Systemic scleroderma

IOURNAL o f t h e

AmeRICaN A C a D e m Y OF

AAD 1938

DerMaTOLOGY

0~

VOLUME 18

NUMBER 3

MARCH 1988 I

Continuing

medical education

Systemic scleroderma Clinical and pathophysiologic aspects Thomas Krieg, M.D., and Michael Meurer, M.D.

Miinchen, Federal Republic of Germany Systemic scleroderma is a generalized disease of connective tissue involving mainly the skin, the gastrointestinal tract, the lungs, the heart, and the kidneys. It can be present in different forms, of which acroscleroderma, with limited cutaneous and extracutaneous involvement, and diffuse scleroderma within a more rapid progression are most characteristic. Circulating antibodies against antinucleolar antigens are present in most patients with systemic scleroderma. They are helpful for establishing a classification and for determining the prognosis of the disease; their involvement in the pathogenesis, however, is still unclear. Alterations of the blood vessels and induction of fibroblasts by potent mediators are thought to play an important role in the early phase of scleroderrna. Therefore early diagnosis is required, which then can initiate vasoactive therapy. In patients with systemic scleroderma, who also suffer from additional myositis, interstitial lung diseases, or arthritis, anti-inflammatory treatment with prednisolone and azathioprine is suggested. Development and progression of fibrosis cannot yet be influenced sufficiently. Only D-penicillamine affecting cross-linking of collagen has been widely used in scleroderma and has some beneficial effect. (J AM ACADDERMATOL 1988;18:457-81.)

Systemic scleroderma is a generalized disease that involves the skin and other connective tissuecontaining organs. The first detailed description

~

The CME articles are made possible through an educational grant from Syntex Laboratories, Inc. From the Dermatology Clinic and Polyclinic, Ludwig-Maximilian University of Miinchen. Work of Thomas Krieg, M.D., was partially supported by a grant from the Deutsche Forschungsgemeinschaft (Kr 558/5-1). Reprint requests to: Dr. Thcmas Krieg, Dermatologische Klinik und Poliklinik der LMU Mtinchen, Frauenlobstr. 9-11, 8000 Mfinchen 2, FRG.

of a scleroderma-like disease came from Curzio, x in Naples, Italy, who reported tension and hardness of skin in a young woman. The name scleroderma was introduced much later, 2 and only in this century has the intensive involvement of other organs been realized. This has been reviewed extensively in the last decade. 37 Recently systemic scleroderma has attracted much attention from several disciplines and now serves as a model for the study of pathophysiologic events leading to fibrosis and sclerosis. In addition, characterization of highly specific circulating antibodies, which are often present in scleroderma

457

458

Journal of the American Academy of Dermatology

Krieg and Meurer

., Scleroderma [

..~'~" ,

,.

II

Acroscleroderma

s

ma

ascendingsclerosis

Diffuse scleroderma

I

Fig. 1. The clinical spectrum of scleroderma.

Table I. Differential diagnosis of

Table II. Classification of

systemic scleroderma

systemic scleroderma

Morphea Seleroedema generalized Buschke Mixed connective tissue disease Shulman syndrome Shoulder-hand syndrome Pseudoscleroderma, e.g., porphyria cutanea tarda, polyvinyl chloride disease, toxic oil syndrome, scleromyxedema, and Wemer's syndrome

patients, had a tremendous impact on the knowledge of basic cellular functions and may lead to a new concept of the understanding of connective tissue diseases. From a clinical point of view it became clear that scleroderma represents a spectrum of different disease entities ranging from localized scleroderma to overlap syndromes such as the mixed connective tissue disease (Fig. 1). This review will, however, focus on systemic scleroderma and will update information concerning prognosis, classification, and the understanding of pathophysiologic processes that have accumulated during the last decade.

Epidemiology and genetic background Epidemiologic studies of systemic scleroderma have turned out to be helpful for the understanding of the underlying defects and have indicated that a certain genetic background is required for the development of this disease. Compared with other connective tissue diseases, systemic scleroderma is relatively rare. However, the true incidence is probably underestimated since early symptoms are

A. Criteria for scleroderma

Major criteria: proximal scleroAmerican derma Rheumatism Association Minor criteria: sclerodactyly, classifipulmonary fibrosis, and digital pitting scars cation ~8 B. Classification Jablonska~ Acroscleroderma, diffuse scleroderma, Thibi~rge-Weissenbach syndrome, CREST syndrome, visceral scleroderma without cutaneous involvement Winkelmann 2~ Vascular scleroderma and inflammatory scleroderma Barnett23 Three types (I, II, III) according to early-stage skin involvement (see Fig. 2) Rodnan et al t9 CREST syndrome ( = acroscleroderma), diffuse scleroderma, and overlap syndrome Sclerosis sine scleroderma, Giordano sclerodactyly, acrosclerosis et al2~ strictu sensu, intermediate syndrome, and acute diffuse scleroderma

often overlooked. The average annual mortality in the United States was reported to be between 2.1 and 2.8 per million population. 8,9 The overall female-to-male (F:M) ratio is 3:1 and seems to be significantly higher in nonwhite patients) The average onset of systemic scleroderma in patients from the United States occurs between 40 and 50 years; in women the average entry age lies in the childbearing years between 30 and 39. ~~ Several

Volume 18 Number 3 March 1988

Systemic scleroderma 459

TYPE I

TYPE ]I

TYPE TIT

Fig. 2. Classification of systemic scleroderma into three types according to skin involvement. Type I and mild type II represent acroscleroderma (Iirnited cutaneous scleroderma), whereas patients with type III are often classified as having diffuse scleroderma. (Modified from Arbeitsgruppe Sklerodermie der Arbeitsgemeinschaft Dermatologische Forschung (ADF). Klinik der progressiven systemischen Skleroderrnie (PSS). Hautarzt 1986;37: 320-4; Barnett AJ. Scleroderma. Progressive systemic sclerosis. Springfield: Charles C Thomas, 1974.) large survival studies have indicated a 5-year survival rate between 34% and 73%. 8 Men and older patients with systemic scleroderma were reported t o have a shorter survival rate and thus a poorer prognosis than women and younger patients. ~~ Only 10% of the patients develop the disease before the age of 20. 7 Well-documented reports of familial systemic scleroderma, including cases where the disease occurred in siblings, parent and child, and seconddegree relatives, are rare. 8 These case reports have, however, been the basis of several studies concerning the association of systemic scleroderma with human lymphocyte (HLA) antigens. Some of these indicated an association of diffuse scleroderma with A~, Bs, DR5, and DR3 antigens and of the calcinosis, Raynaud's disease, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome (see below) with the presence of anticentromere antibodies with DR5 and DR1 antigens. H-~4There have been, however, considerable variations in reports from different centers probably because of geographic/ethnic characteristics and the small numbers of patients. T M Chromosomal instability has also been suggested

as playing a role in scleroderma, ~7but the relation of these findings to the disease process is still unclear. Recently a strong genetic background was found for polyvinyl chloride workers developing a scleroderma-like disease.* From this information it seems likely that, as in other collagen diseases, a certain genotype may have a predisposition for the development of systemic scleroderma; further studies will be required to determine whether the occurrence of distinct antibodies in different types of scleroderma might reflect such a specific genetic background involving the immune response to a certain pathogenetic event. Classification of scleroderma The American Rheumatism Association has established criteria for the diagnosis of scleroderma ~8 (Table I). However, systemic scleroderma is a very heterogenous disease with a large variation of clinical manifestations in individual patients. It is therefore not surprising that many attempts have been made to establish a classification (Ta*Black C. Personal communication.

460

Krieg and Meurer

Journal of tile American Academy of Dermatology

]Fig. 3. Clinical symptoms of systemic scleroderma, with involvement of the face with radial furrowing around the mouth, beaked nose, disappearing of wrinkles, and hyperpigmentation. Fig. 4. Clinical symptoms of systemic scleroderma showing sclerosis of the hands with contractures of joints. Fig. 5. Clinical symptoms of systemic scleroderma showing ulcers on fingertips. Fig. 6. Sclerosis of the frenulum in a patient with systemic scleroderma.

ble II). These classifications distinguish either vascular and inflammatory forms of systemic scleroderma ~9,2~ or different degrees of skin involvement~-:~ or distinct clinical manifestations such as the CREST syndrome. 25,26 Most authors differentiate between acroscleroderma and diffuse scleroderma. Acroscleroderma is characterized mainly by vascular alterations and by sclerosis of the skin, which is usually limited

to acral areas, whereas diffuse scleroderma has also vascular alterations and can involve both the trunk and the extremities and shows a more rapid progression with pronounced inflammatory symptoms. ~9,2oHowever, since acroscleroderma can be limited to the digits for many years or can also rapidly spread over the trunk, another classification was proposed. 2z It combines the American Rheumatism Association criteria with the classi-

Volume 18 Number 3 March 1988

fication by Barnett23 and differentiates three types of systemic scleroderma according to the extent of skin involvement (Fig. 2). Type I: Involvement of the fingers and hands to the wrist Type II: Proximal ascending sclerosis including the forearm q-'ype III: Beginning of development of sclerosis at the trunk Recently several groups agreed on a new concept distinguishing diffuse cutaneous systemic sclerosis from limited cutaneous systemic sclerosis and the overlap syndromes,* in which limited cutaneous systemic sclerosis covers the acroscleroderma (types I and II) and the diffuse cutaneous systemic sclerosis includes diffuse (truncal) scleroderma (types II and III). These classifications can be helpful for the distinction of large patient groups but they are preliminary; ultimately a precise knowledge of the pathogenetic background of systemic scleroderma is required to recognize distinct disease entities. Clinical symptoms Systemic scleroderma can involve all connective tissue-containing organs; however, some represent the main target of the disease. These include the skin, the gastrointestinal tract, the heart, the lungs, and the kidneys.

Cutaneous manifestations Cutaneous manifestations, often accompanied or preceded by Raynaud's syndrome, are usually early symptoms and therefore are helpful in establishing diagnosis and initiating treatment of systemic scleroderma. However, they have to be differentiated from similar symptoms that occur in other diseases (Table I). Cutaneous involvement can be divided into an early edematous phase, a sclerotic phase, and a late atrophic phase. In the initial stages of the disease the skin appears to be thickened, edematous, and often shows a slight erythema indicating inflammation. In almost all cases the alterations start at acral areas and first involve the fingers and the hands, later the face, and often the frenulum of the tongue *LeRoy EC. Personal communication.

