Systemic Sclerosis - Scleroderma

74
DOJ Contents Systemic sclerosis - scleroderma U.-F. Haustein, MD Dermatology Online Journal 8(1): 3 Department of Dermatology, University of Leipzig, Germany Abstract Systemic sclerosis is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. This review discusses epidemiology and survival, clinical features including subsets and internal organ involvement, pathophysiology and genetics, microvasculature, immunobiology, fibroblasts and connective tissue metabolism and environmental factors. Early diagnosis and individually tailored therapy help to manage this disorder, which is treatable, but not curable. Therapy involves immunomodulation as well as the targeting of blood vessel mechanics and fibrosis. Physical therapy and psychotherapy are also important adjunctive therapies in this multifactorial disease. Introduction Systemic sclerosis (SSc) is a clinically heterogeneous generalized disorder which affects the connective tissue of the skin and internal organs such as gastrointestinal tract, lungs, heart and kidneys. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen. The first detailed description of a scleroderma-like disease was published by Curzio in Naples in 1753.[ 1] The patient, a young woman suffered from excessive tension and hardness of the skin. Nearly 100 years later, in 1847 Gintrac introduced the term scleroderma, as the skin was the most obvious organ involved.[ 2] The extensive involvement of internal organs has only been realized in the second half of the 20th century.[ 3, 4, 5] The spectrum of sclerodermatous diseases comprises a wide variety of clinical entities such as morphea (patchy, linear, generalized), pseudo-scleroderma and the overlap-syndromes with Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein... 1 of 74 2/21/2013 2:24 AM

Transcript of Systemic Sclerosis - Scleroderma

Page 1: Systemic Sclerosis - Scleroderma

DOJ

ContentsSystemic sclerosis - sclerodermaU.-F. Haustein, MDDermatology Online Journal 8(1): 3

Department of Dermatology, University of Leipzig, Germany

Abstract

Systemic sclerosis is a clinically heterogeneous, systemicdisorder which affects the connective tissue of the skin, internalorgans and the walls of blood vessels. It is characterized byalterations of the microvasculature, disturbances of the immunesystem and by massive deposition of collagen and other matrixsubstances in the connective tissue. This review discussesepidemiology and survival, clinical features including subsets andinternal organ involvement, pathophysiology and genetics,microvasculature, immunobiology, fibroblasts and connective tissuemetabolism and environmental factors. Early diagnosis andindividually tailored therapy help to manage this disorder, which istreatable, but not curable. Therapy involves immunomodulation aswell as the targeting of blood vessel mechanics and fibrosis.Physical therapy and psychotherapy are also important adjunctivetherapies in this multifactorial disease.

Introduction

Systemic sclerosis (SSc) is a clinically heterogeneousgeneralized disorder which affects the connective tissue of the skinand internal organs such as gastrointestinal tract, lungs, heart andkidneys. It is characterized by alterations of the microvasculature,disturbances of the immune system and by massive deposition ofcollagen. The first detailed description of a scleroderma-like diseasewas published by Curzio in Naples in 1753.[1] The patient, a youngwoman suffered from excessive tension and hardness of the skin.Nearly 100 years later, in 1847 Gintrac introduced the termscleroderma, as the skin was the most obvious organ involved.[2]The extensive involvement of internal organs has only beenrealized in the second half of the 20th century.[3,4,5]

The spectrum of sclerodermatous diseases comprises a widevariety of clinical entities such as morphea (patchy, linear,generalized), pseudo-scleroderma and the overlap-syndromes with

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

1 of 74 2/21/2013 2:24 AM

Page 2: Systemic Sclerosis - Scleroderma

Figure 1

Figure 1. The clinical spectrum of scleroderma

similar cutaneous and histopathologic manifestations. [7](Fig 1)However, these variants will not be discussed further. For thedifferential diagnosis see Table 1. Due to the complexity of theinternal organ involvement SSc has attracted much attention fromseveral disciplines (e. g. rheumatologists,pulmonologists,nephrologists) and therefore, a close cooperationwith them is recommended, concerning diagnostic procedures andtherapeutic regimens. In addition, the complex pathophysiology ofSSc, involving genetic factors, environmental factors, vascular andimmune system functions, as well as fibroblasts and matrixsubstances made SSc attractive to study events leading toautoimmune diseases or connective tissue diseases, in general.Basic functions of various cell types (endothelial cells,T-lymphocytes, monocytes, fibroblasts, mast cells) as well as theproduction and effects of cytokines, growth factors, and adhesionmolecules have been studied and animal models have beendeveloped to give closer insights into the pathophysiology of thisdisease.

Table 1: Differential diagnoses of SScMorphea (generalised, linear)Scleroedema generalised BuschkeScleromyxoedemaMixed connective tissue diseaseShulman syndromeShoulder-hand syndromePseudoscleroderma, e. g. porphyria

cutanea tarda,polyvinyl chloride diseasetoxic oil syndromedrug induced pseudosclerodermaorganic solvents syndrome

Werner's syndrome

Definition, Criteria

Definition, Criteria

The American College of Rheumatology (former AmericanRheumatism Association - ARA) has defined criteria, that are 97 %sensitive and 98 % specific for SSc as follows[8]:

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

2 of 74 2/21/2013 2:24 AM

Page 3: Systemic Sclerosis - Scleroderma

Major criterion:

proximal diffuse (truncal) sclerosis (skin tightness, thickening,non-pitting induration)

Minor criteria:

sclerodactyly (only fingers and/or toes)digital pitting scars or loss of substance of the digital fingerpads (pulp loss)bibasilar pulmonary fibrosis

The patient should fulfill the major criterion or two of thethree minor criteria.

Raynaud's phenomenon is observed in 90-98 % of SScpatients.[9] It may precede SSc for years and its presence may havepredictive value for the subsequent development of SSc, inparticular in association with abnormal nailfold capillaries and theoccurrence of antinuclear antibodies (ANA).[9,10]

In our experience, the American College of Rheumatologycriteria from 1980 urgently need revision, particularly to moreadequately incorporate patients with limited SSc. We supportarguments that new advances in medical technology provide theopportunity to detect disease in patients who do not meet criteriaestablished in 1980. In accordance with Poormoghin et al. andLonzeti et al. we support the addition of simple clinical variablessuch as nail capillary microscopy and anticentromere antibody(ACA) positivity as novel minor criteria. [11,12] With these twonew criteria the sensitivity of ARA preliminary criteria wasimproved from 33 to 97 %.[12,13]

Classification

Over the years several attempts have been made to establish aclassification system. Such classifications differentiate eitherdifferent degrees of skin involvement,[14,15] distinct clinicalmanifestations such as CREST-syndrome (calcinosis, Raynaud'sphenomenon, esophagus dysmotility, sclerodactyly,teleangiectasia),[16,17] SSc sine scleroderma,[18] vascular andinflammatory forms,[19] or associations with differentautoantibodies.

In the past, acroscleroderma and diffuse scleroderma weredistinguished. Acroscleroderma was mainly defined by vascularalterations and by skin sclerosis, limited to acral areas (fingers),while diffuse scleroderma involved both the trunk and theextremities with pronounced inflammation and more rapidprogression. On the other hand Barnett et al.[14] and the workinggroup of the German Dermatological Research Community

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

3 of 74 2/21/2013 2:24 AM

Page 4: Systemic Sclerosis - Scleroderma

(Arbeitsgemeinschaft Dermatologische Forschung)[15]differentiated three types:

Type I Involvement of the fingers and hands to wrist(acrosclerosis) and faceType II Proximal (extremity) ascending sclerosis includingthe forearmType III Beginning of development of sclerosis at the trunk.

During the last 10 years the majority of researchers have usedthe classification into limited versus diffuse cutaneous SScaccording to Le Roy et al.[20] These categories are described asfollows (Table 2):

Table 2. SSc subsets according to LeRoy at al. J Rheumatol1988;15:202-05

Limited Cutaneous SScRaynaudÕs phenomenon for years at presentationSkin sclerosis limited to hands, feet, face, andforearms, or absentSignificant late incidence of pulmonary hypertension,trigeminal neuralgia, calcinosis, and teleangiectasiaDilated nailfold capillary loops, usually withoutcapillary dropouts Detected by widefield nailfoldcapillaroscopy

Diffuse cutaneous SScOnset of Raynaud's phenomenon within 1 year ofonset of skin changesTruncal and acral skin involvementPresence of tendon friction rubsEarly and significant incidence of interstitial lungdisease, oliguric renal failure, diffuse gastrointestinaldisease, and myocardial involvementPresence of anti-DNA topoisomerasi I (anti-Scl-70)antibodiesAbsence of anticentromere antibodiesNailfold capillary dilatation and destruction detectedby widefield nailfold capillaroscopy

SSc subsets according to LeRoy at al[20]

Limited Cutaneous SSc

Raynaud's phenomenon for years at presentationSkin sclerosis limited to hands, feet, face, and forearms, orabsentSignificant late incidence of pulmonary hypertension,trigeminal neuralgia, calcinosis, and teleangiectasiaDilated nailfold capillary loops, usually without capillarydropouts

Diffuse cutaneous SSc

Onset of Raynaud's phenomenon within 1 year of onset of

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

4 of 74 2/21/2013 2:24 AM

Page 5: Systemic Sclerosis - Scleroderma

skin changesTruncal and acral skin involvementPresence of tendon friction rubsEarly and significant incidence of interstitial lung disease,oliguric renal failure, diffuse gastrointestinal disease, andmyocardial involvementPresence of anti-DNA topoisomerase I (anti-Scl-70)antibodiesAbsence of anticentromere antibodiesNailfold capillary dilatation and destruction

Detected by widefield nailfold capillaroscopy

More than 50 % of SSc patients belong to the limited SSc.They have a more insidious onset of illness, a long history ofRaynaud's phenomenon and swelling of digits, a more benigncourse, and a lower incidence of renal involvement and restrictivepulmonary disease with a much better prognosis. [21] Some casesare associated with anticentromere antibodies (ACA).

Patients with diffuse cutaneous SSc have a short history.These patients often have acral sclerosis, arthritis, Raynaud'sphenomenon, and rapid progression of skin involvement includingarms and trunk. In addition, they have a higher incidence of renal,[21,22] cardiac, [23] pulmonary disease, [24] and tendon frictionrub. [21] Antitopoisomerase antibodies (ATA) or antifibrillarinantibodies (against U3 RNA associated protein) may be present.When associated with anti-RNA polymerase, patients with diffuseSSc have the shortest survival time and worst prognosis.[25]

Three phases of dermal involvement can be distinguished[26]:

edematous phase (stiff, puffy fingers)1.

indurative phase (hard, tight, hidebound)2.

atrophic phase (softened skin, burned out).3.

Epidemiology

Compared with other connective tissue diseases SSc isrelatively rare. A certain genetic background in combination withthe typical immune reactivity determines the susceptibility toexpress SSc. The true incidence is obviously underestimated sinceearly features are frequently overlooked. The prevalence of SSc isreported to be between 13 to 105 and 13 to 140 per million inNorth America, Australia and Europe, respectively,[27,28,29] andas high as 290 in South Carolina.[30]

The incidence of SSc is between 2.6 and 20 to 28 per millionper year. [29,301,32,33,34] The overall female/male ratio wasreported as 3:1..[29,34] However, this ratio is larger in GreatBritain (6:1) and in the USA (8:1)...[34,35] The femalepreponderance is most marked early in adult life (7:1), narrowingtoward the fifth decade to 2 - 3:1.[36] The average onset of SScoccurs between 40 and 50 years,[36] but in women it is in the late

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

5 of 74 2/21/2013 2:24 AM

Page 6: Systemic Sclerosis - Scleroderma

childbearing years between 30 and 39.[36] Less than 10 % ofpatients develop SSc before the age of 20.[6]

Survival

Several survival studies have indicated a distinct dependencyon the internal organ involvement. In general, the survival rate liesbetween 34 and 73 %.[37] It is, however, shorter with a poorerprognosis in men and older patients than in women and youngerpatients. Survival differences are also notable in whites ascompared to blacks.[36]

The average annual mortality was reported to be between 0.9and 3.8 per million population per year;[37] in Australia it was4.1.[28] The overall 5 and 10 year survival rates were 86 % and 69%, respectively in Sweden.[38] There is a 4.6 fold risk of deathcompared with the general population, it is even worse among malepatients with the diffuse subset.[38] Most patients die ofcardiopulmonary or renal disease.[38] There is also an increasedcancer mortality, particularly of the lung.[29]

A logistic regression model identified 3 factors: proteinuria,elevated ESR and low carbon monoxide diffusing capacity, that incombination, had an accuracy of 80 % in predicting mortality. Theabsence of these 3 factors was associated with 93 % survival.[39]

The extent of skin sclerosis (skin score) was revealed to be auseful marker of both severity and prognosis.[40] Sclerodactylyalone is associated with 79 84 % survival at 5 years and 47 % to 75% survival at 10 years, while truncal SSc at disease onset reducessurvival to 48 to 50 % at 5 years and 22 % to 26 % at 10 years.[41]Five year follow-up resulted in the following predictive factors ofsurvival in 264 patients: older age ( 64 years), reduced renalfunction (blood urea nitrogen 16 mg/dl), anemia (haemoglobin 11gm/dl), reduced pulmonary diffusing capacity for carbon monoxide( 50 %), total serum protein level ( 6 gm/dl), and reducedpulmonary reserve (forced vital capacity 80 %).[31,32] Out of 646patients studied before angiotensin converting enzyme inhibitortreatment was available, none of the 24 patients with kidneydisease at onset survived for 6 years and the 1-year survival wasonly 25 %.[37]

Clinical symptoms

SSc in general affects the connective tissue, predominantly ofthe skin and vessel wall and, to a lesser extent, of thegastrointestinal tract, heart, lungs and kidneys.

Cutaneous symptoms

Cutaneous symptoms, often associated or preceded by

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

6 of 74 2/21/2013 2:24 AM

Page 7: Systemic Sclerosis - Scleroderma

Raynaud's phenomenon and arthralgias of the fingers, are usuallyearly signs in the course of SSc and therefore helpful forestablishing the diagnosis and initiating therapy.

Raynaud's phenomenon is episodic digital ischaemiaprovoked by cold or emotion. It is characterized by three phases:(1) palor due to vasospasm (2) cyanosis due to ischaemia (reducedoxygen content) and (3) rubor due to reactive hyperemia.Raynaud's phenomenon can be observed in 3-4 % of the generalpopulation[42] and as a benign transient condition in 20-30 % ofyoung women.[43] However, it is associated particularly withconnective tissue diseases and is seen in 98 % of SSc patients,occurring as the first symptom in up to 70 % of SSc. [44] Raynaud'sphenomenon is associated with the following in SSc:

Very early or late age onset and pulp ulceration1.

Abnormal nailfold capillary pattern, e. g. dilatation of allthree parts of the capillary loop: arterial, apical and venular,and loss of capillaries (drop out) either diffusely or inlocalized areas

2.

Occurrence of ANAs that are detectable in up to 95 % of SSc3.

Signs of endothelial cells injury by increase in the plasmab-thromboglobulin and factor VIII (v. Willebrand factorantigen) level[44]

4.

Figure 2 Figure 3

Figure 2: Involvement of the face with swollen scleroticmask-like skin including teleangiectasias

Figure 3: Sclerotic hidebound face with radial furrowingaround the mouth, shrinken nose, teleangiectasias andmicrocheily

Figure 4 Figure 5

Figure 4. Sclerodactyly with acral trophic ulcerations at boththumbs

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

7 of 74 2/21/2013 2:24 AM

Page 8: Systemic Sclerosis - Scleroderma

Figure 5. Ulcer at the finger tip (rat bite necrosis)

Figure 6 Figure 7

Figure 6. Dermatogenic contracture due to hidebound skinstiffness

Figure 7. Sclerosis of the frenulum

Sclerosis of the skin is the leading feature of SSc. It starts atacral areas, particularly at the fingers and hands, later at the faceincluding lips and the frenulum of the tongue (Figure 2-7). Inseveral patients skin manifestations remain limited to acral areas foryears. In others, however, sclerosis ascends progressively from theextremities to the trunk and finally, affects the whole integument.On the contrary, in a few cases skin alterations appear at the trunkand then spread over the whole body surface within a short periodof time. As a rule these patients suffer from severe internal organinvolvement and have a poor prognosis.

In the course of the disease sclerosis develops gradually. Itstarts with edema, turns into sclerosis and ends in an atrophic stage.Thus, fingers are initially swollen with nonpitting edema, and arelater hardened. Besides hypo- and hyperpigmented areas,teleangiectasias and trophic painful ulcerations, in particular atacral locations such as fingertips and knuckles (rat bite necroses),and atrophy are found. Hair loss and anhidrosis reflect thedegeneration of appendages due to surrounding fibrosis. In somecases calcinosis, with secondary infection of slowly healingulcerations leading to gangrene and acroosteolysis, may causearticular deformities and dissolution of terminal phalanges. Typicalfeatures of the face involvement are shrunken nose, microcheily,reduced mouth aperture and microglossy. In addition, radialfurrowing around the lips, teleangiectasias and changes in thepigmentation ( mottled or diffuse hyperpigmentation resemblingAddison's disease or focal hypopigmentation as postinflammatorypigment incontinence) are typical. Sclerosis limits expression,leading to a mask-like stiffness of the face.

A subgroup of patients characterized by extensive calcinosis,Raynaud's phenomenon, esophageal dysmotility, sclerodactyly andwidespread teleangiectasias is described as CREST-syndrome[16]which has been previously reported as Thibièrge-Weissenbachsyndrome.[45] This entity is now classified within the subset oflimited SSc.

It is generally accepted that the survival of SSc patientsdecreases as skin sclerosis extends proximally and progressively, inparticular when evaluated within the first 2 to 3 years of disease

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

8 of 74 2/21/2013 2:24 AM

Page 9: Systemic Sclerosis - Scleroderma

onset.[31,32,37,40,41] Therefore semiquantitative measures of theskin score are well advised and are performed by clinical palpationand evaluation on a scale of 0 to 3 in 10 to 15 body areas,[46] ormore objectively by ultrasonographic measurement of skinthickness[47,48] or by using both wet and dry forearm skin biopsyweight, which correlates well with the forearm skin score (seetherapy). [49]

Again, the usefulness of the skin thickness score has recentlybeen confirmed as a predictor and correlate of the outcome inSSc.[50] In addition, the degree of skin involvement can beassessed by therapists and patients themselves using a questionnaireregarding functional ability and disability, respectively.[51] Theneck sign consists of ridging and tightening of the skin of the neckon extension of the head. It is positive in more than 90 % of SScpatients.[52]

Histopathology of the skin

Histopathologic findings are not very characteristic in SSc andsimilar to morphea. At the early stage one observes mildinflammatory infiltrates consisting of lymphocytes (mostly T helpercells), monocytes, histiocytes and plasma cells around the bloodvessels and ducts of the eccrine sweat glands, and partly also in theinterstitial tissue and subcutaneous fat tissue. The collagen fibersare edematous.

In the later stage these infiltrates are reduced or disappearcompletely. The vessel walls are thickened and hyalinized; theirlumen is narrowed leading to devascularization. The collagenbundles are thickened and densely packed with eosinophilicstaining. Only very few fibroblasts are seen (acellular sclerosis).This is true for the reticular dermis and their septae deeplyextending into the subcutis. The eccrine sweat glands are atrophicdue to surrounding fibrosis and they are located in the upper part ofthe dermis.[5,23]

Abundant accumulation of connective tissue and matrixproteins is first seen in the vicinity of blood vessels in the reticulardermis and at the border of the subcutaneous tissue. By electronmicroscopy, irregular, thin, newly synthesized collagen fibrils with adiameter of 10-30 nm are seen. Later, in addition to the smallfibers, large diameter fibers occur as a sign of aging, in a bimodaldistribution.[53,54,55] Ultrastructural studies of the vessel revealedvacuolization and damage of endothelial cells, reduplication of thebasement membrane and activation of the rough endoplasmicreticulum of pericytes and fibroblasts.[56]

Involvement of internal organs

Prognosis of SSc largely depends on involvement of internalorgans, particularly the lungs, heart and kidneys. Thegastrointestinal tract, although most frequently affected, is less life

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

9 of 74 2/21/2013 2:24 AM

Page 10: Systemic Sclerosis - Scleroderma

Figure 8

Figure 8. Stiff glass tubeesophagus as shown bybarium swallow

threatening. It has been demonstrated that severe organinvolvement often occurs early in the course of diffuse SSc.[57] Astheir survival is markedly reduced, these patients should bemonitored very closely during the first three years and potentialdisease modifying therapies must be initiated early.

Esophagus and gastrointestinal tract

The gastrointestinal tract isfrequently involved in SSc. Theesophagus in is involved in morethan 85 % of cases with resultantdysphagia and phagodynia due tohypomotility, reflux, pepticesophagitis, Barrett's metaplasiaand fibrotic strictures.[58]Esophageal involvement isdiagnosed by conventionalradiography (barium swallow)which shows a stiff glass tubeappearance (figure 8), by manometric measurements,[59] and bysensitive scintigraphic procedures that are quantitative andnon-invasive.[60] The occurrence of malignancies in the esophagusis low as shown in a follow-up study of long-standing refluxesophagitis and Barrett's esophagus.[61]

Peristaltic abnormalities may delay gastric empting(watermelon stomach) and may affect motility of the small andlarge intestinum leading to pseudoobstruction or malabsorption dueto bacterial overgrowth. In addition, diverticular ulcerations,stenosis, chronic obstipation, megacolon and rectal prolapse havebeen described.[62,63,64,65,66] The histopathology of thegastrointestinal tract shows mild inflammatory infiltrates of thelamina propria and in certain segments, atrophy and fragmentationof the smooth muscles followed by collagen deposition and changesof the blood vessels.[58,66] Liver is rarely involved primarily inSSc. It may be secondarily affected, a sequela of right ventricularheart disease.[67] However, the association of SSc with primarybiliary cirrhosis is more often described. This disorder is seen in17 % of 189 patients, predominantly in the CREST variant withanticentromere and antimitochondrial antibodies[68,69]Pancreatic exocrine function is often reduced, but is usually ofminor clinical impact in SSc.[70] The gastrointestinalmanifestations are summarized in Table 3.

Lungs

The frequency of lung involvement in SSc ranks second togastrointestinal manifestation; it varies from 40 to 90 %. The risks

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

10 of 74 2/21/2013 2:24 AM

Page 11: Systemic Sclerosis - Scleroderma

for severe pulmonary manifestation are the following: male sex,diffuse SSc, presence of ATA and inflammatory signs, andsignificantly reduced diffusion capacity.[71] Pulmonaryhypertension and lung fibrosis are to be differentiated. Pulmonaryhypertension is a significant cause of death, thus it decreases the 5years survival from 90 % to 50-70 % .[72,73] The early clinicalfeatures may often be missed and lead to greater morbidity andmortality.

