1,263 research outputs found

    Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis

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    Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparatio

    Criteria to select molecular targets for anti-fibrotic therapy

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    Tissue fibrosis is a major cause of morbidity and mortality in SSc. An increasing number of promising molecular targets for anti-fibrotic therapies have been described recently. However, the number of patients eligible for clinical trials is limited in SSc. The present article discusses criteria to select the most promising molecular targets for clinical trials in SSc. Based on consensus among experts, important criteria for the selection of molecular-based therapies were as follows: First, there should be strong experimental evidence that targeting the molecule of interest inhibits fibrosis. Optimally, the anti-fibrotic effects should be confirmed in at least two complementary animal models of SSc. Second, inhibitors of the molecule of interest should be clinically available. Third, clinical experience with the drug of interest in other diseases hastens the initiation of clinical trials and reduces the risk of unexpected side-effects. Finally, funding for clinical trials with the drug of interest in SSc should be available. We propose that the priority of novel targets for evaluation in clinical trials in SSc might be selected based on these consensus criteri

    Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases?

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    Tissue fibrosis causes organ failure and death in patients with systemic sclerosis (SSc), but clearly effective anti-fibrotic therapies are not available. The tyrosine kinase inhibitor (TKI) imatinib, which blocks the pro-fibrotic c-Abl kinase and PDGF receptor, is currently evaluated in clinical proof-of-concept trials for the treatment of patients with SSc. In experimental models, imatinib efficiently prevented and reduced tissue fibrosis. First clinical case studies demonstrated anti-fibrotic effects of imatinib in selected patients with SSc and other fibrotic diseases, and observational studies in sclerotic chronic graft-versus-host disease showed promising results. Besides imatinib, the two novel TKIs of c-Abl and PDGF receptor nilotinib and dasatinib have recently proven efficacy in experimental models of SSc. The potential of TKIs of the VEGF receptor (e.g., semaxinib, vatalanib, sutent, and sorafenib) and the EGF receptor (e.g., erlotinib, gefitinib, lapatinib, and canertinib) as anti-fibrotic treatments are also discussed in this review. Prior to clinical use, however, controlled trials need to address efficacy as well as tolerability of TKIs in patients with different fibrotic diseases

    Overview of pathogenesis of systemic sclerosis

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    The aetiology of SSc is subject to ongoing research, as the precise events that underlie the development of this disease remain unclear. The pathogenesis is known to involve endothelium, epithelium, fibroblasts, innate and adaptive immune systems and their component immunological mediators. Endothelial cell damage may be the initiating factor, but the precise triggering event(s) remain elusive. Angiogenesis also appears to be dysregulated. Vasculopathy shows similarities in different organs (e.g. pulmonary arterial hypertension, renal disease, digital tip ulcers). Endothelin-1 is a potent mediator of vasculopathy, and hence represents a highly relevant target for intervention of vascular features in SS

    Genetik in der Rheumatologie

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    Angiogenese - therapeutische Interventionsmöglichkeiten bei rheumatischen Erkrankungen

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    Zusammenfassung: Im Gegensatz zur Vaskulogenese bedeutet Angiogenese die Formation neuer Blutgef√§√üe aus bereits bestehenden Gef√§√üen. Dieser vielschrittige Prozess tritt beim Erwachsenen physiologisch nur w√§hrend des Reproduktionszyklus und der Schwangerschaft auf, pathophysiologisch bei Wundheilung und Entz√ľndung, aber auch bei Tumorwachstum und Metastasierung. Zugrunde liegende Mechanismen sind Vasodilatation und Steigerung der Gef√§√üpermeabilit√§t, gefolgt von einer Destabilisierung der Gef√§√üw√§nde und der extrazellul√§ren Matrix mit anschlie√üender Endothelzellproliferation und -migration, die zur Bildung eines neuen Gef√§√üsystems f√ľhrt, das schlie√ülich durch Perizyten und glatte Muskelzellen stabilisiert wird. Dieser Ablauf wird durch ein komplexes Zusammenspiel proangiogener und angiostatischer Faktoren kontrolliert. Im Gegensatz zur Karzinogenese ist die Bedeutung der Angiogenese f√ľr die Pathogenese und Therapie rheumatischer Erkrankungen bisher weniger gut untersucht. In diesem √úbersichtsartikel werden verschiedene Aspekte pathologischer Angiogenese im Hinblick auf therapeutische Optionen bei der rheumatoiden Arthritis (RA) und der systemischen Sklerose (SSc) diskutier

