Interstitial lung disease in systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterised by fibrosis of the skin and internal organs, autoimmune abnormalities and widespread vasculopathy. A degree of interstitial lung involvement is present in the majority of patients, although clinically significant lung fibrosis is present in approximately a third. Autoantibodies are significant clinical markers; anti-topoisomerase is tightly linked to lung fibrosis, whereas anti-centromere antibodies are protective. Further evaluation of markers of progression of lung fibrosis, such as markers of epithelial permeability, will be crucial in clinical management. The clinical course of SSc-associated interstitial lung disease is highly variable, with stability observed in a significant proportion of patients. Therefore, the decision of whether to treat is a challenging one, and should be based on evaluation of disease severity (on the basis of CT extent and lung function) and longitudinal disease behaviour. Two recently published placebo controlled randomized trials have shown a significant, if small, effect of cyclophosphamide on preventing FVC decline. However, because of the significant toxicity of cyclophosphamide, the assessment of alternative, less toxic, immunosuppressive agents for the long term management of SSc-associated interstitial lung disease is needed

Temporal build-up of electromagnetically induced transparency and absorption resonances in degenerate two-level transitions

The temporal evolution of electromagnetically induced transparency (EIT) and absorption (EIA) coherence resonances in pump-probe spectroscopy of degenerate two-level atomic transition is studied for light intensities below saturation. Analytical expression for the transient absorption spectra are given for simple model systems and a model for the calculation of the time dependent response of realistic atomic transitions, where the Zeeman degeneracy is fully accounted for, is presented. EIT and EIA resonances have a similar (opposite sign) time dependent lineshape, however, the EIA evolution is slower and thus narrower lines are observed for long interaction time. Qualitative agreement with the theoretical predictions is obtained for the transient probe absorption on the $^{85}Rb$ $D_{2}$ line in an atomic beam experiment.Comment: 10 pages, 9 figures. Submitted to Phys. Rev.

Results of the standard set forpulmonary sarcoidosis: Feasibility and multicentre outcomes

Our study presents findings on a previously developed standard set of clinical outcome data for pulmonary sarcoidosis patients. We aimed to assess whether changes in outcome varied between the different centres and to evaluate the feasibility of collecting the standard set retrospectively. This retrospective observational comparative benchmark study included six interstitial lung disease expert centres based in the Netherlands, Belgium, the UK and the USA. The standard set of outcome measures included 1) mortality, 2) changes in pulmonary function (forced vital capacity (FVC), forced expiratory volume in 1 s, diffusing capacity of the lung for carbon monoxide), 3) soluble interleukin-2 receptor (sIL-2R) change, 4) weight changes, 5) quality-of-life (QoL) measures, 6) osteoporosis and 7) clinical outcome status (COS). Data collection was considered feasible if the data were collected in ⩾80% of all patients. 509 patients were included in the retrospective cohort. In total six patients died, with a mean survival of 38±23.4 months after the diagnosis. Centres varied in mean baseline FVC, ranging from 110 (95% CI 92–124)% predicted to 99 (95% CI 97–123)% pred. Mean baseline body mass index (BMI) of patients in the different centres varied between 27 (95% CI 23.6–29.4) kg·m−2 and 31.8 (95% CI 28.1–35.6) kg·m−2. 310 (60.9%) patients were still on systemic therapy 2 years after the diagnosis. It was feasible to measure mortality, changes in pulmonary function, weight changes and COS. It is not (yet) feasible to retrospectively collect sIL-2R, osteoporosis and QoL data internationally. This study shows that data collection for the standard set of outcome measures for pulmonary sarcoidosis was feasible for four out of seven outcome measures. Trends in pulmonary function and BMI were similar for different hospitals when comparing different practices

Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis

BACKGROUND: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. METHODS: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. RESULTS: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04 x 10(-17); OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. CONCLUSIONS: We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association

Sarcoidosis and cancer risk : systematic review and meta-analysis of observational studies

BACKGROUND: An increased cancer risk in patients with sarcoidosis has been suggested, although results are conflicting in a number of case-control and cohort studies. We conducted a systematic review of all available data and performed a meta-analysis to better define and quantify the association between sarcoidosis and cancer. METHODS: We searched Medline and Embase for all original articles on cancer and sarcoidosis published up to January 2013. Two independent authors reviewed all titles/abstracts to identify studies according to predefined selection criteria. We derived summary estimates using a random-effects model and reported them as relative risk (RR). Publication bias was evaluated using a funnel plot and was quantified by the Egger test. RESULTS: Sixteen original studies, involving > 25,000 patients, were included in the present review. The summary RR to develop all invasive cancers was 1.19 (95% CI, 1.07-1.32). The results for selected cancer sites indicated a significantly increased risk of skin (RR, 2.00; 95% CI, 1.69-2.36), hematopoietic (RR, 1.92; 95% CI, 1.41-2.62), upper digestive tract (RR, 1.73; 95% CI, 1.07-2.79), kidney (RR, 1.55; 95% CI, 1.21-1.99), liver (RR, 1.79; 95% CI, 1.03-3.11), and colorectal cancers (RR, 1.33; 95% CI, 1.07-1.67). There was no evidence of publication bias for all cancers(P 5.9), nor for any specific cancer site. CONCLUSIONS: The present meta-analysis suggests a significant, though moderate, association between sarcoidosis and malignancy

Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including α-smooth muscle actin (α-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce α-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of α-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins α-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis