Publications by authors named "Kamran Ghoreschi"

128 Publications

The Effect of TNF-α Inhibitors on Nail Psoriasis and Psoriatic Arthritis-Real-World Data from Dermatology Practice.

J Pers Med 2021 Oct 25;11(11). Epub 2021 Oct 25.

Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.

Patients with psoriatic arthritis (PsA) often develop joint symptoms years after their initial diagnosis of psoriasis disease; therefore, dermatologists should test for and detect PsA early. In this study, we focused on patients with psoriasis with both nail and joint disease being treated with tumor necrosis factor-α inhibitors by dermatologists. We performed a noninterventional, prospective, multicenter, and open-label study to evaluate the effectiveness of adalimumab, etanercept, or infliximab over 24 months of continuous therapy in patients with moderate to severe plaque-type psoriasis (Pso) and PsA. Disease assessments with the Psoriasis Area and Severity Index, Nail Psoriasis Severity Index (NAPSI), joint assessment, Dermatology Life Quality Index (DLQI), and Health Assessment Questionnaire (HAQ) instruments were performed every 3 months for the first year and twice annually thereafter. The cohort included 100 patients with Pso, nail psoriasis, and PsA. A significant reduction of NAPSI was observed 3 months after therapy initiation compared with the baseline (mean ± SD, 22.9 ± 17.8 vs. 33.8 ± 21.4; < 0.001). Similarly, the mean ± SD number of both tender and swollen joints decreased significantly within the first 3 months of treatment, from 10.8 ± 11.5 to 6.4 ± 10.3 ( < 0.001) and from 6.4 ± 9.5 to 3.1 ± 7.2 ( < 0.001), respectively. Additionally, the distal interphalangeal joint involvement improved throughout the observation time, and DLQI and HAQ scores decreased. Improvements in control of skin, nail, and joint symptoms were seen, as well as in patients' quality of life and functionality. Dermatologists have an important role not only in PsA diagnosis but also in PsA long-term care.
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http://dx.doi.org/10.3390/jpm11111083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620057PMC
October 2021

Charakteristika von Dermatomyositis-Patienten mit und ohne Malignom-Assoziation.

J Dtsch Dermatol Ges 2021 Nov;19(11):1601-1612

Universitäts-Hautklinik, Eberhardt-Karls-Universität Tübingen.

Hintergrund: Die Dermatomyositis gehört zur Gruppe der seltenen, idiopathischen, inflammatorischen Myositiden. Für die paraneoplastische Form der Dermatomyositis wurde in der Vergangenheit ein Zusammenhang mit Malignomen erkannt. Faktoren, die für eine Malignom-Assoziation sprechen, werden bis heute untersucht.

Patienten Und Methodik: Es wurden retrospektiv über einen Zeitraum von 15 Jahren die Daten von 63 Patienten mit Dermatomyositis analysiert.

Ergebnisse: Folgende Faktoren gaben einen Hinweis für eine Dermatomyositis mit Malignom-Assoziation: ein höheres Patientenalter (> 52 Jahre [P = 0,001], > 65 Jahre [P = 0,002], ≥ 75 Jahre [P = 0,002]), eine kürzere Zeit zwischen Erstmanifestation und Erstdiagnose (Malignom-Gruppe: 59 Tage vs. Nicht-Malignom-Gruppe: 137 Tage [P = 0,022]), eine Hautbeteiligung in Form von Gottron-Zeichen (P = 0,045), zentrofazialen Erythemen (P = 0,036) oder typischen Erythemen an den Ober-/Unterarmen (P = 0,019), eine oropharyngeale Beteiligung (P = 0,015) und eine GPT-Erhöhung (P = 0,031). Folgende Faktoren sprachen eher gegen eine Malignom-Assoziation: ein jüngeres Patientenalter (≤ 52 Jahre [P = 0,001], 40-65 Jahre [P = 0,045]) und Juckreiz (P = 0,026).

