Anda di halaman 1dari 10

REVIEwS

Assessing microvascular changes in systemic


sclerosis diagnosis and management
Maurizio Cutolo, Alberto Sulli and Vanessa Smith
Abstract | Microvascular damage and dysfunction represent the earliest morphological and functional
markers of systemic sclerosis (SSc), a progressive connective tissue disease characterized by vascular
abnormalities and diffuse fibrosis in the skin and internal organs. These early microvascular changes are
clinically mirrored by Raynaud phenomenon, which can be primary (idiopathic) or secondary to several different
conditions including SSc. Morphological and functional assessment of the cutaneous microvasculature have
crucial implications for diagnosis, prognosis and therapy in SSc and secondary Raynaud phenomenon. Most
importantly, imaging with nailfold videocapillaroscopy (NVC) enables the early differentiation between primary
and secondary Raynaud phenomenon by identifying morphological patterns specific to various stages of
SSc (early, active and late patterns); the inclusion of these NVC patterns could increase the sensitivity
of classification criteria for SSc. Findings on NVC are also markers of SSc severity and progression, as
reduced capillary density has been associated with a high risk of developing digital skin ulcers and pulmonary
arterial hypertension. Laser Doppler imaging and thermal imaging demonstrate the dysfunctional cutaneous
blood flow in response to cold stimuli. Therapies targeting underlying vascular disease in SSc have been
successfully designed to improve the symptoms of Raynaud phenomenon and to reduce ischemic injury to
involved organs, and NVC patterns have been found to improve following targeted therapy; however, treatment
of later fibrosis remains a challenge.
Cutolo, M. et al. Nat. Rev. Rheumatol. 6, 578587 (2010); published online 10 August 2010; doi:10.1038/nrrheum.2010.104

Continuing Medical Education online


This activity has been planned and implemented in accordance
with the Essential Areas and policies of the Accreditation Council
for Continuing Medical Education through the joint sponsorship of
Medscape, LLC and Nature Publishing Group. Medscape, LLC is
accredited by the ACCME to provide continuing medical education
for physicians.
Medscape, LLC designates this educational activity for a maximum
of 0.75 AMA PRA Category 1 CreditsTM. Physicians should only
claim credit commensurate with the extent of their participation
in the activity. All other clinicians completing this activity will
be issued a certificate of participation. To participate in this
journal CME activity: (1) review the learning objectives and author
disclosures; (2) study the education content; (3) take the post-test
and/or complete the evaluation at http://www.medscapecme.com/
journal/nrrheum; and (4) view/print certificate.
Research Laboratory
and Academic Unit of
Clinical Rheumatology,
Department of Internal
Medicine, University of
Genova, Viale
Benedetto XV, 6-16132
Genova, Italy
(M. Cutolo, A. Sulli).
Department of
Rheumatology, Ghent
University, De Pintelaan
185, 9000 Ghent,
Belgium (V. Smith)
Correspondence to:
M. Cutolo
mcutolo@unige.it

Learning objectives
Upon completion of this activity, participants should be able to:
1 Distinguish the best study to evaluate patients for
secondary Raynauds phenomenon.
2 Analyze different patterns of microvascular damage in
patients with systemic sclerosis (SSc).
3 Account for potential microvascular complications in SSc.
4 Devise an appropriate treatment plan to reduce the risk for
microvascular complications of SSc.

Competing interests
The authors, the Journal Chief Editor J. Buckland and the CME
questions author C. P. Vega declare no competing interests.

Introduction
Systemic sclerosis
Systemic sclerosis (SSc) is a rare and progressive connective tissue disease of multifactorial origin that is characterized by vascular abnormalities and diffuse fibrosis in
the skin and joints, and by progressive involvement of the
internal organs.1 SSc is about eight times more common
among women than men.2 It is most common in the third
to fifth decades of life and is rare in children.3
The diagnosis of early SSc is partially clinical and
laboratory tests, including assays of SSc-specific serum
autoantibodies, can help to confirm the diagnosis.
Clinical symptoms of overt disease include peripheral
and persistent microvascular vasocontriction, swelling
of the fingers, skin tightening and contractures of the
fingers, polyarthralgia and possibly dysphagia. The most
common initial symptoms and signs are vascular, such
as Raynaud phenomenon, which is often long-lasting, as
well as insidious swelling of the distal extremities (that is,
puffy fingers), followed by gradual thickening of the skin
of the face and fingers with late skin ulcers (Figure 1).4
Most SSc-related deaths are attributable to heart,
kidney and lung involvement. In the heart, diffuse myocardial fibrosis and cardiac conduction abnormalities can
occur. In the kidneys, renal ischemia and hypertension
can result from the development of intimal hyperplasia
of interlobular and arcuate arteries. Lung involvement
can arise from interstitial and peribronchial fibrosis or

578 | october 2010 | volume 6

www.nature.com/nrrheum
2010 Macmillan Publishers Limited. All rights reserved

ReViewS
intimal hyperplasia of the small pulmonary arteries,
which, in the long term, can lead to the development
pulmonary arterial hypertension (PaH).
The pathophysiology of SSc involves endothelial and
vascular damage and the activation of fibroblasts; consequently, collagen and other extracellular matrix proteins are overproduced in almost all tissues. The innate
and adaptive immune systems are activated in the perivascular areas, release their component immunological
mediators such as cytokines and growth factors (transforming growth factor [TGF]-, platelet-derived growth
factor [PDGF], endothelin-1) and extensive fibrosis in
the dermal and subcutaneous layers develops.5
In the skin, SSc is characterized by more-compact collagen fibers and other extracellular matrix proteins in
the reticular dermis, epidermal thinning, loss of interpapillary ridges, and atrophy of dermal appendages. on
the basis of the extent of skin involvement, SSc can be
categorized into two forms: diffuse cutaneous SSc and
limited cutaneous SSc.
Peripheral microvascular damage in SSc is characterized by dynamic alterations to the capillaries that lead
to a progressive decrease in their density. In the nailfolds,
where it is possible to easily detect the morphological
changes, capillary loops dilate owing to damage from the
inflammatory reaction and gradually lose their content
of red blood cells, and microvascular loops are lost as a
consequence of their progressive destruction.
Specific treatment of SSc is difficult, and as a result
the emphasis is often on the management of symptoms
and complications. as yet, no treatment is available that
completely halts the natural progression of clinically
recognizable disease. Consequently, efforts are being
made to study the disease in its early stages, before overt
disease and irreversible organ damage have occurred.
Since microvascular damage and dysfunction represent the earliest morphological and functional markers
of SSc, and these are mainly clinically mirrored by
Raynaud phenomenon, capillary morphological analysis
(capillaroscopy) and functional assessment are fundamental. This Review discusses the diagnostic, prognostic
and therapeutic implications of these assessments.

