BACKGROUND Early diagnosis is key to prevent bowel damage in inflammatory bowel disease (IBD). Risk factor analyses linked with delayed diagnosis in European IBD patients are scarce and no data in German IBD patients exists. AIM To identify risk factors leading to prolonged diagnostic time in a German IBD cohort. METHODS Between 2012 and 2022, 430 IBD patients from four Berlin hospitals were enrolled in a prospective study and asked to complete a 16-item questionnaire to determine features of the path leading to IBD diagnosis. Total diagnostic time was defined as the time from symptom onset to consulting a physician (patient waiting time) and from first consultation to IBD diagnosis (physician diagnostic time). Univariate and multivariate analyses were performed to identify risk factors for each time period. RESULTS The total diagnostic time was significantly longer in Crohn’s disease (CD) compared to ulcerative colitis (UC) patients (12.0 vs 4.0 mo; P < 0.001), mainly due to increased physician diagnostic time (5.5 vs 1.0 mo; P < 0.001). In a multivariate analysis, the predominant symptoms diarrhea (P = 0.012) and skin lesions (P = 0.028) as well as performed gastroscopy (P = 0.042) were associated with longer physician diagnostic time in CD patients. In UC, fever was correlated (P = 0.020) with shorter physician diagnostic time, while fatigue (P = 0.011) and positive family history (P = 0.046) were correlated with longer physician diagnostic time. CONCLUSION We demonstrated that CD patients compared to UC are at risk of long diagnostic delay. Future efforts should focus on shortening the diagnostic delay for a better outcome in these patients.

Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller "freckle-like" macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated.

The recognition of the unpredictable latent phase before frequent progression of melanoma is a real unmet need in melanoma care. Approximately 50% of melanoma-related deaths were early stage at the moment of diagnosis. There are no novel biomarkers with prognostic values at the early identification of the advanced melanoma attributes, therefore, we investigated the main driver mechanisms of the progression of early-stage melanomas. We analyzed a cohort of 12 primary melanomas with < Breslow level 1.6 mm divided into recurrent and non-recurrent within five years after surgical intervention. Tumor and stromal compartments in each tissue section were isolated and collected using laser-capture microdissection and submitted to quantitative proteomics. In the progression group of melanomas, the mitochondrial translation, especially 39S ribosomal proteins were upregulated in tumor cells (p<0.05). On the contrary, proteins from immune system response were downregulated (p<0.05). Interestingly, when analyzing the stromal components, a similar pattern was observed. These results shed light on the not well-understood tumor-stroma interaction, revealing a possible phenotype transferring from cancer cells to their microenvironment. In summary, by separating tumor and stromal components, our results added an additional layer of information to enrich our analysis. We have identified proteins and pathways which have key roles in molecular mechanisms of melanoma progression. The bioinformatics analysis highlighted that mitochondrial functions might play a role in melanoma pathogenesis.

Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic T helper cell (TH1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4+ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4+ T cell responses in patients with CD.

Hand eczema (HE) is a highly prevalent chronic disease affecting 15% of the population. Clinical grading systems are time-intensive and require training, making overall coarse assessment the default approach in practice. We present an image-based deep learning method to automatically evaluate HE lesion surface and determine their anatomical repartition. This retrospective study was based on two datasets: (A) 312 HE pictures and (B) 215 hand pictures. Eleven dermatologists annotated HE lesions in (A) and a student labeled (B) pictures with 37 hand anatomical sub-regions. Separate segmentation deep learning models (DLM) were trained for A and B. Predictions from both DLMs were merged and used to generate textual reports of patient conditions. DLM performance was evaluated using precision and sensitivity with 95% confidence interval. Intra-class correlation of predicted lesion surface with experts' annotations was also evaluated. The HE DLM achieved a precision and sensitivity of respectively 75% (64-82) and 69% (55-81), while the anatomy DLM achieved in average 83% (80-85) and 85% (82-88) for the same. The lesion surface intra-class correlation was 0.94 (0.90-0.96). An example of textual report is: "Both hands show eczema on the palmar side, namely on 51% of the fingertips, 34% of the fingers, 27% of the palms and 4% of the wrists." Our approach can automatically generate a precise anatomical stratification of HE lesions. It is reproducible and has no intra- and inter-observer variability. The method could be performed remotely to enable frequent follow-up and teledermatology treatment.

