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Keywords:

  • systemic scleroderma;
  • pathogenesis;
  • clinical findings;
  • Raynaud phenomenon;
  • digital ulcers;
  • organ involvement

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

Systemic sclerosis is a chronic inflammatory multiorgan disease belonging to the group of collagen-vascular disorders. With a prevalence of 10/100,000 inhabitants it may be regarded a rather rare disease. Its etiology and pathogenesis have still not been elucidated in detail, especially with regard to the differential involvement of skin and the cause of the clinically heterogeneous disease courses. Various components of the vasculature, connective tissue as well as the immune system are involved in a yet unknown sequence and significance. Patients need to be cared for in an interdisciplinary fashion depending on the individual organ involvement. Apart from the skin, the heart, kidneys and lungs are mainly affected in addition to frequent gastrointestinal and musculoskeletal symptoms. Clinically two distinct subsets may be separated, acral (also termed limited) and diffuse scleroderma, which are characterized by anti-centromere and anti-Scl-70/topoisomerase-1 antibodies, respectively. Recent data demonstrate a poor prognosis even in limited disease when pulmonary arterial hypertension develops at an early stage. In diffuse disease sudden and rapid onset will result in a sclerosis of major internal organs and early death in many cases.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

The term scleroderma describes in a general way thickening and hardening of the skin and does not address causes and clinical consequences. It is thus more a description of clinical findings than a disease name. While in internal medicine and rheumatology, scleroderma is synonymous with a systemic disease – namely systemic sclerosis; in dermatology a series of sclerotic alterations and disease entities can be differentiated, of which the most important are circumscript or localized scleroderma and systemic scleroderma. A multitude of different causes and triggers can result in sclerotic processes that are usually irreversible in the sense of a scarred final state. An exclusive or predominant involvement of the skin as an isolated organ disease can be separated from sclerotic lesions of internal organs that can be classified in the disease group termed collagen-vascular disorders or inflammatory connective tissue diseases [1].

The term is used for a series of very different chronic inflammatory systemic diseases that classically affect the organ skin. As in the other collagen-vascular disorders, systemic lupus erythematosus and dermatomyositis, the skin involvement is name-giving and is of great significance for quality of life, but less decisive for the prognosis for survival. In the strict sense of the word, only systemic sclerosis is a disease prominently affecting collagenous connective tissue. All diseases of this group are characterized by inflammatory, immunologically mediated processes that affect the skin – and prognostically of more significance – internal organs, especially heart, lungs and kidneys. Which mechanisms determine the organ involvement is still unclear to date. Besides the term (progressive) systemic scleroderma (PSS), in the English-language literature the term systemic sclerosis (SSc) has gained acceptance, while sparing of the skin, i.e. systemic sclerosis without skin involvement, is rare [2]. In this and a subsequent article, the pathogenetic relationships, clinical findings, diagnostic approach, differential diagnostic considerations and therapeutic options of systemic sclerosis will be presented.

Pathogenesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

The fundamental pathogenetic components are the vasculature with endothelial and adventitial cells, the collagenous connective tissue with fibroblasts as the central cell type as well as the immune system with inflammatory and autoimmune phenomena. The relative significance, the sequence of order and the mutual impact of these three components remain unclear [3–5] (Figure 1).

image

Figure 1. Pathogenesis of systemic scleroderma.

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The rareness of the disease as well as the clinical heterogeneity of findings and the individual disease course make well-founded clinical studies difficult; in addition adequate mouse models that at least partially reflect aspects of pathogenesis are available only to a limited extent [6]. Most frequently employed is the model of bleomycin-induced sclerosis in mice which includes inflammatory phenomena and the “tight skin” mouse (TSK mouse) that includes connective tissue aspects. The impact of the innate immune system and its role in fibrosis has increasingly been studied in recent years, with transgenic and knockout mice being particularly helpful. Similarities between systemic scleroderma and graft-versus-host disease (GVHD) and the female predominance of the disease can be explained by the phenomenon of microchimerism, intensely discussed several years ago [7]. In affected women who had delivered sons, Y-chromosome-positive and thus allogenic cells were detected in the peripheral blood and in lesional skin. In the past chronic GVHD was considered a clinical model of systemic scleroderma, but it does display some important differences [8]. Cutaneous GVHD is therefore a good model to examine fibroblast activity, but not the microvascular alterations that are characteristic for systemic scleroderma.

