Dr. Alina Ramming, (geb. Soare)

@article{pmid38396288,

title = {CD200 fibroblasts form a pro-resolving mesenchymal network in arthritis},

author = {Simon Rauber and Hashem Mohammadian and Christian Schmidkonz and Armin Atzinger and Alina Soare and Christoph Treutlein and Samuel Kemble and Christopher B Mahony and Manuel Geisthoff and Mario R Angeli and Maria G Raimondo and Cong Xu and Kai-Ting Yang and Le Lu and Hannah Labinsky and Mina S A Saad and Charles A Gwellem and Jiyang Chang and Kaiyue Huang and Eleni Kampylafka and Johannes Knitza and Rostyslav Bilyy and Jörg H W Distler and Megan M Hanlon and Ursula Fearon and Douglas J Veale and Frank W Roemer and Tobias Bäuerle and Hans M Maric and Simone Maschauer and Arif B Ekici and Christopher D Buckley and Adam P Croft and Torsten Kuwert and Olaf Prante and Juan D Cañete and Georg Schett and Andreas Ramming},

doi = {10.1038/s41590-024-01774-4},

issn = {1529-2916},

year  = {2024},

date = {2024-04-01},

journal = {Nat Immunol},

volume = {25},

number = {4},

pages = {682–692},

abstract = {Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3/IL6 fibroblasts (high FAP internalization) to pro-resolving CD200DKK3 fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200DKK3 fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3/IL6 fibroblasts colocalize with inflammatory immune cells. CD200DKK3 fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200-CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35459697,

title = {Concise report: a minimal-invasive method to retrieve and identify entheseal tissue from psoriatic arthritis patients},

author = {Milena L Pachowsky and Maria Gabriella Raimondo and Cong Xu and Simon Rauber and Koray Tascilar and Hannah Labinsky and Mario Vogg and Mina Saad Aziz Saad and David Simon and Juergen Rech and Alina Soare and Lars Braeuer and Arnd Kleyer and Georg Schett and Andreas Ramming},

doi = {10.1136/annrheumdis-2021-222061},

issn = {1468-2060},

year  = {2022},

date = {2022-08-01},

journal = {Ann Rheum Dis},

volume = {81},

number = {8},

pages = {1131–1135},

abstract = {OBJECTIVES: To establish a minimally invasive biopsy technique for the analysis of entheseal tissue in patients with psoriatic arthritis (PsA). 

METHODS: Human cadavers were used for establishing the technique to retrieve tissue from the lateral humeral epicondyle enthesis (cadaveric biopsies). After biopsy, the entire enthesis was surgically resected (cadaveric resections). Biopsies and resections were assessed by label-free second harmonic generation (SHG) microscopy. The same technique was then applied in patients with PsA with definition of entheseal tissue by SHG, staining of CD45+immune cells and RNA extraction. 

RESULTS: Entheseal biopsies from five cadavers allowed the retrieval of entheseal tissue as validated by the analysis of resection material. Microscopy of biopsy and resection sections allowed differentiation of entheseal, tendon and muscle tissue by SHG and definition of specific intensity thresholds for entheseal tissue. In subsequent entheseal biopsies of 10 PsA patients: the fraction of entheseal tissue was high (65%) and comparable to cadaveric biopsies (68%) as assessed by SHG microscopy. Furthermore, PsA biopsies showed immune cell infiltration and sufficient retrieval of RNA for further molecular analysis. 

