DOI: 10.1111/j.1610-0387.2012.07998.

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Systemic sclerosis focus on dermatological aspects. Part 2: Diagnostics, therapy

Michael Sticherling
Department of Dermatology, University of Erlangen, Germany

JDDG; 2012 10:783791

Submitted: 27. 4. 2012 | Accepted: 26. 6. 2012

Section Editor Prof. Dr. Jan C. Simon, Leipzig

Keywords
systemic scleroderma diagnostics Rodnan Skin Score capillary microscopy therapy endothelin receptor blocker stem cell transplantation

Summary
Systemic sclerosis is a chronic inflammatory multiorgan disease which may involve the skin and internal organs to a varying extent. Pathogenetically the vasculature, connective tissue and the immune system are involved in a yet to be defined sequence and impact. Case history and results of physical as well as laboratory examinations will determine individually adapted further organ imaging or invasive procedures. Based on their results therapy is initiated which may include supportive measures such as physiotherapy as well as basic skin care and avoidance of any trauma. Many agents are available for the circulatory problems including Raynaud phenomenon and digital ulcers such as calcium channel blockers, ACE inhibitors and intravenous prostacyclin derivatives, as well as endothelin receptor blockers and phosphodiesterase inhibitors. Immunosuppressive and immunomodulatory agents are of varying efficacy depending on organ involvement. Though various therapeutic measures are available, beneficial effects are limited and associated with various unwanted effects. In any case, the therapy has to be individually adapted to the disease stage and course of the disease.

Introduction
Progressive systemic scleroderma (PSS or, alternatively, systemic sclerosis) is a chronic inflammatory multiorgan disease that can affect the skin and internal organs to varying degrees and with different courses. Pathogenetically, the vascular system, the connective tissue and the immune system are involved in as of yet unclear sequence and significance. This results in clinically very heterogeneous findings and courses with different involvement patterns of internal organs and skin. On the skin alone the sclerotic alterations can lead to ulcerations, calcifications and severely impaired mobility. These lead to a severe impairment of quality of life of those affected, but are of secondary significance in comparison to the sclerosis of internal organs with respect to survival. In view of the more or less rapid progression of the disease, early diagnosis and classification of organ involvement and adapted therapy are urgently required. Possible pathogenetic mechanisms and clinical findings were covered in Part 1; diagnostic and therapeutic options for systemic scleroderma will be discussed here.

Diagnostic approach to systemic scleroderma

Dermatologically a series of characteristic clinical signs are found that alone, however, do not justify the diagnosis of systemic scleroderma. Established and evaluated is the

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Table 1: Determining the modified Rodnan Skin Score (mRSS). In the respective 17 regions semiquantitative points for 0 normal , 1 mild but thickened , 2 moderately thickened , 3 severely thickened are assigned and added. The sum lies between 0 and maximally 51 points. Body region Left Fingers Hands Forearms Upper arms Thighs Lower legs Feet Face Ventral chest Abdomen Right

Table 2: Antibody specificities in systemic scleroderma. Target antigen Centromere (CENPB) Topoisomerase-I RNA polymerase U3RNP Fibrillarin PSS overall 30 % 25 % 412 % 6% Limited 50 % 15 % 3.5 % Diffuse 10 % 30 % 8%

With capillary microscopy and ultrasound of the skin, established methods in dermatology, important diagnostic and activity parameters of systemic scleroderma can be assessed. To which extent these parameters are also suitable for monitoring the course must be determined by further studies. Antinuclear antibodies can be detected in 90 % of patients; their antigen specificity can be indicative of form and organ involvement. The lack of ANA, nonetheless, does not exclude systemic scleroderma. Various antibodies have a high specificity, but a relatively low sensitivity. In contrast to anti-DNA and Sm antibodies in systemic lupus erythematosus, their titers do not correlate with disease activity of scleroderma.

