Download Skin disease: a cardinal feature of systemic

Rheumatology 2009;48:iii14–iii18
doi:10.1093/rheumatology/kep108
Skin disease: a cardinal feature of systemic sclerosis
T. Krieg1 and K. Takehara2
Despite the heterogeneity of SSc, almost all patients have skin involvement. As such, skin manifestations are critical in the initial diagnosis of
SSc and in the subsequent sub-classification into the different subsets of disease. The two principal subsets are lcSSc and dcSSc. The main
difference between these two subsets is the speed of disease progression and the extent and severity of skin and visceral involvement; lcSSc
has an insidious onset with skin involvement confined largely to the face and extremities. Whilst vascular manifestations of SSc such as
pulmonary arterial hypertension are typically more common in lcSSc, patients in both subsets can develop ischaemic digital ulcers. In dcSSc,
disease progression is very rapid, with skin thickening extending beyond the extremities and earlier, more widespread internal organ
involvement. DcSSc is generally considered to be the more severe subset of the disease. Skin scores in SSc correlate inversely with survival
and are considered a valuable marker of disease severity. Skin involvement is easily detectable and, using the modified Rodnan skin score,
the degree of skin fibrosis can be quantified. As well as general management measures, a number of targeted therapies are commonly used
for treatment of cutaneous manifestations of SSc. These include the intravenous prostanoid iloprost and the dual endothelin receptor
antagonist bosentan, which is approved in Europe for the prevention of new digital ulcers.
KEY
WORDS:
Systemic sclerosis, Limited, Diffuse, Prognosis, Diagnosis.
a beak-shaped nose and reduced aperture of the mouth (microstomy). There may also be radial furrowing around the mouth. As
the skin thickens and hardens, the patient’s face develops an
expressionless, mask-like stiffness and appears ‘mummified’.
Calcinosis, the abnormal deposition of calcium in the tissues, is
common in lcSSc, and usually occurs over pressure points. Other
common skin manifestations of SSc include hypo- and hyperpigmented areas of skin (salt and pepper), loss of hair follicles
and loss of sebaceous glands (anhydrosis) with resultant dryness.
Pruritis associated with dry skin can be intensely irritating
and bothersome to SSc patients. Joint contracture is another
important cutaneous manifestation of SSc.
While some SSc patients have skin lesions that remain largely
confined to the extremities, others exhibit skin thickening that
extends progressively from the extremities to the trunk.
Introduction
Although SSc (scleroderma) is a clinically heterogeneous disorder,
the loss of cutaneous elasticity and accompanying tightness followed by thickening and hardening of the skin (sclerosis) is an
almost universal manifestation. In fact, the term scleroderma,
coined by Gintrac in 1847 [1], arose from the obvious cutaneous
manifestations of the vascular and fibrotic changes that characterize the disease. It was not until much later that fibrosis of major
internal organs such as the lungs, heart, kidney and gastrointestinal tract, and their adverse clinical sequelae were recognized and
the term SSc came into widespread use [2–4].
Given that the most obvious signs of SSc are its cutaneous
manifestations and that they occur in most patients, the skin is
clearly important in the initial diagnosis of SSc and its subsequent
classification into clinical subsets. In this article, the importance of
the skin in the differential diagnosis of SSc is reviewed and its role
as a marker of disease activity discussed, as well as how the skin
can be used as a model to understand the pathophysiology of SSc.
Finally, skin-specific therapies to treat the different cutaneous
manifestations of the disease are evaluated and discussed.
The importance of skin in the diagnosis of SSc
Cutaneous symptoms—often associated with or preceded by RP
(an episodic digital ischaemia provoked by cold or emotional
stress)—and arthralgias of the fingers are common, early signs
of SSc, and therefore helpful for establishing a diagnosis.
Although there has been much debate about how best to classify
SSc given its heterogeneity, the separation of SSc patients into one
of two principal clinical subsets, dcSSc and lcSSc, is the most
commonly used classification today. This classification, which
has its origins in criteria proposed by the ACR in 1980 [7], is
based on the nature and extent of skin involvement (typical skin
thickening and hardening) together with the presence of certain
autoantibodies and, particularly, with certain organ involvement.