Genetic factors of systemic scleroderma

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

A positive family history is considered an important risk factor with a 12-fold relative risk as opposed to the normal population [9, 10]. While on the one hand both monozygotic and dizygotic twins have a concordance rate of only 5 % for the development of systemic scleroderma, in monozygotic twins in 90 % of the cases, in dizygotic twins only in 40 % are typical antinuclear antibodies found. In studies to date employing coupling analysis in family or case control studies to determine alleles of candidate genes have been replaced in recent studies by genome-wide association studies (GWAS).

In large case control studies genetic variants termed single nucleotide polymorphisms (SNP) can be identified. Of particular relevance is the association with genes of the HLA region, particularly an association with DRB1*1104-, DQA1*0501-and DQB1*0301 haplotypes or specific antoantibodies with certain HLA antigens [9, 10].

Many other investigators have examined polymorphism of various cytokines and mediators such as type-1 interferons (IRF), beta-fibrinogen, TGF-β, fibrillin, proteases and intracytoplasmic tyrosine kinases with respect to their significance in scleroderma, especially in the induction of fibrosis. This gives a quite heterogeneous image of pathogenetically involved factors, whose differential significance and possible role as therapeutic target remain unclear to date.

Further, these risk factors correlate with many autoimmune disorders, but only a few characterize the group of collagen-vascular disorders, individual diseases or a particular phenotype. Further studies to characterize disease-specific markers are therefore required.

Environmental factors

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

Various infections such as CMV, parvovirus B19, HPV and toxoplasmosis are suspected of being important in the etiology and pathogenesis of systemic scleroderma [11]. In view of elevated antibody titers towards bacteria and viruses, the possibility of molecular mimicry with induction of autoimmune responses as the basic mechanism for triggering or maintaining systemic scleroderma has been discussed. In this connection, positive effects of antibiotics on the course of systemic scleroderma are interesting that might, however, possibly be attributed to antiinflammatory or antifibrotic activity. Various environmental substances such as organic solvents and quartz salts, that may be of relevance in occupational medicine, have been suspected as triggers in vitro as well as in vivo [12, 13]. They are possibly significant in predisposed individuals with a specific immunogenetic or inflammatory background. Smoking represents an important inducer and maintenance mechanism for typical circulatory disturbances and should therefore urgently be discontinued.

Vascular system

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

The frequent appearance of the Raynaud phenomenon and other vascular alterations in scleroderma point to a prominent role of the vascular system. Scleroderma is characterized by an antiendothelial environment with an increased apoptosis rate of endothelial cells, endothelial antibodies and a reduced number of endothelial cell progenitors resulting in reduced neovascularization [1, 5, 14]. The increased apoptosis rate of endothelial cells and release of mediators such as endothelin and throm-boxane as well as increased serotonin-induced platelet aggregation are indicators of damage to endothelial cells initiated and maintained by hypoxia and toxic factors such as proteases (granzyme A), free radicals, nitric oxides (NO) or antiendothelial IgG autoantibodies. The increased expression of surface molecules such as ICAM-1, VCAM-1 and E-selectin on endothelial cells facilitate migration of inflammatory cells through the vessel walls into the tissue and the production of profibrogenic growth factors such as tissue growth factor β (TGFβ), connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF) with simultaneous inhibition of the synthesis of endothelial growth factors.

Connective tissue metabolism

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

The fibrosis of skin, vessel walls and internal organs is apparently due to the deposition of components of the extracellular matrix with the collagen content being increased and subcutaneous tissue being partially replaced by collagen [1, 5, 15]. Studies both on the protein as well as RNA level, recently with microarray methods, have demonstrated that fibroblasts are not numerically increased, but that subpopulations are more highly active in producing collagen of types I, III, V, VI, VII and XVI. These are stimulated by inflammatory cytokines such as tissue growth factor β (TGFβ) that is mitogenic for fibroblasts and stimulates the synthesis of collagen, fibronectin and glycosamine glycans. Possibly, the interaction between fibroblasts and extracellular matrix is disturbed, which in addition to increased expression of various proteases such as thrombin and tryptase stimulates the synthesis of matrix. On the other hand matrix metalloproteinases (MMP) responsible for degradation are impaired by an elevation of tissue inhibitors of metalloproteinases (TIMP) or the presence of anti-MMP autoantibodies.