Immunosuppressive Interleukin (IL)−10 production by pro-inflammatory CD4 + T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4 + T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naïve and major effector CD4 + T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4 + T cells from Crohn’s disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3—Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4 + T cells, which is defective in IBD and thus may represent an attractive therapeutic target.

Most rheumatological disorders may have an impact on the gastrointestinal tract. In this context, intestinal manifestations of rheumatological disease (e. g., rheumatoid vasculitis, IgG4-associated pancreatitis and cholangitis, lupus enteritis, polyarteritis nodosa) should be distinguished from associated intestinal diseases (e. g., inflammatory bowel disease (IBD), celiac disease), intestinal complications of the disease (e. g., amyloidosis, reflux disease in sclerodermia) or intestinal complications of their treatment (e. g., gastrointestinal ulcers (NSAID), mucositis (MTX), oesophageal candidiasis, intestinal tuberculosis, herpes oesophagitis, CMV colitis in immunosuppressive therapy). As a result, gastrointestinal symptoms are very common in patients with rheumatological diseases. The correct diagnosis can be only established by the interdisciplinary approach of gastroenterologists and rheumatologists. Especially in the treatment of IBD, synergistic treatment options arise from the overlapping approval of the available drugs in the interdisciplinary consultation between rheumatologists and gastroenterologists.

Pustular psoriasis (PP) encompasses a range of well-defined, severe inflammatory conditions characterized by production of sterile pustules. Our understanding of this rare disease's pathophysiology, clinical course and optimal treatment is as yet limited. The goal of this prospective international registry is to describe the natural course of disease in different subtypes of PP and create phenotype-genotype correlations as well as elucidate therapeutic molecular pathways. The IRASPEN registry plans to include at least 180 patients at approximately 15 sites world-wide, aiming for minimum numbers of 140 Palmoplantar Psoriasis (PPP), 20 Generalized Pustular Psoriasis (GPP) and 20 Acrodermatitis Continua of Hallopeau (ACH) patients and up to 360 non-affected first degree relatives. Within the 5-year observation period, there are scheduled study visits plus additional flexible visits during acute flares. Patient reported outcomes will be collected regularly. Where possible, photography and lesion counts will be performed and biological samples (blood and skin biopsies) will be collected. This registry will facilitate future studies on the clinical course of PP subtypes and genetic course of PP, describe treatment responses, describe clinical phenotyping and molecular biology based inflammation patterns, and develop an image-based machine learning approach. Together with the global psoriasis atlas, our ultimate aim is to identify genetic, clinical and epidemiological data that predicts disease course and response to treatment in PP. Thus, our study holds the promise to improve quality of life for individuals affected by a severe and disabling condition.

Einleitung Der Einfluss einer SARS-CoV-2-Infektion auf chronisch entzundliche Darmerkrankungen (CED) ist bislang nicht gut charakterisiert, und es ist unklar, ob diese eine Anpassung der immunsuppressiven Therapie erfordert. Methodik Fur die retrospektive Dokumentation klinischer Parameter und Veranderungen einer immunsuppressiven Therapie von mit SARS-CoV-2 infizierten CED-Patienten wurde ein nationales Melderegister etabliert. Ergebnisse Insgesamt wurden nur 3 von 185 CED-Patienten (1,6 %) wegen abdomineller Symptome auf eine SARS-CoV-2-Infektion getestet. Im COVID-19-Krankheitsverlauf entwickelten 43,5 % Durchfall, abdominelle Schmerzen oder Hamatochezie (Hospitalisierungsrisiko mit vs. ohne abdominelle Symptome: 20,0 % vs. 10,6 %, p  Diskussion Bei mit SARS-CoV-2 infizierten CED-Patienten traten haufig neue abdominelle Symptome bei Infektion auf. Diese fuhrten aber nur selten zur SARS-CoV-2-Testung. Eine hohe CED-Aktivitat zum Zeitpunkt des SARS-CoV-2-Nachweises war mit einem erhohten Hospitalisierungsrisiko assoziiert.