modified Rodnan Skin Score (mRSS) in which depending on location and extent of skin sclerosis points are assigned and added with a Skin Score > 5 being indicative of scleroderma [1] (Table 1). The score is overall medium sensitive for assessing therapy response or a short-term deterioration. Additional quantifiable functional parameters are, for example, making a fist (distance of fingertips from the thenar) and opening of the mouth. In capillary microscopy typical alterations are seen in the proximal nail folds such as mega- and hairpin capillaries or a rarefaction of blood vessels [2, 3]. To what extent such lesions definitively correlate with collagen-vascular disorders and vary in a stageand activity-dependent manner and to what extent such restructuring processes in the nail fold can possibly regress, is a subject for further studies. Using ultrasound with 20 MHz probes skin thickness can be measured at defined sites and monitored during the course of the disease in order to record progression of the disease or improvement due to therapy. Diagnostically and prognostically significant is the detection of antinuclear antibodies (ANA) that are positive in high titers in over 90 % of affected patients and in contrast to systemic lupus erythematosus are against only few target antigens [4, 5] (Table 2). The typical anti-Scl-70 (topoisomerase-I) antibodies characterize the diffuse form; the anti-centromere antibodies with the target protein CENPB define limited scleroderma. Antibodies against RNA polymerase indicate potential renal involvement, PM/Scl antibodies muscle involvement, anti-fibrillarin antibodies pulmonary fibrosis. The lack of ANA, nonetheless, does not exclude systemic scleroderma. Further serological parameters are a moderate elevation of the erythrocyte sedimentation rate and of C-reactive protein (CRP) as well as the positive detection of IgM rheumatoid factors in maximally one-third of cases. A skin biopsy will usually give hardly characteristic results and reveals sclerosis of the dermis and homogenization of the collagen fiber bundles in the subcutis. Fibroblasts

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Table 3: Diagnostic approach in systemic scleroderma. Organ examination At the time of diagnosis Modified Rodnan Skin Score Skin 20 MHz ultrasound (Biopsy) Capillary microscopy of the nail folds (Chest x-ray) HR-CT Pulmonary diffusion capacity (CO) Lung Pulmonary function parameters Bronchoalveolar lavage (depending on clinical symptoms) Heart Kidneys Esophagus Electrocardiogram, cardiac sonography Sonography, creatinine clearance, renal function parameters Esophageal manometry (esophagram) Gastroscopy Gastrointestinal tract Colonoscopy (depending on clinical symptoms) Follow-up examination 12 3 yearly (depending on course, earlier if indicated) 12 3 yearly (depending on course, earlier if indicated) Depending on course 12 3 yearly (depending on course, earlier if indicated) 1 3 yearly (depending on course) 12 3 yearly (depending on course, earlier if indicated) 12 3 yearly (depending on course, earlier if indicated) Depending on course 12 3 yearly (depending on course, earlier if indicated) 12 3 yearly (depending on course, earlier if indicated) 1 3 yearly (depending on course, earlier if indicated) 1 3 yearly (depending on course, earlier if indicated) Depending on course

can be detected in only low numbers. The eccrine sweat glands are walled in and appear to be pushed upward by the thickening of the dermis. Additionally, in the blood vessels extending into the subcutis vessel walls are thickened and hyalinized and vessel lumina are narrowed. Immunohistologically no characteristic findings are seen, only in the event of very high ANA titers IgG in a nuclear distribution in the keratinocytes. Presumably, these have been deposited during the technical work-up of the specimen. This phenomenon is particularly characteristic in the mixed connective tissue disease with presence of anti-U1RNP antibodies. A bandlike deposit of IgG and complement factor C3 along the basement membrane zone is more indicative of a mixed connective tissue disease with participation of systemic lupus erythematosus. Extensiveness, frequency and timing of organ-related examinations are still controversially discussed today and must be evaluated critically in view of possible radiation exposure and economic considerations [5, 6] (Table 3). Detailed recommendations have been presented by the German (DNSS) and European Network for Scleroderma (EUSTAR). With respect to lung involvement initially and in the event of stable disease once a year a chest x-ray or better high-resolution computed tomography should be performed to detect pulmonary fibrosis. In addition, functional parameters such as vital capacity and diffusion capacity should be measured. In individual cases bronchoscopy with bronchoalveolar lavage should be performed to detect alveolitis and differentiate inflammatory cells. With respect to cardiac involvement, an ECG should be performed to detect conduction disorders or signs of infarction as well as Doppler echocardiography. Here, pulmonary arterial pressure can be measured non-invasively as well as right ventricular function and pericardial involvement be recognized. When pulmonary arterial pressure is elevated over 25 mmHg, catheterization of the right side of the heart may be indicated for direct measurement of pressure. The nephrologic work-up includes measurement of blood pressure, serum creatinine and urea as well as creatinine clearance in 24-hour urine. The determination of cystatin C as a serological parameter of function and testing for protein in the urine should be performed on a regular basis. When there are indications of muscular involvement, creatine kinase (CK) should be

When the diagnosis is made tests to determine the extent of or to exclude internal organ involvement must be performed adapted to the individual history and clinical data; depending on the results and the further clinical course these should be repeated regularly, at least yearly.