Schlussfolgerungen: In der Literatur finden sich heterogene Ergebnisse zu den genannten Faktoren hinsichtlich ihrer Eignung als Marker für eine Malignom-Assoziation. Erschwert ist die Faktorenfindung aufgrund kleiner Studienpopulationen, wenigen prospektiven und kontrollierten Studien, die Einordnung von Populationen als Myositis-Patienten ohne Differenzierung und eine inkonsistente Verwendung der Nomenklatur. Mit unserer Studie wollen wir einen wichtigen Beitrag zur Identifizierung von Risikofaktoren bei Dermatomyositis mit Malignom-Assoziation leisten.
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http://dx.doi.org/10.1111/ddg.14566_gDOI Listing
November 2021

Prevalence of Candida species in Psoriasis.

Mycoses 2021 Nov 17. Epub 2021 Nov 17.

Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Psoriasis patients are more frequently colonised with Candida species. The correlation between fungal colonisation and clinical severity is unclear, but may exacerbate psoriasis and the impact of antipsoriatic therapies on the prevalence of Candida is unknown.

Objectives: To examine the prevalence of C species in psoriasis patients compared to an age- and sex-matched control population, we investigated the influence of Candida colonisation on disease severity, immune cell activation and the interplay on psoriatic treatments.

Methods: The prevalence of C species was examined in 265 psoriasis patients and 200 control subjects by swabs and stool samples for fungal cultures. Peripheral mononuclear blood cells (PBMCs) were collected from 20 fungal colonised and 24 uncolonised patients and stimulated. The expression of interferon (IFN)-γ, IL-17A, IL-22 and tumour necrosis factor (TNF)-α from stimulated PBMCs was measured by quantitative real-time polymerase chain reaction (qPCR).

Results: A significantly higher prevalence for Candida was detected in psoriatic patients (p ≤ .001) compared to the control subjects; most abundant in stool samples, showing Candida albicans. Older participants (≥51 years) were more frequent colonised, and no correlation with gender, disease severity or systemic treatments like IL-17 inhibitors was found.

Conclusions: Although Candida colonisation is significantly more common in patients with psoriasis, it does not influence the psoriatic disease or cytokine response. Our study showed that Candida colonisation is particularly more frequent in patients with psoriasis ≥51 years of age. Therefore, especially this group should be screened for symptoms of candidiasis during treatment with IL-17 inhibitors.
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http://dx.doi.org/10.1111/myc.13399DOI Listing
November 2021

Characteristics of dermatomyositis patients with and without associated malignancy.

J Dtsch Dermatol Ges 2021 Nov 5;19(11):1601-1611. Epub 2021 Nov 5.

Department of Dermatology, University of Tübingen, Tübingen, Germany.

Background: Dermatomyositis belongs to the rare idiopathic, inflammatory myositis group. A previously postulated link between some cases of dermatomyositis and malignancy has been established in recent years. Criteria suggestive of a malignancy association are still being explored.

Patients And Methods: We retrospectively analyzed data from 63 patients with dermatomyositis over a period of 15 years.

Results: The following criteria argue for cancer-associated dermatomyositis: older age (> 52 years [P = 0.001], > 65 years [P = 0.002], ≥ 75 years [P = 0.002]), shorter time between manifestation and diagnosis of dermatomyositis (malignancy group: 59 days vs. non-malignancy group: 137 days [P = 0.022]), typical skin involvement such as Gottron sign (P = 0.045), centrofacial erythema (P = 0.036) and typical erythema on the upper arms and forearms (P = 0.019), oropharyngeal involvement (P = 0.015) and increased ALT (P = 0.031). The following criteria argue for non-cancer-associated dermatomyositis: younger age (≤ 52 years [P = 0.001], 40-65 years [P = 0.045]) and pruritus (P = 0.026).

Conclusions: The aforementioned criteria have been documented in the literature, but reported findings are heterogenous concerning the suitability of their markers for malignancy association. Small study populations, few prospective controlled studies, summarization of different forms of myositis and inconsistent use nomenclature contribute to biased results. Our study aims to make an important contribution toward the identification of risk factors in cancer-associated dermatomyositis.
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http://dx.doi.org/10.1111/ddg.14566DOI Listing
November 2021

TYK2-Inhibition: Potenzial bei der Behandlung chronisch-entzündlicher Immunerkrankungen.

