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: Early Origins of Psoriatic Arthritis - Simon, David; Watad, Abdulla; Rodrigues-Manica, Santiago; Perricone, Carlo (Frontiers in Medicine, 2021)
CRIS-Team Scopus Importer:2021-12-03
Keywords: enthesitis; intervention; Psoriasis; psoriatic arthritis; risk factors; transition

Editorial: Nano- and Microparticle-Induced Cell Death, Inflammation and Immune Responses - Mulay, Shrikant R.; Herrmann, Martin; Bilyy, Rostyslav; Gabibov, Alexander; Anders, Hans-Joachim (Frontiers in Immunology, 2019)
CRIS-Team WoS Importer:2019-05-03

Editorial: NETosis 2: The Excitement Continues - Munoz, Luis Enrique; Kaplan, Mariana J.; Radic, Marko; Herrmann, Martin; Munoz Becerra, Luis (Frontiers in Immunology, 2017)
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Editorial - NETs in autoimmune diseases - Boeltz, Sebastian; Herrmann, Martin (Autoimmunity, 2018)
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Editorial: Oral neutrophils - the good, the bad, and the ugly - Vitkov, Ljubomir; Herrmann, Martin; Knopf, Jasmin (Frontiers in Immunology, 2023)
CRIS-Team Scopus Importer:2023-06-30
Keywords: dysbiosis; dysregulated immunity; innate immunity; maladaptive trained immunity; systemic low-grade inflammation

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

Educational needs and preferences of young European clinicians and physician researchers working in the field of rheumatology - Beyer, Christian; Ramiro, Sofia; Sivera, Francisca; Mandl, Peter; MacHado, Pedro M.; Ospelt, Caroline; Moltó, Anna; Radner, Helga; Iagnocco, Annamaria; Bijlsma, Johannes W.; Lundberg, Ingrid E.; Grigoriou, Antigoni; et al. (RMD Open, 2016)
To understand the educational needs and preferences of young clinicians and physician researchers in the field of rheumatology in Europe.An international online survey was performed as a joint venture of ESCET and EMEUNET. The survey assessed the acceptance of and the access to the current European League Against Rheumatism (EULAR) educational portfolio, as well as the unmet educational needs and learning preferences among individuals below the age of 40 years working in rheumatology in Europe.Among 568 European clinicians and physician researchers, 65% indicated that the existing EULAR educational portfolio adequately covers their educational needs. Within the EULAR portfolio, the online course on rheumatic diseases and the postgraduate course were the most appreciated. Participants were very much in favour of new educational courses on imaging techniques, and 63% of participants indicated a particular interest in musculoskeletal ultrasound. A strong interest in refresher (60%) and general review (55%) courses was observed. Lack of funding was considered the major obstacle to participating in existing EULAR programmes. Finally, participants showed diverse preferences regarding learning modalities with common interests in live courses and conferences.EULAR's training opportunities are well appreciated among young clinicians and physician researchers in rheumatology. The results from this survey will help to develop EULAR's future educational portfolio.
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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 AGEING ON FAT INFILTRATION OF THIGH AND PARASPINAL MUSCLES IN MEN - Engelke, Klaus; Ghasemikaram, Mansour; Chaurdy, O.; Uder, Michael; Nagel, Armin Michael; Jacob, F.; Kemmler, Wolfgang (AGING CLINICAL AND EXPERIMENTAL RESEARCH, 2022)
CRIS-Team WoS Importer:2022-10-14

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

Effect of Radiotherapy and Chemotherapy on the Immunophenotype of Head and Neck Cancer Cells and the consecutive Activation of dendritic Cells - Grottker, F.; Frey, Benjamin; Gehre, S.; Reichardt, Clara; Sengedorj, Azzaya; Hecht, Markus; Fietkau, Rainer; Rieckmann, T.; Gostian, Antoniu-Oreste; Gaipl, Udo; Rückert, Michael (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

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.
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Effects of Autoantibodies on Osteoclasts - Sokolova, Maria; Steffen, Ulrike (Osteologie, 2021)
The balance between bone forming osteoblasts and bone resorbing osteoclasts can be disturbed in autoimmune diseases resulting in local and systemic bone loss. It was long time believed that autoantibodies only indirectly contribute to bone loss by fueling the overall inflammation. However, in the last decade, more and more evidence emerged that autoantibodies and immune complexes directly activate osteoclasts and pre-osteoclasts by binding to Fc gamma receptors (Fc gamma Rs) on the (pre)osteoclast cell surface. This pro-osteoclastogenic effect seems to be dependent on the absence of sialic acid in the IgG Fc glycan, which is a typical feature of many autoantibodies. Clinical studies revealed the importance of autoantibody-mediated bone loss mainly in rheumatoid arthritis, but also in other diseases, such as celiac disease. In summary, the gained knowledge about autoantibody-mediated bone loss helps to better understand bone pathologies of autoimmune diseases. However, studies are still relatively limited and more research is needed to fully understand the impact of autoantibodies on bone and to develop future therapeutic strategies.
CRIS-Team WoS Importer:2021-10-08