TGFβ is closely connected with the expression of CTGF (connective tissue growth factor), the strongest inducer of collagen production, as well as PDGF (platelet-derived growth factor) that are activated in an autocrine and paracrine manner and represent fibrogenic growth factors. Antibodies against the PDGF receptor are apparently capable of activating the gene expression of collagen and are possibly involved in the pathogenic process in vivo [16].

Organ fibrosis is thus based on a cytokine-mediated imbalance between synthesis and degradation of components of the extracellular matrix that involves intracytoplasmic activation and transcription of the collagen genes as well as extracellular mechanisms. The temporal relationship and the mutual impact of events involved in this cascade – important for understanding pathogenesis and targeted therapy of sclerosis – have not yet been clarified in detail as of yet.

Immune system

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

In systemic scleroderma lymphocytes and both cellular and humoral immune phenomena can be detected in the inflammatory infiltrates in sclerotic skin. Activated lymphocytes produce a series of cytokines that affect endothelial cells and fibroblasts but also peripheral mononuclear cells. The serum levels of IL-1, 2, 4, 6, 8, 10 and 13 as well as well as TNFα are elevated in affected patients. A series of matrix proteins such as type I collagen, fibronectin, laminin and tenascin are capable of stimulating T cells and inducing collagen synthesis via soluble cytokines and growth factors such as TGFβ. Polymorphisms of CD19, a surface molecule of B lymphocytes, possibly result in a loss of tolerance and the production of autoantibodies. Besides in part specific but possibly pathogenetically significant antibodies against endothelial cells, matrix metalloproteinases and fibrillin, highly specific but only questionably pathogenically significant antibodies, antinuclear antibodies (ANA), are found in over 90 % of patients with progressive systemic scleroderma. Certain autoantibodies define subgroups of the diseases or courses and prognosis, others facilitate an early diagnosis.

Clinical findings of systemic scleroderma

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

The American College of Rheumatology (ACR; formerly American Rheumatology Association [ARA]) has defined criteria for the diagnosis of systemic scleroderma [20]. As major criterion proximal diffuse sclerosis, as minor criteria a basal lung fibrosis, sclerodactyly and necrosis of the fingertips are listed. One major criterion or two minor criteria allow for the diagnosis of systemic scleroderma. Current proposals include further diagnostic criteria such as Raynaud phenomenon, pathologic capillary microscopy as well as antinuclear antibodies (ANA) [21, 22]. Early forms of systemic scleroderma are often a diagnostic challenge, while the most recent publications, among others by the European Network for Scleroderma (EUSTAR), have recommended the corresponding clinical manifestations. Scleroderma forms overlapping with other collagen-vascular disorders often make a definitive diagnosis and thus classification difficult due to their overlapping signs and symptoms. Unusual and very rapid courses as well as poor therapy response should prompt considering paraneoplasia and respective diagnostics to search for an underlying malignancy.

Based on the diagnostic criteria different classifications have been proposed including that of the Working Group Dermatological Research (Arbeitsgruppe Dermatologische Forschung, ADF) from 1986 [23] as well as the in the meantime generally accepted division into a limited systemic scleroderma and a diffuse systemic scleroderma [24]. Recent data from European and US-American registries confirm the usefulness of this division, as a correlation of immunoserologic parameters and the course as well as type and extent of organ involvement is possible (Table 1).

Table 1.  Characteristics of both subtypes of systemic scleroderma.
LimitedDiffuse
• Raynaud long-term• Raynaud short-term
• Hands, limbs, face• Trunk
• PAH late• Pulmonary fibrosis early
• Calcinosis (CREST)• Internal organs early
• anti-centromere antibodies• anti-Scl-70 (topo-1) antibodies

Two fundamentally different clinical courses

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

In the limited form acral sites are predominantly affected; in the ADF classification involvement up to the hand and ankle joint is defined as type 1 and involvement of the more proximal limbs and the face as type 2. Internal organ involvement occurs in a delayed fashion and becomes clinically manifest only after years or decades. Typical is the occurrence of the Raynaud phenomenon already in young adulthood, bur peripheral skin sclerosis manifests only during the further course in the 4th and 5th decade of life, which frequently delays the definitive clinical diagnosis. CREST syndrome (an acronym encompassing calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly and telangiectases and typically associated with anti-centromere antibodies) also belongs to this subtype.

Diffuse systemic scleroderma presents with often rapidly progressive cases in face of only short-term, one or two years preexisting Raynaud symptoms and frequently in men. Here firm edema primarily of the trunk that develops into sclerosis of the entire skin as well as rapid and extensive involvement of internal organs are found. Pulmonary fibrosis with only later development of secondary pulmonary arterial hypertension is typical for this form.

