737 research outputs found
Response to: 'Idiopathic inflammatory myopathies and antisynthetase syndrome: Contribution of antisynthetase antibodies to improve current classification criteria' by Greco et al
No full textIn an effort to improve and harmonise the classification of ASSD, the CLASS (classification criteria of ASSD) project
has recently been funded by the American College of Rheumatology and the European League Against Rheumatism. It will be interesting to see if similar results can be repeated using a large
and carefully selected cohort
COVID-19 revisiting inflammatory pathways of arthritis
No full textCoronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19
Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes.
No full textClodronate liposomes (Clo-Lip) have been widely used to deplete mononuclear phagocytes (MoPh) to study the function of these cells in vivo. Here, we revisited the effects of Clo-Lip together with genetic models of MoPh deficiency, revealing that Clo-Lip exert their anti-inflammatory effects independent of MoPh. Notably, not only MoPh but also polymorphonuclear neutrophils (PMN) ingested Clo-Lip in vivo, which resulted in their functional arrest. Adoptive transfer of PMN, but not of MoPh, reversed the anti-inflammatory effects of Clo-Lip treatment, indicating that stunning of PMN rather than depletion of MoPh accounts for the anti-inflammatory effects of Clo-Lip in vivo. Our data highlight the need for a critical revision of the current literature on the role of MoPh in inflammation.This work was supported by the Deutsche Forschungsgemeinschaft (FG 2886 “PANDORA” – B01/B02/A03/
B04 to G. Kronke, F. Nimmerjahn, G. Schett, and M.H. Hoff- ¨
mann, respectively, and the CRC1181-A03/A01/A02/A07/C03 Z2
to G. Kronke, G. Schett, F. Nimmerjahn, and M.H. Hoffmann), ¨
the Emerging Field Initiative of the Friedrich-Alexander University Erlangen-Nürnberg (EFI_Verbund_Med_05_MIRACLE
to G. Kronke), the Bundesministerium für Bildung und For- ¨
schung (MASCARA to G. Kronke and G. Schett; MelAutim to G. ¨
Kronke), and the European Union (Horizon 2020 ERC-2014-StG ¨
640087 – SOS and ERC-2020-CoG 101001866 – INSPIRE to G.
Kronke; and ERC-2018-SyG nanoSCOPE and RTCure to G. ¨
Schett). This work was supported by grants R01AI165661
from the National Institutes of Health/National Institute of
Allergy and Infectious Diseases, H2020-FET-OPEN-2018-
2020 (no. 861878) from the European Commission to A. Hidalgo and M.H. Hoffmann, and HR17_00527 from Fundacion
La Caixa to A. Hidalgo. The CNIC is supported by the Ministerio de Ciencia e Innovacion and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN
award CEX2020-001041-S).S
Fine-Tuning the Treatment of Psoriatic Arthritis: Focus on the IL-23 Pathway
No full textThe symposium ‘Fine-tuning the treatment of PsA: Focus on the IL-23 pathway’ took place during the 2019 European League Against Rheumatism (EULAR) Annual Congress in Madrid, Spain. The presentations covered the rationale for targeting IL-23 in psoriatic arthritis (PsA), details of the IL-23 pathway relevant to psoriatic disease, practical implications and consequences of targeting IL-23, and experiences of targeting IL-23 in psoriasis from the dermatologists’ perspective. Dr Stefan Siebert set the scene by outlining the pathophysiology of psoriatic diseases, particularly PsA, describing disease heterogeneity, explaining the role of inflammation, and highlighting the rationale for targeting the IL-12/23 pathway. He summarised key findings on the IL-12/23 inhibitor ustekinumab in PsA from clinical trials and real-world data available to date. Delving deeper into the IL-23 pathway, Prof Georg Schett explained the function of IL-23 and its role in inflammatory disease and autoimmunity. After briefly describing the history of the relatively recent discovery of this cytokine, Prof Schett discussed preclinical and clinical studies underlying today’s understanding of IL-23 and why it is an appropriate target in PsA. Multiple biologic or small-molecule treatments for PsA have been investigated in clinical trials. Prof Peter Taylor discussed the practical implications of targeting IL-23 and provided more details about the specific effects of targeting not only IL-23 (with risankizumab, tildrakizumab, or guselkumab) but also IL-12/23 (with ustekinumab) and IL-17 (with ixekizumab, secukinumab, or brodalumab). In the final presentation, Prof Lluís Puig described clinical experience of targeting IL-23 in psoriasis and provided an overview of findings from several clinical trials, including: VOYAGE 1 and 2 (guselkumab versus the TNF inhibitor [TNFi] adalimumab); NAVIGATE (guselkumab versus ustekinumab); and the head-to-head ECLIPSE study (guselkumab versus secukinumab). The symposium concluded with a lively panel discussion in which the speakers addressed a variety of questions and comments from the audience