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 High-Intensity Resistance Training on Visceral Adipose Tissue and Abdominal Aortic Calcifications in Older Men with Osteosarcopenia – Results from the FrOST Study - Knauer, Kira; Chaudry, Oliver; Uder, Michael; Kohl, Matthias; Kemmler, Wolfgang; Bickelhaupt, Sebastian; Engelke, Klaus (Clinical Interventions in Aging, 2023)
Purpose: To evaluate the effect of a high-intensity resistance training (HIT-RT) on visceral adipose tissue (VAT) and abdominal aortic calcifications (AAC). Patients and Methods: We conducted a post hoc analysis of the Franconian Osteopenia and Sarcopenia Trial (FrOST). 43 community-dwelling men with osteosarcopenia aged 72 years and older were randomly allocated to a supervised high-intensity resistance training (HIT-RT) twice weekly for 18 months (EG; n=21) and a non-training control group (CG; n=22). Non-contrast enhanced 2-point Dixon MRI scans covering mid L2 to mid L3 were acquired to measure VAT volume inside the abdominal cavity. Volume of AAC and hard plaques in renal arteries, truncus celiacus and superior mesenteric artery was measured by computed tomography (CT) scans covering mid T12 to mid L3. Intention-to-treat analysis with imputation for missing data was used to determine longitudinal changes in VAT and AAC volume. Correlations were used to determine associations between VAT and AAC. Results: Significant reduction of VAT volume in the EG (−7.7%; p<0.001) combined with no change in the CG (−1.3%; p=0.46) resulted in a significant 6.4% between group effect (p=0.022). We observed a significant increase of AAC volume in EG (+10.3%; p<0.001) and CG (12.0%; p<0.001). AAC differences between groups were not significant (p=0.57). In vascular outlets increases in volume of the hard plaques were observed in both groups, however, not all of them were significant. There was no significant correlation between changes in VAT and AAC volumes. Conclusion: The study confirmed a positive impact of HIT-RT on the metabolic and cardiovascular risk profile with respect to reduction of VAT volume. No positive exercise effect on AAC was observed. However, there was a further progression of AAC volume independent of group affiliation. Whether different exercise regimen may show a positive effect on AAC remains subject to further studies.
CRIS-Team Scopus Importer:2023-02-03
Keywords: AAC; HIT-RT; osteopenia; sarcopenia; VAT

Effects of high-intensity training on fatty infiltration in paraspinal muscles in elderly males with osteosarcopenia – the randomized controlled FrOST study - Kircher, Kaja; Chaudry, Oliver; Nagel, Armin Michael; Ghasemikaram, Mansour; Uder, Michael; Jakob, Franz; Kohl, Matthias; Kemmler, Wolfgang; Engelke, Klaus (BMC Geriatrics, 2024)
Background: Osteosarcopenia is a common geriatric syndrome with an increasing prevalence with age, leading to secondary diseases and complex consequences such as falls and fractures, as well as higher mortality and frailty rates. There is a great need for prevention and treatment strategies. Methods: In this analysis, we used magnetic resonance imaging (MRI) data from the randomised controlled FrOST trial, which enrolled community-dwelling osteosarcopenic men aged > 72 years randomly allocated to 16 months of twice-weekly high-intensity resistance training (HIRT) or a non-training control group. MR Dixon imaging was used to quantify the effects of HIRT on muscle fat infiltration in the paraspinal muscles, determined as changes in muscle tissue, fat faction and intermuscular adipose tissue (IMAT) in the erector spinae and psoas major muscles. Intention-to-treat analysis with multiple imputation was used to analyse the data set. Results: After 16 months of intervention, 15 men from the HIRT and 16 men from the CG were included in the MRI analysis. In summary, no positive effects on the fat infiltration of the erector spinae and psoas major muscles were observed. Conclusions: The previously reported positive effects on lumbar spine bone mineral density (BMD) suggest that mechanotransduction induces tropic effects on bone, but that fat infiltration of the erector spinae and psoas major muscles are either irreversible or, for some unknown reason, resistant to exercise. Because of the beneficial effects on spinal BMD, HIRT is still recommended in osteosarcopenic older men, but further research is needed to confirm appropriate age-specific training exercises for the paraspinal muscles. The potential of different MRI sequences to quantify degenerative and metabolic changes in various muscle groups must be better characterized. Trial registrations: FrOST was approved by the University Ethics Committee of the Friedrich-Alexander University of Erlangen-Nürnberg (number 67_15b and 4464b) and the Federal Office for Radiation Projection (BfS, number Z 5–2,246,212 – 2017–002). Furthermore, it fully complies with the Declaration of Helsinki and is registered at ClinicalTrials.gov: NCT03453463 (05/03/2018). JAMA 310:2191–2194, 2013.
CRIS-Team Scopus Importer:2024-02-23
Keywords: BMD; Dixon imaging; HIRT; IMAT; MRI; Osteosarcopenia

Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis - Efe, Cumali; Lammert, Craig; Tascilar, Koray; Dhanasekaran, Renumathy; Ebik, Berat; Higuera-De La Tijera, Fatima; Caliskan, Ali R.; Peralta, Mirta; Gerussi, Alessio; Massoumi, Hatef; Catana, Andreea M.; Purnak, Tugrul; et al. (Liver International, 2021)
Background We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.
CRIS-Team WoS Importer:2021-12-24

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.
EVALuna2:13269

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

Effects of vibration training on bone metabolism: results from a short-term bed rest study - Baecker, Natalie; Frings-Meuthen, Petra; Heer, Martina; Mester, Jochen; Liphardt, Anna-Maria (European Journal of Applied Physiology, 2012)
The absence of mechanical loading leads to a prompt increase in bone resorption measured by bone resorption markers. There is high potential that vibration training can positively influence bone metabolism in immobilized subjects, reduce the increase in osteoclastic activity and increase bone formation processes. We investigated whether vibration training at 20 Hz with an amplitude of 2-4 mm influences bone metabolism during immobilization. Eight male subjects (26.4 ± 4.9 years; 78.1 ± 9.5 kg) performed a 14 day bed rest in 6°-head down tilt (HDT). Subjects received vibration training for 2 × 5 min/day or a control intervention without vibration (crossover design). Calcium excretion and bone resorption markers C-telopeptide (CTX) and N-telopeptide (NTX) were analyzed from 24 h urine samples. Bone formation markers, bone alkaline phosphatase (bAP) and procollagen-N propeptide (PINP) were analyzed from fasting blood samples. Our results show an increase in bone resorption very early during HDT bed rest in both interventions (CTX: p < 0.01; NTX: p < 0.001). Vibration training did not have any different effect on bone resorption markers (CTX: p = 0.10; NTX: p = 0.58), bone formation markers (PINP: p = 0.21; bAP: p = 0.12) and calcium excretion (p < 0.64) compared to the control condition. Mere vibration training with 20 Hz for 2 × 5 min/day does not prevent increase in bone resorption as measured with the described methods in our short-term HDT bed rest.
EVALuna2:13505

