Differentiation of osteophyte types in osteoarthritis - proposal of a histological classification - Junker, Susann; Krumbholz, Grit; Frommer, Klaus W.; Rehart, Stefan; Steinmeyer, Juergen; Rickert, Markus; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (Joint Bone Spine, 2016)
Osteoarthritis is not only characterized by cartilage degradation but also involves subchondral bone remodeling and osteophyte formation. Osteophytes are fibrocartilage-capped bony outgrowths originating from the periosteum. The pathophysiology of osteophyte formation is not completely understood. Yet, different research approaches are under way. Therefore, a histological osteophyte classification to achieve comparable results in osteophyte research was established for application to basic science research questions.The osteophytes were collected from knee joints of osteoarthritis patients (n=10, 94 osteophytes in total) after joint replacement surgery. Their size and origin in the respective joint were photo-documented. To develop an osteophyte classification, serial tissue sections were evaluated using histological (hematoxylin and eosin, Masson's trichrome, toluidine blue) and immunohistochemical staining (collagen type II).Based on the histological and immunohistochemical evaluation, osteophytes were categorized into four different types depending on the degree of ossification and the percentage of mesenchymal connective tissue. Size and localization of osteophytes were independent from the histological stages.This histological classification system of osteoarthritis osteophytes provides a helpful tool for analyzing and monitoring osteophyte development and for characterizing osteophyte types within a single human joint and may therefore contribute to achieve comparable results when analyzing histological findings in osteophytes.
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Differenzialdiagnose Rückenschmerzen mit Entzündungsparametern: Fallvorstellung: Manifestation einer CPPD als Crowned Dens Syndrom mit Befall peripherer Gelenke - Kleyer, Arnd; Roemer, Frank; Schett, Georg; Manger, Bernhard (Aktuelle Rheumatologie, 2021)
This case report describes the case of a patient with back pain of unknown origin and high inflammatory markers. After an infectious cause was ruled out, he was diagnosed with CPPD disease with spinal infestation. New radiological segmentation methods also allowed the detection of CPPD crystals in peripheral joints. Treatment with prednisolone and short-term Kineret was initiated and the symptoms were treated successfully.
CRIS-Team Scopus Importer:2021-03-05
Keywords: chondrocalcinosis; CPPD; crowned dens syndrome; crystal arthropathies; pseudogout

Difficult-to-Treat Psoriatic Arthritis: A Conceptual Approach. - Fagni, Filippo; Motta, Francesca; Schett, Georg; Selmi, Carlo (Arthritis and Rheumatology, 2024)
EVALuna2:551950

DIFFUSING CAPACITY AND CLINICAL CHARACTERISTICS OF PATIENTS WITH SYSTEMIC SCLEROSIS - DATA FROM THE GERMAN NETWORK FOR SYSTEMIC SCLEROSIS - Moinzadeh, P.; Blank, N.; Siegert, E.; Henes, J.; Worm, M.; Sunderkoetter, C.; Schmalzing, M.; Kreuter, A.; Gunther, C.; Susok, L.; Zeidler, G.; Koetter, I.; et al. (2017)
EVALuna2:35043

Digital health transition in rheumatology: A qualitative study - Müehlensiepen, Felix; Kurkowski, Sandra; Krusche, Martin; Mucke, Johanna; Prill, Robert; Heinze, Martin; Welcker, Martin; Schulze-Koops, Hendrik; Vuillerme, Nicolas; Schett, Georg; Knitza, Johannes (International Journal of Environmental Research and Public Health, 2021)
The global COVID-19 pandemic has led to drastic changes in the management of patients with rheumatic diseases. Due to the imminent risk of infection, monitoring intervals of rheumatic patients have prolonged. The aim of this study is to present insights from patients, rheumatologists, and digital product developers on the ongoing digital health transition in rheumatology. A qualitative and participatory semi-structured fishbowl approach was conducted to gain detailed insights from a total of 476 participants. The main findings show that digital health and remote care are generally welcomed by the participants. Five key themes emerged from the qualitative content analysis: (1) digital rheumatology use cases, (2) user descriptions, (3) adaptation to different environments of rheumatology care, and (4) potentials of and (5) barriers to digital rheumatology implementation. Codes were scaled by positive and negative ratings as well as on micro, meso, and macro levels. A main recommendation resulting from the insights is that both patients and rheumatologists need more information and education to successfully implement digital health tools into clinical routine.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Chronic disease; Content analysis; Digital health; EHealth; Fishbowl discussion; Patient perspective; Qualitative research; Remote care; Rheumatology; Telemedicine

DIGITALLY ENHANCED TREAT-TO-TARGET AND SHARED DECISION-MAKING APPROACH WITH A DIGITAL HEALTH APPLICATION: INTERIM RESULTS FROM A RANDOMIZED CONTROLLED TRIAL - Knitza, Johannes; Grahammer, M.; Böltz, Sebastian; Lang, Johannes; Detert, M.; Bader, M.; Kleyer, Arnd; Simon, David; Kronke, G.; Schett, Georg; Detert, J. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Digitally supported shared decision-making and treat-to-target in rheumatology: a qualitative study embedded in a multicenter randomized controlled trial - Muehlensiepen, Felix; May, Susann; Hadaschik, Katharina; Vuillerme, Nicolas; Heinze, Martin; Grahammer, Manuel; Labinsky, Hannah; Böltz, Sebastian; Detert, Jacqueline; Petersen, Jana; Krönke, Gerhard; Schett, Georg; et al. (Rheumatology International, 2022)
Patient-reported outcomes (PRO) represent a cornerstone in the management of patients with rheumatoid arthritis (RA). However, PRO are currently recorded mainly on paper and only during on-site appointments. Electronic PRO (ePRO) enable continuous remote monitoring and could improve shared decision-making (SDM) and implementation of a treat-to-target (T2T) approach. This study aims to investigate patient and physician experiences, perceived drawbacks and benefits of using an ePRO web-app (ABATON RA) to digitally support SDM and T2T. A qualitative study embedded in a multicenter randomized controlled trial (RCT) consisting of interviews with RA patients and physicians that were subsequently analyzed using deductive-inductive qualitative content analysis. Between August 2021 and May 2022, interviews with ten RA patients and five physicians were completed. Three key themes emerged in the analysis: (i) App user experiences; (ii) perceived drawbacks of app-supported rheumatology care; and (iii) perceived benefits of app-supported rheumatology care. Continuous ePRO collection and a high level of standardization strained some RA patients. Certain ePRO seemed outdated and were hard to understand. Patients and physicians appreciated having an improved overview of disease activity, capturing disease flares and continuous remote monitoring. Paper- and time-saving were associated with using ePRO. Physicians feared to become too focused on ePRO data, stressed the lack of ePRO monitoring reimbursement and app interoperability. For RA patients and physicians, benefits seemed to outweigh observed drawbacks of the digitally supported SDM using ePRO. The software was easy to use and could lead to a better understanding of the individual disease course, resource allocation and treatment of rheumatoid arthritis.
CRIS-Team Scopus Importer:2022-10-28
Keywords: ePRO; Health Services Research; mHealth; Qualitative research; Rheumatology; SDM

Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: a study from the EUSTAR cohort - Hughes, Michael; Heal, Calvin; Henes, Joerg; Balbir-Gurman, Alexandra; Distler, Jörg; Airo, Paolo; Mueller-Ladner, Ulf; Hunzelmann, Nicolas; Kerzberg, Eduardo; Rudnicka, Lidia; Truchetet, Marie-Elise; Stebbings, Simon; et al. (Rheumatology, 2021)
Objective Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P <= 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P <= 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.
CRIS-Team WoS Importer:2022-03-04

Digital ulcers in systemic sclerosis : A retrospective heath service study analysing treatment with bosentan and other vasoactive therapies - Riemekasten, G.; Beissert, S.; Distler, Jörg; Kreuter, A.; Mueller-Ladner, U. (Zeitschrift für Rheumatologie, 2016)
Digital ulcers (DU) affect up to 60 % of patients with systemic sclerosis (SSc) and have a considerable impact on quality of life and morbidity. It is unclear to what extent authorised medicines are used, and if therapy guidelines are implemented in everyday practice.This retrospective health care study examined current standards of treatment for therapy and prevention of SSc-associated DU in an online survey with 83 physicians. Additionally, data from 161 case studies of SSc patients with DU were analysed, and the effect of DU treatment on the course of the disease determined.For treatment and prevention of active DU, physicians predominantly indicated topical therapies, calcium channel blockers, iloprost and endothelin receptor antagonists. According to the case studies, 90 % of episodes with acute DU were treated with bosentan and iloprost in mono- or combination therapy. Preventive treatment was only administered during 50 % of episodes without DU, even after three or more phases with active DU. For the prevention of new DU, bosentan was used in mono- or combination therapy in 57 % of episodes without DU. Bosentan therapy during prevention shortened the following acute phase by 32 %. Additionally, continuous treatment with bosentan in acute and prevention phases reduced the duration of the following acute phase and increased the time to onset of new DU by 16 %. Moreover, bosentan stabilised the number of new DU.In summary, these data confirm the efficacy of bosentan in preventing new DU when used in DU-free episodes and possibly also in phases of acute DU. Therapy recommendations for the treatment of DU are currently not fully implemented. In the future, even more attention should be paid to DU therapy.
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Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis - Soare, Alina; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Dees, Clara; Rauber, Simon; Wohlfahrt, Thomas; Chen, Chih Wei; Ludolph, Ingo; Horch, Raymund E.; Bäuerle, Tobias; von Hörsten, Stephan; Mihai, Carina; et al. (Arthritis and Rheumatology, 2020)
Objective: Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods: Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results: The expression of DPP-4 and the number of DPP-4–positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)–dependent manner. DPP-4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion: DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.
CRIS-Team Scopus Importer:2020-01-10

DIPEPTIDYL-PEPTIDASE-4 (DPP4) IS A POTENTIAL NEW MOLECULAR TARGET FOR TREATMENT OF FIBROSIS - Soare, A. M.; Gyoerfy, H.; Matei, Alexandru-Emil; Dees, Clara; Zhang, Yun; Wohlfahrt, T.; Chen, Chih-Wei; Ramming, A.; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34995

Dipeptidyl-Peptidase-4 (DPP4) Positive Fibroblast Subpopulation Promotes Fibrosis and Are a Molecular Target for Treatment of Fibrosis - Soare, Alina; Rauber, Simon; Wohlfahrt, Thomas; Dees, Clara; Liang, Ruifang; Zhang, Yun; Chen, Chih-Wei; Distler, Oliver; Mihai, Carina; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
EVALuna2:35065

Dipeptidyl-Peptidase-4 (DPP4) Promotes Fibroblast Activation and Is a Potential Molecular Target for Treatment of Fibrosis - Soare, Alina; Gyoerfy, Hermina; Matei, Alexandru-Emil; Dees, Clara; Chen, Chih-Wei; Ramming, Andreas; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33443

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study - Peytrignet, Sebastien; Denton, Christopher P.; Lunt, Mark; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan; Pan, Xiaoyan; Brown, Edith; Czirjak, Laszlo; Distler, Jörg; Distler, Oliver; Fligelstone, Kim; et al. (Rheumatology, 2017)
Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean ( s . d .) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (? = 0.34, P < 0.0001 and ? = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers ( P = 0.004), pulmonary fibrosis ( P = 0.005), cardiac ( P = 0.005) and muscle involvement ( P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (? = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (? = 0.40, P < 0.0001), decreasing hand function (? = 0.57, P < 0.0001) and increasing fatigue (? = -0.53, P < 0.0001).The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.
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DISEASE INTERCEPTION IN PSORIASIS PATIENTS WITH SUBCLINICAL JOINT INFLAMMATION BY INTERLEUKIN 17 INHIBITION WITH SECUKINUMAB - DATA FROM A PROSPECTIVE OPEN LABEL STUDY - Kamoylafka, E.; Oliveira, I. D.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (2018)
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Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation - Data from the prospective IVEPSA study - Kampylafka, Eleni; Simon, David; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Englbrecht, Matthias; Rech, Jürgen; Kleyer, Arnd; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Background: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Interleukin-17; Magnetic resonance imaging; Psoriasis; Psoriatic arthritis

DISEASE PROGRESSION IN 282 PATIENTS WITH UNDIFFERENTIATED SSC - DATA FROM THE GERMAN NETWORK FOR SYSTEMIC SCLERODERMA - Moinzadeh, P.; Blank, N.; Siegert, E.; Henes, J.; Susok, L.; Distler, Jörg; Juche, A.; Worm, M.; Gil, H. C.; Schmeiser, T.; Zeidler, G.; Gaebelein-Wissing, N.; et al. (2016)
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Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis - Moinzadeh, Pia; Aberer, Elisabeth; Ahmadi-Simab, Keihan; Blank, Norbert; Distler, Jörg; Fierlbeck, Gerhard; Genth, Ekkehard; Günther, Claudia; Hein, Ruediger; Henes, Joerg; Herich, Lena; Herrgott, Ilka; et al. (Annals of the Rheumatic Diseases, 2014)
Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status.To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc).The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed.Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies.These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset.These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
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Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging - Schmidkonz, Christian; Rauber, Simon; Atzinger, Armin; Agarwal, Rahul; Götz, Theresa Ida; Soare, Alina; Cordes, Michael; Prante, Olaf; Prante, Olaf; Bergmann, Christina; Kleyer, Arnd; Ritt, Philipp; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG 4 -related disease. Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG 4 -related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68 Ga-FAP inhibitor (FAPI)-04), 18 F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18 F-FDG and 68 Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Results Using combination of 68 Ga-FAPI-04 and 18 F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG 4 -related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18 F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG 4 + cells in histology, while 68 Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Conclusion FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG 4 -related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG 4 -related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
CRIS-Team Scopus Importer:2020-10-30
Keywords: fibroblasts; health care; inflammation; outcome assessment

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging - Schmidkonz, Christian; Rauber, Simon; Atzinger, Armin; Götz, Theresa Ida; Soare, A.; Cordes, Michael; Prante, Olaf; Ritt, Philipp; Bäuerle, Tobias; Köhner, Markus; Haberkorn, U.; Kuwert, Torsten; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
Ziel/Aim To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. Methodik/Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), magnetic resonance imaging (MRI) and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Ergebnisse/Results Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4 + cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Schlussfolgerungen/Conclusions FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
CRIS-Team WoS Importer:2022-01-07

Distinct Metabolism of Bone Marrow Adipocytes and their Role in Bone Metastasis - Li, Yixuan; Cao, Shan; Gaculenko, Anastasia; Zhan, Yifan; Bozec, Aline; Chen, Xiaoxiang (Frontiers in Endocrinology, 2022)
Bone marrow adipocytes (BMAs) represent 10% of the total fat mass of the human body and serve as an energy reservoir for the skeletal niche. They function as an endocrine organ by actively secreting fatty acids, cytokines, and adipokines. The volume of BMAs increases along with age, osteoporosis and/or obesity. With the rapid development of multi-omic analysis and the advance in in vivo imaging technology, further distinct characteristics and functions of BMAs have been revealed. There is accumulating evidence that BMAs are metabolically, biologically and functionally unique from white, brown, beige and pink adipocytes. Bone metastatic disease is an uncurable complication in cancer patients, where primary cancer cells spread from their original site into the bone marrow. Recent publications have highlighted those BMAs could also serve as a rich lipid source of fatty acids that can be utilized by the cancer cells during bone metastasis, particularly for breast, prostate, lung, ovarian and pancreatic cancer as well as melanoma. In this review, we summarize the novel progressions in BMAs metabolism, especially with multi-omic analysis and in vivo imaging technology. We also update the metabolic role of BMAs in bone metastasis, and their potential new avenues for diagnosis and therapies against metastatic cancers.
CRIS-Team Scopus Importer:2022-07-22
Keywords: bone marrow adipocytes; bone metastasis; lineage-tracing; metabolism; multi-omic analysis

Does an 18f-FDG-PET/CT in Patients with Giant Cell Arteritis in Clinical Remission Make Sense? - Schoenau, Verena; Roth, Jan-Peter; Englbrecht, Matthias; Rech, Jürgen; Schett, Georg (2018)
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Does anti-acid treatment influence disease progression in SSc-ILD ? data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Norbert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

Does methotrexate influence COVID-19 infection? Case series and mechanistic data - Schaelter, Fabian; Dürholz, Kerstin; Bucci, Laura; Burmester, Gerd; Caporali, Roberto; Figuereido, Camille; Cobra, Jaime Fogagnolo; Manger, Bernhard; Zaiss, Mario; Schett, Georg (Arthritis Research & Therapy, 2021)
Background: To investigate whether methotrexate treatment may affect the susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Clinical assessment of symptoms, SARS-CoV-2 RNA, and anti-SARS-CoV-2 IgG in an initial case series of four families and confirmatory case series of seven families, within which one family member developed coronavirus disease 19 (COVID-19) and exposed another family member receiving methotrexate treatment; experimental part with methotrexate treatment of mice and organoids followed by the assessment of mRNA and protein expression of the SARS-CoV-2 receptor angiotensin-converting enzyme (ACE)-2. Results: In the initial case series, three of four women on a joint ski trip developed COVID-19, while the fourth woman, under treatment with methotrexate, remained virus-free. Two of the three diseased women infected their husbands, while the third husband treated with methotrexate remained virus-free. In addition, 7 other families were identified in a follow-up case series, in which one member developed COVID-19, while the other, receiving methotrexate, remained healthy. Experimentally, when mice were treated with methotrexate, ACE2 expression significantly decreased in the lung, in the intestinal epithelium, and in intestinal organoids. Conclusion: These clinical and experimental data indicate that methotrexate has certain protective effects on SARS-CoV-2 infection via downregulating ACE2.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Coronavirus disease 19; Infection; Methotrexate

Does methotrexate influence COVID-19 infection? Case series and mechanistic data - Schälter, Fabian; Dürholz, Kerstin; Bucci, Laura; Burmester, Gerd R.; Caporali, Roberto; Figuereido, Camille; Cobra, Jaime Fogagnolo; Manger, Bernhard; Zaiss, Mario; Schett, Georg (Arthritis Research & Therapy, 2021)