J Dtsch Dermatol Ges 2021 Oct;19(10):1409-1420

Institut für Entzündungsmedizin, Universitätsklinikum Schleswig- Holstein, Campus Lübeck.

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http://dx.doi.org/10.1111/ddg.14585_gDOI Listing
October 2021

Targeting Immune Checkpoints and Cytokines to Protect From Psoriasis Relapse.

Authors:
Kamran Ghoreschi

JAMA Dermatol 2021 Nov;157(11):1269-1271

Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.

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http://dx.doi.org/10.1001/jamadermatol.2021.3491DOI Listing
November 2021

TYK2 inhibition and its potential in the treatment of chronic inflammatory immune diseases.

J Dtsch Dermatol Ges 2021 10 27;19(10):1409-1420. Epub 2021 Sep 27.

Institute for Inflammatory Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Immune-mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non-receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune-mediated diseases, with a special focus on inflammatory diseases of the skin.
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http://dx.doi.org/10.1111/ddg.14585DOI Listing
October 2021

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

Eur J Cancer 2021 10 8;156:202-216. Epub 2021 Sep 8.

First Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece.

Background: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice.

Objective: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians.

Methods: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included.

Results: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images.

Conclusions: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.
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http://dx.doi.org/10.1016/j.ejca.2021.06.049DOI Listing
October 2021

A benchmark for neural network robustness in skin cancer classification.

Eur J Cancer 2021 09 11;155:191-199. Epub 2021 Aug 11.

Digital Biomarkers for Oncology Group, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: One prominent application for deep learning-based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data.

Objective: The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured.

Methods: Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it.

Results: The benchmark contains three data sets-Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)-and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations.

Conclusions: This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.
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http://dx.doi.org/10.1016/j.ejca.2021.06.047DOI Listing
September 2021

Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours.

Eur J Cancer 2021 09 20;154:227-234. Epub 2021 Jul 20.

Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; Department of Dermatology, University Hospital (UKSH), Kiel, Germany.

Aim: Sentinel lymph node status is a central prognostic factor for melanomas. However, the surgical excision involves some risks for affected patients. In this study, we therefore aimed to develop a digital biomarker that can predict lymph node metastasis non-invasively from digitised H&E slides of primary melanoma tumours.

Methods: A total of 415 H&E slides from primary melanoma tumours with known sentinel node (SN) status from three German university hospitals and one private pathological practice were digitised (150 SN positive/265 SN negative). Two hundred ninety-one slides were used to train artificial neural networks (ANNs). The remaining 124 slides were used to test the ability of the ANNs to predict sentinel status. ANNs were trained and/or tested on data sets that were matched or not matched between SN-positive and SN-negative cases for patient age, ulceration, and tumour thickness, factors that are known to correlate with lymph node status.

Results: The best accuracy was achieved by an ANN that was trained and tested on unmatched cases (61.8% ± 0.2%) area under the receiver operating characteristic (AUROC). In contrast, ANNs that were trained and/or tested on matched cases achieved (55.0% ± 3.5%) AUROC or less.

Conclusion: Our results indicate that the image classifier can predict lymph node status to some, albeit so far not clinically relevant, extent. It may do so by mostly detecting equivalents of factors on histological slides that are already known to correlate with lymph node status. Our results provide a basis for future research with larger data cohorts.
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http://dx.doi.org/10.1016/j.ejca.2021.05.026DOI Listing
September 2021

Seven- and 23-year-old Siblings with Papulonodular Lesions after Sun Exposure: A Quiz.

Acta Derm Venereol 2021 Jul 30;101(7):adv00513. Epub 2021 Jul 30.

Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin, Berlin, Germany.

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http://dx.doi.org/10.2340/00015555-3885DOI Listing
July 2021

Integrating Patient Data Into Skin Cancer Classification Using Convolutional Neural Networks: Systematic Review.

J Med Internet Res 2021 07 2;23(7):e20708. Epub 2021 Jul 2.