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; Schett, Georg; Kleyer, Arnd; Hartmann, Fabian (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 a mobile app intervention in patients with inflammatory arthritis: a prospective pilot study - Fedkov, Dmytro; Berghofen, Andrea; Weiss, Christel; Peine, Christine; Lang, Felix; Knitza, Johannes; Kuhn, Sebastian; Kraemer, Bernhard K.; Leipe, Jan (Rheumatology International, 2022)
EULAR highlighted the essential role of digital health in increasing self-management and improving clinical outcomes in patients with arthritis. The objective of this study was to evaluate the efficacy and safety of the digital health application (DHA) in patients with inflammatory arthritis. We assessed demographic parameters, treatment regimen, disease activity, and other patient-reported outcomes at baseline and after 4 weeks of DHA use added to standard care treatment. Of 17 patients, who completed the study, 7 (41.2%) patients were male, ranging from 19 to 63 (40.5 +/- 12.2) years. No significant change in antirheumatic treatment was observed during the study. Statistically significant improvements (p < 0.05) were noted for health-related quality of life (increase in Physical Component Summary of Short Form-36 (SF-36) by 23.6%) and disease activity (decrease of Clinical Disease Activity Index and Simple Disease Activity Index by 38.4% and 39.9%, respectively). Clinically significant improvement was demonstrated for SF-36 Total Score (+ 14.4%), disease activity (Rheumatoid Arthritis Disease Activity Index- 5 to 15.9%), and depression (Patient Health Questionnaire- 9 to 13.5%). None of the efficacy parameters showed negative trends. No adverse events were reported throughout the study. The usability level was high i.e., the mean mHealth Application Usability Questionnaire Score of 5.96 (max.: 7.0) demonstrated a high level of application usability. This suggests that using a personalized disease management program based on DHA significantly improves several measures of patient-reported outcomes and disease activity in patients with inflammatory arthritis in a timely manner. These findings highlight the potential of complementary digital therapy in patients with inflammatory arthritis.
CRIS-Team WoS Importer:2022-09-23

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 and Safety of Tocilizumab in Patients with Giant Cell Arteritis: Primary and Secondary Outcomes from a Phase 3, Randomized, Double-Blind, Placebo-Controlled 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; Spiera, Robert F.; et al. (2016)
EVALuna2:35066

EFFICACY OF UST IN ACTIVE PSA IS INDEPENDENT FROM CONCOMITANT MTX USE, EVEN IN PATIENTS WITH MORE SEVERE SKIN PSORIASIS: SUBGROUP ANALYSIS FROM A RANDOMIZED PLACEBO-CONTROLLED INVESTIGATOR INITIATED CLINICAL TRIAL - Koehm, M.; Rossmanith, T.; Foldenauer, A. C.; Kellner, H.; Kiltz, U.; Rech, Jürgen; Burmester, G. R.; Kofler, D. M.; Brandt-Juergens, J.; Jonetzko, C.; Burkhardt, H.; Behrens, F. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

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, and pharmacokinetics after switching from infliximab originator to biosimilar SB2 in inflammatory bowel disease patients: A long-term observational, prospective cohort study - Fischer, Sören; Mesfin, Sarah Ellen; Klenske, E.; Schmitt, Heike; Vitali, Francesco; Hirschmann, Simon; Ramming, A.; Zundler, Sebastian; Rath, Timo; Krebs, Sabine; Dörje, Frank; Uter, Wolfgang; et al. (JOURNAL OF CROHNS & COLITIS, 2020)
CRIS-Team WoS Importer:2020-04-10

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

Efficient antibody evasion but reduced ACE2 binding by the emerging SARS-CoV-2 variant B.1.640.2 - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Schulz, Sebastian; Cossmann, Anne; Dopfer-Jablonka, Alexandra; Winkler, Martin S.; Jäck, Hans-Martin; Behrens, Georg M. N.; Pohlmann, Stefan; Hoffmann, Markus (Cellular & Molecular Immunology, 2022)
CRIS-Team WoS Importer:2022-06-03

EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction - Mielenz, Dirk; Reichel, Martin; Jia, T.; Quinlan, E. B.; Stöckl, Thomas; Mettang, M.; Zilske, Daniel; Kirmizi Alsan, Elif; Schoenberger, P.; Praetner, M.; Huber, Sabine; Amato, Davide; et al. (Molecular Psychiatry, 2017)
In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with β-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.
EVALuna2:4036

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

Eine Patientin mit Arthrose - Von Waltering, Isabel; Rech, Jürgen; Derendorf, Hartmut (Deutsche Apotheker Zeitung, 2014)
CRIS-Team Scopus Importer:2021-02-03

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

ELECTRONIC PATIENT-REPORTED OUTCOMES: A SURVEY ABOUT ACCEPTANCE, USAGE AND BARRIERS AMONG GERMAN RHEUMATOLOGISTS - Krusche, M.; Klemm, P.; Grahammer, M.; Mucke, J.; Vossen, D.; Kleyer, Arnd; Sewerin, P.; Knitza, Johannes (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

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 Na+ levels dampen the antibacterial activity of neutrophils in a phagocyte oxidase-dependent way - Krampert, L.; Bauer, K.; Ebner, S.; Neubert, P.; Ossner, T.; Weigert, A.; Schatz, V.; Toelge, M.; Schroeder, A.; Herrmann, Martin; Schnare, M.; Dorhoi, A.; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

