Rheumatology Advance Access published April 25, 2013

RHEUMATOLOGY 260, 262

Review doi:10.1093/rheumatology/ket153

State of art on nailfold capillaroscopy: a reliable

diagnostic tool and putative biomarker in
rheumatology?
Maurizio Cutolo1 and Vanessa Smith2

Abstract
Capillaroscopy is a non-invasive and safe tool to morphologically study the microcirculation. In rheuma-
tology it has a dual use. First, it has a role in differential diagnosis of patients with RP. Second, it may

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have a role in the prediction of clinical complications in CTDs. In SSc, pilot studies have shown predictive
associations with peripheral vascular and lung involvement hinting at a role of capillaroscopy as putative

R EV I E W
biomarker. Also and logically, in SSc, microangiopathy, as assessed by capillaroscopy, has been asso-
ciated with markers of the disease such as angiogenic/static factors and SSc-specific antibodies.
Moreover, morphological assessments of the microcirculation (capillaroscopy) seem to correlate with
functional assessments (such as laser Doppler). Because of its clinical and research role, eyes are
geared in Europe to expand the knowledge of this tool. Both the European League Against
Rheumatism (EULAR) and the ACR are stepping forward to this need.
Key words: capillaroscopy, microcirculation, Raynaud’s phenomenon, differential diagnosis, connective tissue
diseases, classification criteria, systemic sclerosis, clinical complications, EULAR.

Background century was characterized by the optimization of capil-

Capillaroscopy is a tool for looking at the microcirculation.
The history of capillaroscopy started in 1663, when Johan
Christophorous Kolhaus was the first clinician to use a
primitive microscope to observe the small blood vessels
surrounding the nails. Giovanni Rasori (1776–1873), using
a magnifying glass, first reported the close relationship
between conjunctival inflammation and the presence of
an inextricable knot of capillaries [1].
From the time that Maurice Raynaud (1834–1881)
presented his thesis on local ischaemic damage of the
hands, feet, nose and tongue, intravital microscopy (or
capillaroscopy) became recognized as an important in-
vestigation in identifying and analysing microvascular
involvement, which is the key feature of RP. The last
1
Research Laboratory and Academic Unit of Clinical Rheumatology,
Department of Internal Medicine, University of Genova, Genova, Italy
and 2Department of Rheumatology, Ghent University Hospital, Ghent,
Belgium.
Submitted 23 October 2012; revised version accepted 13 March 2013.
Correspondence to: Maurizio Cutolo, Research Laboratory and
Academic Unit of Clinical Rheumatology, Department of Internal
Medicine, University of Genova, Viale Benedetto XV, No. 6, 16132
Genova, Italy. E-mail: mcutolo@unige.it
laroscopic tools (Fig. 1).
Nowadays the role of capillaroscopy lies in making a
differential diagnosis between a primary RP (PRP), not
related to any clinical condition, and a secondary RP
(SRP), related to a CTD. In addition, a recent meta-ana-
lysis showed capillaroscopy to be the best predictor of
transition from a PRP to an SRP [2]. Besides this, eyes
are geared towards investigation of its possible role as a
biomarker in CTDs.
Irreplaceable role of capillaroscopy for
early differential diagnosis between PRP
and SRP
Microvascular dysfunction and damage seem to consti-
tute an important initial pathological event in several CTDs
and in SSc they seem to represent even the origin of pro-
gression towards a systemic fibrotic disease [3, 4]. Still, as
stated in a recent review, almost 10–12 years ago it could
have been justifiably argued that there was relatively lim-
ited interest in differentiating between PRP and the very
early stages of SRP due to SSc or other CTD [5].
The advent of discriminatory criteria incorporating a
central role for capillaroscopy has changed this attitude.
In fact, nailfold capillaroscopy is able to distinguish in a
reliable manner a PRP from an SRP due to SSc [6].

! The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com 1
Maurizio Cutolo and Vanessa Smith

FIG. 1 Capillaroscope of the early 20th century compared with the new digitalized nailfold videocapillaroscope of the
21st century.

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FIG. 2 NVC images in PRP and SRP.

Left: NVC picture of PRP characterized by normal capillary array and no structural alterations of the microvessels. Right:
NVC picture of SRP characterized by non-homogeneously and homogeneously (giant) enlarged capillaries (in this case
early NVC scleroderma pattern—magnification 200).