Pulmonary hypertension occurs more frequently in limitedSSc, while restrictive fibrotic lung alterations are more frequentlyobserved in patients with diffuse SSc.[74] In the CREST-syndrome,irreversible pulmonary hypertension can develop despite theabsence of fibrosis.[75] In pulmonary hypertension arterioles showconcentric intima proliferation, media hypertrophy and, in part,myxomatoid degeneration, finally leading to narrowing of thelumen and increase of pressure in the pulmonary circulation.[71]The pulmonary blood pressure is best diagnosed by Dopplerechocardiography (Table 4). Pulmonary hypertension with dyspneaand right-sided failure occurs in 5 to 10 % of patients.

Table 4, Diagnostic algorithm ofpulmonary manifestation

Screeninghistory, statusbodyplethysmographydiffusion capacityblood gas analysis

alveolitis/fibrosis?pulmonary hypertension?

basic diagnosticchest X-ray (two levels)echocardiographyoxyergometry

enlarged diagnosticHR-CTperfusion szintigraphycompliance measurement

diagnostic certaintybronchoscopy with BALright heart katheter

course controlbodyplethysmographyechocardiography vblood gas analysisdiffusion capacityoxyergometry

Lung fibrosis develops after alveolitis with proliferation ofconnective tissue by fibroblasts under the influence of growth

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

11 of 74 2/21/2013 2:24 AM

Page 12: Systemic Sclerosis - Scleroderma

Figure 9

Figure 9. Honey comb lungas sign of lung fibrosis inhigh resolution computertomography

factors and chemokines such asplatelet -derived growth factor(PDGF), insulin growth factor(IGF-1),[76] MCP-1, and MIP-1a..[76,77] The disturbance of lungfunction is characterized byrestrictive changes with reducedrespiratory volume and by impaireddiffusion capacity. In addition,obstructive changes involving bothsmall and large airways may bepresent.[78,79] Radiographicfindings are characterized byfine-reticular, partly nodular,fibrosis of the lung areas. There are also thickened septae andnetlike stripes near the blood vessels. Later, with increased fibrosis,a cystic transformation takes place, representing the so-called³end-stage-lung² or ³honeycomb lung² (Figure 9). The introductionof high resolution computer tomography has significantly increasedthe sensitivity of radiographic diagnosis, particularly in terms of theearly detection of alveolitis. Bronchoalveolar lavage (BAL) is ableto evaluate the activity of florid alveolitis as shown by an increasein the number of alveolar macrophages, neutrophilic and/oreosinophilic granulocytes, and immune complexes. The number oflymphocytes is normal.[80] In prospective studies, BAL have beenshown to be a useful predictor of the course of SSc lung disease:the presence of alveolitis is associated with worsening dyspnea,worsening of chest radiographic findings, and a significant declinein both forced vital capacity and carbon monoxide transferfactor.[80]

Heart

Cardiac involvement is often present, but rarely significantclinically. Even dyspnea and retrosternal pain are attributed mainlyto other organs such as the lung or esophagus. In addition, syncopeand angina pectoris may be caused by either endothelial damage ofsmall coronary arteries or myocardial fibrosis due to other basicdiseases. It is hard to prove the specificity of this involvement dueto SSc itself. The prevalence reported in the literature dependsupon the diagnostic methods chosen. Myocardial perfusionscintigraphy, ventriculography and echocardiography are the mostsensitive techniques. Clinically manifested forms have beendescribed in 20-25 % with a 70 % mortality after 5 years. However,autopsy revealed alterations such as myocardial fibrosis andpericardial effusion in 30-80 % of patients.[81,82] Myocardialfibrosis occurs as patchy or diffuse forms. Repeated episodes ofischemia and reperfusion lead to the destruction of the myocardiumand replacement by connective tissue.[83] In electrocardiographicstudies of 80 SSc patients, hypokinetic alterations of the leftventricle were found.[84] Electrocardiographic abnormalities suchas conduction system disturbances (27 %), signs of infarction (13.8%), and non-specific ST and T-wave changes (13.8 %) wereobserved in agreement with echocardiographic findings.[85]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

12 of 74 2/21/2013 2:24 AM

Page 13: Systemic Sclerosis - Scleroderma

Arrhythmias are common and adversely affect survival. Ventriculartachycardia can occur in up to 19 % of patients.[86]Echocardiography is very sensitive in detecting even smallpericardial effusions and heart valve alterations.[87] Very usefulalso is the thallium scintigraphy. The involvement of coronaryarteries may lead to myocardial infarction. In addition tomorphological alterations of the coronary arteries, also acold-induced coronary spasm (cardial Raynaud's phenomenon) isdiscussed.[88] Clinical pericarditis is present in only 10 to 15 % ofpatients with SSc and is more common in patients with limiteddisease.[82,89]

Kidney

Affection of the kidney has the worst prognosis and highestmortality of all internal organs involved. Clinically 10 40 % areaffected, but by autopsy, the figure is 80 %.[90] Patients withdiffuse skin involvement carry a high risk of an acute renal crisischaracterized by malignant arterial hypertension with headache,vision disturbances, cramps, left ventricular hypertrophy andretinopathy. It generally manifests itself within the first 4 years.However, the chronic form develops slowly over years and leads, in50 % of affected patients, to a moderate reduction of kidneyfunction, often clinically inapparent. Diagnostic criteria areproteinuria (< 1 g/24 h), azotemia (blood urea nitrogen (BUN) > 25mg/100 ml), arterial hypertension (> 140/90 mmHg) and reductionof the glomerular filtration rate. Factors predictive to renal crisisare listed in Table 5.[91]

Table 5. Factors predictive to renal crisisdiffuse skin involvementrapid progression of skin thickeningdisease course < 4 yearsanti-RNA-polymerase III-antibodiesnewly manifested anaemianewly manifested cardiac involvement

pericardial effusionheart insufficiency

preceded high-dose corticoid therapy

The pathogenetic events are not completely understood. Theprimary event seems to be the damage of endothelial cells withthickening and proliferation of the intima with deposits ofglycoproteins and mucopolysaccharides in the interlobular andsmall arcuade arteries.[92] These changes lead to narrowing oreven obliteration of vessel lumina and ultimately to infarction ofglomeruli and tubuli. This is followed by platelet aggregation,adhesion and liberation of growth factors.

These morphological changes in combination with functionalvasospasm due to cold (renal Raynaud's phenomenon) reduce thecortical blood circulation resulting in the liberation of renin,increase in the plasma rennin levels, and hyperplasia of the juxta-

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

13 of 74 2/21/2013 2:24 AM

Page 14: Systemic Sclerosis - Scleroderma

glomerular apparatus. The angiotensin converting enzyme(ACE)inhibitors were shown to significantly improve the 5 year survivalof SSc patients. While under no treatment only 16 % with renalinvolvement survived after 1 year; the 5 year survival of thetreatment group was 45 %.[93] Thus, ACE inhibitors are able tolimit kidney failure and prolong survival.

Muscles, joints and bones

Weakness of muscles is a common (60-80 %) finding in SScand is associated with minimal elevation of creatinin kinase andaldolase and polyphasic motor unit potentials onelectromyography.[94] However, in 6 to 12 % an inflammatorymyositis indistinguishable from polymyositis, associated withPM-Scl antibodies, can develop, sometimes accompanied bymyocarditis.[94,95,96] The most consistent electromyographicabnormalities are a decrease in amplitude and duration of singlepotentials with a concomitant increase in polyphasic potentials.[97]

Arthritis is the initial symptom in 2/3 of SSc patients, oftenpreceding the typical skin changes. It may resemble rheumatoidarthritis at the onset of the disease. It is less destructive,however.[98] Contractures are generally dermatogenic due tosclerotic changes of the overlying skin or surrounding connectivetissue. Alterations of the bones occur in 6% of patients and consistof resorption of the tufts of the terminal phalanges, juxta-articularosteoporosis, erosions of the dorsal heads of metacarpal andproximal phalangeal bones. Joint space narrowing with marginalerosions may be present in up to 9 15 % of patients.[99]

Periarticular subcutaneous calcification can be complicatedby painful ulcerations which may also be located around the iliaccrest, spine protuberances, elbows, and knees. The juxta articulartendons of the fingers, forearms, legs, and neck can be altered byfibrosis causing audible friction rubs as a characteristic clinical signof SSc.

Sjögren Syndrome

Sjögren Syndrome is defined as an inflammatory disorder ofsalivary glands often characterized by circulating antibodies to Ro(SSA) and La (SSB) antigen. Depending on the diagnostic criteriaused it occurs in 5 to 90 % of SSc patients, in particular those withlimited disease.[100,101]

Nerves

Neurological manifestations include peripheral neuropathywith reduction in the conduction velocity and patients often show aprolonged response to local anaesthesia.[102] Trigeminal neuralgia

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

14 of 74 2/21/2013 2:24 AM

Page 15: Systemic Sclerosis - Scleroderma

is found in about 4 % of patients; carpal tunnel syndrome occurs in3 % of patients.[103,104]

Hematological abnormalities

Hematological abnormalities are mostly related to renaldisease, microangiopathic hemolytic anaemia or from bleedinggastrointestinal teleangiectasias.[105]

Pregnancy

Although pregnancies are less frequent in SSc, women cansafely have healthy deliveries. Steen has prospectively observed 91pregnancies during a 10-year period.[106] No increase in thefrequency of miscarriage was found except in those withlong-standing diffuse scleroderma. In 29 % of pregnancies, pretermbirth occurred and all but one of the infants survived. WhileRaynaud's phenomenon improved during pregnancy, esophagealreflux became worse. After delivery some women with diffuse SSchad increased skin thickening. In early diffuse SSc three patientssuffered from renal crisis.[106] Therefore patients with earlydiffuse SSc should wait until their disease stabilizes beforebecoming pregnant. High risk pregnancy management is required.The higher risk of premature birth is explained by decidualvasculopathy, which is similar to that seen in hypertension and isassociated with poor perinatal outcome.[107] A trend toward areversed ratio of decidual CD4 to CD8 positive T cells is seen inSSc which is not seen in normal or hypertensive pregnancies. PDGFand TGFb do not appear to be involved in the pathogenesis ofdecidual vasculopathy in SSc.[107]

Pathophysiology of SSc

The course and even the initial events in the pathogenesis ofSSc are still poorly understood. The microvasculature (endothelialcells, platelets, capillaries) is one of the first affected systems,sometimes preceding the outbreak of the disease even by years(Raynaud's phenomenon). There is evidence that the disease maybe immunologically triggered, again as an early event.[108]T-lymphocytes in collaboration with monocytes, endothelial cells,platelets and mast cells act as mediators and targets in thepathophysiological network. They express and release adhesionmolecules, interleukins, and growth factors which act uponfibroblasts. Nevertheless, the excessive tissue fibrosis is due toexpansion of fibrogenic clones of tissue fibroblasts, which behaverelatively autonomously[109] and overexpress genes encodingextracellular matrix components. [109,110] This leads to excessivedeposition of collagen and other connective tissue matrix proteinsin the skin and internal organs as well as in the walls of bloodvessels.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

15 of 74 2/21/2013 2:24 AM

Page 16: Systemic Sclerosis - Scleroderma

Figure 10

Figure 10. Pathophysiology of SSc

As in various autoimmune diseases, the pathogenesis is partlybased on genetic background and modulated by environmentalfactors.[111] In the following chapters the three main pathogeneticpathways will be discussed. These include microvasculatureabnormalities, abnormal immune response, and dysregulation offibroblast activity. It is important to remember that theseabnormatities occur in the context of the necessary genetic andenvironmental background. (Figure 10)

Genetics

The most prominent genetic factor is gender (female:male = 3to 6:1). Another factor is the human major histocompatibilitycomplex (MHC). An increased frequency of class I and II MHCalleles were found. However, their nature and association werecontroversial (i.e. HLA Bw35, DR1, DR5 or HLA1-B8-DR3).[112]On the other hand, the linkage of DR5 and DR3 to DRw52 issuggested to be the primary MHC class II allele associated withSSc. In addition, there is an association between the developmentof lung fibrosis and B8-DR3-DRw52-DQB2. Pulmonary diseasecan be predicted if DR52a and ATA are present (relative risk 16.7).In addition, HLA DRw11 and a DQ sequence were associated withsevere SSc and ATA positivity.[113]

Racial and ethnic origin also plays a role in diseasesusceptibility; diffuse disease is significantly more likely in blackthan white women.[114] Takeuchi et al. found an extremedifference of genetic background of Scl-70-positive SSc with regardto HLA-DR betweeen Japanese and other ethnic groups.[115] In

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

16 of 74 2/21/2013 2:24 AM

Page 17: Systemic Sclerosis - Scleroderma

particular, the association of TAP1 and TAP2 with DRB1*1502was increased in Japanese SSc patients with the diffuse form andwith ATA.[115] In Mexican patients DR5 (DRB1*1104) plays arole in genetic susceptibility for the disease.[116]

A cluster of structurally unrelated gene products such ascomplement components (C2, factor B, C4A and C4B), heat shockprotein (HSP70), 21 hydroxylase (CYP), and tumor necrosis factor(TNF) exhibit a high degree of polymorphism.[117] In these studiesHLA C4A null alleles provide the strongest correlation of the MHCwith SSc, and HLA-DQA2 is an additional primary susceptibilitymarker.

Finally, clastogenic activity has been described in sera and cellextracts from SSc patients.[118] Chromosomal breakage, deletions,and acentric fragments were increased in lymphocytes andfibroblasts (15.5 % versus 1.7 % breaks in healthy controls).Interestingly, bleomycin exerts clastogenic activity and is able toinduce a scleroderma-like disease.[111] The increased spontaneousand clastogen-induced chromosomal damage rates indicate that SSclymphocytes may have a general susceptibility to DNA damagecaused by free radicals.[119]

Microchimerism

Numerous clinic features of SSc are similar to chronic graftversus host-disease (GvH). Several years ago the hypothesis wasdiscussed, that persistent cellular microchimerism might play a rolein the pathogenesis of SSc.[120] Microchimerism results from themovement of fetal cells (perhaps also stem cells) through theplacenta during pregnancy into the maternal circulation[121] andtheir persistent survival even for decades due to HLA class IIcompatibility or minor differences.[122,123,124]

Among 86 female SSc patients, 16 experienced spontaneousabortion as compared to 9 % in healthy women.[125] In 17 % ofwomen SSc started during their pregnancy.[126] In female SScpatients the presence of fetal CD3 positive T cells in the maternalcirculation[121,127] and of fetal cells in the affected tissue[128]has been identified through y chromosome specific DNA sequencesby means of quantitative PCR in statistically increased amounts ascompared to healthy controls[123]. The persistent microchimerismmight cause SSc in certain patients by initiating a fetalanti-maternal GvH like response.[123] Again, other trigger factorsare required to prevent tolerance and to convert this type of GvHfrom the latent into the manifested form. In male SSc patients,allogenic cells from the mother or a twin, or white blood cells afterblood transfusion may survive and act in a similar way.[129]

Microvasculature

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

17 of 74 2/21/2013 2:24 AM

Page 18: Systemic Sclerosis - Scleroderma

Figure 11

Figure 11. Sublobulararteriole of the kidney withnarrowing of the lumen andwall fibrosis (HE, x 120)

Figure 12

Figure 12. Irregular nailfold capillaries as shown bycapillaroscopy

Raynaud's phenomenon,increased vascular wall thickness,vascular occlusion,devascularization, and thickeningof the basement membrane arefeatures which were describedmany years ago. Changes in thenailfold capillaries are one of thefirst signs in SSc.[130,131]Furthermore, vascular injury is thebasis for the major clinicalmanifestations of SSc includingpulmonary hypertension,myocardial dysfunction and renal involvement.

In internal organs, in particular the kidney, arteriols arecharacterised by intimal proliferation, thinning of the media, andfibrosis of the adventitia, and exhibit accumulation ofproteoglycans and collagens[132], probably produced bymyofibroblasts (Figure 11).

In addition, the vascular pathology is associated with alteredvascular function, with increased vasospasm, reduced vasodilatorycapacity, and increased adhesiveness of the blood vessels toplatelets and lymphocytes.

The role of endothelial cells (EC) is still poorly understood. Onthe one hand, EC are targets of immune activity. On the other hand,they may act as immune costimulators.[133] One of the prevailinghypotheses suggests an origin in repeated insults to the vascularendothelium, in particular after cold exposure. The vascularabnormality may be caused by repeated episodes ofvasoconstriction leading to hypoxia, ischemia, and intravascularocclusion

Nail fold capillaries

Prominent SSc vascularabnormalities are noted incapillaries and small blood vessels.Affected capillaries arecharacterized by distorted andirregular loops. The changesinclude reduced numbers ofcapillaries and the presence ofavascular areas as shown by nailfold capillaroscopy, even in thepreclinical stages (figure 12).[134]On the ultrastructural level theearliest changes consist of large gaps between endothelial cells,vacuolisation of endothelial cytoplasm, an increase in the numberof basal lamina-like layers, and disruption of endothelial cell

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

18 of 74 2/21/2013 2:24 AM

Page 19: Systemic Sclerosis - Scleroderma

cytoplasmic membranes.[135,136]

Raynaud's phenomenon

The most prominent clinical vascular dysfunction in SSc isrelated to dysregulation of the vascular tone leading to vascularspasm and reduction in blood flow, best illustrated byRaynaud's'phenomenon. It results from digital arterial closure aftercold exposure.[137] In SSc, an imbalance in endothelial signals(increased vasoconstrictory endothelin release), impairedvasodilatory mechanisms (nitric oxide - NO, - endothelialdependent relaxation factor - EDRF), enhanced plateletaggregation and deficient neuropeptide levels lead to the wellrecognized vasospastic propensity in the disease. Other damaginginfluences, such as toxic factors, proteases (granzyme 1),lipoperoxides, and IgG anti-endothelial autoantibodies (seeautoantibodies) may contribute to this process.[138,139]

The increased level of urinary F2-isoprostanes supports thehypothesis that free radical-catalyzed peroxidation of arachidonicacid occurs in SSc.[140,141] The increased release of endothelin,thromboxane, factor VIII antigen, and thrombomodulin are signs ofsuch injury to EC, partly also mediated by anti-EC-antibodies.[139,142]

Endothelin

Increased plasma endothelin levels have been associated withRaynaud's phenomenon and SSc, particularly diffuse SSc.[143]Endothelin exerts a prolonged vasoconstriction and is profibrogenicas well, enhancing fibroblast proliferation and collagensynthesis.[143] Thus, it may be a major link between vascularpathology and the abundant deposition of connective tissue matrixmaterials in SSc. Increased endothelin expression in microvascularendothelial cells of the upper dermis in association with anincreased number of endothelin-binding sites is also reported inSSc.[144] In addition, this occurrence is related to lung fibrosis.

Endothelial dependent relaxation factor (EDRF), nitroxide(NO)

Deficient endothelial dependent relaxation in SSc is suggestedby impaired maximal responses to endothelial dependentvasodilators such as bradykinin and substance P in conjunctionwith defective endothelial production of the vasodilator NO.[145]Presumably, the endothelial NO synthase gene expression isinhibited, in particular by TGFβ.[146] Thus the impaired NOproduction may contribute to platelet activation and to oxidativeinjury of endothelial cells, as well as promote inflammation andenhance the arteriolar internal proliferation in SSc.[147]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

19 of 74 2/21/2013 2:24 AM

Page 20: Systemic Sclerosis - Scleroderma

Endothelial cell apoptosis

Endothelial cell apoptosis may also be a primary event inscleroderma.[148] It may be related to viral infection, includingcytomegalovirus (CMV), in view of the increased levels ofanti-CMV antibodies measured in SSc and the remarkablesimilarities between CMV vasculopathies and SSc vascular disease.On the other hand, endothelial apoptosis may be related to immunereactions to environmental factors, reperfusion injury, or toantiendothelial antibodies.[147]

Angiotensin converting enzyme (ACE)

Angiotensin converting enzyme (ACE) is located on theluminal surface of the endothelium. Decreased plasma ACEactivity was reported in SSc patients.[149] ACE levels inverselyrelated to levels of vWF have been proposed as markers of ECinjury. It is not clear yet if ACE plasma activity is a reflection ofdecreased synthesis or inhibition of enzyme activity.[147] Furtherindicators of vascular injury include increased serotonin-inducedplatelet aggregation. In addition, platelets releasethromboglobulin, platelet factor 4150, cytokines, and growthfactors [platelet derived growth factor (PDGF) and transforminggrowth factor (TGF)], which can themselves activate EC. Thisindicates an imbalance between endothelial and platelet function.

In SSc, EC expressing increased numbers of ligands of1-integrins as well as MadCAM1, CD34, ELAM-1, and ICAM-1facilitate the interaction with lymphocytes, which express 1- and2-integrins.[151] In this way the transcapillary migration ofinflammatory cells is mediated, leading to prominent T-cellinfiltrates around blood vessels in early skin lesions.[152] Theantiendothelial autoantibodies also induce leukocyte adhesion toEC.[139] Circulating levels of endothelin-1, P-selectin, E-selectin,VCAM-1 and ICAM-1 are useful markers of vascular and fibroticchange in SSc.[153] They correlate well with their in situ activity.

Abnormalities in fibrinolysis have often been seen.[154]Evidence for accelerated fibrinogen turnover, fibrin deposition, andaltered regulation of plasma fibrinolysis have been obtained.[154]Finally, deficiencies in complement regulatory molecules with aprotecting function, such as membrane cofactor protein and decay-accelerating factor, may contribute to the vascular damage.[155]

Mast cells

Increased numbers of mast cells have been described inpatients with diffuse SSc.[156] These mast cells are activated andtheir granules can regulate fibroblast biologic activity.[157,158].Mast cell heparin is a potent stimulus for bFGF and TGFβ,

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

20 of 74 2/21/2013 2:24 AM

Page 21: Systemic Sclerosis - Scleroderma

suggesting the contribution of mast cells to the inflammatory andfibrotic components of SSc.[159,160]

Immune system

T-lymphocytes

The location of inflammatory infiltrates, mainly CD4-T-cells,around blood vessels and at sites of active connective tissueformation suggests their pathogenetic role.[152,161]. The majorityof T-cells are HLA DR-positive. The absolute lymphocyte countsand the relative amounts of lymphocyte subsets in sera arecontroversially described (CD4+ or CD8+ T-cells, memory andnatural killer cells).[162] However, an increased ratio of helperCD4+ T lymphocytes to suppressor/cytotoxic T lymphocytes hasbeen reported in patients with SSc.[163,164] The T-cell function isnot uniform as far as the response to various mitogens or the resultsof the autologous mixed lymphocyte reaction. Skin extracts andcollagen act as antigenic stimuli for T cells in scleroderma patients.Vδ1 + γ/δ T-cells are increased in both the blood and lungs andshow evidence of antigen-driven selection.[165] Increasedexpression of c-myc, c-myb and c-ras protooncogenes, asdetermined by the RNA hybridization technique was found inperipheral T lymphocytes, but not in B cells in SSc patients,indicating early and late activation of T cells.[166] The antibodyproduction to primary immunization and recall antigens isnormal.[161]

Lymphocyte as well as monocyte derived cytokines, such asinterleukin (IL)-1, IL-2, IL-4, IL-6, and receptors, such as solubleCD4 and IL-2R, were elevated in the circulation.[161] Most IL-2 issecreted by T lymphocytes, while monocytes/macrophages expresshigh affinity IL-2 receptors and respond to exogeneous IL-2.[167]IL-2 can induce up to 40-fold elevations in the secretion of activeTGFβ by monocytes.[168] These data suggest that activated T cellsproduce IL-2 which upregulates TGFβ in monocytes, which in turnactivates fibroblasts to secrete and organize the elements of theextracellular matrix. Thus, the scenario for fibrosis is complete. Inaddition, it has been shown, that type 2 cytokine producing T cells,not only CD4+ T cells but also CD8+ T cells, play important rolesin the pathogenesis of SSc, especially in the early phase.[169]Peripheral blood T-lymphocytes showed both TH1 and TH2activation.[170]

Lymphocyte and monocyte ligands, L-selectin, sialatedglycoproteins, LFA-1 (CD11a, CD18), and Mac1 (CD11b, CD18)bind to the EC receptors and modulate the migration of these cells.In addition, lymphocytes respond to chemotactic stimuli, produceactivation of fibroblasts via ICAM-1, and bind to non-cellularintegrins expressed on collagen and fibronectin via surface VLA-1(CD49a, CD29) and VLA-4 (CD49d, CD29). These processesexplain the reciprocal activation of both immune cells and

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

21 of 74 2/21/2013 2:24 AM

Page 22: Systemic Sclerosis - Scleroderma

fibroblasts by direct cell contact as well as by the indirect effects ofsoluble cytokines.[161,162] Finally, the late phase of graft versushost disease (GVHD) resembles an immune-cell-mediated reactionwith scleroderma-like features (see also microchimerism).[171]

The non-specific humoral immunity leads to abnormalitiessuch as hypergamma-globulinemia, polyclonal B-cell stimulation,autoantibody production and immune complex formation.