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

Elevated Serum Lysophosphatidylcholine in Patients with Systemic Lupus Erythematosus Impairs Phagocytosis of Necrotic Cells In Vitro - Grossmayer, Gerhard E.; Keppeler, Hildegard; Boeltz, Sebastian; Janko, Christina; Rech, Jürgen; Herrmann, Martin; Lauber, Kirsten; Munoz, Luis Enrique; Munoz Becerra, Luis (Frontiers in Immunology, 2017)
Impaired clearance of dying and dead cells by professional and amateur phagocytes plays a crucial role in the etiology of systemic lupus erythematosus (SLE). While dying, cells expose and release a plethora of eat-me and find-me signals to ensure their timely removal before entering the dangerous stage of secondary necrosis. A well-described chemoattractant for macrophages is dying cell-derived lysophosphatidylcholine (LPC). However, its implications for and/or its association with SLE disease, so far, have not been examined. In the present study, we analyzed the LPC serum concentrations of patients with SLE and rheumatoid arthritis (RA). Subsequently, we examined if and to which extent the measured serum concentrations of LPC and an LPC-rich environment can impact the phagocytosis of necrotic cells.Sera from patients with SLE, RA, and normal healthy donors (NHD) were characterized for several parameters, including LPC concentrations. Phagocytosis of dead cells by human macrophages in the presence of SLE and NHD sera was quantified. Additionally, the impact of exogenously added, purified LPC on phagocytosis was analyzed.Patients with SLE had significantly increased LPC serum levels, and high serum LPC of SLE patients correlated significantly with impaired phagocytosis of dead cells in the presence of heat-inactivated serum. Phagocytosis in the presence of sera from NHD showed no correlation to LPC levels, but exogenous addition of purified LPC in the range as measured in SLE patients' sera led to a concentration-dependent decrease.Our data show that high levels of LPC as observed in the sera of SLE patients have a negative impact on the clearance of dead cells by macrophages. Chemoattraction requires a concentration gradient. The higher the LPC concentration surrounding a dying or dead cell, the smaller the achievable gradient upon LPC release will be. Thus, it is feasible to assume that elevated LPC levels can interfere with the build-up of a local LPC gradient during cell death, and hence might play a role in the establishment and/or perpetuation of SLE disease.
EVALuna2:13530

Elevated serum lysophosphatidylcholine in patients with systemic lupus erythematosus impairs phagocytosis of necrotic cells in vitro - Grossmayer, Gerhard E.; Keppeler, Hildegard; Böltz, Sebastian; Janko, Christina; Rech, Jürgen; Herrmann, Martin; Lauber, Kirsten; Munoz, Luis Enrique (Frontiers in Immunology, 2018)
Keywords: Lysophosphatidylcholine; Necrotic cells; Clearance deficiency; Efferocytosis; Serum; Systemic lupus erythematosus; Phagocytosis; Rheumatoid arthritis

Emergency scrotal exploration in children: Following a change in mindset in the UK - Gopal, Milan; Thattaruparambil, Vinayak; McLaran, Pearly; Weisser, Swantje; Auth, Janina (Journal of Pediatric Urology, 2023)
A survey of 200 emergency scrotal explorations done over four paediatric surgical centres in the UK revealed that the incidence of finding testicular torsion (TT) was 24% and the preoperative utilisation of Doppler ultrasound (DUS) was 10% [1]. We changed our practice to include better preoperative utilisation of a clinical risk score (TWIST) and DUS. This led to a significant increase in the incidence of finding TT from 18% to 53%. Obtaining a DUS did not lead to an increase in our orchidectomy rate. Adopting this change is possible in an NHS setting and it has significant clinical and economic benefits.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Doppler ultrasound; Testicular torsion; TWIST; UK

EMG and heart rate responses decline within 5 days of daily whole-body vibration training with squatting - Rosenberger, Andre; Liphardt, Anna-Maria; Bargmann, Arne; Mueller, Klaus; Beck, Luis; Mester, Joachim; Zange, Jochen (PLoS ONE, 2014)
In this study, we examined the acute effects of a 5-day daily whole-body vibration (WBV) training on electromyography (EMG) responses of the m. rectus femoris and m. gastrocnemius lateralis, heart rate (HR, continuously recorded), and blood lactate levels. The purpose of the study was to investigate the adaptation of muscle activity, heart rate and blood lactate levels during 5 days of daily training. Two groups of healthy male subjects performed either squat exercises with vibration at 20 Hz on a side alternating platform (SE+V, n = 20, age = 31.9±7.5 yrs., height = 178.8±6.2 cm, body mass = 79.2±11.4 kg) or squat exercises alone (SE, n = 21, age = 28.4±7.3 years, height = 178.9±7.4 cm, body mass = 77.2±9.7 kg). On training day 1, EMG amplitudes of the m. rectus femoris were significantly higher (P<0.05) during SE+V than during SE. However, this difference was no longer statistically significant on training days 3 and 5. The heart rate (HR) response was significantly higher (P<0.05) during SE+V than during SE on all training days, but showed a constant decline throughout the training days. On training day 1, blood lactate increased significantly more after SE+V than after SE (P<0.05). On the following training days, this difference became much smaller but remained significantly different. The specific physiological responses to WBV were largest on the initial training day and most of them declined during subsequent training days, showing a rapid neuromuscular and cardiovascular adaptation to the vibration stimulus.
EVALuna2:13504

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

Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks - Ruhl, Louisa; Pink, Isabell; Kuehne, Jenny F.; Beushausen, Kerstin; Keil, Jana; Christoph, Stella; Sauer, Andrea; Boblitz, Lennart; Schmidt, Julius; David, Sascha; Jäck, Hans-Martin; Roth, Edith; et al. (Signal Transduction and Targeted Therapy, 2021)
The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.
CRIS-Team WoS Importer:2021-12-24

Endothelial dysfunction determines severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks - Ruhl, L.; Pink, I.; Kuehne, J. F.; Beushausen, K.; Keil, J.; Christoph, S.; Sauer, A.; Boblitz, L.; Schmidt, J.; David, S.; Jäck, Hans-Martin; Roth, Edith; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