Systemic scleroderma 461

(Figs. 3-6). The fingers and hands appear swollen, usually with nonpitting edema, tumid, and cannot be fully extended (Figs. 4 and 8). Gradually sclerosis develops, with hardening of the skin followed by ulcerations, telangiectasias, and atrophy. Hair loss and anhidrosis in affected areas are common signs reflecting the degeneration of appendages due to the surrounding fibrosis. Slow healing and painful ulcers usually develop around the fingertips (Fig. 5), or in areas with underlyirig calcinosis, and over the knuckles. Secondary infections in these areas may sometimes lead to gangrene, which, together with osseous resorption, can cause severe articular deformities of the hands and even complete dissolution of terminal phalanges. Involvement of the feet can be very similar but is usually less frequent. Sclerosis of the face results in the typical appearance of beaked nose, radial furrowing around the lips, and constricted opening of the mouth (Figs. 3 and 6). Frequently telangiectasia develops on the face and trunk and may, in some patients, become the most prominent feature (Fig. 7). Periungual telangiectasia reflecting dilated nail fold capillaries may also be present (Fig. 8) and has been used for the study of vascular abnormalities in scleroderma. 27 A subgroup of patients presenting widespread telangiectasia associated with extensive calcinosis (Figs. 7-10), involvement of the esophagus, and Raynaud's phenomenon fulfills the clinical criteria of the CREST syndrome, 25 which has been described previously as Thibi~rge-Weissenbach syndrome. 28 Along with the sclerotic changes of the skin, marked cutaneous pigmentations can develop, either with mottled or diffuse hyperpigmentation resembling Addison's disease or with focal hypopigmentation probably due to postinflammatory changes. In some patients skin manifestations remain confined to acral areas for several years. In others, however, sclerosis progresses proximally to forearms and upper part of legs, to upper aspect of trunk, and, finally, includes the whole integument. On rare occasions scleromatous skin changes first appear at the trunk and then spread over the integument within a relatively short period of time. These are patients who suffer from severe internal manifestations and have a poor prognosis.

462

Krieg and Meurer

Journal of the American Academy of Dermatology

Fig. 7. Typical clinical symptoms of the CREST syndrome showing sclerosis of the face with occurrence of multiple telangieetasias. Fig. 8. Clinical symptoms of CREST syndrome showing diffuse, edematous swelling of the hands in a patient in the edematous stage of systemic scleroderma. Pronounced nail fold hyperkeratosis. Fig. 9. Ulcerating calcinosis in a patient with CREST syndrome. Fig. 10. X-ray photograph demonstrating subcutaneous calcinosis in a patient with CREST syndrome.

Histopathology and electron microscopy of skin manifestations Histopathologic alterations in scleroderma are not very characteristic and are similar in systemic

scleroderma and localized scleroderma. In early lesions one observes a usually mild cellular infiltrate, consisting of lymphocytes, monocytes, and histiocytes, which is mainly present in the vicinity

Volume 18 Number 3 March 1988

Systemic scleroderma

463

Fig. 11. Histology of scleroderma skin. A, The biopsy specimen was taken from a patient in a sclerotic phase of the disease. The collagen fibrils appear tightly packed, homogenous, and extend into the subcutaneous tissue. Sweat glands are atrophic and appear to be located in the papillary dermis. (Magnification, • 150.) B, Lymphocytic infiltration in a patient with early phase of systemic scleroderma. Mainly around blood vessels in the reticular dermis infiltrations are found that consist of lymphocytes, monocytes, and histiocytes. (Magnification, x 600.)

of small blood vessels and at the interface between the dermis and the subcutaneous tissue (Fig. 11, A). These infiltrates are reduced in number or disappear completely in later stages of the disease. Here one sees sclerotic, homogenous, or hyalinized bundles of collagen extending from the reticular dermis into the subcutaneous tissue. Collagen bundles can be thickened, closely packed, and stain more eosinophilic. Sweat glands appear markedly atrophic because of surrounding fibrosis, and they are typically located in the papillary dermis (Fig. 11, B). Dermal vessels may show thickening and hyalinization of vessel walls (for review see references 6 and 29). Deposition of connective tissue is first seen in the reticular dermis around blood vessels, and accumulation of newly synthesized procollagens can be demonstrated in this area. 3~ Routine histology shows this collagen to be composed mainly of fine fibers that stain positive with silver and periodic acid-Schiff (PAS) stains. Electron microscopic exarnination, however, reveals thin, irregular collagen fibrils with a diameter of 10 to 30 nm; these are found mainly in early stages of scleroderma. Later, besides small fibrils larger fibrils also

are seen, along with others in a bimodal distribution.Zg.3

Involvement of internal organs Depending on the individual expression of the disease, scleroderma shows manifestations in several internal organs? -5 Involvement of the gastrointestinal tract, the lungs, the heart, and the kidneys is found most frequently. Alteration of the internal organs often determines the prognosis of scleroderma and should therefore be discussed in detail in the following chapters.

Esophagus and gastrointestinal tract Most systemic scleroderma patients suffer from involvement of the esophagus with hypomotility, peptic esophagitis, and fibrotic strictures. Esophageal involvement can be diagnosed by conventional radiography and by manometric measurements. 32,33 Recently extremely sensitive scintigraphic procedures, which can be quantitative and are noninvasive, have become availabIe? 4'35 They seem to be most suitable for the diagnosis of early esophageal involvement and for repeated follow-up studies.

464

Krieg and Meurer

Journal of the American Academy of Dermatology

Figs. 12-15. Pattern of circulating antibodies in scleroderma patients. Indirect immunofluorescence on HEp cells. (Serum dilution, 1:40; fluorescein isothiocyanate [FITC]antihuman IgG diluted 1:120 in phosphate-buffered saline; magnification, • 160.) Fig. 12, Homogenous nucleolar staining reaction of antibodies with the nucleolar PM-Scl antigen. Fig. 13, Centromere staining: the antibodies clearly recognize ki, netoehore proteins in interphase and metaphase chromosomes. Fig. 14, Speckled nucleolar staining: reaction of antibodies with nucleolar RNA polymerase I. Fig. 15, Fine-speckled nuclear and additional weak nucleolar staining: reaction of antibodies with the Scl-70 antigen.

The occurrence of malignancies in the esophagus is low. While one study found Barrett's esophagus in patients with scleroderma and longstanding reflux esophagitis,36 a follow-up study on

680 patients with scleroderma did not reveal a significant increase in the frequency of esophageal carcinoma. 37 Hypomotility is not restricted to the esophagus and may also be present in the lower

Volume 18 Number 3 March 1988

part of the gastrointestinal tract. Chronic constipation leading to rectal prolapse and decreased anorectal motility has been described in patients with systemic scleroderma? 8 Other manifestations of the disease include megacolon, transverse and sigmoid colonic volvulus, stenoses, and diverticular ulcerations? 9 Dysfunction of the small bowel with stagnation often leads to an altered bacterial growth in the intestine. This is thought to be mainly responsible for the malabsorption syndrome frequently present in scleroderma patients. 4~ In addition, severe gastrointestinal bleeding was seen in some patients with either diffuse scleroderma or with the CREST syndrome. This was found to be caused by multiple telangiectasias mainly in the upper part of the gastrointestinal tract but also in the colon. 42,43 Liver and pancreas Primary involvement of the liver in scleroderma is rare44; in most cases altered liver functions are secondary effects of right ventricular heart disease. Very few cases of nodular regenerative hyperplasia of the liver and idiopathic portal hypertension associated with systemic scleroderma have been described. 45The association of scleroderma with primary biliary cirrhosis, which was present in 17% of 189 patients with systemic scleroderrna in one study, is much more frequent. 46 Most of these patients develop signs of the CREST variant of scleroderma and are serologically characterized by the presence of both anticentromere and antimitochondrial antibodies. 47 Involvement of the pancreas is rare in patients with systemic scleroderma and seems to be much less important for malabsorption than other factors such as intestinal bacterial overgrowth.

Heart Primary cardiac involvement is very common in systemic scleroderma. It was found in 80% of patients at autopsy. 48 However, during the course of the disease cardiac involvement is still frequently overlooked. With the development of more sensitive techniques such as myocardial perfusion scintigraphy, ventriculography, and echocardiography, abnormalities of cardiac function can now be detected already in the early phases of scleroderma49-53(Table III). They usually indicate a poor prognosis and can result in congestive heart

Systemic scleroderma 465

Table III. Myocardial involvement in systemic scleroderma Myocardial fibrosis Pericarditis Contraction band necrosis Conduction system fibrosis Intramural coronary artery lesions Vascular disease failure, myocardial infarction, and sudden death. The symptoms include chest pain, dyspnea, syncope, and angina pectoris. They are probably caused by either endothelial damage of small coronary arteries or myocardial fibrosis. Early diagnosis of cardiac involvement is therefore important and should include all diagnostic tools available because symptomatic treatment can prevent lifethreatening complications for many years.

Lungs Pulmonary involvement is one of the most important clinical features in systemic scleroderma and has been studied in detail. 54,55 In addition to x-ray procedures and functional tests, scintigraphy and the bronchoalveolar lavage have offered new insights into the pathophysiologic events. The disturbance of lung function is characterized by restrictive changes with reduced respiratory volume and by impaired diffusion capacity. In addition, obstructive changes involving both large and small airways may be present. 56-5~The histologic feature of scleroderma lung disease includes interstitial inflammation, vasculitis, and fibrosis that is indistinguishable from that in idiopathic pulmonary fibrosis. However, in a large study no close correlation was found between fibrosis and abnormalities in pulmonary functions? 9 This discrepancy was particularly noted in patients with the CREST syndrome, who can develop irreversible pulmonary hypertension in a late stage of the disease despite the absence of obvious pulmonary fibrosis. 6~The bronchoalveolar lavage fluid of patients with systemic scleroderma has been shown to contain elevated numbers of lymphocytes, neutrophils, and circulating immune complexes, which may be factors leading to the development of pulmonary fibrosis? 6 The overall prognosis is worse in patients with restrictive lung disease, although death is usually not due to respiratory problems? 9

466

Journal of the American Academyof Dermatology

Krieg and Meurer

Table IV. Musculoskeletal involvement in systemic scleroderma Myalgia Myositis Arthralgia Arthritis Tendovaginitis Acro-osteolysis__

)

Joint contractions Muscular atrophy Calcification

Kidneys The presence of renal involvement in scleroderma is regarded as one of the features associated with the poorest prognosis. 6~,6zIn their study on survival of scleroderma patients, Medsger and Masi ~~ reported that all patients with clinically evident renal disease died within less than 1 year of observation. The clinical criteria for renal disease in scleroderma include persistent proteinuria (>500 mg/24 hr), hypertension (> 140/90 mmHg), and azotemia (blood urea nitrogen [BUN], >25 rag/100 ml). With these criteria, 15% to 45% of scleroderma patients (mainly type II[) were found to have renal involvement.9"63 The occurrence of severe renal failure, however, was noted in only 3% to 5% of scleroderma patients.9'1~ The most characteristic histologic changes similar to those in malignant hpertension are seen in the smaller renal arteries and include marked intimal proliferation with deposition of PAS-positive material, adventitial fibrosis, fibrinoid necrosis, and thrombus formation. 63These changes can lead to narrowing or even obliteration of vessel lumina and ultimately to infarction of glomeruli and tubuli. Immunofluorescence studies of scleroderma kidney have revealed vascular deposits of complement components (predominantly C3) and immunoglobulins (frequently IgM).64 The pathogenic :relevance of these immunohistologic findings, however, remains unclear because similar findings can occasionally be present in scleroderma patients without clinical evidence of renal involvement.