Digital Biomarkers for Oncology Group (DBO), National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Recent years have been witnessing a substantial improvement in the accuracy of skin cancer classification using convolutional neural networks (CNNs). CNNs perform on par with or better than dermatologists with respect to the classification tasks of single images. However, in clinical practice, dermatologists also use other patient data beyond the visual aspects present in a digitized image, further increasing their diagnostic accuracy. Several pilot studies have recently investigated the effects of integrating different subtypes of patient data into CNN-based skin cancer classifiers.

Objective: This systematic review focuses on the current research investigating the impact of merging information from image features and patient data on the performance of CNN-based skin cancer image classification. This study aims to explore the potential in this field of research by evaluating the types of patient data used, the ways in which the nonimage data are encoded and merged with the image features, and the impact of the integration on the classifier performance.

Methods: Google Scholar, PubMed, MEDLINE, and ScienceDirect were screened for peer-reviewed studies published in English that dealt with the integration of patient data within a CNN-based skin cancer classification. The search terms skin cancer classification, convolutional neural network(s), deep learning, lesions, melanoma, metadata, clinical information, and patient data were combined.

Results: A total of 11 publications fulfilled the inclusion criteria. All of them reported an overall improvement in different skin lesion classification tasks with patient data integration. The most commonly used patient data were age, sex, and lesion location. The patient data were mostly one-hot encoded. There were differences in the complexity that the encoded patient data were processed with regarding deep learning methods before and after fusing them with the image features for a combined classifier.

Conclusions: This study indicates the potential benefits of integrating patient data into CNN-based diagnostic algorithms. However, how exactly the individual patient data enhance classification performance, especially in the case of multiclass classification problems, is still unclear. Moreover, a substantial fraction of patient data used by dermatologists remains to be analyzed in the context of CNN-based skin cancer classification. Further exploratory analyses in this promising field may optimize patient data integration into CNN-based skin cancer diagnostics for patients' benefits.
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http://dx.doi.org/10.2196/20708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285747PMC
July 2021

Advisory opinion of the AWMF Ad hoc Commission In-vitro Diagnostic Medical Devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the Union according to Regulation (EU) 2017/746 (IVDR).

Ger Med Sci 2021 1;19:Doc08. Epub 2021 Jun 1.

Deutsche Gesellschaft für Pharmazeutische Medizin (DGPharMed).

In view of the approaching application date of Regulation (EU) 2017/746 ("IVDR") and the resulting EU-wide, harmonized requirements for in-vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products. The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences. At the same time, the IVDR requirements have to be regarded under a pragmatic view and in accordance with the quality management systems approved within the different EU Member States. On the one hand, the mandatory requirements of the RiLiBÄK play an essential role in Germany. On the other hand, elements of voluntarily applicable international standards may support the fulfilment of product requirements for safety and performance according to Annex I of the IVDR. Both the complexity and possible solutions for the implementation of the IVDR requirements are discussed on the basis of examples such as the required documentation, performance evaluation and software validation. The Ad hoc Commission IVD recommends that, while aiming at a preferably EU-wide harmonized interpretation of the IVDR requirements, the flexibility in medical laboratory diagnostics necessary for patient care, including the use of IVD from in-house production, should be emphasized.
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http://dx.doi.org/10.3205/000295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204380PMC
October 2021

Lichen planus - ein Klinikleitfaden.

J Dtsch Dermatol Ges 2021 Jun;19(6):864-883

Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin.

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http://dx.doi.org/10.1111/ddg.14565_gDOI Listing
June 2021

Lichen planus - a clinical guide.

J Dtsch Dermatol Ges 2021 06 7;19(6):864-882. Epub 2021 Jun 7.

Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Lichen planus (LP) is a chronic lichenoid inflammatory disorder of the skin, mucosa and of the appendages. LP is classically characterized by the presence of a rich infiltration of inflammatory T cells, which migrate in the upper part of the dermis, arranged in a band-like pattern. Different sub types of the disease have been so far described. Albeit LP is clinically well defined, the disease still represents a therapeutic enigma. Especially with regard to mucosal or scalp affecting LP types, which often present a recalcitrant and treatment unresponsive course, efficacious therapeutic options are still lacking. Thus, LP represents a disease with a high psychosocial burden. Yet, development in the deciphering of LP pathogenesis reveals possible new druggable targets, thus paving the way for future therapeutic options. In this clinical guide, we summarize the current clinical knowledge and therapeutic standards and discuss the future perspective for the management of LP.
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http://dx.doi.org/10.1111/ddg.14565DOI Listing
June 2021

Combining CNN-based histologic whole slide image analysis and patient data to improve skin cancer classification.

Eur J Cancer 2021 05 7;149:94-101. Epub 2021 Apr 7.

Digital Biomarkers for Oncology Group, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany.

Background: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses.

Objectives: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone.

Methods: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as 'uncertain' (CNN output score <0.7), the decision of the CNN was replaced by the decision of the patient data classifier.

Results: The CNN on its own achieved the best performance (mean ± standard deviation of five individual runs) with AUROC of 92.30% ± 0.23% and balanced accuracy of 83.17% ± 0.38%. While the classification performance was not significantly improved in general by any of the tested fusions, naive strategy of replacing the image classifier with the patient data classifier on slides with low output scores improved balanced accuracy to 86.72% ± 0.36%.

Conclusion: In most cases, the CNN on its own was so accurate that patient data integration did not provide any benefit. However, incorporating patient data for lesions that were classified by the CNN with low 'confidence' improved balanced accuracy.
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http://dx.doi.org/10.1016/j.ejca.2021.02.032DOI Listing
May 2021

Immunotherapy in psoriasis.

Immunotherapy 2021 05 6;13(7):605-619. Epub 2021 Apr 6.

Department of Dermatology, Venereology & Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Over the past two decades, significant progress has been achieved in the treatment of psoriasis by targeting the human cytokine network. At present, 11 biologicals - antibodies, and a soluble receptor - are used to neutralize key inflammatory cytokines. Based on their targets, they can be grouped into the following four classes: TNF-α-, IL-12/23-, IL-17- and IL-23-inhibitors. The range of available substances, as well as their different modes of action can be challenging when selecting the right drug for an individual patient. In this article, we provide an overview of the approved biologicals for the treatment of psoriasis, including their advantages and limitations, and summarize criteria for therapy selection.
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http://dx.doi.org/10.2217/imt-2020-0292DOI Listing
May 2021

Janus kinase signaling as risk factor and therapeutic target for severe SARS-CoV-2 infection.

Eur J Immunol 2021 05 22;51(5):1071-1075. Epub 2021 Mar 22.

Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Cytokine signaling, especially interferon (IFN) signaling is closely linked to several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During initial SARS-CoV-2 infection, symptomatic patients present with impaired type I/III IFN-mediated antiviral responses. Interestingly, IFNs regulate the cellular entry receptor for SARS-CoV-2 on epithelial and endothelial cells. As reported recently, critically ill COVID-19 patients show genetic polymorphisms in one IFN receptor gene (IFNRA2) and in a gene locus near the Janus kinase (JAK) TYK2, which is key for IFN, interleukin (IL)-12 and IL-23 signaling, and T helper (Th) 1/Th17 cell-mediated antiviral immune responses. In the advanced stage of the disease, critically ill COVID-19 patients develop a cytokine storm where many inflammatory mediators using the JAK/STAT signaling pathway such as IL-6, IFN-γ, the granulocyte colony-stimulating factor (G-CSF) or IL-2, and chemokines result in an influx of macrophages and neutrophils damaging the lung tissue. The knowledge on the cytokine and JAK/STAT signaling pathways in severe COVID-19 disease explains the promising first results with JAK inhibitors like baricitinib, which not only dampen the inflammation but in the case of baricitinib also affect virus replication and endocytosis in target cells. Here, we summarize the current immunological associations of SARS-CoV-2 infection with cytokine signaling, the JAK/STAT pathway, and the current clinical stage of JAK inhibitors for improving severe COVID-19 disease.
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http://dx.doi.org/10.1002/eji.202149173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250126PMC
May 2021

Arginase 1 IL-10 polymorphonuclear myeloid-derived suppressor cells are elevated in patients with active pemphigus and correlate with an increased Th2/Th1 response.

