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Rheumatology 2009;48:iii8–iii13


The complexity of managing systemic sclerosis: screening
and diagnosis
M. Matucci-Cerinic1, V. Steen2, P. Nash3 and E. Hachulla4



SSc, Early diagnosis, Capillaroscopy, Cross-disciplinary communication.

initiation of treatment is therefore of paramount importance in
improving outcome.

SSc is a chronic connective tissue disease of unknown aetiology,
with an estimated prevalence of 1 in 10 000. As this uncommon
but severe disorder is characterized by a high level of clinical
heterogeneity, an unpredictable course, high mortality and resistance to therapy [1], it has long represented one of the greatest
challenges in the management of autoimmune rheumatic diseases.
Diagnostic and therapeutic standards vary widely across the
global clinical community, and no consensus has been reached on
the optimum approach to screening and diagnosis.

Digital ulceration
The most common and most visible manifestation of the widespread vascular pathology observed in SSc is RP, which is almost
universal among patients with the disease [3]. RP is characterized
by excessive vasoconstrictive responses to cold stimuli, leading to
pallor and cyanosis of the distal extremities, infarction and DU.
DU affects approximately half of the patients with SSc, and an
estimated 75% of the affected patients experience their first
episode within 5 yrs of their first non-RP symptom [4]. Occurring
in 30% of the SSc patients each year [3], DU is a major clinical
problem; not only does it cause severe pain and functional
impairment, but it may also result in significant disfiguration and
infection that can lead to gangrene, osteomyelitis and eventual
amputation [3–5].

The complexity of SSc
The difficulties inherent in diagnosing, screening and treating SSc
are due to the complex pathology of the disease, which involves
interplay between the immune system, vasculature and components of connective tissue [2]. These interactions contribute
towards the development of severe organ-based complications,
including digital ulceration [DU; often secondary to RP], renal
disease, cardiac or gastrointestinal (GI) manifestations of SSc and
pulmonary disease. In turn, organ-based complications produce
the high case-specific mortality rate observed among patients with
SSc [1, 2]. Data from the Royal Free Hospital in London show
that over two-thirds of deaths attributable to SSc between the
years 1990 and 2002 were caused by internal-organ complications,
and that pulmonary complications carry the worst prognosis.
From a total of 302 deaths attributed to SSc in this cohort, the
deaths of 128 patients (42%) were attributed to pulmonary
manifestations. Early detection of such problems and prompt

Renal complications
Despite the use of angiotensin-converting enzyme inhibitors
to prevent scleroderma renal crisis (SRC), it occurs in 6% of
all patients with SSc, and in 10–15% of those with diffuse SSc.
The outcome remains inadequate for many patients. Up to half of
them will require dialysis and the early mortality rate approaches
10% [2].
The course of SRC is characterized by rapidly progressive renal
impairment, hyperreninaemia, new-onset accelerated phase hypertension and acute renal failure with vascular lesions that may
occur without hypertension at presentation [6]. Early diagnosis
and treatment may thus be crucial in improving outcomes.
Fortunately, the following factors can be used to identify those
SSc patients who have a high risk of developing SRC: (i) early
diffuse SSc in which skin thickening is rapidly progressing;
(ii) recent onset of SSc without evidence of RP; (iii) presence of
tendon friction rubs; and (iv) RNA polI/III antibodies.


Department of Biomedicine, Centre DenoThe, Division of Rheumatology, AOUC
University of Florence, Florence, Italy, 2Department of Medicine, Georgetown
University, Washington DC, USA, 3Rheumatology Research Unit, Sunshine Coast
Queensland Department of Medicine, University of Queensland, Queensland,
Australia and 4Hoˆpital Claude-Huriez, University of Lille, Lille, France.