Secondary Raynaud phenomenon


In general terms, Raynaud phenomenon is an episodic
vasospasm of the peripheral blood vessels that results
from dysregulation of cutaneous vasoconstriction and
vasodilatation. altered sympathetic nerve activity and a
host of neuronal regulators, including adrenergic and nonadrenergic neurotransmitters, as well as redox signaling,
have been implicated in this dysregulation.
In the general population, Raynaud phenomenon
presents as episodic altered microcirculation in the digits
leading to cold hands, usually in response to exposure to
cold or stress, although the thumb is not usually involved.6
Raynaud phenomenon is associated with a classic triphasic color change arising from local modifications to
blood flow (Figure 1a). at the start of an attack the digits
turn white when blood flow to the area ceases (ischemia),
then to blue as deoxygenated blood returns, and then to

Key points
Systemic sclerosis (SSc) is a complex systemic connective tissue disease
characterized by vasculopathy and progressive involvement of the skin and
internal organs with diffuse fibrosis
Raynaud phenomenon as a clinical marker of altered microvascular structure
can be primary (idiopathic) or secondary to various conditions, in particular SSc
Nailfold videocapillaroscopy (NVC) represents the best and safest method to
analyze microvascular abnormalities in SSc, and enables the early differential
diagnosis between primary and secondary Raynaud phenomenon
The dysfunctional cutaneous blood flow in patients with both SSc and
secondary RP in response to temperature stimuli have been demonstrated by
use of laser Doppler imaging techniques
Reduced capillary density on NVC correlates with a high risk of developing
digital skin ulcers and the presence of pulmonary arterial hypertension, and
can therefore be used as a marker of SSc severity and progression
Therapies targeting underlying vascular disease in SSc improve symptoms
of Raynaud phenomenon and reduce ischemic injury to involved tissue and
organs; however, targeted treatment of fibrosis remains a challenge

Figure 1 | Common clinical aspects of SSc. a | Raynaud phenomenon generally


presents as episodic modified blood flow of the digits, usually in response to
exposure to cold or stress. The classic triphasic color change progresses from
white (ischemia) to blue (deoxygenation) then red (reperfusion). b | Common early
symptoms of SSc include swelling, skin tightening and contractures of the fingers
with polyarthralgia. c | Gradual thickening of the skin of the face and presence of
teleangiectasias is characteristic of advanced SSc. d | Digital ulcers are one of the
most frequent clinical manifestations of microangiopathy in patients with SSc. A
decreased number of capillary loops is associated with progressive thickening of
the skin and the development of ulcers in the late stages of the disease.
Abbreviation: SSc, systemic sclerosis.

red upon reperfusion. The late stages of an attack are


associated with pain and sometimes paresthesia, and,
rarely, ulceration of the fingers and toes are observed.
Raynaud phenomenon can be primary (idiopathic),
that is, not associated with an underlying disease, or
secondary to several different conditions and causes,
especially connective tissue diseases such as SSc.7 In
contrast to secondary Raynaud phenomenon, however,
primary Raynaud phenomenon does not progress

naTuRe RevIewS | RheuMAToLogy

voLuMe 6 | oCTobeR 2010 | 579


2010 Macmillan Publishers Limited. All rights reserved

ReViewS
Raynaud phenomenon.16 Thermography has also revealed
dysfunction during reperfusion following the response to
a cold stimulus.17

Figure 2 | The videocapillaroscope. In systemic sclerosis, structural cutaneous


microvascular abnormalities have been demonstrated with both wide-field and
high-magnification optical microscopy of the nailfold and most efficiently by the
use of videocapillaroscopy (pictured). Nailfold videocapillaroscopy represents the
best and safest method to analyze microvascular abnormalities in systemic
sclerosis, and enables the early differential diagnosis between primary and
secondary Raynaud phenomenon.

to irreversible tissue injury; therefore, comparisons


between primary and secondary Raynaud phenomenon
are of interest for the differential diagnosis of the early
stages of SSc, in which secondary Raynaud phenomenon
features.8 Primary Raynaud phenomenon occurs more
often in females (male to female ratio 1:4) and usually
develops before age 20. The onset of primary Raynaud
phe nomenon in later years should always raise the
suspicion of an underlying cause. Primary Raynaud
phenomenon affects 515% of individuals in the general
population9 and an underlying disorder, most often SSc
or a scleroderma-spectrum disease, will be detected in
almost 15% of cases after 1.53 years.10

Characterization of early SSc

The most important issue for the early diagnosis of SSc is


to detect the earliest microvascular markers that identify
secondary Raynaud phenomenon. Specific and early as
well as advanced microvascular changes in morphology
and function in patients with SSc and secondary Raynaud
phenomenon are most easily detected in the skin, especially at the nailfold bed. Structural cutaneous microvascular abnormalities have been demonstrated with both
wide-field and high-magnification optical microscopy of
the nailfold (nailfold capillaroscopy) and most efficiently
by the use of videocapillaroscopy (nvC) (Figure 2).1113
both the severity of capillary structural damage and
the related altered capillary permeability in secondary
Raynaud phenomenon have been evaluated by use of
large-window fluorescein videodensitometry, which
reveals a characteristic pericapillary halo, but this method
does not seem very practicable.14,15 Microvascular function, on the other hand, can be readily evaluated with laser
Doppler imaging, laser Doppler flowmetry and thermal
imaging. These methods have successfully demonstrated
the dysfunctional cutaneous blood flow that occurs in
response to temperature stimuli and to application of
local vasodilators in patients with both SSc and secondary