CONCLUSION: Entheseal biopsy of the lateral epicondyle is feasible in patients with PsA allowing reliable retrieval of entheseal tissue and its identification by SHG microscopy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34285225,

title = {TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy},

author = {Ariella Zehender and Yi-Nan Li and Neng-Yu Lin and Adrian Stefanica and Julian Nüchel and Chih-Wei Chen and Hsiao-Han Hsu and Honglin Zhu and Xiao Ding and Jingang Huang and Lichong Shen and Andrea-Hermina Györfi and Alina Soare and Simon Rauber and Christina Bergmann and Andreas Ramming and Markus Plomann and Beate Eckes and Georg Schett and Jörg H W Distler},

doi = {10.1038/s41467-021-24601-y},

issn = {2041-1723},

year  = {2021},

date = {2021-07-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {4404},

abstract = {Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38279381,

title = {Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study},

author = {Christina Bergmann and Jörg H W Distler and Christoph Treutlein and Koray Tascilar and Anna-Theresa Müller and Armin Atzinger and Alexandru-Emil Matei and Johannes Knitza and Andrea-Hermina Györfi and Anja Lück and Clara Dees and Alina Soare and Andreas Ramming and Verena Schönau and Oliver Distler and Olaf Prante and Philipp Ritt and Theresa Ida Götz and Markus Köhner and Michael Cordes and Tobias Bäuerle and Torsten Kuwert and Georg Schett and Christian Schmidkonz},

doi = {10.1016/S2665-9913(20)30421-5},

issn = {2665-9913},

year  = {2021},

date = {2021-03-01},

journal = {Lancet Rheumatol},

volume = {3},

number = {3},

pages = {e185–e194},

abstract = {BACKGROUND: Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a Ga-labelled selective inhibitor of prolyl endopeptidase FAP (Ga-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. 

METHODS: Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent Ga-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline Ga-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of Ga-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6-10 months) to assess change over time. 

FINDINGS: Ga-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0·80 (IQR 0·60-2·10) in the systemic sclerosis-ILD group and 0·50 (0·40-0·50) in the control group (p<0·0001) and a mean whole lung maximal SUV of 4·40 (range 3·05-5·20) in the systemic sclerosis-ILD group compared with 0·70 (0·65-0·70) in the control group (p<0·0001). Whole-lung FAPI metabolic active volume (wlFAPI-MAV) and whole-lung total lesion FAPI (wlTL-FAPI) were not measurable in control participants, because no Ga-FAPI-04 uptake above background level was observed. In the systemic sclerosis-ILD group the median wlFAPI-MAV was 254·00 cm (IQR 163·40-442·30), and the median wlTL-FAPI was 183·60 cm (98·04-960·70). Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression, or high EUSTAR activity scores than in those with with limited disease, previously stable ILD, or low EUSTAR activity scores. Increased Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive Ga-FAPI-04 PET-CTs, changes in Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic drug nintedanib. 

INTERPRETATION: Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that Ga-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. 

FUNDING: German Research Foundation, Erlangen Anschubs-und Nachwuchsfinanzierung, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, Deutsche Stiftung Systemische Sklerose, Wilhelm-Sander-Foundation, Else-Kröner-Fresenius-Foundation, European Research Council, Ernst-Jung-Foundation, and Clinician Scientist Program Erlangen.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{RN9671,

title = {Accuracy, patient-perceived usability, and acceptance of two symptom checkers (Ada and Rheport) in rheumatology: interim results from a randomized controlled crossover trial},

author = {J. Knitza and J. Mohn and C. Bergmann and E. Kampylafka and M. Hagen and D. Bohr and H. Morf and E. Araujo and M. Englbrecht and D. Simon and A. Kleyer and T. Meinderink and W. Vorbruggen and C. B. Decken and S. Kleinert and A. Ramming and J. H. W. Distler and N. Vuillerme and A. Fricker and P. Bartz-Bazzanella and G. Schett and A. J. Hueber and M. Welcker},

url = {https://www.ncbi.nlm.nih.gov/pubmed/33849654 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042673/pdf/13075_2021_Article_2498.pdf},

doi = {10.1186/s13075-021-02498-8},

issn = {1478-6362 (Electronic) 