Einleitung Der Covid-19-Verlauf bei Patienten mit chronisch entzündlichen Darmerkrankungen (CED) war zu Beginn der Pandemie ungewiss. CED-Patienten befürchteten insbesondere einen negativen Einfluss einer immunsuppressiven Therapie auf den Covid-19-Schweregrad.

Zusammenfassung Die meisten rheumatologischen Krankheitsbilder können Einfluss auf den Gastrointestinaltrakt haben. Dabei können intestinale Manifestationen (z. B. rheumatoide Vaskulitis, IgG4-assoziierte Pankreatitis, IgG4-assoziierte Cholangitis, Lupus-Enteritis, Polyarteriitis nodosa, Purpura Schoenlein-Henoch, nekrotisierende Vaskulitis), assoziierte intestinale Erkrankungen (chronisch-entzündliche Darmerkrankungen (CED), Zöliakie) und intestinale Komplikationen der rheumatologischen Erkrankung (z. B. Amyloidose, erosive Refluxerkrankung bei Sklerodermie) bzw. ihrer Behandlung (z. B. NSAR-Magenulcus, MTX-Mukositis, Soor-Ösophagitis, intestinale Tuberkulose, ulzerierende HSV-Ösophagitis, CMV-Kolitis) voneinander abgegrenzt werden. Dadurch kommen gastrointestinale Symptome bei Patienten mit rheumatologischen Erkrankungen sehr häufig vor. Die Diagnosestellung (er)fordert Gastroenterologen im interdisziplinären Behandlungsnetzwerk mit Rheumatologen. Insbesondere bei Behandlung von CED ergeben sich für die überschneidenden Zulassungsindikationen der zur Verfügung stehenden Medikamente in der interdisziplinären Absprache zwischen Rheumatologen und Gastroenterologen synergistische Behandlungsoptionen.

ZusammenfassungDie vollständige und reproduzierbare Erfassung und Dokumentation endoskopischer Befunde ist als Grundlage der Behandlung von Patienten mit chronisch entzündlichen Darmerkrankungen wie Morbus Crohn und Colitis ulcerosa von entscheidender Bedeutung. Diese Befunde sind zum einen Grundlage therapeutischer Entscheidungen und zum anderen ein unverzichtbarer Parameter der Bewertung des Ansprechens auf eine Behandlung. Endoskopische Befunde sollten daher nach standardisierten Kriterien erstellt werden, um eine Vergleichbarkeit der Befunde unterschiedlicher Untersucher wie auch die valide Erfassung von Veränderungen im zeitlichen Verlauf der Erkrankung zu gewährleisten. Vor diesem Hintergrund haben 15 Mitglieder der AG Bildgebung des Kompetenznetzes Darmerkrankungen ein Positionspapier erarbeitet, in dem eine Befundstruktur für die Dokumentation endoskopischer Untersuchungen entworfen wird. Die Empfehlungen adressieren neben den formalen Angaben zu jeder Untersuchung insbesondere eine Vielzahl von Attributen akuter und chronisch entzündlicher mukosaler Veränderungen sowie endoskopisch detektierbarer Komplikationen, die detailliert erläutert und anhand charakteristischer Abbildungen illustriert werden. Zudem werden häufiger verwendete endoskopische Aktivitätsindizes vorgestellt, und ihre Nutzung im klinischen Alltag wird diskutiert.