Exp Dermatol 2021 Jun 23;30(6):782-791. Epub 2021 Feb 23.

Molecular Immunology Charité (MIC), Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität of Berlin, and Berlin Institute of Health, Berlin, Germany.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which are characterized by their capability to suppress T-cell responses. While MDSCs have been traditionally associated with cancer diseases, their role as regulators of autoimmune diseases is emerging. Pemphigus is a chronic autoimmune blistering skin disease characterized by dysregulated T-cell responses and autoantibody production. The role of MDSCs in pemphigus disease has not been defined yet. The aim of this study was to characterize MDSCs in pemphigus patients and to dissect their relationship with CD4 T-cell subsets and clinical disease assessments. For this purpose, we performed a cross-sectional analysis of 20 patients with pemphigus. Our results indicate that a population of CD66b CD11b polymorphonuclear-like MDSCs (PMN-MDSCs) is expanded in the peripheral blood mononuclear cell fraction of pemphigus patients compared to age-matched healthy donors. These PMN-MDSCs have the capability of suppressing allogeneic T-cell proliferation in vitro and show increased expression of characteristic effector molecules such as arginase I and interleukin-10. We further demonstrate that PMN-MDSCs are especially expanded in patients with active pemphigus, but not in patients in remission. Moreover, MDSC frequencies correlate with an increased Th2/Th1 cell ratio. In conclusion, the identification of a functional PMN-MDSC population suggests a possible role of these cells as regulators of Th cell responses in pemphigus.
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http://dx.doi.org/10.1111/exd.14298DOI Listing
June 2021

Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis.

Lancet 2021 02 27;397(10275):754-766. Epub 2021 Jan 27.

Psoriasis Research and Treatment Centre, Charité-Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Berlin, Germany.

Psoriasis is a chronic inflammatory disease characterised by sharply demarcated erythematous and scaly skin lesions accompanied by systemic manifestations. Classified by WHO as one of the most serious non-infectious diseases, psoriasis affects 2-3% of the global population. Mechanistically, psoriatic lesions result from hyperproliferation and disturbed differentiation of epidermal keratinocytes that are provoked by immune mediators of the IL-23 and IL-17 pathway. Translational immunology has had impressive success in understanding and controlling psoriasis. Psoriasis is the first disease to have been successfully treated with therapeutics that directly block the action of the cytokines of this pathway; in fact, therapeutics that specifically target IL-23, IL-17, and IL-17RA are approved for clinical use and show excellent efficacy. Furthermore, inhibitors of IL-23 and IL-17 intracellular signalling, such as TYK2 or RORγt, are in clinical development. Although therapies that target the IL-23 and IL-17 pathway also improve psoriatic arthritis symptoms, their effects on long-term disease modification and psoriasis-associated comorbidities still need to be explored.
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http://dx.doi.org/10.1016/S0140-6736(21)00184-7DOI Listing
February 2021

Robustness of convolutional neural networks in recognition of pigmented skin lesions.

Eur J Cancer 2021 03 7;145:81-91. Epub 2021 Jan 7.

Digital Biomarkers for Oncology Group, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: A basic requirement for artificial intelligence (AI)-based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems.

Objective: To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)-mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing).

Methods: We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes ('brittleness') was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions.

Results: All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor.

Conclusions: Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic.
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http://dx.doi.org/10.1016/j.ejca.2020.11.020DOI Listing
March 2021

Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions.

Theranostics 2021 1;11(2):470-490. Epub 2021 Jan 1.

Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91), myeloperoxidase-deficient (MPO), and inducible nitric oxide synthase-deficient (iNOS) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. The L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91 mice, up to 90 % decreased ROS/RNS production in the ears of MPO mice and unaffected ROS/RNS production in the ears of iNOS mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91 mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91 mice with chronic DTHR, while the inflamed ears of MPO mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91 mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.
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http://dx.doi.org/10.7150/thno.51462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738859PMC
August 2021

Non invasive in vivo monitoring of dimethyl fumarate treatment in EAE by assessing the glucose metabolism in secondary lymphoid organs.