Autoantibodies

The various autoantibodies in SSc are not closely related to thepathogenesis. Although the majority of autoantibodies areepiphenomena, some others are quite specific for SSc and itssubsets (Table 6).

Table 6. SSc-associated autoantibodiestotal SSc lim. SSc dif. SSc

Centromere 28 % (21-37 %) 48 % (40-57 %) 10 % (1-26 %)

Topo-I 23 % (16-34 %) 13 % (5-18 %) 30 % (21-40 %)

RNA polym. 21 % (12-31 %) 9 % (6-15 %) 41 % (35-46 %)

U3RNP(Fibrillarin)

6 % (4-8 %) 3,5 % (3-4 %) 8 % (2-13 %)

In the majority of SSc sera, autoantibodies to intracellularantigens are recognized. However, an individual patient's seracontains only a limited number of self antigens, often in a diseasespecific manner. The particular autoantibody present is oftenindicative of clinical expression, disease course and overallseverity. In SSc with highly variable clinical features suchinformation is a valuable aid to the diagnosis and prognosis of anindividual patient.

Anti nuclear antibodies (ANA) have been detected inapproximately 85% of SSc patients. With repeated investigationsduring the course of the disease, they have been found inapproximately 98%.[172]

Three main serological subgroups in SSc were described, eachcharacterized by a distinctive pattern of clinical features: seracontaining anti-DNA-topoisomerase I (anti-topo I) antibodies, seracontaining antibodies recognizing one or more centromere proteins(CENPs-A, -B, -C and -D), and sera containing antibodies toRNA-polymerase III (RNAP III) (Table 6). Each of these ANAscan be detected in roughly 20-25 % of patients, and they aregenerally considered to be mutually exclusive.[173,174,175,176,177]

Antitopoisomerase antibodies (ATA)

ATA are detected in a speckled staining pattern in HEP2 cells

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

22 of 74 2/21/2013 2:24 AM

Page 23: Systemic Sclerosis - Scleroderma

by indirect immunofluorescence in a total of 23% SScpatients.[178] A 70 kD protein found in SDS polyacrylamide gelelectrophoresis is the antigenetically active, proteolytic fragment ofthe native 100 kD molecule. It mediates the relaxation of thesupercoiled DNA. ATA occur more frequently in Thai and Japanesepatients than in African Americans. ATA are associated withspecific amino acid sequences of the first domain of the HLADQb1 tyrosinase residue at position 30 and HLA DR11. They aredirected against at least seven different epitopes; some arehomologous to certain mammalian n35gag retroviral proteins.[179]The association of ATA with DR3 and DRW52a means asignificantly higher risk of pulmonary interstitial fibrosis. ATAcorrelate with diffuse cutaneous SSc (dSSc). While anti-topo Ipositive patients are associated with the highest frequency ofpulmonary interstitial fibrosis, risks are intermediate with respect tocumulative survival times and frequencies of dSSc and renalinvolvement.

Anticentromer antibodies (ACA)

ACA have been described by Moroi et al. in 1980.[180] Inindirect immunofluorescence they appear as punctate spotsdispersed in the interphase nucleus, localized to the constriction(centromer, kinetochor) on metaphase chromosomes. In theWestern blot they reflect 4 different proteins (Cenp A, B, C, D).Cenp B (80 kD) is almost universally found, while A (19 kD) and C(140 kD) are the next most common. They correlate with thepresence of polar amino acids at position 26 of the HLA DQb1 firstdomain. In general, ACA are associated with HLA DR1, DR4,DR8, DR11, DQ7 (DQb1*0301). In combination with Raynaud'sphenomenon they predict the evolution of SSc. ACA occur nearlymutually exclusive with ATA. ACA interact with cell division(mitosis) and are closely associated with CREST-syndrome. Theyoccur in a total of 28% of SSc patients. The ACA group has thebest prognosis of the three with the longest cumulative survivaltimes and the lowest frequency of dSSc, pulmonary involvementand renal disease.[177]

Anti RNA polymerase antibodies (A RNA PA)

A RNA PA are again of major significance, reflecting theworst prognosis. RNA polymerase represents multiple subunits ofthree enzymes (Pol I, II, III), which are responsible for the proteinbiosynthesis by ribosomes. A RNA PA are shown in a punctate finespeckled nucleolar pattern. Patients with anti-RNAP III antibodiesexhibit the greatest risk of dSSc, the highest mean maximum skinsickness score, the shortest cumulative survival times, and thegreatest likelihood of renal involvement compared with patients ineither of the other two groups. These mutually exclusive serologicalsubgroups of SSc may be associated with etiologically distinctdisease processes or alternatively, the different antibody patternsmay reflect differences in patient's vulnerability.[181,182]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

23 of 74 2/21/2013 2:24 AM

Page 24: Systemic Sclerosis - Scleroderma

Antibodies to fibrillarin (U3RNP) (AFA)

Fibrillarin represents a 34 kD basic protein associated withU3RNP and is responsible for the processing of the periribosomalRNA.[183] AFA occur in 7 - 9% of SSc patients, more frequentlyin African Americans (56%). They are of minor significance. AFAcan be detected in the fibrillar region of the nucleus byimmunoelectronmicroscopy, in a clumpy pattern of nucleolarstaining by indirect immunofluorescence, or most reliably, byimmunoprecipitation of radiolabelled cell extracts. AFA areassociated with diffuse skin and multiple organ involvement,pulmonary arterial hypertension, skeletal muscle involvement,teleangiectasias and early disease onset.[183]

In addition, minor serological subgroups of other antinucleolarantibodies also occur in SSc. For instance, anti-PM/Scl antibodies(4 % to 11 % in SSC) are usually associated with limited SSc or theSSc/polymyositis overlap, sclerodermatomyositis (70% of SSc/PMoverlap cases).[184] PM-Scl antigen consists of 11 to 16polypeptides of which two proteins of 75 and 100 kD have beenidentified as the major antigenic components. Anti PM-Sclantibodies appear in a homogeneous nucleolar pattern by indirectimmunofluorescence. Autoantibodies to PM-Scl bind to an areawith homology to the nuclear localization signal found in HIV tatprotein and SV40 large T antigen. This indicates that viral antigens,which share epitopes of the host, may initiate an autoimmuneresponse via molecular mimicry.[179] Antibodies against HIVproteins in HIV-negative SSc patients can be explained in thisway.[185] They are associated with HLA DR3, A1, B8. AntiPM/Scl positive patients had a favourable outcome in terms ofresponse to corticosteroids or immunsuppressive therapy as well asdecreased disability due to muscle weakness. Such patients have agood prognosis. Anti PM/Scl antibodies predict no serious visceralinvolvement.

On the other hand, anti-To/ThRNP antibodies (4%) arerecognized in limited SSc, hypothyroidism, and small bowelinvolvement.[186] To/Th represent the mitochondrial RNAsresponsible for the endoribonucleolytic cleavage of mitochondrialprimer RNA involved in the replication of mitochondrial DNA. It isdistributed in different cellular components such as nucleus,nucleolus, cytoplasm, and mitochondria and on different proteins aswell. It shows a homogeneous nucleolar pattern.

Anti-U1-RNP antibodies are found in about 6% of patients,often associated with the SSc/systemic lupus erythematosus (SLE)overlap syndrome or mixed connective tissue disease (MCTD),arthritis, isolated pulmonary arterial hypertension, and early diseaseonset.[187]

Anti Ro-antibodies (9%) are indicative of a very severe andrapidly progressive disease course, including renal failure andpulmonary hypertension.[188]

Finally, anti-Ku, anti-Jo1 (anti-histidyl tRNA-synthetase) and

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

24 of 74 2/21/2013 2:24 AM

Page 25: Systemic Sclerosis - Scleroderma

anti-PL7 (anti-treonyl-tRNA-synthetase) antibodies occur in asmall proportion (5%) of SSc patients, particularly those withSSc/polymyositis overlap syndrome.[188] Anti-Jo1, whenassociated with dermatomyositis/polymyositis, interstitial lungfibrosis, arthritis and Raynaud's phenomenon, is termedanti-synthetase syndrome. Jo1 represents a family of 20 enzymes,which must properly recognize the tRNA and the amino acid tomaintain fidelity of translation.

Anti-agalactosyl IG antibodies were detected in 52 of 70 SScpatients (74%). Elevated levels were associated with the presenceof contracture of phalanges, pulmonary fibrosis and with moresevere SSc (diffuse ATA positive form).[189]

Spencer Green et al. investigated the test performance ofATA and ACA in SSc in a metaanalysis of 479 articles.[190] Thirtyof them fulfilled the inclusion criteria. They evaluated thesensitivity of ACA in 32% (57% in limited SSc) and of ATA in 34%(40% in dSSc). Either test was positive in 58 %. In only 3 patientsboth antibodies were present. In other connective tissue diseasesACA occured in 5% and ATA in 2 % compared to the controls (<1%). They concluded that both antibodies are highly specific. As 40% of SSc patients are likely to have neither antibody (ACA, ATA)present, the negative result does not exclude the diagnosis. Whenconsidering anti-RNA polymerase antibodies the percentage ofantibody negative SSc patients is only about 20.

The pathogenetic role of these autoantibodies is mostlyunknown. Although some of these SSc specific autoantibodies arecapable of inhibiting the cellular function of the autoantigens theyrecognize in vitro, they are unlikely to have access to theintracellular locations of these antigens in vivo. On the other hand,some of the autoantibodies may recognize extracellular antigens orthose exposed on the cell surface. These autoantibodies could beinvolved in the disease pathogenesis.

It has been shown that anti-endothelial cell-antibodies, afterbinding to vascular endothelial cells, can induce endothelialactivation, upregulation of cell adhesion molecules, and consequentmonocyte adhesion, possibly via an autocrine IL-1 mediated effect.In addition, these EC-antibodies are able to increase the synthesisand release of coagulation factors such as factor VIII andthrombomodulin as well as induce EC apoptosis.[191] Altogetheranti-EC-antibodies may affect microvessels more distinctly thanmacrovessels. Their prevalence in SSc is between 28 and 85%,approximately 44% in limited SSc (lSSc) and 84% in dSSc. The lowaffinity anti-EC-antibodies may indicate an epiphenomenon ofvascular injury, while the high affinity antibodies are ratherpathogenic. For example anti-EC- antibodies have been associatedwith vascular involvement, digital ischemic ulcers, and alveolo-capillary impairment.[192,193] In addition, they can mediate ECcytotoxicity by direct complement activation.

In SSc certain human lymphocyte antigen (HLA) allelesoccur in an increased frequency, with major differences in variousethnic groups (see also genetics). The HLA-DR associations areparticularly strong when clinical subsets and/or autoantibody

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

25 of 74 2/21/2013 2:24 AM

Page 26: Systemic Sclerosis - Scleroderma

defined subgroups of SSc are considered, thus explaining anincreased susceptibility to express the clinical features of SSc incertain subgroups (Table 7). [176,194,195] Furthermore, someautoimmune responses might be due to linkage disequilibrium ofcertain DR-alleles with particular DQ-alleles.[196]

Finally, an association between anti-topo I positive silica-associated SSc (SI-SSc) and the HLA-A-DR3 alleles has beenshown.[197] Anti-topo I positive idiopathic SSc cases wereassociated with DR2 and DR5[198]. Obviously differentpathogenetic mechanisms lead to the production of anti-topo Iantibodies in the two groups and a different topo I derived peptidewas presented by MHC class II molecules in SI-SSc. Probablydifferent kinds of antigen-presenting cells (APC) containingdifferent proteases are involved or alternatively, the alteredantigen-processing was caused by macrophage derived cytokinesfollowing silica exposure.

In conclusion, the here described autoantibodies arerelatively disease specific for SSc. Although they may not bedirectly involved in the disease pathogenesis, they are extremelyreliably associated with disease specific pathologic phenomena andare therefore valuable predictors of the different subtypes of SSc.The main three antibodies are highly disease specific. However,approximately 20% of SSc patients are likely to have no antibodypresent which means that negative results do not exclude thediagnosis of SSc. Consequently, it is now possible to identify over80 % of SSc patients by these main three autoantibodies. Bothantigen-driven and molecular mimicry hypotheses have beenproposed for ANA induction in SSc. Some autoantibodies are

homologous to certain mammalien p30gag retroviral proteins.[179,185] Autoantibodies are important for the early diagnostics of thespecific type of SSc and the initiation of the appropriate therapy. Inthe future, autoantibody testing may - at least in part - be used todetermine the clinical activity of the disease and monitor a patient'sresponse to immunological therapies. Clinical studies are requiredto show whether the course of the titer or the immunglobulin classof the autoantibodies correlate with the disease activity.

Fibroblasts

Physiologically, skin fibroblasts synthesize little extracellularmatrix (ECM) because of various inhibitory influences andnegative feedback through non-cellular matrix components. Withactivation signals from lymphocytes and monocytes, endothelialcells and platelet fibroblast properties are altered either directly, bycell contact, or indirectly, via specific cytokines, such as IL-1, IL-2,IL-4 (proliferation, collagen synthesis) and IL-6 (matrix metallo-proteinases).[199] Interferons potentially suppress collagensynthesis. The activating factors, PDGF and TGFβ, are alsoreleased from platelets. Ultimately, activated fibroblasts releasecytokines and growth factors, such as IL-1, prostaglandin E,

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

26 of 74 2/21/2013 2:24 AM

Page 27: Systemic Sclerosis - Scleroderma

TGF&beta, connective tissue growth factor (CTGF), PDGF, andIL-6, which may exercise self-activation via an autocrineloop.[200,201] In this way ICAM-1 is expressed on fibroblasts,which augments adhesion and retention of immune cells within thetissue.[202,203] Up to now, there are no data showing apoptosis offibroblasts in SSc lesions or in culture. This is in agreement withresults reporting unchanged numbers of fibroblasts in SSc lesionscompared to healthy skin.[204] Therefore, the fibrotic events inSSc would be due to the changed synthesic activity of matrixproteins rather than to changed cell numbers present in the skin.

Cytokines and growth factors

Several cytokines and growth factors, such as IL-1, IL-2, IL-4,IL-6, IL-8, IL-10, IL-13, TGFβ, PDGF, TNFα, interferon (IFN)-γand particularly the high-affinity IL-2 receptor, can also be foundelevated in the serum of SSc patients.[205,206,207] To some extentthey are correlated with the degree of organ involvement anddisease activity.

IL-2 is produced by activated T-cells. IL-2 receptor is shedfrom them, particularly in the early active stage of SSc. Collagenpromotes IL-2 production and laminin induces IL-2 receptorexpression on lymphocytes. Endothelial cell membranes increasec-fos expression in T-cells, which themselves induce IL-2expression. This may explain the presence of activated T-cells inthe perivascular infiltrate of SSc skin.

IL-4 promotes T-cell adhesion to EC, promotes differentiationof lymphocytes, and stimulates fibroblast proliferation andextracellular matrix (ECM) synthesis. In SSc sera, IL-4 iscorrelated to the extent of skin fibrosis. IL-4 induces TH2 cells,resulting in low levels of IFN-γ, a potent inhibitor of collagensynthesis. Its lack may enhance the fibrotic reaction.

IL-6 is produced by various cells in the skin and is elevated inserum in a high percentage. IL-6 is synthesized by fibroblasts andinduces ECM production, also in an autocrine loop. Finally, itregulates the high-affinity IL-2R in lymphocyte cultures, mostlikely regulating the effect of IL-2 on immune activation inSSc.[201,208]

TGFβ clearly activates fibroblasts to produce increasedamounts of ECM components such as collagen I, III, V and VII,and fibronectin.[200] In human fibroblast cultures, TGFβ1 inducesits own expression. In involved and uninvolved skin, TGFβ1, wasdetected by some authors by in situ hybridization andimmunohistochemical staining. The presence of TGFβ1 prior to theonset of fibrosis indicates an early involvement of this factor in thepathogenesis of SSc.[209] It was shown that TFGβ1 increases thepromoter activity and type I collagen mRNA and protein synthesisin fibroblasts.[210,211] In addition, TNFα, IL-1 and IFN-γmodulate the expression of the collagen I gene, partly by theirinfluence on transcription factors acting on collagen I gene

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

27 of 74 2/21/2013 2:24 AM

Page 28: Systemic Sclerosis - Scleroderma

regulatory elements. TGFβ2 was shown to co-localize withenhanced collagen type I gene expression in the perivascularinfiltrate of SSc skin. TGFβ is the only known inducer ofconnective tissue growth factor (CTGF). CTGF gene expressionand skin sclerosis are correlated in SSc.[212] Contrary to the resultswith normal fibroblasts, TGFβ1 does not upregulate tissue inhibitorof metalloproteinases 1 (TIMP-1) in SSc fibroblasts with alreadyelevated spontaneous secretion of TIMP-1; it is suggested to be anautocrine growth factor in SSc.[213]

CTGF is a potential mediator in terms of the maintenance ofthe fibrotic phenotype of fibroblasts. Besides promoting mitogenicstimulation, CTGF acts chemotactically on fibroblasts and inducesthe synthesis of extracellular matrix proteins. In addition, it is ableto induce fibrosis in mice after subcutaneous injection.[214] CTGFexhibits a permanent overexpression of mRNA in fibrotic lesions ofSSc skin and in isolated fibroblasts, indicating its involvement in thepathogenesis of SSc.[215] CTGF maintains fibrosis, as its increasedbasal expression can not be inhibited in vitro.[216] Its effect on theresponsive element within the collagen promoter was shown.Contrary to TGFβ the mRNA expression of CTGF is higher in thefibrotic phase than in the inflammatory one.[212,217]

PDGF acts as a strong mitogen for fibroblasts. As SScfibroblasts are previously exposed to elevated PDGF in vivo, theyrespond less to PDGF in vitro when compared with normalfibroblasts. Again, PDGF and its β-receptor subunits areimmunohistochemically located in the perivascular inflammatoryinfiltrates of SSc skin, but not in healthy skin. In vitro TGFβselectively increases the expression of the β-receptor subunit in SScfibroblasts and the subsequent incubation with PDGF AA distinctlyenhances the proliferation of this "clonally selected" fibroblast typein SSc. In addition, c-myc and c-myb mRNA protooncogeneexpression is increased in intralesional fibroblasts, as already shownin activated T-cells of SSc.[218]

Matrix protein metabolism

In SSc, abundant deposits of collagen type I are found in theperivascular region of the dermis and at the border between deepdermis and subcutis, as demonstrated by immunohistochemistryand in situ hybridization (using 1 chain-specific cDNAs). Inaddition, collagen types III, V, VI, VII, fibronectin and tenascin arealso overexpressed in the skin.[219,220,221] Tenascin can inhibitthe attachment and spreading of fibroblasts. Glycosaminoglycansand decorin, which have also been found in the skin, may serve ascytokine receptors and modulators of collagen fiber diameter. Thus,altered dermatan sulfate proteoglycans may affect the organizationof matrix fiber in SSc.[222] In addition, decreased collagenaseexpression is characteristic of most SSc fibroblasts. Both increasedcollagen synthesis and decreased collagenase expression may resultin excessive accumulation of collagen, indicating that the balancebetween these synthesizing and degrading processes is crucial andmay be modulated by TIMP-1 expression.[223]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

28 of 74 2/21/2013 2:24 AM

Page 29: Systemic Sclerosis - Scleroderma

Recently, it was shown that elevated TIMP-1 levels in SScpatients support the hypothesis that matrix accumulation occurs inSSc at least in part owing to decreased degradation. Moreover, theincrease in TIMP-levels at early stages of SSc explain the earlyprogressive course of dermal fibrosis.[224] Altogether tissue matrixaccumulation may be due to increased inhibitors rather than todecreased metalloproteinases.

Fibrogenic phenotype

One of the most interesting phenomena in the pathophysiologyof SSc is the persistence of the fibrogenic phenotype. In situ as wellas in vitro fibroblasts with different synthesizing capacities forextracellular matrix proteins could be found, indicating theheterogenicity of fibroblasts in SSc. Heterogenity in geneexpression in SSc is not limited to collagen. Recently it has beendemonstrated that protease nexin1 (PN-1) is overexpressed in SSc.This may play a role in increasing collagen gene transcription.[225]Le Roy characterized the so-called collagen high-producers offibroblasts isolated from the deep reticular dermis of patients at theearly stage of SSc.[226] This altered gene expression may be due toturning on autocrine signals in the fibroblasts, that, once activated,stimulate a continuous feedback loop. Alternatively, a certainsubpopulation of fibroblasts may be selected with the preferentialproperty of proliferation and matrix protein synthesis in vivo.[227]On the other hand, fibroblasts from unaffected skin do not showexaggerated matrix production, which indicates that a basicfibroblast defect does not exist.[228]

Interestingly, these different properties are maintained ex vivofor several generations under laboratory culture conditions. Thisphenomenon found in vitro can be explained either by clonalselection of fibroblasts in vivo, by clonal selection during outgrowthfrom the biopsies or by the influence of artificial culture conditions.Freshly isolated SSc fibroblasts are significantly and selectivelyinsensitive to exposure to PDGF and to deprivation of serumderived factors.[229] Therefore it was proposed that SSc fibroblastscan produce their own autocrine growth factors.[230]

When fibroblasts are cultured in 3-dimensional collagen gels,they change their morphology into elongated bipolar shapes withfilopodia due to interaction with the ECM, and they contract thegels into a dense connective tissue matrix. Consequently, fibroblastfunctions are altered (protein synthesis and, in particular, collagensynthesis at the protein and mRNA level). Gel contraction ismediated via the α2 and α1 subunit of integrins. In SSc severalfibroblast lines did not show downregulation of collagen synthesis,particularly when they maintained elevated mRNA stability.[231,232] Finally, the (2 integrin subunits are less expressed in SScfibroblasts,indicating a disturbance of the feedback between ECMand fibroblasts, which are unable to adjust their collagen synthesisto the amount of surrounding ECM molecules.[233] On the otherhand, integrin α2 production by TGFβ stimulation is not impaired in

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

29 of 74 2/21/2013 2:24 AM

Page 30: Systemic Sclerosis - Scleroderma

SSc fibroblasts.[234] No significant changes in α1 integrinexpression could be observed. In addition, altered fibroblastsusceptibility to apoptosis may play a role in the pathogenesis offibroblast abnormalities. Thus, SSc fibroblasts are more resistent toFas-mediated apoptosis than normal fibroblasts.[235] While TGFβ1can induce such resistence in normal fibroblasts, there is anincrease in TGFβ1 receptors on SSc fibroblasts.[236] Thus, TGFβmay alter fibroblast sensitivity to apoptosis and have long termeffects on collagen synthesis. In addition, endothelin-1,overexpressed in SSc protects fibroblasts from c-myc dependentapoptosis[237,238]. Finally, hypoxia can also select for apoptosisresistent cells by inducing apoptosis in c-myc overexpressingcells.[235]

It is now evident that persistent overproduction of collagen isresponsible for the progressive nature of tissue fibrosis in SSc.Upregulation of collagen gene expression in SSc fibroblasts appearsto be a critical event in this process, reflecting a fundamentalalteration in the regulatory control of gene expression in SScfibroblasts.[239] Trans-acting nuclear factors which bind tocis-acting elements in enhancer (intronic) and promoter regions ofthe genes modulate the basal and inducible transcriptional activityof collagen genes.[239]

Concerning regulation of collagen synthesis, there are severalcandidates to inhibit the fibrotic process, such as antibodies toTGFβ[240] or lysylhydroxylase inhibitors, which interact withcross-link formation between the collagen chains. The mostexciting approach might be the direct inhibition of transcriptionfactors by antisense oligonucleotides, which interact with specificDNA elements that control the activity of these genes in fibroblasts.