A patient with a PRP meets, among other criteria (see
below), the following criterion: having a normal capillaro-
scopy (in a normal capillary pattern, capillaries of the distal
row of the nailfold have an open hairpin shape, are homo-
geneously sized and regularly arranged in a parallel fash-
ion and their number ranges in linear mm from 6 to 14 with
a mean of 9) [7–9]. In contrast, the capillaroscopic image
of a patient with RP due to SSc is characterized by path-
ognomonic microvessel structural damage (Fig. 2) con-
sisting of the presence of giant capillaries, capillary loss
and other morphologic anomalies such as progressive
neoangiogenesis (see later) [8, 10, 11]. These pathogno-
monic changes can be reliably distinguished from normal
images [12].
In addition, patients with merely RP, who are to develop
a secondary RP due to SSc in the long run, can nowadays
be detected early, before clinically overt disease sets in.
In this way, prospective follow-up of a cohort of patients
with only RP as clinical presentation has shown that
the combination of pathognomonic scleroderma-type
changes on capillaroscopy with the presence of SSc-
specific antibodies renders progression to definite SSc
in 47%, 69% and 79% over 5, 10 and 15 years of fol-
low-up [13].
Interestingly, when using only capillaroscopy (without
testing specific SSc antibodies) in the follow-up (29 ± 10
months) of patients with merely RP at baseline, transition
from a normal (and non-specific changes) to a patho-
gnomonically abnormal pattern can be seen in 15% of
patients [14].
Of note, the role of capillaroscopy in CTD other than
SSc is not indispensable. Even though structural changes