Joints and bones Joint involvement in systemic scleroderma is frequent65 and may resemble rheumatoid arthritis

at the onset of the disease; it is less destructive, however. 66 Pain and inflammatory signs, with erythema, warmth, and synovial effusions, occur most often in the fingers, wrists, knees, and ankles. Contractures are generally due to sclerotic changes of the overlying skin or surrounding connective tissue, although in some patients a nonerosive hand deformity resembling Jaccoud's arthropathy may be present67 (Table IV). The most common roentgenographic abnormalities are resorption of the tufts of the terminal phalanges, juxta-articular osteoporosis, periarticular bone erosions (often associated with subcutaneous calcinosis), and joint space narrowing. 68'69 Osteolysis can also occur at other sites, such as feet, ribs, and mandible, and is probably related to ischemia and compression. Only 20% of patients with systemic scleroderma show radiographic evidence of inflammatory arthritis, which is usually not associated with rheumatoid factor. 7~ The coexistence of true rheumatoid arthritis and scleroderma has been reported only rarely. Periarticular subcutaneous calcification also occurs around the iliac crest, spine protuberances, knees, and elbows and can be complicated by painful ulcerations of superficial deposits. Fibrotic changes in juxta-articular tendons of the forearms, legs, fingers, and neck occasionally cause audible friction rubs, which are a characteristic clinical sign of scleroderma. Fibrosis of tendons may also lead to peripheral entrapment neuropathy and to the carpal tunnel syndrome?

Sjrgren's syndrome and polymyositis In addition to scleroderma-specific changes of skin and internal organs, many patients with systemic scleroderma demonstrate clinical features such as polymyositis and Sjrgren's syndrome, which are also seen in other inflammatory connective tissue diseases. Sj6gren's syndrome has been reported in 5% to 90% of patients with systemic scleroderma, depending on the criteria used to define this disorder of salivary glands. 7~ These patients often demonstrate circulating antibodies to the Ro(SSA) antigen and the nuclear La(SSB) antigen. ~2 In patients with scleroderma and polymyositis, muscle wasting and weakness most frequently in-

Volume I8 Number 3 March 1988

Systemic scleroderma

467

Table V. Circulating antibodies in patients with systemic scleroderma Antibodies

Antinucleolar antibodies (nucleolar) Anticentromere antibodies (centromerespecific) Scl-70 antibody (diffuse fine speckles)

Clinical type of systemic scleroderma

Scleroderma polymyositis overlap syndrome CREST syndrome Diffuse scleroderma

volvo the proximal muscles, such as the pectoral girdle, the forearm flexors, and the small muscles of the hands7~ (Table IV). Myositic changes can also occur in muscles underneath apparently normal s k i n 73 but are generally accompanied by only mild elevation of serum creatine and/or creatinuria. In a subgroup of patients, however, polymyositis can be the most prominent clinical feature. EIectromyographic changes can be found in approximately 25% to 40% of patients with systemic scleroderma, comparable to those with polymyositis. 7 The most consistent electromyographic deviations are a decrease in amplitude and duration of single potentials and a concomitant increase of polyphasic potentials. 73

Circulating antibodies in systemic scleroderma Similar to other connective tissue diseases, circulating autoantibodies have been detected in patients with systemic scleroderma. Whereas in the beginning these antibodies have been defined only by their pattern in immunofluorescence, it has recently been possible to identify the antigens (Table V). Detection and characterization of circulating antibodies have then become an important tool for the diagnosis of scleroderma and for defining subsets of the diseases. Their involvement in the pathogenesis of systemic scleroderma, however, is still questionable. By indirect immunofluorescence, using tissue culture cells such as human laryngeal tumor cells (HEp-2) as substrate, antinuclear antibodies (ANA) can be found in the sera of more than 95% of patients with systemic scleroderma. 74,75 The antibody titers can be very high but in general do not show any correlation with disease activity.

Antigens

PM-Scl; Mr = 20,000-110,000 Kinetochore proteins; Mr = 14,000140,000 Nuclear enzyme, DNA topoisomerase I; Mr = 95,000-100,000

Therefore the pathogenic significance of these antibodies is questionable and they are often thought to represent secondary phenomena. Nevertheless, some of the antibodies are highly specific and are found only in distinct patients with certain clinical features, thus representing subgroups of the disease. Identification and characterization of circulating antibodies have therefore turned out to be extremely valuable for the classification of scleroderma and for establishing a diagnosis and prognosis for individual patients. By indirect immunofluorescence on HEp-2 cells, three characteristic fluorescence patterns can be distinguished on these cells: a nucleolar stain (Figs. 12 and 14), a centromere stain (Fig. 13), and a finespeckled nuclear stain often combined with nucleolar staining produced by antibodies against the Scl-70 antigen (Fig. 15).

Antinucleolar antibodies Antinucleolar antibodies are mostly seen in patients with diffuse scleroderma and are rarely seen in other connective tissue diseases. 75 Several antigens reacting with antinucleolar antibodies have been characterized: low molecular weight 4-6 S ribonucleic acid (RNA), v6 a novel nucleolar 7-2 ribonucleoprotein,7v and a basic protein of Mr = 34,000, termed "fibrillarin," which is associated with nucleo~ar U3 RNA. 7~ Antinucleolar antibodies producing a distinct speckled nucleolar pattern (Fig. 15) were recently shown to react with the RNA polymerase I complex localized in the fibrillar regions of nucleoli. 79 These anti-RNA polymerase I antibodies were mainly detected in sera from patients with diffuse scleroderma. Another class of antinucleolar antibodies producing homogenous nucleolar staining and additional

468

Journal of the American Academy of Dermatology

Krieg and Meurer

weak staining of the nucleoplasm (Fig. 12) is directed against the PM-Scl antigen, which compromises a distinct group of 11 possibly preribosomal proteins of Mr = 20,000-110,000. 8~ Anti-PMScl antibodies can also be detected by double immunodiffusion with the use of an extract of calf thymus nuclei (extractable nuclear antigens; ENA) as antigen source. These precipitating antibodies are identical to the previously reported antiPM-1 antibodies s~ and were found in about 10% of patients with scleroderma and polymyositis. Antieentromere antibodies Anticentromere antibodies were first identified by Moroi and Tan and coworkers 74'82 in sera of patients with systemic scleroderma. By immunoelectron microscopy the binding region for anticentromere antibodies could be located within the centromere portion of the chromosome, s3 The antigens recognized by anticentromere antibodies have been biochemically characterized as nonhistone chromosomal proteins (Mr = 14,00019,000, 84 8 0 , 0 0 0 , and 140,000. s5 These proteins are likely to be components of the human kinetochore and may be involved in the organization of chromosomes and microtubules in mitotic cells, s4 Anticentromere antibodies can be detected in 12% to 43% of all patients with systemic scleroderma,86'87 mostly in patients with the CREST variant of scleroderma. The frequency of anticentromere antibody in CREST patients or in patients with acroscleroderma and sclerosis limited to the digits varies between 49% and 96%. 8s-9~In contrast, anticentromere antibodies were found in only 3% to 12% o f patients with diffuse scleroderma. When systemic scleroderma patients with and without anticentromere antibody were compared, occurrence of anticentromere antibody was associated with a higher mean duration of the disease, a higher frequency of calcinosis, often with telangiectasia, and the absence of renal disease. In some studies pulmonary fibrosis and restrictive lung disease were found to be less frequent in anticentromere antibody-positive patients compared to anticentromere antibody-negative patients. 87 However, in a small percentage of cases, occurrence of anticentromere antibody can be associated with severe pulmonary hypertension 88,9o and with

gastrointestinal involvement. Anticentromere antibodies are also present in 10% to 15% of patients with primary biliary cirrhosis, of whom about half have some evidence of scleroderma, usually of the CREST variety. 91 In other connective tissue diseases, anticentromere antibodies are very rare. They are present, however, in about 20% of patients with idiopathic Raynaud's disease or Raynaud's syndrome as a prodrome of systemic scleroderma, 89where they may be detected several years prior to the onset of other scleroderma symptoms. The finding of a higher ratio of women to men and an increased frequency of the HLA-DR1 antigen in CREST patients with anticentromere antibody suggests that hormonal and genetic factors may be important in the expression of these antibodies in a subgroup of patients with scleroderma. Anti-Sei-70 antibodies Precipitating antibodies reacting with saline extracts of calf or rabbit thymus (extractable nuclear antigen) in double immunodiffusion can be detected in more than 50% of scleroderma sera. These include antibodies directed against the PM-Scl antigen or against the Ku antigen, which were detected frequently in patients with scleroderma/polymyositis overlap syndromes. 9z More frequent are antibodies against the Scl-70 antigen, which were first described by Douvas et al. 93 The trypsin-sensitive, nonhistone protein Scl-70 was originally reported to have a molecular weight of 70,000 but was recently shown by immunoblotting methods to be a 95-100 kd polypeptide from which smaller species may be derived by proteolysis.94'95 The same authors provided evidence that Scl-70 is identical to the nuclear enzyme deoxyribonucleic acid (DNA) topoisomerase I, which is presumably functioning in the control of chromosomal supercoiling during the cell cycle. By immunodiffusion antibodies to Scl-70 can be detected in about 20% to 30% (or even more frequently) of sera from patients with scleroderma. 87,93Sci-70 antibodies are highly specific for systemic scleroderma and were only occasionally found in patients with related disorders such as polymyositis or Raynaud's syndrome. They are

Volume I8 Number 3 March 1988

Systemic scleroderma 469

immunoregulation

altered Vascular damages

L FIbrosls

/ / disturbed control of l collagen metabolism

I

Fig. 16. Pathogenesis of scleroderma. Three major pathways are thought to play a role in the development of scleroderma; all finally result in the activation of connective tissue metabolism.

more frequent in patients with diffuse scleroderma where they may be present in 60% of the patients? 7,93 Scl-70-positive sera may also contain other antinuclear or antinucleolar antibodies. However, the presence of both Scl-70 antibodies and anticentromere antibodies in one patient is extremely rare.

Pathogenesis of systemic sderoderma The initial events in the pathogenesis of scleroderma are still poorly understood. Nevertheless, the final step is the development of fibrosis of the involved tissues, and scleroderma has become a model disease for studying pathophysiologic alterations occurring in fibrotic and sclerotic reactions. From clinical, immunologic, and histopathologic observations three pathways are proposed to be involved in early events in scleroderma. These include vascular alterations, an abnormal immune response, and disturbances in the regulation of connective tissue metabolism (Fig. 16).