Does subclinical inflammation contribute to impairment of function of knee joints in aged individuals? High prevalence of ultrasound inflammatory findings - D'Agostino, Maria Antonietta; Iagnocco, Annamaria; Aegerter, Philippe; Kleyer, Arnd; Zwerina, Jochen; Perricone, Carlo; Lorenzini, Rolando; Aschenbrenner, Franz; Willeit, Johann; Kiechl, Stefan; Schett, Georg (Rheumatology, 2015)
To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (>=60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters.Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis.A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively].The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age.
EVALuna2:13126

Does Subjectively Perceived Loss Of Hand Function Sufficiently Represent Ultrasonography-Detected Synovitis And Tenosynovitis In Patients With Psoriasis And Psoriatic Arthritis? - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Fagni, Filippo; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Schett, Georg; Kleyer, Arnd; et al. (poster, European Alliance of Association for Rheumatology (EULAR) Congress, 2023)

DOSING OF BDMARDS IN AXSPA AND PSA IN A REAL WORLD SETTING - Regierer, Anne C.; Weiss, Anja; Poddubnyy, Denis; Kellner, H.; Behrens, Frank; Schett, Georg; Braun, Jürgen; Sieper, Joachim; Strangfeld, Anja (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Downregulation of miR-193b in systemic sclerosis regulates the proliferative vasculopathy by urokinase-type plasminogen activator expression - Iwamoto, Naoki; Vettori, Serena; Maurer, Britta; Brock, Matthias; Pachera, Elena; Juengel, Astrid; Calcagni, Maurizio; Gay, Renate E.; Whitfield, Michael L.; Distler, Jörg; Gay, Steffen; Distler, Oliver (Annals of the Rheumatic Diseases, 2016)
To investigate the role of microRNA-193b-3p (miR-193b) in the vascular pathophysiology of systemic sclerosis (SSc).Expression of miR-193b in skin biopsies and fibroblasts from patients with SSc and normal healthy (NH) controls were determined by real-time PCR. Transfection with miR-193b precursor and inhibitor were used to confirm targets of miR-193b. Proliferative effects of urokinase-type plasminogen activator (uPA) were determined by water-soluble tetrazolium salt-1 assay and by analysis of proliferating cell nuclear antigen expression. Fluorescence activated cell sorting analysis was performed to investigate the effect of uPA on apoptosis. For inhibition of the uPA-cellular receptor for uPA (uPAR) pathway, uPAR neutralising antibodies and low molecular weight uPA were used.We found that miR-193b was downregulated in SSc fibroblasts and skin sections as compared with NH controls. The expression of miR-193b was not affected by major profibrotic cytokines and hypoxia. Induction of miR-193b in SSc fibroblasts suppressed, and accordingly, knockdown of miR-193b increased the levels of messenger RNA and protein for uPA. uPA was found to be upregulated in SSc as compared with NH controls in a transforming growth factor-? dependent manner, and uPA was strongly expressed in vascular smooth muscle cells in SSc skin section. Interestingly, uPA induced cell proliferation and inhibited apoptosis of human pulmonary artery smooth muscle cells, and these effects were independent of uPAR signalling.In SSc, the downregulation of miR-193b induces the expression of uPA, which increases the number of vascular smooth muscle cells in an uPAR-independent manner and thereby contributes to the proliferative vasculopathy with intimal hyperplasia characteristic for SSc.
EVALuna2:13080

DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY - Canneva, Fabio; Golub, Yulia; Distler, Jörg; Dobner, Julia; Meyer, Sarah Katharina; von Hörsten, Stephan (Psychoneuroendocrinology, 2015)
Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression.Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls.Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.
EVALuna2:13098

Drei Generationen Leiden: Cryopyrin-assoziiertes periodisches Syndrom mit familiärer NLRP3-Mutation - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-02-04

DUAL NEUTRALISATION OF IL-17A AND IL-17F WITH BIMEKIZUMAB IN PATIENTS WITH ACTIVE PSA: OVERALL AND TNF-INHIBITOR-NAIVE POPULATION RESULTS FROM A 48-WEEK PHASE 2B RANDOMISED STUDY - Ritchlin, Christopher T.; Kavanaugh, Arthur; Merola, Joseph F.; Schett, Georg; Scher, Jose U.; Warren, Richard B.; Assudani, Deepak; Kumke, Thomas; Ink, Barbara; Mcinnes, Iain (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

DURABILITY OF APREMILAST RESPONSE IN PATIENTS WITH PSORIATIC ARTHRITIS: LONG-TERM (208-WEEK) RESULTS FROM THE PALACE 1 TRIAL - Kavanaugh, A.; Gladman, D. D.; Gomez-Reino, J. J.; Hall, S.; Lespessailles, E.; Mease, P. J.; Schett, Georg; Mcilraith, M.; Delev, N.; Paris, M.; Teng, L.; Wollenhaupt, J. (2017)
EVALuna2:35038

Durability of apremilast response through 5 years of treatment in subjects with psoriatic arthritis - Kavanaugh, Arthur; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Lespessailles, Eric; Mease, Philip J.; Schett, Georg; Pari, Maria; Teng, Lichen; Wollenhaupt, Juergen (2018)
EVALuna2:34974

DYNAMIC CHANGES IN O-GLCNACYLATION REGULATE OSTEOCLAST DIFFERENTIATION AND BONE LOSS IN ARTHRITIS - Chen, Chih-Wei; Li, Y. N.; Trinh, Minh Thuong; Honglin, Z.; Matei, Alexandru-Emil; Ding, Xiao; Tran Manh, Cuong; Xu, Xiaohan; Liebel, C.; Liang, Ruifang; Huang, M. C.; Lin, N. Y.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153 - Li, Yi-Nan; Chen, Chih-Wei; Trinh, Minh Thuong; Zhu, Honglin; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Kuwert, Frederic; Hubel, Philipp; Ding, Xiao; Tran Manh, Cuong; Xu, Xiaohan; Liebel, Christoph; et al. (Bone Research, 2022)
Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.
CRIS-Team Scopus Importer:2022-08-05

Early detection of rheumatoid arthritis through patient empowerment by tailored digital monitoring and education: a feasibility study - Pfeuffer, Nicola; Hartmann, Fabian; Grahammer, Manuel; Simon, David; Schuster, Louis; Kuhn, Sebastian; Krönke, Gerhard; Schett, Georg; Knitza, Johannes; Kleyer, Arnd (Rheumatology International, 2025)
Patients at risk for rheumatoid arthritis (RA) describe fluctuating and nonspecific symptoms, making it difficult to quantify symptom burden and recognize RA progression. This study aimed to assess feasibility and diagnostic value of a multimodal digital self-monitoring program in preclinical RA. This prospective cohort study included individuals at-risk for RA, who first watched self-produced educational videos about (preclinical) RA and joint self-examination techniques and then started the REMOTRA symptom monitoring. Key outcomes measured included patient acceptance (Net Promoter Score: NPS), monitoring program usability (System usability scale: SUS), monitoring adherence, diagnostic accuracy, and reported symptom burden. A total of 43 participants (65.9% female, mean age 50.1 years) were enrolled. The educational and self-examination videos received NPS ratings of 54.4 and 31.6, respectively. The monitoring software received usability scores of 88.1/100 (SD: 5.5) at three months and 85.4/100 (SD: 16.0) at 6 months. 24/41 (58.5%) completed all questionnaires, and the average app usage was 4.8 months (SD: 1.8). None of the patients with a REMOTRA score below 10 developed RA, yielding a negative predictive value and sensitivity of 100%. However, the positive predictive value was 12%, and the specificity was 42.1%. Analgesic and cortisone usage was reported by 58.5% and 29.3% of participants, respectively. The strong patient acceptance, ease of use, and high adherence rates, combined with encouraging diagnostic outcomes, underscore the potential of this personalized digital monitoring and education approach. These findings suggest that further validation through multicenter studies is warranted.
CRIS-Team Scopus Importer:2025-02-28
Keywords: Digital health; Patient education; Remote monitoring; Rheumatoid arthritis

Early Histopathological Changes of the Salivary Glands Associated with the Development of Primary Sjogren's Syndrome - Shan, Xiaomei; Reichardt, Clara; Singh, Jeeshan; Zeitler, Anne; Schauer, Christine; Knopf, Jasmin; Herrmann, Martin; Grossmayer, Gerhard; Schett, Georg; Munoz, Luis Enrique (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Editorial overview: Osteoimmunology - Schett, Georg; Takayanagi, Hiroshi (Bone, 2022)
CRIS-Team Scopus Importer:2022-07-01

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells - Hecht, Markus; Erber, Sonja; Harrer, Thomas; Klinker, Hartwig; Roth, Thomas; Parsch, Hans; Fiebig, Nora; Fietkau, Rainer; Distel, Luitpold (PLoS ONE, 2015)
Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data.The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5 ?mol/l (= 9944 ng/ml), Nevirapine 239 ?mol/l (= 63,786 ng/ml), Etravirine 89.0 ?mol/l (= 38,740 ng/ml), Lersivirine 543 ?mol/l (= 168,523 ng/ml), Delavirdine 171 ?mol/l (= 78,072 ng/ml), Rilpivirine 24.4 ?mol/l (= 8941 ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587 ng/ml (range 162-15,363 ng/ml), of Rilpivirine 144 ng/ml (range 0-572 ng/ml) and of Nevirapine 4955 ng/ml (range 1856-8697 ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.
EVALuna2:13144

Effective and safe treatment of anti-CD38 therapy in systemic lupus erythematosus-associated refractory cerebral vasculitis induces immune tolerance - Yalcin Mutlu, Melek; Wacker, Jochen; Tascilar, Koray; Taubmann, Jule; Manger, Bernhard; Krönke, Gerhard; Schett, Georg; Simon, David (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-08-26

"EFFECTIVE LUNG AGE" IN SUBJECTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) IN THE SENSCIS TRIAL - Maher, T.; Bourdin, A.; Volkmann, E.; Vettori, S.; Distler, Jörg; Alves, M.; Stock, C.; Distler, O. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

EFFECTIVENESS AND SAFETY OF TOCILIZUMAB IN PATIENTS WITH SYSTEMIC SCLEROSIS: A PROPENSITY SCORE CONTROL MATCHED OBSERVATIONAL STUDY OF THE EUSTAR COHORT - Kuster, S.; Jordan, S.; Elhai, M. D.; Held, U.; Steigmiller, K.; Bruni, C.; Iannone, F.; Vettori, S.; Siegert, E.; Rednic, S.; Codullo, V.; Airo, P.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort - Kuster, Simon; Jordan, Suzana; Elhai, Muriel; Held, Ulrike; Steigmiller, Klaus; Bruni, Cosimo; Cacciapaglia, Fabio; Vettori, Serena; Siegert, Elise; Rednic, Simona; Codullo, Veronica; Airo, Paolo; et al. (RMD Open, 2022)
Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.
CRIS-Team Scopus Importer:2022-11-25
Keywords: autoimmune diseases; biological therapy; systemic sclerosis

Effect of Anti-Topoisomerase I Antibody Status on Decline in Lung Function in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: Data from the SENSCIS Trial - Mayes, Maureen; Highland, Kristin; Gahlemann, Martina; Fischer, Aryeh; Raghu, Ganesh; Girard, Mannaig; Alves, Margarida; Stowasser, Susanne; Distler, Jörg; Matucci-Cerinic, Marco; Volkmann, Elizabeth; Kuwana, Masataka; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Effect of disease-modifying anti-rheumatic drugs on bone structure and strength in psoriatic arthritis patients - Simon, David; Kleyer, Arnd; Bayat, Sara; Tascilar, Koray; Kampylafka, Eleni; Meinderink, Timo; Schuster, Louis; Petrov, Ramona; Liphardt, Anna-Maria; Rech, Jürgen; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Objectives: To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA). Methods: This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively. Results: One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17-or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness. Conclusion: Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs.
CRIS-Team Scopus Importer:2019-07-16
Keywords: Biological agents; Bone; Computed tomography; Disease-modifying anti-rheumatic drugs; Methotrexate; Psoriatic arthritis

Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study - Schett, Georg; Chen, Warner; Gao, Sheng; Chakravarty, Soumya D.; Shawi, May; Lavie, Frederic; Zimmermann, Miriam; Sharaf, Mohamed; Coates, Laura C.; Siebert, Stefan (Arthritis Research & Therapy, 2023)
Background: Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). Methods: Adults with active PsA (≥ 3 swollen joints, ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon ɣ (IFNɣ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. Results: Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNɣ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNɣ levels versus nonresponders. Conclusions: Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. Trial registration: ClinicalTrials.gov: NCT03796858.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Guselkumab; IL-17 pathway; IL-23; Psoriatic arthritis; Serum biomarkers

EFFECT OF HIGH FAT DIET ON SYSTEMIC AND LOCAL INFLAMMATION IN THE CONTEXT OF OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS MOUSE MODELS - Sauermilch, H. M.; Huelser, M-L; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

EFFECT OF NINTEDANIB ON PROGRESSION OF INTERSTITIAL LUNG DISEASE (ILD) IN PATIENTS WITH AUTOIMMUNE DISEASE-RELATED ILDS: FURTHER DATA FROM THE INBUILD TRIAL - Matteson, E.; Kelly, C.; Distler, Jörg; Hoffmann-Vold, A. M.; Seibold, J.; Mittoo, S.; Distler, O.; Dellaripa, P. F.; James, A.; Schlenker-Herceg, R.; Stowasser, S.; Quaresma, M.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group - Jordan, Suzana; Distler, Jörg; Maurer, Britta; Huscher, Doerte; Van Laar, Jacob M.; Allanore, Yannick; Distler, Oliver (Annals of the Rheumatic Diseases, 2015)
To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design.Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures.63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases.The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.
EVALuna2:13208

EFFECTS OF BASELINE PREDNISONE DOSE ON REMISSION AND DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB IN A PHASE 3 RANDOMIZED CONTROLLED TRIAL - Stone, John; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-16

EFFECTS OF BASELINE PREDNISONE DOSE ON REMISSION AND DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB IN THE GIACTA TRIAL - Stone, John H.; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-13

Effects of casirivimab/imdevimab on systemic and mucosal immunity against SARS-CoV-2 in B-cell depleted patients with autoimmune rheumatic diseases refractory to vaccination - Fagni, Filippo; Schmidt, Katja; Bohr, Daniela; Valor-Mendez, Larissa; Tascilar, Koray; Manger, Karin; Manger, Bernhard; Kleyer, Arnd; Simon, David; Schett, Georg; Harrer, Thomas; Hartmann, Fabian (RMD Open, 2022)
CRIS-Team WoS Importer:2022-06-03

Effects of Conventional Uric Acid-Lowering Therapy on Monosodium Urate Crystal Deposits - Ellmann, Hanna; Bayat, Sara; Guilhon de Araujo, Elizabeth; Manger, Bernhard; Kleyer, Arnd; Cavallaro, Alexander; Lell, Michael; Schenker, Hannah; Simon, David; Tascilar, Koray; Baraf, Herbert S. B.; Schett, Georg; et al. (Arthritis and Rheumatology, 2019)
Objective Few studies have systematically and quantitatively addressed the impact of urate-lowering therapy on monosodium urate (MSU) deposits. This study was undertaken to analyze the effect of lifestyle measures and conventional urate-lowering therapy on MSU deposits in patients with gout. Methods In this prospective study, subjects with gout according to the American College of Rheumatology/European League Against Rheumatism classification criteria and presence of MSU deposits seen on dual-energy computed tomography (DECT) scans received either lifestyle intervention or conventional urate-lowering therapy for a mean period of 18 months before a follow-up DECT scan. Detected MSU deposits were quantified by volumetric measurement and validated by semiquantitative scoring, and baseline and follow-up measurements were compared. Results Baseline and follow-up DECT scans were available for all 83 subjects. Six subjects discontinued treatment, and 77 subjects underwent a lifestyle intervention (n = 24) or were treated with allopurinol (n = 29), febuxostat (n = 22), or benzbromarone (n = 2) over the entire observation period. The mean serum uric acid (UA) level decreased from 7.2 to 5.8 mg/dl in the overall population. In patients who discontinued treatment, no change in MSU deposits or serum UA levels was observed. The burden of MSU deposits significantly decreased in patients undergoing lifestyle intervention (MSU volume P = 0.007; MSU score P = 0.001), and in patients treated with allopurinol (MSU volume and score P < 0.001) or febuxostat (MSU volume P < 0.001; MSU score P = 0.001). No significant decline in MSU deposits was noted in patients who discontinued treatment. Conclusion These data show that lifestyle intervention and xanthine oxidase inhibitors significantly decrease the MSU deposit burden. Hence, conventional gout therapy not only lowers serum UA levels, but also reduces pathologic MSU deposits.
CRIS-Team WoS Importer:2019-12-20

Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts - Gocht, Annika; Distler, Jörg; Spriewald, Bernd; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, Stephan M.; Heim, Christian (Transplant Immunology, 2018)
BACKGROUND: Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS: CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS: Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION: Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.
EVALuna2:35106

Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-A longitudinal analysis - Wunderlich, Carolin; Oliviera, Isabelle; Figueiredo, Camille P.; Rech, Juergen; Schett, Georg (Seminars in Arthritis and Rheumatism, 2016)
To study whether stable treatment with DMARDs affects anti-CCP2 antibody levels in patients with rheumatoid arthritis.In this longitudinal observational study 100 RA patients were followed for anti-CCP2 IgG antibody (U/L) and total IgG level (mg/dL) every 6 months for a total period of 2.5 years. All patients received stable DMARD treatment during this period. Five groups comprising each 20 patients were analyzed as follows: (1) methotrexate (MTX) alone, (2) tumor necrosis factor inhibitors (TNFi), (3) tocilizumab (TCZ), (4) rituximab (RTX), and (5) abatacept (ABA).Baseline demographic and disease-specific characteristics were comparable between the 5 groups. Anti-CCP2 antibody levels did not show significant changes in patients treated with MTX (mean ± SEM: -24.1 ± 8.1%), TNFi (-14.0 ± 11.1%) or TCZ (-24.3 ± 11.3%) between baseline and the 2.5 years follow-up. In contrast, anti-CCP2 antibody levels significantly decreased during treatment with RTX (-75.6 ± 4.4%) and ABA (-82.5 ± 3.7%). With respect to total IgG levels, no significant changes were observed with MTX (-1.6 ± 3.5%), TNFi (2.5 ± 3.4%), TCZ (-4.4 ± 3.1%), or ABA (-2.4 ± 3.8%) over 2.5 years. In contrast, total IgG levels significantly decreased during treatment with RTX (-22.0 ± 3.7%).DMARDs targeting the adaptive immune response such as ABA and RTX significantly lowered anti-CCP2 IgG levels, while cytokine inhibitors and methotrexate had no significant effects on anti-CCP2 IgG levels. RTX is the only DMARD, which also lowers total IgG level.
EVALuna2:13350

Effects of DMARD Tapering on Treatment Costs and Work Productivity in Rheumatoid Arthritis Patients- an Analysis from the Prospective Randomized Controlled Retro- Study - Hagen, Melanie; Figueiredo, Camille P.; Cobra, Jayme Fogagnolo; Haschka, Judith; Reiser, Michaela; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Finzel, Stephanie; Tony, Hans-Peter; Kleinert, Stefan; et al. (2016)
EVALuna2:34455

EFFECTS OF DMARD TAPERING ON TREATMENT COSTS IN RHEUMATOID ARTHRITIS PATIENTS-AN ANALYSIS FROM THE PROSPECTIVE RANDOMIZED CONTROLLED RETROSTUDY - Hagen, Melanie; Figueiredo, C.; Cobra, J. F.; Reiser, M.; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Finzel, S.; Tony, H. -P.; Wendler, J.; et al. (2016)
EVALuna2:13486

EFFECTS OF GUSELKUMAB, A MONOCLONAL ANTIBODY THAT SPECIFICALLY BINDS TO THE P19-SUBUNIT OF INTERLEUKIN-23, ON DACTYLITIS AND ENTHESITIS IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: POOLED RESULTS THROUGH WEEK 24 FROM TWO PHASE 3 STUDIES - Mcgonagle, D.; Mcinnes, I.; Deodhar, A.; Schett, Georg; Mease, P. J.; Shawi, M.; Kafka, S.; Karyekar, C.; Kollmeier, A.; Hsia, E. C.; Xu, X. L.; Sheng, S.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Effects of In utero environment and maternal behavior on neuroendocrine and behavioral alterations in a mouse model of prenatal trauma - Golub, Yulia; Canneva, F.; Funke, R.; Frey, Silke; Distler, Jörg; von Hörsten, Stephan; Freitag, C. M.; Kratz, Oliver; Moll, Gunther; Solati, Jalal (Developmental Neurobiology, 2016)
Maternal posttraumatic stress disorder (PTSD) following trauma exposure during pregnancy is associated with an increased risk of affective disorders in children. To investigate the mechanisms by which prenatal trauma and/or maternal PTSD affect brain development and behavior we established a mouse model of prenatal traumatic (PT) experience based on the application of an electric foot shock to C57Bl/6N female mice on the gestational day 12 during their pregnancy. The model is based on a previously validated animal model of PTSD. We found high anxiety levels and poor maternal care along with reduced serum prolactin and increased corticosterone levels in dams following maternal trauma (MT). PT-pups were born smaller and stayed smaller throughout their life. We show increased time and frequency of ultrasonic calls in PT-pups when separated from the mothers on the postnatal day (PND) 9. Cross-fostering experiments reveal lower anxiety levels in PT pups raised by healthy mothers as compared to trauma-naive pups raised by MT-dams. Importantly, the combination of prenatal trauma and being raised by a traumatized mother leads to: (1) the highest corticosterone levels in pups, (2) longest USV-call time and (3) highest anxiety levels in comparison to other experimental groups. Our data indicates a distinct change in maternal care following MT which is possibly associated with trauma-induced decrease in prolactin levels. Furthermore, we show that maternal behavior is crucial for the development of the offspring anxiety and specific aspects in maternal care overwrite to a significant extend the effects of in utero and postnatal environment. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1254-1265, 2016.
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Effects of nintedanib in patients with SSc-ILD and preserved and highly impaired lung function - Wuyts, Wim A.; Azuma, Arata; Distler, Jörg; Sondergaard, Klaus; Proudman, Susanna; Cottin, Vincent; Erhardt, Elvira; Quaresma, Manuel; Gahlemann, Martina; Alves, Margarida; Maher, Toby M. (EUROPEAN RESPIRATORY JOURNAL, 2020)
CRIS-Team WoS Importer:2021-02-12

Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension - D'Agostino, Maria Antonietta; Carron, Philippe; Gaillez, Corine; Conaghan, Philip G.; Naredo, Esperanza; López-Rdz, Alejandra; Šenolt, Ladislav; Burgos-Vargas, Ruben; Hanova, Petra; Padovano, Ilaria; Cazenave, Tomas; Stoenoiu, Maria S.; et al. (Seminars in Arthritis and Rheumatism, 2023)
Objectives: In the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). Methods: This randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12–24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24–52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. Results: Of the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. Conclusions: ULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Clinical response; Enthesitis; OMERACT; Power Doppler ultrasonography; Psoriatic arthritis; Synovitis

Effects of targeted therapies on the bone in arthritides - Szentpetery, Agnes; Horvath, Agnes; Gulyas, Katalin; Petho, Zsofia; Bhattoa, Harjit Pal; Szanto, Sandor; Szucs, Gabriella; Fitzgerald, Oliver; Schett, Georg; Szekanecz, Zoltan (Autoimmunity Reviews, 2017)
Inflammatory arthritides, such as rheumatoid arthritis (RA) and spondyloarthritides (SpA) have been associated with both localized bone resorption and/or formation, and generalized osteoporosis. Systemic inflammation may be the major driver for bone loss in arthritis. In RA and peripheral SpA the RANK-RANKL-OPG network is involved in bone resorption, while in axial SpA the Wnt-?-catenin axis and its inhibitors (DKK-1, sclerostin) are the most relevant. Targeted therapies including biologics and small molecule tyrosine kinase inhibitors may interfere with inflammatory bone metabolism. Most of these compounds are able to slow down radiographic progression and osteoporosis in arthritides. In very early cases of non-radiological SpA, there may be a window of opportunity allowing to prevent syndesmophyte formation. The inability of targeted therapies to increase the production of DKK-1 and sclerostin may explain the lack of efficacy of TNF inhibitors to halt syndesmophyte formation in SpA. Further clinical trials are needed to better understand the bone effects of targeted therapies.
EVALuna2:13349

EFFECTS OF THE AUTOTAXIN INHIBITOR ZIRITAXESTAT ON SKIN AND LUNG FIBROSIS IN A MURINE GRAFT-VERSUS-HOST DISEASE MODEL OF SYSTEMIC SCLEROSIS - Zhang, Yun; Summa, L.; Heckmann, B.; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis - Gravallese, Ellen M.; Schett, Georg (Nature Reviews Rheumatology, 2018)
Over the past several years, a pathophysiological role for the IL-23-IL-17 pathway in human disease has been defined. A subset of rheumatic diseases, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are now acknowledged to be triggered by dysregulated IL-23-IL-17 pathway activation. Genetic evidence links the IL-23-IL-17 pathway to inflammation in these rheumatic diseases, and mechanistic data from mice support a functional role for IL-23-IL-17 pathway activation in the development of enthesitis and in entheseal bone formation. Furthermore, analysis of human tissue samples, as well as data from clinical trials, also supports a role for activation of the IL-23-IL-17 pathway in these diseases. The unique bone phenotype that occurs in PsA and AS is a surprising coexistence of both systemic bone loss and periosteal and entheseal bone formation and is likely to be the result of the actions of IL-23 and/or IL-17 on bone. However, the effects of these cytokines on bone cells are complex, and controversy remains regarding their exact roles in the specific bone microenvironments relevant to PsA and AS.
EVALuna2:34664

Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: Results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study - Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Höpken, Sabrina; Finzel, Stephanie; Kampylafka, Eleni; Kleyer, Arnd; Bayat, Sara; Schoenau, Verena; Hueber, Axel; Rech, Jürgen; Schett, Georg (Seminars in Arthritis and Rheumatism, 2018)
OBJECTIVES: To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients. METHODS: Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24weeks. RESULTS: 51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ± SD SPARCC index at baseline was 4.8 ± 2.6 in the UST group and 3.5 ± 2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95). CONCLUSION: These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.
EVALuna2:34482

Efficacy and drug persistence of baricitinib monotherapy is similar to combination therapy in patients with active RA: a prospective observational study - Bayat, Sara; Tascilar, Koray; Bohr, Daniela; Krönke, Gerhard; Simon, David; Knitza, Johannes; Hartmann, Fabian; Schett, Georg; Kleyer, Arnd (RMD Open, 2022)
BACKGROUND: Baricitinib (BARI) is approved for the treatment of rheumatoid arthritis (RA) after failure of conventional synthetic and biologic disease modifying anti-rheumatic drugs (cs/bDMARDs) in combination with methotrexate (MTX) or as monotherapy. However, real-world data are scarce regarding efficacy and drug persistence for BARI monotherapy (BARI-mono) versus its combination with MTX (BARI-combo). OBJECTIVE: To evaluate efficacy and drug persistence of BARImono compared with BARI-combo in routine clinical practice METHODS: Patients with RA who were switched to BARI were included in a prospective, monocentric cohort. Demographics, clinical outcomes, adverse events and medication were prospectively recorded every 3 months. Clinical efficacy was measured by DAS-28 ESR while drug persistence was measured as the time on drug. We estimated least-square mean DAS-28 scores over time using linear mixed effects models including time-group interactions. Kaplan-Meier method was used to estimate BARI survival and probability of remission over time. RESULTS: 139 patients (98 women; aged 58.4 (12.8) years; mean disease duration of 9.7 years) were included between 2017 and 2021. 46 patients received BARI-combo, 93 patients received BARI-mono. Mean DAS-28 ESR were not significantly but only numerically different between both groups at baseline and multiple timepoints over follow-up. DAS-28 ESR remission was attained at least once upto 48 weeks in 62% and 51% patients in BARI-combo versus BARI-mono group (log-rank p=0.64). Drug persistence was high (69 vs 67% at 48 weeks and 62% vs 56% at 96 weeks) and similar in BARI-combo-treated and BARI-mono-treated patients. b/ts DMARD naïve patients had lower mean DAS-28 scores over the follow-up and attained DAS-28 ESR remission earlier than patients with inadequate response to b/ts DMARDs (p=0.11). BARI was discontinued in 11/139 patients (7.9%) due to adverse effects. CONCLUSION: In routine practice, BARI is effective as monotherapy in case of MTX intolerance with overall high drug persistence rates. No new safety signals were observed.
CRIS-Team Scopus Importer:2022-12-02
Keywords: Baricitinib; Combination treatment; Drug survival; Remission; Rheumatoid Arthritis

Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: A proof-of-concept study - Glatt, Sophie; Taylor, Peter C.; McInnes, Iain B.; Schett, Georg; Landewe, Robert L.; Baeten, Dominique; Ionescu, Lucian; Strimenopoulou, Foteini; Watling, Mark I.L.; Shaw, Stevan (Annals of the Rheumatic Diseases, 2019)
Objective: Evaluate the efficacy and safety of dual neutralisation of interleukin (IL)-17A and IL-17F with bimekizumab, a monoclonal IgG1 antibody, in addition to certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) and inadequate response (IR) to certolizumab pegol. Methods: During this phase 2a, double-blind, proof-of-concept (PoC) study (NCT02430909), patients with moderate-to-severe RA received open-label CZP 400 mg at Weeks 0, 2 and 4, and 200 mg at Week 6. Patients with IR at Week 8 (Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP))>3.2) were randomised 2:1 to CZP (200 mg every 2 weeks (Q2W)) plus bimekizumab (240 mg loading dose then 120 mg Q2W) or CZP plus placebo. The primary efficacy and safety variables were change in DAS28(CRP) between Weeks 8 and 20 and incidence of treatment-emergent adverse events (TEAEs). Results: Of 159 patients enrolled, 79 had IR at Week 8 and were randomised to CZP plus bimekizumab (n=52) or CZP plus placebo (n=27). At Week 20, there was a greater reduction in DAS28(CRP) in the CZP-IR plus bimekizumab group compared with the CZP-IR plus placebo group (99.4% posterior probability). The most frequent TEAEs were infections and infestations (CZP plus bimekizumab, 50.0% (26/52); CZP plus placebo, 22.2% (6/27)). Conclusions: PoC was confirmed based on the rapid decrease in disease activity achieved with 12 weeks of CZP plus bimekizumab. No unexpected or new safety signals were identified when neutralising IL-17A and IL-17F in patients with RA concomitantly treated with CZP, but the rate of TEAEs was higher with dual inhibition.
CRIS-Team Scopus Importer:2019-06-21
Keywords: anti-tnf; DAS28; dmards (biologic); rheumatoid arthritis; treatment

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who are inadequate responders to tumour necrosis factor inhibitors: results through one year of a phase IIIb, randomised, controlled study (COSMOS) - Coates, Laura C.; Gossec, Laure; Theander, Elke; Bergmans, Paul; Neuhold, Marlies; Karyekar, Chetan S.; Shawi, May; Noel, Wim; Schett, Georg; Mcinnes, Iain B. (Annals of the Rheumatic Diseases, 2021)
Objective To evaluate efficacy and safety of guselkumab, an anti-interleukin-23p19-subunit antibody, in patients with psoriatic arthritis (PsA) with prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFi).
CRIS-Team WoS Importer:2021-12-03

EFFICACY AND SAFETY OF GUSELKUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS WHO DEMONSTRATED INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITION: WEEK 24 RESULTS OF A PHASE 3B, RANDOMIZED, CONTROLLED STUDY - Coates, L. C.; Gossec, L.; Theander, E.; Bergmans, P.; Neuhold, M.; Karyekar, C.; Shawi, M.; Noel, W.; Schett, Georg; Mcinnes, I. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Efficacy and Safety of Nintedanib in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease by Use of Mycophenolate at Baseline: Subgroup Analysis of the SENSCIS Trial - Highland, Kristin; Distler, Oliver; Kuwana, Masataka; Allanore, Yannick; Assassi, Shervin; Azuma, Arata; Bourdin, Arnaud; Denton, Christopher; Distler, Jörg; Hoffmann-Vold, Anna Maria; Khanna, Dinesh; Mayes, Maureen; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial - Highland, Kristin B.; Distler, Oliver; Kuwana, Masataka; Allanore, Yannick; Assassi, Shervin; Azuma, Arata; Bourdin, Arnaud; Denton, Christopher P.; Distler, Jörg; Hoffmann-Vold, Anna Maria; Khanna, Dinesh; Mayes, Maureen D.; et al. (The Lancet Respiratory Medicine, 2021)
Background: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. Methods: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. Findings: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was –40·2 mL per year (SE 19·8) with nintedanib and –66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI –27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was –63·9 mL per year (SE 19·3) with nintedanib and –119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. Interpretation: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. Funding: Boehringer Ingelheim.
CRIS-Team Scopus Importer:2021-01-15

Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease - Simon, David; Tascilar, Koray; Fagni, Filippo; Schmidt, Katja; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Schönau, Verena; Bohr, Daniela; Knitza, Johannes; Harrer, Thomas; Manger, Karin; et al. (Annals of the Rheumatic Diseases, 2021)
Objectives To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. Methods Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. Results 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. Conclusions Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.
CRIS-Team WoS Importer:2021-12-03

EFFICACY AND SAFETY OF SECUKINUMAB IN PATIENTS WITH ROTATOR CUFF TENDINOPATHY: A 24-WEEK, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE II PROOF-OF-CONCEPT TRIAL - Millar, N. L.; Mcinnes, I.; Mindeholm, L.; Seroutou, A.; Praestgaard, J.; Schramm, U.; Levitch, R.; Weber, E.; Laurent, D.; Rosen, J.; Schett, Georg; Roubenoff, R.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

EFFICACY OF WNT PATHWAY INHIBITORS FOR THE PREVENTION OF CARDIAC ALLOGRAFT VASCULOPATHY IN A MOUSE MODEL - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, B.; Ensminger, S.; Weyand, Michael; Heim, Christian (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies - Borte, M.; Krivan, G.; Derfalvi, B.; Marodi, L.; Harrer, Thomas; Jolles, S.; Bourgeois, C.; Engl, W.; Leibl, H.; Mccoy, B.; Gelmont, D.; Yel, L. (Clinical and Experimental Immunology, 2016)
A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were >= 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.
EVALuna2:13342

EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation - Linder, Markus; Hecking, Manfred; Glitzner, Elisabeth; Zwerina, Karin; Holcmann, Martin; Bakiri, Latifa; Ruocco, Maria Grazia; Tuckermann, Jan; Schett, Georg; Wagner, Erwin F.; Sibilia, Maria (Cell Death and Differentiation, 2018)
Mice deficient in epidermal growth factor receptor (Egfr-/- mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr-/- mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr-/- bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr-/- fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.
EVALuna2:34469

Eighty years of rheumatology—Milestones in diagnosis, treatment and research Achtzig Jahre Rheumatologie – Meilensteine in Diagnose, Therapie und Forschung - Burmester, G. R.; Schett, Georg (Zeitschrift für Rheumatologie, 2021)
CRIS-Team Scopus Importer:2021-07-16

ELDERLY PATIENTS ARE NOT AT INCREASED RISK OF SERIOUS INFECTIONS WHEN RECEIVING BDMARDS OR JAK INHIBITORS COMPARED TO CSDMARD TREATMENT - Strangfeld, A.; Manger, Bernhard; Worsch, M.; Schmeiser, T.; Zink, A.; Schaefer, M. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