The role of capillaroscopy


nailfold videocapillaroscopy (nvC) represents the best
and safest method to detect and to analyze morphological
microvascular abnormalities, especially in presence of
secondary Raynaud phenomenon.18 In normal conditions
or in primary Raynaud phenomenon (but not during the
cold-exposure test), the nailfold capillaroscopic pattern
shows regular disposition of capillary loops along the nailfold bed and no abnormal enlargements or capillary loss.
In patients with Raynaud phenomenon, however, one or
more abnormal capillaroscopic findings should alert the
physician to the possibility of secondary Raynaud phenomenon, owing to the presence of a previously undetected
connective autoimmune disease.19 Morphological markers
of microvascular damage include giant capillaries, microhemorrhages, loss of capillaries, the presence of avascular
areas and angiogenesis; these features characterize more
than 95% of patients with overt SSc even if they are not
observed concomitantly (Figure 3).20 These sequential
and dynamic capillaroscopic changes are typical of the
microvascular involvement in SSc, and can be described
by the term SSc pattern.
Peripheral microangiopathy can be easily recognized
and studied early in the disease course by use of nailfold
capillaroscopy or, better, with nvC.21,22 Described below
are the most important globally accepted capillaroscopic
changes associated with SSc in the presence of secondary
Raynaud phenomenon.23
Giant capillaries
Homogeneously enlarged microvascular loops (giant
capillaries) are the earliest and most striking feature
of secondary Raynaud phenomenon (Figure 3a). The
enlargements show a characteristic symmetrical shape.
The detection of even a single loop with a homogeneous
increase in diameter to more than 50 m at the level of
the nailfold bed should be considered a potential marker
of microangiopathy related to an early sclerodermaspectrum disorder if not SSc itself. The dilatation could
represent the first sign of microvessel wall damage
(lamina elastica).
Microhemorrhages
Local microhemorrhages are also associated with early
microvascular damage (Figure 3b). The appearance of
this feature, which arises from microvascular extravasation of red blood cells from the capillary loop,
bridges the appearance of giant capillaries and the subsequent loss of capillaries. Microhemorrhage is linked to
the altered integrity of the microvessel wall and altered
endothelial cell array.
Capillary loss and avascular areas
a decreased number of capillary loops (fewer than six
or seven within 1 mm of the distal row of the nailfold
bed) should be considered highly specific for secondary

580 | october 2010 | volume 6

www.nature.com/nrrheum
2010 Macmillan Publishers Limited. All rights reserved

ReViewS
a

Figure 3 | Markers of scleroderma patterns. Images obtained by routine nailfold videocapillaroscopy analysis of patients
with systemic sclerosis (magnification 200) reveal the morphological markers of microvascular disorganization that
characterize overt systemic sclerosis and related nailfold videocapillaroscopy patterns (early,active and late systemic
sclerosis) in the presence of secondary Raynaud phenomenon. a | Giant capillaries (arrows), the earliest and most striking
morphological feature of secondary Raynaud phenomenon, are homogeneously enlarged microvascular loops that serve as
potential markers of microangiopathy. b | Microhemorrhages (arrows) result from the microvascular extravasation of red
blood cells from damaged capillaries. c | Loss of capillaries (arrows) can lead to the presence of avascular areas in the
nailfold bed and subsequent local tissue hypoxia. d | Neoangiogenesis is characterized by the clustering of twisted and
bushy capillaries (arrows) and represents a local reaction to tissue hypoxia.

Raynaud phenomenon (Figure 3c). It has been estimated


that the number of normal capillaries is reduced to 20%
in patients with active SSc.24 The extensive disappearance
of capillaries can generate large avascular areas, which
have a desert-like appearance in the nail-bed microvascular array. Loss of capillaries could be relevant in
determining the severe tissue hypoxia that is involved
in the development of digital skin ulcers.11 In patients with
recent onset of Raynaud phenomenon, the appearance of
rapidly progressive capillary loss can represent the first
dramatic capillaroscopic evidence of destruction of the
microvessels and the development of severe SSc.
Ramified capillaries
Capillary loss induces local hypoxia and the consequent
local production of vessel growth factors (such as vascular
endothelial growth factor), which in turn stimulating the
formation of new capillariesneoangiogenesis.25 a range
of morphological features of the micro vasculature
attributable to neoangiogenesis is seen almost exclusively
in patients with late SSc and secondary Raynaud phenomenon (Figure 3d). The main morphological hallmark

of angiogenesis in advanced SSc is the clustering of twisted


capillaries, with pronounced heterogeneity in shape and
size, winding together with bushy capillaries. Highly convoluted and branched capillary loop clusters, surrounded
by loss of normal capillary loops, are characteristic
features of neoangiogenesis in advanced SSc.
Characterization of SSc-specific patterns
Historically, the capillaroscopic aspects of vascular
damage in SSc were partially graded into two major patterns: active and slow.26 Since the year 2000, new classifications related to selected characteristics of disease
progression have been proposed to improve the diagnostic and prognostic power of capillaroscopic analysis.27
Consequently, microvascular lesions detected by nvC in
patients with SSc can be reclassified into three different
nvC patterns, early, active and late, which are clearly
distinguishable from the normal pattern (Figure 4).28
The early SSc pattern is considered the most important
since it is fundamental to the differentiation of primary
and secondary Raynaud phenomenon. This pattern is
characterized by the presence of a small number of giant

naTuRe RevIewS | RheuMAToLogy

voLuMe 6 | oCTobeR 2010 | 581


2010 Macmillan Publishers Limited. All rights reserved

ReViewS
a

Figure 4 | Nailfold videocapillaroscopic patterns of scleroderma (magnification 200). Microvascular lesions in patients with
SSc detected by nailfold videocapillaroscopy can be classified into three distinct patternsearly, active and latethat
are clearly distiguishable from the normal pattern. a | Normal nailfold capillaroscopic pattern. b | The early SSc pattern is
characterized by few giant capillaries, few capillary microhemorrhages, no evident loss of capillaries, and relatively wellpreserved capillary distribution. c | The active SSc pattern that emerges with disease progression is characterized by
frequent giant capillaries, frequent capillary microhemorrhages, moderate loss of capillaries, absent or mildly ramified
capillaries and mild disorganization of the capillary architecture. d | In the late SSc pattern, giant capillaries and
microhemorrhages are almost absent, but severe loss of capillaries with extensive avascular areas are evident, with ramified
or bushy capillaries and severe disorganization of the normal capillary array. Abbreviation: SSc, systemic sclerosis.

