The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases.

Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.

Myocardial fibrosis detected by magnetic resonance imaging, elevated U-CRP and higher mRSS are predictors of cardiovascular complications in systemic sclerosis (SSc) patients.

INTRODUCTION: In previous studies we showed that prevalence of myocardial fibrosis as assessed by late enhancement on cardiac MRI in SSc patients is 45% and is associated to diffuse disease (dcSSc) and lower left ventricle ejection fraction; microvascular damage defined as decreased perfusion on cardiac MRI after adenosine infusion, was also very frequent (79%). Our aim was to identify baseline characteristics associated to the development of cardiovascular outcomes (heart failure, coronary artery disease, arrhythmias, vasculopathy, elevated systolic pulmonary artery pressure and death) in SSc patients with previously documented myocardial fibrosis and microvascular damage. PATIENTS AND METHODS: We included 62 SSc patients who participated in the study of prevalence of myocardial fibrosis (2008-2010) and in our local SSc cohort. We performed baseline clinical evaluation, cardiac MRI, coronary CT angiography, transthoracic echocardiogram, and yearly clinical and cardiovascular evaluation that included Medsger's severity scale items, electrocardiogram, echocardiogram, chest X-ray or HRCT and spirometry; we registered presence and severity of internal organ involvement and cardiovascular outcomes. Ordinal variables were analyzed using Chi square test and Fisher test when appropriate, numeric variables were compared using Student's t-test or Mann Whitney U when appropriate, logistic regression and Cox proportional hazard ratio were used to perform multivariable analysis. RESULTS: We obtained follow-up information from 62 patients (29 dcSSc, 33 lcSSc), mean follow-up was 43.5 months. Multivariable analysis showed that elevated basal ultrasensitive CRP was associated to mortality (p = 0.004, OR: 11.9, 95% CI 2.1-65.7) and recurrent digital tip ischemic ulcers (p = 0.001, OR 26.8, 95% CI 3,9-181.3) on follow-up. Myocardial fibrosis, particularly in the middle segments (p = 0.01, OR: 11.49, 95% CI 1.6-83), and older age (p = 0.02, OR: 1.11, 95% CI 1.01-1.22) were associated to heart failure on follow-up. Higher maximum mRSS was associated to coronary artery disease (p = 0.02, OR: 1.2, 95% CI 1.02-1.38), while insertion point fibrosis (p = 0.001, OR: 12.5 95% CI 2.7-56.6) was associated to recurrent digital tip ischemic ulcers. CONCLUSIONS: This study shows that myocardial fibrosis, elevated ultrasensitive CRP, and higher maximum mRSS are independent predictors of cardiovascular outcomes in SSc patients. Future studies should focus on early preventive and therapeutic strategies for this group of patients.

Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast.

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.