Cardiac manifestations
Cardiac manifestations of SSc include pericardial effusion,
myocardial inflammation, conduction abnormalities and, eventually, cardiac failure. Such complications are usually underdiagnosed. Autopsy studies suggest that subclinical cardiac
involvement is very common, but in vivo evaluation is inherently

Submitted 12 February 2008; revised version accepted 1 December 2008.
Correspondence to: M. Matucci-Cerinic, Department of Biomedicine, Centre
DenoThe, Division of Rheumatology, AOUC University of Florence, Florence
50139, Italy. E-mail:

ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email:

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The difficulties inherent in diagnosing, screening and treating SSc are reflected by the complex pathology of the disease, which involves the
development of severe organ-based complications that reduce both quality of life and overall survival. Early detection and prompt treatment of
such complications depend upon a successful and timely screening strategy, which, in turn, requires cooperation between disciplines and
good collaborative links at all stages of the disease. Establishment of a disease registry for SSc may also be of benefit, as such registries
facilitate longitudinal observation of trends in disease presentation, management and outcome. They may also help to determine potential risk
factors and identify those patient subgroups that face the highest risk of developing disease. In patients with known or suspected SSc, a panel
of disease-specific markers—such as autoantibodies, cell activation markers and markers of organ involvement—may help to establish the
diagnosis and assess prognosis; however, changes in serum levels of such markers throughout the course of SSc should be interpreted
with caution, as they may not always correlate with disease activity. Nail-fold capillaroscopy is a promising tool for SSc assessment
and may provide useful diagnostic and prognostic information, although further research is required to clarify its role in evaluating disease

The complexity of managing SSc


problematic: biopsies can be hazardous and might not sample
affected tissue. Gated cardiac MRI has shown some promise as a
research tool, but other diagnostic approaches—including nuclear
studies and detailed electrophysiological investigation of SSc
patients—have yielded inconsistent results [2].

GI manifestations
Complications involving the GI tract are common among patients
with SSc. Reflux and difficulty with swallowing are two of the
main features of GI involvement, though other problems may
include malabsorption, weight loss, bleeding, diarrhoea/constipation, colonic perforation, bowel pseudo-obstruction, faecal
incontinence, early satiety and bloating. Affected patients often
have a very poor quality of life.

FIG. 1. Lung disease dramatically affects prognosis in SSc. Image adapted from
[14]. Permission granted from the British Society for Rheumatology.

Pulmonary disease

FIG. 2. The accuracy of Doppler echocardiography in assessing pulmonary
hypertension. Image adapted from [11] with permission from the American
Thoracic Society.

capacity and any symptoms or signs that are suggestive of PAH or
right heart failure. Finally, the goal of cross-disciplinary collaboration should be the development of a combined clinic in which
specialists from different areas work together towards optimal
detection and treatment of SSc-associated PAH.

The importance of cross-disciplinary collaboration

Limitations of echocardiographic assessment of PAH

In order to illustrate the importance of cross-disciplinary collaboration in the management of patients with SSc, we consider
the potential impact of PAH in patients with SSc—a key area in
which strong collaborative links are crucial for optimal screening
and diagnosis.

Doppler echocardiography is a simple, reliable and non-invasive
method for estimating pulmonary arterial pressures and detecting
pulmonary hypertension. However, its use is associated with a
number of limitations, foremost among which is a tendency to
over- or underestimate the prevalence of PH. In one study by
Arcasoy and colleagues [11], Doppler echocardiography was more
likely to overestimate systolic pulmonary artery pressure (sPAP)
in patients without PH, yet was just as likely to overestimate as
underestimate sPAP in patients with evidence of PH (Fig. 2). The
use of echocardiography alone for the diagnosis of PAH may
result in a misleading diagnosis in almost 10% of the cases [12].
These findings suggest that, while Doppler echocardiography
represents a convenient tool for screening and identifying those
SSc patients who face a high risk of developing PAH, it may be
imprecise in determining actual pressures. Therefore, it should not
be used alone to diagnose PAH.