ELEVATED MULTI-BIOMARKER DISEASE ACTIVITY (MBDA) PREDICTS RELAPSES IN RA PATIENTS IN SUSTAINED REMISSION TAPERING TUMOUR NECROSIS FACTOR INHIBITOR THERAPY-RESULTS FROM THE RANDOMIZED CONTROLLED RETRO STUDY - Rech, Jürgen; Hagen, M.; Englbrecht, M.; Haschka, J.; Reiser, M.; Kleyer, A.; Hueber, A.; Manger, Bernhard; Figuereido, C.; Cobra, J. Fogagnolo; Tony, H-P.; Finzel, S.; et al. (2017)
EVALuna2:34452

Elevated serum levels of free interleukin-18 in adult-onset Still's disease - Girard, Charlotte; Rech, Juergen; Brown, Michael; Allali, Daniele; Roux-Lombard, Pascale; Spertini, Francois; Schiffrin, Eduardo J.; Schett, Georg; Manger, Bernhard; Bas, Sylvette; Del Val, Greg; Gabay, Cem (Rheumatology, 2016)
IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases.An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients.Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM.Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.
EVALuna2:13254

Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis - Beyer, Christian; Huscher, Doerte; Ramming, Andreas; Bergmann, Christina; Avouac, Jerome; Guiducci, Serena; Meier, Florian; Vettori, Serena; Siegert, Elise; Jaeger, Veronika K.; Maurer, Britta; Riemekasten, Gabriela; et al. (Annals of the Rheumatic Diseases, 2017)
EVALuna2:12881

Enasidenib in IDH-2 mutant AML patients with relapse after allogeneic stem cell transplantation - Vasova, Ingrid; Spörl, Silvia; Guggenberger, Valentin; Berisha, M.; Rech, D.; Behzad, Ali; Brandt, Amelie; Kremer, A.; Mackensen, Andreas; Rösler, Wolf; Winkler, J. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

ENGRAILED 1 COORDINATES CYTOSKELETAL ORGANIZATION TO PROMOTE MYOFIBROBLAST DIFFERENTIATION AND FIBROTIC TISSUE REMODELING - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Fuchs, Maximilian; Rigau, Aleix; Hong, Xuezhi; Honglin, Z.; Luber, M.; Bergmann, Christina; Dees, Clara; Ludolph, Ingo; Horch, Raymund E.; Distler, O.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Fuchs, Maximilian; Liang, Chunguang; Rigau, Aleix; Hong, Xuezhi; Zhu, Honglin; Luber, Markus; Bergmann, Christina; Dees, Clara; Ludolph, Ingo; Horch, Raymund E.; et al. (Journal of Experimental Medicine, 2021)
Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
CRIS-Team Scopus Importer:2021-07-30

Enhancing student understanding of rheumatic disease pathologies through augmented reality: findings from a multicentre trial. - Pfeil, Alexander; Klemm, Philipp; Hueber, Axel J.; Hoffmann, Tobias; Weise, Tobias; Oelzner, Peter; Knop, Stefan; Müller-Ladner, Ulf; Lange, Uwe; Wolf, Gunter; Schett, Georg; Simon, David; et al. (Rheumatology, 2024)
OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymized patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO! app. All participants evaluated the course after completion, assessing the benefit of the app from a student's perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO! improved the understanding of pathologies in RA, PsA and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from the medical students' perspective, an AR-based concept like the Rheumality GO! app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.
EVALuna2:540323

Entheseal Biopsy Approach: An Ultrasound-guided Method for Retrieval of Entheseal Tissue from Psoriatic Arthritis Patients - Raimondo, Maria Gabriella; Pachowsky, Milena; Xu, Cong; Rauber, Simon; Tascilar, Koray; Labinsky, Hannah; Vogg, Mario; Saad, Mina saad aziz; Simon, David; Rech, Jürgen; Soare, Alina; Bräuer, Lars; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Enthesitis: from pathophysiology to treatment - Schett, Georg; Lories, Rik J.; D'Agostino, Maria-Antonietta; Elewaut, Dirk; Kirkham, Bruce; Soriano, Enrique R.; Mcgonagle, Dennis (Nature Reviews Rheumatology, 2017)
Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.
EVALuna2:13515

ENTHESITIS IN PATIENTS WITH PSORIATIC ARTHRITIS TREATED WITH SECUKINUMAB OR ADALIMUMAB: A POST HOC ANALYSIS OF EXCEED - Kaeley, G. S.; Schett, Georg; Conaghan, P. G.; Mcgonagle, D.; Behrens, F.; Goupille, P.; Gaillez, C.; Parikh, B.; Meng, X.; Bakewell, C. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Enthesitis in patients with psoriatic arthritis treated with secukinumab or adalimumab: a post hoc analysis of the EXCEED study. - Kaeley, Gurjit S.; Schett, Georg; Conaghan, Philip G.; McGonagle, Dennis; Behrens, Frank; Goupille, Philippe; Gaillez, Corine; Parikh, Bhumik; Bakewell, Catherine (Rheumatology, 2024)
OBJECTIVES: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. METHODS: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes. RESULTS: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. CONCLUSION: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02745080.
EVALuna2:540351

Enthesitis in psoriatic arthritis (Part 1): pathophysiology - Araujo, Elizabeth G.; Schett, Georg (Rheumatology, 2020)
Enthesitis is a key manifestation of PsA and current knowledge supports the concept that it may be among the primary events in the development of this disease, as well as other forms of SpA. Patients with PsA seem to have a different threshold to mechanical stress, which may be genetically determined. Hence patients with psoriatic disease respond pathologically with inflammation after being exposed to physiological mechanical stress. Activation of pro-inflammatory mediators such as IL-17 and TNF-α as well as the influx of innate immune cells are key events in the development of enthesitis in PsA. Chronic entheseal inflammation is accompanied by new bone formation, leading to bony spurs in peripheral (entheseophytes) and axial (syndesmophytes) structures. This article reviews the current knowledge on the mechanisms involved in the development of enthesitis in patients with PsA.
CRIS-Team Scopus Importer:2020-03-27
Keywords: entheseophyte; enthesitis; interleukin 17; interleukin 23; psoriatic arthritis

Entwicklung von Qualitätsstandards für die Versorgung von Patient*innen mit rheumatoider Arthritis zur Anwendung in Deutschland - Kiltz, U.; Buschhorn-Milberger,; Albrecht, K.; Lakomek, H-J; Lorenz, H-M; Rudwaleit, M.; Schneider, M.; Schulze-Koops, H.; Aringer, M.; Hasenbring, M.; Herzer, P.; Von Hinueber, U.; et al. (Zeitschrift für Rheumatologie, 2021)
Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Care gaps; Quality of care; Quality standards; Rheumatoid arthritis

Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death - O'Donnell, Valerie B.; Aldrovandi, Maceler; Murphy, Robert C.; Krönke, Gerhard (Science Signaling, 2019)
Enzymatically oxidized phospholipids (eoxPLs) are formed through regulated processes by which eicosanoids or prostaglandins are attached to phospholipids (PLs) in immune cells. These eoxPLs comprise structurally diverse families of biomolecules with potent bioactivities, and they have important immunoregulatory roles in both health and disease. The formation of oxPLs through enzymatic pathways and their signaling capabilities are emerging concepts. This paradigm is changing our understanding of eicosanoid, prostaglandin, and PL biology in health and disease. eoxPLs have roles in cellular events such as ferroptosis, apoptosis, and blood clotting and diseases such as arthritis, diabetes, and cardiovascular disease. They are increasingly recognized as endogenous bioactive mediators and potential targets for drug development. This review will describe recent evidence that places eoxPLs and their biosynthetic pathways center stage in immunoregulation.
CRIS-Team WoS Importer:2019-04-09

Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. - Uderhardt, Stefan; Ackermann, Jochen A.; Fillep, Tobias; Hammond, Victoria J.; Willeit, Johann; Santer, Peter; Mayr, Manuel; Biburger, Markus; Miller, Meike; Zellner, Katie R.; Stark, Konstantin; Zarbock, Alexander; et al. (Journal of Experimental Medicine, 2017)
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.

Eosinophils are not essential for maintenance of murine plasma cells in the bone marrow - Haberland, Konrad; Ackermann, Jochen A.; Ipseiz, Natacha; Culemann, Stephan; Pracht, Katharina; Englbrecht, Matthias; Jäck, Hans-Martin; Schett, Georg; Schuh, Wolfgang; Krönke, Gerhard (European Journal of Immunology, 2018)
Eosinophils were reported to serve as an essential component of the plasma cell niche within the bone marrow. As the potential contribution of eosinophils to humoral immunity has remained incompletely understood, we aimed to further characterize their role during antibody responses and to additionally investigate their role in autoimmune disease. Contrary to our expectations and the currently prevailing paradigm, we found that eosinophils are fully dispensable for the survival of murine bone marrow plasma cells and accordingly do not contribute to antibody production and autoantibody-mediated disease. Littermate wild type and eosinophil-deficient ΔdblGATA-1 animals showed similar numbers and frequencies of plasma cells and did not differ in steady state levels of immunoglobulins or their ability to raise antigen-specific antibody responses. Eosinophils were likewise dispensable for autoantibody production or autoantibody-induced disease in a mouse model of systemic lupus erythematosus. Our findings thus argue against a role of eosinophils during the maintenance of the plasma cell pool and challenge the hitherto postulated concept of an eosinophil-sustained bone marrow niche.
EVALuna2:34472

Eosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase. - Andreev, Darja; Kachler, Katerina; Liu, Mengdan; Chen, Zhu; Krishnacoumar, Brenda; Ringer, Mark; Frey, Silke; Krönke, Gerhard; Vöhringer, David; Schett, Georg; Bozec, Aline (Nature Communications, 2024)
Eosinophils are involved in tissue homeostasis. Herein, we unveiled eosinophils as important regulators of bone homeostasis. Eosinophils are localized in proximity to bone-resorbing osteoclasts in the bone marrow. The absence of eosinophils in ΔdblGATA mice results in lower bone mass under steady-state conditions and amplified bone loss upon sex hormone deprivation and inflammatory arthritis. Conversely, increased numbers of eosinophils in IL-5 transgenic mice enhance bone mass under steady-state conditions and protect from hormone- and inflammation- mediated bone loss. Eosinophils strongly inhibit the differentiation and demineralization activity of osteoclasts and lead to profound changes in the transcriptional profile of osteoclasts. This osteoclast-suppressive effect of eosinophils is based on the release of eosinophil peroxidase causing impaired reactive oxygen species and mitogen-activated protein kinase induction in osteoclast precursors. In humans, the number and the activity of eosinophils correlates with bone mass in healthy participants and rheumatoid arthritis patients. Taken together, experimental and human data indicate a regulatory function of eosinophils on bone.
EVALuna2:554518

Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity - Kadur Lakshminarasimha Murthy, Preetish; Xi, Rui; Arguijo, Diana; Everitt, Jeffrey I.; Kocak, Dewran D.; Kobayashi, Yoshihiko; Bozec, Aline; Vicent, Silvestre; Ding, Shengli; Crawford, Gregory E.; Hsu, David; Tata, Purushothama Rao; et al. (Developmental Cell, 2022)
Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
CRIS-Team Scopus Importer:2022-02-11
Keywords: adenocarcinoma; alveolar type II cell; ATAC-seq; club cell; epigenetics; Fosl1; intestinal stem cell; KRAS; lung; NSCLC

EPIGENETIC DEREGULATION OF AUTOPHAGY PROMOTES FIBROSIS IN SYSTEMIC SCLEROSIS - Zehender, A.; Lin, N. Y.; Li, Y. N.; Gyorfi, A. H.; Bergmann, C.; Ramming, Andreas; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Epigenetic factors as drivers of fibrosis in systemic sclerosis - Bergmann, Christina; Distler, Jörg (Epigenomics, 2017)
Prolonged activation of fibroblasts is a central hallmark of fibrosing disorders such as systemic sclerosis (SSc). Fibroblasts are the key effector cells. They differentiate into an activated myofibroblast phenotype. In contrast to normal wound healing with transient activation, myofibroblasts persist in fibrosing disorders. Current hypothesis suggests that profibrotic cytokines might trigger epigenetic changes which contribute to the persistently activated fibroblast phenotype. In the last years, several epigenetic alterations have been described in SSc and have been linked to different pathogenic aspects of the disease, in particular to aberrant fibroblast activation and tissue fibrosis, but also to vascular manifestations and inflammation. The focus of this review is the current knowledge on epigenetic changes in fibroblast activation in SSc.
EVALuna2:13414

Epigenetic modifications in autoimmune diseases - Ramming, A.; Distler, Jörg; Schett, Georg; Gay, S.; Jüngel, A. (Zeitschrift für Rheumatologie, 2014)
EVALuna2:12993

Epigenetic profiling of twins identify repression of KLF4 as a novel pathomechanism in systemic sclerosis - Distler, Jörg; O'Reilly, Steven (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-12-10

EPIGENETIC REGULATION OF FRA2 BY JMJD3 REGULATES FIBROBLAST ACTIVATION IN SYSTEMIC SCLEROSIS - Bergmann, C.; Brandt, Adrian; Dees, Clara; Wohlfahrt, T.; Zhang, Y.; Chen, Chih-Wei; Mallano, T.; Liang, Ruifang; Kagwiria, R.; Kam, P. -S.; Bozec, Aline; Abraham, D.; et al. (2017)
EVALuna2:35037

Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis - Wen, Jinming; Lyu, Pang; Stolzer, Iris; Xu, Jin; Gießl, Andreas; Lin, Zhen; Andreev, Darja; Kachler, Katerina; Song, Rui; Meng, Xianyi; Cao, Shan; Guggino, Giuliana; et al. (Annals of the Rheumatic Diseases, 2022)
To investigate how the mucosal barrier in the intestine influences the development of arthritis, considering that metabolic changes in the intestinal epithelium influence its barrier function. Intestinal HIF2α expression peaked at onset of experimental arthritis and RA. Conditionally, deletion of HIF2α in gut epithelial cells inhibited arthritis and was associated with improved intestinal barrier function and less intestinal and lymphatic Th1 and Th17 activation. Mechanistically, HIF2α induced the transcription of the pore-forming claudin (CLDN)-15, which inhibits intestinal barrier integrity. Furthermore, treatment with HIF2α inhibitor decreased claudin-15 expression in epithelial cells and inhibited arthritis and littermate control mice. The gut intestinal HIF2α target genes were delineated by chromatin immunoprecipitation and luciferase experiments. Furthermore, pharmacological HIF2α inhibitor PT2977 was used for inhibition of arthritis. These findings show that the HIF2α-CLDN15 axis is critical for the breakdown of intestinal barrier function at onset of arthritis, highlighting the functional link between intestinal homeostasis and arthritis.
CRIS-Team WoS Importer:2022-07-01
Keywords: Arthritis; Arthritis; Experimental; Inflammation.

Erdheim-Chester disease. An important differential diagnosis and its main symptoms - Knitza, Johannes; Kampylafka, E.; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
BackgroundDuring the last 3 years 4 patients were admitted to this hospital with a wide variety of different symptoms, in whom Erdheim-Chester disease (ECD) was diagnosed via different diagnostic pathways.ObjectiveBased on four clinical cases of ECD and using additional information from the literature, this article presents the symptoms of ECD. Furthermore, similarities and differences in comparison to important rheumatological differential diagnoses are presented.ResultsThe ECD is amulti-organ orphan disease. Typical for the disease are long bone involvement, periarterial inflammation especially of the aorta, retroperitoneal and perirenal fibrosis with so-called hairy kidneys in abdominal computed tomography (CT) scans. Treatment is increasingly directed towards the presence of a BRAF mutation, which enables targeted and effective treatment with BRAF inhibitors.ConclusionThe ECD is arare differential diagnosis to rheumatic diseases that causes various and often nonspecific symptoms. Due to modern diagnostic methods with imaging procedures and biopsies it is possible to establish aprecise diagnosis and provide a targeted and effective treatment.
CRIS-Team WoS Importer:2019-02-21

Erhöhtes Gichtrisiko bei Patienten unter Diuretikatherapie - Hoffmann, Markus; Manger, Bernhard (Tägliche Praxis, 2020)
CRIS-Team Scopus Importer:2020-10-09

Erratum to: Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: A study from the EUSTAR cohort(Rheumatology 2021DOI: 10.1093/rheumatology/keab510) - Hughes, Michael; Heal, Calvin; Henes, Joerg; Balbir-Gurman, Alexandra; Distler, Jörg; Airo, Paolo; Mueller-Ladner, Ulf; Hunzelmann, Nicolas; Kerzberg, Eduardo; Rudnicka, Lidia; Truchetet, Marie-Elise; Stebbings, Simon; et al. (Rheumatology, 2022)
In the originally published version of this manuscript, there was an error in the abstract. The relevant passage should read, “joint synovitis (P ¼ 0.021)” instead of, “joint synovitis (P0.021)”. This error has been corrected.
CRIS-Team Scopus Importer:2022-09-02

Establishment and evaluation of a sensor-based method to assess hand function in patients with rheumatoid arthritis - Coppers, Birte; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Verena; Heinrich, Simon; Bayat, Sara; et al. (conference, World Biomechanics Congress 2022, 2022)

Estimated glomerular filtration rate is a marker of mortality in the European Scleroderma Trials and Research Group (EUSTAR) database - Gigante, Antonietta; Hoffmann-Vold, Anna-Maria; Fegatelli, Danilo Alunni; Gabrielli, Armando; Leodori, Giorgia; Coleiro, Bernard; De Santis, Maria; Dagna, Lorenzo; Alegre-Sancho, Juan Jose; Montecucco, Carlomaurizio; Carreira, Patricia E.; Balbir-Gurman, Alexandra; et al. (Rheumatology, 2022)
Objectives. The study aim was to evaluate the estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with respect to mortality in SSc patients from the European Scleroderma Trials and Research Group (EUSTAR) database.
CRIS-Team WoS Importer:2022-02-18

Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women - Engdahl, Cecilia; Bondt, Albert; Harre, Ulrike; Raufer, Jasmin; Pfeifle, Rene; Camponeschi, Alessandro; Wuhrer, Manfred; Seeling, Michaela; Martensson, Inga-Lill; Nimmerjahn, Falk; Krönke, Gerhard; Scherer, Hans U.; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation. METHODS: Postmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells. RESULTS: E2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG. CONCLUSIONS: E2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.
EVALuna2:34145

ESTROGEN INFLUENCES THE SIALYLATION PROFILE AND INFLAMMATORY PROPERTIES OF ANTIBODIES - A POTENTIAL EXPLANATION FOR THE SEX DIFFERENCES AND INCREASED RISK FOR RA IN POSTMENOPAUSAL WOMEN - Engdahl, C.; Raufer, Jasmin; Harre, Ulrike; Bondt, A.; Pfeifle, René; Krönke, Gerhard; Scherer, H. U.; Forsblad, H.; Schett, Georg (2017)
EVALuna2:35033

Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss - Meng, Xianyi; Lin, Zhen; Cao, Shan; Janowska, Iga; Sonomoto, Koshiro; Andreev, Darja; Knab, Katharina; Wen, Jinming; Knaup, Karl; Krönke, Gerhard; Rizzi, Marta; Schett, Georg; et al. (Bone Research, 2022)
In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1 alpha signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1 alpha in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1 alpha protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1 alpha protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1 alpha signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1 alpha axis may serve as a new therapeutic target for osteoporosis.
CRIS-Team WoS Importer:2022-03-04

Ethanol consumption decreases autoantibody titers by blocking IL-21 secretion of Tfh cells during the development of arthritis - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, Jörg; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Sarter-Zaiss, Kerstin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis - Azizov, Vugar; Dietel, Katharina; Steffen, Franziska; Dürholz, Kerstin; Meidenbauer, Julia; Lucas, Sébastien; Frech, Michael; Omata, Yasunori; Tajik, Narges; Knipfer, Lisa; Kolenbrander, Anne; Seubert, Silvia; et al. (Nature Communications, 2020)
Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
CRIS-Team Scopus Importer:2020-05-05

Ethanol consumption inhibits the development of autoimmunity by blocking IL-21 secretion in T-FH cells - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, J.; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Herrmann, Martin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis - Van Steenbergen, Hanna W.; Aletaha, Daniel; Beaart-Van De Voorde, Liesbeth J. J.; Brouwer, Elisabeth; Codreanu, Catalin; Combe, Bernard; Fonseca, Joao E.; Hetland, Merete L.; Humby, Frances; Kvien, Tore K.; Niedermann, Karin; Nuno, Laura; et al. (Annals of the Rheumatic Diseases, 2016)
During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration >=60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.
EVALuna2:13385

EULAR definition of difficult-To-Treat rheumatoid arthritis - Nagy, György; Roodenrijs, Nadia M.T.; Welsing, Paco M.J.; Kedves, Melinda; Hamar, Attila; Van Der Goes, Marlies C.; Kent, Alison; Bakkers, Margot; Blaas, Etienne; Senolt, Ladislav; Szekanecz, Zoltan; Choy, Ernest; et al. (Annals of the Rheumatic Diseases, 2021)
Background Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have difficult-To-Treat RA'. However, uniform terminology and an appropriate definition are lacking. Objective The Task Force in charge of the "Development of EULAR recommendations for the comprehensive management of difficult-To-Treat rheumatoid arthritis"aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-To-Treat RA, as the first step. Methods The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-To-face meeting until sufficient agreement was reached (assessed through voting). Results The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-To-Treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: At least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. Conclusions The proposed EULAR definition for difficult-To-Treat RA can be used in clinical practice, clinical trials and can form a basis for future research.
CRIS-Team Scopus Importer:2021-01-08
Keywords: arthritis; immune system diseases; rheumatoid; synovitis

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis - Zabotti, Alen; De Marco, Gabriele; Gossec, Laure; Baraliakos, Xenofon; Aletaha, Daniel; Iagnocco, Annamaria; Gisondi, Paolo; Balint, Peter V.; Bertheussen, Heidi; Boehncke, Wolf Henning; Damjanov, Nemanja S.; De Wit, Maarten; et al. (Annals of the Rheumatic Diseases, 2023)
Background: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. Objective: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. Methods: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. Results: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. Conclusion: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.
CRIS-Team Scopus Importer:2023-07-21
Keywords: inflammation; psoriatic arthritis; synovitis

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis - Nagy, Gyorgy; Roodenrijs, Nadia M. T.; Welsing, Paco M. J.; Kedves, Melinda; Hamar, Attila; Van Der Goes, Marlies C.; Kent, Alison; Bakkers, Margot; Pchelnikova, Polina; Blaas, Etienne; Senolt, Ladislav; Szekanecz, Zoltan; et al. (Annals of the Rheumatic Diseases, 2021)
Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.
CRIS-Team WoS Importer:2021-12-10

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update - Gossec, Laure; Baraliakos, Xenofon; Kerschbaumer, Andreas; de Wit, Maarten; McInnes, Iain; Dougados, Maxime; Primdahl, Jette; McGonagle, Dennis G.; Aletaha, Daniel; Balanescu, Andra; Balint, Peter V.; Bertheussen, Heidi; et al. (Annals of the Rheumatic Diseases, 2020)
OBJECTIVE: To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA). METHODS: According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined. RESULTS: The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed. CONCLUSION: These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.
CRIS-Team Scopus Importer:2020-06-02
Keywords: DMARDs (biologic); psoriatic arthritis; treatment

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update - Gossec, Laure; Kerschbaumer, Andreas; Ferreira, Ricardo J.O.; Aletaha, Daniel; Baraliakos, Xenofon; Bertheussen, Heidi; Boehncke, Wolf Henning; Esbensen, Bente Appel; McInnes, Iain B.; McGonagle, Dennis; Winthrop, Kevin L.; Balanescu, Andra; et al. (Annals of the Rheumatic Diseases, 2024)
Objective: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. Methods: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. Results: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. Conclusion: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.
CRIS-Team Scopus Importer:2024-04-05
Keywords: Biological Therapy; Biosimilar Pharmaceuticals; Psoriatic Arthritis; Treatment

EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice - Mandl, P.; Navarro-Compan, V.; Terslev, L.; Aegerter, P.; Van Der Heijde, D.; D'Agostino, M. A.; Baraliakos, X.; Pedersen, S. J.; Jurik, A. G.; Naredo, E.; Schueller-Weidekamm, C.; Weber, U.; et al. (Annals of the Rheumatic Diseases, 2015)
A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.
EVALuna2:13132

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update - Gossec, Laure; Smolen, J. S.; Ramiro, S.; De Wit, M.; Cutolo, M.; Dougados, Maxime; Emery, P.; Landewe, R.; Oliver, S.; Aletaha, D.; Betteridge, N.; Braun, J.; et al. (Annals of the Rheumatic Diseases, 2016)
Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations.A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated.The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used.These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.
EVALuna2:13226

Evaluating the Use of Neonatal Colonization Screening for Empiric Antibiotic Therapy of Sepsis and Pneumonia - Bär, Alisa; Schmitt-Grohé, Sabina; Held, Jürgen; Lubig, Julia; Hanslik, Gregor; Fahlbusch, Fabian; Reutter, Heiko Martin; Wölfle, Joachim; van der Donk, Adriana; Schleier, Maria; Hepp, Tobias; Morhart, Patrick (Antibiotics, 2023)
(1) Background: Since 2013, weekly screening for multidrug-resistant Gram-negative (MDRGN) bacteria has been performed in German neonatal intensive care units (NICU). National guidelines recommend considering these colonization analyses for antibiotic treatment regimens. Our retrospective single center study provides insight into the clinical dichotomy of bacterial colonization and infection rates in neonates. (2) Methods: We analyzed microbiological data of neonates admitted to our tertiary level NICU over nine years. Colonization with MDRGN/Serratia marcescens (SERMA) was compared to microbiological findings in sepsis and pneumonia. (3) Results: We analyzed 917 blood and 1799 tracheal aspirate samples. After applying criteria from the Nosocomial Infection Surveillance for Neonates (NEO-KISS), we included 52 and 55 cases of sepsis and pneumonia, respectively; 19.2% of sepsis patients and 34.5% of pneumonia patients had a prior colonization with MDRGN bacteria or SERMA. In these patients, sepsis was not attributable to MDRGN bacteria yet one SERMA, while in pneumonias, ten MDRGN bacteria and one SERMA were identified. We identified late-onset pneumonia and cesarean section as risk factors for MDRGN/SERMA acquisition. (4) Conclusions: Colonization screening is a useful tool for hygiene surveillance. However, our data suggest that consideration of colonization with MDRGN/SERMA might promote extensive use of last resort antibiotics in neonates.
CRIS-Team Scopus Importer:2023-03-10
Keywords: colonization; MDR; MDRGN; multidrug-resistant bacteria; multidrug-resistant Gram-negative bacteria; neonatal infection; neonates; pneumonia; screening; sepsis

Evaluation of a hybrid telehealth care pathway for patients with axial spondyloarthritis including self-sampling at home: results of a longitudinal proof-of-concept mixed-methods study (TeleSpactive) - Labinsky, Hannah; May, Susann; Boy, Katharina; von Rohr, Sophie; Grahammer, Manuel; Kuhn, Sebastian; Rojas-Restrepo, Jessica; Vogt, Ekaterina; Heinze, Martin; Schett, Georg; Muehlensiepen, Felix; Knitza, Johannes (Rheumatology International, 2024)
Patients with axial spondyloarthritis (axSpA) require close monitoring to achieve the goal of sustained disease remission. Telehealth can facilitate continuous care while relieving scarce healthcare resources. In a mixed-methods proof-of-concept study, we investigated a hybrid telehealth care axSpA pathway in patients with stable disease over 6 months. Patients used a medical app to document disease activity (BASDAI and PtGA bi-weekly, flare questionnaire weekly). To enable a remote ASDAS-CRP (TELE-ASDAS-CRP), patients used a capillary self-sampling device at home. Monitoring results were discussed and a decision was reached via shared decision-making whether a pre-planned 3-month on-site appointment (T3) was necessary. Ten patients completed the study, and eight patients also completed additional telephone interviews. Questionnaire adherence was high; BASDAI (82.3%), flares (74.8%) and all patients successfully completed the TELE-ASDAS-CRP for the T3 evaluation. At T3, 9/10 patients were in remission or low disease activity and all patients declined the offer of an optional T3 on-site appointment. Patient acceptance of all study components was high with a net promoter score (NPS) of +50% (mean NPS 8.8 ± 1.5) for self-sampling, +70% (mean NPS 9.0 ± 1.6) for the electronic questionnaires and +90% for the T3 teleconsultation (mean NPS 9.7 ± 0.6). In interviews, patients reported benefits such as a better overview of their condition, ease of use of telehealth tools, greater autonomy, and, most importantly, travel time savings. To our knowledge, this is the first study to investigate a hybrid approach to follow-up axSpA patients including self-sampling. The positive results observed in this scalable proof-of-concept study warrant a larger confirmatory study.
CRIS-Team Scopus Importer:2024-04-26
Keywords: Axial spondyloarthritis; axSpA; Electronic patient-reported outcome; ePRO; Shared decision-making; Surveys and questionnaires; Treat-to-target

EVALUATION OF A VIRTUAL REALITY-BASED APPLICATION TO EDUCATE HEALTHCARE PROFESSIONALS AND MEDICAL STUDENTS ABOUT INFLAMMATORY ARTHRITIS - Klemm, Philipp; Kleyer, Arnd; Tascilar, Koray; Schuster, Louis; Meinderink, Timo; Steiger, F.; Lange, Uwe; Müller-Ladner, Ulf; Knitza, Johannes; Sewerin, Philipp; Mucke, Johanna; Pfeil, Alexander; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

EVALUATION OF A VIRTUAL REALITY TEACHING CONCEPT FOR MEDICAL STUDENTS DURING THE SARS-COV-2 PANDEMIC - Pfeil, A.; Marcus, F.; Hoffmann, T.; Klemm, P.; Oelzner, P.; Muller-Ladner, U.; Hueber, A.; Lange, U.; Wolf, G.; Schett, Georg; Simon, David; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

EVALUATION OF FREQUENCY AND TYPE OF PHYSICAL THERAPY IN MORE THAN 3400 PATIENTS WITH SYSTEMIC SCLEROSIS - Belz, D.; Moinzadeh, P.; Blank, N.; Siegert, E.; Henes, J.; Worm, M.; Sunderkoetter, C.; Schmalzing, M.; Kreuter, A.; Gunther, C.; Susok, L.; Zeidler, G.; et al. (2017)
EVALuna2:35042

Evaluation of marker-based motion capturing to charactherize basic hand movements in rheumatic patients - Coppers, Birte; Heinrich, Simon; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Verena; Bayat, Sara; et al. (27th Congress of the European Society of Biomechanics, 2022)

Evaluation of Optical and Radar Based Motion Capturing Technologies for Characterizing Hand Movement in Rheumatoid Arthritis — A Pilot Study - Phutane, Uday; Liphardt, Anna-Maria; Bräunig, Johanna; Penner, Johann; Klebl, Michael; Vossiek, Martin; Kleyer, Arnd; Schett, Georg; Leyendecker, Sigrid (Sensors, 2021)
In light of the state-of-the-art treatment options for patients with rheumatoid arthritis (RA), a detailed and early quantification and detection of impaired hand function is desirable to allow personalized treatment regiments and amend currently used subjective patient reported outcome measures. This is the motivation to apply and adapt modern measurement technologies to quantify, assess and analyze human hand movement using a marker-based optoelectronic measurement system (OMS), which has been widely used to measure human motion. We complement these recordings with data from markerless (Doppler radar) sensors and data from both sensor technologies are integrated with clinical outcomes of hand function. The technologies are leveraged to identify hand movement characteristics in RA affected patients in comparison to healthy control subjects, while performing functional tests, such as the Moberg-Picking-Up Test. The results presented discuss the experimental framework and present the limiting factors imposed by the use of marker-based measurements on hand function. The comparison of simple finger motion data, collected by the OMS, to data recorded by a simple continuous wave radar suggests that radar is a promising option for the objective assessment of hand function. Overall, the broad scope of integrating two measurement technologies with traditional clinical tests shows promising potential for developing new pathways in understanding of the role of functional outcomes for the RA pathology.<br

Evaluation of the RABBIT Risk Score for serious infections - Zink, A.; Manger, Bernhard; Kaufmann, J.; Eisterhues, C.; Krause, A.; Listing, J.; Strangfeld, A. (Annals of the Rheumatic Diseases, 2014)
To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA).The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample.The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor ? (TNF?) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk.The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.
EVALuna2:12955

Evidence-based recommendations for diagnostics and treatment of gouty arthritis in the specialist sector : S2e guidelines of the German Society of Rheumatology in cooperation with the AWMF - Kiltz, U.; Alten, R.; Fleck, M.; Kruger, K.; Manger, Bernhard; Nuesslein, H.; Reuss-Borst, M.; Schwarting, A.; Schulze-Koops, H. .; Tausche, A. K.; Braun, J.; Muller-Ladner, U. (Zeitschrift für Rheumatologie, 2017)
Due to the increasing prevalence of gout, particularly in old age, the disease is becoming of increasing importance in Germany. Gout is one of the most common forms of recurrent inflammatory arthritis and is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. The principal goals of therapy in chronic gout are the symptomatic treatment of the acute joint inflammation and the causal treatment of the underlying metabolic cause, the hyperuricemia. Only a consistent and permanent reduction of the serum uric acid level ultimately results in an efficient avoidance of further gout attacks and therefore the prevention of structural damage. Due to an often inadequate treatment of gout, the target of healing the disease is often not achieved. A correct and timely diagnosis and adequate assessment of comorbidities associated with gout are, however, of substantial importance for patient and physician to achieve remission of the disease. In order to create a solid basis for a timely and effective treatment of affected patients, in 2016 the German Society of Rheumatology (DGRh) initiated the development of S2e guidelines on gouty arthritis for specialists. This article summarizes these S2e guidelines on the management of gouty arthritis in the specialist sector.
EVALuna2:13392

Evidence-based recommendations for the management of undifferentiated peripheral inflammatory arthritis (UPIA). The German perspective on the international 3e initiative - Tarner, I. H.; Albrecht, K.; Fleck, M.; Gromnica-Ihle, E.; Keysser, G.; Koehler, L.; Koetter, I.; Krueger, K.; Kuipers, J.; Nuesslein, H.; Rubbert-Roth, A.; Wollenhaupt, J.; et al. (Zeitschrift für Rheumatologie, 2014)
Peripheral arthritis is the most common presenting complaint in clinical rheumatology. Unequivocal identification of the underlying entity can be difficult, particularly at an early stage. Such cases are commonly referred to as undifferentiated peripheral inflammatory arthritis (UPIA). Since evidence-based recommendations for the clinical management of UPIA are lacking, this international 3e initiative convened 697 rheumatologists from 17 countries to develop appropriate recommendations.Based on a systematic literature research in Medline, EMBASE, Cochrane Library, and the ACR/EULAR abstracts of 2007/2008, 10 multinational recommendations were developed by 3 rounds of a Delphi process. In Germany, a national group of experts worked on 3 additional recommendations using the same method. The recommendations were discussed among the members of the 3e initiative and the degree of consensus was analyzed as well as the potential impact of the recommendations on clinical practice.A total of 39,756 references were identified, of which 250 were systematically reviewed for the development of 10 multinational recommendations concerning differential diagnosis, diagnostic and prognostic value of clinical assessments, laboratory tests and imaging techniques, and monitoring of UPIA. In addition, 3 national recommendations on the diagnostic and prognostic value of a response to anti-inflammatory therapy on the analysis of synovial fluid and on enthesitis were developed by the German experts based on 35 out of 5542 references.The article translates the 2011 published original paper of the international 3e initiative (Machado et al., Ann Rheum Dis 70:15-24, 2011) and reports the methods and results of the national vote and the additional 3 national recommendations.
EVALuna2:12975