1478-6354 (Linking)},

year  = {2021},

date = {2021-01-01},

journal = {Arthritis Res Ther},

volume = {23},

number = {1},

pages = {112},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{RN9669,

title = {SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases},

author = {D. Simon and K. Tascilar and F. Fagni and G. Kronke and A. Kleyer and C. Meder and R. Atreya and M. Leppkes and A. E. Kremer and A. Ramming and M. L. Pachowsky and F. Schuch and M. Ronneberger and S. Kleinert and A. J. Hueber and K. Manger and B. Manger and C. Berking and M. Sticherling and M. F. Neurath and G. Schett},

url = {https://www.ncbi.nlm.nih.gov/pubmed/33958324},

doi = {10.1136/annrheumdis-2021-220461},

issn = {1468-2060 (Electronic) 

0003-4967 (Linking)},

year  = {2021},

date = {2021-01-01},

journal = {Ann Rheum Dis},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32719042,

title = {Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging},

author = {Christian Schmidkonz and Simon Rauber and Armin Atzinger and Rahul Agarwal and Theresa Ida Götz and Alina Soare and Michael Cordes and Olaf Prante and Christina Bergmann and Arnd Kleyer and Philipp Ritt and Simone Maschauer and Peter Hennig and Johannes Toms and Markus Köhner and Bernhard Manger and John H Stone and Uwe Haberkorn and Tobias Baeuerle and Jörg H W Distler and Abbas Agaimy and Torsten Kuwert and Georg Schett and Andreas Ramming},

doi = {10.1136/annrheumdis-2020-217408},

issn = {1468-2060},

year  = {2020},

date = {2020-11-01},

journal = {Ann Rheum Dis},

volume = {79},

number = {11},

pages = {1485–1491},

abstract = {OBJECTIVES: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG-related disease. 

METHODS: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; Ga-FAP inhibitor (FAPI)-04), F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, F-FDG and Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. 

RESULTS: Using combination of Ga-FAPI-04 and F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG cells in histology, while Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. 

CONCLUSION: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32998972,

title = {Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis},

author = {Debomita Chakraborty and Honglin Zhu and Astrid Jüngel and Lena Summa and Yi-Nan Li and Alexandru-Emil Matei and Xiang Zhou and Jingang Huang and Thuong Trinh-Minh and Chih-Wei Chen and Robert Lafyatis and Clara Dees and Christina Bergmann and Alina Soare and Hui Luo and Andreas Ramming and Georg Schett and Oliver Distler and Jörg H W Distler},

doi = {10.1126/scitranslmed.aaz5506},

issn = {1946-6242},

year  = {2020},

date = {2020-09-01},

journal = {Sci Transl Med},

volume = {12},

number = {563},

abstract = {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 β 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32182396,

title = {Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis},

author = {Yun Zhang and Honglin Zhu and Florian Layritz and Hui Luo and Thomas Wohlfahrt and Chih-Wei Chen and Alina Soare and Christina Bergmann and Andreas Ramming and Florian Groeber and Christian Reuter and GianFranco Fornasini and Nadejda Soukhareva and Brian Schreiber and Santosh Ramamurthy and Kerstin Amann and Georg Schett and Jörg H W Distler},

doi = {10.1002/art.41259},

issn = {2326-5205},

year  = {2020},

date = {2020-08-01},

journal = {Arthritis Rheumatol},

volume = {72},

number = {8},

pages = {1385–1395},

abstract = {OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. 

METHODS: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2 ) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model. RESULTS: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice. 

CONCLUSION: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31350829,

title = {Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis},

author = {Alina Soare and Hermina A Györfi and Alexandru E Matei and Clara Dees and Simon Rauber and Thomas Wohlfahrt and Chih-Wei Chen and Ingo Ludolph and Raymund E Horch and Tobias Bäuerle and Stephan Hörsten and Carina Mihai and Oliver Distler and Andreas Ramming and Georg Schett and Jörg H W Distler},

doi = {10.1002/art.41058},

issn = {2326-5205},

year  = {2020},

date = {2020-01-01},

journal = {Arthritis Rheumatol},

volume = {72},

number = {1},

pages = {137–149},

abstract = {OBJECTIVE: Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). METHODS: Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). 