Fibroblasts subjected to mechanical strain proliferate,elongate, and become bipolar and oriented along the plane of theforce.[241] Prominent action stress fibers develop within the cellsas in myofibroblasts. These specialized fibroblasts have been foundin excess in SSc skin and are required for generation of force inmechanically stressed lattices.[242] They are characterized as"synthetic" phenotype: synthesis of collagen is induced, whereasthat of metalloproteinases is repressed.[241] Mechanical stress alsoregulates the expression of cytokines such as TGFβ1, -β3 andCTGF which have been previously shown to play an important rolein the development of fibrosis.

Models of SSc

Several animal models can help to better understand thepathogenesis of SSc, although there are distinct differences in theclinical features. One of the most important models in livinghumans are the environmentally induced forms of SSc, such assilica-induced SSc, which cannot be distinguished from idiopathicSSc by clinical or laboratory features.[111]

Induced animal models include GvHD, bleomycin-inducedfibrosis, injection of glycosaminoglycans from the urine of SSc

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

30 of 74 2/21/2013 2:24 AM

Page 31: Systemic Sclerosis - Scleroderma

patients, and fibrosis due to exposure to organic solvents.Hereditary models are the avian SSc of the UCD200 chicken andthe tight skin mouse 1 and 2. Among these models, the tight skin-2mouse seems to be the most promising model because it shows, atthe same time, enhanced collagen synthesis and deposition as wellas infiltration of mononuclear blood cells in the dermis.[243]

Environmental factors

Environmental factors induce SSc-like diseases.[197] Severalreports describe chemical compounds within our environment andtheir ability to induce SSc-like diseases uponexposure[244,245,246] (Table 8). These substances can induceSSc-like diseases that can be distinguished from SSc by thefollowing features:[244,245]

Type of skin manifestation, in particular acrosclerosis,circumscribed and generalized morphea, fibrotic nodules,joint contractures.Visceral involvement due to toxic damage of the liver,kidney, nervous system and muscles, angiosarcoma of theliver.Laboratory findings of partial thrombocytopenia, andabsence of autoantibodies.Cessation or reversibility of the disease process after earlydiscontinuation of the exposure.

Table 8. Environmental substances inducing scleroderma-likedisease and their exposure

Substance Exposure

Chemical compounds

Plastics (monomers)(vinyl chlorideepoxy resins)

Cleaners of vinyl chloride reactorsConstruction workers

Solvents

(chlorinated) aliphaticand aromatichydrocarbons

Workers in dry cleaning chemicalindustry, pump attendants

PesticidesWorkers in agriculture, gardeners,chemical industry, patients (iatrogen,abuse)

Drugs

Bleomycinpentazocineethoxisuximidepenicillamine

Patients

Other

Paraffin (silicone*) Patients (breast augmentation*)

aniline contaminatedrapeseed oil, salad oil(toxic oil syndrome),L-tryptophan

consumers

Minerals

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

31 of 74 2/21/2013 2:24 AM

Page 32: Systemic Sclerosis - Scleroderma

Silica

Miners, foundryworkers/foremen,quarrymen, sandblaster,sandstone sculptors, glass grinders, castpolishe rs, dental mechanics

Chlorinated hydrocarbons may induce systemic diseases, butaromatic hydrocarbons are associated with local fibrosis restrictedto the areas of direct contact.[247] Other substances such as bis(4-amino-3-methylcyclo-hexyl)-methan, bleomycin, pentazocin, and5-hydroxy-tryptophan and carbidopa, are not discussed here.Tryptophan, used for insomnia and depression, can trigger aneosinophilic fasciitis similar to Shulman syndrome or theeosinophilia myalgia syndrome, due to a synthetic contaminant.[248,249] In the early 1980s the toxic oil syndrome caused by rapeseed oil contaminated with aniline derivatives, attracted a greatdeal of attention when more than 300 of the 20,000 people affecteddied.[250]

In contrast to these other environmental substances, silica isable to induce a form of SSc-like disease indistinguishable fromidiopathic SSc.[251,252,253]

The clinical and laboratory data reveal that the commonmarkers of idiopathic SSc are also present in silica induced SSc.Due to this, and together with the similar pathophysiology, silicashould be accepted as an inducer of SSc. This is in agreement withRodnan et al., Rustin et al., and Gabay and Kahn.[251,254,255]

Our experimental data concerning the exposure of various cellcultures such as macrophages/monocytes, endothelial cells, andfibroblasts to silica support the hypothesis that silica mediated cellactivation can play a role in the pathogenesis of SSc.[197]

However, the long exposure times needed for the onset ofsilica induced SSc and the fact that not all exposed persons developboth silicosis and SSc suggest that silica alone does not cause SSc.The development of SSc in a silica exposed individual will dependnot only on the length of exposure but also on the individualgenetic background of the host (see also genetics, autoantibodies).

In addition, exacerbation of SSc or even the new onset ofcases of SSc have been observed after X-ray treatment in ageneralized form.[256]

Trauma

In 1996, five cases of SSc which occurred shortly afterepisodes of physical trauma were described.[257] In addition,physical exertion was reported as a possible precipitating factor inboth adult and paediatric eosinophilic fasciitis.[258,259] In 1996,Vancheeswaran et al. noticed a significant association betweentrauma and childhood SSc.[260] Trauma has been associated withlinear scleroderma, which often occurred in the same site as traumawithin 6 months.[261,262]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

32 of 74 2/21/2013 2:24 AM

Page 33: Systemic Sclerosis - Scleroderma

The question of whether the trauma actually caused thedisease or was only coincidental has a major legal implication. Themost probable hypothesis is that physical trauma and/or emotionalstress may activate subclinical or aggravate preexisting disease. Theobservation of ANA, anticentromere antibodies, and the theparticular HLA pattern favours this hypothesis.[263]

Treatment of SSc

SSc is characterised by a variety of clinical features and a longterm life threatening course. Therapy has to be planned individuallybecause of inadequate knowledge of the point at which therapeuticaction is appropriate and the difficulty of obtaining objectivemeasurements of the treatment results. Beside basicrecommendations, physiotherapeutic activities and competentpsychological guidance are important. The therapy is directed at 3pathogenic compartments.

vascular systemimmune system (inflammation, immunmodulation,autoimmunity)fibrosis

A critical attitude to therapy and a great deal of patience aswell as psychological empathy are important for successfulguidance of patients, because very often treatment results can onlybe seen after several months.

In SSc is a rare disease with a chronic, and occasionally alsoself-limiting course, with a variety of possible internal organspathologies and different stages of disease. To add confusion to theevaluation of treatment results, most published trials have fewpatients enrolled. This lack of large well designed, multicenter(multinational), double-blind, and placebo controlled trials leaves amajor gap in our efforts to evaluate current recommended therapy,the more so as natural improvement and spontaneous regressionconfound the picture. Objective measures, such as the skin scorewhich evaluates skin thickness at various locations, must bestandardized to allow accurate comparisons. Other measurementsrelated to signs of inflammation and autoimmunity or organfunction are also required to adequately evaluate treatments.Therefore clinical trials in SSc must (semi) quantitatively definedisease activity, specific stage of disease, joint motility and level ofinternal organ involvement as published recently by Medsger etal.[264] They developed a severity grading scale from 0 (nodocumented involvement) to 4 (endstage disease) for 9 potentiallyaffected organ systems and tested it in 579 SSc patients.[265] Inaddition, they validated this scale by using an independent group of680 SSc patients and achieved international agreement. Theseverity scale will assist in the design and conduct of clinical trialsand serve as a framework for developing a SSc disease index.[265]

In 1995, the European Scleroderma Study Group initiated amulticenter prospective one year study for this reason. 290 patients

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

33 of 74 2/21/2013 2:24 AM

Page 34: Systemic Sclerosis - Scleroderma

were consecutively recruited by 19 different research centers indifferent countries: 173 with limited and 117 with diffuse SSc. Ahigh degree of variability in epidemiological and clinical featuresemerged, indicating the necessity to draw up a standardizedprocedure for the management of patients with SSc.[266] For thisreason, three separate 10-point indices of disease activity wereconstructed: one for patients with diffuse SSc, the second forpatients with limited SSc and the third for all patients with SSc. Theparameters were revealed to be feasible, reliable and validpreliminary indices to define disease activity in SSc.[266]

Basic recommendations

Thorough education and councelling is necessary to achievegood compliance.

Easily chewable and swallowable food of high protein andvitamin content is recommendable. Nicotine must be omitteddue to its vasoconstrictory effect."Keep the body warm" by protective clothes such as warmpants, gloves, socks and shoes, in particular before coldexposure during the cool winter season. Hands and fingersremain warm by means of spinal reflexes due to vasodilationand perspiration. Warming up of hands for five minutes everyfour hours in a warm water bath led to significant clinicalimprovement of Raynaud's phenomenon.[267]Physiotherapy is a very important part of supportivemanagement. The application of warmth such as warmcompresses, baths, hot paraffin or infrared A whole bodyirradiation (800-1400 nm for 30 min.), appeared to be veryhelpful.[268] The same is true for lymph drainage, underwater massages and connective tissue massages, but also foractive exercises, at least to stop the progression of stiffness.Dry sclerotic and atrophic skin can be lubricated by creamsand ointments.In a few cases the exposure to environmental noxioussubstances such as silica, chlorinated ethylens, solvents,monomers of plastics or certain drugs is to be omitted to stoptheir pathogenetically progressive effects.[247]

Psychological guidance

Arranging patient consultations with skilled psychotherapists isvery important. This creates confidence, increases compliance, andassists the patients in their ability to maintain a comfortable qualityof life. Furthermore, the positive influence of autogenic trainingcould be shown by the following criteria in the Raynaud'sphenomenon: reduction of the number of attacks and increase inthe skin temperature, even though the increased blood levels ofneuropeptides could not be modified.[269] Relaxation hypnosis canbe recommended as additional complementary therapy of SSc. Theexchange of experience and councelling is very helpful in self helpgroups. Their work should be actively supported by

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

34 of 74 2/21/2013 2:24 AM

Page 35: Systemic Sclerosis - Scleroderma

dermatologists.[270]

SSc is non curable, but treatable, though therapeutic generallymoves slowly.

Vascular treatment

Vasoactive substances are used to induce vasodilation,normalize platelet function, and eventually, to increase fibrinolysis.The profound upregulation of 2-adenergic receptors responsible forabnormal smooth muscle tone and the repeated episodes ofischaemia-reperfusion and tissue hypoxia with endothelial celldysfunction have been suggested as targets of therapy.[271]

Prostacyclin-analogous substances

Prostacyclin (PgI2) and its analogue (Iloprost) mediatevasodilation, inhibit platelet aggregation, α production and adhesionof granulocytes to endothelial cells. In addition, they increasefibrinolysis and exert a cytoprotective effect on endothelial cells.Finally, they mediate the formation of vasodilatory molecules, likeendothelial cell dependent relaxation factor (EDRF), and inhibit theproduction of free oxygen radicals. Besides vascular effects,prostacyclins are thought to regulate immune responses, influencefibrous tissue formation and modulate red cell deformity.

After intravenous infusion for 5 to 10 days the function ofblood vessels was improved for several weeks. All together therehave been five trials of I.V. iloprost compared with placebo in SScrelated Raynaud's phenomenon.[272,273] This therapy can becontinued with intervals during the cold season. The initialintravenous dose is increased from 0.5 ng/kg/min. to 2 ng/kg/min.This therapy promoted the healing of ischemic finger tipulcerations.[274,275]

In our own experience the serum levels of s ICAM-1, sVCAM-1 and soluble E-selectin were initially elevated andsignificantly reduced after 5 days of iloprost infusion.[276] Themeasurement of the serum concentrations of VEGF andendothelin-1 revealed decreased levels after therapy, too. Theseresults indicate that the well-known clinical benefit of iloprostinfusions on Raynaud's phenomenon is serologically detectable bythe reduction of serum levels of endothelin-associated adhesionmolecules, cytokines and growth factors reflecting an improvementin endothelial function.

Headache, flushing, vomiting, abdominal pain, fatigue, andwater retention have to be considered as these are common sideeffects. Continuous intravenous or inhalative application of iloprostor epoprostenol was effective in SSc associated pulmonaryhypertension.[277,278] Aerosolic iloprost might be potentiallyuseful as treatment for CREST syndrome associated pulmonaryhypertension. However, patients have to be carefully selected.[279]

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

35 of 74 2/21/2013 2:24 AM

Page 36: Systemic Sclerosis - Scleroderma

100 µg/d aerosolic iloprost improved the quality of life in all 5patients, decreased the NYHA functional class, and increased thedistance walked within 6 minutes.

Oral application of iloprost (50 µg twice daily) wasdisappointing.[280] Beraprost sodium, another oral prostacyclinanalogue showed a trend towards decreasing digital ulcers in amulticenter double-blind placebo controlled trial over 6-12months.[281]

Anecdotal reports suggest that iloprost improves skin fibrosisby blocking TGFβ -induced synthesis of collagen by fibroblasts.[282,283]

Calcium channel blocker

Calcium channel blockers inhibit the intracellular uptake ofcalcium and consequently the contraction of smooth muscle cells inthe vessel wall, mediated by calcium dependent protein kinases.Three doses of 10 mg nifedipin or nicardipin, which exerts less sideeffects than nifedipin, are able to reduce frequency and severity ofRaynaud's attacks, to increase the digital blood flow, and to inhibitthe formation of new finger ulcerations as shown in double-blindstudies after 6 weeks[284,285]. In addition, there has also beenshown a platelet aggregation inhibiting effect. The reducedmyocard perfusion due to primary or secondary heart involvementcan be improved by nifedipin. Typical side-effects have to beconsidered: hypotension, headache, flush, tachycardia, andvomiting.

Inhibitors of angiotensin converting enzymes (ACE)

The ACE-inhibitor, captopril, (75-150 mg per day orally)exerts protective effects on the kidney and decreases the bloodpressure. In patients suffering from nephrogenic hypertension andkidney involvement it is effective and helps to prolong the intervaluntil kidney transplantation becomes necessary, and may evenprevent renal failure or facilitate patients' withdrawal from chronicdialysis.[286] The drastically reduced survival rate of 16% withinthe first year is significantly increased by captopril toapproximately 55% in SSc patients suffering from kidneydisease.[286] The increased plasma renin levels are reduced bycaptopril and indirectly the levels of bradykinin and prostaglandinare increased, leading to improvement of kidney perfusion.

In addition, the healing of finger ulcerations is accelerated andthe frequency and severity of Raynaud's attacks are positivelyinfluenced.[287] As side-effects, gastrointestinal complaints, bonemarrow depression (leucopenia), and hypotensive dysregulationhave to be considered.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

36 of 74 2/21/2013 2:24 AM

Page 37: Systemic Sclerosis - Scleroderma

α-receptor blockers

These drugs including reserpin, prazosin, phenoxybenzaminand methyldopa act by blocking sympathic vasoconstriction. Theycan improve Raynaud's phenomenon only in higher doses, so thatorthostatic side-effects are frequently observed, limiting theapplication of these drugs.[288]

Pentoxyphyllin

Pentoxyphyllin is able to reduce the number of rat bitenecroses and to improve the peripheral blood circulation.[289] Onthe other hand, the frequency and severity of Raynaud'sphenomenon remains unaltered by pentoxyphyllin. Other propertiesof pentoxyphyllin are, however, very interesting:

certain immunomodulatory effects (inhibition of TFN-αproduction)inhibition of the synthesis of collagen, fibronectin andglycosaminoglycan[290]increase in the synthesis and activity of collagenase

Low molecular dextran

This compound applied as an infusion inhibits the plateletaggregation and increases fibrinolytic activity in plasma.[291] Asserious side-effects, anaphylactic reactions due to the formation ofImmunoglobulin G antibodies have to be considered.

Stanozolol

In SSc patients with reduced fibrinolytic activity in serumapplication of stanozolol, urokinase, or recombinant tissueplasminogen activator can be tried. The efficacy was ranked asrelatively low.[292,293,294,295]

Calcitonin

This hormone exerts its vasoactive effect by release of a stableprostacyclin degradation product (6 ketoprostaglandin F1alpha).[296] After 10 days of infusions of 100 IU per day, 89% ofSSc patients reported the long term improvement of acral bloodcirculation and Raynaud's attacks. Similarly positive effects wereseen after application of calcitonin gene-related-peptides.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

37 of 74 2/21/2013 2:24 AM

Page 38: Systemic Sclerosis - Scleroderma

Endothelin-1 (ET-1) receptor antagonists

The use of an ET-1 antagonist in SSc is an attractive idea,because it may act not only as a vasodilator but also may reducethe pro-fibrotic action of ET-1.[297] Bosentan (Roche Holding AG)is being tested as an ET-1 receptor antagonist in the treatment ofprimary and secondary forms of pulmonary hypertension.[298]

Nitric oxide (NO)

Despite the evidence of increased NO production in SSc thereis also evidence of injury to the endothelium, downregulation ofendothelial NOS, and defective production of NO.[299] Attemptsto improve blood flow by administering the substrate for NO,L-arginine, significantly decreased laboratory-induced Raynaud'sphenomenon in SSc patients but did not alter vascular responses toacetylcholine or sodium nitroprusside.[300] In addition, aNO-generating gel applied topically increases skin blood flow asmeasured by photoplethysmography.[301] Inhaled NO allowsselective pulmonary vasodilation and reduction of pulmonaryarterial pressure.[301] Studies of inhalation therapy with NO andprostacyclins (iloprost) are underway.

Inhibitors of angiotensin II

Angiotensin II is a profibrotic hormone. It induces angiotensinII receptor type I (AT1) on fibroblasts and also induces thesynthesis of TGFβ1 and of extracellular connective tissue.[302,303]Studies with angiotensin II inhibitors to reduce fibrosis in SSc havenot been done yet. In addition, the AT1 receptor antagonist,Losartan, decreases plasma levels of TGFβ1 in chronic allograftnephropathy and reduces heart fibrosis and radiation-induced lungfibrosis in animal models.[304] When comparing Losartan withnifedipin, Losartan led to a greater reduction in the severity ofRaynaud's phenomenon and in pro-collagen type I N-terminalpropeptide.[305] Finally, the outcome of the high renin state of SScrenal crisis has improved.

Antioxidants

Raynaud's phenomenon also occurring in internal organsinvolved in SSc leads to hypoperfusion and ischaemia with freeradical and other reactive oxygen species production.[306] SScautoantigens are susceptible to fragmentation by oxidative stress,thus potentially promoting the autoimmune process in SSc.[307] Anabnormal level of oxidative stress and a deficiency of dietaryantioxidants are reported in SSc.[308,309] Intravenousadministration of superoxide dismutase inhibits fibrosis in an animalmodel.[310] The antioxidant probucol exerted beneficial effects in

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

38 of 74 2/21/2013 2:24 AM

Page 39: Systemic Sclerosis - Scleroderma

the treatment of Raynaud's phenomenon in SSc.[311] The powerfulthiol-containing antioxidant, N-Acetylcysteine, was administeredto 22 patients with SSc in a 1-year, parallel, double-blind, placebo-controlled prospective study.[312] Most parameters remainedunchanged, however, most patients belonged to the late stage ofSSc. In addition, N-acetylcysteine was applied in a multicenter,open clinical trial for 11 weeks as intravenous infusions for 5 daysstarting with a 2 h loading dose of 150 mg/kg, subsequentlyadjusted to 15 mg/kg/h. Twenty-two patients completed the 5 dayinfusion and 20 of them the posttreatment follow-up. Frequencyand severity of Raynaud's attacks were significantly reduced; thesame was true for ulcerations. The cold challenge test meanrecovery time fell by approximately 70 % between the beginning oftreatment and day 12 and 61.[313] These preliminary data supportthe hypothesis that N-acetylcysteine may ameliorate damageinduced by reactive oxygen species.

Immune modulation

At the early stage of SSc infiltrations of inflammatory andimmune cells, such as neutrophils and/or eosinophils, in the alveolarspace of lungs, monocytes, T-lymphocytes, and mast cells inlesional skin and involvement of joints and muscles are prominentclinical features of the disease. Traditional anti-inflammatorymedication such as non-steroidal anti-inflammatory drugs orcorticosteroids provide only little benefit.

Corticosteroids

Prednisolone (initially: 40-100 mg/d, maintenance dose: 10-15mg/d) or methylprednisolone in general inhibit inflammation whilethey exert a catabolic effect on collagen synthesis (atrophy) andstabilize the cross linking of collagen fibrils. In addition, synthesisof other extracellular matrix proteins is inhibited. (Methyl)prednisolone is indicated in the treatment of inflammatory episodesof SSc, sclerodermatomyositis and overlap-syndromes, in particularin arthritis, myositis, alveolitis and vasculitis. However, there isevidence that corticosteroids (> 15 mg/d prednisolone) increase therisk of triggering a SSc renal crisis.[314] In addition, varioussignificant side-effects due to long-term maintenance treatmentsuch as hyperglycemia, osteoporosis, hypertension, pepticulceration of, muscle atrophy, and suppression of the cortex ofadrenal glands have to be considered. Altogether the clinicalexperience is disappointing for a dramatic effect of corticosteroids.