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes - Sighart, Regina; Rech, J.; Hueber, Axel; Blank, N.; Löhr, S.; Reis, André; Sticht, Heinrich; Hüffmeier, Ulrike (Rheumatology International, 2017)
Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD.We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD.We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment.Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.
EVALuna2:9382

Evidence of innate lymphoid cell redundancy in humans - Vely, Frederic; Barlogis, Vincent; Vallentin, Blandine; Neven, Benedicte; Piperoglou, Christelle; Perchet, Thibaut; Petit, Maxime; Yessaad, Nadia; Touzot, Fabien; Bruneau, Julie; Mahlaoui, Nizar; Zucchini, Nicolas; et al. (Nature Immunology, 2016)
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common ?-chain cytokine receptor subunit IL-2R? or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
EVALuna2:13272

Excretion of urinary histamine and N-tele methylhistamine in patients with gastrointestinal food allergy compared to non-allergic controls during an unrestricted diet and a hypoallergenic diet - Raithel, Martin; Hagel, Alexander; Albrecht, Heinz; Zopf, Yurdagül; Naegel, Andreas; Baenkler, Hanns-Wolf; Buchwald, Fred; Schultis, Hans-Wolfgang; Kressel, Juergen; Hahn, Eckhart Georg; Konturek, Peter (BMC Gastroenterology, 2015)
Patients with gastrointestinal food allergy are characterised by increased production of mast cell derived mediators upon allergen contact and present often with unspecific symptoms. The aim of this study was to evaluate urinary histamine and methylhistamine excretion in patients with food allergy and to compare their values with food-tolerant controls.In a retrospective case control study the urinary excretion parameters were analysed from 56 patients (40.9, 19 - 58 years) in whom later food challenge tests confirmed food allergy. During their diagnostic work-up urine was collected during a 12-h period under an unrestricted diet with staple foods and a hypoallergenic potato-rice-diet (each 2 days). Healthy controls underwent the same diet types to define normal excretion parameters. Urinary histamine and n-methylhistamine were determined by ELISA or tandem mass spectrometry, respectively, and were expressed as median (25 - 75% range, ?g/mmol creatinine x m(2)BSA).During unrestricted diet urinary histamine was significantly higher in gastrointestinal food allergy than healthy controls (1.42, 0.9 - 2.7 vs 0.87, 0.4 - 1.3; p < 0.0001), while the difference between both groups became marginal during potato-rice diet (1.30, 0.7 - 2.1 vs 1.05, 0.5 - 1.5; p = 0.02). N-methylhistamine was found to be significantly elevated in gastrointestinal food allergy both during unrestricted diet (7.1, 5.0 - 11.2) and potato-rice diet (5.7, 3.7 - 8.7) compared to controls (p < 0.0001). Interestingly, urinary methylhistamine excretion (p < 0.004) and clinical symptom score (p < 0.02) fell significantly when the diet was switched from unrestricted to hypoallergenic food, but was not correlated with symptom scores.In gastrointestinal food allergy significantly higher levels of urine histamine and methylhistamine excretion were found under unrestricted diet, reflecting an increased secretion of histamine due to offending foods. Measurement of urinary n-methylhistamine levels may help to find out patients with increased histamine production and/or food-allergen induced clinical symptoms, respectively.
EVALuna2:2029

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps - Kienhofer, Deborah; Hahn, Jonas; Stoof, Julia; Csepregi, Janka Zsofia; Reinwald, Christiane; Urbonaviciute, Vilma; Johnsson, Caroline; Maueröder, Christian; Podolska, Malgorzata; Biermann, Mona; Leppkes, Moritz; Harrer, Thomas; et al. (JCI Insight, 2017)
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.
EVALuna2:1833

Exploratory Analysis to Identify Factors Associated with Risk of Structural Progression, Defined As Change from Baseline - Van Der Heijde, Desiree; Durez, Patrick; Schett, Georg; Naredo, Esperanza; Ostergaard, Mikkel; Meszaros, Gabriella; Lopez-Romero, Pedro; De Leonardis, Francesco; Fleischmann, Roy (2017)
EVALuna2:33445

Exploring CAR T-Cell Dynamics: Balancing Potent Cytotoxicity and Controlled Inflammation in CAR T-Cells Derived from Systemic Sclerosis and Myositis Patients - Dingfelder, Janin; Taubmann, Jule; von Heydebrand, Franziska; Aigner, Michael; Bergmann, Christina; Knitza, Johannes; Park, Soo; Cheng, Joseph K.; Van Blarcom, Thomas; Schett, Georg; Mackensen, Andreas; Lutzny-Geier, Gloria (International Journal of Molecular Sciences, 2025)
Systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myositis (IIM) are autoimmune diseases managed with long-term immunosuppressive therapies. Hu19-CD828Z, a fully human anti-CD19 chimeric antigen receptor (CAR) with a CD28 costimulatory domain, is engineered to potently deplete B-cells. In this study, we manufactured Hu19-CD828Z CAR T-cells from peripheral blood of SLE, IIM, and SSc patients and healthy donors (HDs). CAR-mediated, CD19-specific activity of these cells was evaluated in vitro by assessing cytotoxicity, cytokine release, and proliferation assays in response to autologous CD19+ B-cells, the CD19+ NALM-6 B-cell line, or a CD19− U937 non-B-cell line as targets. The results demonstrated an increased proliferation of Hu19-CD828Z CAR T-cells and dose-dependent cytotoxicity against primary autologous and NALM-6 B-cells compared to non-transduced controls or co-cultures with non-B-cells. Notably, autoimmune-patient-derived CAR T-cells produced lower levels of inflammatory cytokines than healthy-donor-derived CAR T-cells in response to CD19+ B-cell targets. These data support the potential of Hu19-CD828Z and its therapeutic cell product KYV-101 as a therapeutic strategy to achieve deep B-cell depletion in SLE, IIM, and SSc patients, and highlights its promise for broader application in B-cell-driven autoimmune disorders.
CRIS-Team Scopus Importer:2025-01-31
Keywords: autoimmune diseases; chimeric antigen receptor; cytokines; idiopathic inflammatory myositis; systemic lupus erythematosus; systemic sclerosis; T-cells

Exploring Epipolar Consistency Conditions for Rigid Motion Compensation in In-vivo X-ray Microscopy - Thies, Mareike; Wagner, Fabian; Gu, Mingxuan; Mei, Siyuan; Huang, Yixing; Pechmann, Sabrina; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Uderhardt, Stefan; Schett, Georg; Christiansen, Silke; et al. (Bildverarbeitung für die Medizin 2024. BVM 2024, 2024)
Intravital X-ray microscopy (XRM) in preclinical mouse models is of vital importance for the identification of microscopic structural pathological changes in the bone which are characteristic of osteoporosis. The complexity of this method stems from the requirement for high-quality 3D reconstructions of the murine bones. However, respiratory motion and muscle relaxation lead to inconsistencies in the projection data which result in artifacts in uncompensated reconstructions. Motion compensation using epipolar consistency conditions (ECC) has previously shown good performance in clinical CT settings. Here, we explore whether such algorithms are suitable for correcting motion-corrupted XRM data. Different rigid motion patterns are simulated and the quality of the motion-compensated reconstructions is assessed. The method is able to restore microscopic features for out-of-plane motion, but artifacts remain for more realistic motion patterns including all six degrees of freedom of rigid motion. Therefore, ECC is valuable for the initial alignment of the projection data followed by further fine-tuning of motion parameters using a reconstruction-based method.
CRIS-Team Scopus Importer:2024-03-29

Exploring IL-17 in spondyloarthritis for development of novel treatments and biomarkers - Groen, Solveig Skovlund; Sinkeviciute, Dovile; Bay-Jensen, Anne Christine; Thudium, Christian S.; Karsdal, Morten A.; Thomsen, Simon Francis; Schett, Georg; Nielsen, Signe Holm (Autoimmunity Reviews, 2021)
Spondyloarthritis (SpA) is an umbrella term describing a family of chronic inflammatory rheumatic diseases. These diseases are characterised by inflammation of the axial skeleton, peripheral joints, and entheseal insertion sites throughout the body which can lead to structural joint damage including formation of axial syndesmophytes and peripheral osteophytes. Genetic evidence, preclinical and clinical studies indicate a clear role of interleukin (IL)- 23 and IL-17 as mediators in SpA pathogenesis. Targeting the IL-23/−17 pathways seems an efficient strategy for treatment of SpA patients, and despite the remaining challenges the pathway holds great promise for further advances and improved therapeutic opportunities. Much research is focusing on serological markers and imaging strategies to correctly diagnose patients in the early stages of SpA. Biomarkers may facilitate personalised medicine tailored to each patient's specific disease to optimise treatment efficacy and to monitor therapeutic response. This narrative review focuses on the IL-17 pathway in SpA-related diseases with emphasis on its role in pathogenesis, current approved IL-17 inhibitors, and the need for biomarkers reflecting core disease pathways for early diagnosis and measurement of disease activity, prognosis, and response to therapy.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Biomarker; IL-17; pathogenesis; Spondyloarthritis; treatment

Exploring preferences of at-risk individuals for preventive treatments for rheumatoid arthritis - Simons, Gwenda; Bywall, K. Scholin; Englbrecht, Matthias; Johansson, E. C.; Disantostefano, R. L.; Radawski, C.; Veldwijk, Jorien; Raza, Karim; Falahee, Marie (Scandinavian Journal of Rheumatology, 2022)
Objective Some immunomodulatory drugs have been shown to delay the onset of, or lower the risk of developing, rheumatoid arthritis (RA), if given to individuals at risk. Several trials are ongoing in this area; however, little evidence is currently available about the views of those at risk of RA regarding preventive treatment. Method Three focus groups and three interviews explored factors that are relevant to first degree relatives (FDRs) of RA patients and members of the general public when considering taking preventive treatment for RA. The semi-structured qualitative interview prompts explored participant responses to hypothetical attributes of preventive RA medicines. Transcripts of focus group/interview proceedings were inductively coded and analysed using a framework approach. Results Twenty-one individuals (five FDRs, 16 members of the general public) took part in the study. Ten broad themes were identified describing factors that participants felt would influence their decisions about whether to take preventive treatment if they were at increased risk of RA. These related either directly to features of the specific treatment or to other factors, including personal characteristics, attitude towards taking medication, and an individual's actual risk of developing RA. Conclusion This research highlights the importance of non-treatment factors in the decision-making process around preventive treatments, and will inform recruitment to clinical trials as well as information to support shared decision making by those considering preventive treatment. Studies of treatment preferences in individuals with a confirmed high risk of RA would further inform clinical trial design.
CRIS-Team WoS Importer:2022-10-21

Exposure-Adjusted Incidence Rate for Adverse Events of Special Interest in Patients with Psoriatic Arthritis Treated with Apremilast - Mease, Philip J.; Gladman, Dafna; Schett, Georg; Paris, Maria; Cheng, Sue; Richter, Sven; Teng, Lichen; Kavanaugh, Arthur (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Expression of adipokines in osteoarthritis osteophytes and their effect on osteoblasts - Junker, Susann; Frommer, Klaus W.; Krumbholz, Grit; Tsiklauri, Lali; Gerstberger, Rüdiger; Rehart, Stefan; Steinmeyer, Jürgen; Rickert, Markus; Wenisch, Sabine; Schett, Georg; Müller-Ladner, Ulf; Neumann, Elena (Matrix Biology, 2016)
Osteophyte formation in osteoarthritis (OA) is mediated by increased osteoblast activity, which is -in turn- regulated by the Wnt signaling pathway. Obesity is regarded a risk factor in OA, yet little is known about the interaction between adipose tissue-derived factors, the adipokines, and bone formation, although adipokines are associated with the pathogenesis of OA. Therefore, the effect of adipokines on bone and cartilage forming cells and osteophyte development was analyzed.Human OA osteophytes were histologically characterized and adipokine expression was evaluated by immunohistochemistry. Osteoblasts and chondrocytes were isolated from OA tissue and stimulated with adiponectin, resistin, or visfatin. Cytokine and osteoblast/chondrocyte markers were quantified and activation of Wnt and p38 MAPK signaling was analyzed.Adiponectin, resistin, and visfatin were expressed in OA osteophytes by various articular cell types. Stimulation of OA osteoblasts with adiponectin and of OA chondrocytes with visfatin led to an increased release of proinflammatory mediators but not to osteoblast differentiation or activation. Additionally, visfatin increased matrix degrading factors in chondrocytes. Wnt signaling was not altered by adipokines, but adiponectin induced p38 MAPK signaling in osteoblasts.Adipokines are present in OA osteophytes, and adiponectin and visfatin increase the release of proinflammatory mediators by osteoblasts and chondrocytes. The effects of adiponectin were mediated by p38 MAPK but not Wnt signaling in osteoblasts. Therefore, the results support the idea that adipokines do not directly influence osteophyte development but the proinflammatory conditions in OA.
EVALuna2:13376

Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery - Lyu, Pang; Wen, Jinming; Zhang, Wenshuo; Liu, Ning; Stolzer, Iris; Gießl, Andreas; Jia, Yewei; Mauro, Daniele; Zhang, Fulin; Ciccia, Francesco; Soulat, Didier; Günther, Claudia; et al. (Annals of the Rheumatic Diseases, 2024)
Objectives: To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis. Methods: IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1aΔIEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1aΔIEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA. Results: IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis. Conclusion: Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis.
CRIS-Team Scopus Importer:2024-04-05
Keywords: Arthritis; Experimental; Arthritis; Rheumatoid; Immune System Diseases; Inflammation

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis - Leppkes, Moritz; Maueröder, Christian; Hirth, Sebastian; Nowecki, Stefanie; Günther, Claudia; Billmeier, Ulrike; Paulus, Susanne; Biermann, Mona; Munoz, Luis Enrique; Hoffmann, Markus; Wildner, Dane; Croxford, Andrew L.; et al. (Nature Communications, 2016)
Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.
EVALuna2:2052

Extracellular DNA traps in inflammation, injury and healing - Daniel, Christoph; Leppkes, Moritz; Munoz, Luis Enrique; Muñoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin (Nature Reviews Nephrology, 2019)
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
CRIS-Team Scopus Importer:2019-07-09

Ex Vivo Blockade of the PD-1 Pathway Improves Recall IFNγ Responses of HIV-Infected Persons on Antiretroviral Therapy - Fischhaber, Natalie; Schmiedeberg, Moritz; Kübel, Sabrina; Harrer, Ellen; Harrer, Thomas; Nganou-Makamdop, Krystelle (Vaccines, 2023)
Despite antiretroviral therapy (ART), immune exhaustion persists in HIV infection and limits T cell responses to HIV or other pathogens. Moreover, HIV infection results in the loss of pre-existing immunity. Here, we investigated the effect of blocking the PD-1 pathway on recall IFNγ responses to tetanus toxoid (TT) and measles virus (MV) antigens in HIV-infected persons on ART with prior TT and MV immunity. The ex vivo treatment of lymphocytes with anti-PD-1 and anti-PD-L1 antibodies significantly increased TT- and MV-specific IFNγ responses. The responses to TT and MV antigens alone or in combination with antibodies blocking the PD-1 pathway positively correlated with CD4 T cell levels. Furthermore, T cell PD-1 expression levels inversely correlated with recall IFNγ responses in combination with antibodies blocking the PD-1 pathway but not with IFNγ responses to antigens only. Our study suggested that targeting the PD-1 pathway may boost vaccine-induced pre-existing immunity in HIV-infected persons on ART depending on the degree of immune exhaustion.
CRIS-Team Scopus Importer:2023-03-17
Keywords: anti-PD-1; anti-PD-L1; HIV infection; PD-1 pathway; T cell exhaustion; vaccine-induced immunity

Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells - Schödel, Johannes; Bohr, Daniela; Klanke, Bernd; Schley, Gunnar; Schlötzer-Schrehardt, Ursula; Warnecke, Christina; Kurtz, Armin; Amann, Kerstin Ute; Eckardt, Kai-Uwe; Willam, Carsten (Kidney International, 2010)
The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and-independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis. In order to better understand the regulation of hypoxia-inducible genes, we determined the expression of FIH1 in the kidney and its functional role in isolated renal cells. FIH1 was expressed only in distal tubules and in podocytes, thus showing a very distinct expression pattern, partially overlapping with sites of HIF-1α expression. In tubular cells, RNA silencing of FIH1 caused transcriptional activation of HIF target genes during hypoxia. In contrast, FIH1 silencing in podocytes enhanced transcription of hypoxia-inducible genes in an HIF-independent manner. Using the anti-Thy.1 rat model of glomerulonephritis, we found a gradual decrease of glomerular FIH1 expression during disease progression paralleled by an increase in hypoxia-inducible genes including CXCR4, a mediator of glomerular inflammation. Thus, FIH1 appears to be a suppressor of oxygen-dependent genes in the kidney, operating through HIF-dependent and-independent mechanisms. © 2010 International Society of Nephrology.
CRIS-Team Scopus Importer:2024-05-13
Keywords: cell biology and structure; hypoxia; immunohistochemistry; podocyte; tubule cells

Factors and Situations Affecting the Value of Patient Preference Studies: Semi-Structured Interviews in Europe and the US - Whichello, Chiara; Van Overbeeke, Eline; Janssens, Rosanne; Bywall, Karin Scholin; Russo, Selena; Veldwijk, Jorien; Cleemput, Irina; Juhaeri, Juhaeri; Levitan, Bennett; Kuebler, Juergen; Smith, Meredith; Hermann, Richard; et al. (Frontiers in Pharmacology, 2019)
Objectives: Patient preference information (PPI) is gaining recognition among the pharmaceutical industry, regulatory authorities, and health technology assessment (HTA) bodies/payers for use in assessments and decision-making along the medical product lifecycle (MPLC). This study aimed to identify factors and situations that influence the value of patient preference studies (PPS) in decision-making along the MPLC according to different stakeholders.
CRIS-Team WoS Importer:2019-10-01