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measured and, if indicated, electromyography or MRT imaging of the shoulder or pelvic girdle and a muscle biopsy should be performed. The often reported and during the course progressive difficulties in swallowing can best be objectified by esophageal manometry [7, 8]. The frequently performed contrast esophagram as radiological test of esophageal motility is distinctly less sensitive and pathological only in later stages, when the clinical symptoms alone already indicate esophageal involvement. When retrosternal pain and acidic regurgitation are present, gastroscopy should be performed to exclude reflux esophagitis, esophageal varicosities and Barrett esophagus.

Differential diagnoses
A series of other chronic inflammatory skin lesions can lead to clinically manifest skin sclerosis. Above all generalized morphea must be mentioned here; this is, nevertheless, usually ANA-negative, has no organ involvement and especially is not associated with the Raynaud phenomenon. Through history, clinical and organ examination other collagen-vascular disorders in terms of overlap syndromes can be excluded. Sclerotic lesions of other etiologies such as eosinophilia-myalgia syndrome, eosinophilic fasciitis (Shulman syndrome), chronic graft-versus-host disease, scleroderma of Buschke, scleromyxedema (Arndt-Gottron syndrome) and nephrogenic gadolinium-associated fibrosing dermopathy can be differentiated on the basis of history, clinical findings, histology and clinical chemistry.

The differential diagnosis includes the many other forms of cutaneous sclerosis.

Therapy
The therapy of systemic scleroderma as an inflammatory multiorgan disease depends on the acuteness of the disease, its progression and the spectrum of organ involvement. Based on current pathogenetic understanding it is targeted at the three most important components: the vascular system, the connective tissue and the immune system [911] (Table 4). To which extent therapeutic measures targeted at specific organs also affect fibrosis of other organs and the overall clinical findings has only been started to be studied [1214]. Basic measures include textile protection from the cold, consistent skin care with emollients, when indicated topical preparations containing urea as well as strict avoidance of smoking. In view of swallowing disturbances and reflux symptoms several small, well-chewed meals should be taken with plenty of fluid. Due to the reflux symptoms proton pump inhibitors or gastric juice-binding medications should be administered as well as elevation of the upper body during sleep. Physiotherapeutic measures including supervised exercises, connective tissue massage and manual lymphatic drainage as well as use of warm paraffin baths on hands and feet are important supportive measures. With respect to vascular lesions and Raynaud attacks calcium channel blockers and ACE inhibitors have proven useful in reducing severity and frequency of Raynaud attacks and improve myocardial perfusion. Above and beyond this ACE inhibitors are employed due to their nephroprotective effects, but are currently being discussed critically with respect to their effects. A therapy-limiting side effect is hypotensive dysregulation due to a too great reduction in blood pressure with headaches and dizziness. The same is true for pentoxifylline that in addition possesses only a low level of evidence. Therapeutic options have improved due to the availability of prostacyclin derivatives, inhibitors of phosphodiesterase such as sildenafil and particularly the endothelin receptor antagonists. The care of digital ulcers including topical and systemic therapy should also remain within the domain of the dermatologist and be based on wellfounded knowledge [15]. Prostacyclin derivatives including the stable derivative iloprost are only available for infusions and administered over 519 days at a dose of 0.52 ng/kg/min over 6 hours will result in a distinct reduction in number and severity of Raynaud attacks. Here, too, headaches and cardiac symptoms due to a steal effect can be therapy-limiting. Experimental data also demonstrate a reduction of fibrosis here. The dual endothelin receptor antagonist bosentan (Tracleer) has been licensed for pulmonary arterial hypertension of NYHA grade II or above as well as for prevention of recurrent acral skin ulcerations [15, 16]. In studies only a reduced recurrence rate,

Therapy is on an individual basis adapted to the clinical symptoms and is targeted at the three pathogenetically important components: the vascular system, the connective tissue and the immune system.

Numerous therapeutic approaches are targeted at the vasculopathy and serve to improve perfusion by way of pharmacological vasodilation. Lowering of blood pressure can be limiting. To what extent such approaches impact the course of the disease is not definite. Nevertheless, there is good evidence for the nephroprotective effects of calcium channel blockers.