These latter criteria, as well as the addition of RP and nail-fold
capillary microscopy [to separate idiopathic RP (primary) from
Raynaud’s secondary to SSc (secondary)], have greatly increased
the sensitivity of the original ACR criteria [8, 9]. For example, in
dcSSc, there is a high frequency of interstitial lung disease (ILD),
whereas in lcSSc, there is a closer association with pulmonary
vascular disease and pulmonary arterial hypertension (PAH).
ACAs are most frequently seen in patients with lcSSc, whereas
anti-DNA topo I (anti-Scl-70) antibodies are associated with diffuse cutaneous involvement, increased frequency of pulmonary
fibrosis and higher mortality [10].
As data from the German scleroderma network have shown,
lcSSc is the most common form of SSc, affecting 45.5% of the
1483 patients included in the database. Just under a third of
patients (32.7%) exhibited dcSSc and the remainder were
Principal skin manifestations in SSc
Skin sclerosis is a cardinal feature of SSc that usually develops
first in the fingers and hands. Non-pitting oedema of the fingers is
often an early cutaneous manifestation of SSc (Fig. 1), after which
the skin of the swollen fingers starts to thicken and highly disabling sclerosis of the fingers (sclerodactyly) develops. Pitted scarring of fingertips due to loss of substance from digital pulp, with
tapering of fingertips is commonly seen. Painful digital ulcers that
occur on the fingertips as a result of local ischaemia and vascular
insufficiency are a frequent complication [5, 6]. Secondary bacterial infection of these slowly healing digital ulcers can lead to gangrene, atrophy and auto-amputation. The face, including the
lips and frenulum of the tongue, may also be affected in SSc.
Typical facial features associated with SSc include telangiectases,
1
Department of Dermatology, University of Cologne, Cologne, Germany and
Department of Dermatology, Kanazawa University Graduate School of Medical
Science, Ishikawa, Japan.
2
Submitted 2 May 2008; revised version accepted 2 April 2009.
Correspondence to: T. Krieg, Department of Dermatology, University of
Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
E-mail: [email protected]
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ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Skin disease: a cardinal feature of SSc
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FIG. 1. Typical early signs of SSc, including RP, oedematous swelling and nail-fold
hyperkeratosis.
FIG. 3. The mRss for quantitative assessment of skin sclerosis. The body is divided
into 17 regions, which are scored from 0 to 3 (0 ¼ normal, 1 ¼ weak,
2 ¼ intermediate and 3 ¼ severe skin thickening). R, right; L, left. Reproduced
from [18] with permission from Elsevier.
FIG. 2. Patient with localized scleroderma.
classified with either overlap syndromes (10.9%), undifferentiated
(8.8%) or SSc sine scleroderma (1.5%) [11]. Overlap syndrome
describes patients who display characteristics of scleroderma in
association with characteristics of SS, SLE, RA, DM/PM and
early MCTD. SSc sine scleroderma, which it has been argued
should be included in the spectrum of lcSSc [12], describes the
very small number of SSc patients that have exclusively visceral
involvement (visceral scleroderma).
The ACR criteria are not only important in differentiating
between the two major clinical forms of SSc, but also in differentiating between SSc and other scleroderma-related disorders.
Differential diagnosis of scleroderma
Localized scleroderma is a disorder characterized by excessive
collagen deposition leading to thickening of the dermis, subcutaneous tissues or both. Depending on clinical presentation and
depth of tissue involvement, localized scleroderma is described
as either plaque, generalized, linear or deep subtype. In plaquetype morphoea, the most common type of localized scleroderma,
the skin lesions are typically oval or round. In the active phase of
the disease, a lilac-coloured border (lilac ring) may surround the
indurated region. As they evolve, the plaques become hyperpigmented (Fig. 2). In linear localized scleroderma, the sclerotic
lesions appear as one or more discrete linear streaks and induration that can involve the dermis and subcutaneous tissue, as well
as occasionally muscle and bone. Generalized morphoea and disabling pansclerotic morphoea are more serious forms of localized
scleroderma, the latter causing severe disability as a result of atrophy of underlying muscle and joint contractures. Unlike SSc, there
is an absence of sclerodactyly, RP and internal organ involvement
in patients with localized scleroderma.