The complete and reliable documentation of endoscopic findings make up the crucial foundation for the treatment of patients with inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. These findings are, on the one hand, a prerequisite for therapeutic decisions and, on the other hand, important as a tool for assessing the response to ongoing treatments. Endoscopic reports should, therefore, be recorded according to standardized criteria to ensure that the findings of different endoscopists can be adequately compared and that changes in the course of the disease can be traced back. In consideration of these necessities, fifteen members of the Imaging Working Group of the German Kompetenznetz Darmerkrankungen have created a position paper proposing a structure and specifications for the documentation of endoscopic exams. In addition to the formal report structure, the recommendations address a large number of attributes of acute and chronic inflammatory alterations as well as endoscopically detectable complications, which are explained in detail and illustrated using exemplary images. In addition, more frequently used endoscopic activity indices are presented and their use in everyday clinical practice is discussed.

BACKGROUND & AIMS:A substantial proportion patients with inflammatory bowel disease (IBD) have a primary non-response to infliximab; markers are needed to identify patients most likely to respond to treatment. We investigated whether production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMCs) can be used as a marker to predict response.METHODS:We performed a prospective study of 41 adults with IBD (mean age, 38 years; 21 male; 21 with Crohn's disease and 20 with ulcerative colitis) not treated with a biologic agent within the past 6 months; patients were given their first infusion of infliximab at a hospital or clinic in Berlin, Germany. We collected data on clinical scores, levels of C-reactive protein, and ultrasound results (Limberg scores) at baseline (before the first infusion) and after 6 weeks (3rd infliximab infusion). PMBCs were obtained from patients at baseline and 10 healthy individuals (controls) and incubated with lipopolysaccharide. We measured production of cytokines (TNF, interleukin 1 [IL1], IL6, IL8, IL10, IL12p70, and IL22) by ELISA and performed cytometric bead array and flow cytometry analyses. The primary endpoint was clinical response (decrease in Harvey Bradshaw Index scores of 2 or more or decrease in partial Mayo scores of 3 or more at week 6) in patients with PBMCs that produced high vs low levels of TNF.RESULTS:Responders had a shorter median disease duration (P = .018) and higher median Limberg score (P = .021), than nonresponders. Baseline PBMCs from responders produced significantly more TNF (P = .049) and IL6 (P = .028) than from nonresponders; a level of 500 pg/ml TNF identified responders with 82% sensitivity and 78% specificity. In patients with Crohn's disease, this cutoff value (500 pg/ml TNF) identified responders with 100% sensitivity and 82% specificity; TNF levels above this level were independently associated with response to infliximab in multivariate analysis (odds ratio, 16.2; 95% CI, 1.8-148.7; P = .014). The percentage of TNF-positive cells was higher among CD14+ monocytes than lymphocytes after stimulation.CONCLUSIONS:Production of a high level of TNF by PBMCs (specifically CD14+ cells) from patients with IBD can identify those most likely to have a clinical response to infliximab therapy. In patients with Crohn's disease, a cutoff value of 500 pg/ml TNF identified responders with 100% sensitivity and 82% specificity.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human antifungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

Introduction:Psoriasis is a chronic systemic disease causing erythrosquamous plaques on the skin and is associated with a number of internal co-morbidities. As the aging population is usually not specifically studied in clinical trials, it remains unclear whether current drugs demonstrate equal efficacy in the elderly. Methods:The data from 5345 patients with moderate to severe psoriasis patients, which are included in the German (Pso-Best) and Swiss (SDNTT) psoriasis networks, were collected. The cohort was stratified into a group ≥65 years old (controls) and another for patients below age 65 (elderly). Results: Response rates were equal between younger and older psoriasis patients with the exception of methotrexate, which was more effective in older patients until month 6 Discussion: This study showed that patients ≥65 years have a comparable treatment response to patients below this age threshold.