2 www.rheumatology.oxfordjournals.org

may be present in other CTDs, they are not a conditio
sine qua non and they are moreover non-specific.
Consequently, capillaroscopy finds its primary aim in
daily practice in detecting those patients with RP who
have, or are to have, SSc.
Place for capillaroscopy in classification
criteria of SSc
For a long time, even though their importance was already
well alluded on in 1973, capillaroscopic markers of the
scleroderma pattern were not included in the classification
criteria of SSc, and only after 2000 were they introduced
in published classification criteria [8, 15, 16].
Interestingly, in 2001 the sensitivity of the ACR criteria
to identify patients with limited cutaneous disease was
found to be significantly improved with addition of nailfold
capillary abnormalities (definite enlargement and loss of
capillaries) and visible telangiectasias from 34% to 89%
in a cohort of 259 patients with a diagnosis of SSc based
on expert opinion [17].
In line with this, the year 2001 was also the year in which
the hallmark article, definitely establishing the paramount
role of capillaroscopy in differentiating a PRP from an SRP
due to SSc, was published by LeRoy and Medsger [8]. In
this LeRoy stated that a PRP must have a normal capil-
laroscopic image, absence of antinuclear factors, no sedi-
mentation and no signs reflecting peripheral vascular
disease.
In addition, the presence of a scleroderma pattern on
capillaroscopy and SSc-specific antibodies were stated to
be sufficient to diagnose the patient as having early
(preclinical) SSc [8]. These criteria, mainly focusing on
the vascular component of the disease, were intended
to be more sensitive than the ACR criteria (based on
skin involvement, the fibrotic component of the disease).
Besides that, the LeRoy criteria have been validated both
in a retrospective and in one large prospective study (see
above) [13].
In 2011, the following criteria (based on expert opinion,
obtained through three Delphi rounds within an interna-
tional forum of experts in SSc) for the very early diagnosis
of SSc (VEDOSS criteria) have been proposed to have
high clinical relevance for SSc: RP, puffy swollen fingers
turning into sclerodactyly, abnormal capillaroscopy with
scleroderma pattern, positive ACAs and positive anti-
topoisomerase antibodies. These VEDOSS criteria are in
line with the LeRoy criteria but differ as to the extent of
cutaneous signs of the disease [18].
In addition, in 2012, an international working group
(supported by the ACR and EULAR), with the aim of revis-
ing the classification criteria for SSc, proposed (based on
consensus techniques such as the Delphi and nominal
group technique) capillaroscopy as one of the top poten-
tial items useful for classification of SSc [19]. Clearly, all
these investigations over the past decade have confirmed
and enhanced interest in and the need for capillaroscopy,
at least in the early diagnosis of SSc.
www.rheumatology.oxfordjournals.org
Nailfold capillaroscopy
Use of qualitatively and quantitatively
assessed scleroderma capillaroscopic
patterns for the diagnosis and follow-up
of SSc
More than 90% of patients with clinically overt SSc show
a scleroderma pattern on capillaroscopy (Fig. 3). This
pattern may be recognized on visual inspection (= quali-
tative assessment) by several types of microscope, at dif-
ferent magnifications [9, 10].
Last century the most frequently used magnification
was the widefield technique (low magnification, e.g. mag-
nification 12) with which a whole nailfold can be evalu-
ated in one capillaroscopic image. With this technique
Maricq described the hallmark articles attesting a specific
pattern to be present in a SSc population vs healthy con-
trols and other CTDs [16, 20, 21].
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This century, with the high magnification (e.g. magnifi-
cation 200) technique (which better visualizes the capil-
laries themselves but only one-fourth of the nailfold per
capillaroscopic image) Cutolo et al. [10] classified these
scleroderma patterns into early, active and late sclero-
derma patterns [10].
Logically, as SSc is characterized by progressive oblit-
eration of the microcirculation, each of these consecutive
patterns consists of a higher proportion of capillary loss
[10, 22].
Besides that, each of the patterns is also characterized
by a different prevalence of characteristic markers of
the disease, more specifically giant capillaries, haemor-
rhages (both present in the early and frequent in the
active SSc pattern), SSc and aberrant morphological
microvascular shapes (so-called neoangiogenetic capil-
laries, present in the active and frequent in the late
pattern).
Pathognomonic in preclinical SSc (presence of merely
RP and an SSc-specific antibody, see above) is the pres-
ence of giant capillaries (defined when using the widefield
technique as definitely enlarged capillaries, with a loop
width of 90–150 mm and apical limb diameter of >50 mm
and in line with this when using the high magnification
technique as homogeneously enlarged capillaries, with
apical diameter >50 mm) [13, 23, 24]. The occurrence of
clinically overt disease coincides with the occurrence of
loss of capillaries, as attested in a large longitudinal
follow-up study of patients with RP, with the evolution of
capillaroscopic parameters in those who were to develop
SSc [13].
Inter-rater reliability in distinguishing scleroderma pat-
terns from normal capillaroscopic images has been
confirmed by both low and high magnification techniques
[12, 25–27].
Besides visual inspection (qualitative assessment) of
the scleroderma patterns, characteristic capillary changes
can also be counted (quantitative assessment), usually
per linear mm [22, 28, 29].
Of those quantified capillaroscopic parameters
for which inter-rater reliability has been establis-
hed, the count of capillaries, giant capillaries and
3
Maurizio Cutolo and Vanessa Smith
FIG. 3 NVC scleroderma patterns early, active and late vs normal capillary array—magnification 200.
haemorrhages diminishes over time and neoangiogenetic
capillaries augment over time when evaluated at group
level [22].
Given this change over time of capillaroscopic para-
meters, capillaroscopy has been used as outcome meas-
ure in small therapeutic trials with different agents [30–33].
Further large randomized controlled trials are needed to
investigate the role of capillaroscopy in quantification of
treatment response in terms of improvement in micro-
vascular structure.
Predictive role of capillaroscopy for SSc
clinical complications
Next to its role in discerning a primary from a secondary
RP due to SSc, focus is on a possible role in informing the
clinical researcher of possible future clinical complica-
tions. Cross-sectional associations have been made be-
tween qualitative and quantitative capillaroscopic
parameters and clinical complications of the disease.
In this way, a principal role of loss of capillaries has
been attested in associations with pulmonary arterial
hypertension, interstitial lung disease, peripheral vascular
disease and severity of peripheral vascular disease, heart
and lung involvement assessed by the disease severity
scale of Medsger [34–37].
Prospective predictive associations, in which baseline
capillaroscopy (either qualitatively or quantitatively as-
sessed) is associated with future clinical complications,
4 www.rheumatology.oxfordjournals.org
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are scarce, but there is evidence of a putative role of
capillaroscopy as biomarker in SSc (Table 1) [38–41].
Links between SSc serum biomarkers
and capillaroscopic scleroderma
patterns
Two main categories of serum SSc biomarker have been
investigated in correlation with the different nailfold video-
capillaroscopic (NVC) patterns: angiogenic/static, vasculo-
genic factors and autoantibodies. Angiogenesis is heavily
disturbed in SSc as mirrored by pathognomonic capillaro-
scopic changes (see above). In addition, despite the hyp-
oxic conditions induced by the progressive SSc fibrosis
and capillary number decrease, there is no evidence for
sufficient compensatory angiogenesis in SSc.
One culprit may be an imbalance between angiogenic
and angiostatic factors [42]. Also vasculogenesis may be
impaired. Cross-sectional associations have been
described between microangiopathy (as assessed by
capillaroscopy) and three angiogenic [vascular endothelial
growth factor (VEGF), angiopoietin 2 (Ang-2) and endothe-
lin-1 (ET-1)], one angiostatic factor (endostatin) and one
vasculogenetic factor (Table 2) [43–48].
The following associations between antibodies and
capillaroscopy have been described in SSc: associations
with anti-endothelial cell antibody (AECA) and with SSc-
specific antibodies. AECA serum levels were recently
found to be higher in patients with the late NVC pattern
 Nailfold capillaroscopy