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

Environmental arginine controls multinuclear giant cell metabolism and formation - Brunner, Julia S.; Vulliard, Loan; Hofmann, Melanie; Kieler, Markus; Lercher, Alexander; Vogel, Andrea; Russier, Marion; Brüggenthies, Johanna B.; Kerndl, Martina; Saferding, Victoria; Niederreiter, Birgit; Junza, Alexandra; et al. (Nature Communications, 2020)
Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
CRIS-Team Scopus Importer:2020-02-04

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.
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Epigenetic analysis of HIV-1 proviral genomes from infected individuals: predominance of unmethylated CpG's - Weber, Stefanie; Weiser, Barbara; Kemal, Kimdar S.; Burger, Harold; Ramirez, Christina M.; Korn, Klaus; Anastos, Kathryn; Kaul, Rupert; Kovacs, Colin; Dörfler, Walter (Virology, 2014)
Efforts to cure HIV-1 infections aim at eliminating proviral DNA. Integrated DNA from various viruses often becomes methylated de novo and transcriptionally inactivated. We therefore investigated CpG methylation profiles of 55 of 94 CpG's (58.5%) in HIV-1 proviral genomes including ten CpG's in each LTR and additional CpG's in portions of gag, env, nef, rev, and tat genes. We analyzed 33 DNA samples from PBMC's of 23 subjects representing a broad spectrum of HIV-1 disease. In 22 of 23 HIV-1-infected individuals, there were only unmethylated CpG's regardless of infection status. In one long term nonprogressor, however, methylation of proviral DNA varied between 0 and 75% over an 11-year period although the CD4+ counts remained stable. Hence levels of proviral DNA methylation can fluctuate. The preponderance of unmethylated CpG's suggests that proviral methylation is not a major factor in regulating HIV-1 proviral activity in PBMC's. Unmethylated CpG's may play a role in HIV-1 immunopathogenesis.
EVALuna2:8239

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)
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Epigenetic modifications in children associated with maternal emotional stress during pregnancy - Stonawski, Valeska; Frey, Silke; Golub, Yulia; Moll, Gunther; Heinrich, Hartmut; Eichler, Anna (Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie, 2018)
Besides typical physical and hormonal changes during pregnancy, this life period is often associated with an increased emotional and mental stress for women. For the child, the time in utero is regarded as a critical developmental period since adverse stimuli during pregnancy can have lasting consequences for the fetal and postnatal health and development. Thus, prenatal depression, anxiety and stress are considered as risk factors for developmental delay, emotional and behavioral problems. Epigenetic modifications, especially modifications in DNA methylation, are discussed as a possible biological mechanism that could explain the association between prenatal emotional stress and altered developmental and health outcomes of the child. This review summarizes evidence for DNA methylation changes related to prenatal emotional stress from studies with a candidate-gene approach as well as epigenome-wide association studies. Problematic issues are discussed and recommendations for future research are presented.
EVALuna2:36372

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: Diagnosis and treatment of adult-onset Still’s disease: a concise summary of the German society of rheumatology S2 guideline (Zeitschrift für Rheumatologie, (2022), 10.1007/s00393-022-01294-2) - Vordenbäumen, Stefan; Feist, Eugen; Rech, Jürgen; Fleck, Martin; Blank, Norbert; Haas, Johannes Peter; Kötter, Ina; Krusche, Martin; Chehab, Gamal; Hoyer, Bimba; Kiltz, Uta; Fell, Dorothea; et al. (Zeitschrift für Rheumatologie, 2023)
In the original version of the article, there is unfortunately an error in the legend to .Fig. 2. Please refer to the corrected version: We apologize for our oversight.
CRIS-Team Scopus Importer:2023-02-17

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

Essential control of early B-cell development by Mef2 transcription factors - Herglotz, Julia; Unrau, Ludmilla; Hauschildt, Friderike; Fischer, Meike; Kriebitzsch, Neele; Alawi, Malik; Indenbirken, Daniela; Spohn, Michael; Mueller, Ursula; Ziegler, Marion; Schuh, Wolfgang; Jäck, Hans-Martin; et al. (Blood, 2016)
The sequential activation of distinct developmental gene networks governs the ultimate identity of a cell, but the mechanisms involved in initiating downstream programs are incompletely understood. The pre-B-cell receptor (pre-BCR) is an important checkpoint of B-cell development and is essential for a pre-B cell to traverse into an immature B cell. Here, we show that activation of myocyte enhancer factor 2 (Mef2) transcription factors (TFs) by the pre-BCR is necessary for initiating the subsequent genetic network. We demonstrate that B-cell development is blocked at the pre-B-cell stage in mice deficient for Mef2c and Mef2d TFs and that pre-BCR signaling enhances the transcriptional activity of Mef2c/d through phosphorylation by the Erk5 mitogen-activating kinase. This activation is instrumental in inducing Krüppel-like factor 2 and several immediate early genes of the AP1 and Egr family. Finally, we show that Mef2 proteins cooperate with the products of their target genes (Irf4 and Egr2) to induce secondary waves of transcriptional regulation. Our findings uncover a novel role for Mef2c/d in coordinating the transcriptional network that promotes early B-cell development.
EVALuna2:13638

Essential respiratory chain subunits encoded by mitochondrial DNA control plasma cell development - Urbanczyk, Sophia; Baris, Olivier; Mougiakakos, Dimitrios; Wiesner, Rudolf; Jäck, Hans-Martin; Mielenz, Dirk (JOURNAL OF IMMUNOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-08

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.
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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; Tascilar, Koray (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 an ACE2-Independent Entry Pathway That Can Protect from Neutralization by an Antibody Used for COVID-19 Therapy - Hoffmann, Markus; Sidarovich, Anzhalika; Arora, Prerna; Krueger, Nadine; Nehlmeier, Inga; Kempf, Amy; Graichen, Luise; Winkler, Martin S.; Niemeyer, Daniela; Goffinet, Christine; Drosten, Christian; Schulz, Sebastian; et al. (Mbio, 2022)
The interaction of the SARS-CoV-2 spike protein (S) with the cellular receptor ACE2 is considered essential for infection and constitutes the key target for antibodies induced upon infection and vaccination. Here, using a surrogate system for viral entry, we provide evidence that a naturally occurring mutation can liberate SARS-CoV-2 from ACE2-dependence and that ACE2-independent entry may protect the virus from neutralization by an antibody used for COVID-19 therapy.
CRIS-Team WoS Importer:2022-05-13

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.
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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-analytical approach to assessing mechanosensitive cartilage blood marker kinetics in healthy adults: Dose-response relationship and interrelationship of nine candidate markers - Mündermann, Annegret; Herger, Simon; Vach, Werner; Liphardt, Anna-Maria; Nüesch, Corina; Egloff, Christian (F1000Research, 2022)
Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load. Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II). Results. COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6. Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Cartilage biomarkers; Cartilage mechanosensitivity; Dose-response relationship; Mechanical loading; Walking stress test

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 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.
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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

Expression of Membrane-Bound CC Chemokine Ligand 20 on Follicular T Helper Cells in T-B-Cell Conjugates - Lee, Adrian Y. S.; Reimer, Dorothea; Zehrer, Annette; Lu, Ming; Mielenz, Dirk; Korner, Heinrich (Frontiers in Immunology, 2017)
The CC chemokine receptor 6 (CCR6) and its sole chemokine ligand CC chemokine ligand 20 (CCL20) display an emerging role in the coordination of humoral immune responses. Recent studies demonstrate a role of this chemokine axis in the migration of B cells to key immunological sites during an immune response, and facilitating the generation of high-quality antibodies. Very little, however, is known about CCL20 and its role in these functions. We undertook a preliminary investigation into the expression and function of CCL20 and demonstrate its well-noted upregulation in the spleen during immunization. Furthermore, we show that most follicular T helper (Tfh) cells can be CCR6+ and can produce CCL20. Surprisingly, CCL20 cannot only be found in the cytoplasm but also on the surface of these cells and their precursors. Analysis of T-B-cell conjugates revealed that mature Tfh cells, but not their precursors, are highly enriched in the conjugates. Further functional studies are needed to unravel the precise role of CCL20 in coordinating T and B cell interactions during the humoral immune response.
EVALuna2:36044

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

Facharztweiterbildung quo vadis? - Krusche, M.; Sewerin, P.; Kleyer, Arnd; Mucke, J.; Vossen, D.; Morf, H. (Zeitschrift für Rheumatologie, 2019)
Background: In May 2018 a revision of the training regulations for German doctors (MWBO) was passed which will significantly impact the medical training for German rheumatologists. The goal of this paper was to create an overview of the status quo in advanced medical training in this field. Methods: A quantitative and qualitative analysis was conducted to identify the strengths and weaknesses of the current continuous education in the field of rheumatology in Germany. The number of newly trained specialists in rheumatology in the years 2015 to 2017 was determined from the regional medical associations. Furthermore, an online survey assessing the training conditions of assistant physicians was conducted. 71 physicians participated in the nationwide survey. Results: In 2015 (53 specialists), in 2016 (43 specialists) and in 2017 (43 specialists) completed their training in the field of rheumatology. The online survey of assistant physicians found that the medical training was graded 3.1 on a scale of 1 to 6 (SD ± 1.1). 19.4% of respondents reported that they had regular mentoring, and 41.7% had on-the-job evaluations. Deficits were evident concerning practical diagnostic skills: 22.8% of the physicians were not practicing joint ultrasonography and another 20% performed it only once a month. As points of criticism 46.6% mentioned a missing structure in training programme and 33.3% noted a lack of supervision. The majority of respondents wanted more training options, supervision and better practical training in ultrasound diagnostics. Conclusion: The nationwide number of newly acquired specialist qualifications (between 2015 and 2017) showed a decreasing trend. It is to be feared that the numbers will continue to stagnate, which increases the importance to invest further in medical education. The online survey also showed that the current medical training in Germany has deficits. Here, the new MWBO could create better guidelines for a structured training, which should be guided by the principle of “Teach to Target”.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Advanced training; Investigation techniques; Model continuing training regulations; Specialist numbers; Teach to target

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

Factors Associated With Telemedicine Use Among German General Practitioners and Rheumatologists: Secondary Analysis of Data From a Nationwide Survey. - Muehlensiepen, Felix; Petit, Pascal; Knitza, Johannes; Welcker, Martin; Vuillerme, Nicolas (Journal of Medical Internet Research, 2022)
BACKGROUND: Previous studies have demonstrated telemedicine (TM) to be an effective tool to complement rheumatology care and address workforce shortage. With the outbreak of the SARS-CoV-2 pandemic, TM experienced a massive upswing. However, in rheumatology care, the use of TM stagnated again shortly thereafter. Consequently, the factors associated with physicians' willingness to use TM (TM willingness) and actual use of TM (TM use) need to be thoroughly investigated. OBJECTIVE: This study aimed to identify the factors that determine TM use and TM willingness among German general practitioners and rheumatologists. METHODS: We conducted a secondary analysis of data from a German nationwide cross-sectional survey with general practitioners and rheumatologists. Bayesian univariate and multivariate logistic regression analyses were applied to the data to determine which factors were associated with TM use and TM willingness. The predictor variables (covariates) that were studied individually included sociodemographic factors (eg, age and sex), work characteristics (eg, practice location and medical specialty), and self-assessed knowledge of TM. All the variables positively and negatively associated with TM use and TM willingness in the univariate analysis were then considered for Bayesian model averaging analysis after a selection based on the variance inflation factor (≤2.5). All analyses were stratified by sex. RESULTS: Univariate analysis revealed that out of 83 variables, 36 (43%) and 34 (41%) variables were positively or negatively associated (region of practical equivalence≤5%) with TM use and TM willingness, respectively. The Bayesian model averaging analysis allowed us to identify 13 and 17 factors of TM use and TM willingness, respectively. Among these factors, being female, having very poor knowledge of TM, treating <500 patients per quarter, and not being willing to use TM were negatively associated with TM use, whereas having good knowledge of TM and treating >1000 patients per quarter were positively associated with TM use. In addition, being aged 51 to 60 years, thinking that TM is not important for current and future work, and not currently using TM were negatively associated with TM willingness, whereas owning a smart device and working in an urban area were positively associated with TM willingness. CONCLUSIONS: The results point to the close connection between health care professionals' knowledge of TM and actual TM use. These results lend support to the integration of digital competencies into medical education as well as hands-on training for health care professionals. Incentive programs for physicians aged >50 years and practicing in rural areas could further encourage TM willingness.
EVALuna2:521237