FACTORS ASSOCIATED WITH PERSISTENT DRUG-FREE REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS - Valor, Larissa; Hagen, Melanie; Reiser, Michaela; Kleyer, Arnd; Hartmann, Fabian; Manger, Bernhard; Schett, Georg; Rech, Jürgen; Tascilar, Koray; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival - Eisenhut, Felix; Heim, Lisanne; Trump, Sonja; Mittler, Susanne; Sopel, Nina; Andreev, Katerina; Ferrazzi, Fulvia; Ekici, Arif Bülent; Rieker, Ralf; Springel, Rebekka; Assmann, Vera Elisabeth; Lechmann, Matthias; et al. (OncoImmunology, 2017)
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1? levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1? and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells. TGF?, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGF? levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGF? accelerated this process by inducing cell migration, HIF1?, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1?. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGF? and HIF1?, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression.
EVALuna2:6835

FAPI PET Opens a New Window to Understanding Immune-Mediated Inflammatory Diseases - Kuwert, Torsten; Schmidkonz, Christian; Prante, Olaf; Schett, Georg; Ramming, Andreas (Journal of Nuclear Medicine, 2022)
CRIS-Team Scopus Importer:2022-08-19

Fatal Puumala Hantavirus Infection in a Patient with Common Variable Immunodeficiency (CVID) - Steininger, Philipp; Herbst, Larissa; Bihlmaier, Karl; Willam, Carsten; Koerper, Sixten; Schrezenmeier, Hubert; Klueter, Harald; Pfister, Frederick; Amann, Kerstin Ute; Weiss, Sabrina; Krueger, Detlev H.; Zimmermann, Robert; et al. (Microorganisms, 2023)
Puumala hantavirus (PUUV) infections usually show a mild or moderate clinical course, but may sometimes also lead to life-threatening disease. Here, we report on a 60-year-old female patient with common variable immunodeficiency (CVID) who developed a fatal PUUV infection with persistent renal failure, thrombocytopenia, and CNS infection with impaired consciousness and tetraparesis. Hantavirus-specific antibodies could not be detected due to the humoral immunodeficiency. Diagnosis and virological monitoring were based on the quantitative detection of PUUV RNA in blood, cerebrospinal fluid, bronchial lavage, and urine, where viral RNA was found over an unusually extended period of one month. Due to clinical deterioration and virus persistence, treatment with ribavirin was initiated. Additionally, fresh frozen plasma (FFP) from convalescent donors with a history of PUUV infection was administered. Despite viral clearance, the clinical condition of the patient did not improve and the patient died on day 81 of hospitalization. This case underlines the importance of the humoral immune response for the course of PUUV disease and illustrates the need for PCR-based virus diagnostics in those patients. Due to its potential antiviral activity, convalescent plasma should be considered in the therapy of severe hantavirus diseases.
CRIS-Team Scopus Importer:2023-03-10
Keywords: common variable immunodeficiency; convalescent plasma; encephalitis; Puumala hantavirus; ribavirin

Fatty Lesions Detected on MRI Scans in Patients with Ankylosing Spondylitis Are Based on the Deposition of Fat in the Vertebral Bone Marrow - Baraliakosi, Xenofon; Boehm, Heinrich; Samir, Ahmed; Schett, Georg; Braun, Juergen; Ramming, Andreas (2018)
EVALuna2:34955

FATTY LESIONS DETECTED ON MRI SCANS IN PATIENTS WITH ANKYLOSING SPONDYLITIS ARE BASED ON THE DEPOSITION OF FAT IN THE VERTEBRAL BONE MARROW - Baraliakos, X.; Boehm, H.; Barakat, A. Samir; Schett, Georg; Braun, J. (2018)
EVALuna2:34979

Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis. - Stock, Michael; Distler, A.; Distler, Jörg; Beyer, Christian; Ruiz-Heiland, G.; Ipseiz, N.; Seeling, Michaela; Krönke, Gerhard; Nimmerjahn, Falk; Schett, Georg (Osteoarthritis and Cartilage, 2015)
OBJECTIVE Fc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis (OA)-related cartilage degradation. METHODS FcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. RESULTS Expression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice. CONCLUSION While FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis.

Feasibility of using optoelectronic measurement of hand movement for characterizing hand function in rheumatoid arthritis - Coppers, Birte; Heinrich, Simon; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Johanna; Bayat, Sara; et al. (75th EULAR (European Alliance of Associations for Rheumatology), European Congress of Rheumatology 2022, 2022)

FEVER OF UNKNOWN ORIGIN (FUO) AND INFLAMMATION OF UNKNOWN ORIGIN (IUO): IS 18F-FDG-PET/CT A USEFUL FIRST LINE DIAGNOSTIC STRATEGY? - Schoenau, V.; Vogel, Kristin; Engelbrecht, M.; Schmidt, D.; Kuwert, Torsten; Manger, Bernhard; Schett, Georg (2016)
EVALuna2:13472

Fever of unknown origin, giant cell arteritis, and aortic dissection - Hofheinz, K.; Bertz, Simone; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2017)
Giant cell arteritis is one of the most frequent causes of pyrexia of unknown origin after infectious or malignant causes have been ruled out. In this case report we describe a 66-year old female patient, who after five weeks of remitting fever developed a life-threatening, painless severe aortic dissection. The timely use of modern imaging technologies such as magnetic resonance angiography or positron emission computed tomography could in the future be of help to recognize aortic involvement early and to avoid this devastating complication in patients with fever of unknown origin.
EVALuna2:6833

FGFR3/FGF9 Regulates the Activity of Profibrotic Cytokine and Growth Factor Pathways to Drive Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis - Summa, Lena; Thuong Trinh-Minh,; Chen, Chih-Wei; Soare, Alina; Distler, Oliver; Schett, Georg; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2018)
EVALuna2:34956

Fibroblast Activation in Psoriasis Patients Assessed by Ga-68-FAPI-04 PET-CT Is Associated with Progression to Psoriatic Arthritis - Fagni, Filippo; Simon, David; Kleyer, Arnd; Tascilar, Koray; Taubmann, Jule; Bayat, Sara; Minopoulou, Ioanna; Mutlu, Melek Yalcin; Atzinger, Armin; Kuwert, Torsten; Schett, Georg; Schmidkonz, Christian (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis - Pedersen, Rasmus S.; Thorlacius-Ussing, Jeppe; Raimondo, Maria Gabriella; Langholm, Lasse L.; Schett, Georg; Ramming, Andreas; Karsdal, Morten; Willumsen, Nicholas (Biomedicines, 2024)
Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and treatment. Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity. FAP is a type II transmembrane serine protease that has been shown to cleave collagens and other ECM components. In this study, we developed an ELISA assay (C3F) targeting a circulating type III collagen fragment derived from FAP cleavage to reflect FAP activity. We demonstrated that C3F was specific to the neoepitope of the cleavage site and that the fragment was generated through FAP cleavage of type III collagen. We measured C3F in serum from a cohort of patients with non-small cell lung cancer (NSCLC) (n = 109) matched to healthy subjects (n = 42) and a cohort of patients with spondyloarthritis (SpA) (n = 17) matched to healthy subjects (n = 19). We found that C3F was significantly elevated in patients with NSCLC and in patients with SpA compared to healthy controls (p < 0.0001 and p = 0.0015, respectively). These findings suggest that C3F is a promising non-invasive biomarker reflecting FAP activity, which may aid in understanding tumor heterogeneity and potentially FAP-targeted therapies.
CRIS-Team Scopus Importer:2024-04-05
Keywords: extracellular matrix remodeling; fibroblast activation protein (FAP); non-small cell lung cancer (NSCLC); serum biomarker; spondyloarthritis

Fibroblast Activation Protein (FAP) PET-CT for Depicting Inflammatory Joint Damage in Patients with Psoriatic Arthritis - Rauber, Simon; Mohammadian, Hashem; Schmidkonz, Christian; Atzinger, Armin; Raimondo, Maria Gabriella; Labinsky, Hannah; Treutlein, Christoph; Knitza, Johannes; Maschauer, Simone; Roemer, Frank; Prante, Olaf; Kuwert, Torsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

FIBROBLAST ACTIVATION PROTEIN (FAP) PET-CT IMAGING ALLOWS TO DEPICT INFLAMMATORY JOINT REMODELING IN PATIENTS WITH PSORIATIC ARTHRITIS - Schmidkonz, Christian; Rauber, Simon; Raimondo, Maria Gabriella; Labinsky, Hannah; Atzinger, Armin; Treutlein, Christoph; Knitza, Johannes; Maschauer, Simone; Roemer, Frank; Prante, Olaf; Kuwert, Torsten; Canete, J. D. D.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Fibroblast Activation Protein Inhibitor Imaging in Nonmalignant Diseases: A New Perspective for Molecular Imaging - Schmidkonz, Christian; Kuwert, Torsten; Atzinger, Armin; Cordes, Michael; Schett, Georg; Ramming, Andreas; Götz, Theresa (Journal of Nuclear Medicine, 2022)
Fibroblast activation protein-α (FAP-α) is a type II transmembrane glycoprotein that is overexpressed in activated fibroblasts such as those in the stroma of tumors or in the fibrotic processes accompanying various benign diseases. The recent development and clinical implementation of radiolabeled quinolone-based tracers suitable for PET that act as FAP inhibitors (FAPIs) have opened a new perspective in molecular imaging. Although multiple studies have investigated the use of FAPI imaging in cancer, evidence concerning its use in nonmalignant diseases is still scarce. Herein, we provide a comprehensive review of FAPI imaging in nonmalignant diseases to clarify the current and potential role of this class of molecules in nuclear medicine.
CRIS-Team Scopus Importer:2022-12-16
Keywords: fibroblast activation protein; fibrosis; inflammatory diseases; molecular imaging; PET

Fibroblast Growth Factor 9/Fibroblast Growth Factor Receptor 3 Signaling Is Upstream of Several Profibrotic Pathways and Induces Fibroblast Activation and Tissue Fibrosis in SSc - Mallano, Tatjana; Distler, Alfiya; Dees, Clara; Huang, Jingang; Distler, Oliver; Schett, Georg; Distler, Jörg; Chakraborty, Debomita (2016)
EVALuna2:35061

Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis - Chakraborty, Debomita; Zhu, Honglin; Juengel, Astrid; Summa, Lena; Li, Yi-Nan; Matei, Alexandru-Emil; Zhou, Xiang; Huang, Jingang; Thuong Trinh-Minh,; Chen, Chih-Wei; Lafyatis, Robert; Dees, Clara; et al. (Science Translational Medicine, 2020)
Aberrant activation of fibroblasts with progressive deposition of extracellular matrix is a key feature of systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease. Here, we demonstrate that the profibrotic cytokine transforming growth factor. selectively up-regulates fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 to promote fibroblast activation and tissue fibrosis, leading to a prominent FGFR3 signature in the SSc skin. Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 induces multiple profibrotic pathways including endothelin, interleukin-4, and connective tissue growth factor signaling mediated by transcription factor CREB (cAMP response element-binding protein). Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 blocked fibroblast activation and attenuated experimental skin fibrosis in mice. These findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and as a potential target for the treatment of fibrosis.
CRIS-Team WoS Importer:2020-10-16

FIBROBLAST GROWTH FACTOR RECEPTOR 3 REGULATES THE ACTIVITY OF PROFIBROTIC CYTOKINE AND GROWTH FACTOR PATHWAYS TO DRIVE FIBROBLAST ACTIVATION AND TISSUE FIBROSIS IN SYSTEMIC SCLEROSIS - Chakraborty, Debomita; Zhu, H.; Juengel, A.; Summa, L.; Li, Y. N.; Bergmann, C.; Matei, Alexandru-Emil; Trinh-Minh, T.; Chen, Chih-Wei; Dees, Clara; Ramming, Andreas; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

FIBROBLASTS: THEIR ROLES IN MATRIX AND VESSELS - Distler, Jörg (2018)
EVALuna2:34981

Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features - Zhu, Honglin; Luo, Hui; Skaug, Brian; Tabib, Tracy; Li, Yi; Tao, Yongguang; Matei, Alexandru-Emil; Lyons, Marka A.; Schett, Georg; Lafyatis, Robert; Assassi, Shervin; Distler, Jörg (Journal of Investigative Dermatology, 2024)
Fibroblasts constitute a heterogeneous population of cells. In this study, we integrated single-cell RNA-sequencing and bulk RNA-sequencing data as well as clinical information to study the role of individual fibroblast populations in systemic sclerosis (SSc). SSc skin demonstrated an increased abundance of COMP+, COL11A1+, MYOC+, CCL19+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblasts signatures and decreased proportions of CXCL12+ and PI16+ fibroblast signatures in the Prospective Registry of Early Systemic Sclerosis and Genetics versus Environment in Scleroderma Outcome Study cohorts. Numerical differences were confirmed by multicolor immunofluorescence for selected fibroblast populations. COMP+, COL11A1+, SFRP4/SFRP2+, PRSS23/SFRP2+, and PI16+ fibroblasts were similarly altered between normal wound healing and patients with SSc. The proportions of profibrotic COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ and proinflammatory CCL19+ fibroblast signatures were positively correlated with clinical and histopathological parameters of skin fibrosis, whereas signatures of CXCL12+ and PI16+ fibroblasts were inversely correlated. Incorporating the proportions of COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblast signatures into machine learning models improved the classification of patients with SSc into those with progressive versus stable skin fibrosis. In summary, the profound imbalance of fibroblast subpopulations in SSc may drive the progression of skin fibrosis. Specific targeting of disease-relevant fibroblast populations may offer opportunities for the treatment of SSc and other fibrotic diseases.
CRIS-Team Scopus Importer:2024-02-16
Keywords: Dermal fibrosis; Disease outcomes; Fibroblasts; SSc; Subpopulations

FINE STRUCTURE ANALYSIS OF THE INTER-RELATION BETWEEN TOPHUS DEPOSITION AND BONE LESIONS IN GOUT USING A COMBINATION OF DUAL ENERGY AND HIGH-RESOLUTION CT - Bayat, Sara; Simon, David; Pecherstorfer, Caroline; Ellmann, Hanna; Figueiredo, C.; Englbrecht, Matthias; Hueber, A.; Kleyer, Arnd; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

First Presentation of idiopathic Mast Cell Activation Syndrome (MCAS) in a Young Person: Association with Histamine and Salicylate Intolerance as well as an important Differential Diagnosis in gastroenterological Problem Patients - Raithel, Martin; Rechenauer, Tobias; Goetze, Thomas; Siebenlist, Gregor; Rueckel, Aline; Baenkler, Hanns-Wolf; Hartmann, Arndt; Haller, Florian; Hoerning, Andre (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Fluctuation in electrical hearing in a Morbus Meniere's patient - Hast, Anne; Meßbacher, Maria-Elena; Liebscher, Tim; Hornung, Joachim; Hoppe, Ulrich (Clinical Case Reports, 2021)
The glycerol test is an easy-to-use instrument to elucidate fluctuations of electrical hearing in patients with Meniere's disease and it might be also used as a therapeutic option.
CRIS-Team WoS Importer:2021-08-13

Focus on Content not Noise: Improving Image Generation for Nuclei Segmentation by Suppressing Steganography in CycleGAN - Utz, Jonas; Weise, Tobias; Schlereth, Maja; Wagner, Fabian; Thies, Mareike; Gu, Mingxuan; Uderhardt, Stefan; Breininger, Katharina (Proceedings - 2023 IEEE/CVF International Conference on Computer Vision Workshops, ICCVW 2023, 2023)
Annotating nuclei in microscopy images for the training of neural networks is a laborious task that requires expert knowledge and suffers from inter- and intra-rater variability, especially in fluorescence microscopy. Generative networks such as CycleGAN can inverse the process and generate synthetic microscopy images for a given mask, thereby building a synthetic dataset. However, past works report content inconsistencies between the mask and generated image, partially due to CycleGAN minimizing its loss by hiding shortcut information for the image reconstruction in high frequencies rather than encoding the desired image content and learning the target task. In this work, we propose to remove the hidden shortcut information, called steganography, from generated images by employing a low pass filtering based on the discrete cosine transform (DCT). We show that this increases coherence between generated images and cycled masks and evaluate synthetic datasets on a downstream nuclei segmentation task. Here we achieve an improvement of 5.4 percentage points in the F1-score compared to a vanilla CycleGAN. Integrating advanced regularization techniques into the CycleGAN architecture may help mitigate steganography-related issues and produce more accurate synthetic datasets for nuclei segmentation.
CRIS-Team Scopus Importer:2024-12-16
Keywords: cycle gan; data generation; dct; fluorescence microscopy; nuclei; segmentation; steganography; synthetic data

Formation of atherosclerotic lesions is independent of eosinophils in male mice - Hofheinz, Katharina; Seibert, Fabian; Ackermann, Jochen; Dietel, Barbara; Tauchi, Miyuki; Oszvar-Kozma, Maria; Kühn, Hartmut; Schett, Georg; Binder, Christoph J.; Krönke, Gerhard (Atherosclerosis, 2020)
Background and aims: Oxidation of low-density lipoprotein (LDL) and oxidized LDL-mediated activation of the innate immune system have been recognized as early key events during the pathogenesis of atherosclerosis. Recent evidence identified eosinophils as a major source of enzymatic lipid oxidation and suggested a potential role of type 2 immunity in atherogenesis. However, the involvement of individual type 2 immune cell subsets involved in this process has been incompletely defined. We therefore sought to determine the role of eosinophils during LDL oxidation and the pathogenesis of this disease. Methods: Using eosinophil-deficient dblGATA1 mice, we studied the role of eosinophils in two established mouse models of atherosclerosis. Results: These experiments revealed that the presence of eosinophils did neither affect biomarkers of LDL oxidation nor atherosclerotic lesion development. Conclusions: The obtained results show that LDL oxidation and development of atherosclerosis are largely independent of eosinophils or eosinophil-mediated LDL oxidation.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Atherosclerosis; Eosinophils; Lipid oxidation

