Rheumatology 2008 47(Supplement 5):v21-v22; doi:10.1093/rheumatology/ken281
© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Biomarkers of vascular disease in scleroderma
L. K. Hummers1
1Johns Hopkins Scleroderma Center, Johns Hopkins University, Baltimore, MD, USA.
Correspondence to: L. K. Hummers, Johns Hopkins Scleroderma Center, 5501 Hopkins Bayview Circle, Room 1B.7, Baltimore, MD 21224, USA. E-mail: lhummers{at}jhmi.edu
 |
Abstract
|
|---|
Vascular disease is present in every patient with scleroderma
and is a major source of morbidity and mortality. There is a
subset of patients who will develop severe and sometimes life-threatening
vascular events. We have good evidence that an insult to the
microvasculature occurs early in the disease course, but there
is a subset of patients who have an ongoing chronic process,
the end result of which are events such as digital loss and
pulmonary arterial hypertension. The ability to detect this
process at an early stage by simple means would be of great
value as our ability to treat these vascular complications improves
with time. We have a significant amount of evidence of vascular
perturbation from studies of peripheral blood in scleroderma,
but know very little about the ability of these biomarkers to
predict vascular outcomes. In this review, we will critically
assess our current knowledge of the use of biomarkers of vascular
disease in scleroderma and the possible directions of future
research in this area.
KEY WORDS: Scleroderma, Pulmonary hypertension, Biomarkers, N-terminal pro-BNP, Diffusing capacity for carbon monoxide
|
The potential utility of biomarkers in scleroderma vascular disease
|
|---|
The term biomarker is commonly found in the medical literature
but is often misused. The NIH Biomarkers Definitions Working
Group defines a biomarker as ‘A characteristic that is
objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes or pharmacologic
responses to a therapeutic intervention’ [
1]. An ideal
biomarker reflects the underlying biologic process, predicts
clinical events in the absence of treatment and is easily obtainable.
This typically requires validation in a longitudinal cohort
study. For the study of scleroderma vascular disease, biomarkers
may serve three important roles:
- Help understand pathological mechanisms.
- Predict the development of vascular complications (i.e. pulmonary hypertension) in a susceptible population.
- Define response to therapy.
|
Selected data from biomarker studies in scleroderma
|
|---|
An exhaustive review of all of the data on potential biomarkers
of scleroderma vascular disease is beyond the scope of this
article. We highlight here some examples of the potential of
certain biomarkers to serve as surrogates for the vascular disease
process in patients with scleroderma.
|
Biomarkers to investigate pathogenesis
|
|---|
Numerous cross-sectional studies have investigated markers of
possible pathogenic processes of scleroderma vascular disease.
Typically, these studies have shown clear evidence of perturbation
of the vascular bed suggesting possible endothelial cell dysfunction,
abnormalities of vascular smooth muscle, altered fibrinolysis
and coagulation or angiogenic imbalance. Almost all of these
studies have examined a cross-section of unselected scleroderma
patients, measuring the possible biomarkers at one point in
time. A smaller number of studies have correlated these measures
with clinical data (e.g. the presence of diagnosed vascular
disease such as pulmonary hypertension) or have measured factors
longitudinally. For example, Hesselstrand
et al. [
2] examined
several circulating markers [von Willebrand factor as a marker
of endothelial perturbation, thrombomodulin as a marker of vascular
injury, pro-brain natriuretic peptide (BNP) as a marker of right
ventricular dysfunction and calcitonin gene-related peptide]
in a longitudinal study of patients with and without echocardiographic
evidence of pulmonary hypertension. Only pro-BNP correlated
with a tricuspid gradient in a group of scleroderma patients
with serial echocardiograms. Distler
et al. [
3] found increased
VEGF levels in scleroderma compared to controls; higher levels
were found in early disease and in topoisomerase positive patients
but were negatively associated with finger ulcerations. Others
have suggested that VEGF levels may also be modified by therapy
directed at the vascular disease [
4].
Many studies have attempted to investigate pathological mechanisms of a poorly understood process. This is clearly a worthwhile endeavour. However, there are multiple limitations to this approach (Fig. 1). The biological effects of many markers (such as VEGF) are pleiotropic and may vary over time and vary with different stages of disease. Many of these studies have been limited by lack of good control populations; therefore, the specificity of the marker to the scleroderma disease process is unknown. It is unclear if these markers are measuring ongoing vascular events or terminal damage to the vascular bed. Despite these limitations, we are likely to learn some incremental information about the vascular disease process with the accumulation of data from these investigations. Validation of these biomarkers, however, will require longitudinal, well-controlled, prospective studies.
