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
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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.
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
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Raynaud phenomenon.16 Thermography has also revealed
dysfunction during reperfusion following the response to
a cold stimulus.17
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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.
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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.
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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
Score
0 More than 9 capillaries per linear mm
1
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38 C
36
34
32
30
28
26
24
22
20
18
17 C
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Box 2 | Current and prospective therapies for SSc
Therapies targeting the immune system
Cyclophosphamide
Methotrexate
Rituximab
Infliximab
Intravenous immunoglobulins
Ciclosporin
Conclusions
2.
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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.
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