This article appears in the following Rheumatology issue: Update in systemic sclerosis [View the issue table of contents]
Biomarkers in systemic sclerosis
1Department of Rheumatology, Bone and Joint Unit, St Vincent's University Hospital and Dublin Academic Healthcare, Dublin, Ireland.
Correspondence to: D. J. Veale, Department of Rheumatology, Bone and Joint Unit, Dublin Academic Healthcare, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. E-mail: douglas.veale{at}ucd.ie
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Abstract |
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 Top Abstract IntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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SSc is a CTD, which may cause critical organ fibrosis. It has a highly variable clinical presentation and course. While it is more common in females, this heterogeneity has led to significant problems with classification. Biomedical (clinical) and biomolecular markers to identify diagnostic, prognostic and therapeutic response have been elusive in part as a result of difficulties with classification and also due to the rarity of the disease. Existing biomarkers have been identified largely in small cohorts and larger cross-sectional or occasional longitudinal observational cohorts. The nature of biomarkers requires well-defined clinical characteristics and/or defined clinical outcomes and this has been extremely challenging to the international SSc research community. This brief review summarizes the current level of knowledge; however, it most importantly highlights the potential now to find biomarkers through a large, multicentre, international collaborative group approach.
KEY WORDS: Systemic sclerosis, Scleroderma, Raynaud's phenomenon, Biomarkers, Collagen breakdown products, Acute-phase reactants, Immunoserological markers, Serum pro-brain natriuretic peptide, Serum N-terminal pro-brain natriuretic peptide, Endothelin
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Introduction |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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SSc has a prevalence of between 3 and 24 per million and a 4 : 1 female : male preponderance [1]. In addition to a highly variable clinical presentation, the immunoserological features are absent in up to 70% of the patients. SSc is characterized by excessive fibrosis, collagen deposition and microvascular injury. Inappropriate activation of endothelial and/or smooth muscle cells are key features in the pathogenesis of this disease. Until recently there was no evidence that this disease responded to medical therapy.
There are many classification schemes to separate the different presentations of SSc. Recently, the Scleroderma Clinical Trial Consortium (SCTC) developed a core set of measures for clinical trials of SSc including 11 pre-defined domains (skin, musculoskeletal, cardiac, pulmonary, cardiopulmonary, gastrointestinal, renal, RP and digital ulcers, health-related quality of life and function, global health and biomarkers) [2]. The biomarkers included in the core set include acute-phase reactant, CRP and ESR. Many other biomarkers were identified for future research as they have been shown to correlate with disease activity, survival and/or are present at the early stages of disease.
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Immunoserological biomarkers |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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Immunoserological biomarkers may prove useful to differentiate between subtypes of SSc or correlate with specific organ involvement, e.g. anti-centromere, anti-Scl 70 antibodies, anti-RNA polymerase III, anti-fibrillarin/U3 RNP and anti-U1RNP.
Early diagnosis is aided by examination of the nail-fold capillaries [3] at a time when RP plus disease-specific circulating ANAs (anti-topoisomerase-I or ACA) are present in the absence of diagnostic criteria suggesting a preclinical state. Indeed, serological factors when present have been shown to differentiate clinical subsets of disease; however, circulating antibodies vary widely within studies and with ethnicity [1]. dSSc is usually associated with a rapid onset of skin changes (puffy or hidebound) within 1 yr of onset of Raynaud's; truncal and acral skin involvement; presence of tendon friction rubs; early and significant incidence of interstitial lung disease, and myocardial involvement; nail-fold capillary dilatation and dropout; and anti-topoisomerase-I (Scl 70) antibodies (up to 20% of patients). lcSSc is associated with RP for years (occasionally decades); skin involvement limited to hands, face, feet and forearms (acral); a significant (10–15%) late incidence of pulmonary hypertension, with or without interstitial lung disease, skin calcification, telangiectasia and gastrointestinal involvement; high prevalence of ACA (up to 30%); and dilated nail-fold capillary loops, usually without capillary dropout. Scleroderma sine scleroderma is associated with RP; no skin involvement; and presentation with pulmonary fibrosis, scleroderma renal crisis, cardiac or gastrointestinal disease; and ANAs may be present (Scl 70, ACA, nucleolar).
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Acute-phase reactants and haemoglobin |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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An ESR >25 mm/h has been shown to be independently associated with death with an odds ratio of 3.89 in a study of 309 French Canadian patients with scleroderma using multivariate analysis [4]. A high ESR and low haemoglobin has also been shown in other studies including a UK [5] and an Italian population [6] as predictive of death in multivariate and univariate analysis.
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Soluble biomarkers |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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New screening tools are of great importance in patients with SSc where there is a lack of clinical signs and symptoms such as early in the progression of pulmonary hypertension. Pulmonary hypertension has become one of the most important factors contributing to morbidity and mortality, especially in patients with limited SSc. Serum pro-brain natriuretic peptide (pro-BNP)/serum N-terminal pro-BNP (NT pro-BNP) may be biomarkers for pulmonary hypertension as they both appear to be increased in the early stages of disease and correlate with haemodynamic measures and survival [7]. In another study, high serum NT pro-BNP levels predicted development of pulmonary hypertension with 90% sensitivity, 90.3% specificity and 90% negative predictive value in SSc patients [8].
