Frontiers of antifibrotic therapy in systemic sclerosis

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, targeted anti-fibrotic therapies are still not approved for most fibrotic disorders. However, intense research over the last decade has improved our understanding of the underlying pathogenesis of fibrotic diseases. We now appreciate fibrosis as the consequence of a persistent tissue repair responses, which, in contrast to normal wound healing, fails to be effectively terminated. Profibrotic mediators released from infiltrating leukocytes, activated endothelial cells and degranulated platelets may predominantly drive fibroblast activation and collagen release in early stages, whereas endogenous activation of fibroblasts due epigenetic modifications and biomechanical or physical factors such as stiffening of the extracellular matrix and hypoxia may play pivotal role for disease progression in later stages. In the present review, we discuss novel insights into the pathogenesis of fibrotic diseases using systemic sclerosis (SSc) as example for an idiopathic, multisystem disorder. We set a strong translational focus and predominantly discuss approaches with very high potential for rapid transfer from bench-to-bedside. We highlight the molecular basis for ongoing clinical trials in SSc and also provide an outlook on upcoming trials. This article is protected by copyright. All rights reserved

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: subgroup analyses by autoantibody status and skin score

OBJECTIVE: We used data from the SENSCIS trial to assess the effects of nintedanib versus placebo in subgroups of patients with SSc-ILD based on characteristics associated with progression of SSc-ILD in previous studies. METHODS: Patients with SSc-ILD were randomized to receive nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks in subgroups by baseline ATA status, modified Rodnan skin score (mRSS) ( 0.05 for all). CONCLUSION: In patients with SSc-ILD, no heterogeneity was detected in the treatment effect of nintedanib in reducing the annual rate of decline in FVC across subgroups based on ATA status, mRSS, and SSc subtype

The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation

Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders

Molecular targets for therapy in systemic sclerosis

Despite significant advances have been made in the recent years regarding organ-specific therapies, there is no approved 'disease-modifying' antifibrotic drug for systemic sclerosis (SSc) available to date. Although non-selective immunosuppressive agents are routinely used to treat patients with SSc, large well-controlled studies are lacking for almost all immunosuppressive agents and further evidence is required for long-term beneficial effects of these drugs. Considering these facts about immunosuppressive agents in SSc and also considering the high mortality of SSc, other therapeutic strategies are urgently needed. Recently an important role of the 5-hydroxytryptamine (5-HT: serotonin) pathway in fibrosis was reported. In this review, we discuss the role of 5-HT in fibrosis and therapeutic potential of this molecule. Besides 5-HT, there are a number of promising targets that have been extensively characterized in recent years. For many of these molecular targets, modifiers are readily available for clinical studies, and often these modifiers are used already in clinical use for other diseases. Results from these studies will show, in how far the promising preclinical results for novel antifibrotic strategies can be translated to clinical practice

Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo (p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction ( p ! 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis ( annexin V staining, p ! 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n=3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth. Copyright (C) 2007 S. Karger AG, Basel

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field

Higgsing M2 to D2 with gravity: N=6 chiral supergravity from topologically gauged ABJM theory

We present the higgsing of three-dimensional N=6 superconformal ABJM type theories coupled to conformal supergravity, so called topologically gauged ABJM theory, thus providing a gravitational extension of previous work on the relation between N M2 and N D2-branes. The resulting N=6 supergravity theory appears at a chiral point similar to that of three-dimensional chiral gravity introduced recently by Li, Song and Strominger, but with the opposite sign for the Ricci scalar term in the lagrangian. We identify the supersymmetry in the broken phase as a particular linear combination of the supersymmetry and special conformal supersymmetry in the original topologically gauged ABJM theory. We also discuss the higgsing procedure in detail paying special attention to the role played by the U(1) factors in the original ABJM model and the U(1) introduced in the topological gauging.Comment: 53 pages, Late

Effects and safety of rituximab in systemic sclerosis: An analysis from the European Scleroderma Trial and Research (EUSTAR) group

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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

On thermodynamics of N=6 superconformal Chern-Simons theory

We study thermodynamics of N=6 superconformal Chern-Simons theory by computing quantum corrections to the free energy. We find that in weakly coupled ABJM theory on R(2) x S(1), the leading correction is non-analytic in the 't Hooft coupling lambda, and is approximately of order lambda^2 log(lambda)^3. The free energy is expressed in terms of the scalar thermal mass m, which is generated by screening effects. We show that this mass vanishes to 1-loop order. We then go on to 2-loop order where we find a finite and positive mass squared m^2. We discuss differences in the calculation between Coulomb and Lorentz gauge. Our results indicate that the free energy is a monotonic function in lambda which interpolates smoothly to the N^(3/2) behaviour at strong coupling.Comment: 29 pages. v2: references added. v3: minor changes, references added, published versio