Non-steroidal antiinflammatory drugs (NSAIDs)

NSAIDs are useful to ameliorate the pains of joints, musclesand tendons symptomatically. Major side-effects are ulceration ofthe stomach, in particular when combined with corticosteroids.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

39 of 74 2/21/2013 2:24 AM

Page 40: Systemic Sclerosis - Scleroderma

Minocycline

There is one uncontrolled study in a small group of 11 SScpatients that minocycline (50 mg BID) had beneficial effects.[315]One patient died; two patients dropped out due to non compliance;two patients suffered from an acute renal crisis. Minocycline issuggested to exert anti-inflammatory effects and to inhibit theformation of free oxygen radicals. In our laboratory we were notable to show in-vitro effects on fibroblast function.[316] Inaddition, there is concern about the tetracycline-inducedautoimmune disorders including lupus-like disease.

Cyclophosphamide

Cyclophosphamide combined with prednisolone is able toinhibit the progression of lung fibrosis in smaller groups of patientswith SSc and idiopathic lung fibrosis more distinctly than afterprednisolone monotherapy.[317,318] Patients with earlyinflammatory changes, such as alveolitis of the lung, showed themost beneficial effects. However, side-effects such as infections,leucopenia, and hemorrhagic cystitis often force dose reductions.Intravenous pulse therapy seems to be better tolerated than dailyoral administration.[319]

Methotrexate

In a 24 week randomized double-blind trial, methotrexate in aweekly dose between 15 and 25 mg, achieved improvement of skinscore, creatinin-clearance and general well-being in 68%.[320]

Azathioprine

Azathioprine in a dose of 2-3 mg/kg/d is characterized by abetter spectrum of side-effects when compared to otherimmunosuppressants. In a prospective double-blind, randomizedand placebo-controlled study Ragun et al. showed improvement ofparameters of lung function and a marginally significant survivaladvantage due to prednisolone/azathioprine therapy in comparisonto prednisolone monotherapy in idiopathic lung fibrosis, which issimilar to SSc lung fibrosis.[321]

Cyclosporin A

Cyclosporin A inhibits effects due to T helper cells and IL-2secretion. It decreased procollagen III levels, improved skin lesionsand healed acrosclerotic ulcerations. However, lung function did

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

40 of 74 2/21/2013 2:24 AM

Page 41: Systemic Sclerosis - Scleroderma

not improve. Above 3 mg/kg body weight nephrotoxic side-effectshave to be taken into consideration. Thus, besides hypertension andincrease creatinine levels, fatal outcome due to renal complicationshave been described.[322,323]

Plasmapheresis

Plasmapheresis is expected to remove immune complexes,mediators and autoantibodies from the blood circulation and to stopthe progression of the disease or even to improve the disorder.[324,325] Long-term follow-up studies are ratherdisappointing.[326]

Other immunosuppressive principles

Antilymphocyte globulin, CD4 antibodies, and IL-2 receptor(CD25) antibodies, have been used in anecdotal cases.[327,328]Concerning CD4 antibodies, reports have been published inpsoriasis and rheumatoid arthritis, in particular.[329,330]

Extracorporal photochemotherapy

Extracorporal photochemotherapy has been introduced in thetreatment of malignant T-cell lymphoma and autoimmune diseases.In an interesting study two treatments on two consecutive days permonth for 6-10 months were performed and compared to 750 mg/dpenicillamine.[331] The improvement of the skin score wasrelatively small. A recently designed European study endeddisappointingly after an enthusiastic beginning, when improvementof the internal organs involved, could not be achieved. In addition,a new controlled trial shows no significant difference in skinscore.[332]

Autologous stem cell transplantation

Case reports of allogenic bone marrow transplantation (BMT)performed for malignancy have shown that autoimmune diseaseswere eradicated concurrently. Due to significant morbidity andmortality, allogenic BMT is no longer utilized for the treatment ofhuman autoimmune diseases. Instead of BMT, autologous stem celltransplantation (ASCT) was performed after immunoablativepretreatment in 64 centers of 20 countries in 70 SSc patients with amean follow up of approximately 2 years.[333] Inclusion criteriafor this trial were diffuse SSc, disease duration < 3 years,progressive course, skin score > 20 and involvement of one or moreinternal organs such as lung, heart and kidney, however, with minorabnormalities in their function. The mortality rate was 17%, in partcaused by interstitial pneumonitis, possibly due to an exaggerated

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

41 of 74 2/21/2013 2:24 AM

Page 42: Systemic Sclerosis - Scleroderma

response to total body irradiation. 70% of patients had a > 25 %improvement in their skin score and stabilization of lung function.This is still an experimental therapy, and currently limited topatients with severe, progressive life-threatening disease.[334] Inaddition, there are also risks of the infusion of untreatedauto-reactive lymphocyte clones despite immunoablativepretreatment regimens or defective stem cells reactive to chronicauto-antigenic stimulation. Thus, ATA were not eliminatedindicating that no "new or healthy" immune system could bereconstituted. Even high dose cyclophosphamide (4 g/m_) alonenot followed by ASCT resulted in improvement of some SScpatients.[333]

Oral tolerance to collagen

A phase I trial using ingestion of bovine type I collagen in SScpatients demonstrates significant reductions in levels of IFN andIL-10 in the in vitro response of peripheral blood monocytes,indicating that oral administration of collagen could induce oraltolerance as measured by T cell reactivity.[335] However, thetarget of this therapy may only be a secondary mechanism.

Thalidomide

Thalidomide is known as an immune modulator which alterscytokine production. Thalidomide was given to 44 patients withchronic GvHD skin disease and a complete response occurred in 14patients, a partial response in 12 and no response in 18patients.[336] Ten SSc patients were treated in an open-labeldose-escalating trial with improvement of skin fibrosis.[337]However, severe peripheral neuropathy and chronic dermatitishave to be considered.

Inhibitors of fibrosis

The inhibition of geranylgeranyltransferase I causes aninhibition of expression of genes encoding type I and type IIIcollagen without effecting cell viability.[338] This might be aninteresting target of therapy. Thus, rotterlin, a protein kinaseinhibitor exerted a powerful dose-dependent inhibition of type Icollagen synthesis and reduction of collagen A1 mRNAsteady-state levels in normal and SSc fibroblasts.[339] Polypeptidesincluding relaxin and interferons may also limit fibrogenesis.Inhibitors of post-translational modification of collagen such asinhibitors of prolyl 4 hydroxylase and lysyl oxidase may alsoprevent deposition of collagens.[340] However, generalmanipulation of collagen metabolism may cause adverse effectsprohibiting clinical trials with these substances.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

42 of 74 2/21/2013 2:24 AM

Page 43: Systemic Sclerosis - Scleroderma

Penicillamine

Penicillamine has been used for many years as a first choicedrug. It labilizes the cross links of lysin/hydroxylysin-aldehydegroups of collagen and maintains collagen in a soluble form,sensitive to degradation.[341] In addition, certainimmunomodulating and zytostatic effects have beendiscussed.[342] In slowly increasing doses from 150 to 750 mg/dfor years numerous side-effects such as proteinuria, leucopenia,thrombocytopenia, ulcerations of the mucosa, gastrointestinalproblems, dysgeusia, cholestasis, myasthenia, myositis, pemphigusand lupus erythematosus were found in up to 47 % of patients.Thus, therapy had to be stopped in 29 % of patients.[343] Thetherapeutic effects were moderate: softening of the skin andcessation of the progression of lung fibrosis.[344,345] A recentlyperformed double-blind randomised controlled study has shownthat the high dose D-penicillamin therapy (750-1000 mg/d) is notsuperior in terms of skin softening, frequency of renal crisis anddeath rate as compared to low dose therapy (125 mg/alternateday).[346] On the other hand, there was no significant clinicaldifference between penicillamine and placebo, either.

Furst and Clements would use D-penicillamine only in apatient who has been on this drug for a prolonged period of time(without significant adverse events) and who refuses to discontinuethe drug.[347] However, recently, Medsger concluded from hisexperience that D-penicillamine favourably alters the naturalhistory of skin involvement in diffuse SSc even when used in lowdose.[348] Furthermore, recurrence of diffuse skin change afterdiscontinuation and improvement in skin thickening afterre-initiation of the drug support its effectiveness. Nevertheless, dueto its high rate of side-effects and the questionable therapeuticeffect, penicillamine should, in our opinion, no longer be used inthe treatment of SSc. A: Penicillin G

Penicillin G belongs to the prolylhydroxylase-inhibitors andhas been used therapeutically by our group for many years in adosis of 10 Mega IU/day as an intravenous short-term infusion over30 minutes for 10-15 days. Although clinical studies do not exist,we use this regimen at the early edematous stage of SSc and havefound improvement of the skin score (softening of sclerosis) and adecrease in the frequency and severity of Raynaud's attacks.[319]However, we were not able to influence the collagen metabolism infibroblast cultures in vitro.[349]

Other prolylhydroxylase inhibitors such as hydralazin,diphenylhydantoin and chlorpromazin as well as L-Dopa andglutamine did not achieve therapeutic relevance.[344]

Bucillamine

Bucillamine is a derivative of D-penicillamine. It inhibits theproliferation of TH1 cells and transendothelial T cell migration. Six

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

43 of 74 2/21/2013 2:24 AM

Page 44: Systemic Sclerosis - Scleroderma

SSc patients were treated with 200-300 mg/d bucillamine for 12-36months with some improvement of skin thickening and lungfunction.[350]

Photochemotherapy (PUVA)

Oral psoralen-UVA light (PUVA) may provide a successfultreatment for cutaneous lesions in limited SSc.[351] Kercher et al.used bath-PUVA and achieved improvement in generalizedmorphea as well as in SSc.[352] UVA increases the synthesis ofcollagenase in fibroblasts of the skin and generates singulet oxygen.In addition, it exerts anti-inflammatory effects.

Inhibitors of cytokines and growth factors

Agents that decrease the amount of TGFβ or interfere with itsaction may be of benefit in SSc. For example, antibodies to TGFβwere able to reduce bleomycin-induced fibrosis, prevent chronicGvHD in mice, or inhibit the activation of tissue fibroblasts.[353,354,355]. However, CTGF might be a more reasonable targetin the treatment of SSc. On the other hand, an open label trial ofentanercept, the TNF inhibitor, in 10 SSc patients demonstrated animproved skin score in 4 of 9 evaluable patients.[356] An IL-1receptor antagonist prevented development of pulmonary fibrosis inmice.[357] Finally, this anticytokine therapy requires patients at theearly inflammatory stages of disease before late stage fibrosis hasdeveloped.

Interferons (IFN)

IFNγ and α inhibit the synthesis of collagen I, II and III,reduce the expression of collagen mRNA and enhance theproduction of collagenase by fibroblasts in vitro.[358] Severaluncontrolled trials of IFNγ suggest improvement in skin score andother objective parameters.[359,360,361] However, no benefit wasshown for skin score or change in the collagen type I mRNA levelsin skin tissue from 32 SSc patients in another open-labeluncontrolled trial.[362] In a randomized, controlled multicentertrial, 44 SSc patients showed improvement in their skin score, butquality of life measurements were superior in the placebogroup.[363] IFN may also activate endothelial cells and upregulateadhesion molecules, thus aggravating inflammation, Raynaud'sphenomenon and digital ischaemia. Side-effects are headache,fatigue, muscle pain, sweating at night, fever, vomiting andarthralgia (flu-like syndrome).

Studies with IFNα did not show improvement of skin and mayworsen associated lung disease.[364] Finally, IFNβ may be acandidate for clinical trials, but it has not been studied yet.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

44 of 74 2/21/2013 2:24 AM

Page 45: Systemic Sclerosis - Scleroderma

Relaxin

Relaxin is a member of the insulin-growth factor family with amolecular weight of 5000-6000. Obviously it plays a role inconnective tissue remodelling during pregnancy. Relaxin inhibitscollagen synthesis and increases production of procollagenase.[365]In addition, it acts as a renal vasodilator improving glomerularfiltration.[366] SSc patients with the stable diffuse form for lessthan 5 years received 25 or 100 µg/kg body weight of recombinantrelaxin through continuous s.c. infusion. While the higher dose didnot achieve benefit, the lower dose at week 4, 12 and 24 did showsome benefit compared to placebo.[367,368] The large nation-wideplacebo-controlled follow up study with 25 mg/kg body weightdemonstrated no difference compared to placebo in the outcomesof skin score and pulmonary function testing. The dose given was50 fold higher than achieved during pregnancy. In addition, itshould be noted that softening of connective tissue in pregnancy isrestricted to the environment of the birth canal and does not occurover the whole body.

Halofuginone

Halofuginone is an alcaloid, which reduces collagen synthesisand collagen I (I) gene expression in humans.[369] Its effect inanimal models of skin fibrosis (murine GvHD and tight skin (TSK)mouse) demonstrated decreased collagen content and reducedclinical signs of sclerosis.[370] In addition, halofuginone causes adose dependent inhibition of collagen I (I) gene expression andcollagen synthesis in skin fibroblast cultures from patients withGvHD and SSc.[371] The application of a topical formulationachieved clinical improvement in GvHD patients.[372]

Aromatic retinoids

(Neo) tigason and cis-retinoid acid showed moderateimprovement or even healing of ischemic ulcerations in SScpatients after several weeks of treatment.[373] Effects on themicrotubule system and collagen metabolism (inhibition offibroblast proliferation and collagen synthesis) were discussed. Thefollowing side-effects have to be considered: teratogenicity, liverfunction disturbances and increase in serum lipids.

Other substances

Cyclophenyl (antagonist of estrogen), colchizin (inhibitor oftubulin polymerisation and microtubulus dependent collagensynthesis) and griseofulvin (inhibitor of fibroblast proliferation invitro) could not achieve therapeutic relevance. The same is true for

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

45 of 74 2/21/2013 2:24 AM

Page 46: Systemic Sclerosis - Scleroderma

factor XIII as an inhibitor of collagen synthesis.[374] Potassiumpara-aminobenzoate has been used for many years in doses of 4 gTID. However, initial effects appeared to be non-significant aftercorrection for patients groups.[375]

Additional symptomatic treatment

Metoclopramide, 5-10 mg (Paspertin) before each meal and atbedtime, is indicated for the treatment of esophageal dysmotility. Inreflux esophagitis the following medications are recommended: H2antagonists such as cimetidin (400 mg TID), ranitidine (150 mgBID) as well as proton pump inhibitors like omeprazol (20-60mg/d). Antibiotics are given in gastroenteritis (bacterialovergrowth) and infection of the lung and kidney according togeneral therapeutic standards.[376]

Cardial involvement is treated with digitalis and diuretics,while renal crisis and malignant hypertension require ACEinhibitors such as captopril or enalapril, and in severe cases,dialysis.[377] In pulmonary hypertension the administration ofanticoagulants, calcium channel blockers and prostacyclinanalogues are indicated, the latter ones as inhalation therapy.[279]

Hydrocolloid dressings help in the healing of ulcerations.[378]Calcium deposits can be excised or their perforation may befacilitated by adhesive tapes. Colchicine (0.5 mg BID) is able toreduce local inflammation surrounding the calcified lesions.[379]

Table 9. Therapeutic recommendationsvasoactive substancescalcium channelblockers

Nifedipin 3 x 10 mg/d

ACE-inhibitors Captopril 12,5 - 100 mg/d

Enalapril 5 - 15 mg/d

prostacyclin analogs Iloprost0,5 - 2 ng/kg/min for 6 hi.v.; 5-10 days

antiinflammatory and immunesuppressive substances

Glucocorticoids Methylprednisoloneinitially 60-80 mg/d;reduction tomaintenance dose

Azathioprine 1,5 - 3 mg/d

Cyclophosphamide2,0 - 2,5 mg/kg/d p.o. or0,5 - 1 g/m_/month i.v.

antifibrotic substances

D-Penicillamin150 - 300 - (750) mg/dslow dose increase

Penicillin G10 Mega IE i.v. (30 min)for 10 - 14 days

PUVA

gastroenterologicsproton pumpinhibitor

Omeprazol 20 - 40 mg/d

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

46 of 74 2/21/2013 2:24 AM

Page 47: Systemic Sclerosis - Scleroderma

H2-receptor blocker Ranitidin 150 - 300 mg/d

gastroprocinetics Metoclopramid 3 x 10 mg/d p.o.

Conclusion

There is no ideal drug available for the treatment of SSc.Symptomatic treatment helps to improve quality of life. Variousdisease modifying agents address different pathways of the diseasepathogenesis such as vascular disease, autoimmunity and tissuefibrosis. Beside current recommendations (see Table 9) a variety ofnovel strategies have been reviewed. But more well designedplacebo-controlled trials are needed to evaluate the benefit of anynew medication, especially as SSc is a challenging disease with aheterogeneous clinical phenotype. In addition, the paucity ofobjective criteria renders the evaluation of improvement ordeterioration more difficult. Physiotherapy to maximize the rangeof motion of all large joints and psychological counselling arenecessary components of the successful management of SSc.

References

1. Curzio C. Discussionil anatomico-pratiche di un raro, estravagante morbo cutaneo in una giovane donna felicementecurato in questo grande ospedale degl' incurabili. Napoli, PressoGiovanni di Simone, 1753. Curzio C. An account of anextraordinary disease of the skin and its cure. Translated by R.Watson. Philosophical Trans 1754;48:579.

2. Gintrac M. Note sur la sclerodermie. Rev Med Chir. Paris1847;2:263-81.

3. Sackner MA. The visceral manifestations of scleroderma.Arthritis Rheum 1962;5:184-96.

4. Rodnan GP, Benedek TG. A historical account of the study ofprogressive systemic sclerosis (diffuse scleroderma). Ann InternMed 1962;57:305-19.

5. Jablonska S. Scleroderma and pseudoscleroderma. Warsaw:Polish Med, 1975.

6. Tuffanelli D, Winkelmann RK. Systemic scleroderma. A clinicalstudy of 727 cases. Arch Dermatol 1961;84:359-71.

7. Haustein UF, Ziegler V, Herrmann K. Pseudosklerodermien.Hautnah "Dermatologie" 1991;1:67-71.

8. Subcommittee for Scleroderma Criteria of the AmericanRheumatism Association Diagnostic and Therapeutic CriteriaCommittee. Preliminary criteria for the classification of systemicsclerosis (scleroderma). Arthritis Rheum 1980;23:581-90.

9. Maricq HR, Harper FE, Khan MM. Microvascular abnormalitiesas possible predictors of disease subsets in Raynaud's phenomenon

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

47 of 74 2/21/2013 2:24 AM

Page 48: Systemic Sclerosis - Scleroderma

and early connective tissue disease. Clin Exp Rheumatol1983;1:195-205.

10. Silman AJ. Epidemiology of scleroderma. Ann Rheum Dis1991;50:846-53.

11. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemicsclerosis sine scleroderma: demographic, clinical, and serologicfeatures and survival in forty-eight patients. Arthritis Rheum2000;43:444-51.

12. Lonzetti LS, Joyal F, Raynauld JP. Updating the AmericanCollege of Rheumatology preliminary classification criteria forsystemic sclerosis: addition of severe nailfold capillaroscopyabnormalities markedly increases the sensitivity for limitedscleroderma. Arthritis Rheum 2001;3:735-738.

13. LeRoy EC, Medsger TA Jr. Criteria for the classification ofearly systemic sclerosis. J Rheumatol 2001;28:1573-6.

14. Barnett AJ. Scleroderma. Progressive systemic sclerosis.Springfield: Charles C Thomas, 1974.

15. Arbeitsgruppe Sklerodermie der ArbeitsgemeinschaftDermatologische Forschung (ADF). Klinik der progressivensystemischen Sklerodermie (PSS). Hautarzt 1986;37:320-4.

16. Winterbauer RH. Multiple teleangiectasia, Raynaud'sphenomenon, sclerodactyly and subcutaneous calcinosis: asyndrome mimicking hereditary hemorrhagic teleangiectasia. BullJohns Hopkins Hosp 1964;114:361-83.

17. Velagos EE, Masi AT, Stevens MB, Shulman LE. The CRESTsyndrome. Comparison with the systemic sclerosis (scleroderma).Arch Intern Med 1979;139:1240-4.

18. Lomeo RM, Cornella RJ, Schabel SI. Progressive systemicsclerosis sine scleroderma presenting as pulmonary interstitialfibrosis. Am J Med 1989;87:525-7.

19. Winkelmann RK. Pathogenesis and staging of scleroderma.Acta Derm Venereol (Stockh) 1976;56:83-92.

20. LeRoy EC, Black C, Fleischmajer R. Scleroderma (systemicsclerosis): classification, subsets and pathogenesis. J Rheumatol1988;15:202-5.

21. Steen VD, Powell DL, Medsger T Jr. Clinical correlations andprognosis based on serum autoantibodies in patients with systemicsclerosis. Arthritis Rheum 1988;31:196-203.

22. Traub YH, Shapiro AP, Rodnan GP. Hypertension and renalfailure (scleroderma renal crisis) in progressive systemic sclerosis:review of a 25-year experience with 68 cases. Medicine1983;62:335-52.

23. Clements PJ, Furst DE, Cabeen W. The relationship ofarrhythmias and conduction disturbances to other manifestations of

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

48 of 74 2/21/2013 2:24 AM

Page 49: Systemic Sclerosis - Scleroderma

cardiopulmonary disease in progressive systemic sclerosis (PSS).Am J Med 1981;71:38-46.

24. McCarthy DS, Baragar FD, Dhingra S. The lungs in systemicsclerosis (scleroderma): a review and new information. SeminArthritis Rheum 1988;17:271-83.

25. Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinicaland prognostic associations based on serum antinuclear antibodiesin Japanese patients with systemic sclerosis. ArthritisRheum1994;1:75-83.

26. Silver RM. Clinical aspects of systemic sclerosis (scleroderma).Ann Rheum Dis 1991;50:846-53.

27. Maricq HR, Weinrich MC, Keil JE, Smith EA, Harper FE,Nussbaum AI, LeRoy EC, McGregor AR, Diat F, Rosal EJ.Prevalence of scleroderma spectrum disorders in the generalpopulation of South Carolina. Arthritis Rheum 1989;32:998-1006.

28. Englert H, O'Connor H, Small-McMahon J, Chambers P, DavisK, Brooks P. Systemic sclerosis prevalence and mortality in Sydney1974-88. Aust NZ J Med 1999;29:42-50.

29. Silman AJ. Scleroderma - Demographics and survival. JRheumatol 1997;24:58-61.

30. Maricq HR, Weinrich MC, Keil JE. Prevalence of sclerodermaspectrum disorders in the general population of South Carolina.Arthritis Rheum 1989;32:998-1006.

31. Medsger TA, Masi AT, Rodnan GP, Benedek TG, Robinson H.Survival with systemic sclerosis (scleroderma): a life-table analysisof clinical and demographic factors in 309 patients. Ann InternMed 1971;75:369-76.

32. Altman RD, Medsger TA Jr, Bloch DA, Beat AM. Predictors ofsurvival in systemic sclerosis (scleroderma). Arthritis Rheum1991;34:403-13.

33. Silman AJ, Jannini S, Symmons D, Bacon P. An epidemiologicalstudy of scleroderma in the West Midlands. Br J Rheumatol1988;27:286-290.