IL-17-22-23 PATHWAYS IN PSORIATIC ARTHRITIS AND PSORIASIS
No full textAnnual European Congress of Rheumatology -- JUN 14-17, 2017 -- Madrid, SPAIN[Abstract Not Available
The gut–joint axis in rheumatoid arthritis
No full textRheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA
Proteinkinasen G als nachgeschaltete Mediatoren der antifibrotischen Effekte der löslichen Guanylylcyclase-Stimulatoren
No full textBackground and objectives. Systemic sclerosis (SSc) is a prototypical fibrotic disease with high morbidity and mortality. Effective antifibrotic therapies are not currently available for clinical practice. Stimulators of soluble guanylate cyclase (sGC) are currently evaluated in clinical trials for the treatment of fibrosis in SSc. We aimed in this work to evaluate the role of protein kinases G (PKG) as potential downstream mediators of sGC and of cyclic guanosine monophosphate (cGMP) and to characterize the dysregulation of this signaling pathway in SSc.
Methods. Immunofluorescence and/or Western Blot were used to determine the expression levels of PKG 1 and 2, of sGC and of p-VASP and VASP. An ELISA kit was used to determine the levels of intracellular cGMP. The expression levels of the molecules above in human skin or in cultured fibroblasts was compared between healthy donors and SSc patients.
Cultured fibroblasts from healthy donors, SSc patients or PKG 1 and 2 – double knockout mice were stimulated with TGF-β1 and/or treated with the sGC stimulator BAY 41-2272 or the PKG inhibitor KT5823. Stress fibers formation, the levels of α-smooth muscle actin (α-SMA) protein, of Col1a1 mRNA and type 1 collagen protein were evaluated in treated cultured fibroblasts.
Knockout mice for PKG1 and 2 were challenged with bleomycin and subsequently treated with BAY 41-2272. Skin thickness, hydroxyproline content and myofibroblast counts were determined to evaluate the fibrotic remodeling in these mice.
Observations and results. We observed a dysregulation of the signaling pathway sGC-cGMP-PKG1 and 2 in SSc patients, for which the elevated levels of TGF-β1 could be responsible. sGC and cGMP are downregulated in SSc patients, whereas PKG1 and 2 and upregulated, most likely as a futile compensatory mechanism.
Fibroblast activation is inhibited by sGC stimulation by blocking TGF-β1-induced ERK activation, whereas inhibition or knockout of PKG 1 and 2 renders sGC stimulation ineffective.
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Treatment with sGC stimulators protects wildtype mice, but not PKG1 and 2 – double knockout mice from bleomycin-induced fibrosis.
Conclusions. We can conclude from our data that PKG 1 and 2 are essential downstream mediators of the antifibrotic effects of sGC stimulators, effects mediated by blocking TGF-β1-induced activation of ERK. We show moreover a reduced activity of the sGC-cGMP-PKG signaling pathway in SSc, likely induced by TGF-β1.Hintergrund und Ziele. Die Systemische Sklerose (SSc) ist eine prototypische fibrosierende Erkrankung, gekennzeichnet durch hohe Morbidität und Mortalität. Effektive antifibrotische Therapien sind bis jetzt für die klinische Anwendung nicht vorhanden. Stimulatoren der löslichen Guanylylcyclase (lGC, englisch sGC) werden derzeit in klinischen Studien für die Behandlung von Fibrose in SSc untersucht. Ziel dieser Arbeit war die Untersuchung der Rolle von Proteinkinasen G (PKG) als nachgeschaltete Mediatoren der sGC und des cyclischen Guanosinmonophosphat (cGMP) sowie die Charakterisierung der Fehlregulierung dieses Signalweges in SSc.
Methoden. Zur Bestimmung der Expression von Proteinkinasen G 1 und 2, von sGC und von p-VASP und VASP wurden Immunfluoreszenz und/oder Western Blot eingesetzt, zur Bestimmung des Spiegels von intrazellulärem cGMP wurde ein ELISA Kit verwendet. Die Spiegel der oben genannten Proteine und Mediatoren in der Haut oder in kultivierten dermalen Fibroblasten bei gesunden Spendern wurden mit denen bei SSc Patienten verglichen.