Screening and diagnosis of PAH in SSc
Between 12% and 16% of SSc patients have PAH [15], and
untreated mortality rates remain high (Fig. 1). In view of these
unfavourable observations, it becomes evident that screening
of SSc patients is essential to permit early detection of PAH
and timely therapeutic intervention. International and European
guidelines recommend the systematic screening of SSc patients
with annual Doppler echocardiography [16, 17], a pivotal tool for
PAH screening.
Of course, a screening programme that involves echocardiography necessitates the involvement of a cardiopulmonary specialist. Engaging the services of a cardiologist can be difficult, and
it is often necessary to convince him/her that optimal investigation
and management is justified in this patient population. It is
important to highlight any suspicion of PAH and to emphasize the
need to focus on the right side of the heart, as most echocardiographers only deal routinely with the left side. Crucially, the
cardiopulmonary specialist should be provided with specific
details of the clinical picture, including details of functional

Right heart catheterization in PAH
PAH is primarily a disease of pulmonary vascular resistance
(PVR) caused by proliferation and contraction of vascular smooth
muscle cells. In order to diagnose PAH, it is therefore necessary
to establish whether or not the patient has an elevated PVR.
Currently, the only available method for detecting and assessing
PVR and other important haemodynamic parameters (i.e. cardiac
output) is right heart catheterization (RHC). RHC should be

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Pulmonary complications are among the most common and
deadly manifestations of SSc and most often comprise fibrosis
or interstitial lung disease and pulmonary vascular disease leading to pulmonary arterial hypertension (PAH) [7]. Interstitial
lung disease in SSc may account for 16% of the deaths, [8] and
during post-mortem examination, evidence of pulmonary fibrosis is detectable in most SSc patients [9]. The clinical significance
of lung fibrosis in SSc is best defined by high-resolution CT,
and can be monitored optimally using pulmonary function
testing [10].
PAH is a devastating life-threatening condition that signals
advanced stages of disease in the pulmonary vasculature, parenchyma and airways [11]. PAH is defined as a mean pulmonary
arterial pressure of 525 mmHg at rest or 530 mmHg during
exercise, with a normal pulmonary capillary wedge pressure
(<15 mmHg) [12]. Currently, identification of PAH often occurs
late in the course of SSc, with up to 81% of the patients categorized as New York Heart Association (NYHA) Class III or IV
at the time of PAH diagnosis [13]. Unsurprisingly, PAH and lung
disease without PAH have a dramatic effect on survival in patients
with SSc (Fig. 1) [14]. Screening for pulmonary complications may
therefore enable earlier diagnoses, and treatment initiated earlier
may modify the course of disease.

M. Matucci-Cerinic et al.


performed in all cases in which PAH is suspected following
Doppler echocardiography: it not only confirms the presence of
PH and enables a specific diagnosis of PAH to be established,
but it also aids the diagnostic process by eliminating other
cardiac aetiologies and by assessing the degree of right heart

Screening algorithm for PAH

Screening for PAH: evidence of benefit

TABLE 1. Evidence of screening benefit: survival rates in patients with sclerodermarelated PAH at the Royal Free Hospital
Survival rates (%)


1997–2002 (n ¼ 82)

2002–2004a (n ¼ 102)

2004–2006b (n ¼ 74)




Introduction of endothelin receptor antagonists; bIntroduction of combination therapy.
Adapted from Royal Free Hospital Cohort database (unpublished data), permission granted
from Chris Denton and Gerry Coghlan.

An algorithm for screening patients with SSc has been proposed.
It involves the conduct of pulmonary function tests, echocardiography and catheterization of any patient who raises concern
(Fig. 3a). Once screened, a patient is referred and, at this point,
cross-disciplinary collaboration must be intensified—a practice
made much easier by the establishment of combined clinics. After
referral and initial telephone contact with the patient, it is
necessary to decide whether the case is urgent; if so, appropriate
treatment is administered within 2 weeks. If the case is not urgent,
the system will run its 3-month course from referral to diagnosis
(Fig. 3b). The time from referral to diagnosis must therefore be
managed, and a team should be established to ensure that this
happens on a continuous basis.

