Update on biomarkers in systemic sclerosis: tools for diagnosis and treatment

Semin Immunopathol (2015) 37:475–487 DOI 10.1007/s00281-015-0506-4 REVIEW Update on biomarkers in systemic sclerosis: tools for diagnosis and treatment Alsya J. Affandi 1,2 & Timothy R. D. J. Radstake 1,2 & Wioleta Marut 1,2 Received: 24 April 2015 / Accepted: 16 June 2015 / Published online: 14 July 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Systemic sclerosis (SSc) is a complex autoimmune disease in which immune activation, vasculopathy, and extensive fibrosis of the skin and internal organs are among the principal features. SSc is a heterogeneous disease with varying manifestations and clinical outcomes. Currently, patients’ clinical evaluation often relies on subjective measures, nonquantitative methods, or requires invasive procedures as markers able to predict disease trajectory or response to therapy are lacking. Therefore, current research is focusing on the discovery of useful biomarkers reflecting ongoing inflammatory or fibrotic activity in the skin and internal organs, as well as being predictive of future disease course. Recently, remarkable progress has been made towards a better understanding of numerous mechanisms involved in the pathogenesis of SSc. This has opened new possibilities for the development of novel biomarkers and therapy. However, current proposed biomarkers that could reliably describe various aspects of SSc still require further investigation. This review will summarize studies describing the commonly used and validated biomarkers, the newly emerging and promising SSc biomarkers identified to date, and consideration of future directions in this field. This article is a contribution to the Special Issue on Immunopathology of systemic sclerosis – Guest Editors: Jacob M. van Laar and John Varga Keywords Autoantibodies . Biomarker . miRNAs . Pulmonary fibrosis . Skin fibrosis . Systemic sclerosis Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, preceded by vascular and immune dysfunction [1]. Depending on the extent of cutaneous fibrosis, SSc is classified into two major subtypes: limited cutaneous (lcSSc) and diffuse cutaneous SSc (dcSSc). In lcSSc, skin thickening is restricted to the areas distal to the elbows and/ or knees, such as hands and fingers. In dcSSc, the presence of skin lesions is more extensive and internal organs involvement is relatively more severe. This classification is supported by the association with specific autoantibodies that specifically define the two types of clinical phenotypes. Both SSc phenotypes can be complicated by severe internal organ dysfunction. Pulmonary fibrosis and pulmonary arterial hypertension (PAH) are the two most feared complications, representing the major causes of mortality in SSc patients [2]. Owning to its complex nature and heterogeneity, SSc remains one of the greatest challenges to both investigators and physicians. Despite intense investigation, so far, only a few biomarkers for SSc have been fully validated and widely accepted. Herein, we present a review of the literature on promising prognostic biomarkers, biomarkers of disease activity, skin fibrosis, and lung involvement, with the aim to provide a comprehensive update on usability of biomarkers for research and clinical guidance. * Timothy R. D. J. Radstake Diagnostic and prognostic biomarkers 1 2 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands SSc-specific autoantibodies as predictive markers Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands The presence of autoantibodies is a central defining aspect of autoimmune diseases. Autoantibodies are seen at the first 476 diagnosis in more than 95 % of SSc patients and have been associated with distinct disease subtypes and with differences in disease severity. Antitopoisomerase I (ATAs) and anticentromere antibodies (ACAs) are the most widely used diagnostic biomarkers for SSc [3–5]. Anti-Scl-70 antibodies originally identified by Douvas et al. [6] are directed against DNA topoisomerase I [7] and therefore should be more accurately termed antitopoisomerase I antibodies (ATAs). These autoantibodies are seen predominantly in dcSSc patients; however, their presence is not entirely restricted to this clinical subset since a subgroup of lcSSc patients was also found to be ATA-positive [8, 9]. ATA has been associated with poorer prognosis, increased mortality, pulmonary fibrosis, and cardiac involvement [9–12]. Another recent study of clinical outcomes in patients with digital ulcers showed that patients positive for ATAs developed Raynaud’s phenomenon earlier and had double rate of lung fibrosis as compared with ACA-positive patients [13]. Some reports indicate that changes in ATA titers over time can be useful in monitoring disease activity and progression and therefore useful for prognostic purposes [14]. ACAs recognize centromeric protein from CENP-A to CENP-F, of which CENP-B is reported to be a major autoantigen reacting with virtually all anti-CENP-positive SSc sera [15, 16]. ACAs are found in 20 to 30 % of SSc patients, and in up to 90 % of lcSSc patients [4, 17]. In patients with Raynaud’s phenomenon, ACAs have been reported to predict the onset of lcSSc [3, 18]. While severe interstitial fibrosis and renal crisis occur rarely, pulmonary arterial hypertension occurs in about 20 % of anti-CENP patients [9, 10, 19]. Anti-CENPs are often associated with other antibodies, such as anti-Sjogren’s-syndrome-related antigen A (anti-Ro) [20] or antimitochondrial antibodies [21]. Moreover, it has been reported that ACA positivity correlated with a more favorable prognosis and lower mortality compared with the positivity of other SSc-related autoantibodies [22]. Antibodies against RNA polymerase I and III (anti-RNP I and III) are detected with high specificity in SSc patients (98– 100 %) [23, 24]. Their prevalence varies from 10 to 25 % in different SSc cohorts. Anti-RNP I and III are associated with dcSSc involvement and renal crisis [25]. More recently, it has been shown that the presence of anti-RNP is associated with rapid onset of the disease and skin thickening. Therefore, they are still among the best predictive markers available for rapid skin progression [26]. Autoantibodies to RNP II are uncommon and are not specific for SSc since they can be also be found in the sera of systemic lupus erythematosus (SLE) and overlap syndrome [27]. Additional SSc-specific autoantibodies with diagnostic or prognostic utility include the anti-Th/To and anti-U3 RNP (antifibrillarin) antibodies. Th/To autoantibodies are directed against subunit of RNase P and RNase MRP [28]. They are found in 2–5 % of SSc patients and are clinically associated Semin Immunopathol (2015) 37:475–487 with lcSSc (8.4 % of lcSS (...truncated)