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Table 4: Therapy of systemic scleroderma. Name Calcium channel blockers (e.g. nifedipine) ACE inhibitors (captopril, enalapril) Pentoxifylline Iloprost Bosentan Sildenafil Corticosteroids Prednisolone initially 0.51 mg/kg daily, maintenance 515 mg daily; rapid discontinuation due to renal crises 50200 mg daily (2 mg/kg KG) Pulse therapy 200 mg daily i.v. over 36 days, maintenance with 50 mg daily orally (total dose 910 g) 1525 mg weekly orally/s.c. 2.55 mg/kg daily 50 g/ m2 body surface 3x weeks s.c. 375 mg/ m body surface every 2 months, alternatively 1,000 mg initially every 2 weeks, then every 24 weeks 5 mg/kg every eight weeks
2

Dose 1560 mg daily 12,5100 mg daily 4001,200 mg daily 0.52 ng/kg/min over several hours 2 3 62.5 mg daily for 4 weeks, thereafter 125 mg/d

Side effects Arterial hypotension, headache, dizziness Arterial hypotension, nausea, gastrointestinal complaints, leukopenia Arterial hypotension, headache, dizziness Arterial hypotension, headache, dizziness, flush, nausea, abdominal pain, cardiac symptoms Hepatotoxicity

Renal crises! Diabetes mellitus, hyperlipidemia, osteoporosis, arterial hypertension Hepatotoxicity, leukopenia, bone marrow damage Beware: combination with allopurinol! Leukopenia! Cystitis/urethritis, fertility disturbances Hepatotoxicity, leukopenia, bone marrow damage Arterial hypertension, nephrotoxicity Fever, joint pain Tendency for infections, pancytopenia Tendency for infections

Azathioprine

Cyclophosphamide Methotrexate Cyclosporin D-penicillamine Interferon-g Rituximab Infliximab

Initially 150 mg daily, max. dose 1.2 g daily Nephrotoxicity, osteoporosis, exanthema

but not more rapid healing of ulcerations could be shown. Initially administered in a dose of 2 3 62.5 mg daily over 4 weeks, it is increased to 2 3 125 mg daily. The main side effect is hepatotoxicity. The efficacy of the phosphodiesterase inhibitor (sildenafil, Viagra) in Raynaud syndrome and digital ulcers has been shown in clinical studies; it has, nonetheless, not yet been licensed for this indication [17]. A direct effect on tissue fibrosis appears difficult. The substance employed for the longest time D-penicillamine is hardly used in Europe in face of its extensive spectrum of side effects coupled with low efficacy [18]. Interferon-g and -b have been employed in clinical studies for inhibition of fibroblast proliferation and collagen synthesis, but demonstrate only low efficacy. In recent years biologicals with clearly defined target proteins in vitro have been employed in clinical studies or off-label to treat PSS. Despite desirable theoretical effects and promising in vitro results, the effects of a monoclonal anti-PDGF antibody were disappointing in clinical studies [19]. The use of rituximab (Mabthera), an antibody directed against B cells seems barely plausible, as the significance of antibodies in the pathogenesis of the diseases is questionable. On the other hand, the mechanisms of action of rituximab appear to be diverse [20]. If stable organ parameters represent efficacy remains an open question in view of the short follow-up period in available studies and the open, one-arm study design. Similar considerations

With bosentan and sildenafil two substances are available that positively impact digital vasculopathy, Raynaud phenomenon and digital ulcers.

The efficacy of biologicals for scleroderma is questionable and a suitable goal is not defined in view of the heterogeneity of the disease. The result of anti-PDGF antibodies were disappointing despite promising in vitro results.

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Systemic corticosteroids have no substantial long-term effect and should be administered only on a short-term basis due to the risk of renal crisis.

Adjuvant corticosteroid-sparing or -replacing therapeutic agents are sensible for systemic scleroderma; the level of evidence is, nonetheless, low. The most convincing results at least with respect to the involvement of internal organs exist for cyclophosphamide.