34. Haustein UF, Albrecht M. Zur Epidemiologie und Klinik dersystemischen Sklerodermie. Z Hautkrankh (H+G)1993;10:651-658.

35. Steen VD, Medsger TA Jr. Epidemiology and natural history ofsystemic sclerosis. Rheum Dis Clin North Am 1990;16:1-10.

36. Medsger TA, Masi AT. The epidemiology of systemic sclerosis(scleroderma). Ann Intern Med 1971;74:714-21.

37. Medsger TA Jr. Epidemiology of progressive systemic sclerosis.In: Black CM, Myers AR, eds. Systemic sclerosis (scleroderma).New York: Gower, 1985:53-9.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

49 of 74 2/21/2013 2:24 AM

Page 50: Systemic Sclerosis - Scleroderma

38. Hesselstrand R, Scheja A, Akesson A. Mortality and causes ofdeath in a Swedish series of systemic sclerosis patients. Ann RheumDis 1998;57:682-686.

39. Bryan C, Knight C, Black CM, Silman AJ. Prediction offive-year survival following presentation with scleroderma.Arthritis Rheum 1999;12:2660-2665.

40. Lally EV, Jimenez SA, Kaplan SR. Progressive systemicsclerosis: mode of presentation, rapidly progressive disease course,and mortality based on an analysis of 91 patients. Semin ArthritisRheum 1988;18:1-13.

41. Barnett AJ, Miller MH, Littlejohn GO. A survival study ofpatients with scleroderma diagnosed over 30 years (1953-1983):the value of a simple cutaneous classification in the early stages ofthe disease. J Rheumatol 1988;15:276-83.

42. Maricq HR, Weinrich MC, Keil JE. Prevalence of Raynaud'sphenomenon in the general population. J Chronic Dis1986;39:423-7.

43. Olsen N, Neilsen SL. Prevalence of primary Raynaudphenomena in young females. Scand J Clin Invest 1978;37:761-4.

44. Belch, JJP. Raynaud's phenomenon: its relevance toscleroderma. Ann Rheum Dis 1991;50:839-45.

45. Thibi?rge G, Weissenbach RJ. Une forme de concr?tionscalcaires sous cutanZes en relation avec la scl?rodermiZ. Bull SocMed Hp (Paris) 1910;30:10-39.

46. Clements PJ, Lachenbruch PA, Cheng S. Skin score: asemiquantitative measure of cutaneous involvement that improvesprediction of prognosis in systemic sclerosis. Arthritis Rheum1990;33:1256-63.

47. Myers SL, Cohen JS, Sheets PW. B-mode ultrasound evaluationof skin thickness in progressive systemic sclerosis. J Rheumatol1986;13:577-80.

48. Cole GW, Handler SJ, Burnett K. The ultrasonic evaluation ofskin thickness in scleroderma. J Clin Ultrasound 1981;9:501-3.

49. Furst DE, Clements PJ, Steen VD. The modified Rodnan skinscore is an accurate reflection of skin biopsy thickness in systemicsclerosis. J Rheumatol 1998;25:84-8.

50. Clements PJ, Hurwitz EL, Wong WK. Skin thickness score as apredictor and correlate of outcome in systemic sclerosis. ArthritisRheum 2000;11:2445-2454.

51. Silman A, Akesson A, Newman J. Assessment of functionalability in patients with scleroderma: a proposed new disabilityassessment instrument. J Rheumatol 1998;25:79-83.

52. Barnett AJ. The "neck sign" in scleroderma. Arthritis Rheum1989;32:209-11.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

50 of 74 2/21/2013 2:24 AM

Page 51: Systemic Sclerosis - Scleroderma

53. Fleischmajer R, Damiano V, Nedwich A. Scleroderma and thesubcutaneous tissue. Science 1971;171:1019-21.

54. Kobayasi T, Asboe Hansen G, Serup J. Ultrastructuralhistopathology of scleroderma. Ugeskr Laeger1984;146:22:1617-1619.

55. Varga J, Rudnicka L, Uitto J. Connective tissue alterations insystemic sclerosis (review). Clin Dermatol 1994;12:387-396.

56. Haustein UF, Klug H. Ultrastrukturelle Untersuchungen bei derSklerodermie. Dermatol Monatsschr 1975;161:530-535.

57. Steen VD, Medsger TA Jr. Severe organ involvement insystemic sclerosis with diffuse scleroderma. Arthritis Rheum2000;11:2437-2444.

58. Mittag M, Haustein UF. Die progressiv systemischeSklerodermie - prognosebestimmender Befall innererOrgansysteme. Hautarzt 1998;49:545-551.

59. Weihrauch TR, Korting GW. Manometric assessment ofoesophageal involvement in progressive systemic sclerosis,morphea and Raynaud's disease. Br J Dermatol 1982;107:325-32.

60. Davidson A, Russell C, Littlejohn GO. Assessment ofesophageal abnormalities in progressive systemic sclerosis usingradionuclide transit. J Rheumatol 1985;12:472-7.

61. Segel MC, Campbell WL, Medsger TA Jr, Roumm AD.Systemic sclerosis (scleroderma) and esophageal adenocarcinoma:is increased patient screening necessary? Gastroenterology1985;89:485-8.

62. Hamel-Roy J, Devroede G, Arhan P. Comparative esophagealand anorectal motility in scleroderma. Gastroenterology1985;88:1-7.

63. Cohen S. The gastrointestinal manifestations of scleroderma:pathogenesis and management (clinical conference).Gastroenterology 1980;79:155-66.

64. Cobden I, Axon AT, Ghoneim AT, McGoldrick J, Rowell NR.Small intestinal bacterial growth in systemic sclerosis. Clin ExpDermatol 1980;5:37-42.

65. Allende HD, Ona FV, Noronha AI. Bleeding gastricteleangiectasia. Complication of Raynaud's phenomenon,esophageal motor dysfunction, sclerodactyly and teleangiectasia(REST) syndrome. Am J Gastroenterol 1981;75:354-6.

66. Young MA, Rose S, Reynolds JC. Gastrointestinalmanifestation of scleroderma. Rheum Dis Clin North Am1996;22:797-823.

67. Bartholomew CG, Cain JC, Winkelmann RC, Baggenstoss AH.Chronic disease of the liver associated with systemic scleroderma.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

51 of 74 2/21/2013 2:24 AM

Page 52: Systemic Sclerosis - Scleroderma

Am J Dig Dis 1964;9:43.

68. Clarke AK, Galbraith RM, Hamilton EBD, Williams R.Rheumatic disorders in primary biliary cirrhosis. Ann Rheum Dis1978;37:42-7.

69. Makinen D, Fritzler JM, Davis P, Sherlock S. Anticentromereantibodies in primary biliary cirrhosis. Arthritis Rheum1983;26:914-7.

70. Hendel L, Worning H. Exocrine pancreatic function in patientswith progressive systemic sclerosis. Scand J Gastroenterol1989;24:461-6.

71. Steen VD, Conte C, Owens GR, Medsger TA. Severe restrictivelung disease in systemic sclerosis. Arthritis Rheum1994;37:1283-1289.

72. Alton E, Turner-Warwick M. Lung involvement in scleroderma.In: Jayson MIV, Black CM (eds) Systemic sclerosis: scleroderma,John Wiley & Sons, Chichester, 1988, pp 181-205.

73. Steen VD, Owens GR, Fino GJ, Rodnan GP, Medsger TA.Pulmonary involvement in systemic sclerosis (scleroderma).Arthritis Rheum 1985;28:759-767.

74. Medsger TA Jr, Masi AT. Survival with scleroderma-II: alife-table analysis of clinical and demographic factors in 358 maleUS veteran patients. J Chron Dis 1973;26:647.

75. Stupi AM, Steen VD, Owens GR, Barnes L, Rodnan GP,Medsger TA. Pulmonary hypertension in the CREST syndromevariant of systemic sclerosis. Arthritis Rheum 1986;29:515-24.

76. Thornten SC, Robbins JM, Shelley L. Fibroblast growth factorsin connective tissue disease associated interstitial lung disease:association with disease activity and identification as TNF-a,PDGF, and fibronectin. Clin Exp Immunol 1992;90:447-452.

77. Hasegawa M, Sato S, Takehara K. Augmented production ofchemokines (MCP-1, MIP-1( and MIP-1() in patients with systemicsclerosis: MCP-1 and MIP-1( may be involved in the developmentof pulmonary fibrosis. Clin Exp Immunol 1999;117:159-165.

78. Rossi GA, Bitterman PB, Rennard SI, Ferrans VJ, Crystal RG.Evidence for chronic inflammation as a component of theinterstitial lung disease associated with progressive systemicsclerosis. Am Rev Respir Dis 1985;131:612-7.

79. Bjerke RD, Tashkin DP, Clements PJ, Chopra SK, Gong H Jr,Bein M. Small airways in progressive systemic sclerosis (PSS). AmJ Med 1979;66:201-8.

80. Silver RM, Miller KS, Kinsella MB, Smith EA, Schabel SI.Evaluation and management of scleroderma lung disease usingbronchoalveolar lavage. Am J Med 1990; 88:470-476.

81. Lee P, Langevitz P, Alderdice CA, Aubrey M. Mortality in

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

52 of 74 2/21/2013 2:24 AM

Page 53: Systemic Sclerosis - Scleroderma

systemic sclerosis (scleroderma). Q J Med 1992;298:139-148.

82. Follansbee WP. The cardiovascular manifestations of systemicsclerosis (scleroderma). Curr Probl Cardiol 1986;11:241-98.

83. Reichenbach DD, Benditt EP. Myofibrillar degeneration: aresponse of the myocardial cell to injury. Arch Pathol1968;46:189-99.

84. Hegedus I, Czirjak L. Left ventricular wall motionabnormalities in 80 patients with systemic sclerosis. Clin Rheumatol1995;14:161f.

85. Candell-Riera J, Armandans-Gil L, Simeon CP. Comprehensivenoninvasive assessment of cardiac involvement in limited systemicsclerosis. Arthritis Rheum 1996;39:1138-1145.

86. Kostis JB, Seibold JR, Turkevich D. Prognostic importance ofcardiac arrhythmias in systemic sclerosis. Am J Med1988;84:1007-15.

87. Clements PJ, Furst DE. Heart involvement in systemic sclerosis.Clin Dermatol 1994;12:267-275.

88. Alexander EL, Firestein GS, Weiss JL. Reversible cold-inducedabnormalities in myocardial perfusion and function in systemicsclerosis. Ann Intern Med 1986;105:661-8.

89. Follansbee WP, Curtiss EI, Rahko PS. The electrocardiogram insystemic sclerosis (scleroderma): a study of 102 consecutive caseswith functional correlations and review of literature. Am J Med1985;79:183-92.

90. Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am1996;22:861-878.

91. Steen VD, Medsger TA, Osial TA, Ziegler GL, Shapiro AP,Rodnan GP. Factors predicting development of renal involvementin progressive systemic sclerosis. Am J Med 1984;76:779-786.

92. Haustein UF. Elektronenmikroskopische Untersuchungen zurNierenbeteiligung bei der progressiven Sklerodermie. DermMonatsschr 1975;161:22-31.

93. Steen VD, Costantino JP, Shapiro AP. Outcome of renal crisis insystemic sclerosis. Ann Int Med 1990;113:352-357.

94. Clements PJ, Furst DE, Campion DS. Muscle disease inprogressive systemic sclerosis: diagnostic and therapeuticconsiderations. Arthritis Rheum 1978;21:62-71.

95. Mathews MB, Bernstein RM. Myositis autoantibody inhibitshistidyl tRNA synthetase: a model for autoimmunity. Nature1983;304:177-9.

96. Carette S, Turcotte J, Mathon G. Severe myositis andmyocarditis in progressive systemic sclerosis. J Rheumatol1985;12:997-9.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

53 of 74 2/21/2013 2:24 AM

Page 54: Systemic Sclerosis - Scleroderma

97. Hausmanowa-Petrusewick I, Jablonska S, Blaszczyk M, MatzB. Electrmyographic findings in various forms of progressivesystemic sclerosis. Arthritis Rheum 1982;25:61-5.

98. Baron M, Lee P, Keystone EC. The articular manifestations ofprogressive systemic sclerosis (scleroderma). Ann Rheum Dis1982;41:147-52.

99. Block KL, Bassett LW, Furst DE. The arthropathy of advancedprogressive systemic sclerosis: a radiographic survey. ArthritisRheum 1981;24:874-84.

100. Osial TA Jr, Whiteside TL, Buckingham RB. Clinical andserologic study of Sjsgren's syndrome in patients with progressivesystemic sclerosis. Arthritis Rheum 1983;26:500-8.

101. Cipoletti JF, Buckingham RB, Barnes EL. Sjsgren's syndromein progressive systemic sclerosis. Ann Intern Med 1977;87:535-41.

102. Berth-Jones J, Coates PAA, Graham-Brown RAC.Neurological complications of systemic sclerosis: a report of threecases and review of the literature. Clin Exp Dermatol1990;15:91-4.

103. Teasdall RD, Frayha RA, Shulman LE. Cranial nerveinvolvement in systemic sclerosis (scleroderma): a report of 10cases. Medicine (Baltimore) 1980;59:149-59.

104. Lee P, Bruni J, Sukenik S. Neurological manifestations insystemic sclerosis (scleroderma). J Rheumatol 1984;11:480-3.

105. Frayha RA, Shulman LE, Stevens MB. Hematologicalabnormalities in scleroderma: a study of 180 cases. Acta Haematol(Basel) 1980;64:25-30.

106. Steen VD. Pregnancy in women with systemic sclerosis.Obstet Gynecol 1999;94:15-20.

107. Doss BJ, Jacques SM, Mayes MD, Qureshi F. Maternalscleroderma: placental findings and perinatal outcome. Hum Pathol1998;12:1524-1530.

108. Black CM. The aetiopathogenesis of systemic sclerosis. JIntern Med 1993;234:3-8.

109. Kahari VM. Activation of dermal connective tissue inscleroderma. Ann Intern Med 1994;25:511-518.

110. Jimenez S, Feldman G, Bashey R. Co-ordinate disease in theexpression of type II and type III collagen genes in progressivesystemic sclerosis fibroblasts. Biochem J 1986;237:837-843.

111. Haustein UF, Herrmann K. Environmental scleroderma. ClinDermatol 1994;12:467-473.

112. Black CM, Welsh KI. Genetics of scleroderma. Clin Dermatol1994;12:337-347.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

54 of 74 2/21/2013 2:24 AM

Page 55: Systemic Sclerosis - Scleroderma

113. Morel PA, Chang HJ, Wilson JW. Severe systemic sclerosiswith anti-topoisomerase I antibodies is associated with anHLA-DRw 11 allele. Human Immunol 1994;40:101-110.

114. Laing TJ, Gillespie BW, Toth MB. Racial differences inscleroderma among woman in Michigan. Arthritis Rheum1997;40:734-742.

115. Takeuchi F, Kuwata S, Nakano K. Association of TAP1 andTAP2 with systemic sclerosis in Japanese. Clin Exp Rheumatol1996;14:513-521.

116. Vargas-Alarc‹n G, Granados J, Ibanez de Kasep G.Association of HLA-DR5 (DR11) with systemic sclerosis(scleroderma) in Mexican patients. Clin Exp Rheumatol1995;13:11-16.

117. Reveille JD. Molecular genetics of systemic sclerosis. CurrOpin Rheumatol 1995;7:522-528.

118. Arnett FC. HLA and autoimmunity in scleroderma (systemicsclerosis). Int Rev Immunol 1995;12:107-128.

119. Wolff DJ, White Needleman B, Wasserman SS. Spontaneousand clastogen induced chromosomal breakage in scleroderma. JRheumatol 1991;18:837-840.

120. Black CM, Stevens WM. Scleroderma. Rheum Dis Clin NorthAm 1989;15:193-212.

121. Schroder J, Tiilikainen A, De la Chapelle A. Fetal leukocytesin the maternal circulation after delivery. I. Cytological aspects.Transplantation 1974;17:346-354.

122. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMariaMA. Male fetal progenitor cells persist in maternal blood for as longas 27 years postpartum. Proc Natl Acad Sci USA 1996;93;705-708.

123. Nelson JL, Furst DE, Maloney S. Microchimerism andHLA-compatible relationship of pregnancy in scleroderma. Lancet1998;351:559-562.

124. Arlett CM, Welsh KI, Black CM, Jimenez SA. Fetal-maternalHLA compatibility confers susceptibility to systemic sclerosis.Immunogenetics 1997;47:17-22.

125. Kitridou RC. Pregnancy in mixed connective tissue disease,poly/dermatomyositis and scleroderma. Clin Exp Rheumatol1988;6:173-178.

126. Johnson TR. Scleroderma and pregnancy. Obstet Gynecol1964;23:467-469.

127. Evans PC, Lambert N, Maloney S, Furst DE, Moore JM,Nelson JL. Long-term fetal microchimerism in peripheral bloodmononuclear cell subsets in healthy women and women withscleroderma. Blood 1999;6:2033-2037.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

55 of 74 2/21/2013 2:24 AM

Page 56: Systemic Sclerosis - Scleroderma

128. Arlett CM, Smith JB, Jimenez SA. Identification of fetal DNAand cells in skin lesions from women with systemic sclerosis. NewEngl J Med 1998;338:1186-1191.

129. Haustein UF. Mikrochimerismus - Neuer Denkansatz fr diePathogenese der systemischen Sklerodermie. Hautarzt2000;2:59-62.

130. Maricq H. Comparison of quantitative and semiquantitativeestimates of nailfold capillary abnormalities in sclerodermaspectrum disorders. Microvasc Res 1986;32:271-276.

131. Scheja A, Akesson A, Niewierowicz I. Computer basedquantitative analysis of capillary abnormalities in systemic sclerosisand its relation to plasma concentration of von Willebrand factor.Ann Rheum Dis 1996;55:52-56.

132. Rodnan GP, Myerowitz RL, Justh GO. Morphologic changesin the digital arteries of patients with progressive systemic sclerosis(scleroderma) and Raynaud phenomenon. Medicine1980;59:393-408.

133. Kahaleh MB. The vascular endothelium in scleroderma. IntRev Immunol 1995;12:227-245.

134. Maricq HR, Leroy EC, D'Angelo WA, Medsger TA Jr, RodnanGP, Sharp GC, Wolfe JF. Diagnostic potential of in vivo capillarymicroscopy in scleroderma and related disorders. Arthritis Rheum1980;23:183-189.

135. Fleischmajer R, Perlish JS, Shaw KV, Pirozzi DJ. Skin capillarychanges in early systemic scleroderma. Electron microscopy and"in vitro" autoradiography with tritiated thymidine. Arch Dermatol1976;112:1553-1557.

136. Haustein UF. Das GefS§system bei der progressivenSklerodermie. Dermatol Monatsschr 1976;162:721-725.

137. Kahaleh B, Matucci-Cerinic M. Raynaud's phenomenon andscleroderma. Dysregulated neuroendothelial control of vasculartone. Arthritis Rheum 1995;38:1-4.

138. Carvalho D, Savage COS, Black CM. IgG antiendothelial cellautoantibodies from scleroderma patients induce leukocyteadhesion to human vascular endothelial cells in vitro. J Clin Invest1996;97:111-119.

139. Salojin KV, LeTonqu?ze M, Saraux A. Antiendothelial cellantibodies: useful markers of systemic sclerosis. Am J Med1997;102:178-185.

140. Stein CM, Tanner SB, Awad JA. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma.Arthritis Rheum 1996;39:1146-1150.

141. Murrell DF. A radical proposal for the pathogenesis ofscleroderma. J Am Acad Dermatol 1993;28:78-85.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

56 of 74 2/21/2013 2:24 AM

Page 57: Systemic Sclerosis - Scleroderma

142. Herrick AL, Illingworth K, Blann A. Von Willebrand factor,thrombomodulin, thromboxane, (-thromboglobulin and markers offibrinolysis in primary Raynaud's phenomenon and systemicsclerosis. Ann Rheum Dis 1996;55:122-127.

143. Kahaleh MB. Endothelin, an endothelial-dependentvasoconstrictor in scleroderma. Enhanced production andprofibrotic action. Arthritis Rheum 1991;34:978-983.

144. Tabata H, Yamakage A, Yamazaki S. Cutaneous localization ofendothelin-1 in patients with systemic sclerosis: immunoelectronmicroscopy study. Int J Dermatol 1997;36:272-275.

145. Tomita M, Fan P, Santoro T, Kahaleh B. Impaired response tomechanical fluid shear stress (MFSS) by scleroderma (SSc)microvascular endothelial cells (MVEC) from involved anduninvolved skin. Arthritis Rheum 1997;40:S297.

146. Sobey CG, Dusting GJ, Stewart A, Woodman OL. Rabbitpolymorphonuclear leukocytes cause endothelium-dependentcontraction of rabbit aorta. J Vasc Med Biol 1990;2:107-115.

147. Kahaleh MB, LeRoy EC. Autoimmunity and vascularinvolvement in systemic sclerosis. Autoimmunity 1999;31:195-214.

148. Sgonc R, Gruschwitz MS, Dietrich H. Endothelial cellapoptosis is a primary pathogenetic event underlying skin lesions inavian and human scleroderma. J Clin Invest 1996;98:785-792.

149. Matucci-Cerinic M, Borsotti M, Barbieri R, Lombardi A.Angiotensin converting enzyme (ACE) in scleroderma. ClinRheumatol 1987;6:300-301.

150. Haustein UF, Scheel H, Siegemund A. Parameter derGefS§funktion bei der progressiven Sklerodermie. Hautarzt1993;44:717-722.

151. Sollberg S, Peltonen J, Uitto J, Jimenez SA. Elevatedexpression of (1 and (2 integrins, intercellular adhesion molecule I,and endothelial leukocyte adhesion molecule I in the skin ofpatients with systemic sclerosis of recent onset. Arthritis Rheum1992;35:290-298.

152. Prescott RJ, Freemont AJ, Jones CJ. Sequential dermalmicrovascular and perivascular changes in the development ofscleroderma. J Pathol 1992;166:255-263.

153. Gruschwitz MS, Hornstein OP, von den Driesch P. Correlationof soluble adhesion molecules in the peripheral blood ofscleroderma patients with their in situ expression and with diseaseactivity. Arthritis Rheum 1995;18:184-189.

154. Fritzler MJ, Hart DA. Altered regulation of fibrolysis inscleroderma and potential for thrombolytic therapy. In:Glas-Greenwalt P, editor. Fibrinolysis in disease - molecular andhemovascular aspects of fibrinolysis. Boca Raton, FL: CRC Press,1996;35:245-252.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

57 of 74 2/21/2013 2:24 AM

Page 58: Systemic Sclerosis - Scleroderma

155. Venneker GT, van den Hoogen FHJ, Boerbooms AMT.Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemicsclerosis. Labor Invest 1994;70:830-835.

156. Nishioka K, Kobayashi Y, Katayama I. Mast cell numbers indiffuse scleroderma. Arch Dermatol 1987;123:205-8.

157. Claman HN. Mast cell changes in a case of rapidly progressivescleroderma: ultrastructural analysis. J Invest Dermatol1989;92:290-5.

158. Subba Rao PV, Friedman MM, Atkins FM. Phagocytosis ofmast cell granules by cultured fibroblasts. J Immunol1983;130:341-9.

