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WOS: 000291117200007, PubMed ID: 21586217, Objective: To obtain experiences and expert opinion on treatment of SSc patients with TNF-alpha antagonists. Methods: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-alpha antagonists. Assessment forms on the frequency of TNF-alpha inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-alpha inhibitors in SSc. Results: Seventy-nine centres returned information on use of TNF-alpha antagonists in SSc patients. A total of 65 patients were treated with TNF-alpha inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-alpha inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-alpha antagonists in SSc. Arthritis was suggested as an indication for TNF alpha antagonists by 75% of the experts. However; after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-alpha antagonists decreased and 59% recommended that TNF-alpha antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-alpha antagonists for arthritis associated with SSc. Conclusions: Most of the experts do not recommend the routine use of TNF-alpha antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-alpha antagonists are needed before general recommendations can be given., Novartis; Bayer Schering Pharma; Cell Gen Therapeutics; NicOx; Array BioPharma; Bristol-Myers Squibb; Ergonex Pharma GmbH; Actelion Pharmaceuticals; Pfizer; GlaxoSmithKline; Merck; Amgen; Abbott; Roche; EUSTAR/EULAR; Sanofi-Aventis; United BioSource Corporation; Medac; Biovitrium; Active Biotech; Ergonex, Dr Jorg Distler has served as a consultant for Actelion Pharmaceuticals, Pfizer, and GlaxoSmithKline; has received grant support from Novartis, Bayer Schering Pharma, Cell Gen Therapeutics, NicOx, Array BioPharma, Bristol-Myers Squibb, and Ergonex Pharma GmbH; has received payment for development of educational presentations (including service on speakers' bureaus) from Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer Schering Pharma.; Dr F. lannone has received speaker's and consultancy fees from Merck.; Dr Riemekasten has been invited for a meeting by Humira-People (Amgen) and has received speaker's fees and support for travel costs riembursed by Amgen.; Dr M.F. Seidel has received research grants from Pfizer and Abbott.; Dr J. van Laar has received speaker's and consultancy fees and research grants from Roche.; Dr U. Muller-Ladner has received research grants from EUSTAR/EULAR.; Dr Oliver Distler has a consultancy relationship and/or has received research funding from Actelion Pharmaceuticals, Pfizer, Ergonex Pharma GmbH, Bristol-Myers Squibb, Sanofi-Aventis, United BioSource Corporation, Medac, Biovitrium, Novartis and Active Biotech in the area of potential treatments of scleroderma and its complications. He has received lecture honoraria from Actelion Pharmaceuticals, Pfizer and Ergonex.

Background: Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc. Methods: The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice. Results: Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-β-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses. Conclusions: We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.

ObjectiveType 2 innate lymphoid cells (ILC2s), a recently identified population of lymphoid cells lacking lineage-specific receptors, promote type 2 immunity and tissue remodelling. However, the contributive role of ILC2s in the pathogenesis of systemic sclerosis (SSc) is unknown. We aimed to evaluate the levels and correlations with fibrotic manifestations in SSc.Methods69 patients with SSc and 47 healthy controls were included. Blood samples and skin sections were analysed by flow cytometry and immunohistochemically by staining two complementary panels of markers.ResultsDermal and circulating ILC2s were significantly elevated in patients with SSc compared with controls. Dermal, but not circulating ILC2s were activated. Stratification of the SSc population in patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) demonstrated increased levels of ILC2s in both subgroups with significantly higher frequencies in dcSSc compared with lcSSc. Moreover, dermal and circulating ILC2 counts correlated closely with the modified Rodnan skin score and with the presence of pulmonary fibrosis.ConclusionsILC2 counts are elevated in patients with SSc and correlate with the extent of skin fibrosis and the presence of interstitial lung disease providing compelling evidence for profibrotic effect of ILC2s in SSc.

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 NH(2)-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 SSc.

OBJECTIVE: Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc). METHODS: The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo. RESULTS: Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGFbeta and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. CONCLUSION: These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.