capillaries and capillary microhemorrhages, no evident


loss of capillaries and relatively well-preserved capillary
distribution (Figure 4b). as the disease progresses, the
active SSc pattern becomes more evident. Giant capillaries and capillary microhemorrhages are numerous,
there is moderate capillary loss, ramified capillaries are
absent or mildly branched and the capillary architecture is mildly disorganized (Figure 4c). Finally, the late
SSc pattern is evident in advanced disease. This pattern
is characterized by the near-absence of giant capillaries and microhemorrhages but involves severe loss of
capillaries and the development of extensive avascular
areas, ramified and bushy capillaries (indicative of neoangiogenesis), and severe disorganization of the normal
capillary array (Figure 4d).
The progression of uncontrolled SSc is characterized by the gradual and dynamic progression of these
vascular patterns. notably, the three SSc-specific nvC
patterns have been found to correlate with duration of
both Raynaud phenomenon and SSc, and possibly reflect
both the evolution of the disease process and disease
severity.29 Qualitative and semiquantitative scoring of

the SSc patterns by nvC has been recently introduced and


validated (box 1).3032

The role of functional microvessel evaluation


whereas nvC measures capillary morphology, methods
such as laser Doppler imaging and thermography can
be used to measure cutaneous blood vessel function
(Figures 5 and 6).16 a study comparing various noninvasive methods for distinguishing patients with SSc
from those with primary Raynaud phenomenon and
healthy controls reported that laser Doppler imaging
and thermography yielded correct classification rates of
72% and 74%, respectively, on the basis of blood vessel
function. nailfold capillaroscopy, however, was found
to be the superior discriminator with a rate of correct
classification of 89%.16
The three techniques, therefore, independently discriminate between patients with secondary Raynaud
phenomenon and those with primary Raynaud phenomenon and healthy controls, with nailfold capillaroscopy
being the most suitable technique for classifying patient
groups. a combination of all three techniques increased

582 | october 2010 | volume 6

www.nature.com/nrrheum
2010 Macmillan Publishers Limited. All rights reserved

ReViewS
the rate of correct classification from 89% to 94%, but did
not improve the sensitivity.16
Generally, laser Doppler imaging and thermography
provide equivalent information on dynamic changes
in the cutaneous microcirculation but this information only weakly corresponds to capillary morphology.16 However, patients with SSc showing the late SSc
pattern of microangiopathy on nvC have been shown
to display lower blood flow on laser Doppler flowmetry
than patients with active and early SSc patterns on
nvC.33

Serum antibody markers in SSc diagnosis


In addition to specific capillary alterations, SSc is also
characterized by serum autoantibodies, including antibodies against centromeric proteins (primarily centromere protein b [CenP-b]]), Th/To, topoisomerase I
(topo I or Scl70), and Rna polymerases I and III
(RnaP I/III). Combined, anti-CenP-b, anti-Th/To,
anti-topo I and anti-RnaP I/III antibodies account for
almost 85% of autoantibodies specific for SSc.34 In addition, anti-CenP-b and antitopo I antibodies are established predictors of progression from isolated Raynaud
phenomenon to definite SSc.35,36 Several studies on the
relevance of antibody expression in SSc have been limited
by small sample sizes, the erroneous classification of
patients with connective tissue disease manifestations as
having primary rather than secondary Raynaud phenomenon, a lack of standardized methods for determining antinuclear antibodies (anas), the omission of tests
for anti-Th/To and antiRnaP I/III antibodies, and the
absence of multivariable analyses.
In 2001, LeRoy and Medsger 37 proposed that patients
with Raynaud phenomenon who have abnormal findings on nvC and a positive test for an SSc-specific
autoantibody should be classified as having early SSc.
However, this proposed set of criteria was not validated
for several years. 2008 saw the publication of the results of
a prospective study conducted over a period of 20 years,
in which 586 patients referred to a single center for evaluation of Raynaud phenomenon were followed up for 3,197
person-years.38 The study aimed to identify the strongest
independent predictors of progression to definite SSc, to
determine by use of nvC the type and time-course of
microvascular damage, to determine the relationship
of microvascular damage to specific SSc autoantibodies
and, finally, to validate the LeRoy and Medsger criteria
for early SSc. by the end of the observation period, 74/586
(12.6%) patients had developed definite SSc.38
nailfold capillaroscopy identified a dynamic and progressive sequence of microvascular damage, which began
with the presence of enlarged (giant) capillaries that
identify the early SSc pattern, followed by the capillary
loss that typifies the active SSc pattern, and then by the
development of capillary telangiectases, which are indicative of the neoangiogenesis that characterizes the late
SSc pattern. of note, the clinical diagnosis of definite SSc
occurred close in time to the loss of capillaries.
The presence of enlarged capillaries, capillary loss, and
SSc-specific autoantibodies each independently predicted

Box 1 | Qualitative and semiquantitative scoring of the SSc patterns by NVC


The scoring system reported here, which provides a score of 03 points, is
applicable to all morphological markers of microvascular damage on NVC; that
is, number of giant capillaries, number of microhemorrages, number of lost
capillaries, and number of bushy or ramified capillaries. Number of lost capillaries
is used as an example in the scoring system below.

Score
0 More than 9 capillaries per linear mm
1

Less than 33% reduction in capillaries, or 79 capillaries per mm

3366% reduction in capillaries, or 46 capillaries per mm

Capillary reduction of more than 66%, or 13 capillaries per mm

Abbreviations: NVC, nailfold capillaroscopy; SSc, systemic sclerosis.

Figure 5 | Laser Doppler imaging of cutaneous blood flow in secondary Raynaud


phenomenon and normal conditions. a | Laser Doppler flowmeter. b | Recording of
cutaneous blood flow. c | Noninvasive probe attached to the patients fingertip.
d | Blood flow shows detectable and quantifiable circulation in a healthy individual
(upper panel); by contrast, the waves are flat but still quantifiable in a patient with
systemic sclerosis (lower panel). The blue line reports the peripheral blood waves
as detected at the patients fingertips (fingers 2, 3 and 4). The score is reported in
the final assessment in international perfusion units (not shown).

progression to definite SSc. Interestingly, anti-CenP-b


and anti-Th/To antibodies predicted the development of
enlarged capillaries and together with antiRnaP I/III
also predicted capillary loss.38 each autoantibody was
found to be associated with a distinct time-course of the
progressive microvascular damage as assessed by nailfold
capillaroscopy. at the end of the follow-up period, 79.5%
of patients with findings on nvC at baseline together
with an SSc-specific autoantibody had developed definite SSc.38 Practically, these data validated the criteria for
early SSc proposed by LeRoy and Medsger.37

The prognosis value of capillaroscopy

In patients with active SSc, damage to the microvascular


array as detected and quantified by capillaroscopy can
be used to predict the development of several common
complications.

naTuRe RevIewS | RheuMAToLogy

voLuMe 6 | oCTobeR 2010 | 583


2010 Macmillan Publishers Limited. All rights reserved

ReViewS
38 C

36
34
32
30
28

in data collection and the predictive value of the CSuRI


still needs to be confirmed in a validation study.42
The results of these morphological studies suggest that
the routine use of nvC could enable the early identification of patients at high risk of developing digital skin
ulcers. Moreover, the presence of a reduced number of
capillaries in the late nvC pattern and reduced blood
flow as shown by laser Doppler flowmetry have already
been shown to predict the development of digital skin
ulcers in patients with SSc.31,43,44

26
24
22
20
18
17 C

Figure 6 | Thermal imaging of cutaneous blood vessel function in secondary


Raynaud phenomenon. Classic aspect of reduced finger skin temperature after
exposure to cold temperatures in a patient with Raynaud phenomenon. Inset:
condition in a normal individual after exposure to the same cold stimulus.