159. Gospodarowicz D, Cheng J. Heparin protects basic and acidicFGF from inactivation. J Cell Physiol 1986;128:475-84.

160. McCaffrey TA, Falcone DJ, Brayton CF. Transforming growthfactor-B activity is potentiated by heparin via dissociation of thetransforming growth factor B/(2 macroglobulin inactive complex. JCell Biol 1989;109:441-8.

161. Needleman-White B, Wigley FM, Stair RW. Interleukin-1,interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor (,and interferon-( levels in sera from patients with scleroderma.Arthritis Rheum 1992;35:67-72.

162. Yurovsky VV. The repertoire of T-cell receptors in systemicsclerosis. Crit Rev Immunol 1995;15:155-165.

163. Freundlich B, Jimenez S. Phenotype of peripheral bloodlymphocytes in patients with progressive systemic sclerosis:activated T lymphocytes and the effect of D-penicillamine therapy.Clin Exp Immunol 1987;69:375-84.

164. Gustafsson R, Totterman TH, Klareskog L. Increase inactivated T-cells and reduction in suppressor inducer T-cells insystemic sclerosis. Ann Rheum Dis 1990;49:40-5.

165. White B. Immunologic aspects of scleroderma. Curr OpinRheumatol 1995;7:541-545.

166. Kahan A, Gerfaux J, Kahan A. Increased proto-oncogeneexpression in peripheral blood lymphocytes from patients withsystemic sclerosis. Arthritis Rheum 1989;32:430-6.

167. Cox GW, Mathieson BJ, Giardina SL. Characterization of IL-2receptor expression and function on murine macrophages. JImmunol 1990;145:1719-26.

168. Girardi M, Heald P, Kelleher M. Abnormal circulatingmonocytes in progressive systemic sclerosis (Abstract). Clin Res1990;38:625A.

169. Tsuji-Yamada J, Nakazawa M, Minami M, Sasaki T. Increased

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

58 of 74 2/21/2013 2:24 AM

Page 59: Systemic Sclerosis - Scleroderma

frequency of interleukin 4 producing CD4+ and CD8+ cells inperipheral blood from patients with systemic sclerosis. J Rheumatol2001;28:1252-8.

170. Valentini G, Baroni A, Esposito K. Peripheral blood Tlymphocytes from systemic sclerosis patients show both Th1 andTh2 activation. J Clin Immunol 2001;3:210-217.

171. Jaffee BD, Claman HN. Chronic graft versus host disease as amodel for scleroderma. I. Description of the model systems. CellImmunol 1983;77:1-12.

172. Okano Y. Antinuclear antibody in systemic sclerosis(scleroderma). Rheum Dis Clin North Am 1996;22:709-735.

173. Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ, PeeblesC. Diversity of anti-nuclear antibodies in progressive systemicsclerosis. Anti-centromere antibody and its relationship to CRESTsyndrome. Arthritis Rheum 1980;23:617-625.

174. Fritzler MJ. Autoantibodies in Scleroderma. J Dermatol1993;20:257-268.

175. Bona C, Rothfield N. Autoantibodies in scleroderma andtightskin mice. Curr Opin Immunol 1994;6:931-937.

176. Fanning GC, Welsh KI, Bunn C, Du Bois R, Black CM. HLAassociations in three mutually exclusive autoantibody subgroups inUK systemic sclerosis patients. Br J Rheumatol 1998;37:201-207.

177. Harvey GR, McHugh NJ. Serologic abnormalities in systemicsclerosis. Curr Opin Rheumatol 1999;11:495-502.

178. Douvas AS, Achten M, Tan EM. Identification of a nuclearprotein (Scl-70) as a unique target of human antinuclear antibodiesin scleroderma. J Biol Chem 1979;254: 10514-10522.

179. Jimenez SA, Batuman O. Immunopathogenesis of systemicsclerosis: possible role of retroviruses. Autoimmunity1993;16:225-233.

180. Moroi Y, Peebles C, Fritzler MJ, Steigerwald J, Tan EM.Autoantibody to centromere (kinetochore) in scleroderma sera.Proc Natl Acad Sci USA 1980;77:1627-1631.

181. Steen VD, Powell DL, Medsger TA Jr. Clinical correlationsand prognosis based on serum autoantibodies in patients withsystemic sclerosis. Arthritis Rheum 1988;31:196-203.

182. Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger TAJr, Wright TM. Influence of ethnic background on clinical andserological features in patients with systemic sclerosis andanti-DNA topoisomerase I antibody. Arthritis Rheum 1999;42:465-474.

183. Okano Y, Steen VD, Medsger TA Jr. Autoantibody to U3nucleolar ribonucleoprotein (fibrillarin) in patients with systemicsclerosis. Arthritis Rheum 1992;35:95-100.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

59 of 74 2/21/2013 2:24 AM

Page 60: Systemic Sclerosis - Scleroderma

184. Oddis CV, Okano Y, Rudert WA, Trucco M, Duquesnoy RJ,Medsger TA Jr. Serum autoantibody to the nucleolar antigenPM-Scl. Clinical and immunogenetic associations. Arthritis Rheum1992;35:1211-1217.

185. Haustein UF, Pustowoit B, Krusche U. Antibodies to retrovirusproteins in scleroderma. Acta Dermato-Venereol (Stockh)1993;73:116-118.

186. Okano Y, Medsger TA Jr. Autoantibody to Thribonucleoprotein (nucleolar 7-2 RNA protein particle) in patientswith systemic sclerosis. Arthritis Rheum 1990;33:1822-1828.

187. Jacobsen S, Halberg P, Ullman S, Van Venrooij WJ, Hoier-Madsen M, Wiik A, Petersen J. Clinical features and serumantinuclear antibodies in 230 Danish patients with systemicsclerosis. Br J Rheumatol 1998;37:39-45.

188. Parodi A, Puiatti P, Rebora A. Serological profiles asprognostic clues for progressive systemic scleroderma. the Italianexperience. Dermatologica 1991;183:15-20.

189. Nishijima S, Sato S, Takehara K. Anti-Agalactosyl IgGantibodies in sera from patients with systemic sclerosis. JRheumatol 2001;28:1847-51.

190. Spencer-Green G. Test Performance in Systemic Sclerosis:Anti-Centromere and Anti-Scl-70 Antibodies. Am J Med1997;103:242-248.

191. Youinou P, Revelen R, Bordron A. Is antiendothelial cellantibody the murder weapon in systemic sclerosis? Clin ExpRheumatol 1999;17:35-36.

192. Renaudineau Y. Anti-Endothelial Cell Antibodies in SystemicSclerosis. Clin Diagn Lab Immunol 1999;6:156-160.

193. Pignone A, Scaletti C, Matucci-Cerinic M, Vazques-Abad D,Meroni PL, De-Papa N, Falcini F, Generini S, Rothfield N, CagnoniM. Anti-endothelial cell antibodies in systemic sclerosis: significantassociation with vascular involvement and alveolo-capillaryimpairment. Clin Exp Rheumatol 1998;16:527-632.

194. Genth E, Mierau R, Genetzky P, Von Muhlen CA, KaufmannS, Von Wilmowsky H, Meurer M, Krieg T, Pollman HJ, Hartl PW.Immunogenetic associations of scleroderma-related antinuclearantibodies. Arthritis Rheum 1990;33:657-665.

195. Messer G. Diagnostik bei Autoimmunerkrankungen. In:Fortschritte der praktischen Dermatologie und Venerologie / hrsg.von G. Plewig u. K. Degitz. - Berlin [u.a.]: Springer (2000) 17:94-100

196. McHugh NJ, Whyte J, Arlett C, Briggs DC, Stephene CO,Olsen NJ, Gusseva NG, Maddison PJ, Black CM, Welsh K.Anti-centromere antibodies (ACA) in systemic sclerosis patientsand their relatives: a serological and HLA study. Clin Exp Immunol

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

60 of 74 2/21/2013 2:24 AM

Page 61: Systemic Sclerosis - Scleroderma

1994;96:267-274.

197. Haustein UF, Anderegg U. Silica induced scleroderma -clinical and experimental aspects. J Rheumatol 1998;25:1917-1926.

198. Frank KH, Fussel M, Conrad K, Rihs HP, Koch R, GebhardtB, Mehlhorn J. Different distribution of HLA Class II and tumornecrosis factor alleles (TNF-308.2, TNFa2 microsatellite) inanti-topoisomerase I responders among scleroderma patients withand without exposure to quartz/metal dust. Arthritis Rheum1998;41:1306-1311.

199. LeRoy EC. The control of fibrosis in systemic sclerosis: astrategy involving extracellular matrix, cytokines, and growthfactors. J Dermatol 1994;21:1-4.

200. Postlethwaite AE. Connective tissue metabolism includingcytokine in scleroderma. Curr Opin Rheumatol 1995;7:535-540.

201. Feghali CA, Bost KL, Boulware DW. Control of IL-6expression and response in fibroblasts from patients with systemicsclerosis. Autoimmunity 1994;17:309-318.

202. Abraham D, Lupoli S, McWhirter A. Expression and functionof surface antigens on scleroderma fibroblasts. Arthritis Rheum1991;34:1164-1172.

203. Gruschwitz MS, Vieth G. Up-regulation of class II majorhistocompatibility complex and intercellular adhesion molecule 1expression on scleroderma fibroblasts and endothelial cell byinterferon-( and tumor necrosis factor ( in the early disease stage.Arthritis Rheum 1997;40:540-550.

204. KShSri VM, Sandberg M, Kalimo H. Identification offibroblasts responsible for increased collagen production inlocalized scleroderma by in situ hybridization. J Invest Dermatol1988;90:664-670.

205. Kahaleh MB, Yin T. Enhanced expression of high-affinityinterleukin-2 receptors in scleroderma: possible role for IL-6. ClinImmunol Immunopathol 1992;62:97-102.

206. Hasegawa M, Fujimoto M, Kikuchi K. Elevated serum levelsof interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemicsclerosis. J Rheumatol 1997;24:328-332.

207. Bruns M, Hofmann C, Herrmann K, Haustein UF. Serumlevels of soluble IL-2 receptor, soluble ICAM-1, TNF-alpha,interleukin-4 and interleukin-6 in scleroderma. J Eur AcadDermatol Venereol 1997;8:222-228.

208. Fagundus DM, LeRoy EC. Cytokines and systemic sclerosis.Clin Dermatol 1994;12:407-417.

209. Higley H, Persichitte K, Chu S. Immunocytochemicallocalization and serologic detection of transforming growth factor(1. Arthritis Rheum 1994;37:278-288.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

61 of 74 2/21/2013 2:24 AM

Page 62: Systemic Sclerosis - Scleroderma

210. Rossi P, Karsenty G, Roberts AB. A nuclear factor 1 bindingsite mediates the transcriptional activation of a type I collagenpromoter by TGFβ. Cell 1988;52:405-414.

211. Slack JL, Liska D, Bornstein P. Regulation of expression ofthe type I collagen genes. Am J Med Genet 1993;45:140-151.

212. Igarashi A, Nashiro K, Kikuchi K. Significant correlationbetween connective tissue growth factor gene expression and skinsclerosis in tissue sections from patients with systemic sclerosis. JInvest Dermatol 1995;105:280-284.

213. Kikuchi K, Kadono T, Furue M. Tissue inhibitor ofmetalloproteinase 1 (TIMP-1) may be an autocrine growth factor inscleroderma fibroblasts. J Invest Dermatol 1997;108:281-284.

214. Frazier K, Williams S, Kothapalli D, Klapper H, GrotendorstGR. Stimulation of fibroblast cell growth, matrix production, andgranulation tissue formation by connective tissue growth factor. JInvest Dermatol 1996;107(3):404-11.

215. Shi-wen X, Pennington D, Holmes A, Leaask A, Bradham D,Beauchamp JR, Fonseca C, du Bois RM, Martin GR, Black CM,Abraham DJ. Autocrine overexpression of CTGF maintainsfibrosis: RDA analysis of fibrosis genes in systemic sclerosis. ExpCell Res 2000;259:213-224.

216. Abraham DJ, Shiwen X, Black CM, Sa S, Xu Y, Leask A.TNFα suppresses the induction of CTGF by TGFβ in normal andSSc-FB. JBC 2000;275:15220-225.

217. Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Fujimoto M,Grotendorst GR, Takehara K. Connective tissue growth factor geneexpression in tissue sections from localized scleroderma, keloid,and other fibrotic skin disorders. J Invest Dermatol1996;106(4):729-33.

218. Feghali CA, Boulware DW, Ferriss JA. Expression of c-myc,c-myb, and c-sis in fibroblasts from affected and unaffected skin ofpatients with systemic sclerosis. Autoimmunity 1993;16:167-171.

219. Sollberg S, Mauch C, Eckes B. The fibroblast in systemicsclerosis. Clin Dermatol 1994;12:279-285.

220. Varga J, Bashey RI. Regulation of connective tissue synthesisin systemic sclerosis. Int Rev Immunol 1995;12:187-199.

221. Peltonen J, KahSri I, Uitto J. Increased expression of type VIcollagen genes in systemic sclerosis. Arthritis Rheum1990;33:1829-1835.

222. Westergren-Thorsson G, Csster L, Akesson A. Altereddermatan sulfate proteoglycan synthesis in fibroblast culturesestablished from skin of patients with systemic sclerosis. JRheumatol 1996;23:1398-1406.

223. Takeda K, Hatamochi A, Ueki H. Decreased collagenaseexpression in cultured systemic sclerosis fibroblasts. J Invest

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

62 of 74 2/21/2013 2:24 AM

Page 63: Systemic Sclerosis - Scleroderma

Dermatol 1994;103:359-363.

224. Young-Min SA, Beeton C, Laughton R. Serum TIMP-1,TIMP-2, and MMP-1 in patients with systemic sclerosis, primaryRaynaud's phenomenon, and in normal controls. Ann Rheum Dis2001;60:846-851.

225. Strehlow D, Jelaska A, Strehlow K, Korn JH. A potential rolefor protease nexin 1 overexpression in the pathogenesis ofscleroderma. J Clin Invest 1999;103:1179.

226. LeRoy EC. Increased collagen synthesis by sclerodermafibroblasts in vitro. J Clin Invest 1974;54:880-889.

227. Botstein GR, Sherer GK, LeRoy EC. Fibroblast selection inscleroderma: an alternative model of fibrosis. Arthritis Rheum1982;26:186-195.

228. Kahari V-M, Multimaki P, Vuorio E. Elevated pro-alpha-2 (I)collagen mRNA levels in cultured scleroderma fibroblasts resultsfrom an increased transcription rate of the corresponding gene.FEBS Lett 1987;215:331-4.

229. LeRoy EC, Mercurio S, Sherer GK. Replication andphenotypic expression of control and scleroderma humanfibroblasts: responses to growth factors. Proc Natl Acad Sci USA1982;79:1286-90.

230. LeRoy EC, Smith EA, Kahaleh MB. A strategy fordetermining the pathogenesis of systemic sclerosis: Is transforminggrowth factor B the answer? Arthritis Rheum 1989;32:817-25.

231. Mauch C, Kozlowska E, Eckes B, Krieg T. Altered regulationof collagen metabolism in scleroderma fibroblasts grown withinthree-dimensional collagen gels. Exp Dermatol 1992;1:185-190.

232. Eckes B, Mauch C, Hppe G, Krieg T. Down-regulation ofcollagen synthesis in fibroblasts within three-dimensional collagenlattices involves transcriptional and posttranscriptional mechanism.FEBS Lett 1993;318:129-133.

233. Kozlowska E, Sollberg S, Mauch C. Decreased expression ofalpha2 beta1 integrin in scleroderma fibroblasts. Exp Dermatol1996;5:57-63.

234. Osada K, Seishima M, Kitajima Y. Decreased integrin (2, butnormal response to TGFβ in scleroderma fibroblasts. J Dermatol Sci1995;9:169-175.

235. Jelaska A, Strehlow D, Korn JH. Fibroblast heterogeneity inphysiological conditions and fibrotic disease. Springer SeminImmunopathol 2000;21:385-395.

236. Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, TrojanowskaM. Increased expression of TGFβ receptors by sclerodermafibroblasts: evidence for contribution of autocrine TGFβ signalingto scleroderma phenotype. J Invest Dermatol 1998;110:47.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

63 of 74 2/21/2013 2:24 AM

Page 64: Systemic Sclerosis - Scleroderma

237. Tabata H, Yamakage A, Yamazaki S. Cutaneous localization ofendothelin 1 in patients with systemic sclerosis: immuno-electronmicroscopic study. Int J Dermatol 36;272.

238. Shichiri M, Sedivy JM, Marumo F, Hirata Y. Endothelin-1 is apotent survival factor for c-Myc-dependent apoptosis. MolEndocrinol 12:172.

239. Jimenez SA, Saitta B. Alterations in the regulation ofexpression of the (1 (I) collagen gene (COL1A1) in systemicsclerosis (scleroderma). Springer Semin Immunopathol2000;21:397-414.

240. Border WA, Noble NA. TGFβ in tissue fibrosis. N Engl J Med1994;331:1286-1292.

241. Lambert CA, Soudant EP, Nusgens BV, Lapiere CM.Pretranslational regulation of extracellular matrix macromoleculesand collagenase expression in fibroblasts by mechanical forces. LabInvest 1992;66:444.

242. Kirk TZ, Mark ME, Chua CC, Chua BH, Mayes MD.Myofibroblasts from scleroderma skin synthesize elevated levels ofcollagen and tissue inhibitor of metalloproteinase (TIMP-1) withtwo forms of TIMP-1. J Biol Chem 1995;270:3423.

243. Christner PJ, Peters J, Hawkins D. The tight skin 2 mouse. Ananimal model displaying cutaneous fibrosis and mononuclear cellinfiltration. Arthritis Rheum 1995;38:1791-1798.

244. Haustein UF, Ziegler V. Environmentally induced systemicsclerosis-like disorders. Int J Dermatol 1985;24:147-51.

245. Haustein UF, Ziegler V, Herrmann K. Pseudosklerodermien.Hautnah Dermatologie 1991;1:67-71.

246. Fishman SJ, Russo GG. The toxic pseudosclerodermas. Int JDermatol 1991;30:837-42.

247. Haustein UF, Herrmann K. Environmental scleroderma. ClinDermatol 1994;12:467-473.

248. Varga J, Jimenez SA, Uitto J. L-tryptophan and theeosinophilia-myalgia syndrome: Current understanding of theetiology and pathogenesis. J Invest Dermatol 1993;100:97-105.

249. Kaufman LD, Seidman RJ, Philips ME, Gruber BL. Cutaneousmanifestation of the L-tryptophan-associated eosinophilia-myalgiasyndrome: A spectrum of sclerodermatous skin disease. J Am AcadDermatol 1990;23:1063-69.

250. Phelps RG, Fleischmajer R. Clinical, pathologic, andimmunopathologic manifestations of the toxic oil syndrome. J AmAcad Dermatol 1988;18:313-24.

251. Rustin MHA, Bull HA, Ziegler V. Silica-associated systemicsclerosis is clinically, serologically indistinguishable from idiopathicsystemic sclerosis. Br J Dermatol 1990;123:725-34.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

64 of 74 2/21/2013 2:24 AM

Page 65: Systemic Sclerosis - Scleroderma

252. Haustein UF, Ziegler V, Herrmann K, Mehlhorn J, Schmidt C.Silica-induced scleroderma. J Am Acad Dermatol 1990;22:444-8.

253. Ziegler V, Haustein UF, Mehlhorn J, Mnzberger H, Rennau H.Quarzinduzierte Sklerodermie. SklerodermieShnliches Syndromoder echte Sklerodermie? Dermatol Monatsschr 1986;172:80-90.

254. Rodnan GP, Benedek TG, Medsger TA, Cammarata RJ. Theassociation of progressive systemic sclerosis (scleroderma) withcoal miners' pneumoconiosis and other forms of silicosis. AnnIntern Med 1966;66:323-34.

255. Gabay C, Kahn MF. Les sclZrodermies masculines; rle del'exposition professionelle. Schweiz med Wschr 1992;122:1746-52.

256. Varga J, Haustein UF, Creech RH, Dwyer J, Jimenez SA.Exaggerated radiation-induced fibrosis in patients with systemicsclerosis. J Am Med Assoc 1991;265:3292-3296.

257. Rahman MAA, Jayson MIV, Black CM. Five patients whodeveloped systemic sclerosis shortly after episodes of physicaltrauma. J Rheumatol 1996;23:1816-1817.

258. Shulman LE. Diffuse fasciitis with eosinophilia: a newsyndrome. Arthritis Rheum 1977;20:5205-5217.

259. Farrington ML, Haas JE, Nazar-Stewart V, Mellins ED.Eosinophilic fasciitis in children frequently progresses toscleroderma-like cutaneous fibrosis. J Rheumatol 1993;20:128-132.

260. Vancheeswaran R, Black CM, David J, Hasson N, Harper J,Atherton D. Childhood-onset scleroderma. Arthritis Rheum1996;39:1041-1049.

261. Falanga V, Medsger TA, Reichlin M, Rodnan GP. Linearscleroderma: clinical spectrum, prognosis and laboratoryabnormalities. Ann Intern Med 1986;104:849-857.

262. Varga J, Jimenez SA. Development of severe limitedscleroderma in complicated Raynaud's phenomenon after limbimmobilization: report of two cases and study of collagenbiosynthesis. Arthritis Rheum 1986;29:1160-1165.

263. Haustein UF. Systemic sclerosis following physical trauma.Acta Derm Venereol 2000;80:1.

264. Medsger TA Jr, Silman AJ, Steen VD. A disease severity scalefor systemic sclerosis: development and testing. J Rheumatol1999;26:2159-2167.

265. Della Rossa A, Valentini G, Bombardieri S, Bencivelli W,Silman AJ. European multicentre study to define disease activitycriteria for systemic sclerosis. I. Clinical and epidemiologicalfeatures of 290 patients from 19 centres. Ann Rheum Dis2001;60:585-591.

266. Valentini G, Della Rossa A, Bombardieri S, Bencivelli W,

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

65 of 74 2/21/2013 2:24 AM

Page 66: Systemic Sclerosis - Scleroderma

Silman AJ. European multicentre study to define disease activitycriteria for systemic sclerosis. II. Identification of disease activityvariables and development of preliminary activity indexes. AnnRheum Dis 2001;60:592-598.

267. Goodfield MJD, Rowell NR. Hand warming as a treatment forRaynaud's phenomenon in systemic sclerosis. Br J Dermatol1988;119:643-646.

268. Meffert H, Buchholtz I, Brenke A. Milde Infrarot-A-Hyperthermie zur Behandlung der systemischen Sklerodermie.Dermatol Monatsschr 1990;176:683-686.

269. Haustein UF, Weber B, Seikowski K. Substanz P undvasoaktives intestinales Peptid bei Patienten mit progressiverSklerodermie. Hautarzt 1995;46:102-106.

270. Seikowski K, Weber B, Haustein UF. Effect of hypnosis andautogenic training on acral circulation and coping with the illness inpatients with progressive scleroderma. Hautarzt 1995;46:94-101.