Epidemiology and prognosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

Systemic scleroderma has an incidence of 0.3–2.8/100,000/year and a prevalence of 1–15/100,000 [25]. The distinct female predominance is seen in the female: male ratio of 3: 1. Certain HLA types or anti-topoisomerase antibodies indicate severe organ complications of scleroderma, such as renal crisis or interstitial lung disease [26–29]. Regular monitoring and prompt initiation of therapy are essential for these patients. Definitive biomarkers for diagnostics and characterization of clinical subtypes, assessment of prognosis and therapy response must still be established and evaluated [29–32]. Mortality varies greatly depending on the patient group examined and their organ involvement. The 5-year survival rate is estimated to be 85 %, the 10-year survival rate just under 70 %[25, 33].

Classification and epidemiologic data of PSS are usually based on studies on heterogeneous patient cohorts with different definition criteria. Prospective and defined collection of patient data is essential in order to perform clinical research and therapy studies in a reliable and comparative fashion. Due to this fact and the overall rarity of scleroderma and the collagen-vascular disorders as whole, in recent years national and international networks have been founded. The first analyses of collected data have been published by the European (EUSTAR) and German Network for Scleroderma (DNSS) [30, 34].

Dermatological signs

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA

Both forms of scleroderma have in common the Raynaud phenomenon that is characterized by attacks of acute constriction of digital arteries provoked by cold and stress factors [35, 36] (Figure 2). Initially there is painful white discoloration of the fingers and toes, then blue discoloration and in the third phase reactive hyperemia with intensive redness. This sequence of colors white-blue-red is also termed the tricolor phenomenon. Absolutely essential for the diagnosis of Raynaud phenomenon is the occurrence of at least two color phases including the white phase. Often Raynaud phenomenon is mixed-up with acrocyanosis that occurs in collagen-vascular disorders including scleroderma, but describes a persistent, often painfully burning blue discoloration of acral sites. A further sign of a vasculopathy and disturbed vascularization is the appearance of telangiectases, especially on the face and the palms.

image

Figure 2. Disturbed acral circulation: Raynaud phenomenon with attack-like white discoloration of fingers.

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With respect to skin lesions, two sequential stages are differentiated: the edematous and the sclerotic stages. In the first, doughy swelling of fingers and hands, initially of variable intensity, also termed sausage fingers, is observed; in the further course there is increasing sclerosis with what are termed Madonna fingers, i.e. spindle-like, pointed fingers with the skin almost immovably affixed to the underlying bone without substantial subcutaneous fatty tissue (Figure 3). Various nail lesions develop such as onycholysis and onychodystrophy as well as ulcerations of the fingertips termed rat-bite ulcers that are highly painful and have a poor tendency to heal.

image

Figure 3. Sclerosis of the fingers, termed Madonna fingers.

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The problem of digital ulcers in PSS patients has attracted increasing interest in recent years, as they lead to significant morbidity, impair the quality of life massively and often result in inpatient treatment [34–36] (Figure 4). Overall, patients with initial symptoms of PSS at a younger age, with a high modified Rodnan Skin Score (mRSS) and without vasodilator therapy are in greater danger of developing digital ulcerations [35]. A further problem causing severe impairment for the patients are subcutaneous calcifications that occur at acral sites, but also over large joints and can lead to painful ulcerations (Figure 5). Reduced local perfusion and inflammatory processes are held responsible for these.

image

Figure 4. Digital ulcers.

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image

Figure 5. Calcification over joints.

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Further typical clinical manifestations of skin sclerosis are limited mimics and smoothness and firmness of the skin not compatible with age, also termed mask face, limitation in opening the mouth with microstomia and the in fact typical, but rare shortening and sclerosis of the frenulum with limited mobility of the tongue (Figure 6). What is termed tobacco pouch mouth with radial perioral folds is also characteristic (Figure 7). Due to sclerosis of the skin the individual physiognomy is lost, so that scleroderma patients appear quite similar at first glance.

image

Figure 6. Shortened frenulum.

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image

Figure 7. Perioral radial folds, termed tobacco pouch mouth.