Role of the vessel wall in the pathogenesis of scleroderma Alterations of the vessel wall have been detected by histology and on the ultrastructural level. For example, gaps between endothelial ceils were seen in capillaries of scleroderma skin, 9~ and the cells show granular degenerations of the nucleus as well as multiple vacuoles. In addition, reduplication of the basal lamina was noted in scleroderma capillaries, often followed by disruption of the endothelial cells and obstruction of the vessel lumina. Recently much progress has been made in char-

acterizing the protein components of the basement membrane outlining the vessels on a molecular level (for review, see reference 97). The main constituents are type IV collagen, laminin, nidogen entactin, and heparin sulfate proteoglycan. Involvement of the metabolism of these proteins in the pathogenesis of scleroderma is suggested by an altered staining with antibodies directed against type IV collagen and laminin in indirect immunofluorescence microscopy3~ and by the detection of elevated levels of fragments for type IV collagen and laminin in the serum of patients with systemic scleroderma.* In addition, autoantibodies directed against type IV collagen have been reported in patients with scleroderma98; their pathogenetic role, however, is unclear. They may reflect a secondary phenomenon caused by the availability of normally masked antigenetic determinants of type IV collagen. Probably of greater importance are alterations of endothelial cells resulting in vacuolization, swelling, and disruption. Several attempts have been made to elucidate these pathologic events. An endothelial cell cytotoxic activity was detected in scleroderma seI'~lm, 99'100 which is thought to be caused by a proteolytic activity probably associated with a functional deficiency of protease inhibitors. This is supported by a report describing a trypsin-sensitive factor with a molecular weight similar to serum albumin, which was present in 40% of sera from patients with active systemic scleroderma, t~ However, other studies could not demonstrate the specificity of such endothelial cell *Gerstmeier H, Gabnelli A, Meuw M, Brocks D, Braun-Falco O, Krieg T. Unpublished observations.

470

Krieg and Meurer

cytotoxic activity for scleroderma.~~ Clearly, biochemical characterization of these factors is required before their role in the pathogenesis of vascular alterations in scleroderma can be studied. Damage of the endothelial cells often leads to platelet aggregation, and in scleroderma enhanced platelet adhesion to collagen was observed. 1~ Since platelets contain a large number of active mediators that have the potential for modulation of fibroblast functions once released into the tissue, endothelial cell damage can represent a key event in the development of the fibrotic reaction. These factors include the platelet-derived growth factor and the transforming growth factor-t3, which, in conjunction with the epidermal growth factor, is an effective promoter of wound healing and can cause fibrosis when injected into nude mice. 1o4,105 An altered permeability of the vessel wall also allows an increased passage of mononuclear cells into the tissue and thus formation of perivascular infiltrates that are seen in early stages of scleroderma. Injury of the endothelial cells, with exposure and breakdown of type IV collagen and laminin in the basement membrane, could therefore activate circulating cells to liberate highly potent mediators. These could then easily diffuse through the defective basement membrane into the surrounding tissue, where induction of fibroblasts can occur. Role of the immune system in scleroderma

Evidence for alterations in the immune system in scleroderma comes from clinical symptoms, the presence of lymphohistiocytic infiltrations around blood vessels, and the presence of autoantibodies against nuclear and cellular antigens. Although some of these antibodies are highly specific for scleroderrna, there is still no evidence that they are directly involved in the pathogenesis of the disease. Therefore, the study of the cell-mediated immune response and its role in local fibrotic processes has attracted more attention during recent years. While peripheral white blood cell counts are slightly elevated in most patients with systemic scleroderma, differential blood counts often demonstrate an absolute lymphopenia that mainly af-

Journal of the American Academyof Dermatology fects the T cell population.l~176 An elevated ratio of T4/T8 lymphocytes was noted in some patients with sclerodermal~176 this T cell imbalance could be accounted for mainly by a reduction of T8 cells since T4 cells tend to be normal in number in most patients with systemic scleroderma. Studies measuring the in vitro functional capacity of peripheral blood mononuclear cells have yielded divergent results: both normal1~ and decreasedt t0 autologous mixed lymphocyte reactions have been reported in systemic scleroderma. An enhanced in vitro immunoglobulin synthesis by mitogenstimulated normal B ceils cocultured with T cells from systemic scleroderma patients was also reported.~l~ This increased B cell activity is thought to be due to an augmented T helper cell function because T suppressor cell activities have been found unaltered in all patients with systemic scleroderma. On a local level, an increased T helper cell function may stimulate the production of soluble factors released by lymphocytes in cutaneous or systemic inflammatory lesions of systemic scleroderma, which, together with mediators released from monocytes or macrophages, can regulate chemoattraction, mitosis, and collagen synthesis of fibroblasts. Although there is evidence that various lymphokines can influence fibroblast functions, some contradictory reports have been published; this probably results from the fact that in most of these studies crude extracts containing various factors with stimulating or inhibiting activities have been used. A collagen-stimulating factor was detected in supematants from phytohemagglutinin (PHA)-stimulated normal human lymphocyte culturesll2; additionally, several factors that affect the proliferation of fibroblasts and stimulate collagen and glycosaminoglycan synthesis in scleroderma fibroblasts were identifed in activated mononuclear cell cultures.l~3-~ts However, sometimes inhibition of collagen production was found. Hr.~t7 Only recently was it possible to isolate and characterize individual lymphokines, which can now be studied in clean systems for their effect on fibroblast metabolism; for example, interleukin 1 could be identified as one of the factors present in activated mononuclear cell superna-

Volume I8 Number 3 March I988

Systemic scleroderma

"~::::::::~~

471

tissueinjury - growthfactors chemotacticfactors ~oblasts

fibroblas~subpopulation

clonolgrowthof activoted fi broblosts

I deposition of colIogen

Fig. 17. Clonal selection theory in systemic scIeroderma, Clonal growth of fibroblasts leads to selection of a distinct population of fibroblasts, which is characterized by high production of connective tissue components.

tants, which have the potential to modulate fibroblast metabolism.~8 A unifying concept explaining the interaction of mononuclear cells and fibroblasts on the basis of one potent mediator is therefore still missing; a more complex picture is emerging that indicates the presence of a variety of different inhibitory and stimulating substances responding to complex control mechanisms.

Activation of connective tissue metabolism Activation of connective tissue metabolism represents a final step in the pathogenesis of scleroderma. The cellular and molecular basis of the development of fibrosis is still not elucidated in detail, but it involves the selection and accumulation of distinct fibroblast subpopulations by growth factors, a chemotactic activity leading to

invasion of fibroblasts into the injured tissue, and the specific activation of collagen synthesis. Role of fibroblast subpopulations for development of fibrosis There is considerable evidence now that fibroblasts are not homogenous and rather represent a broad class of mesenchymal ceils with distinct features. For example, tendon fibroblasts differ from skin fibroblasts,t~9 and within skin fibroblasts from the reticular and the papillary dermis are distinct.~2~ In scleroderma distinct populations of fibroblasts can be obtained from the same biopsy specimen that differ in their collagen biosynthesis. 12~ In addition, various activated fibroblast strains were characterized in which either collagen synthesis or production of collagen and fibronectin was induced, m Implication of a selection o f fibroblast

472

Krieg and Meurer

subpopulations for the pathogenesis of scleroderma is in agreement with other results indicating that even in normal skin different clones of fibroblasts are present that show either a high or a low synthesis of collagen. When normal fibroblasts were grown in the presence of serum obtained from scleroderma patients, those clones that are characterized by a high collagen production were preferentially stimulated, t23 Presence of distinct activated fibroblasts in the tissue of scleroderma patients was further corroborated by experiments using in situ hybridization with collagen complementary DNA clones. These experiments demonstrated that fibroblasts adjacent to blood vessels contain high amounts of collagen messenger ribonucleic acid (mRNA), whereas fibroblasts in other areas of the dermis do not show labetirtg after autoradiography.* These observations are in agreement with a clonaI selection of fibroblasts in scleroderma (Fig. 17), which has been suggested as an altemative model o f fibrosis. ~24 However, identification of subpopulations of fibroblasts, especially in vivo, is still very difficult; only few attempts have been made to develop markers recognizing distinct fibroblast populations and to apply them in the study of scleroderma.125 It remains to be seen whether further development of these marker proteins, together with in situ hybridization techniques, allows us to identify distinct populations of activated fibroblasts in the involved tissues. Fibroblast chemotactic factors and their role in scleroderma Accumulation of fibroblasts plays a major role in fibrotic processes. Therefore many attempts have been made to identify fibroblast growthpromoting activities. ~26 It has been shown that accumulation of fibroblasts can be the result of chemotactic factors (for review see reference 127). These include fibronectin, collagen fragments, collagens, plateletderived growth factor, epidermal growth factor, and eicosanoids. In addition, activation of the complement system leads to the generation of the *Scharffetter K, Krieg T. Personal communication.

Journal of the American Academy of Dermatology

C5a fragment, which also attracts fibroblasts. In scleroderma, many cells are involved in the pathogenic events, for example, platelets, lymphocytes, and endothelial cells; all are capable of producing these mediators; no information is available, however, regarding whether the response of scteroderma fibroblasts to chemotaxis is normal or not. Differential response to these factors could be another mechanism leading to selection of distinct populations of fibroblasts, as has been suggested for growth factors. Role of extracellular matrix in scleroderma The main feature in scleroderma is the excessive deposition of connective tissue, mainly collagen, in the involved organs. Although it is not clear whether a disturbance in the metabolism of collagen is a prime event in scleroderma, deposition of collagen determines the main clinical symptoms. Therefore several attempts have been made to characterize the connective tissue and to investigate its synthesis in detail. Connective tissue is composed of structural proteins, for example, collagens and fibronectin, and nonstructuraI components such as proteoglycans. Chemical analysis of proteoglycans of sclerodermatous skin revealed divergent results. Some investigators reported an increase in dermatan sulfate,128 others an increase in chondroitin sulfate,129 and immunoelectron microscopy studies suggested an uncontrolled local accumulation of proteoglycans in the interfibrillar matrix around irregularly arranged collagen fibrils.~3~ Collagen is not a single entity but represents a large number of genetically different collagen types (for review see reference 13 1), which determine the biologic property of distinct connective tissues. In early edematous stages of scleroderma an increase of type III collagen was reported, m However, these studies are based on immunofluorescence microscopy, which usually does not allow quantification. Biochemical analysis of lung collagen in scleroderma revealed an unaltered ratio of collagens I and III. In all biosynthetic studies in scleroderma fibroblast cultures the ratio of collagen types was comparable to controls. 121'I22'm In contrast, evidence for enhanced biosynthesis

Volume I8 Number 3 March 1988

Systemic scleroderma

473

In~ern~~ PN -peplides and \ ~ inhibition of collogen \ synthesis \ \

]

L

Procollogen il[~~Cteavage of the arninoterminal procollagenpeptides

Fig. 18. Feedback control of collagen synthesis by procollagen peptides. Procollagen is

synthesized and secreted by fibroblasts. The enzymatically controlled cleavage of the aminoterminal procollagen peptide occurs in the extracellular space. Free aminoterminal peptides are then taken up by the cells and can act as feedback inhibitors.