Risk of digital skin ulcers


Digital skin ulcers are one of the most frequent clinical
manifestations of microangiopathy in patients with SSc.
as mentioned above, loss of capillaries could be relevant
in determining severe tissue hypoxia, and, in patients
with recent-onset Raynaud phenomenon, the appearance of rapidly progressive capillary loss can represent
the first dramatic capillaroscopic evidence of severe SSc
and destruction of microvessels.25,31,33,39 The consequence
of capillary loss is the progressive appearance of avascular
areas and an increased risk of skin ulcers.40
The early identification of patients with SSc who are at
high risk of developing digital skin ulcers could enable
the initiation of treatment to prevent these complications, with consequent reductions in morbidity as well as
reductions in direct and indirect costs to society. a 2007
study showed that patients with a pattern of late SSc
on nvC analysis had an increased risk of having active
disease (oR [odds ratio]) 3.50; 95% CI 1.319.39) and
digital skin ulcers (oR 5.74; 95% CI 2.0815.89).29 also,
advanced stages of capillary loss (as detected by a semiquantitative scoring system, described in box 1) have
been associated with digital trophic lesions. 31 a 2009
study of 130 patients with SSc examined at study entry
and after 20 months of follow-up found that the diffuse
cutaneous form of SSc with avascular areas on capillaroscopy represented, among other factors (for example,
increased levels of interleukin-6), the major risk factor
for ulcer development.41 another study published in the
same year showed that a quantitative capillaroscopic
score (Capillaroscopic Skin ulcer Risk Index; CSuRI)
was highly predictive of the development of new digital
skin ulcers within 3 months after nailfold capillaroscopy
evaluation. The test seems limited by some restrictions

Risk of pulmonary arterial hypertension


SSc is the main connective tissue disease associated with
PaH. This complication arises in an estimated 12% of
patients with SSc, and is a leading cause of death in this
disease.45,46 evidence now shows that the severity of capillary density loss in patients with SSc differs between those
with PaH and those without,47 indicating that capillary
loss is a marker of SSc progression and severity.
Interestingly, loss of capillary density was also shown
to be higher in patients with idiopathic PaH, a condition
not known to be characterized by systemic microvascular
changes, than in healthy controls, but did not occur to the
same extent as in patients with SSc and PaH.47 Despite
the occurrence of capillary density loss in both idiopathic and SSc-related PaH, however, this complication
is not necessarily attributable to the same mechanism in
both disorders.
In SSc, structural changes in the systemic microcirculation presumably precede changes in the pulmonary circulation, since systemic microvascular changes
can precede the development of SSc by many years. 45
Therefore, abnormalities in the nailfold capillaries, including capillary loss, might reflect events in the pulmonary
circulation. This might not be the case for other capillary
abnormalities such as neoangiogenesis and the development of giant capillaries, because, although these other
capillary irregularities occur in most patients with SSc,
only a minority of those patients develop PaH.47

Targeting therapy to vascular changes

Immunosuppressive therapies for SSc aim to reduce


inflammation and prevent secondary tissue injury and
fibrosis (box 2). Ciclosporin has been tested in patients
with SSc, with a substantial impact on clinical symptoms
after 12 months of treatment.48,49 In addition, the b-celldepleting agent rituximab has shown promise in patients
with diffuse cutaneous SSc.50,51 Further trials are needed
of other biological agents, such as infliximab, or intravenous immunoglobulins.52 Hematopoietic stem cell
transplantation also seems promising as it ameliorates the
SSc pattern on nvC; the results of controlled trials of this
approach are awaited.53,54
Therapies that target underlying vascular disease have
been successfully designed to improve symptoms of
Raynaud phenomenon and to reduce ischemic injury to
involved organs (box 2).55 Cyclophosphamide has shown
promise for the treatment of SSc-associated interstitial
lung disease in randomized controlled trials. vascular
disease of the lungs (PaH) and digits (skin ulcers) have

584 | october 2010 | volume 6

www.nature.com/nrrheum
2010 Macmillan Publishers Limited. All rights reserved

ReViewS
Box 2 | Current and prospective therapies for SSc
Therapies targeting the immune system
Cyclophosphamide
Methotrexate
Rituximab
Infliximab
Intravenous immunoglobulins
Ciclosporin

Therapies targeting underlying vascular disease


Selective endothelin A receptor and nonselective
endothelin A/B receptor antagonists (e.g. sitaxentan,
bosentan)
Phosphodiesterase-type-5 inhibitors (e.g. sildenafil)
Prostacyclins (e.g. iloprost)
Calcium-channel blockers
Angiotensin-converting-enzyme inhibitors
Angiotensin-receptor inhibitor (e.g. losartan)
Topical nitroglycerin formulations (e.g. glycerin trinitrate)
Statins (e.g. atorvastatin)

Conclusions

Prospective therapies targeting established fibrosis


Inhibitors of the tyrosine kinase c-Abl (e.g. imatinib)
PDGF-receptor inhibitor
Anti-TGF- monoclonal antibody or small-molecule
inhibitors of TGF--receptor
Abbreviations: PDGF, platelet-derived growth factor; SSc, systemic
sclerosis; TGF-, transforming growth factor .

been successfully treated with selective endothelin a


receptor and nonselective endothelin a/b receptor
antagonists (sitaxentan56 and bosentan,57 respectively), the
phosphodiesterase-type-5 inhibitor sildenafil58 and prostacyclins (iloprost).59 Methotrexate has shown only modest
benefit in controlling SSc-associated skin disease.57,58 In a
recent study, the progression of nvC pattern was inversely
correlated to cyclophosphamide treatment, and the drug
was demonstrated to be effective for scleroderma microvascular damage as directly observed by nvC.60
Prostacyclins (including iloprost, which can be administered orally or intravenously) are a particularly useful
therapeutic option for patients with secondary Raynaud
phenomenon.59 Modest benefits have also been achieved
with calcium-channel blockers,61 while the effect of angiotensin-converting-enzyme (aCe) inhibitors has been
variable in secondary Raynaud phenomenon.62
Since plasma levels of endothelin have been detected
in patients with the more-advanced stage of SSc
1.

