Biomarkers in Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)

PURPOSE OF REVIEW: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis, a rare autoimmune disease characterised by fibrosis and vasculopathy. The variety of phenotypes in SSc-ILD have inspired multiple studies aimed at the identification of biomarkers which can provide disease-specific information but due to the complex pathogenesis of SSc-ILD, it has been challenging to validate such markers. We provide a comprehensive update on those most studied along with emerging biomarkers. RECENT FINDINGS: We review the up-to-date findings with regard to the use of well-studied molecular biomarkers in SSc-ILD along with novel biomarkers offering promise as prognostic markers such as IGFBP-2 and IGFBP-7, the adipokine CTRP9, endothelial progenitor cells, and cellular markers such as CD21lo/neg B cells. Expression profiling data is being used in SSc patients to determine genetic and epigenetic clusters which shed further light on mechanisms involved in the pathogenesis of SSc-ILD and are likely to uncover novel biomarkers. SUMMARY: With the exception of autoantibodies, there are no routinely measured biomarkers in SSc-ILD and reliable validation of the many potential biomarkers is lacking. Identifying biomarkers which can offer diagnostic and prognostic certainty may help patients to receive preventative treatment as part of a personalised medicine approach

Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need

Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients' quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials

Renal Disease and Systemic Sclerosis: an Update on Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) with a mortality of 20% at 6 months. Once the leading cause of mortality in scleroderma (SSc), it remains a serious complication, often necessitating level three care for patients affected. Whilst renal outcomes have significantly improved following the advent of angiotensin-converting enzyme inhibitor (ACEi) therapy, SRC remains a precarious challenge for clinicians, due to lack of preventative measures and the fact that patients can rapidly decline despite best medical management. Large cohort studies spanning decades have allowed clear identification of phenotypes particularly at risk of developing SRC thus allowing enhanced monitoring and early identification in those individuals. Novel urinary biomarkers for renal disease in SSc may offer a new window for early identification of SRC patients and response to treatment. Multiple studies have demonstrated increased activity of complement pathways in SRC with some anecdotal cases exhibiting serological response to treatment with eculizumab where ACEi and therapeutic plasma exchange (TPE) were not successful. Endothelin-1 blockade, a therapeutic strategy in other SSc vasculopathies, has shown potential as a target but clinical trials are yet to show a clear treatment benefit. Clear guidelines for the management of SRC are in place to standardise care and facilitate early collaboration between rheumatology and renal physicians. Outcomes following renal transplant have improved but the mortality of SRC remains high, indicating the need for continued exploration of the mechanisms precipitating and exacerbating SRC in order to develop novel therapies

Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p 100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment

Clinical trials and basic research: defining mechanisms and improving treatment in connective tissue disease

Despite advances in elucidating the pathogenic factors responsible for its development, systemic sclerosis remains complex and poorly understood, and treatment options are limited. Multidisciplinary collaborative efforts are needed to better characterize clinical and prognostic parameters and to design and implement large-scale clinical trials in well defined populations with therapies that target potential disease modulators

Pericytes display increased CCN2 expression upon culturing

By providing a source of α-smooth muscle actin (α-SMA)-expressing myofibroblasts, microvascular pericytes contribute to the matrix remodeling that occurs during tissue repair. However, the extent to which pericytes may contribute to the fibroblast phenotype post-repair is unknown. In this report, we test whether pericytes isolated from human placenta can in principle become fibroblast-like. Pericytes were cultured in vitro for 11 passages. The Affymetrix mRNA expression profile of passage 2 and passage 11 pericytes was compared. The expression of type I collagen, thrombospondin and fibronectin mRNAs was induced by passaging pericytes in culture. This induction of a fibroblast phenotype was paralleled by induction of connective tissue growth factor (CTGF/CCN2) and type I collagen protein expression and the fibroblast marker ASO2. These results indicate that, in principle, pericytes have the capacity to become fibroblast-like and that pericytes may contribute to the population of fibroblasts in a healed wound

Systemic sclerosis and related connective tissue diseases: present and future

Greece, to discuss systemic sclerosis (SSc) and related connective tissue diseases (CTDs). SSc is a clinically heterogeneous and complex disease that is characterized by vascular dysfunction, vascular and extravascular fibrosis, and characteristic immune derangements, and for which few treatment options are available. The aims of the CTD International Scientific Advisory Board were threefold: to define the role of local mediators in CTDs, in particular to identify the nature of the initial insult in CTDs and to consider the role of genetic perturbations in CTDs; to translate what has been learned from clinical trials into clinical practice and to evaluate current treatment options for CTDs and their complications; and to address future directions for the management of CTDs and associated rare diseases, based on the biologic mechanisms elucidated. This supplemen

Relapsing polychondritis in systemic sclerosis: A rare vasculitic mimic

INTRODUCTION: Relapsing polychondritis is a rare, immune-mediated disease characterised by inflammation of cartilaginous structures. Auricular chondritis, sparing the fatty lobule, is the most typical feature, followed by nose and laryngotracheal involvement. Albeit rare, neurologic involvement is reported with relapsing polychondritis. Cranial nerve involvement is the most frequent neurologic manifestation and is probably due to an underlying vasculitic process. Approximately one-third of relapsing polychondritis patients can overlap with other systemic diseases, including other autoimmune connective tissue diseases, but association with systemic sclerosis has very rarely been described. CASE DESCRIPTION: A 63-year-old woman presented with acute new-onset severe dysphagia, accompanied by hoarseness and preceded by pain, swelling and erythema of the left pinna, unresponsive to antibiotics. She had a history of long-standing limited cutaneous systemic sclerosis. Cranial nerve examination revealed right-sided palatal palsy, and left vocal cord palsy was found on fibreoptic nasendoscopy. Magnetic resonance imaging of the head and neck showed bilateral enhancement of an extracranial segment of the glossopharyngeal and vagus nerves. Clinical features and imaging findings were consistent with relapsing polychondritis, which successfully responded to high-dose steroids. CONCLUSIONS: This is a case of relapsing polychondritis mimicking progression of systemic sclerosis, showcasing its challenging features. It emphasises the importance of early diagnosis and prompt management with potential impact on the outcome, while highlighting the complex interplay between these two disease entities and vasculitic mechanisms, which may reflect the shared network of genetic predisposition across autoimmune rheumatic diseases

Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups

OBJECTIVES: The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs). METHODS: We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups. RESULTS: Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFβ response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc. CONCLUSIONS: We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc