection. These findings expand the known repertoire of cutaneous β-defensins and reveal stromal cells as an important source of cutaneous antimicrobial defense.

Background:Psoriasis and mental health are closely intertwined; however, certain aspects remain underexplored. Thus, continued research on this topic is important to deepen our understanding. Objectives:To explore the mental health of individuals with psoriasis - specifically depressive symptoms, mental functioning, stress symptoms and coping strategies - and to find associations with physical manifestations of psoriasis. Methods:A cross-sectional sample of 214 individuals with psoriasis (107 with illness duration >16 years and 107 with illness duration ≤16 years; cut-off: median) completed the Beck Depression Inventory-II, the SF-12 measuring mental and physical functioning, and the Stress and Coping Inventory. Additionally, the Psoriasis Area and Severity Index (PASI) was assessed. The study was conducted during the COVID-19 pandemic. Results:Individuals with psoriasis reported worse mental and physical health than the general population (norm sample of SF-12) but did not differ significantly from each other. While individuals with illness duration >16 years had lower psoriasis severity than those with illness duration ≤16 years, mean PASI scores indicated low illness severity overall. PASI scores did not show significant correlations with mental health inventories in either group. Conclusions:Individuals with psoriasis reported lower mental health during the COVID-19 pandemic than a healthy, prepandemic norm sample, independent of psoriasis severity. Age and illness duration seem to facilitate coping with the disease. Nevertheless, individuals with psoriasis are in need of continued mental health support, regardless of illness duration.

BACKGROUND:Granuloma annulare is a chronic, benign skin condition characterized by small erythematous patches, plaques or papules in annular or disseminated order. Due to the cosmetic impact, many patients experience a significant level of distress. Nevertheless, selecting the optimal treatment method often poses a challenge due to the limited available data. A remission of skin lesions can be achieved through topical, systemic, or intralesional therapies, and various forms of phototherapy. PATIENTS AND METHODOLOGY:This retrospective study included 58 patients diagnosed with granuloma annulare and evaluated a total of 73 cycles of phototherapy (UVA-1, oral-PUVA, bath-PUVA) concerning treatment response and adverse events. It was conducted at the outpatient phototherapy clinic of the University Department for Dermatology and Venereology, Medical University of Graz. The Data was collected over the period from February 2011 and February 2021. RESULTS:Complete response was achieved in 37.5% of the 16 bath-PUVA therapy cycles, 25.7% of the 35 oral-PUVA therapy cycles, and 35.3% of the 17 UVA-1 therapy cycles. Partial response was noted in 62.5% of the oral-PUVA therapies, 50% of the bath-PUVA therapies, and 41.2% of the UVA-1 therapies. Generally, the adverse events of phototherapy were mild, with the highest incidence of adverse events associated with oral-PUVA and the lowest with UVA-1 therapy. CONCLUSIONS:No significant differences in efficacy were found between UVA-1 therapy, oral-PUVA, and bath-PUVA. However, UVA-1 therapy resulted in the fewest adverse events. Given the frequent occurrence of recurrences, the risk-benefit profile of each therapy should be carefully assessed in advance.