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The involvement of internal organs is typical for systemic scleroderma, but is quite variable with respect to the temporal course, extent and involvement of individual organs [5, 24, 30, 32] (Table 2, Figure 8). This heterogeneity due to the lack of clearly defined biomarkers can be foreseen only to a limited extent. Some antinuclear antibodies are indicators for specific organ manifestations, as for example the detection of anti-RNP antibodies and anti-Sm antibodies for renal involvement. Organ involvements detected post mortem are often extensive and a discrepancy exists between them and the slight or lacking clinical symptoms. This is particularly true for the gastrointestinal tract, where pathological lesions are found in 80–90 % of patients at autopsy [37].

Table 2.  Organ involvement in systemic scleroderma.
OrganClinical signs and symptomsFrequency
 • Skin sclerosis 
 • Raynaud phenomenon 
Skin• Impaired facial expression90 %
 • Tobacco pouch mouth 
 • Digital ulcers 
 • Fibrosing alveolitis 
Lungs• Pulmonary fibrosis40–80 %
 • Pulmonary arterial hypertension 
 • Renal crises 
Kidneys• Arterial hypertension30 %
 • Nephrosclerosis 
 • Proteinuria 
 • Myocardial fibrosis 
 • Pericarditis 
Heart• Pericardial fibrosis10–25 %
 • Heart block 
 • Cardiac insufficiency 
Musculoskeletal system Variable
 • Myositis/myopathy10 %
 • Arthritis70 %
Mucous membranesEyes, oral/genital mucosaVariable
image

Figure 8. Temporal course of skin and organ involvement.

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Cardiac involvement is found in 10–25 % of patients, with involvement of both the myocardium as well as the pericardium being possible [38]. Presumably repeated local circulatory disturbances lead to myocardial fibrosis that can affect both chambers of the heart equally. Clinically this involvement can manifest as cardiac insufficiency, partial or complete heart block as well as recurrent pericarditis and pericardial effusions.

Clinically symptomatic lung involvement is most frequent with 40–80 % of patients being affected [39]. Here fibrosing alveolitis (75 %), pulmonary fibrosis and pulmonary arterial hypertension in 21 % can be differentiated. Lung involvement is an important parameter for the 5-year survival rate that declines to 50–70 % in lung involvement [32, 33]. Fibrotic lesions are particularly observed in diffuse systemic scleroderma, while pulmonary arterial hypertension (PAH) characterizes the limited form [31, 39, 40, 41]. In contrast to the previous assessment of the limited form as milder and prognostically more favorable, recent studies reveal that PAH is equally common in both groups. PAH develops due to progressive, damaging restructuring of the pulmonary arteries with initial proliferation of the intima leading via hypertrophy of the media and myxoid degeneration to permanent stenosis of the vessels. The continual inflammatory processes with production of cytokines and components of the extracellular matrix subsequently lead to fibrotic alterations of the surrounding lung tissue. Clinically lung involvement manifests as progressive exertional dyspnea, in final stages also as dyspnea at rest.

Renal involvement manifests clinically in about 30 % of patients with systemic scleroderma. In recent years the significance of renal crises in systemic scleroderma has been recorded in various studies a well as registry data [26, 30, 42]. They are seen apparently particularly often in patients with diffuse scleroderma and initial long-term therapy with systemic corticosteroids. Here arterial hypertension with corresponding symptoms such as headaches, visual disturbances, seizures and a reduction of the glomerular filtration rate are observed. During the further course about one-half of the patients develop a moderate impairment of renal function, initially detectable only through laboratory chemistry. Similar to pulmonary involvement lesions develop via intima swelling in the vessels with increasing deposition of extracellular matrix substances in the renal arteries. Through reduced perfusion of the renal cortex the renin-angiotensin system is activated resulting in arterial hypertension. Besides these processes there is increasing fibrotic restructuring of the kidney up to the end stage of nephrosclerosis.

Other organ systems such as the musculoskeletal system are involved to variable degrees and often only with clinically unspecific symptoms. Myopathies and myositides are found in about 10 % of patients correlating here especially with antibodies against PM/Scl. Muscle involvement is particularly frequent in overlap syndromes with manifestation of dermatomyositis. Arthritic lesions resembling rheumatoid arthritis are observed already in early stages and when inquired a compatible history is found in up to two-thirds of patients.