of collagens I and II[ in scleroderma comes from several different approaches: there is an increase in total collagen in the involved skin, TM and biosynthetic studies in organ cultures revealed enhancement of collagen production and of proline hydroxylase activity.'135,t36 In addition, increased circulating type III collagen propeptides have been found in scleroderma patients, and the level of the aminopropeptides could be correlated with the fibrotic activity in these patients. 137 In many studies fibroblasts grown from the reticular dermis of scleroderma patients have been used and revealed increased synthesis of collagen. ~2~,~38 Although very high levels of collagen production were mainly seen in primary cultures of scleroderma fibroblasts and tended to decline with passage of the cells, ~39 the culture systems allowed a detailed investigation of the different cantrol levels of collagen biosynthesis. Collagenase activity and collagen degradation were found to be normal in all fibroblast cultures. ~3_~Increased synthesis has been found on the protein level after biosynthetic labeling of cultured cells and also in a cell-free system with the use of mRNA isolated from scleroderma fibroblasts. ~4~ In addition, evidence of a disturbance of the transcriptional control came from experiments demonstrating increased mRNA levels for type I collagen in scleroderma fibroblasts. TM In agreement with this assumption are earlier studies, in which the physiologically functioning feedback inhibition of collagen synthesis by the aminopropeptides of procollagen was investigated, demonstxating a nor-

mal response of sclemderma fibroblasts to these peptides 142 (Fig. 18). Later a similar study was carried out revealing a somewhat reduced response in some fibroblast strains obtained from scleroderma patients, m Collagen synthesis also involves several posttranslational modifications that are controlled by specific enzyme activities (for review see Reference 144), some of which are essential for the production of functional molecules (prolylhydroxylase). Others play a role in the cross-linking reaction (lysylhydroxylase, lysyloxydase), the glucosylation, and the galactosylation. In addition, cleavage of procollagen peptides by two specific proteases represents another posttranslational modification of the molecule. Activity of the intracellular enzymes has been studied in detail in scleroderrna fibroblasts, revealing increased activity of prolyl- and lysylhydroxylase in those cell strains characterized by an overproduction of collagen, whereas the sugar transferases were found to have normal activity in all cultures. ~45Whether dissociation of both enzyme activities might cause altered glycosylation in vivo is not clear. Newly synthesized collagen in cell culture, however, was not found to be underglycosylated, indicating that the activity of the sugar transferases is sufficient under these culture conditions. In contrast, no direct evidence is available concerning activity of the proteases responsible for cleavage of the N- and C-terminal procollagen peptides--yet there is indirect information indicating their involvement in scleroderma. This

474

Journal of the American Academy of Dermatology

Krieg and Meurer

Table 3/-1. Vasoactive substances in therapy

Table VII. Anti-inflammatory treatment of

of systemic scleroderma

systemic scleroderma

Fibrinolytic agents Plasma expanders Prostacyclin Calcium channel blockers (nifedipine) Angiotensin-converting enzyme inhibitor (captopriI) Serotonin receptor blocker (ketanserin)

comes from studies demonstrating that the aminoterminal propeptides are not only involved in the feedback inhibition of collagen synthesis but also control fibril formation. By immunoelectron microscopy, it could be shown that collagen fibrils with adiameter of < 3 0 nm still contain molecules with the aminopropeptide attached. In thick fibrils (>30 nm) no N-terminal procollagen peptides could be detected. ~46 Until now it has not been determined whether the thin collagen fibrils found in scleroderma still contain the aminopropeptides or whether they represent type III collagen. Defective cleavage of the aminopropeptides, however, would explain the formation of thin fibrils and, in addition, would result in a reduced number of free procollagen peptides available for the feedback control o f collagen biosynthesis.

Therapeutic considerations Although a large number of different substances have been used in the therapy of scleroderma, there is still no potent drug available to cure the disease. However, several components can reduce the clinical symptoms of the patients. These can be divided into vasoactive agents, substances with antiinflammatory activity, and drugs that influence the connective tissue metabolism.

Vasoactive agents Various vasoactive agents have been used, especially in patients with acroscleroderma and Raynaud's disease (Table VI). These include fibrinolyric agents, substances that reduce platelet adhesiveness, and plasma expanders. ~47:4s Calcium channel blockers, especially nifedipine, have been investigated in several studies and are among the few agents in which a positive effect could be

Corticosteroids Azathiopdne Cyclophosphamide Cyclosporine Plasmapheresis

demonstrated in double-blind trials. 149'15~ Captotril, an inhibitor of the angiotensin-converting enzyme, is well established for treatment of renal crises occurring in patients with scleroderma ~5~ but, because of severe side effects, a generalized application cannot be recommended. During recent years the serotonin-receptor blocking agent ketanserin has attracted attention and was used in several trials. Ketanserin could be shown to be an effective agent in reducing the number and severity of Raynaud's attacks in scleroderma patients.~52 However, no significant effect on the further progression of the disease was demonstrated. Several other vasoactive agents have also been used in scleroderma, but they have been shown to be ineffective in double-blind trials.

Anti-inflammatory agents Alterations of the immune system play as a primary or secondary event a role in scleroderma and cause many symptoms severely affecting the patients. Therefore, anti-inflammatory treatment is widely used in those patients showing inflammatory reactions such as myositis or interstitial lung disease (Table VII). There is often a good symptomatic response, but no proved evidence that sclerosis of skin and internal organs or the prognosis of the disease can be influenced. In addition, wellcontrolled studies demonstrated that the 5-year cumulative survival rate in patients with scleroderma was not altered by immunosuppressive agents, is3 Immunosuppressive agents that have been tried in systemic scleroderma include corticosteroids, azathioprine, and cyclophosphamide (for review see reference 154). Plasmapheresis has also been tried, but the success has not been convincing. From these reports it can be concluded that immunosuppressive agents in scleroderma can be used to achieve a better quality of life, especially in those

Volume 18 Number 3 March 1988

Systemic scleroderma 475

Table VIII. Antifibrotic agents in treatment of systemic scleroderma

/

unknown primaryeven~

",,

Vascular factors ~

i

tissue mediators

Cyclofenil Proline analogs Prolyl hydroxylase inhibitor Procollagen peptides ~/-Interferon D-Penicillamine ~clo

patients with accompanying myositis, serositis, or arthritis. They have also been recommended for the treatment of interstitial lung disease but should not be expected to influence the disease process. In addition, nonsteroidal antiphlogistic substances can be successful in reducing symptomatic pain in this disease.

Rbcobtastactivation I nal selection of activated fibroblasts :

col:~.

,nRNAI"-~,

Excessive deposilion of connective tissue ~ottered macromolecutar organization)

Fig. 19. Pathogenesis of scleroderma and hypothetic steps for interfering with therapeutic agents.

Agents influencing the metabolism of connective tissue Many substances have been introduced in the treatment of scleroderma that were thought to inhibit the biosynthesis of collagen (Table VIII). Probably the most important is D-penicillamine, which could be shown to reduce the cutaneous involvement and to result in a greater 5-year cumulative survival rate when given as a long-term low-dosage treatment beginning in the early stages of the disease./53 However, this drug is also known for considerable side effects. The antiestradiol compound cyclofenil has been shown to reduce connective tissue synthesis in fibroblast cultures but did not prove to be effective in a double-blind clinical study. :55 Colchicine was applied to scleroderma patients because it was thought to inhibit secretion of collagen. The evaluation of therapeutic trials, however, has been controversial. 156Recently it has been shown that factor XIII inhibits collagen synthesis and can improve the sclerosis in patients with systemic scleroderma. 157 A/so, glucocorticoids can inhibit collagen synthesis in vitro, but this activity does not seem to be part of the beneficial effects observed in scleroderma. Since it is known that hydroxylation of prolyl residues is essential for the biosynthesis of collagen, several drugs have been developed that can inhibit this enzymatically catalyzed step

in vitro. Some of these interfere with cofactors (Fe §247Mn §247of the enzyme and have already been used in therapeutic trials. 158 Others, for example, proline analogs, have given convincing resuits in vitro but show a high toxicity in vivo. Recently a new class of components was developed that competitively inhibit the enzyme prolylhydroxylase. 159 These substances lead to the production of underhydroxylated collagen in organ cultures. Further development may result in improved agents that specifically inhibit collagen production in vivo. Interestingly, penicillin, often used in Germany in the treatment of scleroderrna, has a structure similar to prolylhydroxylase inhibitors. Also, N-terminal procollagen peptides can specifically inhibit collagen synthesis in vitro. 142 Further identification of the active site of these peptides could open another way, allowing specific control of the production of collagen. 160

General treatment Since a specific treatment for scleroderma is missing, the main intention of physicians should be to use substances discussed herein that have been shown to improve the quality of life for the patients and that have tolerable side effects. This has to be combined with intensive physical therapy and special nutrition, especially in those pa-

Journal of the American Academy of Dermatology

476 Krieg and Meurer

tients with gastrointestinal involvement. Cutaneous trauma shouId be minimized and the patients should be advised to avoid cold temperatures, nicotine, and ergot alkaloids in order to minimize vasospasm. CONCLUSION Systemic scleroderma is a generalized disease leading to fibrosis of the skin and internal organs. There are many new sensitive techniques available for the detection of internal manifestations, and detailed diagnostic analysis has been shown to be extremely important in scleroderma where an early detection of heart involvement, for example, can result in symptomatic therapy, possibly preventing sudden death due to heart failure. Although scleroderma is a heterogenous disease, there is no commonly recognized classification. Nevertheless, most authors agree on the distinction between acroscteroderma (limited cutaneous seleroderma) and diffuse scleroderma (diffuse cutaneous scleroderma). Presence of autoantibodies directed against several cellular antigens had a valuable impact on defining subgroups of scleroderma patients and, in addition, points to an involvement of the immune system in the pathogenesis of this disease. Vascular alterations have been observed as an early symptom in most patients with scleroderma, and defects of endothelial ceils and the vessel wall are thought to represent prime events in the pathogenesis (Fig. 19). Mediators released from platelets or by mononuclear cells present around blood vessels in early phases of scleroderma can act as chemoattractants and can activate proliferation of fibroblasts or induce connective tissue synthesis. Alternatively, these factors may select out distinct populations of fibroblasts that possess an activated phenotype. The activation of collagen synthesis is partially due to disturbance of transcriptional control, resulting in an overproduction of structurally normal collagen types I and III. It has been postulated that thin collagen fibrils observed by electron microscopy in scteroderma could result from an altered glycosylation of newly synthesized molecules, which, in turn, is caused by dissociation of the activation of enzymes catalyzing the posttranslational modifications. There is also some indication that cleavage of the aminopropeptides is

altered in scleroderma, which could explain the occurrence of thin collagen fibrils and at the same time a disturbance of the normal feedback control of collagen synthesis. Management of scleroderma patients is still extremely difficult because most of the drugs available are probably of value only for treating specific symptoms of the disease. This applies to all immunosuppressive agents and probably also to vasoactive substances. Currently, several substances are available that show promising effects on connective tissue metabolism in vitro, but further development is necessary to make them suitable for clinical trials. Nevertheless, connective tissue production is probably not the prime event in scleroderma, and it seems to be more reasonable to inhibit the pathogenetic events much earlier. Because it has become feasible during recent years to investigate activation of fibroblasts in more detail and to use highly purified mediators produced by mononuclear cells for testing their activity on fibroblasts, there is hope that the complex interaction between different cellular systems involved in the pathogenesis of scleroderma will become more clear in the near future. This, then, would also allow for the de'~elopment of therapeutic approaches that are based on the pathogenesis of the disease and can interfere already in the early stages of the disease.