TABLE 1 Role of videocapillaroscopy as putative biomarker

Capillaroscopic assessment

Author Qualitative Quantitative Prospective association

Sebastiani et al. [38]
Smith et al. [39]
Sebastiani et al. [40]
Smith et al. [41]
— Formula based on number of
giants, maximum diameter of
the largest giant and number of
capillaries as quantified in the
most representative image.
— Formula based on a mean
score of loss of capillaries as
quantified over eight fingers
(one field per finger).
— Multicentre validation of formula
as proposed in 2009.
Early, active and late — Odds that rise through early/active/late of
Specificity of 85.9% and sensitivity of
94.3% to predict development of new
digital ulcers within 3 months after the
capillaroscopic visit.
Specificity of 69.77% and sensitivity of
70.00% in predicting development of
digital trophic lesions within 6 or 12
months after the capillaroscopic visit.
Specificity of 81.4% and sensitivity of
92.98% in predicting development of
new digital ulcers within 3 months after
the capillaroscopic visit.

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scleroderma pat- developing severe peripheral vascular
terns according to or lung disease within 18 or 24 months
Cutolo et al. [10] after the capillaroscopy visit.

Prospective associations between individual capillaroscopic quantified characteristics (quantitative assessment) or between
qualitative scleroderma patterns (qualitative assessment [10]) and future clinical complications in SSc.

TABLE 2 Association between angiogenic/angiostatic factors and qualitative scleroderma/quantitative patterns

according to Cutolo et al. [10]

Author Comments

VEGF Distler et al. [46] Higher levels in scleroderma patterns vs healthy controls (P < 0.001).
No association within scleroderma patterns (P = 0.32).
Avouac et al. [44] Association between higher VEGF and late scleroderma pattern (P = 0.0008) within an
SSc population.
Ang-2 Riccieri et al. [45] Association with late vs early/active pattern (P = 0.05) within an SSc population.
ET-1 Sulli et al. [48] Higher levels in the active and late scleroderma pattern vs healthy controls (P = 0.003).
Kim et al. [47] Association with capillary dimension (P < 0.05) within an SSc population.
Endostatina Distler et al. [46] Inverse association with presence of giants (P 4 0.02) within an SSc population.
EPCb Avouac et al. [44] Inverse association with the late scleroderma pattern (P = 0.007) within an SSc
population.

EPC: endothelial progenitor cell. aAngiostatic factors; bimpaired vasculogenesis.

compared with the early and active ones (P = 0.04 and
P < 0.02). In addition, higher skin scores and cardiovas-
cular involvement were related to the presence of AECA
and more severe microvascular changes, suggesting that
AECA may have a role in the progression of endothelial
damage and SSc disease [49].
Concerning SSc-specific antibodies, studies in
populations with established and early SSc have been
described. In established SSc, the prevalence of anti-
Scl70 antibodies is significantly higher in the active and
late vs the early patterns (P < 0.001), whereas the preva-
lence of ACA was highest in patients with the early NVC
pattern [50].
In early SSc, prospective follow-up in those patients
with RP who are prone to develop SSc has attested a
sequence in the occurrence of microcirculatory changes,
more specifically, first, appearance of giants, before the
onset of clinically overt SSc and second, loss of capil-
laries, around the same time as occurrence of clinically
overt disease. Also a varying time course for occurrence
of microcirculatory damage after onset of RP depending
on SSc antibody specificity has been described in this
early SSc population.
In this way, giant capillaries occur earliest in patients
with anti-RNAP III antibodies, latest in those with anti-
CENP-B antibodies, whereas time of occurrence was
intermediate with anti-Th/To (P = 0.002). A similar tem-
poral development occurred for capillary loss in relation-
ship to these three antibodies (P = 0.021) [13]. Further
research, based on these associations, will clarify the
role of the immune response in the pathogenesis and pro-
gression of SSc.