Factors Associated With Telemedicine Use Among Patients With Rheumatic and Musculoskeletal Disease: Secondary Analysis of Data From a German Nationwide Survey. - Muehlensiepen, Felix; Petit, Pascal; Knitza, Johannes; Welcker, Martin; Vuillerme, Nicolas (Journal of Medical Internet Research, 2023)
BACKGROUND: Previous studies have demonstrated telemedicine (TM) to be an effective tool to complement rheumatology care and address workforce shortage. With the outbreak of the COVID-19 pandemic, TM experienced a massive upswing. A previous study revealed that physicians' willingness to use TM and actual use of TM are closely connected to their knowledge of TM. However, it remains unclear which factors are associated with patients' motivation to use TM. OBJECTIVE: This study aims to identify the factors that determine patients' willingness to try TM (TM try) and their wish that their rheumatologists offer TM services (TM wish). METHODS: We conducted a secondary analysis of data from a German nationwide cross-sectional survey among patients with rheumatic and musculoskeletal disease (RMD). Bayesian univariate and multivariate logistic regression analyses were applied to the data to determine which factors were associated with TM try and TM wish. The predictor variables (covariates) studied individually included sociodemographic factors (eg, age and sex) and health characteristics (eg, disease type and health status). All the variables positively or negatively associated with TM try or TM wish in the univariate analyses were then considered for the Bayesian model averaging analysis after a selection based on the variance inflation factor (≤2.5). All the analyses were stratified by sex. RESULTS: Of the total 102 variables, 59 (57.8%) and 45 (44.1%) variables were found to be positively or negatively associated (region of practical equivalence ≤5%) with TM try and TM wish, respectively. A total of 16 and 8 determinant factors were identified for TM try and TM wish, respectively. Wishing that TM services were offered by rheumatologists, having internet access at home, residing 5 to 10 km away from the general practitioner's office, owning an electronic device, and being aged 40 to 60 years were among the factors positively associated with TM try and TM wish. By contrast, not yet being diagnosed with an RMD, having no prior knowledge of TM, having a bad health status, living in a rural area, not documenting one's health status, not owning an electronic device, and being aged 60 to 80 years were negatively associated with TM try and TM wish. CONCLUSIONS: Our results suggest that health status, knowledge, age, and access to technical equipment and infrastructure influence the motivation of patients with RMD to use telehealth services. In particular, older patients with RMD living in rural areas, who could likely benefit from using TM, are currently not motivated to use TM and seem to need additional TM support.
EVALuna2:521253

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.

FcγRIIa genotype is associated with acute coronary syndromes as first manifestation of coronary artery disease - Raaz, Dorette; Herrmann, Martin; Ekici, Arif Bülent; Klinghammer, Lutz; Lausen, Berthold; Voll, Reinhard E.; Leusen, Jeanette H.W.; van de Winkel, Jan G.J.; Daniel, Werner; Reis, André; Garlichs, Christoph (Atherosclerosis, 2009)
Objective: Identification of clinically relevant determinants for acute coronary syndromes (ACS) promises reduction of ACS-associated mortality. C-reactive protein (CRP) has proved to be useful identifying people at risk for cardiovascular events. However, it is unknown whether genetic variants at Fcγ receptor IIa (FcγRIIa), the main receptor for CRP, are involved in CRP-related cardiovascular risk. We evaluated the potential impact of FcγRIIa through a genetic association study in patients with ACS. Methods and results: We conducted a genetic association study among 701 consecutive patients with first event of ACS compared to 467 patients with stable angina pectoris. All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa, where the arginine (R) allele results in an increased signal transduction upon CRP binding. In our study, the R/R131 genotype was significantly associated with ACS as the first manifestation of coronary artery disease (P = 1.2 × 10-9, odds ratio 2.86, 95% CI: 2.06-3.99) compared to the non-R/R131 genotype. Conclusions: Our data show a genetic association of the FcγRIIa R/R131 genotype with a more frequent occurrence of ACS as the first manifestation of coronary artery disease, probably mediated via its interaction with CRP. Genotyping of this FcγRIIa variant could help to improve risk stratification in the course of coronary disease in the future. © 2009 Elsevier Ireland Ltd. All rights reserved.
CRIS-Team Scopus Importer:2023-07-10
Keywords: Acute coronary syndrome; Fcγ receptor IIa; Gene polymorphism; Inflammation

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)

Female Psoriatic Arthritis Patients Show Differences in Treatment Response to IL12/23 Inhibition in Combination with or Without MTX Compared to Male - Results from a Multicenter Investigator-initiated Randomized Placebo-controlled Clinical Trial - Koehm, Michaela; Foldenauer, Ann Christina; Rossmanith, Tanja; Kellner, Herbert; Kiltz, Uta; Rech, Jürgen; Burmester, Gerd; Kofler, David; Brandt-Juergens, Jan; Finzel, Stephanie; Bergner, Raoul; Sieburg, Maren; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