2.

3.

Black, C. M., Matucci-Cerinic, M. & Guillevin, L.


Progress in systemic sclerosis: a 10-year
perspective. Rheumatology (Oxford)
48 (Suppl. 3), iii1iii2 (2009).
Bernatsky, S. et al. Scleroderma prevalence:
demographic variations in a population-based
sample. Arthritis Rheum. 61, 400404 (2009).
Arias-Nuez, M. C. et al. Systemic sclerosis in
northwestern Spain: a 19-year epidemiologic

microangiopathy (those showing the late SSc pattern


on nvC), namely the more fibrotic phase of the disease,
the use of selective (sitaxentan) or nonselective (bosentan) endothelin-receptor antagonists might reduce the
progression of microvascular and fibrotic SSc damage.63
Further studies also suggest possible benefits to the
use of other formulations in treating Raynaud attacks,
including sildenafil,58 the angiotensin-receptor inhibitor losartan64 and topical nitroglycerin (glycerin trinitrate).65,66 Substantial reductions in Raynaud Condition
Score have also been obtained following treatment with
statins such as atorvastatin.58
with regard to prospective therapies, recent data indicate that the combined inhibition of the tyrosine kinase
c-abl and PDGF receptor (with imatinib) might be
effective in the treatment of established fibrosis.68,69 an
anti-TGF- monoclonal antibody has been evaluated in a
small trial of early SSc, with disappointing results;70 smallmolecule inhibitors of TGF--receptor activity might
prove more effective.71

4.

5.

Since microvascular damage and dysfunction represent


early markers of SSc that are clinically mirrored by secondary Raynaud phenomenon, the diagnostic, prognostic
and therapeutic implications of microvessel morphological analysis (by nvC) and functional assessment (by
laser Doppler and thermal imaging) is a major task. In
addition, abnormal findings on nvC at baseline together
with the presence of SSc-specific autoantibodies indicate a
very high probability of developing definite SSc, whereas
their absence rules out this outcome. The introduction
of specific nvC patterns as a new entry in classification criteria for SSc promises to substantially increase
their sensitivity.72,73 early diagnosis of SSc could enable
the early start of treatment, which could slow disease
progression and clinical complications.74,75

Review criteria
PubMed was searched using several key words such as
capillaroscopy, systemic sclerosis, scleroderma
pattern, microcirculation in scleroderma, Raynauds
phenomenon and therapy of scleroderma, among others,
alone and in combination. Reported results ranged from
early papers on capillaroscopy and related topics of the late
1970s up to June 2010. 93% are full papers published in
English. The reference lists of identified papers were used
to search for further studies related to specific arguments.
Additional articles cited and reported in the text were
retrieved from the authors private collections.

study. Medicine (Baltimore) 87, 272280


(2008).
Gabrielli, A., Avvedimento, E. V. & Krieg, T.
Scleroderma. N. Engl. J. Med. 360, 19892003
(2009).
Abraham, D. J., Krieg, T., Distler, J. & Distler, O.
Overview of pathogenesis of systemic sclerosis.
Rheumatology (Oxford) 48 (Suppl. 3), iii3iii7
(2009).

naTuRe RevIewS | RheuMAToLogy

6.

7.

8.

Herrick, A. L. Diagnosis and management of


scleroderma peripheral vascular disease.
Rheum. Dis. Clin. North Am. 34, 89114 (2008).
Kahaleh, M. B. Raynaud phenomenon and the
vascular disease in scleroderma. Curr. Opin.
Rheumatol. 16, 718722 (2004).
Herrick, A. L. Pathogenesis of Raynauds
phenomenon. Rheumatology (Oxford) 44,
587596 (2005).

voLuMe 6 | oCTobeR 2010 | 585


2010 Macmillan Publishers Limited. All rights reserved

ReViewS
9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

Leppert, J., Aberg, H., Ringqvist, I. &


Srensson, S. Raynauds phenomenon in a
female population: prevalence and association
with other conditions. Angiology 38, 871877
(1987).
Cutolo, M., Pizzorni, C. & Sulli, A. Identification of
transition from primary Raynauds phenomenon
to secondary Raynauds phenomenon by nailfold
videocapillaroscopy. Arthritis Rheum. 56,
21022103 (2007).
Maricq, H. R., LeRoy, E. C. Patterns of finger
capillary abnormalities in connective tissue
disease by widefield microscopy. Arthritis
Rheum. 16, 619628 (1973).
Maricq, H. R., weinberger, A. B. & LeRoy, E. C.
Early detection of scleroderma-spectrum
disorders by in vivo capillary microscopy.
J. Rheumatol. 9, 289291 (1982).
Cutolo, M., Grassi, w. & Matucci Cerinic, M.
Raynauds phenomenon and the role of
capillaroscopy. Arthritis Rheum. 48, 30233030
(2003).
Hettema, M. E. et al. Decreased capillary
permeability and capillary density in patients
with systemic sclerosis using large-window
sodium fluorescein videodensitometry of the
ankle. Rheumatology (Oxford) 47, 14091412
(2008).
Brlisauer, M. & Bollinger, A. Measurement of
different human microvascular dimensions by
combination of videomicroscopy with Nafluorescein (NaF) and indocyanine green (ICG) in
normals and patients with systemic sclerosis.
Int. J. Microcirc. Clin. Exp. 10, 2131 (1991).
Murray, A. K. et al. Noninvasive imaging
techniques in the assessment of scleroderma
spectrum disorders. Arthritis Rheum. 61,
11031111 (2009).
Clark, S. et al. Comparison of thermography and
laser Doppler imaging in the assessment of
Raynauds phenomenon. Microvasc. Res. 66,
7376 (2003).
Cutolo, M., Sulli, A., Secchi, M. E., Olivieri, M. &
Pizzorni, C. The contribution of capillaroscopy to
the differential diagnosis of connective
autoimmune diseases. Best Pract. Res. Clin.
Rheumatol. 21, 10931108 (2007).
Cutolo, M., Pizzorni, C. & Sulli, A. Nailfold videocapillaroscopy in systemic sclerosis [German].
Z. Rheumatol. 63, 457462 (2004).
Cutolo, M., Pizzorni, C., Secchi, M. E. & Sulli, A.
Capillaroscopy. Best Pract. Res. Clin. Rheumatol.
22, 10931108 (2008).
De Angelis, R., Cutolo, M., Salaffi, F., Pablo
Restrepo, J. & Grassi, w. Quantitative and
qualitative assessment of one rheumatology
trainees experience with a self-teaching
programme in videocapillaroscopy. Clin. Exp.
Rheumatol. 27, 651653 (2009).
De Angelis, R., Grassi, w. & Cutolo, M. A growing
need for capillaroscopy in rheumatology. Arthritis
Rheum. 61, 405410 (2009).
Carpentier, P. H. & Maricq, H. R. Microvasculature
in systemic sclerosis. Rheum. Dis. Clin. North Am.
16, 7591 (1990).
Jayson, M. I. The micro-circulation in systemic
sclerosis. Clin. Exp. Rheumatol. 2, 8591
(1984).
Beyer, C., Schett, G., Gay, S., Distler, O. &
Distler, J. H. Hypoxia in the pathogenesis of
systemic sclerosis. Arthritis Res. Ther. 11,
220227 (2009).
Maricq, H. R. et al. Diagnostic potential of in vivo
capillary microscopy in scleroderma and related
disorders. Arthritis Rheum. 23, 183189 (1980).
Cutolo, M., Sulli, A., Pizzorni, C. & Accardo, S.
Nailfold videocapillaroscopy assessment of