    Sklerodermie

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    Zusammenfassung: Die Sklerodermie (Synonyme: systemische Sklerose, systemische Sklerodermie) ist eine Systemerkrankung, die neben der Haut auch innere Organe wie die Lunge, den Gastrointestinaltrakt, die Niere und das Herz bef√§llt. Pathogenetisch ist zwischen einer unkontrollierten Bindegewebsvermehrung (Fibrose) und einer Vaskulopathie zu unterscheiden. Dies f√ľhrt klinisch neben den Organfibrosen auch zu Gef√§√ümanifestationen. Hierzu z√§hlen Fingerkuppenulzera, die pulmonalarterielle Hypertonie und die akute Nierenkrise. Von der systemischen Sklerose sind lokalisierte Sklerodermieformen wie die Morphea abzugrenzen, die ohne Organkomplikationen verlaufen. Aufgrund ihrer klinischen Heterogenit√§t, ihrer hohen Morbidit√§t und Mortalit√§t stellt die systemischen Sklerose f√ľr den klinischen Alltag eine gro√üe diagnostische und therapeutische Herausforderung dar. Dieser √úbersichtsartikel fasst den aktuellen Stand zur Klassifikation und Epidemiologie, Pathogenese, den wichtigsten klinischen Manifestationen wie interstitielle Fibrose, pulmonalarterielle Hypertonie, akute Nierenkrise und periphere Vaskulopathie zusammen und gibt einen √úberblick aktueller und zuk√ľnftiger Therapiem√∂glichkeite

    Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis

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    Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of SSc. The molecular mechanisms underlying the infiltration of inflammatory cells into the skin and the subsequent activation of fibroblasts are still largely unknown. Chemokines are a family of small molecules that are classified according to the position of the NH2-terminal cysteine motif. Recent data indicate that chemokines and in particular two members of the subfamily of monocyte chemoattractant proteins, MCP-1 (CCL-2) and MCP-3 (CCL-7), might be involved in the pathogenesis of SSc. MCP-1 and -3 are overexpressed by SSc fibroblasts and in skin lesions from SSc patients compared to healthy controls. MCP-1 and -3 are chemotactic for inflammatory cells and stimulate their migration into the skin. In addition to their pro-inflammatory effects, MCP-1 and -3 contribute to tissue fibrosis by activating the synthesis of extracellular matrix proteins in SSc fibroblasts. Therapeutic strategies targeting MCP-1 have revealed promising results in several animal models of SSc. Antagonists against the receptor CCR2 are currently tested in clinical trials of a variety of diseases and also represent interesting candidates for target-directed therapy in SS

    Evidenzbasierte Therapie des Raynaud-Syndroms

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    Zusammenfassung: Das Raynaud-Syndrom ist mit einer Pr√§valenz von 3-5% ein h√§ufiges klinisches Problem. Dennoch ist die Wirkung der meisten Therapiem√∂glichkeiten nur unzureichend durch kontrollierte Studien belegt. Zu den Therapien mit h√∂herem Evidenzgrad geh√∂rt der Kalziumantagonist Nifedipin, f√ľr den in Metaanalysen sowohl bei prim√§rem als auch bei sekund√§rem Raynaud-Syndrom eine verbesserte periphere Durchblutung sowie eine Abnahme der Frequenz und des Schweregrades der Raynaud-Attacken nachgewiesen werden konnte. √Ąhnliches gilt f√ľr intraven√∂s appliziertes Iloprost in der Therapie des sekund√§ren Raynaud-Syndroms bei systemischer Sklerose. Intraven√∂s verabreichtes Iloprost verbessert dar√ľber hinaus das Abheilen von Fingerkuppenulzera bei Patienten mit systemischer Sklerose. Vielversprechende Therapieans√§tze stellen Angiotensin-II-Rezeptor-1-Antagonisten (Losartan), die Kalziumantagonisten Felodipin und Amlodipin, Serotonin-Reuptake-Hemmer (Fluoxetin) und Phosphodiesterase-V-Hemmer (Sildenafil, Vardenafil) dar, die sich in kontrollierten Einzelstudien als wirksam erwiesen haben. Jedoch fehlen Erfahrungen mit gr√∂√üeren Patientenzahlen und l√§ngeren Anwendungszeiten, um diese Therapiem√∂glichkeiten abschlie√üend zu beurteile
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