Early diagnosis of PAH: a national programme for early
An alternative screening algorithm for SSc-related PAH based on
symptoms, Doppler echocardiography and RHC has recently
been proposed by Hachulla et al. [12]. By this method, SSc
patients without severe pulmonary function abnormalities
underwent Doppler echocardiography, and all patients with a
peak velocity of tricuspid regurgitation of >3 m/s or 2.5–3 m/s
with unexplained dyspnoea underwent RHC to confirm
diagnosis [12].
Of the 599 patients analysed, 29 had known PAH [12]. A
further 33 had suspected PAH (based on Doppler echocardiography) and underwent RHC; of these 33 patients, 18 had a
diagnosis of PAH confirmed [12]. Newly diagnosed cases of PAH
were mild when compared with known cases, as measured by
RHC [12]. The estimated prevalence of PAH was 7.85% (95% CI
5.7, 10.0).
The algorithm reported by Hachulla et al. [12] is considered to
enable early detection of PAH at a mild-to-moderate stage of
severity, and should be applicable in routine practice. It remains

FIG. 3. Diagnosis of SSc-associated PAH: (a) screening algorithm and (b) assessment procedure at the Royal Free Hospital. DLCO: diffusion capacity for carbon monoxide;
LVEF: left ventricular ejection fraction; TG: tricuspid gradient; TLC: total lung capacity. Images courtesy of Chris Denton. Permission granted by Chris Deighton and Gerry

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The importance of establishing a screening programme for PAH
is highlighted by data from the Royal Free Hospital, which has
a 10-yr history of screening SSc patients. At this centre, early
identification of PAH through screening is followed by prompt
initiation of therapy with endothelin receptor antagonists (ERAs),
with resulting improvements in survival rates. With the recent
introduction of combination therapy, such as ERAs plus phosphodiesterase 5 inhibitors, 1-yr survival data appear to be even
more favourable (Table 1).
These data suggest that screening procedures can be effective
and can allow the clinical outcome of PAH to be altered. If the
disease is identified early in its course, treatment can be introduced
as soon as possible and the survival profile of affected patients can
be improved.
Another benefit provided by screening programmes is the
occasional identification of danger signals that require emergency
treatment. It is therefore important that all clinicians involved in a
screening programme, including the cardiologist and the echocardiographer, are in agreement regarding the clinical criteria
that constitute a medical emergency. At the Royal Free Hospital,
SSc patients with PAH are considered to require immediate


treatment if echocardiography reveals a very high tricuspid
gradient (>4 m/s), right ventricular dilation, pericardial effusion
or an enlarged right atrium (>27 cm2). Such patients are catheterized within 2 weeks of finding these features on an echocardiography scan.

The complexity of managing SSc
to be seen if early detection translates into improved prognosis for
patients with mild PAH [12].

Setting standards of care: establishing a disease registry
Why are disease registries important?

Objectives, patient populations and outcome measures
The most important issue when establishing a registry is the
determination of objectives. The purpose of the registry may be to
collect data on the natural history of a disease, or on the incidence
or prevalence of the features of that disease. Alternatively, the aim
may be to capture data on risk factors or treatment outcomes.
Whatever the goal, it is important to ensure that the objectives
are specific and well-defined if the registry is to be of maximum
Similarly, the type of patients to be included in the registry must
be identified and defined at the outset. All patients with the same
disease may be recruited and analysed, or they may be divided into
disease subsets (e.g. ethnicity, organs affected). Inclusion criteria
may specify that only patients with certain aspects of disease, or
only those treated with specific therapies, should be included.
Whichever way inclusion criteria are determined, a well-defined
patient population is crucial.
Finally, the outcome measures must be established. Specific
measures assessed by disease registries—which may include
patient-derived outcomes, laboratory studies, disease-related
events or survival—should all be defined, standardized and

Logistics and data analysis
A disease registry can take the form of a traditional (paper-based)
or internet-based database, both of which are associated with
advantages and disadvantages. Data submission to a traditional
database typically comprises case report forms submitted to a
clinical research centre; the processing of which can be expensive.
In addition, the monitoring of data and provision of access to data
by research personnel are time-consuming processes. In contrast,
an internet database enables electronic data capture and submission, and facilitates access to data and data analysis by authorized
research staff. However, there are high, short-term, development
costs associated with this approach, and security risks are
increased in comparison with traditional databases. Whichever
format is chosen, physician case report forms and patient questionnaires must be prepared, recruitment and enrolment strategies
described, and guidelines for the protocol, patient recruitment and
data entry developed.
In addition to basic logistics, methods of data analysis should
be defined from the start. The sample size for preliminary
data should be determined, and any specific composite measures or calculations for specific variables should be prepared. It
is important to ensure that data can be transferred easily to
the planned data analysis programme, and that strategies are in
place to manage the data and to deal with any queries or
missing data.