Scleroderma-like skin changes can also occur in endocrine disorders, such as diabetes mellitus and hypothyroidism; in patients
with end-stage renal disease (nephrogenic fibrosing dermopathia);
in conjunction with inflammatory conditions such as eosinophilic
fasciitis, and in infiltrative disorders such as amyloidosis. In
patients with eosinophilic fasciitis, in which peripheral eosinophilia is an early sign, sclerosis involving the subcutaneous tissue
occurs mainly at the extremities. Hypergammaglobulinaemia
and an elevated ESR are other features of eosinophilic fasciitis,
but there is no evidence of RP, autoantibodies or internal organ
involvement. Nephrogenic fibrosing dermopathia, a newly recognized scleroderma-like syndrome, is characterized by renal insufficiency and joint contractures.
Skin as a marker of disease severity and prognosis in SSc
The main difference between lcSSc and dcSSc is the speed with
which the disease progresses and the extent and severity of skin
and visceral involvement. Thus lcSSc, in which sclerosis is confined to the extremities and face, tends to have an insidious onset;
RP may pre-exist for many years. The vascular component of SSc
is much more prominent in lcSSc and is responsible for many of
the clinical manifestations such as PAH, digital ulceration and
scleroderma renal crises. In contrast, patients with dcSSc tend to
have a more rapid onset of disease that is characterized by more
extensive skin thickening, extending beyond the extremities and
face to include the limbs and trunk, often accompanied by early
organ involvement. In dcSSc, symptoms of RP generally occur
contemporaneously with skin changes.
Despite an increased risk of PAH in lcSSc, dcSSc is considered
the more serious of the two clinical subsets being associated with
significant morbidity from skin thickening as well as excess mortality due to severe cardiac, pulmonary, gastrointestinal and renal
involvement [13]. A link between severe skin involvement and
major visceral complications in dcSSc was first established in
the 1960s and has been confirmed in more recent studies [14, 15].
Skin involvement is an easily detectable marker of disease activity in SSc. In SSc patients, the severity of skin sclerosis can be
quantified using the modified Rodnan skin score (mRss) [16–18],
in which a 17-site assessment system is most widely used today
(Fig. 3). Skin thickness is assessed by palpation and rated on a
scale of 0 (normal), 1 (weak), 2 (intermediate) or 3 (severe skin
thickening). The total skin score is the sum of the individual skin
assessments in the 17 body areas, giving a possible range of 051;
the higher the score, the greater the extent and severity of
skin thickening. Using skin score data from patients entered in
The University of Pittsburgh Scleroderma Databank, Steen
and Medsger [19] have found that skin thickening, as measured
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T. Krieg and K. Takehara
by mRss, provides a surrogate measure of disease severity and has
prognostic value, especially in dcSSc. In their study, Steen and
Medsger examined the relationship between changes in skin thickening over a 2-year period and outcome in 278 patients with earlystage (duration <3 years) dcSSc. They found that patients with an
improvement in skin thickening of >25% of their peak skin score
and a rate of improvement of at least 5 U/year had a significantly
better outcome than patients who experienced further skin thickening or no improvement. Survival rates at 5 and 10 years were 90
and 80%, respectively, for the ‘improved skin group’ compared
with 77 and 60%, respectively, for the ‘no improvement group’
(P < 0.0001). Patients with the highest peak skin scores were those
least likely to improve, and patients with no improvement experienced significantly more severe organ involvement, which likely
contributed to their poorer outcome. Interestingly, patients in
the ‘improved skin group’ had an average improvement of
50% in their peak skin score over the 2-year follow-up period
(greater than that documented in other studies), which the authors
attributed to more sustained use of the anti-fibrotic agent D-penicillamine during the first 2 years after initial evaluation.
Histopathology of skin biopsies in SSc
In patients with SSc, an abnormal accumulation of extracellular
matrix constituents, most notably collagen types I and III, is the
most prominent pathological manifestation of the disease in skin.
Two stages are recognizable: an early cellular stage and a later
fibrotic stage [20]. Thus, early skin lesions are characterized by the
presence of thickened collagen bundles within the reticular dermis
that run parallel to the skin surface and inflammatory cell infiltrates between the collagen bundles and around blood vessels
(Fig. 4). This infiltrate may also extend into subcutaneous fat
and entrap sweat glands. The overlying epidermis tends to be
thin and atrophic. As the disease progresses, the lesional skin
becomes relatively avascular and after a period of 12–18 months
there is often little evidence of ongoing inflammation. Thus, in
contrast to early lesions, late skin lesions in dcSSc have few if
any inflammatory cells. Late lesions may show evidence of sclerosis; the collagen appears closely packed and sweat glands are
atrophic or absent. Collagen may replace fat cells in the subcutaneous tissue.