Eur J Immunol 2021 04 28;51(4):1006-1009. Epub 2020 Dec 28.

Department of Dermatology, Venerology and Allergology, Charité Universitätsmedizin Berlin, Charitéplatz1, Berlin, Germany.

[ F]FDG-PET/CT is a high sensitive functional diagnostic imaging modality to monitor tumor but also immune cell activation by determination of the glucose metabolism. Our results show that the anti-inflammatory effects of immunotherapeutics like DMF can be assessed non invasively in vivo during Th1/Th17 cell-mediated encephalomyelitis (EAE) by [ F]FDG-PET/CT imaging of the draining lymph nodes.
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http://dx.doi.org/10.1002/eji.202048879DOI Listing
April 2021

Skin manifestations in spondyloarthritis.

Ther Adv Musculoskelet Dis 2020 8;12:1759720X20975915. Epub 2020 Dec 8.

Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.

Spondyloarthritides (SpA) like psoriatic arthritis, axial spondyloarthritis/ankylosing spondylitis, reactive arthritis and inflammatory bowel disease (IBD)-associated SpA can present with characteristic skin manifestations. These SpA-associated skin disorders may precede joint involvement, reflect a loss of efficacy of a current systemic treatment or can even be treatment associated. Cutaneous manifestations in SpA not only add additional morbidity with physical impact but also impose a psychosocial burden on affected patients. Psoriasis (PsO) - the main skin disease in SpA - has a variety of clinical presentations, including plaque-type PsO, inverse PsO, guttate PsO, erythrodermic PsO, nail PsO and pustular types. SpA associated with IBD presents with neutrophilic and granulomatous skin disorders, including pyoderma gangrenosum, hidradenitis suppurativa and cutaneous Crohn's disease. Reactive arthritides has a favourable prognosis and may feature keratoderma blenorrhagicum or balanitis circinatum as typical skin manifestations. Immunologically, SpA-associated skin diseases share interleukin (IL)-17 and IL-23 dysregulation but show distinctive genetic and immunological profiles. Therefore, they vary in their treatment responses to targeted therapies with biologicals or small molecules. In this review, we highlight the clinical presentation of skin manifestations in SpA and discuss therapeutic approaches in this interdisciplinary field.
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http://dx.doi.org/10.1177/1759720X20975915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727049PMC
December 2020

The impact of extra-musculoskeletal manifestations on disease activity, functional status, and treatment patterns in patients with axial spondyloarthritis: results from a nationwide population-based study.

Ther Adv Musculoskelet Dis 2020 21;12:1759720X20972610. Epub 2020 Nov 21.

Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany.

Objective: The aim of this study was to investigate the association of extra-musculoskeletal manifestations (EMMs) with disease activity, functional status, and treatment patterns in a large population-based cohort of patients with axial spondyloarthritis (axSpA).

Methods: A stratified random sample of patients with axSpA, drawn from health insurance data, received a survey on disease-related characteristics including history (ever presence) of the following EMMs: inflammatory bowel disease (IBD), psoriasis (PSO), and anterior uveitis (AU). Survey data were linked to health insurance data, gathering additional information on current occurrence (within one year) of EMMs and drug prescriptions. Separate multivariable linear regression models were calculated to determine the association of EMMs with disease activity (Bath Ankylosing Spondylitis Disease Activity Index), and functional status (Bath Ankylosing Spondylitis Functional Index) after adjustment for relevant parameters, including treatment.

Results: A total of 1729 patients with axSpA were included in the analyses (response: 47%; mean age: 56 years; 46% female) of whom 6% (9%) had current (ever) IBD, 10% (15%) had current (ever) PSO, and 9% (27%) had current (ever) AU. Ever presence of IBD and history of PSO were significantly associated with higher level of disease activity. Ever presence of PSO was also associated with higher level of functional impairment, whereas current AU was significantly associated with lower disease activity. Patients with current IBD or PSO received more frequently biological and conventional synthetic disease-modifying anti-rheumatic drugs as well as systemic steroids. AU was associated with a higher use of conventional synthetic disease-modifying anti-rheumatic drugs only.