271. Flavahan NA, Flavahan S, Liu Q. Increased alpha-2adrenergic constriction of isolated arterioles in diffuse scleroderma.Arthritis Rheum 2000;43(9):1886-1890.

272. Wigley FM, Wise RA, Seibold Jr. Intravenous iloprost infusionin patients with Raynaud's phenomenon secondary to systemicsclerosis. A multicenter, placebo-controlled, double-blind study.Ann Intern Med 1994;120:199-206.

273. Pope J, Fenlon D, Thompson A. Iloprost and cicaprost forRaynaud's phenomenon in progressive systemic sclerosis. CochraneDatabase Syst Rev 2000 CD000953.

274. Dowd PM, Martin MRF, Cooke ED, Bowcock SA, Jones R,Dieppe PA, Kirby JDT. Treatment of Raynaud's phenomenon byintravenous infusion of prostacyclin (PGI2). Br J Dermatol1982;106:81-89.

275. Rademaker M, Cooke ED, Almond NE, Beacham JA, SmithRE, Mant TGK, Kirby JD. Comparison of intravenous infusionsiloprost and oral nifedipine in treatment of Raynaud's phenomenonin patients with systemic sclerosis: a double blind randomised study.Br Med J 1989;298:561-564.

276. Mittag M, Beckheinrich P, Haustein UF. Systemic sclerosis-related Raynaud's phenomenon: effects of iloprost infusion therapyon serum cytokine, growth factor and soluble adhesion moleculelevels. Acta Derm Venereol 2001;81:294-297.

277. Higenbottam T, Butt AY, McMohan A, Westerbeck R,Sharples L. Long term intravenous prostaglandin (epoprostenol oriloprost) for treatment of severe pulmonary hypertension. Heart1990;80:151-155.

278. Badesch DB, Tapson VF, McGoon MD. Continuousintravenous epoprostenol for pulmonary hypertension due to thescleroderma spectrum of disease. A randomized, controlled trial.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

66 of 74 2/21/2013 2:24 AM

Page 67: Systemic Sclerosis - Scleroderma

Ann Intern Med 2000;132:425-434.

279. Launay D, Hachulla E, Hatron PY. Aerosolized iloprost inCREST syndrome related pulmonary hypertension. J Rheumatol2001;28:2252-6.

280. Wigley FM, Korn JH, Csuka ME. Oral iloprost in patients withRaynaud phenomenon secondary to systemic sclerosis: amulticenter, placebo-controlled, double-blind study. ArthritisRheum 1998;41:670-677.

281. Vayssairat M. Preventive effect of an oral prostacyclinanalogue, beraprost sodium, on digital necrosis in systemicsclerosis, French Microcirculation Society Multicenter Group forthe Study of Vascular Acrosyndromes. J Rheumatol1999;26:2173-2178.

282. Cordioli E, Virgilio S, Ghirardi R. Effects of long-term iloprosttherapy on Raynaud's phenomenon in progressive systemicsclerosis. Minerva Med 1992;83:739-744.

283. Stratton R, Shiwen X, Martini G. Inhibition of connectivegrowth factor (CTGF) synthesis in normal and sclerodermafibroblasts treated with TGFβ and in patients fluids with iloprost.Arthritis Rheum 2000;43(9):Abstract 1156.

284. Wigley FM, Wise RA, Malamet R. Nicardipine in thetreatment of Raynaud's phenomenon. Arthritis Rheum1987;30:281-286.

285. Rodeheffer RJ, Rommer JA, Wigly F. Controlled double-blindtrial of nifedipine in the treatment of Raynaud's phenomenon. NEngl J Med 1980;308:880-883.

286. Steen VD, Constantino JP, Shapiro AP, Medsger TA Jr.Outcome of renal crisis in systemic sclerosis: relation to availabilityof angiotensin converting enzyme (ACE) inhibitors. Ann InternMed 1990;113:352-357.

287. Lopez-Ovejero JA, Saal SD, D'Angelo WA. Reversal ofvascular and renal crisis of scleroderma by oral angiotensin-converting enzyme blockade. N Engl Med 1979;300:1417-1419.

288. Surwit RS, Gilgor RS, Allen LM, Duvic M. A double-blindstudy of prazosin in the treatment of Raynaud's phenomenon inscleroderma. Arch Dermatol 1984;120:329-331.

289. Goodfield MJ, Rowell NR. Treatment of peripheral gangrenedue to systemic sclerosis with intravenous pentoxifylline. Clin ExpDermatol 1989;14:161-162.

290. Berman B, Duncan MR. Pentoxifylline inhibits theproliferation of human fibroblasts derived from keloid, sclerodermaand morphea skin and their production of collagen,glycosaminoglycans and fibronectin. Br J Dermatol1990;123:339-346.

291. Holti G. The effect of intermittent low molecular dextran

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

67 of 74 2/21/2013 2:24 AM

Page 68: Systemic Sclerosis - Scleroderma

infusions upon the digital circulation in systemic sclerosis. Br JDermatol 1965;77:650-658.

292. Lotti T, Matucci Cerinic M. Cutaneous fibrinolytic activity inscleroderma. Clin Exp Rheumatol 1985;3:249-253.

293. Jayson MIV, Holland CD, Keegan A, Illingworth K, Taylor L.A controlled study of stanozolol in primary Raynaud's phenomenonand systemic sclerosis. Ann Rheum Dis 1991;50:41-47.

294. Fritzler MJ, Hart DA. Prolonged improvement of Raynaud'sphenomenon and scleroderma after recombinant tissue plasminogentherapy. Arthritis Rheum 1990;33:274-276.

295. Ghersetich I, Matucci-Cerinic M, Lotti T. A pathogeneticapproach to the management of systemic sclerosis (scleroderma).Int J Dermatol 1990;29:616-622.

296. Hornstein OP, Steffan C, Diepgen TL, Hiller D, Albrecht HP ,Gruschwitz MS. Therapie der progressiven systemischenSklerodermie mit Calcitonin: ein 10jShriger Erfahrungsbericht. ZHautkr 1993;68:437-442.

297. Kawaguchi Y, Suzuki K, Hara M. Increased endothelin-1production I fibroblasts derived from patients with systemicsclerosis. Ann Rheum Dis 1994;53:506-510.

298. Williamson DJ, Wallman LL, Jones R. Hemodynamic effectsof Bosentan, an endothelin receptor antagonist, in patients withpulmonary hypertension. Circulation 2000;102:411-418.

299. Yamamoto T, Katayama I, Nishioka K. Nitric oxide productionand inducible nitric oxide synthase expression in systemic sclerosis.J Rheumatol 1998;25:314-317.

300. Freeman RR, Girgis R, Mayes MD. Acute effect of nitricoxide on Raynaud's phenomenon in scleroderma. Lancet1999;354:739.

301. Olschewski H, Ghofrani HA, Walmrathh D. Inhaledprostacyclin and iloprost in severe pulmonary hypertensionsecondary to lung fibrosis. Am J Respir Crit Care Med 1999;160:600-607.

302. Kawano H, Do YS, Kawano Y. Angiotensin II has multipleprofibrotic effects in human cardiac fibroblasts. Circulation2000;101:1130-1137.

303. Wolf G, Kalluri R, Ziyadeh FN. Angiotensin II induces alpha 3(IV) collagen expression in cultured murine proximal tubular cells.Proc Assoc Am Physicians 1999;111:357-364.

304. Wigley FM, Sule SD. Novel therapy in the treatment ofscleroderma. Exp Opin Invest Drugs 2001;10(1):31-48.

305. Dziadzio M, Denton CP, Smith R. Losartan therapy forRaynaud's phenomenon and scleroderma: clinical and biochemicalfindings in a fifteen-week, randomized, parallel-group, controlled

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

68 of 74 2/21/2013 2:24 AM

Page 69: Systemic Sclerosis - Scleroderma

trial. Arthritis Rheum 1999;42:2646-2655.

306. Stein CM, Tanner SB, Awad JA. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma.Arthritis Rheum 1996;39:1146-1150.

307. Casciola-Rosen L, Wigley F, Rosen A. Sclerodermaautoantigens are uniquely fragmented by metal-catalyzed oxidationreactions: implications for pathogenesis. J Exp Med1997;185:71-80.

308. Herrick AL, Rieley F, Schofield D. Micronutrient antioxidantstatus in patients with primary Raynaud's phenomenon andsystemic sclerosis. J Rheumatol 1994;21:1477-1483.

309. Bashir S, Harris G, Denman MA. Oxidative DNA damage andcellular sensitivity to oxidative stress in human autoimmunediseases. Ann Rheum Dis 1993;52(9):659-666.

310. Yamamoto T, Takagawa S, Katayama I. Effect of superoxidedismutase on bleomycin-induced dermal sclerosis: implications forthe treatment of systemic sclerosis. J Invest Dermatol1999;113:843-847.

311. Denton CP, Bunce TD, Darado MB. Probucol improvessymptoms and reduces lipoprotein oxidation susceptibility inpatients with Raynaud's phenomenon. Rheumatology1999;38:309-315.

312. Furst DE, Clements PJ, Harris R. Measurement of clinicalchanges in progressive systemic sclerosis: a one year double-blindplacebo-controlled trial of N-acetylcysteine. Ann Rheum Dis1979;38:356-361.

313. Sambo P, Amico D, Giacomelli R, Matucci-Cerinic M, SalsanoF. Intravenous N-Acetylcysteine for treatment of Raynaud'sphenomenon secondary to systemic sclerosis: a pilot study. JRheumatol 2001;28:2257-62.

314. Steen VD, Medsger TA Jr. Case-control study ofcorticosteroids and other drugs that either precipitate or protectfrom the development of scleroderma renal crisis. Arthritis Rheum1998;41:1613-1619.

315. Le CH, Morales A, Trentham DE. Minocycline in early diffusescleroderma. Lancet 1998;352(9142):1755-1756.

316. Anderegg U, Prieb J, Saalbach, Hildebrandt G, Haustein UF.Minocycline does not alter collagen type I metabolism of dermalfibroblasts in culture. Arch Dermatol Res (in press).

317. Akesson A, Scheja A, Lundin A, Wollheim FA. Improvedpulmonary function in systemic sclerosis after treatment withcyclophosphamide. Arthritis Rheum 1994;37:729-735.

318. Baughman RP, Lower EE. Use of intermittent, intravenousCyclophosphamide for idiopathic pulmonary fibrosis. Chest1992;102:1090-1094.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

69 of 74 2/21/2013 2:24 AM

Page 70: Systemic Sclerosis - Scleroderma

319. Haustein UF, Mittag M. Zur Behandlung der systemischenSklerodermie. Akt Dermatol 2000;26:1-7.

320. Hoogen FHJ, Boerbooms AMT, Swaak AJG, Rasker JJ, LierHJJ, Putte LBA. Comparison of Methotrexate with Placebo in theTreatment of Systemic Sclerosis: A 24 Week RandomizedDouble-Blind Trial, Followed by a 24 Week Observational Trial.Brit J Rheum 1996;35:364-372.

321. Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, DreisDF, Hutchinson J, Pardee NE, Winterbauer RH. Azathioprinecombined with Prednisone in the treatment of idiopathic pulmonaryfibrosis: A prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991;144:291-296.

322. Clements PJ, Lachenbruch PA, Sterz M, Danovitch G,Hawkins R, Ippoliti A, Paulus HE. Cyclosporine in systemicsclerosis. Arthritis Rheum 1993;36:75-83.

323. Wsrle B, Hein R, Krieg T, Meurer M. Ciclosporin in localizedand systemic scleroderma - a clinical study. Dermatologica1990;181:215-220.

324. Mascaro G, Gardario G, Bordin G, Tarditi M, Ferraris G.Plasma exchange in the treatment of nonadvanced stages ofprogressive systemic sclerosis. J Clin Apheresis 1987;3:219-225.

325. McCune MA, Winkelmann RK, Osmundson PJ. A controlledstudy of plasmapheresis in scleroderma. J Clin Apheresis1983;1:206-214.

326. Guillevin L, Amoura Z, Merviel P, Pourrat J, Bussel A, SobelA, Khuy T, Houssin A, Alcalay D, Stroumza P, Sanderson F, LevyG, Frey G, Ang KS. Treatment of progressive systemic sclerosis byplasma exchange: long-term results in 40 patients. Int J ArtifOrgans 1990;13:125-128.

327. Goronzy JJ, Weyand CM. Long-term immunomodulatoryeffects of T-lymphocyte-depletion in patients with systemicsclerosis. Arthritis Rheum 1990;33:511-519.

328. Waldmann TA. The structure, function and expression of theinterleukin-2 receptor on normal and malignant lymphocytes.Science 1986;232:727-732.

329. Prinz J, Braun-Falco O, Meurer M, Daddona P, Reiter C,Rieber P, Riethmller G. Chimaeric CD4 monoclonal antibody intreatment of generalised pustular psoriasis. Lancet1991;338:320-321.

330. Reiter C, Kakavand B, Rieber EP, Schattenkirchner M,Riethmller G, Krger K. Treatment of rheumatoid arthritis withmonoclonal CD4 antibody M-T151. Arthritis Rheum1991;34:525-536.

331. Rook AH, Freundlich B, Nahass GT, Washko R, Macelis B,Skolnicki M, Bromley P, Witmer WK, Jegasothy BV. Treatment of

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

70 of 74 2/21/2013 2:24 AM

Page 71: Systemic Sclerosis - Scleroderma

autoimmune disease with extracorporal photochemotherapy:progressive systemic sclerosis. Yale J Biol Med 1989;62:639-645.

332. Enomoto DN, Mekkes JR, Bossuyt PM. Treatment of patientswith systemic sclerosis with extracorporeal photochemotherapy(photopheresis). J Am Acad Dermatol 1999;41:915-922.

333. Tyndall A. Haematopoietic stem cell transplantation (HSCT)for severe autoimmune disease- an update of results and plannedtrials. Arthritis Rheum 2000;43(9):1999. Abstract.

334. Clements PJ, Furst DE. Choosing appropriate patients withsystemic sclerosis for treatment by autologous stem celltransplantation. J Rheumatol 1997;48:85-88.

335. McKown KM, Carbone LD, Bustillo J. Induction of immunetolerance to human Type I collagen in patients with systemicsclerosis by oral administration of bovine Type I collagen. ArthritisRheum 2000;43(9):1054-1061.

336. Vogelsang GB, Famer ER, Hess AD. Thalidomide for thetreatment of chronic graft-versus-host disease. N Engl J Med1992;326:1055-1058.

337. Oliver SJ, Moreir A, Kaplan G. Reduced fibrosis andnormalization of skin structure in scleroderma patients treated withthalidomide. Arthritis Rheum 1999;42(9):S187.

338. Rosenbloom J, Saitta B, Gaidarova S. Inhibition of Type Icollagen gene expression in normal and systemic sclerosisfibroblasts by a specific inhibitor of geranylgeranyl transferase I.Arthritis Rheum 2000;43:1624-1632

339. Jimenez SA, Saitta B, Sandorfi N. Protein kinase C regulationof Type I collagen gene expression in normal and systemic sclerosis(scleroderma) fibroblasts. Arthritis Rheum 2000;43(9):611.Abstract.

340. Kagan HM. Intra and extracellular enzymes of collagenbiosynthesis as biological and chemical targets in the control offibrosis. Acta Trop 2000;77:147-152.

341. Nimni ME. Penicillamine and collagen metabolism. Scand JRheumatol 1979;28:71-78.

342. Kreysel HW. D-Penicillamin. Stuttgart: Schattauer, 1977.

343. Steen VD, Blair S, Medsger TA Jr. The toxicity ofD-penicillamine in systemic sclerosis. Ann Intern Med1986;104:699-705.

344. Asboe-Hansen G. Neue Entwicklungen der Pathologie,Pathophysiologie und Therapie der systemischen Sklerodermie.Hautarzt 1980;31:584-587.

345. Steen VD, Medsger TA Jr, Rodnan GP. D-Penicillaminetherapy in progressive systemic sclerosis (scleroderma). Aretrospective analysis. Ann Intern Med 1982;97:652-659.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

71 of 74 2/21/2013 2:24 AM

Page 72: Systemic Sclerosis - Scleroderma

346. Clements PJ, Furst DE, Wong WK, Mayes M, White B,Wigley F, Weisman MH, Barr W, Moreland LW, Medsger TA Jr,Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J,Weiner S, Andrews B, Abeles M, Seibold JR. High-dose versuslow-dose D-penicillamine in early diffuse systemic sclerosis:analysis of two-year, double-blind, randomized, controlled clinicaltrial. Arthritis Rheum 1999;42:1194-1203.

347. Furst DE, Clements PJ. D-penicillamine is not an effectivetreatment in systemic sclerosis. Scand J Rheumatol2001;30:189-91.

348. Medsger TA Jr, Lucas M, Wildy KS, Baker C. D-penicillaminein systemic sclerosis? Yes! Scand J Rheumatol 2001;30:192-4.

349. Anderegg U, Wilczek A, Haustein UF. Penicillin G does notalter collagen type I metabolism of dermal fibroblasts in culture.Dermatology 2000;200:111-114.

350. Ogawa T, Ogawa K, Ogura T. Successful treatment withbucillamine for intractable interstitial lung disease in systemicsclerosis. Arthritis Rheum 2000;43(9) Abstract 1505.

351. Hofer A, Soyer HP. Oral psoralen-UV-A for systemicscleroderma. Arch Dermatol 1999;135:603-604.

352. Kerscher M, Volkenandt M, Gruss C, Reuther T, KobyletzkiG, Freitag M, Dirschka T, Altmeyer P. Low-dose UVAphototherapy for treatment of localized scleroderma. J Am AcadDermatol 1998;38:21-26.

353. Kawakami T, Ihn H, Xu W. Increased expression of TGF (receptors by scleroderma fibroblasts: evidence for contribution ofautocrine TGF b signaling to scleroderma phenotype. J InvestDermatol 1998;110:47-51.

354. McCormick LL, Zhang Y, Tootell E. Anti-TGF ( treatmentprevents skin and lung fibrosis in murine sclerodermatous graft vs.host disease: a model for human scleroderma. J Immunol1999;163:5693-5699.

355. Breuer G, Jelaska A, Ledbetter S. Inhibition of TGFβstimulated collagen synthesis and myofibroblast induction by amonoclonal antibody to TGFβ. Arthritis Rheum 2000;43(9):1957.Abstract.

356. Ellman M, MacDonald P, Hayes FA. Etanercept as treatmentfor diffuse scleroderma: A pilot study. Arthritis Rheum2000;43(9):1955. Abstract.

357. Piguet PF, Vesin C, Grau GE. Interleukin-1 receptor antagonist(IL-1ra) prevents or cures pulmonary fibrosis elicited in mice bybleomycin or silica. Cytokine 1993;5:57-61.

358. Varga J. Recombinant cytokine treatment for scleroderma.Can the antifibrotic potential of interferon-( be realized clinically?Arch Dermatol 1997;133:637-642.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

72 of 74 2/21/2013 2:24 AM

Page 73: Systemic Sclerosis - Scleroderma

359. Vlachoyiannopoulos PG, Tsifetaki N, Dimitriou I. Safety andefficacy of recombinant ( interferon in the treatment of systemicsclerosis. Ann Rheum Dis 1996;55:761-768.

360. Kahan A, Amor B, Menkes CJ. Recombinant interferon-( inthe treatment of systemic sclerosis. Am J Med 1989;87:273-277.

361. Hein R, Behr J, Hundgren M. Treatment of systemic sclerosiswith (-interferon. Br J Dermatol 1992;126:496-501.

362. Freundlich B, Jimenez SA, Steen VD. Treatment of systemicsclerosis with recombinant interferon-(. A Phase I/II clinical trial.Arthritis Rheum 1992;35:1134-1142.

363. Hunzelmann N, Anders S, Fierlbeck G. Systemic scleroderma.Multicenter trial of 1 year of treatment with recombinantinterferon-(. Arch Dermatol 1997;133:609-613.

364. Grassegger A, Schuler G, Hessenberger G. Interferon-( in thetreatment of systemic sclerosis: a randomized controlledmulticenter trial. Br J Dermatol 1998;139:639-648.

365. Unemori EN, Amento EP. Relaxin modulates synthesis andsecretion of procollagenase and collagen by human dermalfibroblasts. J Biol Chem 1990;265:10681-10685.

366. Danielson LA, Sherwood DD, Conrad KP. Relaxin is a potentrenal vasodilator in conscious rats. J Clin Invest 1999;103:525-533.

367. Seibold Jr, Clements PJ, Furst DE. Safety andpharmacokinetics of recombinant human relaxin in systemicsclerosis. J Rheumatol 1998;25:302-307.

368. Seibold Jr, Korn JH, Simms R. Recombinant human relaxin inthe treatment of scleroderma. A randomized, double-blind,placebo-controlled trial. Ann Intern Med 2000;132:871-879.

369. Granot I, Halevy O, Hurwitz S. Halofuginone: an inhibitor ofcollagen Type I synthesis. Biochim Biophys Acta1993;1156:107-112.

370. Levi-Schaffer F, Nagler A, Slavin S. Inhibition of collagensynthesis and changes in skin morphology in murine graft vs. hostdisease and tight skin mice: effect of halofuginone. J InvestDermatol 1996;106:84-88.

371. Halevy O, Nagler A, Levi-Schaffer F. Inhibition of collagenType I synthesis by skin fibroblasts of graft vs. host disease andscleroderma patients: effect of halofuginone. Biochem Pharmacol1996;52:1057-1063.

372. Nagler A, Pines M. Topical treatment of cutaneous chronicgraft-versus-host disease with halofuginone: A novel inhibitor ofcollagen Type I synthesis. Transplantation 1999;68:1806-1809.

373. Maurice PDL, Bunker CB, Dowd PM. Isotretinoin in thetreatment of systemic sclerosis. Br J Dermatol 1989;121:367-374.

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

73 of 74 2/21/2013 2:24 AM

Page 74: Systemic Sclerosis - Scleroderma

374. Paye M, Read D, Nusgens B, Lapiere CM. Factor XIII inscleroderma: in vitro studies. Br J Dermatol 1990;122:371-382.

375. Zarafonetis CJD. Retrospective studies in scleroderma. Effectof potassium paraaminobenzoate on survival. J Clin Epidemiol1988;41:193-205.

376. Oliver GF, Winkelmann RK. The current treatment ofscleroderma. Drugs 1989;37:87-96.

377. Traub YM, Shapiro AP, Rodnan GP, Medsger TA Jr,McDonald RH Jr. Hypertension and renal failure (sclerodermarenal crisis) in progressive systemic sclerosis: review of a 25-yearexperience with 68 cases. Medicine (Baltimore) 1983;62:335-352.

378. Milburn PB, Singer JZ, Milburn MA. Treatment ofscleroderma skin ulcers with a hydrocolloid membrane. J Am AcadDermatol 1989;21:200-204.

379. Fuchs D, Fruchter L, Fishel B, Holtzmann M, Yaron M.Colchicine suppression of local inflammation due to calcinosis indermatomyositis and progressive systemic sclerosis. ClinRheumatol 1986;5:527-530.

© 2002 Dermatology Online Journal

Systemic sclerosis - scleroderma http://dermatology.cdlib.org/DOJvol8num1/reviews/scleroderma/haustein...

74 of 74 2/21/2013 2:24 AM