www.rheumatology.oxfordjournals.org 5
Maurizio Cutolo and Vanessa Smith
Correlations between morphological
analysis of microcirculation
(capillaroscopy) and functional
analysis of microcirculation
While NVC measures capillary morphology, methods such
as laser Doppler imaging and thermography can be used
to measure cutaneous blood vessel function, e.g. blood
flow [11]. Notably, the signal arising from the aforemen-
tioned functional measurements of blood flow is from
more than just the capillary bed. In this way thermography
reports skin temperature, representative of underlying
blood flow, with both muscle and skin perfusion believed
to contribute to the signal. Laser Doppler measures not
only superficial capillary blood flow but also the arterial
and venous vessels of the superficial and mid-dermis [51].
This functional analysis has been used to discriminate
PRP from SRP and has been linked to morphological ana-
lysis (capillaroscopy) within SSc populations.
In patients with RP, a study comparing various non-
invasive methods for distinguishing patients with SRP
due to SSc from those with PRP and healthy controls re-
ported that laser Doppler imaging and thermography
yielded correct classification rates of 72% and 74%,
respectively, on the basis of blood vessel function [52].
However, NVC was found to be the superior discrimin-
ator with a rate of correct disease classification of 89%
[52]. A combination of all three techniques increased the
rate of correct classification from 89% to 94%, but did not
improve the sensitivity.
Interestingly, also other, less common combinations,
such as the combination of laser Doppler and photo-
plethysmography (an optical measurement technique),
both assessing flow in the microvascular bed, may be
useful in the characterization of PRP from SRP due to
SSc [53].
In patients with SSc, a correlation between morpho-
logical evaluation and functional evaluation (at baseline
and after application of a stimulus) has been established.
In this way correlations between microangiopathy (as as-
sessed by capillaroscopy) and blood flow (as assessed by
laser Doppler, measuring blood flow over a certain point)
both at baseline temperature and after heat stimulus
(R = 0.5 and 0.7) have been described [54].
Moreover, SSc patients showing the late NVC pattern of
microangiopathy have been shown to display significantly
lower blood flow on laser Doppler flowmetry at baseline
temperature and after heat stimulus than patients with
active and early NVC patterns (P = 0.05/0.03) and
(P = 0.07/0.05) [54]. This association has also been
shown using a new laser device, laser speckle contrast
imaging (LASCA), which measures perfusion distribution
over an area [55, 56]. The topic deserves further study.
Actual status and progressive diffusion
of capillaroscopy in rheumatology
For several decades, capillaroscopy had difficulties in
becoming an accepted and widely used tool. There is
6 www.rheumatology.oxfordjournals.org
recent growing interest for NVC as witnessed by the re-
sults of a recent survey in 32 EULAR countries in which
the 170 participants selected capillaroscopy as the
second most interesting tool (out of 14 tools) for their
future learning [57, 58]. Training opportunities in
learning NVC are stepping forward to this growing interest
[59].
Up-to-date, NVC full-immersion training courses (held
in Italy in 2004, 2006, 2008, 2010, 2011, 2012) have re-
cently been provided by international faculties and sup-
ported by EULAR. In addition, from 2010, a study group
with yearly meeting and dedicated to capillaroscopy and
rheumatic diseases was started at the ACR. Furthermore,
a new Atlas/Textbook on capillaroscopy has been pub-
lished under the aegis of EULAR and the authorship of
the most prominent world experts (http://www.eular.org/,
search education/bookshelf).
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Interestingly, in line with the growing interest, an expan-
sion in articles on capillaroscopy can be seen throughout
the years. A Medline search performed using the term
capillaroscopy (retrieving a total of 831 articles available
from 1950 to date) revealed only 53 articles published be-
tween 1950 and 1979 (30 years), 557 articles between
1980 and 2007 (28 years) and 221 articles between 2008
and 2012 (almost 4 years).
Further, among 230 articles that focused on capillaro-
scopy and SSc from 1980 to 2012 (32 years), almost 94
articles (40%) were published between 2008 and 2012 (4
years). Further progression and optimization of the poten-
tialities of NVC, linked to widespread training and educa-
tion on its use, may reveal further applications in clinics
and research. In conclusion, nailfold capillaroscopy may
be considered today as a reliable diagnostic tool and pu-
tative biomarker in rheumatology.
Rheumatology key messages
. Capillaroscopy is paramount in the differential diag-
nosis between a PRP and an SRP.
. Capillaroscopy may be used to predict future clin-
ical complications in SSc.
. Capillary changes that characterize the scleroderma
pattern can be counted and quantified.
Disclosure statement: V.S. has received grant/research
support, is a consultant and is a member of a speakers’
bureau for Actelion Pharmaceuticals Ltd. M.C. served as
consultant for Actelion, BMS, Celgene, Abbott and
Mundipharma.
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