Conclusion: Disease activity is higher in patients with axSpA with history of IBD or history of PSO. Functional impairment is also higher in patients with axSpA with history of PSO. The presence of different EMMs was associated with different treatment patterns in axSpA.
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http://dx.doi.org/10.1177/1759720X20972610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682214PMC
November 2020

Immunophenotyping in pemphigus reveals a T17/T17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

J Allergy Clin Immunol 2021 06 20;147(6):2358-2369. Epub 2020 Nov 20.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Background: T2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear.

Objective: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus.

Methods: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of T cell and folliclular helper (T) cell subsets was analyzed by flow cytometry. Finally, the capacity of T and T cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments.

Results: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17 T17, T17, and T17.1 cells. Notably, levels of T17 and T17 cells correlated with levels of Dsg-specific CD19CD27 memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T17 cells. Coculture experiments revealed T17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.

Conclusion: Our findings show that T17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2020.11.008DOI Listing
June 2021

Case Report: Apremilast for Therapy-Resistant Pemphigus Vulgaris.

Front Immunol 2020 27;11:588315. Epub 2020 Oct 27.

Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: In pemphigus, elucidating the disease-causing immune mechanism and developing new therapeutic strategies are needed. In this context, the second messenger 3',5'-cyclic adenosine monophosphate (cAMP) is gaining attention. cAMP is important in hematological and auto-inflammatory disorders. A class of enzymes called phosphodiesterases (PDEs) control intracellular cAMP levels. In pemphigus, cAMP levels increase following IgG binding to Dsg3. This appears to be a mechanism to preserve epithelial integrity.

Objectives: To determine whether apremilast, an inhibitor of the PDE4 normally used in psoriasis, may be of benefit in the blistering skin disorder pemphigus.

Methods: Here we report of a 62 years old patient with chronic debilitating and recalcitrant pemphigus not responding to several previous treatments, who received treatment with apremilast over a period of 32 weeks. Desmoglein autoantibody levels were assessed by Enzyme-linked Immunosorbent Assay (ELISA), whereas disease severity and quality of life were assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). In an attempt to explain the effects of apremilast in pemphigus, peripheral blood mononuclear cells (PBMCs) were analyzed for the duration of treatment by flow cytometry for the distribution of specialized T cell subsets. The frequencies of circulating T helper (Th) 1, Th2, Th17, Th17.1 and T follicular helper (Tfh) 1, Tfh2, Tfh17, and Tfh17.1 were analyzed by CCR6, CXCR3, and CXCR5 expression of CD4 T cells. Further, based on the different expressions of CXCR5, CD127, and CD25, we analyzed the T regulatory (Treg) and T follicular regulatory (Tfreg) compartment.

Results: In response to apremilast treatment, Dsg-specific autoantibody titers decreased, blistering ceased and lesions healed, showing a long-lasting effect. While the frequencies of most of the Th and Tfh cell subsets remained unchanged, we observed a continuous increase in Treg and Tfreg cell levels.

Conclusion: Our findings are encouraging and warrant extension of the beneficial effect of PDE4 inhibition on a larger cohort of pemphigus patients.
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http://dx.doi.org/10.3389/fimmu.2020.588315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653172PMC
July 2021

The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition.

Exp Dermatol 2021 02 12;30(2):262-270. Epub 2020 Nov 12.

Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL-17-disorder, there is some evidence that Th1/IFN-ɣ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well-characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3 CD4 T cells rather than CD3 CD8 . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO-associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL-21, IFN-ɣ and also pSTAT1 in the dermal infiltrate of CLP, while IL-17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti-cytokine therapeutics like JAK inhibitors may be beneficial in CLP.
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http://dx.doi.org/10.1111/exd.14226DOI Listing
February 2021
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