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

microvascular damage in systemic sclerosis.


J. Rheumatol. 27, 155160 (2000).
Cutolo, M., Pizzorni, C. & Sulli, A. Capillaroscopy.
Best Pract. Res. Clin. Rheumatol. 19, 437452
(2005).
Caramaschi, P. et al. Scleroderma patients
nailfold videocapillaroscopic patterns are
associated with disease subset and disease
severity. Rheumatology (Oxford) 46, 15661569
(2007).
Sulli, A., Secchi, M. E., Pizzorni, C. & Cutolo, M.
Scoring the nailfold microvascular changes during
the capillaroscopic analysis in systemic sclerosis
patients. Ann. Rheum. Dis. 67, 885887 (2008).
Smith, V. et al. Validation of the qualitative and
semiquantitative assessment of the
scleroderma spectrum patterns by nailfold
videocapillaroscopy: preliminary results
[abstract]. Arthritis Rheum. 60 (Suppl.),
S164S165 (2009).
Smith, V. et al. Reliability of the qualitative and
semiquantitative nailfold videocapillaroscopy
assessment in a systemic sclerosis cohort:
a two-centre study. Ann. Rheum. Dis. 69,
10921096 (2010).
Cutolo, M. et al. Peripheral blood perfusion
correlates with microvascular abnormalities in
systemic sclerosis: a laser-Doppler and nailfold
videocapillaroscopy study. J. Rheumatol.
doi:10.3899/jrheum.091356.
Senecal, J. L., Henault, J. & Raymond, Y. The
pathogenic role of autoantibodies to nuclear
autoantigens in systemic sclerosis.
J. Rheumatol. 32, 16431649 (2005).
weiner, E. S. et al. Prognostic significance
of anticentromere antibodies and antitopoisomerase I antibodies in Raynauds
disease: a prospective study. Arthritis Rheum.
34, 6877 (1991).
Cutolo, M. et al. Nailfold videocapillaroscopic
patterns and serum autoantibodies in systemic
sclerosis. Rheumatology (Oxford) 43, 719726
(2004).
LeRoy, E. C. & Medsger, T. A. Jr. Criteria for the
classification of early systemic sclerosis.
J. Rheumatol. 28, 15731576 (2001).
Koenig, M. et al. Autoantibodies and
microvascular damage are independent
predictive factors for the progression of
Raynauds phenomenon to systemic sclerosis:
a twenty-year prospective study of 586 patients,
with validation of proposed criteria for early
systemic sclerosis. Arthritis Rheum. 58,
39023912 (2008).
Steen, V., Denton, C. P., Pope, J. E. & MatucciCerinic, M. Digital ulcers: overt vascular disease
in systemic sclerosis. Rheumatology (Oxford)
48 (Suppl. 3), iii19iii24 (2009).
Cutolo, M., Sulli, A., Secchi, M. E. & Pizzorni, C.
Capillaroscopy and rheumatic diseases: state of
the art [German]. Z. Rheumatol. 65, 290296
(2006).
Alivernini, S. et al. Skin ulcers in
systemicsclerosis: determinants of presence
and predictive factors of healing. J. Am. Acad.
Dermatol. 60, 426435 (2009).
Sebastiani, M. et al. Capillaroscopic skin ulcer
risk index: a new prognostic tool for digital skin
ulcer development in systemic sclerosis
patients. Arthritis Rheum. 61, 688694 (2009).
Secchi, M. E., Sulli, A., Pizzorni, C. & Cutolo, M.
Nailfold capillaroscopy and blood flow laserdoppler analysis of the microvascular damage in
systemic sclerosis: preliminary results [Italian].
Reumatismo 61, 3440 (2009).
Caramaschi, P. et al. A score of risk factors
associated with ischemic digital ulcers in

