Skin disease: a cardinal feature of systemic sclerosis

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1 Rheumatology 2009;48:iii14 iii18 doi: /rheumatology/kep108 Skin disease: a cardinal feature of systemic sclerosis T. Krieg 1 and K. Takehara 2 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. 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. 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 2 Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan. Submitted 2 May 2008; revised version accepted 2 April Correspondence to: T. Krieg, Department of Dermatology, University of Cologne, Kerpener Str. 62, Cologne, Germany. thomas.krieg@uni-koeln.de 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. 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 iii14 ß The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Skin disease: a cardinal feature of SSc iii15 FIG. 1. Typical early signs of SSc, including RP, oedematous swelling and nail-fold hyperkeratosis. 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 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. 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 0 51; 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

3 iii16 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 < ). 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 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

4 Skin disease: a cardinal feature of SSc iii17 TABLE 1. Treatment a 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 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. References 1 Gintrac M. Note sur la sclerodermie. Rev Med Chir Paris 1847;2: Sackner MA. The visceral manifestations of scleroderma. Arthritis Rheum 1962;5: Rodnan GP, Benedek TG. A historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med 1962;57: Korn JH. Pathogenesis of systemic sclerosis. 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