|
Biomarkers as a predictor of development of pulmonary hypertension
|
|---|
Biomarkers that predict specific clinical events (such as development
of pulmonary hypertension) have yet to be identified. Multiple
studies have demonstrated circumstantial evidence of an ongoing
vascular insult that predates the clinical diagnosis of pulmonary
hypertension. Steen
et al. [
5] reported a marked decrease in
the diffusing capacity for carbon monoxide (DLCO) years prior
to the diagnosis of pulmonary hypertension in a retrospective
case–control study. The increasing interest in the scleroderma
vascular disease and the presence of multiple scleroderma-specific
centres around the world will allow for prospective evaluations
of potential predictors of adverse outcomes including pulmonary
hypertension. A recent study by Allanore
et al. [
6] investigated
the levels of N-terminal pro-BNP (NT-pro-BNP) and low DLCO as
biomarkers to predict the development of pulmonary arterial
hypertension (PAH). This study followed a prospective cohort
of 101 patients without PAH for a median of 29 months with NT-pro-BNP
and DLCO measured at baseline. This study demonstrated that
both high levels of NT-pro-BNP and a low DLCO (corrected for
alveolar volume) independently predicted the development of
PAH in univariate and multivariate analysis [
6]. One limitation
of this study is that NT-Pro-BNP is a measure of atrial or ventricular
strain and not the underlying pathologic process. This approach,
however, will likely yield the most useful predictive biomarkers
to detect an early pathological process.
|
Biomarkers as surrogate endpoints in clinical trials
|
|---|
Fortunately, several classes of medications are now approved
for the treatment of PAH with data from well-designed clinical
trials that have all included patients with scleroderma. The
primary and secondary outcomes of these trials include functional
capacity (6-min walk testing, WHO classification), clinical
worsening (including change in therapy, hospitalization, need
for lung transplant) and physiological parameters (cardiac index).
All of these outcomes have some limitations and this is an area
where the use of biomarkers as a surrogate endpoint may be of
great value in predicting ‘harder’ outcomes such
as death or clinical worsening (for a complete review on this
topic, refer to [
7]). Unfortunately, published clinical trials
have not included investigations of possible surrogate markers.
ET-1 seems like a logical choice, particularly since levels
are elevated and correlate with the severity of PAH. However,
since dual ET receptor antagonists are likely to increase circulating
levels of ET and due to the very short half-life of the molecule
in circulation, this may not be a good candidate for all clinical
trials [
8]. Sfikakis
et al. [
9] studied markers of endothelial
function in scleroderma patients treated with bosentan for either
pulmonary hypertension or digital ulcerations. They found no
difference in the levels of ICAM-1, E-selectin, VEGF or ET-1
after 4 and 16 weeks of treatment with bosentan.
Multiple studies have investigated BNP and NT-pro-BNP. These markers are increased in patients with PAH, are linked to disease severity [correlates with pulmonary vascular resistance (PVR) and functional class and inversely correlates with 6-min walk distance] and have been correlated with adverse outcomes including mortality [10]. A small study has shown that levels decrease during therapy and correlate with improving haemodynamic parameters [10]. Adjunctive therapies (diuretics, etc.) may impact atrial or ventricular ‘stretch’, which may limit the value of this marker in clinical trials.
|
Summary
|
|---|
Vascular disease is a fundamental part of scleroderma pathogenesis
and is characterized by marked heterogeneity of expression,
long periods of preclinical activity and in a subset of patients
is the major source of morbidity and mortality. Circulating
factors that reflect ongoing vascular perturbation have the
potential of serving as intermediate biological endpoints that
can not only detect and characterize vascular disease activity
but also predict ultimate disease outcome or treatment response.
In order to realize fully the benefit of biomarkers, several
factors must be incorporated into study design. For studies
examining pathogenic mechanisms, appropriate control groups
and longitudinal assessments are necessary to ensure specificity
and reliability. If a marker is investigating predictive ability
for vascular outcomes, prospective cohorts with well-characterized
patients and well-defined outcomes are necessary. Potential
biomarkers should be incorporated into clinical trials, although
confounding factors will have to be taken into account. Our
ability to understand and to manage scleroderma vascular disease
will explode in the upcoming years, making this the ideal time
to investigate the great potential of biomarkers in this field.
|
Acknowledgements
|
|---|
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: The author has declared no conflicts of interest.
|
References
|
|---|
- Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther (2001) 69:89–95.[CrossRef][Web of Science][Medline]
- Hesselstrand R, Ekman R, Eskilsson J, Isaksson A, Scheja A, Ohlin AK, Akesson A. Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992–2001. Rheumatology (2005) 44:366–71.[Abstract/Free Full Text]
- Distler O, Del Rosso A, Giacomelli R, et al. Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res (2002) 4:R11.[CrossRef][Medline]
- Mittag M, Beckheinrich P, Haustein UF. Systemic sclerosis-related Raynaud's phenomenon: effects of iloprost infusion therapy on serum cytokine, growth factor and soluble adhesion molecule levels. Acta Derm Venereol (2001) 81:294–7.[CrossRef][Web of Science][Medline]
- Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum (2003) 48:516–22.[CrossRef][Web of Science][Medline]
- Allanore Y, Borderie D, Avouac D. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum (2008) 58:284–91.[CrossRef][Web of Science][Medline]
- Snow JL, Kawut SM. Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy. Clin Chest Med (2007) 28:75–89. viii.[CrossRef][Web of Science][Medline]
- Williamson DJ, Wallman LL, Jones R. Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation (2000) 102:411–8.[Abstract/Free Full Text]
- Sfikakis PP, Papamichael C, Stamatelopoulos KS. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum (2007) 56:985–93.
- Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol (2006) 98:525–9.[CrossRef][Web of Science][Medline]
Submitted 30 April 2008;
Accepted 19 June 2008
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Abstract
The potential utility of...