Kultivierte Fibroblasten von gesunden Spender, SSc Patienten oder PKG1 und 2 – Doppel-Knockout Mäusen wurden mit TGF-β1 und/oder dem sGC-Stimulator BAY 41-2272, oder dem PKG-Inhibitor KT5823 behandelt. Bei den behandelten Fibroblasten wurde die Bildung von Stressfasern und die Menge von α-Smooth-
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Muscle-Actin (α-SMA) Protein, von Col1a1 mRNA und Kollagen Typ 1 Protein untersucht.
Bei knockout Mäusen für PKG1 und 2 oder für sGC wurde Bleomycin appliziert, und diese anschließend mit BAY 41-2272 behandelt. Um die Fibrosebildung bei diesen Mäusen zu bestimmen, wurde die Hautdicke vermessen, der Hydroxyprolingehalt bestimmt und die Myofibroblastenanzahl quantifiziert.
Ergebnisse und Beobachtungen. Wir stellten eine Fehlregulierung des Signalwegs sGC-cGMP-PKG1 und 2 bei den Patienten mit SSc fest, die auf die erhöhten TGF-β1-Spiegel zurückzuführen zu sein scheint. sGC und cGMP sind bei SSc Patienten herunterreguliert. PKG1 und PKG2 sind hochreguliert, am ehesten als frustraner Kompensationsversuch.
Die Fibroblastenaktivierung wird durch sGC Stimulierung und darauffolgende Hemmung der TGF-β1-induzierten ERK-Phosphorylierung gehemmt, wobei die Hemmung oder der Knockout der PKG1 und 2 den Effekt von sGC Stimulierung aufhebt.
Behandlung mit sGC Stimulatoren schützt Wildtyp-Mäuse, aber nicht die PKG 1 und 2 Doppel-Knockout Mäuse vor der durch Bleomycin-induzierten Fibrose.
Schlussfolgerungen. Aus unseren Daten können wir schließen, dass PKG 1 und 2 wesentliche nachgeschaltete Mediatoren der durch Hemmung der TGF-β1-induzierten ERK-Phosphorylierung hervorgerufenen antifibrotischen Effekte von sGC Stimulatoren sind. Wir zeigen außerdem eine geringere Aktivität des antifibrotischen sGC – cGMP – PKG 1 und 2 Signalwegs in SSc, die wahrscheinlich von TGF-β1 induziert wird
Imaging in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis: An international viewpoint on the current knowledge and future research priorities
No full textImaging is increasingly used in the routine management of rheumatic diseases as well as in the clinical trials of these disorders. This viewpoint, authored by a group of international imaging experts following two meetings dedicated to imaging in rheumatology, reports a consensus about the current knowledge and addresses where further research should be focused based on the views of the international imaging experts and discussion of the evidence with attending imaging practitioners. The goal was to maximize the potential of imaging to improve the clinical management of four rheumatic diseases. These rheumatic diseases include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis
The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium
No full textBACKGROUND: Interleukin (IL)-36α is a recently described member of the IL-1 cytokine family with pro-inflammatory and clearly pathogenic properties in psoriasis. OBJECTIVE: To determine the IL-36α expression in psoriatic arthritis (PsA) compared to rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial tissues obtained from arthritis patients were stained for IL-36α, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by immunohistochemistry and immunofluorescence. Lysates were examined for IL-36α by western blot analysis. Synovial fibroblasts (FLS) cultured in the presence of IL-36α were assayed for cytokine expression by quantitative real time PCR and multiplex assay. IL-36α-induced signal transduction in FLS was analysed by immunoblotting. RESULTS: Expression of IL-36R and its ligands IL-36α and IL-36Ra was detected in the synovial lining layer and cellular infiltrates of patients with inflammatory arthritis. IL-36α was expressed significantly higher in PsA and RA than in OA synovium. CD138-positive plasma cells were identified as the main cellular source of IL-36α. No differences were observed for the expression of IL-36R and IL-36Ra between PsA, RA and OA. Functionally, IL-36α induced the expression of IL-6 and IL-8 in FLS through p38/NFkB activation. CONCLUSIONS: IL-36α is up-regulated in PsA and RA synovium, expressed by tissue plasma cells and leads to IL-6 and IL-8 production by synovial fibroblasts. Hence, IL-36α links plasma cells to inflammatory cytokine production by FLS and may represent a key link between autoimmunity and the induction of synovitis
The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE
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