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

Flares after COVID-19 infection in patients with idiopathic inflammatory myopathies: results from the COVAD study - Ali, Sasha Saadia; Naveen, R.; Sen, Parikshit; Day, Jessica; Joshi, Mrudula; Nune, Arvind; Nikiphorou, Elena; Saha, Sreoshy; Tan, Ai Lyn; Shinjo, Samuel Katsuyuki; Ziade, Nelly; Velikova, Tsvetelina; et al. (Rheumatology, 2023)
CRIS-Team WoS Importer:2023-05-05

Flares in autoimmune rheumatic diseases in the post-COVID-19 vaccination period-a cross-sequential study based on COVAD surveys - Jagtap, Kshitij; Naveen, R.; Day, Jessica; Sen, Parikshit; Vaidya, Binit; Nune, Arvind; Nikiphorou, Elena; Tan, Ai Lyn; Agarwal, Vishwesh; Saha, Sreoshy; Shinjo, Samuel Katsuyuki; Ziade, Nelly; et al. (Rheumatology, 2023)
OBJECTIVE: Flares of autoimmune rheumatic diseases (AIRDs) following COVID-19 vaccination are a particular concern in vaccine-hesitant individuals. Therefore, we investigated the incidence, predictors and patterns of flares following vaccination in individuals living with AIRDs, using global COVID-19 Vaccination in Autoimmune Diseases (COVAD) surveys. METHODS: The COVAD surveys were used to extract data on flare demographics, comorbidities, COVID-19 history, and vaccination details for patients with AIRDs. Flares following vaccination were identified as patient-reported (a), increased immunosuppression (b), clinical exacerbations (c) and worsening of PROMIS scores (d). We studied flare characteristics and used regression models to differentiate flares among various AIRDs. RESULTS: Of 15 165 total responses, the incidence of flares in 3453 patients with AIRDs was 11.3%, 14.8%, 9.5% and 26.7% by definitions a-d, respectively. There was moderate agreement between patient-reported and immunosuppression-defined flares (K = 0.403, P = 0.022). Arthritis (61.6%) and fatigue (58.8%) were the most commonly reported symptoms. Self-reported flares were associated with higher comorbidities (P = 0.013), mental health disorders (MHDs) (P < 0.001) and autoimmune disease multimorbidity (AIDm) (P < 0.001).In regression analysis, the presence of AIDm [odds ratio (OR) = 1.4; 95% CI: 1.1, 1.7; P = 0.003), or a MHD (OR = 1.7; 95% CI: 1.1, 2.6; P = 0.007), or being a Moderna vaccine recipient (OR = 1.5; 95% CI: 1.09, 2.2; P = 0.014) were predictors of flares. Use of MMF (OR = 0.5; 95% CI: 0.3, 0.8; P = 0.009) and glucocorticoids (OR = 0.6; 95% CI: 0.5, 0.8; P = 0.003) were protective.A higher frequency of patients with AIRDs reported overall active disease post-vaccination compared with before vaccination (OR = 1.3; 95% CI: 1.1, 1.5; P < 0.001). CONCLUSION: Flares occur in nearly 1 in 10 individuals with AIRDs after COVID vaccination; people with comorbidities (especially AIDm), MHDs and those receiving the Moderna vaccine are particularly vulnerable. Future avenues include exploring flare profiles and optimizing vaccine strategies for this group.
CRIS-Team Scopus Importer:2023-12-15
Keywords: autoimmunity; COVID-19; flares; rheumatic; vaccination; vaccination hesitancy

Flares of autoimmune rheumatic disease following COVID-19 infection: Observations from the COVAD study - Sandhu, Nimrat Kaur; Ravichandraan, Naveen; Nune, Arvind; Day, Jessica; Sen, Parikshit; Nikiphorou, Elena; Tan, Ai Lyn; Joshi, Mrudula; Saha, Sreoshy; Shinjo, Samuel Katsuyuki; Jagtap, Kshitij; Agarwal, Vishwesh; et al. (International Journal of Rheumatic Diseases, 2023)
CRIS-Team Scopus Importer:2023-12-01

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

Formation and Clearance of NETs in Health and Disease. - Knopf, Jasmin; Mahajan, Aparna; Munoz, Luis Enrique; Herrmann, Martin (Cells, 2022)
Neutrophils are the most abundant innate immune cells in humans and the first line of defense against invading pathogens [...].
EVALuna2:521519

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

Four-and-a-Half LIM-Domain Protein 2 (FHL2) Induces Neuropeptide Y (NPY) in Macrophages in Visceral Adipose Tissue and Promotes Diet-Induced Obesity - Sommer, Judith; Ehnis, Hanna; Seitz, Tatjana; Schneider, Julia; Wild, Andreas; Moceri, Sandra; Buechler, Christa; Bozec, Aline; Weber, Georg; Merkel, Susanne; Beckervordersandforth, Ruth; Steinkasserer, Alexander; et al. (International Journal of Molecular Sciences, 2023)
Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage–adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adipocytes; FHL2; macrophages; MCP-1; NPY; obesity; thermogenesis

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.
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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)
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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)
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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.
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FRAMEWORK FOR MODULATING AMBULATORY LOAD IN THE CONTEXT OF IN VIVO MECHANOSENSITIVITY OF ARTICULAR CARTILAGE - Muendermann, A.; Herger, S.; Liphardt, Anna-Maria; Vach, W.; Egloff, C.; Nueesch, C. (OSTEOARTHRITIS AND CARTILAGE, 2020)
CRIS-Team WoS Importer:2020-06-02

Free Fatty Acids in Bone Pathophysiology of Rheumatic Diseases - Frommer, Klaus W.; Hasseli, Rebecca; Schaeffler, Andreas; Lange, Uwe; Rehart, Stefan; Steinmeyer, Juergen; Rickert, Markus; Sarter, Kerstin; Zaiss, Mario; Culmsee, Carsten; Ganjam, Goutham; Michels, Susanne; et al. (Frontiers in Immunology, 2019)
Obesity-in which free fatty acid (FFA) levels are chronically elevated-is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene alpha, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and beta-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.
CRIS-Team WoS Importer:2020-01-03

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)
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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)
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