Elevated levels of soluble adhesion molecules have been described as raised in patients with SSc compared with normal and disease controls. One study suggested that serial levels of sE-selectin and sVCAM may predict disease severity and/or progression [9]. In another study, we reported that sICAM-1 levels did not differ from controls; however, a dynamic measure of endothelial function using venous occlusion as a stress test showed a significant inverse correlation between the change in sICAM-1 levels and the clinical skin score [10]. ET is a mediator of pro-fibrotic pathways important in the development of fibrosis in the human lungs and potentially other organs [11]. Raised circulating plasma levels of ET have been described in SSc patients. Bosentan, an ET inhibitor used in PAH patients, however, failed to show significant changes in circulating soluble adhesion molecules or ET in one small study [12]. Indeed, there is some evidence to suggest bosentan increases circulating ET possibly via inhibition of type B ET receptor clearance function, which may result in tachyphylaxis.
The soluble form of CD40L (sCD40L), which is released by activated T-cells and involved in B-cell activation, fibrosis and expression of adhesion molecules on endothelial cells, has been shown to be elevated in plasma in SSc by three studies with small numbers of patients [13]. Plasma sCD40L levels were shown to be higher in patients with lcSSc than in those with dcSSc in two studies and sCD40L levels correlated with both pulmonary hypertension and also digital ulceration.
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Markers of collagen breakdown |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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The ongoing fibrotic process in SSc due to deposition of extracellular matrix of collagen forms a major component. Excessive collagen synthesis and deposition was a rationale for collagen turnover measurements to activity and severity in SSc. A systematic review in 2004 identified that previous studies had marked heterogeneity, small sample sizes and lack of standardized results when assessing serum, plasma and blister fluid collagen turnover biomarkers in SSc. One study (n = 33) showed increased serum collagen I carboxyterminal telopeptide in patients with SSc and a correlation with Rodnan skin score and pulmonary involvement [14]. Another study has suggested a role for urinary collagen breakdown products such as pyridinoline (pyr) and deoxypyridinoline (Dpyr) as the severity of skin involvement [15].
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Novel experimental biomarkers |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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In one preliminary study of 96 SSc clinical assessments of skin (modified Rodnan skin score), vascular, lung, heart, renal, gastrointestinal and neurological systems were obtained.
Significant associations were observed between skin score, digital ulceration and high ESR. In contrast, skin score negatively correlated with ACA. Many circulating molecular factors were assessed including IL-1, IL-2r, IL-6, IL-8, IL-10, IFN-g, ICAM-1 and oncostatin M. Regression analysis indicated that IL-10 predicted skin score, while IL-8 and IL-2r levels predicted Raynaud's severity and IL-2r predicted renal crisis and plasma urea (published abstract).
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Discussion |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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Skin, pulmonary, cardiac, renal and gastrointestinal variables have all been shown to have an influence on survival. In the study by Geirsson et al. [16], 100 patients were followed over a 14-yr period. Using a severity score of clinical variables, investigators predicted poor outcome from extensive skin scores, ECG changes, and compromised lung and renal function. Organ dysfunction became manifest during the first 5 yrs of SSc, thereafter organ function remained stable. SSc has a broad spectrum of presentation, from rapidly progressive generalized fibrosis of individual or multiple organs to a more slow-burning pattern over a long time period. Any early potential active treatments must have better clinical- or laboratory-based prognostic markers in a disease with significant morbidity and premature death.
Severity scores have been proposed for patients with SSc. Along with prognostic criteria, these are intended to separate subjects with a favourable outcome from those with a poor outcome. To date, disease activity has only been roughly defined for SSc in a small number of studies. Valentini et al. [17] observed that such a definition would allow the clinician to tailor aggressive or symptomatic treatment for individual patients. However, due to study design problems it was impossible to draw firm conclusions in this study. Defining disease activity in SSc is difficult, particularly in those with limited or overlap disease, who may not present with a clear clinical picture. Nevertheless, from a pathophysiological point of view, two distinct stages can be defined in SSc: first, a potentially reversible inflammatory stage and second, a mostly irreversible stage with vascular occlusion and extensive fibrosis. The combination of immunoserological markers, nail-fold capillaroscopy and well-defined clinical features has improved our ability to characterize patients, but specific and sensitive biomarkers of activity, damage and response to therapy are needed but remain elusive.
It is important, therefore, to identify biomarkers that correlate with disease activity, prognosis and response to therapy allowing physicians to accurately identify patients early, those likely to respond and to predict prognosis. The majority of studies to date have been small cross-sectional or longitudinal observation cohorts, which have failed to provide clear evidence of biomarker validity. This has been compounded by the lack of effective therapies in this disease. The recent evidence from two clinical trials has provided a glimmer of hope in the treatment of SSc. The collaboration of growing members of the international research community through the Scleroderma Clinical Trials Consortium (SCTC) and the European League Against Rheumatism (EULAR)-affiliated EULAR Scleroderma Trials and Research (EUSTAR) groups offer significant hope of achieving this common goal and completing adequately powered, large prospective, cohort studies to validate potential biomarkers.
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Acknowledgements |
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TopAbstractIntroductionImmunoserological biomarkersAcute-phase reactants and...Soluble biomarkersMarkers of collagen breakdownNovel experimental biomarkersDiscussionAcknowledgementsReferences |
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Supplement: This paper forms part of the supplement entitled ‘Update in systemic sclerosis’. This supplement was supported by an unrestricted grant from Encysive.
Disclosure statement: D.J.V. is a member of a speakers' bureau and has received research support from Actelion and Encysive. The other author has declared no conflicts of interest.
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References |
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