REFERENCES 1. Curzio C. Discussionil anatomico-pratiche di un raro, e stravagante morbo cutaneo in una giovane donna felicemente eurato in questo grande ospedale degl' incurabili. Napoli, Presso Giovanni di Simone, 1753. Curzio C. An account of an extraordinary 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, Paris 1847;2:263-81. 3. Sackner MA. The visceral manifestations of scleroderma. Arthritis Rheum 1962;5:184-96. 4. Sackner MA. Scleroderma. New York: Grune & Stratton, 1966. 5. Rodnan GP, Benedek TG. A historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med 1962;57:305-i9. 6. Jabtonska S. Seleroderma and pseudoscleroderma. Warsaw: Polish Med, 1975. 7. Tuffanelli D, Winkelmann RK. Systemic sclemderma. A clinical study of 727 cases. Arch Dermatol 1961; 84:359-71. 8. Medsger TA. Epidemiology of progressive systemic

Volume 18 Number 3 March 1988

9. 10. 11. 12.

13. 14.

15. 16.

17.

18.

19. 20. 21.

22.

23. 24.

25.

sclerosis. In: Black C, Myers AR, eds. Systemic sclerosis (scleroderma). New York: Gower, i985:53. Hochberg MC, Holt PM, Kane MG, Amett FC, Stevens MB. Survival in systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:689-90. Medsger TA, Masi AT. The epidemiology of systemic sclerosis (scleroderma). Ann Intern Med I971;74: 714-21. Gladman DD, Keystone EC, Baron M, Lee P, Cane D, Mervert H. Increased frequency of HLA-DR5 in scleroderma. Arthritis Rheum 1981;24:854-6. Kallenberg CG, van der Voort-Beelen JM, D'Amaro J, The TH. Increased frequency of B8/DR3 in scleroderma and association of the haplotype with impaired cellular immune response. Clin EXp Immuuol 1981;43:478-85. Kuehnl P, Schuetz K, Altmeyer P, Holzmann H, Seidl S. Assoziation yon HLA-Antigenen und Sklerodermic. Z Hautkr 1985;60:866-8. Black CM, Welsh KI, Maddison PJ, Jayson MI, Bernstein RM. HLA antigens, autoantibodies and clinical subsets in scIeroderma. Br J Rheumatol I984; 23:267-71. Alareon GS, Phillips RM, Wasner CK, Acton RT, Barger BO. DR antigens in systemic scIerosis: lack of clinical correlations. Tissue Antigens 1985;26:156-8. Lynch CJ, Singh G, Whiteside TL, Rodnan GP, Medsget TA Jr, Rabin BS. Histocompatibility antigens in progressive systemic sclerosis (PSS; scleroderma). Clin Immunol 1982;2:314-8. Emerit I, Levy A, HoussetE. Scl6rodermi6 g6ner~lisi~e et cassures chromosomiques. Mise en 6vidence d'un "facteur cassant" dans le serum de malades. Ann Genet (Paris) 1973;16:135-8. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581-90. Rodnan GP, Jablonska S, Medsger TA. Classification and nomenclature of progressive systemic sclerosis (scleroderma). Clin Rheum Dis t976;5:5-13. Winkelmann RK. Pathogenesis and staging of scleroderma. Acta Derm VenereoI (Stockh) I976;56:83-92. Giordano M, Capelli L, Tirri G, Valti M. Vorschlag zu einer neuen Klassifizierung und Nomenldatur der progredienten generalisierten Sklerodermie (PGS). Verb Dtsch Ges Rheumatol 1980;6:379-8~. Arbeitsgruppe Sklerodermie der Arbeitsgemeinschaft Dermatologische Forschung (ADF). Klinik der progressiven systemischen Sklerodermie (PSS). Hautarzt 1986;37:320-4. Barnett AJ. Scleroderma. Progressive systemic sclerosis. Springfield: Charles C Thomas, 1974. Holzmann H, Sollberg S, Altmeyer P. Einteilung und Klinik der progressiven systemischen Sklerodermie (PSS). In: Holzmann H, Altmeyer P, Marsch W, Vogel HG, eds. Dermatologic und Rheuma. Heidelberg: Springer, 1987:202-18. Winterbauer RH. Multiple telangiectasia, Raynaud's phenomenon, sclerodactyly and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia. Butl Johns Hopkins Hosp 1964;114: 361-83.

Systemic scleroderma

477

26. Velagos EE, Masi AT, Stevens MB, Shulman LE. The CREST syndrome. Comparison with the systemic sclerosis (scleroderma). Arch Intern Med 1979;139: 1240-4. 27. Maricq HR, Weinberger AB, LeRoy EC. Early detection of scleroderma-spectrum disorders by in vivo capillary microscopy. A prospective study of patients with Raynaud phenomenon. J Rheumatol 1982;9:289-91. 28. Thibi6rge G, Weissenbach RI. Une forme de concretions calcaires sous cutan6es en relation avecla scl~rodermi6. Bull Soc Med H6p (Paris) 1910;30:i0-39. 29. Fleischmajer R, Damiano V, Nedwich A. Scleroderma and the subcutaneous tissue. Science 1971;171: 1019-21. 30. Fleischmajer R, Perlish JS, Dessau W, et al. Immunofluorescence analysis of collagen, fibronectin and basement membrane protein in scleroderma skin. J Invest Dermatol 1980;270-5. 31. Braun-Falco O, Rupec M. Collagen fibrils of the scleroderma in ultrathin sections. Nature 1964;202:708-9. 32. Weihrauch TR, Korting GW. Manometric assessment of oesophageal involvement in progressive systemic sclerosis, morphea and Raynaud's disease. Br J Dermatol 1982;t07:325-32. 33. Blom-Buelow B, Sundstroem G, Jonson B, Tylen U, Wollheim FA. Early changes in oesophageal function in progressive systemic sclerosis: a eomparison of rnanometry and radiology. Clin Physiol 1984;4:147-58. 34. Davidson A, Russell C, Littlejohn GO. Assessment of esophageal abnormalities in progressive systemic sclerosis using radionuclide transit. J Rheumatol 1985;12: 472-7. 35. Carette S, Lacourciere Y, Lavoie S, Halle P. Radionuclide esophageal transit in progressive systemic sclerosis. J Rheumatol 1985;12:478-81. 36. Agha FP, Dabich L. Barrett's esophagus complicating scleroderma. Gastrointest Radiol 1985;10:325-9. 37. Segel MC, Campbell WL, Medsger TA Jr, Roumm AD. Systemic sclerosis (scleroderma) and esophageal adenocarcinoma: is increased patient screening necessary7 Gastroenterology 1985;89:485-8. 38. Hamel-Roy J, Devmede G, Arhan P, Tetreault L, Duranceau A, Menard HA. Comparative esophageal and anorectaI motility in scleroderma. Gastroenterology 1985;88:1-7. 39. Cohen S. The gastrointestinal manifestations of scleroderma: pathogenesis and management [clinical conference]. Gastroenterology 1980;79:I55-66. 40. McBrian DJ, Mummery HEL. Steatorrhoea in progressive systemic sclerosis (scleroderma). Br Med J 1962; 2:1653. 41. Cobden I, Axon AT, Ghoneim AT, McGoldrick J, Rowell NR. Small intestinal bacterial growth in systemic sclerosis. Clin Exp Dermatol 1980;5:37-42. 42. Rosekrans PC, de Rooy DJ, Bosman FT, Eulderink F, Cats A. Gastrointestinal telangiectasia as a cause of severe blood loss in systemic sclerosis. Endoscopy 1980;12:200-4. 43. Allende HD, Ona FV, Noronha AI. Bleeding gastric telangiectasia. Complication of Raynaud's phenomenon, esophageal motor dysfunction, sclerodactyly and telangiectasia (REST) syndrome. Am J Gastroenterol 1981 ;75:354-6.

478 Krieg and Meurer

44. Bartholomew CG, Cain JC, Winkelmann RC, Baggenstoss AH. Chronic disease of the liver associated with systemic scleroderma, Am J Dig Dis 1964;9:43. 45. Umeyama K, Yui S, Fukamizu A, Yoshikawa K, Yamashita T. Idiopathic portal hypertension associated with progressive systemic sclerosis. Am J Gastroenterol 1982;77:645-8. 46. Clarke AK, Gaibraith RM, Hamilton EBD, Willianas R. Rheumatic disorders in primary biliary cirrhosis. Ann Rheum Dis 1978;37:42-7. 47. Makinen D, Fritzler JM, Davis P, Sherlock S. Anticentromere antibodies in primary biliary cirrhosis. Arthritis Rheum 1983;26:914-7. 48. Botstein GR, LeRoy EC. Primary heart disease in systemic sclemsis (sclemderma): advances in clinical and pathologic features, pathogenesis, and new therapeutic approaches. Am Heart J 1981;102:913-9. 49. Montanes P, Lawless C, Black C, Oaldey CM, Hughes G. The heart in scleroderma: noninvasive assessment. Clin Cardiol 1982;5:383-7. 50. Clements PJ, Furst DE, Cabeen W, Tashkin D, Paulus HE, Roberts N. The relationship of arrhythmias and conduction disturbances to other manifestations of cardiopulmonary disease in progressive systemic sclerosis (PSS). Am J IVied 1981;71:38-46. 51. Foltansbee WP, Curtiss EI, Medsger TA Jr, et al. Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scteroderma. N Engt r Med 1984;310:142-8. 52. Kahan A, Niteuberg A, Foult JM, et al. Decreased coronary reserve in primary scleroderma myocardial disease. Arthritis Rheum 1985;28:637-46. 53. Follansbee WP, Curtiss EI, Rahko PS, et al. The electrocardiogram in systemic sclerosis (scleroderma). Study of 102 consecutive cases with functional correlations and review of the literature. Am J Med 1985; 79:183-92. 54, Baldwin E, Coumand A, Riehards DW Jr. Pulmonary insufficiency. II, A study of thirty-nine cases of pulmonary fibrosis. Medicine (Baltimore) 1949;28:1-25. 55. Miller RD, Fowler WS, Helrnholz FH Jr. Scleroderma of the lungs. Mayo Ciin Proc 1959;34:66-75. 56. Koenig G, Ludersehmidt C, Hammer C, AdelmannGrill BC, Braun-Falco O, Fruhmann G. Lung involvement in seleroderma. Chest 1984;85:318-24. 57. Rossi GA, Bitterman PB, Rennard SI, Ferrans VJ, Crystal RG. Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis. Am Rev Respir Dis 1985;I31:612-7. 58. Bjerke RD, Tashkin DP, Clements PJ, Chopra SK, Gong H Jr, Bein M. Small airways in progressive systemic sclerosis (PSS). Am J Med 1979;66:201-8. 59. Steen VD, Owens GR, Fino GJ, Rodnan GP, Medsger TA Jr. Pulmonary involvement in systemic sclerosis (scleroderma). Arthritis Rheum 1985;28:759-67. 60. Stupi AM, Steen VD, Owens GR, Barnes L, Rodnan GP, Medsger TA. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986;29:515-24. 61. Rodnan GP, Schreiner G, Black R, Renal involvement in progressive systemic sclerosis (selemderma). Am J Med 1957;23:445-62.

Journal of the American Academy of Dermatology

62. Traub XM, Shapiro AP, Rodnan GP, et al. Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases. Medicine 1983;62:335-52, 63. Kovalehik MT, Guggenheim S J, Silverman MH, Robertson JS, Steigerwald JC. The kidney in progressive systemic sclerosis. Ann Intern Med 1977;89:881-7. 64. McCoy RC, Tisher CC, Pepe PF, Cleveland LA. The kidney in progressive systemic sclerosis: immunohistochemieal and antibody elution studies. Lab Invest I976;35:124-3t. 65. Rodnan GP. The nature of joint involvement in progressive systemic sclerosis (scleroderma). Clinical study and pathologic examination of synovium in 29 patients. Ann Intern Med 1962;56:422-39. 66. Baron M, Lee P, Keystone EC. The articular manifestations of progressive systemic sclerosis (scleroderma). Ann Rheum Dis 1982;41:147-52. 67. Bradley JD, Pinals RS. Jaccoud's arthropathy in scleroderma. Clin Exp Rheumatol 1984;2:337-40. 68. Lawson JP. The joint manifestations of the connective tissue diseases. Semin Roentgenol 1982;17:25-38. 69. Catoggio LJ, Evison G, Harkness JA, Maddison PJ. The arthropathy of systemic sclerosis (scleroderma); comparison with mixed connective tissue disease. Clin Exp Rheumatol 1983;I:101-12. 70. Medsger TA, Rodnan GP. The nature of skeletal muscle involvement in progressive systemic sclerosis (scleroderma). Arthritis Rheum 1968;11:554-60. 71. Alarcon-Segovia D, Ibanez G, Hernandez-Ortiz J, Velazquez-Forero F, Gonzalez-Jimdnez Y. Sjtgren's syndrome in progressive systemic sclerosis (scleroderma). Am J Med 1974;57:78-85. 72. Osial TA Jr, Whiteside TL, Buckingham RB, et al. Clinical and serologic study of Sj6gren's syndrome in patients with progressive systemic sclerosis. Arthritis Rheum 1983;26:500-8. 73. Hausmanowa-Petrusewick I, Jablonska S, Blaszczyk M, Matz B. Electromyographic findings in various forms of progressive systemic sclerosis. Arthritis Rheum 1982; 25:61-5. 74. Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler M J, Peebles C. Diversity of antinuclear antibodies in progressive systemic sclerosis. Arthritis Rheum 1980;23: 617-25. 75, Bemstein RM, Steigerwand JC, Tan EM. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol 1982;48: 43-51. 76. Pinnas J, Northway JD, Tan EM. Antinucleolar antibodies in human sera. J Immunol 1973;4:996-1004. 77. Reddy R, Tan EM, Henning D, Nohga K, Busch H. Detection of a nucleolar 7-2 ribonucleoprotein and a cytoplasmatic 8-2 ribonucleoprotein with autoantibodies from patients with scteroderma. J Biol Chem 1983; 3:1383-9. 78. Lischwe MA, Reddy R, Ochs RL, et al. Purification and partial characterization of a nucleolar scleroderma antigen (Mr = 34.000; pL 8.5) rich in NG, NGdimethylarginine. J Biol Chem 1985;260:14304-10. 79. Reimer G, Rose KM, Scheer U, Tan EM. Autoantibody to RNA-polymerase I in scleroderma sera. J Clin Invest 1987;79:65-72.

Volume 18 Number 3 March 1988

80. Reimer G, Scheer U, Peters JM, Tan EM. Immunoloealization and partial molecular characterization of a nucleolar autoantigen (PM-Scl) associated with polymyositis/scleroderma overlap syndromes. J Immunol 1987; 137: 3802-8. 81. Wolfe JF, Adelstein E, Sharp GC. Antinuclear antibody with distinct specificity for polymyositis. 1 Clin Invest 1977;59:176-8. 82. Moroi Y, Peebles C, Fritzler MJ, Steigerwald J, Tan EM. Autoantibody to eentromere (kinetochore) in scleroderma sera. Proc Natl Acad Sci USA 1980; 1627-31. 83. Brenner S, Pepper D, Betas MW, Tan EM, Brinkley BR. Kinetochore structure, duplication and distribution in mammalian cells. Analysis by human autoantibodies from scleroderma patients. J Cell B iol 1981;91:102. 84. Cox JV, Schenk EA, Olmsted JB. Human anticentromere antibodies: distribution, characterization of antigens and effect on microtubule organization. Cell 1983; 35:313-9. 85. Eamshaw W, Bordwell B, Marino C, Rothfield N. Three human chromosomal autoantigens are recognized by sera from patients with anti-centromere antibodies. J Clin Invest 1986;77:426-30. 86. Tufanelli DL, McKeon F, Kleinsmith DM, Burnham TK, Kirschner M. Anticentromere and anticentriole antibodies in the scleroderma spectrum. Arch Dermatol 1983; 119:560-6. 87. Meurer M, Seharf A, Luderschmidt CH, BraunFalco O. Zentromerantik(irper und AntikSrper gegen Scl-70-Nucleoprotein bei progressiver systemischer Sklerodermie. Dtsch Med Wochensehr 1985;110:8-14. 88. Steen VD, Ziegler GL, Rodnan GP, Medsger TA. Clinical and laboratory associations of anticentromere antibodies in patients with progressive systemic sclerosis. Arthritis Rheum 1984;27:125-31. 89. Fritzler MJ, Kinsella TD, Garbutt E. The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med 1980;69:520-6. 90. Chorzelski TP, Jablonska S, Beutner EH, et al. Anticentromere antibody: an immunological marker of a subset of systemic sclerosis. Br J Dermatol 1985; ll4:381-9. 91. Makinen D, Fritzler MJ, Davis P, Sherlock S. Anticentromere antibodies in primary biliary cirrhosis. Arthritis Rheum 1983;26:914-7. 92. Mimori T, Akizuki M, Yamagata H, Inada S, Yoshida S, Homma M. Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositisscleroderma overlap. J Clin Invest 1981 ;68:611-20. 93. Douvas AS, Achten M, Tan EM. Identification of a nuclear protein (Scl 70) as a unique target of human antinuclear antibodies in scleroderma. J Biol Chem 1979;254:10514. 94. Shero JH, Bordwell NF, Rothfield NF, Eamshaw WC. High titers of autoantibodies to topoisomerase I (Scl70) in sera from scleroderma patients. Science 1986; 231:737-40. 95. Guldner HH, Szostecki C, Vosberg HP, Lakomek HJ, Penner E, Bautz FA. Scl-70 autoantibodies from scleroderma patients recognize a 95 kD protein-identified as DNA topoisomerase I. Chromosoma 1986;94:132.

Systemic scleroderma

479

96. Fleischmajer R, Perlish JS, Shaw KV, Pirozzi DJ. Skin capillary changes in early systemic scleroderrna. Arch Dermatol 1976;112:1553-7. 97. Timpl R, Dziadek M. Structure, development, and molecular pathology of basement membranes. Int Dev Exp Pathol 1986;29:1-112. 98. Mackel AM, Delustr0 F, Harper TE, LeRoy EC. Antibodies to collagen in scleroderma. Arthritis Rheum 1982;25:522-31. 99. Kahaleh MB, LeRoy EC. Endothelial injury in scleroderma--a protease mechanism. J Lab Clin IVied 1983;101:553-60. 100. Kahaleh MB, Shera GK, LeRoy EC. Endothelial injury in scleroderma. J Exp Med 1979;149:1326-35. 101. Cohen S, Johnson AR, Hurd E. Cytotoxicity of sera from patients with scleroderma. Effects on human endothelial cells and fibroblasts in culture. Arthritis Rheum 1983;26:170-8. 102. Shanahan WR, Korn JH. Cytotoxic activity of sera from scleroderma and other connective tissue diseases. Lack of cellular and disease specificity. Arthritis Rheum 1982;25:1391-5. 103. Kahaleh MB, Scharstein KK, LeRoy EC. Enhanced platelet adhesion to collagen in scleroderma. Effect of scleroderma plasma and scleroderma platelets. J Rheumatol 1985;12:468-71. 104. Sporn MB, Roberts AB, Schull JH, Smith JM, Ward JM, Sodek J. Polypeptide transforming growth factor isolated from bovine sources and used for wound healing in vivo. Science 1983;219:1329-31. 105. Roberts AB, Spore MB, Assoian RK, et al. Transforming growth factor [3: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 1986;83: 4167-71. 106. Baron M, Keystone EC, Gladman DD, et al. Lymphocyte subpopulations and reactivity to mitogens in patients with scleroderma. Clin Exp Immunol 1981;46: 70-6. 107. Whiteside TL, Kumagai Y, Roumm AD, et al. Suppressor cell function and T lymphocyte subpopulations in peripheral blood of patients with progressive systemic sclerosis. Arthritis Rheum 1983;7:841-7. 108. Keystone EC, Lau C, Gladman DD, et al. Immunoregulatory T cell subpopulations in patients with scleroderma using monoclonal antibodies. Clin Exp Irnmunol 1982;48:443-88. 109. Morse JH, Bodi BS. Autologous and allogeneic mixed lymphocyte reactions in progressive systemic sclerosis. Arthritis Rheum 1982;4:390-5. 110. Lode JS, Kallen PS, Lopen IH, et al. Decreased autologous mixed lymphocyte reaction (AMLR) in progressive systemic scleroderma (PSS). Arthritis Rheum 1981;24:91-7. 111. Inoshita T, Whiteside TL, Rodnan GP, et al. Abnormalities of T lymphocyte subsets in patients with progressive systemic sclerosis (PSS scleroderma). J Lab Clin Med 1981;97:264-77, 112. Johnson RL, Ziff M. Lymphokine stimulation of collagen accumulation. J Clin Invest 1976;58:240-52. 113. Wahl SM, Wahl LM, McCarthy JB. Lymphocytemediated activation of fibroblast proliferation and collagen production. J Immunol 1978;121:942-6,