Sicca symptoms due to progressive destruction of secretory glands in the mouth and genital region are significant and a great impairment for patients. Particularly genital disturbances with dryness, irritability of the mucous membranes and problems during sexual intercourse are rarely voluntarily reported by patients and must be asked about. Men must be asked about erectile dysfunction, which only in recent years has been recognized as an important aspect orf systemic scleroderma. Besides somatic causes and symptoms, emotional aspects should also be considered and approached psychotherapeutically. Lifestyle and thus quality of life of patients with PSS are massively limited due to skin sclerosis, reduced pulmonary function or digital ulcers. Emotional disturbances should be diagnosed urgently and be treated adequately [43, 44].

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA
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    Hudson M, Taillefer S, Steele R, Dunne J, Johnson SR, Jones N, Mathieu JP, Baron M. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. Clin Exp Rheumatol 2007; 25: 7547.
  • 22
    Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit 2004; 10: CR615CR621.
  • 23
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  • 24
    Genth E, Krieg T. Systemische Sklerose – Diagnose und Klassifikation. Z Rheumatol 2006; 65: 26874.
  • 25
    Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 2003; 29: 23954.
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    Nguyen B, Mayes MD, Arnett FC, del Junco D, Reveille JD, Gonzalez EB, Draeger HT, Perry M, Hendiani A, Anand KK, Assassi S. HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. Arthritis Rheum 2011; 63: 5304.
  • 27
    Hanke K, Becker MO, Brueckner CS, Meyer W, Janssen A, Schlumberger W, Hiepe F, Burmester GR, Riemekasten G. Anticentromere-A and anticentromere-B antibodies show high concordance and similar clinical associations in patients with systemic sclerosis. J Rheumatol 2010; 37: 254852.
  • 28
    Nihtyanova SI, Parker JC, Black CM, Bunn CC, Denton C P. A longitudinal study of anti-RNA polymerase III antibody levels in systemic sclerosis. Rheumatology (Oxford) 2009; 48: 121821.
  • 29
    Meyer O. Prognostic markers for systemic sclerosis. Joint Bone Spine 2006; 73: 4904.
  • 30
    Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, Muller-Ladner U, Bocelli-Tyndall C, Matucci-Cerinic M. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis 2007; 66: 75463.
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    Clements PJ, Roth MD, Elashoff R, Tashkin DP, Goldin J, Silver RM, Sterz M, Seibold JR, Schraufnagel D, Simms RW, Bolster M, Wise RA, Steen V, Mayes MD, Connelly K, Metersky M, Furst DE. Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis. Ann Rheum Dis 2007; 66: 16417.
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Fragen zur Zertifizierung durch die DDA