Potential target molecules for therapeutic intervention
A number of factors, including TGF-, connective tissue growth
factor (CTGF/CCN2), matrix metalloproteinases (MMPs), protease inhibitors, integrins and endothelins, such as ET-1, have
been implicated in the pathogenic processes that produce fibrosis
of the skin and other organs [21]. TGF-, a pro-fibrotic growth
factor that promotes fibroblast proliferation as well as
matrix synthesis, is an important candidate in the pathogenic
process [22]. Increased TGF- ligand expression in lesional SSc
skin and altered downstream signalling has been reported in SSc
fibroblasts. In fact, a case can be made that sustained activation of
TGF- signalling in fibroblasts is able to induce the defining
features of SSc. Interestingly, in patients with dcSSc, circulating
levels of TGF-1 are reduced in comparison with both healthy
controls and patients with lcSSc. Describing this phenomenon,
Dziadzio et al. [23] have suggested that it occurs because of
sequestration of active TGF- in lesional tissue such as the skin
due to up-regulation of TGF--binding proteins, many of
which are TGF- inducible. Gene profiling studies support this
assertion [24]. Their study also found an inverse relationship
between TGF-1 in the circulation and skin score, and a correlation with disease duration [23].
CTGF is a cysteine-rich mitogenic peptide that is induced in
fibroblasts after activation with TGF-. Elevated levels of CTGF
have been observed in the serum of SSc patients and found to
correlate with both the extent of skin sclerosis and severity of
FIG. 4. Histopathology of skin lesions in scleroderma characterized by an excessive deposition of collagen, deep fibrosis and perivascular lymphohistiocytic
infiltrates.
pulmonary fibrosis [25]. In the development and maintenance of
skin fibrosis in SSc, it has been suggested that a subtle relationship
exists between circulating TGF- and CTGF, whereby skin fibrosis induced by TGF- is maintained by CTGF [26].
There is accumulating evidence to suggest that ET-1 is another
important pathological mediator in SSc, acting not only as a
potent vasoconstrictor in the vasculature but also as an important
mediator in extracellular matrix remodelling and deposition.
Staining for ET-1 in skin biopsies of both lcSSc and dcSSc reveals
up-regulation of ET-1 in microvessels, including capillaries, while
levels of ET-1 in serum have been found to correlate with the
extent of skin fibrosis [27]. In inflammation via the induction of
intracellular adhesion molecule (ICAM)-1, ET-1 activates adhesion molecule expression, which may be important in regulating
the inflammatory response characteristic of early-stage disease.
ET-1 can activate fibroblasts and other mesenchymal cells along
the pathway towards myofibroblast differentiation; myofibroblasts are the cells primarily responsible for tissue remodelling,
repair and ultimately fibrosis in SSc. In contrast to normal skin,
the skin of SSc patients contains large numbers of myofibroblasts,
especially in the deep dermis. Any one of these molecules, and
several others, are potential targets for therapeutic intervention.
Skin-specific therapies for cutaneous manifestations of SSc
As Table 1 illustrates, there are many disabling cutaneous manifestations of SSc, which constitute a major burden for patients and
severely affect their quality of life. These skin manifestations can
and have to be treated.
Simple but important treatment measures for patients with SSc
include physical therapy and regular exercise to maintain circulation, joint flexibility and muscle strength; additionally, patients
with RP should limit their exposure to cold, wear warm clothing
and cease smoking. Topical steroids, topical calcineurin inhibitors, systemic steroids and/or systemic immunosuppressive therapy with drugs such as MTX, cyclophosphamide, cyclosporin and
D-penicillamine have been used with varying success to reduce skin
hardening [19, 28–30]. Recently, a pilot study of mycophenolate
mofetil combined with intravenous methylprednisolone pulses and
oral low-dose glucocorticoids was demonstrated to significantly
improve mRss and quality of life in patients with extensive skin
disease [31].