480

Krieg and Meurer

114. Whiteside TL, Worrall JG, Prince RK, Buckingham RB, Rodnan GP. Soluble mediators from mononuclear cells increase the synthesis of glycosaminoglycan from dermal fibroblast cultures derived from normal subjects and progressive systemic sclerosis patients. Arthritis Rheum 1985;28:188-97. 115. Whiteside TL, Buckingham RB, Prince RK, Rodnan GP. Products of activated mononuclear cells modulate accumulation of collagen by normal dermal and scleroderma fibroblasts in culture. J Lab Clin IVied 1984; 104:355-96. 116. Jiminez SA, McArthur W, Rosenbloom J. Inhibition of collagen synthesis by mononuclear cell supernatants. J Exp Med 1979;150:1421-31. 117. Duncan MR, Perlish JS, Fleischmajer R. Lymphokine/monokine inhibition of fibroblast proliferation and collagen production: role in progressive systemic sclerosis (PSS). J Invest Dermatol 1984;83:377-84. 118. Schmidt JA, Mizel SB, Cohen D, Green J. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol 1982;5:2177-82. 119. Hermann H, Dessau W, Fessler LI, vonder Mark K. Synthesis of types I, III and AB2 collagen by chick tendon fibroblasts in vitro. Eur J Biochem 1982;105: 63-74. 120. Harper RA, Grove G. Human skin fibroblasts derived from papillary and reticular dermis: differences in growth potential in vitro. Science 1979;204:525-7. 121. Fleischmajer R, Perlish JS, Krieg T, Timpl R. Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture. J Invest Dermatol 1981;76:400-3. 122. Krieg T, Perlish JS, Mauch C, Fleischmajer R. Collagen synthesis by scleroderma fibroblasts. Ann NY Acad Sei 1986;460:375-86. 123. Botstein GR, Sherer GK, LeRoy EC. Fibroblast selection in scleroderma. Arthritis Rheum 1982;25:189-95. 124. LeRoy EC, Kahaleh MB, Mereurio S. A fibroblast mitogen present in scleroderma but not control sera: inhibition by proteinase inhibitors. Rheumatol Int 1983; 3:35-8. 125. Sundarraj N, Freeman I, Buckingham RB, Prince RK, Rodnan GP. Surface proteins of scleroderma fibroblasts in culture. J Rheumatol 1984;11:53-5. 126. LeRoy EC, Mercurio S, Shera GK. Replication and phenotypic expression of control and scleroderma human fibroblasts: responses to growth factors. Proc Natl Acad Sci USA 1982;79:1286-90. 127. Grotendorst G, Martin GR. Cell movements in woundhealing and fibrosis. In: Ktihn K, Krieg T, eds. Connective tissue: biological and clinical aspects. Basel: Karger, 1986:385-403. 128. Fleischmajer R, Perlish JS. Glycosaminoglycans in sclemderma and scleredema. J Invest Dermatol 1972; 58:124-32. 129. Uitto J, Helin G, Helin P, Lorenzen T. Connective tissue in scleroderma. Acta Derm Venereol (Stockh) 1971; 51:401-6. 130. Kitabatake M, Ishikawa H, Maeda H. Immunohistochemical demonstration of proteoglycans in the skin of patients with systemic sclerosis. Br J Dermatol 1983; 108:257-62.

Journal of the American Academy of Dermatology

131. Martin GR, Timpl R, Mtlller PK, Kfihn K. The genetically distinct collagens. Trends Biochem Sci 1985; 10:285-7. 132. Fleischmajer R, Gay S, Meigel WN, Perish JA. Collagen in the cellular and fibrotic stages of seleroderrna. Arthritis Rheum 1978;21:418-28. 133. Uitto J, Bauer EA, Eisen AZ. Scleroderma: increased biosynthesis of triple-helical type I and type III procollagens associated with unaltered expression of collagenase by skin fibroblasts in culture. J Clin Invest 1979;64:921-30. 134. Rodnan GP, Lipinski E, Luksick J. Skin collagen content in progressive systemic sclerosis (scleroderma) and localized scleroderma. Arthritis Rheum 1979;22: 130-40, 135. Uitto J, Halme J, Hannuksela M, Petrokallio P, Kivirikko KI. Procollagen proline hydroxylase activity in the skin of normal human subjects and of patients with scleroderma. Scand J Clin Lab Invest 1969;23:241-7. 136. Keiser HR, Stein HD, Sjoerdsma A. Increased protocollagen proline hydroxylase activity in sclerodermatous skin. Arch Dermatol 1971;104:57-60. 137. KriegT, LangerJ, Gerstmeier H, etal. Type III collagen aminopropeptide levels in serum of patients with progressive systemic scleroderma, J Invest Derrnatol 1986; 87:788-91. 138. Buckingham RB, Prince RK, Rodnan GP, Tayler F. Increased collagen accumulation in dermal fibroblast cultures from patients with progressive systemic sclerosis (scleroderma). J Lab Clin Med 1978;92:5-20. 139. Krieg T, Perlish JS, Fleischmajer R, Braun-Falco O. Collagen synthesis in scleroderma: selection of fibroblast populations during subcultures. Arch Dermatol Res 1986;277:373-76. 140. Graves PN, Weiss IK, Perlish JS, Fleischmajer R. Increased procollagen mRNA levels in scleroderma skin fibroblasts. J Invest Dermatol 1983 ;80:130-2. 141. Vuorio T, Maekelae JK, Vuorio E. Activation of type I collagen genes in cultured scleroderma fibroblasts. J Cell Biochem 1985;28:105-13. 142. Kxieg T, H6rlein D, Wiestner M, MiJller PK. Aminoterminal extension peptides from type I procollagen normalize excessive collagen synthesis of scleroderma fibroblasts. Arch Dermatol Res 1978;263:171-80. 143. PerlishJS, TimplR, FleischmajerR. Collagen synthesis regulation by the aminopropeptide of procollagen I in normal and scleroderma fibroblasts. Arthritis Rheum 1985;28:647-51. 144. Kivirikko KI, Myllyl/i R. Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes. Methods Enzymol 1982;82A:245-304. 145. Peltonen L, Palotie A, Myllyl/i R, Krieg T, Oikarinen A. Collagen biosynthesis in systemic scleroderma: regulation of posttranslational modifications and synthesis of procollagen in cultured fibroblasts. J Invest Dermatol 1985;84:14-8. 146. Fleischmajer R. Collagen fibrillogenesis: a mechanism of structural biology. J Invest Dermatol 1986;87:553-4. 147. Belch JJF, Newman P, Drury JK, et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud's syndrome. Lancet 1983;1:313-5. 148. Holti G. The effect of intermittent low molecular dex-

Volume 18 Number 3 March 1988

149.

150.

151.

152.

153.

154.

Systemic scleroderma 481

tran infusions upon the digital circulation in systemic sclerosis. Br J Dermatol 1965;77:560-8. Kahan A, Weber S, Amar B, Saporta L, Hodara M. Nifedipine and Raynaud's phenomenon. Ann Intern Med 1981 ;94:546-52. Rodeheffer R J, Rommer JA, Wigley F. Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon. N Engl J Med 1983;308:880-3. Lopez-Overjero JA, Saal SD, D'Angelo WA, Cheigh JS, Stenzel KH, Lavagh JH. Reversal of vascular and renal crisis of seleroderma by oral angiotensinconverting-enzyme blockade. N Engl J Med 1979; 300:1417. Strandern E, Roald OK, Krogh K. Treatment of Raynaud's phenomenon with 5-HT2-receptor antagonist ketanserin. Br Med J 1982;4:1069-71. Steen VD, Medsger TA, Rodnan GP. o-Penicillamine therapy in progressive systemic sclerosis: a retrospective analysis. Ann Intern Med 1982;97:652-9. Steigerwald JC. Progressive systemic sclerosis. Management. III. Immunosuppressive agents. Clin Rheum Dis 1979;5:284-94.

155. Blom-Boelow B, Oberg K, Wollheim FA, et al, Cyclofenil versus placebo in progressive systemic sclerosis. A one-year double blind crossover study of 27 patients. Acta Med Stand 1981;210:419-28. 156. Alarcdn-Segovia D, Ramos-Niembo F, Ibafiez de Kasep G, Alcocev J, Pdrez Tamayo R. Long-term evaluation of colchieine in the treatment of scleroderma. J Rheumatol 1979;6:705-12. 157. Thivolet J, Perrot H, Meunier F, Bochet B. Therapeutic activity of factor XIII clotting factor in scleroderma. La Nouvel. Presse Med 1975;5:27-9. 158. Asboe-HansenG. Treatment of generalized scleroderma with inhibitors of collagen synthesis. Int J Dermatol 1982;21:159-62. 159. Majarnaa K, Hanauske-Abel H, Gtinzler V, Kivikikko KI. The 2-oxoglutarate binding site of prolyl-4hydroxylase. Eur J Biochem 1984;138:239-45. 160. Hdrlein D, McPherson J, Hanfroh S, Bornstein P. Regulation of protein synthesis: translational control by procollagen derived fragments. Proe Natl Acad Sci USA 1981 ;78:6163-7.

ABSTRACTS

Polycenter evaluation of the activity and tolerability of a new antimycotic drug; Cielopirox olamine (Italian) Cattaneo M, Betti R, Lodi A, Masnada MC. Giorn Ital Derm Vener 1986;121:81-5 A total of 974 patients from the entire area of Italy participated in this study. They were suffering from various skin mycoses, the most frequent being the following: pityfiasis versicolor, 28.8%, tinea corporis, 22.7%, tinea cruris, 17A%, tinea pedis, 10.8%, and candidiasis, 6.8%. Concerning the pathogenetic microorganisms, Pityrosporum ovale orbiculare was demonstrated in 2L5%, Candida albicans in 18.0%, Epidermophyton floccosum in 16.9%, Microsporum canis in 15.2%, and Trichophyton rubrum in 9.1%. After treatment with ciclopirox olamine 1% cream or 1% lotion, good or very good therapeutic results were obtained in 87.7% of patients. Tolerance was good or very good in 96.6% of patients. Yehudi M. Felman, M.D.

Transition of pityriasis lichenoides and varioliformis acuta to pityriasis lichenoides chronica after successful treatment with methotrexate Therstappen I, Wienert V, Grubendorf-Cohen I. Akt Dermatol 1987;13:54-6 (German) This is a report of a patient with pityriasis lichenoides et varioliformis acuta, Because of the worsening skin condition during several treatments, including systemic steroids, methotrexate was administered. Rapid clearing of acute skin symptoms was seen under this

treatment. Conversion of acute to chronic pityriasis lichenoides (guttate parapsoriasis), verified histologically was then noted. Yehudi M. Felman, M.D.

Investigation of the origin and remission of dermal corticosteroid atrophy/Results of discontinuous application with topical corticosteroids (German) Bensmann A, Lubach D. Derm Beruf Umwelt 1987;35: 20-3 It was shown in two earlier papers that a reduction in skin thickness owing to daily topical corticosteroid application (under occlusion) for about 12 hours was measurable within a few days. Dermal atrophy remitted within 1 week. In this study an open mode of topical application with a 0.1% triamcinolone oinm~entonce a day was tested. A decrease in thickness was also registered in the first week under this treatment.. The following noncontinuous modes of application were tested in five test subjects: 7 days of treatment with tfiamcinNone ointment, 7 days free of treatment (7: 7) and 3 days of treatment with triameinolone ointment, 4 days free of treatment (3:4). In the 7:7 mode of application, there was a marked decrease of skin thickness during tdameinolone ointment application, which remitted in the treatment-free interval. In the 3:4 application, almost no dependence on the individual phases could be discerned. Skin thickness decreased for nearly 16 days and began to normalize despite continued interval administration. At the end of the investigation (6 weeks) the skin had almost regained its original thickness. Yehudi M. Felman, M.D.