586 | october 2010 | volume 6

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

patients affected by systemic sclerosis treated


with iloprost. Clin. Rheumatol. 28, 807813
(2009).
Coghlan, J. G. & Handler, C. Connective tissue
associated pulmonary arterial hypertension.
Lupus 15, 138142 (2006).
Mukerjee, D. et al. Prevalence and outcome in
systemic sclerosis associated pulmonary
arterial hypertension: application of a registry
approach. Ann. Rheum. Dis. 62, 10881093
(2003).
Hofstee, H. M. et al. Nailfold capillary density is
associated with the presence and severity of
pulmonary arterial hypertension in systemic
sclerosis. Ann. Rheum. Dis. 68, 191195
(2009).
Filaci, G. et al. Long-term treatment of patients
affected by systemic sclerosis with
cyclosporin A. Rheumatology (Oxford) 40,
14311432 (2001).
Filaci, G. et al. Cyclosporin A and iloprost
treatment of systemic sclerosis: clinical results
and interleukin-6 serum changes after
12 months of therapy. Rheumatology (Oxford)
38, 992996 (1999).
Smith, V. et al. Rituximab in diffuse cutaneous
systemic sclerosis: an open-label clinical and
histopathological study. Ann. Rheum. Dis. 69,
193197 (2010).
Lafyatis, R. et al. B cell depletion with rituximab
in patients with diffuse cutaneous systemic
sclerosis. Arthritis Rheum. 60, 578683
(2009).
Quillinan, N. P. & Denton, C. P. Disease-modifying
treatment in systemic sclerosis: current status.
Curr. Opin. Rheumatol. 21, 636641 (2009).
van Laar, J. M. & Tyndall, A. Cellular therapy of
systemic sclerosis. Curr. Rheumatol. Rep. 10,
189199 (2008).
Miniati, I. et al. Autologous stem cell
transplantation improves microcirculation in
systemic sclerosis. Ann. Rheum. Dis. 68, 9498
(2009).
Henness, S. & wigley, F. M. Current drug therapy
for scleroderma and secondary Raynauds
phenomenon: evidence-based review. Curr. Opin.
Rheumatol. 19, 611618 (2007).
Gholam, P., Sehr, T., Enk, A. & Hartmann, M.
Successful treatment of systemic-sclerosisrelated digital ulcers with a selective endothelin
type A receptor antagonist (sitaxentan).
Dermatology 219, 171173 (2009).
Moore, T. L., Vail, A. & Herrick, A. L. Assessment
of digital vascular structure and function in
response to bosentan in patients with systemic
sclerosis-related Raynauds phenomenon.
Rheumatology (Oxford) 46, 363364 (2007).
Brueckner, C. S. et al. Effect of Sildenafil on
digital ulcers in systemic sclerosisanalysis
from a single centre pilot study. Ann. Rheum. Dis.
doi:10.1136/ard.2009.116475.
Hachulla, E., Launay, D. & Hatron, P. Y. Iloprost for
the treatment of systemic sclerosis [French].
Presse Med. 37, 831839 (2008).
Caramaschi, P. et al. Cyclophosphamide
treatment improves microvessel damage in
systemic sclerosis. Clin. Rheumatol. 28,
391395 (2009).
Thompson, A. E., Shea, B., welch, V., Fenlon, D.
& Pope, J. E. Calcium-channel blockers for
Raynauds phenomenon in systemic sclerosis.
Arthritis Rheum. 44, 18411847 (2001).
Gliddon, A. E. et al. Prevention of vascular
damage in scleroderma and autoimmune
Raynauds phenomenon: a multicenter,
randomized, double-blind, placebo-controlled
trial of the angiotensin-converting enzyme

www.nature.com/nrrheum
2010 Macmillan Publishers Limited. All rights reserved

ReViewS

63.

64.

65.

66.

67.

68.

inhibitor quinapril. Arthritis Rheum. 56,


38373846 (2007).
Sulli, A. et al. Raynauds phenomenon and
plasma endothelin: correlations with
capillaroscopic patterns in systemic sclerosis.
J. Rheumatol. 36, 12351239 (2009).
Dziadzio, M. et al. Losartan therapy for
Raynauds phenomenon and scleroderma:
clinical and biochemical findings in a fifteenweek, randomized, parallel-group, controlled
trial. Arthritis Rheum. 42, 26462655 (1999).
Herrick, A. L. Therapy: A local approach to
Raynaud phenomenon. Nat. Rev. Rheumatol. 5,
246247 (2009).
Anderson, M. E. et al. Digital vascular response
to topical glyceryl trinitrate, as measured by
laser Doppler imaging, in primary Raynauds
phenomenon and systemic sclerosis.
Rheumatology (Oxford) 41, 324348 (2002).
Kuwana, M., Okazaki, Y. & Kaburaki, J. Long-term
beneficial effects of statins on vascular
manifestations in patients with systemic
sclerosis. Mod. Rheumatol. 19, 530535 (2009).
Akhmetshina, A. et al. Treatment with imatinib
prevents fibrosis in different preclinical models

69.

70.

71.

72.

73.

of systemic sclerosis and induces regression of


established fibrosis. Arthritis Rheum. 60,
219224 (2009).
Gabrielli, A. et al. Stimulatory autoantibodies
to the PDGF receptor: a link to fibrosis in
scleroderma and a pathway for novel
therapeutic targets. Autoimmun. Rev. 7,
121126 (2007).
Denton, C. P. et al. Recombinant human antitransforming growth factor beta1 antibody
therapy in systemic sclerosis: a multicenter,
randomized, placebo-controlled phase I/II trial of
CAT-192. Arthritis Rheum. 56, 323333 (2007).
Varga, J. & Pasche, B. Transforming growth factor
beta as a therapeutic target in systemic
sclerosis. Nat. Rev. Rheumatol. 5, 200206
(2009).
Cutolo, M. & Matucci Cerinic, M. Nailfold
capillaroscopy and classification criteria for
systemic sclerosis. Clin. Exp. Rheumatol. 25,
663665 (2007).
Hudson, M. et al. Improving the sensitivity of the
American College of Rheumatology classification
criteria for systemic sclerosis. Clin. Exp.
Rheumatol. 25, 754757 (2007).

naTuRe RevIewS | RheuMAToLogy

74. Matucci-Cerinic, M. et al. The challenge of early


systemic sclerosis for the EULAR Scleroderma
Trial and Research group (EUSTAR) community.
It is time to cut the Gordian knot and develop a
prevention or rescue strategy. Ann. Rheum. Dis.
68, 13771380 (2009).
75. Herrick, A. L. & Cutolo, M. Clinical implications
from capillaroscopic analysis in patients with
Raynauds phenomenon and systemic
sclerosis. Arthritis Rheum. doi:10.1002/
art.27543.
Acknowledgments
Charles P. Vega, University of California, Irvine, CA, is
the author of and is solely responsible for the content
of the learning objectives, questions and answers of
the MedscapeCME-accredited continuing medical
education activity associated with this article.
Author contributions
A. Sulli researched the data for the article. V. Smith
and M. Cutolo provided substantial contributions to
discussions of the content and reviewed and/or
edited the manuscript before submission. M. Cutolo
wrote the article.

voLuMe 6 | oCTobeR 2010 | 587


2010 Macmillan Publishers Limited. All rights reserved

Anda mungkin juga menyukai