Because of its anti-inflammatory and immunosuppressive
effects, phototherapy with ultraviolet (UV) irradiation or
photochemotherapy using UVA plus the photosensitizer
Skin disease: a cardinal feature of SSc
TABLE 1. Treatmenta of skin manifestations of SSc
Skin hardening
Physical exercise
Topical steroids
Topical calcineurin inhibitors
Systemic immunosuppressants
Systemic steroids
Phototherapy (UVA1 and PUVA)
Dryness and itching
Topical steroids
Cannabinoid agonists
Capsaicin
Emollients
Phototherapy
Systemic therapy—anti-histamines, gabapentin
Digital ulcers
Intravenous iloprost
Bosentan (dual endothelin receptor antagonist)
Hydrocolloid dressings
Absorbent dressings
Skin substitutes
Physical therapy
Calcifications
Bisphosphonates
Local corticosteroid injection
Laser therapy
Surgery
Telangiectases
Laser therapy
Camouflage
Hyper- and hypopigmentation
Bleaching agents
Salicylic acid and chemical peels
Hydroquinone, retinoids, corticosteroids
Camouflage
Sunscreens
a
It should be noted that there is only limited evidence for most treatments.
psoralene ultraviolet A (PUVA) has been used to treat a number
of inflammatory skin conditions. Some success in treating skin
hardening in SSc has also been achieved with phototherapy [32];
UVA irradiation appears to inhibit the fibrotic process and induce
softening of sclerotic skin, especially in lcSSc.
A range of treatment options is available for management of
SSc skin manifestations such as dry skin, telangiectases, skin
pigmentation changes, calcifications and digital ulcers (Table 1).
The evidence for most treatments is, however, limited.
Intravenous iloprost is approved for the treatment of severe RP
with evolutive trophic lesions, and is commonly used in patients
with digital ulcers. The oral dual endothelin receptor antagonist
bosentan, which was initially approved for the treatment of PAH,
is now approved in Europe for the prevention of digital ulcers.
There are no available data on trials of single endothelin receptor
antagonists or phosphodiesterase-5 (PDE-5) inhibitors. Treatment
of patients with digital ulcers using antibiotics may also be needed
if dry, ulcerated skin becomes infected.
The recent insights into the molecular signalling pathways
underlying the cutaneous manifestations of SSc have yielded
potential new targets for therapeutic intervention. For example,
as a key mediator of fibrogenesis [33] inhibition of TGF- signalling with anti-TGF- monoclonal antibodies may have therapeutic potential in SSc. CTGF—which mediates the stimulatory
effects of TGF- on extracellular matrix synthesis—is a similarly
intriguing target; studies in a mouse fibrosis model have demonstrated that TGF--induced skin fibrosis can be inhibited with an
anti-CTGF antibody [34]. Other preliminary investigations
suggest that tyrosine kinase inhibitors, such as imatinib, may
limit dermal fibroblast proliferation in SSc by inhibiting PDGF
receptor (PDGFR). Indeed, in patients with SSc, the PDGFR-
subunit is overexpressed in dermal vessels; PDGFR- messenger
RNA is overexpressed in cultured fibroblasts; and increased levels
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of PDGF and stimulatory autoantibodies to PDGFR have been
identified in the serum [35].
Autologous haematopoietic stem cell transplantation (HSCT) is
an alternative therapeutic strategy that may ameliorate the skin
manifestations of SSc. In a small study of HSCT, for which
follow-up data were available for 26 patients with poor prognosis
SSc or severe dcSSc, an improvement in skin thickening and stabilization of organ function was sustained for up to 7 years following the procedure [36].
Conclusions
SSc is a rare heterogeneous connective tissue disorder that is characterized primarily by abnormal collagen deposition in the skin
and internal organs. Skin manifestations are important symptoms
leading to early diagnosis of SSc and its differentiation into lcSSc
and dcSSc, the two major clinical subsets of SSc, as well as differentiation from scleroderma-related disorders. The skin is easily
accessible for biopsies and reflects the pathophysiology of the
disease, while quantitative assessment of skin induration correlates with disease activity. Skin manifestations of SSc are a
major burden for patients and severely affect quality of life; whenever and wherever possible, they should be treated.
Rheumatology key messages
Skin manifestations of SSc are critical to diagnosis and classification into limited and diffuse subtypes.
lcSSc and dcSSc differ in the speed of disease progression and
the extent and severity of skin and visceral involvement.
Acknowledgements
The authors wish to gratefully acknowledge the contributions of
Prof. Eric Hachulla and Dr Lorenzo Beretta to this manuscript.
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: K.T. has participated in a meeting sponsored by Actelion Pharmaceuticals Ltd. T.K. has received lecture
fees from Actelion Pharmaceuticals Ltd and has conducted
research sponsored by Actelion Pharmaceuticals Ltd and Digna
Biotech.
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