RESULTS: The expression of DPP-4 and the number of DPP-4-positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)-dependent manner. DPP-4-positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. 

CONCLUSION: DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{RN9673,

title = {Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion},

author = {D. Simon and K. Tascilar and G. Kronke and A. Kleyer and M. M. Zaiss and F. Heppt and C. Meder and R. Atreya and E. Klenske and P. Dietrich and A. Abdullah and T. Kliem and G. Corte and H. Morf and M. Leppkes and A. E. Kremer and A. Ramming and M. Pachowsky and F. Schuch and M. Ronneberger and S. Kleinert and C. Maier and A. J. Hueber and K. Manger and B. Manger and C. Berking and M. Tenbusch and K. Uberla and M. Sticherling and M. F. Neurath and G. Schett},

url = {https://www.ncbi.nlm.nih.gov/pubmed/32709909},

doi = {10.1038/s41467-020-17703-6},

issn = {2041-1723 (Electronic) 

2041-1723 (Linking)},

year  = {2020},

date = {2020-01-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {3774},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30700907,

title = {PU.1 controls fibroblast polarization and tissue fibrosis},

author = {Thomas Wohlfahrt and Simon Rauber and Steffen Uebe and Markus Luber and Alina Soare and Arif Ekici and Stefanie Weber and Alexandru-Emil Matei and Chih-Wei Chen and Christiane Maier and Emmanuel Karouzakis and Hans P Kiener and Elena Pachera and Clara Dees and Christian Beyer and Christoph Daniel and Kolja Gelse and Andreas E Kremer and Elisabeth Naschberger and Michael Stürzl and Falk Butter and Michael Sticherling and Susetta Finotto and Alexander Kreuter and Mark H Kaplan and Astrid Jüngel and Steffen Gay and Stephen L Nutt and David W Boykin and Gregory M K Poon and Oliver Distler and Georg Schett and Jörg H W Distler and Andreas Ramming},

doi = {10.1038/s41586-019-0896-x},

issn = {1476-4687},

year  = {2019},

date = {2019-02-01},

journal = {Nature},

volume = {566},

number = {7744},

pages = {344–349},

abstract = {Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29311148,

title = {Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators},

author = {Alexandru-Emil Matei and Christian Beyer and Andrea-Hermina Györfi and Alina Soare and Chih-Wei Chen and Clara Dees and Christina Bergmann and Andreas Ramming and Andreas Friebe and Franz Hofmann and Oliver Distler and Georg Schett and Jörg H W Distler},

doi = {10.1136/annrheumdis-2017-212489},

issn = {1468-2060},

year  = {2018},

date = {2018-03-01},

journal = {Ann Rheum Dis},

volume = {77},

number = {3},

pages = {459},

abstract = {OBJECTIVES: Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc. 

METHODS: Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823. 

RESULTS: PKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice. 

CONCLUSIONS: Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{soare2018homeostasis,

title = {Cutting edge: Homeostasis of innate lymphoid cells is imbalanced in psoriatic arthritis},

author = {A Soare and S Weber and L Maul and S Rauber and A. M Gheorghiu and M Luber and I Houssni and A Kleyer and G Pickardt and M Gado and D Simon and J Rech and G Schett and H. W Distler and A Ramming},

doi = {10.4049/jimmunol.1700596},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Immunology},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28814429,

title = {Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis},

author = {Jingang Huang and Christiane Maier and Yun Zhang and Alina Soare and Clara Dees and Christian Beyer and Ulrike Harre and Chih-Wei Chen and Oliver Distler and Georg Schett and Lutz Wollin and Jörg H W Distler},

doi = {10.1136/annrheumdis-2016-210823},

issn = {1468-2060},

year  = {2017},

date = {2017-11-01},

journal = {Ann Rheum Dis},

volume = {76},

number = {11},

pages = {1941–1948},

abstract = {BACKGROUND: Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc). 

METHODS: The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation. 

RESULTS: Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages. 