Advances in hematological stem cell transplantation and its declining risk have in recent years opened the way for new therapeutic approaches. In contrast to the severe and rapidly progressive scleroderma cases treated to date, possibly patients in earlier disease stages might profit even more.

are valid for the use of TNFa blockers [21]. Here, too, further randomized studies must be performed. In vitro studies suggest a therapeutic potential for the tyrosine kinase inhibitor imatinib (Glivec) that inhibits dermal fibroblast proliferation in PSS also in vivo [22, 23]. To what extent collagen synthesis and thus tissue fibrosis are influenced is the subject of studies currently under way. Various modalities of UV therapy such as bath PUVA, UVA-1 whole body high-dose therapy and extracorporal photophoresis have variable effects, but can have a distinctly positive impact on skin sclerosis [24]. As a chronic inflammatory disease, immunosuppressive treatment is sensible; this can demonstrate positive effects particularly in cases with extensive inflammatory activity and in the presence of lung, joint or muscular involvement. The administration of systemic corticosteroids should be viewed very critically, especially at doses of 0.51 mg/kg daily and in early diffuse disease. In the edema stage before the advent of sclerosis or while arthritic symptoms, short-term administration is sensible. Nevertheless, systemic corticosteroids appear not to have substantial positive long-term effects and should be discontinued rapidly due to the risk of renal crisis [25]. Additional or alternative medications in an adjuvant situation such as methotrexate and mycophenolate mofetil are therefore prudent. In this connection, rapamycin appears a well-tolerated alternative, but studies with respect to long-term and disease progress-delaying efficacy of the product must follow. The combination with corticosteroid-sparing adjuvants is a possible solution. Of all immunosuppressive agents cyclophosphamide has been used the longest and evaluated in various studies [26, 27]. It represents an important therapeutic approach in rapidly progressive disease with pulmonary involvement (alveolitis and pulmonary fibrosis) less so of the skin and is administered intravenously as pulse therapy or in low-dose long-term therapy. Methotrexate, in a dosage of 1525 mg once weekly administered orally or subcutaneously demonstrates with good tolerability particularly good effects on pulmonary fibrosis, less so on skin sclerosis [28, 29]. The evidence level with respect to efficacy is, nonetheless, low. Mycophenolate mofetil (MMF) appears to be an interesting immunosuppressive alternative with respect to renal involvement, without extensive prospective and controlled studies being available to date [3032]. Effects on the skin are, nevertheless, ambivalent and the administration in any case represents off-label use. Even though cyclosporine possesses high antiinflammatory activities, its wellknown nephrotoxic effect is therapy-limiting especially in systemic scleroderma [33]. Advances in hematological stem cell transplantation and its declining risk in recent years allow for ablative immunosuppression with subsequent substitution of autologous stem cells. Through prior conditioning the immune system of the recipient is switched off and thus also the pathological immune mechanisms of the autoimmune disease. In the meantime several studies in cases of severe PSS have been reported [34, 35] that demonstrate a response rate of autologous stem cell grafting including improvement of cutaneous fibrosis and stabilization of organ function up to seven years clearly superior to other treatment approaches. Larger, randomized clinical studies must, nevertheless, follow. Possibly patients in early disease stages would profit even more, but currently these modalities are carried out only in severe and rapidly progressive cases in specialized centers.

Commentary
Even though various therapeutic approaches are available for scleroderma, the effects are limited and they are restricted due to numerous side effects. In each case, therapy must be adapted individually to the disease stage. In view of the more or less slow progression of the disease, early therapy with still to be defined targeted agents appears desirable. <<< Conflicts of interest The author is speaker and member of dermatological advisory boards of Abbott, MSD, Pfizer, Janssen and receives research funding by Pfizer and Actelion.

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Correspondence to
Prof. Dr. Michael Sticherling Department of Dermatology University of Erlangen Ulmenweg 18 D-91054 Erlangen, Germany Tel.: +49-9131-85-33851 Fax: +49-9131-85-36175 E-mail: [email protected]

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Fragen zur Zertifizierung durch die DDA