  1. Top of page
  2. Summary
  3. Introduction
  4. Pathogenesis
  5. Genetic factors of systemic scleroderma
  6. Environmental factors
  7. Vascular system
  8. Connective tissue metabolism
  9. Immune system
  10. Clinical findings of systemic scleroderma
  11. Two fundamentally different clinical courses
  12. Epidemiology and prognosis
  13. Dermatological signs
  14. Conflict of interest
  15. References
  16. Fragen zur Zertifizierung durch die DDA
  • 1
    Pathogenetisch sind an der systemischen Sklerodermie folgende Faktoren nicht wesentlich beteiligt:
    • a) 
      Bindegewebe
    • b) 
      T-Lymphozyten
    • c) 
      Blutgefäße
    • d) 
      B-Lymphozyten
    • e) 
      Melanozyten
  • 2
    Welches der folgenden klinischen Symptome ist nicht typisch für die systemische Sklerodermie?
    • a) 
      Tabaksbeutelmund
    • b) 
      weißer Dermographismus
    • c) 
      verkürztes Zungenbändchen
    • d) 
      Sklerodaktylie
    • e) 
      akrale Nekrosen
  • 3
    Folgende Aussage zur systemischen Sklerodermie trifft zu:
    • a) 
      Die limitierte Sklerodermie hat eine deutlich bessere Diagnose als die diffuse Sklerodermie.
    • b) 
      Die systemische Sklerodermie ist mit einer Prävalenz von 1 : 1 000 die häufigste Kollagenose.
    • c) 
      Die zirkumskripte Sklerodermie ist eine umschriebene Form der systemischen Sklerodermie.
    • d) 
      Die Erstmanifestation der systemischer Sklerodermie zeigt sich typischerweise im zweiten Lebensjahrzehnt.
    • e) 
      Antinukleäre Antikörper sind zu einem hohen Prozentsatz positiv, können aber auch fehlen.
  • 4
    Welche Organbeteiligung ist für die systemische Sklerodermie nicht typisch?
    • a) 
      Gastrointestinaltrakt
    • b) 
      Herz
    • c) 
      Lungen
    • d) 
      Knochenmark
    • e) 
      Nieren
  • 5
    Welche der folgenden Aussagen trifft nicht zu?
    • a) 
      Akrale Ulzerationen bei der systemischen Sklerodermie sind in der Regel durch Staphylococcus aureus verursacht.
    • b) 
      Die pulmonale arterielle Hypertonie ist eine typische Komplikation der limitierten Sklerodermie.
    • c) 
      Typische Komplikation der diffusen Sklerodermie ist eine pulmonale Fibrose.
    • d) 
      Die Beteiligung des Gastrointestinaltraktes bleibt häufig klinisch unerkannt.
    • e) 
      Eine Sicca-Symptomatik kann die Augen-, Mundhöhlen- und Genitalschleimhäute einbeziehen.
  • 6
    Welche Aussage zur Epidemiologie der systemischen Sklerodermie trifft nicht zu?
    • a) 
      Die systemische Sklerodermie zeigt eine deutliche Bevorzugung des weiblichen Geschlechtes.
    • b) 
      Durch spezifische Autoantikörper lassen sich prognostisch bedeutsame Untergruppen definieren.
    • c) 
      Die Inzidenz liegt bei 1/100.000 Einwohner/Jahr und zeigt deutliche regionale Unterschiede.
    • d) 
      Die 10-Jahresüberlebensrate liegt bei 40 %.
    • e) 
      Das Überleben ist wesentlich von dem Ausmaß einer Organbeteiligung abhängig.
  • 7
    Welche Aussage zur Pathogenese trifft nicht zu?
    • a) 
      Die Fibroblastenzahl ist in der sklerotischen Haut deutlich erhöht.
    • b) 
      Tissue Growth Factor ß (TGFb) wird als eines der bedeutendsten Zytokine angesehen.
    • c) 
      Bei der systemischen Sklerodermie findet sich ein anti-endotheliales Milieu mit erhöhter Apoptoserate von Endothelzellen und anti-endothelialen Antikörpern.
    • d) 
      Die Organfibrose entsteht aus einer gestörten Balance zwischen Synthese und Degradation der extrazellulären Matrix.
    • e) 
      Teile der zellulären und humoralen Immunität sind an der Pathogenese der systemischen Sklerodermie beteiligt.
  • 8
    Welche der folgenden Verlaufsformen gehört nicht zur systemischen Sklerodermie?
    • a) 
      limitierte Sklerodermie
    • b) 
      diffuse Sklerodermie
    • c) 
      Overlap-Formen
    • d) 
      paraneoplastische Formen
    • e) 
      zirkumskripte Sklerodermie
  • 9
    Welche der folgenden Aussagen zur diffusen und limitierten Sklerodermie trifft nicht zu?
    • a) 
      Nachweis von anti-Zentromer-Antikörpern bei der diffusen Sklerodermie
    • b) 
      schneller Progress bei der diffusen Sklerodermie
    • c) 
      langfristig bestehendes Raynaud-Syndrom bei der limitierten Sklerodermie
    • d) 
      eher akrale Betonung der Sklerose bei der limitierten Sklerodermie
    • e) 
      Bei beiden Formen lassen sich in einem hohen Prozentsatz antinukleäre Antikörper nachweisen.
  • 10
    Welche Aussage zur Organbeteiligung bei der systemischen Sklerodermie trifft nicht zu?
    • a) 
      Diabetes mellitus ist eine typische Komplikation.
    • b) 
      Kardial können sich eine Myokardfibrose, Reizleitungsstörungen oder Perikardfibrose zeigen.
    • c) 
      Nephrologisch kommt es häufig zu einer arteriellen Hypertonie und einer Nephrosklerose, gefürchtet ist eine renale Krise.
    • d) 
      An den Lungen zeigen sich eine Fibrose, fibrosierende Alveolitis und pulmonale arterielle Hypertonie.
    • e) 
      Eine muskuläre Beteiligung findet sich insbesondere bei den Overlap-Syndromen.

Liebe Leserinnen und Leser,

der Einsendeschluss an die DDA für diese Ausgabe ist der 11. November 2012. Die richtige Lösung zum Thema „Kontaktallergie auf Dentalmaterialien“ in Heft 6 (Juni 2012) ist: 1b, 2d, 3c, 4e, 5b, 6c, 7d, 8d, 9d, 10e.

Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.