CONCLUSION: Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28714991,

title = {Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells},

author = {Simon Rauber and Markus Luber and Stefanie Weber and Lisa Maul and Alina Soare and Thomas Wohlfahrt and Neng-Yu Lin and Katharina Dietel and Aline Bozec and Martin Herrmann and Mark H Kaplan and Benno Weigmann and Mario M Zaiss and Ursula Fearon and Douglas J Veale and Juan D Cañete and Oliver Distler and Felice Rivellese and Costantino Pitzalis and Markus F Neurath and Andrew N J McKenzie and Stefan Wirtz and Georg Schett and Jörg H W Distler and Andreas Ramming},

doi = {10.1038/nm.4373},

issn = {1546-170X},

year  = {2017},

date = {2017-08-01},

journal = {Nat Med},

volume = {23},

number = {8},

pages = {938–944},

abstract = {Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (T) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent T activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9 ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27113414,

title = {Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis},

author = {Katrin Palumbo-Zerr and Alina Soare and Pawel Zerr and Andrea Liebl and Rossella Mancuso and Michal Tomcik and Barbora Sumova and Clara Dees and Chih-Wei Chen and Thomas Wohlfahrt and Tatjana Mallano and Alfiya Distler and Andreas Ramming and Kolja Gelse and Carina Mihai and Oliver Distler and Georg Schett and Jörg H W Distler},

doi = {10.1136/annrheumdis-2015-208470},

issn = {1468-2060},

year  = {2017},

date = {2017-01-01},

journal = {Ann Rheum Dis},

volume = {76},

number = {1},

pages = {244–251},

abstract = {OBJECTIVES: TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc). 

METHODS: The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)β receptor I. 

RESULT: The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGFβ/SMAD3-dependent manner. TWIST1 in turn enhanced TGFβ-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGFβ promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1. 

CONCLUSIONS: Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGFβ signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGFβ signalling in SSc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{soare2017tuberculosis,

title = {Risk of active tuberculosis in patients with inflammatory arthritis receiving TNF inhibitors: a look beyond the baseline tuberculosis screening protocol},

author = {A Soare and A. M Gheorghiu and V Arama and D Bumbacea and R Dobrota and R Oneata and S Pintilie and M Milicescu and I Ancuta and A Martin and M Sasu and C Ciofu and L Macovei and V Stoica and M Bojinca and C Mihai},

doi = {10.1007/s10067-017-3916-y},

year  = {2017},

date = {2017-01-01},

journal = {Clinical Rheumatology},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25817717,

title = {Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies},

author = {Clara Dees and Christian Beyer and Alfiya Distler and Alina Soare and Yun Zhang and Katrin Palumbo-Zerr and Oliver Distler and Georg Schett and Peter Sandner and Jörg H W Distler},

doi = {10.1136/annrheumdis-2014-206809},

issn = {1468-2060},

year  = {2015},

date = {2015-08-01},

journal = {Ann Rheum Dis},

volume = {74},

number = {8},

pages = {1621–1625},

abstract = {OBJECTIVES: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate. 

METHODS: The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used. 

RESULT: Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat. 

CONCLUSIONS: These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{soare2015scleroderma,

title = {Patients with systemic sclerosis associating other autoimmune diseases have a milder disease course},

author = {A Soare and S Pintilie and A. M Gherghe and A Radu and R Dobrota and M Sasu and M Bojinca and V Stoica and C Mihai},

year  = {2015},

date = {2015-01-01},

journal = {Romanian Journal of Rheumatology},

volume = {XXIV},

number = {2},

pages = {111–114},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26316302,

title = {A Romanian version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument},

author = {Marilena Gorga and Carina Mihai and Alina-Mihaela Soare and Rucsandra Dobrotă and Ana-Maria Gherghe and Victor Stoica},

issn = {0392-856X},

year  = {2015},

date = {2015-01-01},

journal = {Clin Exp Rheumatol},

volume = {33},

number = {4 Suppl 91},

pages = {S61–S67},

abstract = {OBJECTIVES: UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 2.0) Instrument is a comprehensive, self-administered survey for the assessment of gastrointestinal involvement in scleroderma patients, developed and validated in English. Our objective was to translate and validate a Romanian version of UCLA SCTC GIT 2.0. 

