Biomarkers in Systemic Sclerosis: An Overview

Abstract

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor β (TGF-β) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Keywords: autoimmune disease; chemokines; interleukines; systemic sclerosis (SSc).

Figure 1

A 63-year-old female with the diagnosis of SSc. (A) Axial High-resolution CT scan shows traction bronchiectasis (white arrows) in a back-ground of diffuse ground-glass opacities, related to a fibrotic nonspecific pneumonia (NSIP) patter. (B) Using the mediastinal window setting the dilatation of the main pulmonary artery (32 mm) can also be recognized as sign of pulmonary hypertension, a common complication of the disease. Moreover a dilatation of the esophagus (*) can be seen (operator E.B., Radiology Unit, University of Trieste, University Hospital of Cattinara).

Figure 2

LUS in SSc. Advanced ILD (B-lines, yellow arrows) using a linear probes (7.5 MHz, operator F.S., Pulmonology Unit, University of Trieste, University Hospital of Cattinara).

Figure 3

Nailfold capillaroscopy images (×200). Figure (A) shows the capillaroscopic findings in a healthy subject with capillaries of normal number and shape, i.e., the so-called U-shaped and hairpin-like morphology; (B–D) show the capillaroscopic changes in the scleroderma pattern in the early (B), active (C) and late (D) phases, respectively and associated with a progressive distortion of the architecture of normal capillaries, which gradually deviate from the A pattern. In particular in figures (B,D), megacapillaries (defined as capillaries >50 μm) and an increase (B) and a subsequent decrease (C) in capillary density, respectively, are observed. The later picture (D) is characterised by a further accentuation of these anomalies, with a greater decrease in capillary density and an additional number of giant capillaries. In (B), there are also areas of microhaemorrhages, observable in the early phase but also present in the active phase (operators L.M. and B.R, Pulmonology Unit, University of Trieste, University Hospital of Cattinara).

Figure 4

Graph obtained from a right heart catheterisation procedure performed at our centre in a 68-year-old patient with Systemic Sclerosis with pulmonary involvement and interstitial disease. Pulmonary hypertension is in fact one of the complications of pulmonary involvement by systemic sclerosis and affects about 12% of patients with this rheumatological disease. This graph shows on the y-axis respectively the ECG monitoring (derivation VII) which is performed throughout the procedure (a), in the picture (b) it is also possible to observe the measurement of the pulmonary arterial pressure (PAP) and the end-expiratory pulmonary artery wedge pressure (PAWP) in the picture (c), (operator P.G., Pulmonology Unit, University of Trieste, University Hospital of Cattinara).

Figure 5

Example of measurement of dermal thickness (yellow arrows) by skin high-frequency US (18 MHz probe) in a healthy subject (A) and in an SSc patient (B) at the level of arm (operator L.R, Pulmonology Unit, University of Trieste, University Hospital of Cattinara).