Limitations of data registries
Loss to follow-up. The major challenge of disease registries is to
collect follow-up data on every study subject recruited. Patients
lost to follow-up are a major source of bias, as these participants
do not necessarily have the same outcomes or experience as those
who remain under observation. Multiple sources of information
can be used to obtain complete follow-up information; however, it
may be better to have high follow-up on a limited number of
patients than poor follow-up on many. If many data (e.g. >20%)
are lost to follow-up, the validity of the study results may be
compromised; even if loss to follow-up is low (e.g. 10%), major
problems with data interpretation may still occur. For instance, if
the incidence of a particular finding is very low in the population
yet relatively high among patients lost to follow-up, the observed
point estimate may be severely biased.
Data lost to follow-up must therefore be kept to an absolute
minimum by using vigorous tracking techniques at patient entry
and employing people-finding methods where necessary. Statistical methods to handle losses to follow-up should be applied, and
other biases should be limited.
Types of bias. There are several types of bias that may be
encountered commonly in cohort studies involving disease
registries [18]. One of these is information bias, which can be
minimized by standardizing measurement instruments and administering instruments in the same way to all patients. Strict guidelines for data collection should be established, and observers and/
or interviewers should be trained to obtain data in the same
manner. The use of multiple sources of information may also help
to reduce bias.

Missing data. All studies and registries have some missing
information; to maintain the validity of the results, it is essential
to include rigorous methods for imputing missing data. Such
methods include the following: linear extrapolation for patients
missing a value; use of appropriate imputation techniques for
patients with other types of missing data; and use of sensitivity
analyses to explore the effect of missing data.
Biological markers in SSc
In patients with known or suspected SSc, a panel of diseasespecific markers may help to establish the diagnosis and assess
prognosis. Such markers include autoantibodies, cell activation
markers and markers of organ involvement (Table 2).

The detection and quantification of autoantibodies has become an
important component in the diagnosis and management of SSc, as
specific autoantibodies have been shown to correlate closely with
various clinical and laboratory manifestations of the disease
(Table 3).
However, measurement of autoantibodies is not considered to
be a ‘gold standard’ diagnostic test for SSc; autoantibodies are no
more than markers of disease with significant limitations, and are
best used as part of a diagnostic panel.

Cell activation markers
Numerous markers of cell activation have been correlated with
clinical features of SSc (Table 4).
Several studies have evaluated the effects of treatment on the
levels of various cell activation markers in patients with SSc. In
one study, 13 patients with early diffuse SSc were treated with oral
cyclophosphamide (2–2.5 mg/kg/day) and methylprednisolone
(30 mg/kg every other day) for 1 yr, and followed up for clinical and laboratory parameters. After 1 yr of treatment, patients
showed evidence of clinical improvement; concentrations of the

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The importance of disease registries when evaluating a rare
disease, such as SSc, lies in their ability to aid the longitudinal
observation of trends in disease presentation, management and
outcome. They can help to identify both potential risk factors of
disease and the patient sub-groups that face the highest risk of
disease; importantly, they can also be used to determine long-term
outcomes, establish ‘real life’ natural history and treatment trends,
quantify disease burden and facilitate research. As a result, disease
registries have gained widespread acceptance by the scientific
community, and their use can assist in all aspects of the diagnosis
and management of rare diseases.