METHODS: Translation from English into Romanian has been made using the forward-backward method. Sixty-four patients, attending a referral centre as part of an extensively studied cohort, were approached in a consecutive manner over a period of two years for administration of the questionnaire. We evaluated the reproducibility, internal consistency, construct validity and discriminative capacity of the translation (Romanian GIT). RESULTS: Fifty-four patients returned completed questionnaires. Internal consistency was demonstrated by Cronbach's alpha coefficient (0.931). Construct validity is supported by moderate, but significant correlations of Romanian GIT total score with the Mental Component Summary (MCS) of SF-36 (r=0.541, Spearman correlation) and among subscales, by significant correlations with SHAQ total score (r=0.559, Spearman correlation) and by strong correlations with gastrointestinal subscale of SHAQ (SHAQ GI) (r=0.726, Spearman correlation). Reproducibility was good as well. Divergent validity was supported by significant differences between patients with or without a clinical diagnosis of gastrointestinal disease. Other differences in the Romanian GIT total score were tested among subgroups of patients. 

CONCLUSIONS: The Romanian GIT has acceptable reliability and validity. This questionnaire can be used for the assessment of gastrointestinal involvement in scleroderma patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{soare2013death,

title = {Predictive factors for death in systemic sclerosis: a longitudinal study},

author = {A Soare and A. M Gherghe and C Mihai and R Dobrota and M Gorga and R Ionitescu and R Jurcut and A Calin and T Constantinescu and R Sfrenz-Cornateanu and L Macovei and I Ancuta and M Milicescu and M Sasu and A Martin and C Ghinghina and M Bojinca and V Stoica},

year  = {2013},

date = {2013-01-01},

journal = {Romanian Journal of Rheumatology},

volume = {XXII},

number = {2},

pages = {88–94},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20361534,

title = {Correlation between vaccine coverage against polio and circulation and genetic evolution of the poliovirus strains isolated in Romania in the framework of the global polio eradication strategy},

author = {Anda Băicuş and Ana Persu and Maria Popescu and Alina Penciu and Simona Stavri and Alina Soare and Nicolae Grecu and Camelia Szmal and Gabriela Oprişan},

issn = {1222-3891},

year  = {2009},

date = {2009-01-01},

journal = {Roum Arch Microbiol Immunol},

volume = {68},

number = {3},

pages = {145–150},

abstract = {Until 2008 in Romania poliomyelitis has been controlled by predominantly using trivalent oral poliovirus vaccine (TOPV). The alternative vaccination schedule (formalin inactivated poliovirus vaccine IPV/OPV) has been implemented starting September 2008 and at the begining of 2009 was decided only vaccination with IPV. Between 1995-2006 the risk of the vaccine-associated paralytic poliomyelitis (VAPP) decreased with an average of less than 2 VAPP cases/year and no VAPP case between 2007 - September 2009. Begining with 2007 the number of the poliovirus strains isolated was less. All 9 poliovirus strains (PV) isolated between 2007-2009 and investigated by RT-PCR-RFLP in VP1-2A and VP3-VP1 coding regions showed Sabin-like profiles, and only one strain poliovirus type 3 showed Sabin 2-like profile by RFLP in 3D coding ARN polymerase region. The study about the seroprevalence of antibodies against poliovirus types in serum samples from the acute flaccid paralysis (AFP), facial paralysis (FP) cases showed that the seroprevalence of antibodies against types 1 and 2 Sabin strains was higher (>90%) than for type 3 Sabin strains (average 85%). It was confirmed the necessity of maintaining a proper vaccine coverage in population, after the switch in the vaccination strategy in Romania until all threats of poliovirus are eliminated globally.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}