FOSL-2 IS A REPRESSOR OF FOXP3 EXPRESSION DURING TREG DEVELOPMENT AND CONTROLS AUTOIMMUNITY - Renoux, Florian; Stellato, Mara; Vogetseder, Alexander; Huang, Riyung; Subramaniam, Arun; Blyszczuk, Przemyslaw; Distler, Jörg; Kania, Gabriela; Boyman, Onur; Distler, Oliver (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Fourth-generation chimeric antigen receptor T-cell therapy is tolerable and efficacious in treatment-resistant rheumatoid arthritis - Li, Yujing; Li, Sujun; Zhao, Xiaojuan; Sheng, Jun; Xue, Lei; Schett, Georg; Shi, Ce; Hu, Biliang; Wang, Xingbing; Chen, Zhu (Cell Research, 2025)
CRIS-Team Scopus Importer:2025-02-17

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss - Grötsch, Bettina; Lux, Anja; Rombouts, Yoann; Hoffmann, Alana; Andreev, Darja; Nimmerjahn, Falk; Xiang, Wei; Scherer, Hans Ulrich; Schett, Georg; Bozec, Aline (Journal of Bone and Mineral Research, 2019)
Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG-rheumatoid factor (IgG-RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG-RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG-RF production by plasma cells and regulates autoimmune-mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell ) led to increased IgG1-producing bone marrow plasma cells, enhanced IgG-RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG-RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T-cell-dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast-mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG-RF production and autoimmune-mediated bone loss. © 2019 American Society for Bone and Mineral Research.
EVALuna2:69394

FRA-1 TRANSCRIPTION FACTOR EXPRESSION IN MACROPHAGES FOSTER INFLAMMATION DURING RHEUMATOID ARTHRITIS DEVELOPMENT - Hannemann, Nicole; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Hueber, Axel; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Bogdan, Christian; Schett, Georg; et al. (2017)
EVALuna2:13497

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPAR? and hypoxia - Luther, Julia; Ubieta Hernández, Kenia; Hannemann, Nicole; Jimenez, Maria; Garcia-Cuellar, Maria-Paz; Zech, C.; Schett, Georg; Wagner, E. F.; Bozec, Aline (Cell Death and Differentiation, 2014)
Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2(?adip) mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2(?adip) mice. At the molecular level, Fra-2 directly binds to the PPAR?2 promoter and represses PPAR?2 expression. Deletion of Fra-2 leads to increased PPAR?2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.
EVALuna2:12913

Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b - Chen, Guang Liang; Li, Rui; Chen, Xiao Xiang; Wang, Juan; Cao, Shan; Song, Rui; Zhao, Ming Chun; Li, Li Ming; Hannemann, Nicole; Schett, Georg; Qian, Cheng; Bozec, Aline (Cell Death and Differentiation, 2020)
Metastatic melanoma remains a challenging disease. Understanding the molecular mechanisms how melanoma becomes metastatic is therefore of interest. Herein we show that downregulation of the AP-1 transcription factor member Fra-2 in melanoma cells is associated with an aggressive melanoma phenotype in vitro and in vivo. In vitro, Fra-2 knockdown in melanoma cells promoted cell migration and invasion associated with increased Snail-1, Twist-1/2, and matrix metalloproteinase-2 (MMP-2) expression. In vivo, Fra-2 knockdown in a melanoma cell line led to increased metastasis into the lungs and liver. The increased metastatic potential of Fra-2 knockdown melanoma cells was likely due to an accelerated cell cycle transition and increased tissue angiogenesis. Using Fra-2 knockdown cell lines microarray analysis, we identified the protein Fam212b (family with sequence similarity 212 member B) as a downstream target of Fra-2. By additional knockdown of Fam212b in Fra-2 mutant cells, we mitigated the cell migration, invasion, and cell cycle transition phenotype induced by Fra-2 knockdown. Furthermore, Fam212b overexpression enhanced β-catenin pathway. Finally, Fam212b expression is correlated with increased melanoma metastasis and poor clinical outcomes in human patients. In summary, these findings reveal the Fra-2-Fam212b axis as a new pathway of melanoma metastasis, which can be in the future used as potential marker of the metastatic properties of melanoma.
CRIS-Team Scopus Importer:2020-11-20

Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin - Luo, Yubin; Grötsch, Bettina; Hannemann, Nicole; Jimenez, Maria; Ipseiz, Natacha; Uluckan, Ozge; Lin, Nengyu; Schett, Georg; Wagner, Erwin F.; Bozec, Aline (Molecular and Cellular Biology, 2018)
Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2Ob-tet) induced a systemic inflammatory state with infiltration of neutrophils and proinflammatory macrophages into the spleen and liver as well as increased levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). By in vivo inhibition of osteopontin (OPN) in Fra-2Ob-tet mice, we demonstrated that this process was dependent on OPN expression, which mediates alterations of the bone marrow niche. OPN expression was transcriptionally enhanced by Fra-2 and stimulated mesenchymal stem cell (MSC) expansion. Furthermore, in a murine lung injury model, Fra-2Ob-tet mice showed increased inflammatory responses and more severe disease features via an enhanced and sustained inflammatory response to lipopolysaccharide (LPS). Our findings demonstrate for the first time that molecular changes in osteoblasts influence the susceptibility to inflammation by altering evasion of innate immune cells from the bone marrow space.
EVALuna2:34665
Keywords: Fra-2/AP-1; osteopontin; bone niche; systemic inflammation; lung injury; Fra-2; osteoblasts

FRA2 IS PLAYING A KEY ROLE IN THE CONTROL OF TREG DEVELOPMENT AND AUTOIMMUNITY - Renoux, F.; Stellato, M.; Pachera, E.; Impellizzieri, D.; Dees, Clara; Distler, Jörg; Kania, G.; Boyman, O.; Distler, O. (2016)
EVALuna2:35072

Fra-2 Overexpression Leads to Systemic Autoimmunity By Affecting IL2 Dependent Treg Homeostasis - Renoux, Florian; Stellato, Mara; Impellizzieri, Daniela; Vogetseder, Alexander; Blyszczuk, Przemyslaw; Huang, Riyun; Subramaniam, Arun; Dees, Clara; Distler, Jörg; Kania, Gabriela; Boyman, Onur; Distler, Oliver (2017)
EVALuna2:35020

FRA2 OVEREXPRESSION LEADS TO SYSTEMIC AUTOIMMUNITY BY DECREASING IL-2 RESPONSIVENESS AND THYMIC TREG DEVELOPMENT - Renoux, F.; Stellato, M.; Impellizzieri, D.; Vogetseder, A.; Huang, R.; Subramaniam, A.; Dees, Clara; Distler, Jörg; Kania, G.; Boyman, O.; Distler, O. (2017)
EVALuna2:35027

Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription - Ubieta, Kenia; Garcia, Mireia; Groetsch, Bettina; Uebe, Steffen; Stein, Merle; Ekici, Arif Bülent; Schett, Georg; Mielenz, Dirk; Bozec, Aline; Weber, Georg (Journal of Experimental Medicine, 2017)
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7R? and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.
EVALuna2:9366

From 3D Printed Bones to Arthritis Patients - Arthro-Haptic Experience Supporting Disease Awareness - Kleyer, Arnd; Beyer, Laura; Simon, Christoph; Stemmler, Fabian; Rech, Jürgen; Englbrecht, Matthias; Manger, Bernhard; Kroenke, Gerhard; Schett, Georg; Hueber, Axel (2016)
EVALuna2:34456

FROM BENCH TO BEDSIDE: NINTEDANIB FOR PROGRESSIVE FIBROSING INTERSTITIAL LUNG DISEASES - Wollin, L.; Distler, Jörg; Redente, E.; Riches, D.; Stowasser, S.; Schlenker-Herceg, R. (RESPIROLOGY, 2019)
CRIS-Team WoS Importer:2019-04-02

From pathogenesis to therapy - Perspective on treatment strategies in fibrotic diseases - Dees, Clara; Distler, Jörg; Ramming, Andreas (Pharmacological Research, 2015)
Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, there are very few treatment strategies available that specifically target the pathogenesis of fibrosis. Early in disease, inflammation and vascular changes and an increase in reactive oxygen species play pivotal roles. After inflammation has subsided, fibrosis and scarring are predominant in later phases. Fibrosis is driven by a complex, not-yet fully understood interplay between inflammatory cells on one hand and endothelium and fibroblasts on the other hand. The latter are regarded as the key players due to their extensive synthesis of extracellular matrix components which results in skin and organ fibrosis. Various cytokines orchestrate altered functions of the mentioned cell types. There are promising targets with therapeutic potential that have been extensively characterized in recent years connected with the hope to translate these preclinical results into clinical practice.
EVALuna2:13157

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface - Mahajan, Aparna; Grüneboom, Anika; Petru, Lenka; Podolska, Malgorzata; Kling, Lasse; Maueröder, Christian; Dahms, Florian; Christiansen, Silke; Günter, Lochnit; Krenn, Veit; Jünemann, Anselm; Bock, Felix; et al. (Journal of Leukocyte Biology, 2019)
Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO 2 , neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO 2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs-based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil-rich ocular surfaces.
CRIS-Team Scopus Importer:2019-05-02
Keywords: degranulation; eye rheum; inflammation; NETs; neutrophils; resolution; serine protease

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction - Kurow, Olga; Frey, Benjamin; Schuster, Louis; Schmitt, Verena; Adam, Susanne; Hahn, Madelaine; Gilchrist, Derek; Mcinnes, Iain B.; Wirtz, Stefan; Gaipl, Udo; Krönke, Gerhard; Schett, Georg; et al. (Frontiers in Immunology, 2017)
The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.
EVALuna2:13432

Full version of the S2e guidelines on gouty arthritis : Evidence-based guidelines of the German Society of Rheumatology (DGRh) - Kiltz, U.; Alten, R.; Fleck, M.; Krueger, K.; Manger, Bernhard; Mueller-Ladner, U.; Nusslein, H.; Reuss-Borst, M.; Schwarting, A.; Schulze-Koops, H.; Tausche, A.; Braun, J. (Zeitschrift für Rheumatologie, 2016)
EVALuna2:13340

Fully Human Anti-CD19 CAR T Cells Derived from Systemic Lupus Erythematosus Patients Exhibit Cytotoxicity with Reduced Inflammatory Cytokine Production - Dingfelder, Janin; Aigner, Michael; Taubmann, Jule; Minopoulou, Ioanna; Park, Soo; Kaplan, Charles D.; Cheng, Joseph K.; Van Blarcom, Tom; Schett, Georg; Mackensen, Andreas; Lutzny-Geier, Gloria (Transplantation and Cellular Therapy, 2024)
KYV-101 is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy under investigation for patients with B-cell driven autoimmune diseases. Hu19-CD828Z is a fully human anti-CD19 CAR designed and demonstrated to have a favorable clinical safety profile. Since anti-CD19 CAR T cells target and kill B cells in both circulation and tissues, the treatment with Hu19-CD828Z CAR T cells offers great potential in depleting autoreactive B cells. Demonstrate that Hu19-CD828Z CAR T cells manufactured from cryopreserved leukaphereses from patients with systemic lupus erythematosus (SLE) exhibit CAR-mediated and CD19-dependent cytokine release, proliferation and cytotoxicity when co-cultured with autologous primary B cells. T cells were enriched from cryopreserved leukaphereses from SLE patients or healthy donors (HD). CAR T cells were generated by transducing these cells with a lentiviral vector encoding Hu19-CD828Z. CAR-mediated and CD19-dependent activity was monitored in vitro in a set of cytotoxicity, cytokine release, and proliferation studies, in response to autologous primary CD19+ B cells, a CD19+ cell line (NALM-6), or a CD19− cell line (U937). Hu19-CD828Z CAR T cells produced from SLE patients or HD induced greater proliferation and dose-dependent cytotoxicity against both autologous primary B cells and the CD19+ NALM-6 cells than nontransduced control T cells or co-cultures with a CD19− cell line. Interestingly, there was lower inflammatory cytokine production from SLE patient-derived CAR T cells compared to HD donor-derived CAR T cells with either CD19+ cells or primary B cells. Hu19-CD828Z CAR T cells generated from SLE patient lymphocytes demonstrate CAR-mediated and CD19-dependent activity against autologous primary B cells with reduced inflammatory cytokine production supporting KYV-101 as a novel potential therapy for the depletion of pathogenic B cells in SLE patients.
CRIS-Team Scopus Importer:2024-04-19
Keywords: Chimeric antigen receptor; Cytokines; Systemic Lupus Erythematosus

Ga-68-FAPI-04 PET/CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-related interstitial lung disease - Schmidkonz, Christian; Distler, Jörg; Treutlein, Christoph; Atzinger, Armin; Prante, Olaf; Ritt, Philipp; Goetz, T.; Bäuerle, Tobias; Cordes, Michael; Köhner, Markus; Kuwert, Torsten; Ramming, Andreas; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
CRIS-Team WoS Importer:2022-01-07

gagCEST imaging at 3 T MRI in patients with articular cartilage lesions of the knee and intraoperative validation - Söllner, Stefan; Welsch, G. H.; Gelse, Kolja; Goldmann, A.; Kleyer, Arnd; Schett, Georg; Pachowsky, Milena (Osteoarthritis and Cartilage, 2021)
Objective: The aim of this study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage. Design: Twenty-one patients with cartilage lesions or moderate OA were examined using 3 T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades. Results: A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades. Conclusions: gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Cartilage; Chemical exchange saturation transfer; MRI; Osteoarthritis

Galectin-3 as a novel regulator of osteoblast-osteoclast interaction and bone homeostasis - Simon, Dominic; Derer, Anja; Andes, Fabian T.; Lezuo, Patrick; Bozec, Aline; Schett, Georg; Herrmann, Martin; Harre, Ulrike (Bone, 2017)
Bone tissue undergoes permanent and lifelong remodeling with a concerted action of bone-building osteoblasts and bone-resorbing osteoclasts. A precise cooperation between those two cell types is critical in the complex process of bone renewal. Galectin-3 is a member of the ?-galactoside-binding lectin family playing multiple roles in cell growth, differentiation and aggregation. As it has been described to be expressed in bone, galectin-3 might influence bone homeostasis by regulating the function and/or interplay of osteoblasts and osteoclasts. Here, we investigated the role of galectin-3 in osteoclastogenesis and osteoblast-osteoclast interactions. Bone histomorphometric analysis and ?CT measurements revealed a decreased trabecular bone volume and an increased osteoclast number in 12weeks old male galectin-3 knockout mice compared to wildtype littermates. Galectin-3 deficient bone marrow cells displayed a higher osteoclastogenic capacity in ex vivo differentiation assays, associated with elevated TRAF6 mRNA levels, suggesting an intrinsic inhibition of osteoclastogenesis by galectin-3 interfering with RANKL-mediated signaling. Furthermore, the addition of extracellular galectin-3 to murine or human osteoclastogenesis assays inhibited osteoclast formation and osteoclast numbers were higher in co-culture assays with galectin-3 deficient osteoblasts. In conclusion, our data suggest the secretion of galectin-3 as a novel mechanism for osteoblasts to control osteoclastogenesis and to maintain trabecular bone homeostasis independently of the RANKL/OPG-axis.
EVALuna2:13345

Gender- and site-specific differences of colorectal neoplasia relate to vitamin D - Aigner, E.; Stadlmayr, A.; Huber-Schoenauer, U.; Zwerina, J.; Husar-Memmer, E.; Niederseer, D.; Trauner, M.; Heuberger, A.; Hohla, F.; Schett, Georg; Patsch, W.; Datz, C. (Alimentary Pharmacology & Therapeutics, 2014)
The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion.To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors.One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded.Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016).A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
EVALuna2:13058

GENDER DIFFERENCES IN PSA OUTCOME PARAMETERS AND THEIR CORRELATION WITH SKIN INVOLVEMENT: A CROSS-SECTIONAL ANALYSIS OF RABBIT-SPA PATIENTS - Regierer, A.; Weiss, A.; Behrens, F.; Feuchtenberger, M.; Schett, Georg; Baraliakos, X.; Zink, A.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force - Ovseiko, Pavel; Gossec, Laure; Andreoli, Laura; Kiltz, Uta; Van Mens, Leonieke; Hassan, Neelam; Van Der Leeden, Marike; Siddle, Heidi J.; Alunno, Alessia; Mcinnes, Iain B.; Damjanov, Nemanja S.; Apparailly, Florence; et al. (RMD Open, 2022)
Objectives Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. Methods This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by chi(2) test and t-test. Results Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. Conclusions There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.
CRIS-Team WoS Importer:2022-08-26

Generation and Analysis of Human and Murine Osteoclasts - Steffen, Ulrike; Andes, Fabian T.; Schett, Georg (Current Protocols in Immunology, 2019)
Osteoclasts are the only bone-resorbing cells in the body. Together with bone-forming osteoblasts, they are responsible for bone homeostasis and constant bone remodeling. Aberrant activation of osteoclasts leads to bone loss, as seen in postmenopausal osteoporosis or in autoimmune diseases like rheumatoid arthritis. Although much research has been performed to understand and prevent osteoclast-mediated bone loss, the mechanisms of osteoclast hyperactivation are not completely understood. This unit describes several protocols for ex vivo generation of murine and human osteoclasts, allowing study of the effects of specific cells, cytokines, or chemical substances on osteoclast formation and activity without the need for expensive and time-consuming animal experiments. In addition, we provide protocols for specific staining of osteoclasts and for analysis of resorption activity using calcium phosphate–coated surfaces or bone slices. © 2019 by John Wiley & Sons, Inc.
CRIS-Team Scopus Importer:2019-06-21
Keywords: bone marrow; osteoclast generation; PBMC; resorption; TRAP staining