M. Matucci-Cerinic et al.

TABLE 2. Biological markers in SSc

 Anti-DNA topoisomerase I, anti-centromere, anti-RNA polymerase I–III, antiU3 RNP, anti-Th, anti-PM-Scl.
Anti-endothelial cell antibodies
Anti-fibroblast antibodies
Anti-PDGFr antibodies
Cell activation markers
Endothelial cells
 ET-1, E-selectin, vWFAg, ICAM-1, VCAM-1, ACE
T-B lymphocytes, monocytes
 sIL-2r, IL-4, IL-6, IL-13, IL-17, BAFF, TGF-, CD30, MCP-1, TNF-
 Procollagen III-N propeptide, CTGF, TIMP 1, YKL-40
 B-thrombomodulin, PF-4

ACE: angiotensin converting enzyme; BAFF: B cell activating factor; CTGF: connective tissue
growth factor; ICAM: intercellular adhesion molecule; MCP-1: monocyte chemoattractant
protein; PDGFr: platelet-derived growth factor receptor; PF: platelet factor; sIL-2r: soluble IL-2
receptor; TGF-: transforming growth factor ; TIMP: tissue inhibitor of metalloproteinases;
VCAM: vascular cell adhesion molecule; vWFAg: von Willebrand factor antigen; YKL-40:
chitinase 3-like protein 1. Adapted from [19–21].

Biomarkers for PAH
Several prognostic markers are also available for predicting the
risk of organ involvement in SSc (Table 2). Of particular utility
when assessing the haemodynamics of SSc patients is (pro)natriuretic peptide (proBNP), which has been found to correlate
significantly with mean pulmonary arterial pressure (r ¼ 0.53),
right ventricular end diastolic pressure (r ¼ 0.59) and PVR
(r ¼ 0.49) [32]. These data are extended by a more recent study
in which proBNP levels were significantly higher in SSc patients
with PAH (n ¼ 68) than in those without PAH (n ¼ 41; P ¼ 0.0002)
[33]. ProBNP was also found to be predictive of survival: for every
order of magnitude increase in proBNP levels among patients with
PAH, there was a 4-fold increase in the risk of death (P ¼ 0.002
for baseline proBNP levels; P ¼ 0.006 for proBNP levels after 10
months’ follow-up) [33]. Assessment of proBNP levels in SScrelated PAH may therefore represent a potentially valuable
diagnostic and prognostic tool.

Assessment of microvascular damage: capillaroscopy
TABLE 3. Marker autoantibody specificities in patients with SSc
Anti-DNA topoisomerase I
Anti-RNA polymerase I–III
Anti-U3 RNP
Anti-endothelial cell

dcSSc, pulmonary fibrosis, disease severity
(total skin score [22])
lcSSc, favourable prognosis
dcSSc, renal involvement [23]
dcSSc, males, African–American race,
pulmonary hypertension [24]
lcSSc, intestinal involvement [25]
lcSSc; overlap with myositis [26]
Pro-adhesive and pro-inflammatory phenotype
in fibroblasts [27]
Induction of apoptosis and fibrillin 1 expression
in dermal endothelial cells [28]

TABLE 4. Correlations between clinical and laboratory measures of disease activity
in SSc
Circulating activity marker

Clinical correlate

sIL-2r and IL-8
Oncostatin M
vIL-6, IL-10, VEGF, sIL-2r

Total skin thickness score
Raynaud’s phenomenon
Renal crisis
‘Ground glass’ on HRCTa
Swollen joint count
Total skin thickness score

Refers to a hazy opacity that does not obscure the associated pulmonary vessels. This
appearance results from parenchymal abnormalities that are below the spatial resolution of
HRCT. Ground-glass opacity can be seen with alveolar wall inflammation or thickening, with
partial air-space filling, or with a combination of the two. HRCT: high-resolution CT; ICAM:
intercellular adhesion molecule; sIL-2r: soluble IL-2 receptor; vIL-6: viral IL-6; VEGF: vascular
endothelial growth factor. Adapted from [29] with permission from the Journal of Clinical and
Experimental Rheumatology.

cell activation markers, E-selectin and thrombomodulin, were also
found to be significantly reduced when compared with baseline
[30]. In a more recent study of low-dose cyclophosphamide treatment in patients with SSc, however, significant improvement in
several clinical measures of disease severity were not accompanied

Microvascular lesions are a principal feature of SSc and may
play a central pathogenic role [34]. Microangiopathy appears to
be the best evaluable predictor of SSc development, and may
precede manifestation of symptoms and involvement of the internal organs by many years [34]. Therefore, the activity and severity
of digital vascular disease in patients presenting with RP—often
the earliest clinical sign of vascular involvement in SSc—must be
measured and monitored [35]. Several methods of assessment can
be used, but capillaroscopy is currently viewed as the standard
procedure for evaluating the microcirculation.