1. Welche Aussage zur Diagnostik der systemischen Sklerodermie trifft nicht zu? a) Klinisch-dermatologisch werden kapillarmikroskopische und sonographische Untersuchungen sowie die Bestimmung des PASI durchgefhrt. b) Die Tiefe organbezogener Untersuchungen basiert auf individuellen anamnestischen und klinischen Angaben und Befunden. c) Regelmig sollte eine Lungen-, Herz- und Nierenbeteiligung ausgeschlossen bzw. in ihrer Schwere eingegrenzt werden. d) Sequenzielle Untersuchungen ergeben sich aus dem individuellen Verlauf, hinsichtlich einer Organbeteiligung sollten sie jedoch in etwa jhrlichen Abstnden durchgefhrt werden. e) Hautbiopsien ergeben eher uncharakteristische Befunde, insbesondere in Hinsicht auf eine Abgrenzung der Subtypen einer systemischen und Abgrenzung einer zirkumskripten Sklerodermie. 2. Welche supportiven Manahmen sind bei der systemischen Sklerodermie nicht sinnvoll? a) krankengymnastische bungen b) Lymphdrainage c) glutenfreie Kost d) Bindegewebsmassage e) Paraffinbder 3. Welche Aussage zu systemischen Glukokortikosteroiden bei der systemischen Sklerodermie trifft nicht zu? a) Systemische Glukokortikosteroide sollten nur mit Vorsicht eingesetzt werden, da das Risiko einer renalen Krise besteht. b) Systemische Glukokortikosteroide sollten insbesondere initial nur in niedriger Dosis eingesetzt werden. c) Der morbostatische Effekt von systemischen Glukokortikosteroiden ist fraglich. d) Die Langzeiteffekte von systemischen Glukokortikosteroiden sind fraglich. e) Systemische Glukokortikosteroide sollten als Stotherapie in Dosen ber 1 mg/kg KG eingesetzt werden. 4. Welches Therapeutiknm findet bei der systemischen Sklerodermie eher keine Anwendung? a) Mycophenolatmofetil b) Methotrexat c) Cyclophosphamid d) D-Penicillamin e) Thalidomid 5. Welche Aussage zu durchblutungsfrdernden Therapeutika trifft nicht zu? a) Bosentan ist zur Vorbeugung rezidivierender akraler Hautulzerationen zugelassen. b) Phosphodiesterasehemmer sind eine mgliche Alternative, fr die Indikation akraler Hautulzerationen jedoch nicht zugelassen. c) Prostazyklinderivate knnen nur intravens verabreicht werden. d) ACE-Hemmer sind aufgrund renaler Komplikationen kontraindiziert. e) Calciumantagonisten sind als untersttzende, nephroprotektive Therapie sinnvoll. 6. Welche Aussage zum Einsatz von Immunsuppressiva bei der systemischen Sklerodermie trifft nicht zu? a) Cyclophosphamid eignet sich insbesondere fr rasch fortschreitende Krankheitsbilder mit Lungenbeteiligung. b) Methotrexat zeigt gnstige Effekte auf eine Lungenfibrose. c) Die nephrotoxische Wirkung von Ciclosporin ist therapielimitierend. d) Azathioprin ist bei der systemischen Sklerodermie aufgrund seiner myelosuppressiven Eigenschaften kontraindiziert. e) Alternativ ist eine autologe Stammzelltransplantation mglich, die aktuell jedoch schweren Krankheitsverlufen vorbehalten ist.

7. Welche der folgenden Untersuchungsmethoden eignet sich nicht zur Bestimmung der Hautdicke? a) Modifizierter Rodnan Skin Score b) 20 Mhz-UltraschallUntersuchungen c) Mundffnung d) Kapillarmikroskopie e) Faustschluss

8. Welcher der folgenden antinukleren Antikrper ist nicht charakteristisch fr die systemische Sklerodermie? a) Anti-Zentromer-Antikrper b) Anti-Scl-70-Antikrper c) Anti-dsDNA-Antikrper d) Anti-RNA-Polymerase e) Anti-Fibrillarin-Antikrper

9. Welche der folgenden Untersuchungsmethoden eignet sich eher nicht zur Diagnostik der systemischen Sklerodermie? a) Herzsonographie b) Lungenbiopsie c) sophagusmanometrie d) Lungendiffusionskapazitt e) Kreatininclearance

10. Welche der folgenden Erkrankungen muss nicht differenzialdiagnostisch von der systemischen Sklerodermie abgegrenzt werden? a) chronische Graft-versus-HostReaktion b) Skleromyxdem Arndt-Gottron c) Eosinophilie-Myalgie-Syndrom d) Psoriasis vulgaris e) eosinophile Fasziitis

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CME Article

Liebe Leserinnen und Leser,

der Einsendeschluss an die DDA fr diese Ausgabe ist der 20. Dezember 2012. Die richtige Lsung zum Thema Maligne Epitheliale Tumoren: Teil I. Pathophysiologie und Klinik in Heft 7 (Juli 2012) ist: 1c, 2a, 3e, 4b, 5a, 6e, 7a, 8d, 9b, 10e. Bitte verwenden Sie fr Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lsung online unter http://jddg.akademie-dda.de ein.

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