Nail-fold capillaroscopy
Nail-fold capillaroscopy is a non-invasive, safe and inexpensive
imaging method that allows the in vivo assessment of the cutaneous microvasculature. It is widely regarded as one of the most
useful diagnostic and prognostic tools in the early stages of isolated RP [36], as any patient with RP and abnormal capillaries is
likely to have or develop underlying connective tissue disease, such
as SSc [32, 33]. On widefield capillaroscopy, characteristic nailfold capillary abnormalities are observed in patients with SSc,
including capillary dilatation and loop drop-out.

Capillaroscopic patterns in SSc
SSc microangiopathy has been graded into three distinct
capillaroscopic patterns (early, active and late) using nail-fold
videocapillaroscopy (NVC) [34, 37, 38]. The early appearance of
giant capillaries and haemorrhages (‘early’ stage) is of great
relevance for the early diagnosis of SSc, and allows differentiation
between primary and secondary RP [34]. The microangiopathic
changes observed in the early pattern are more evident in the
‘active’ phase. With severe loss of capillaries, evidence of vascular
architectural disorganization and the presence of ramified or
bushy capillaries, the ‘late’ stage represents the clearest aspect of
SSc microvascular damage [34]. These three distinct patterns seem
to reflect the evolution of SSc pathology—a hypothesis supported
by observations of longer disease duration in patients with the late
NVC pattern than in those with early or active patterns [34].
However, longitudinal studies are needed to confirm this

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Markers of internal organ involvement
Plasma renin activity
Surfactant proteins A, D, KL-6, CC16, CK19, SLX
Vitamin B12, folate, ferritinaemia

by significant changes in the levels of most cellular activation
markers assessed [31].
These findings suggest that, although cellular activation
markers might be useful in monitoring the progress or regression
of a disease, they may not always correlate directly with disease
activity. Any changes in serum levels of such markers following
treatment for SSc should therefore be interpreted with caution.

The complexity of managing SSc


Rheumatology key messages
 Patients with SSc are at high risk of developing severe, organbased complications that reduce quality of life and survival.
 Early detection and prompt treatment of such complications is
critical, and requires vigilance during management.

The authors received editorial assistance from Elements
Communications, supported by an educational grant from
Actelion Pharmaceuticals Limited (Allschwil, Switzerland).
Supplement: This paper forms part of the supplement entitled ‘Ten
years of partnership: translating ideas into progress in systemic
sclerosis’. This supplement was supported by an unrestricted grant
from Actelion Pharmaceuticals Ltd.
Disclosure statement: E.H. has received honoraria from and is
a consultant for Actelion, Roche, GlaxoSmithKline, United
Therapeutics, LFB and Pfizer. M.M.-C. has a consultancy
relationship with Actelion Pharmaceuticals. All other authors
have declared no conflicts of interest.

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Heightened vigilance towards early detection of SSc and its many
organ-based complications may help to improve clinical outcomes. An integrated, methodological and strategic approach to
screening and detection is required—an approach that also necessitates cross-disciplinary cooperation and good collaborative
links at every stage of the disease. As SSc is a rare condition, its
diagnosis and management may benefit from the establishment of
a disease registry that allows assessment of longitudinal patterns
in presentation, treatment and outcomes. Currently, physicians
can rely on some disease-specific biological markers to aid the
diagnosis and assessment of SSc, with proBNP showing particular
promise as a diagnostic and prognostic tool in patients with pulmonary complications. However, until biological markers are
validated as outcome measures, it is important that they are used
as part of a diagnostic panel rather than as definitive indicators
of disease or prognosis. Finally, patients at risk of SSc may be
identified using methods to assess early microangiopathic changes.
NVC has enormous potential in this area, and the identification of
distinct NVC patterns might be useful in assessing and following
microvascular involvement in SSc. However, long-term longitudinal studies are necessary to further assess the correlation
between NVC patterns and clinical manifestations of disease.


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