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Scleroderma
Symposium on Rheumatic Diseases
Scleroderma Robert C. Siegel, M.D. *
Progressive systemic sclerosis (scleroderma) is a multi system disease characterized by varying degrees of vascular change, fibrosis and inflammation in the skin and internal organs. Characteristically, the disease passes through stages of inflammation, fibrosis, and atrophy.9.63 The duration of these stages varies in different organs. The earliest recognizable alteration in affected organs seems to be endothelial cell proliferation and myxomatous degeneration in small arteries 150 to 500 microns in diameter.9 This may be accompanied by a periadventitial mononuclear infiltrate. As patients often estimate the gravity of a surgical procedure by the size of their scar, physicians in the past have often estimated the severity and prognosis of the disease by the extent of cutaneous induration and thickening. Although the cutaneous abnormalities may arrest the attention of the physician and cause the patient considerable discomfort, it is clear that prognosis is related to the type and degree of visceral involvement.3s . 39 Consequently, the principal goals in this article will be to describe the effect of visceral involvement on prognosis, to discuss the known risk factors which may suggest disease of a particular organ, and to show that treatment depends on a thorough assessment of organ involvement. Evaluation and management of the patient with progressive systemic sclerosis may be particularly challenging to the internist since patients develop problems relating to all facets of internal medicine.
DIAGNOSIS OF SCLERODERMA When considering the diagnosis of scleroderma, one should remember that patients with a wide variety of diseases may develop sclerodermatous skin changes. Many of the dramatic cures of scleroderma may actually have been spontaneous remissions of other, selflimited diseases. Ironically, this seems to be true for the first reported "Assistant Professor of Medicine and Orthopaedic Surgery. University of California, San Francisco This research was supported by National Institutes of Health Grant AM 18237, Dr. Siegel is the recipient of NIH Research Career Development Award 5 K04 AM00114.
Medical Clinics of North America- Vo!. 61, No. 2, March 1977
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Table 1. Classification of Progressive Systemic Sclerosis and Diseases with "Scleroderma-Like" Syndromes "SCLERODERMA-LIKE" SYNDROMES
Mixed connective tissue disease Eosinophilic fasciitis Associated with other primary diseases Immunologic Systemic lupus erythematosus Dermatomyositis Scleromyxedema Bone marrow transplantation, graft versus host reaction Genetic Werner's syndrome Phenylketonuria Brandywine triracial isolate Tumor-associated Carcinoid Broncho-alveolar carcinoma En vironmental Vibration-induced Silicosis Polyvinyl chloride Metabolic Porphyria Amyloid Pos tinfectious Buschke's scleredema PROGRESSIVE SYSTEMIC SCLEROSIS
Acrosclerosis CREST syndrome Biliary Cirrhosis Sjogren's syndrome Diffuse scleroderma LOCALIZED FORMS
Linear scleroderma Morphea
case of "scleroderma." In this patient, a 19 year old girl, diffuse cutaneous induration developed and remitted after one year of treatment. Reported in 1659 by Curzio of Naples, this probably represents a case of Buschke's scleredemaP,45 Sclerodermatous skin changes represent one particular reaction to injury rather than a pathognomonic cutaneous finding. As noted in Table 1, indurated, fibrotic to hidebound skin may occur in a wide variety of inflammatory, metabolic, environmental, and genetic2! conditions. Of the "scleroderma-like" syndromes listed in the table, particular care should be taken to exclude the recently recognized conditions mixed connective tissue disease 5! and eosinophilic fasciitis. 52 Patients with mixed connective tissue disease have a high frequency of Raynaud's phenomenon, decreased or absent distal esophageal peristalsis, myositis, indurated skin, sausage-shaped or edematous digits, and polyserositis. They often have high titer, speckled pattern, antinuclear
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antibodies and antibody titers of 1:100,000 or greater to an extractable nuclear antigen (ENA) from calf thymus. 58 The RNA portion of the antigen is necessary for antigenicity since the antibody titer to ENA digested with ribonuclease is considerably decreased. These patients may resemble patients with systemic lupus erythematosus but they rarely have renal involvement and their disease may remit completely with high dose prednisone. Patients with eosinophilic fasciitis are predominantly middle-aged men who have a history of recent unusually heavy exercise. 46 , 50 They do not have Raynaud's phenomenon or arthritis but have indurated skin of the extremities and trunk and a peripheral eosinophilia as high as 35 per cent. They do not have antinuclear antibodies. On full-thickness biopsy of skin, fascia, and muscle, the deep fascia is characteristically infiltrated with eosinophils and thickened. There may be perivascular infiltration of histiocytes and lymphocytes in the dermis and subcutaneous fat as well,5° The natural history of the disease is not well known since only 10 cases have been described. However, in one series, 6 of 7 patients improved or had a complete remission with high dose prednisone. 46 Spontaneous remissions may also occur. Among other diseases with a sclerodermatous pattern of injury, there is particular confusion as to whether patients with systemic lupus erythematosus or dermatomyositis with Raynaud's phenomenon and skin changes represent overlap syndromes, two separate diseases, or the primary disease with a sclerodermatous cutaneous reaction. Examples of each possibility exist. However, it would seem most consistent to attempt to make a single diagnosis based on the spectrum of disease in the entire patient rather than diagnosing an "overlap" syndrome because of limited cutaneous findings. Of the other "sclerodermalike" syndromes in the table, there is particular interest currently in those related to the environment. Workers exposed to vinyl chloride have developed typical progressive systemic sclerosis with Raynaud's phenomenon and visceral involvement. 62 In addition, the incidence of progressive systemic sclerosis in coal miners and others chronically inhaling high concentrations of silica is much higher than in a control population.63 These facts suggest that this pattern of injury in certain patients may have developed as a result of exposure to other, unknown environmental factors. Among the conditions listed in Table 1 under the category of progressive systemic sclerosis, the most common form is acrosclerosis. Since 95 per cent of patients have acrosclerosis,58 most of the subsequent discussion will be concerned with this form. The incidence has been estimated at 2 to 12 per million per year with the peak onset in the third to fifth decade. 9 Over 75 per cent of patients have either Raynaud's phenomenon or skin tightening as their initial symptoms. 58 The rest usually present with a symmetric polyarthritis. Since the initial physical findings may be minimal, certain findings specific for progressive systemic sclerosis should be sought. If the patient does not have a history of Raynaud's phenomenon, an attempt should be made to provoke an attack with cold water. Although not all patients with Raynaud's phenomenon may develop typical changes, a positive test is extremely helpful. Early changes in the hands include loss of wrinkles over the knuckles,
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atrophy of distal digital pads so that they do not protrude beyond the fingernails, and loss of uniform pigmentation and sweat glands. With an ophthalmoscope at +40 or +20 plus immersion oil on the nail fold, it may be possible to observe decreased numbers of capillaries that are dilated and have very sluggish fiOW. 44 In addition, patients may have palpable or audible tendon friction rubs. Squared telangiectasias are usually not present for several years after onset of the disease. The initial laboratory evaluation may be nonspecific. Fifty per cent have hypergammaglobulinemia. Positive antinuclear antibodies occur in 50 to 60 per cent. This is often a nucleolar or speckled pattern.63 Hand x-rays usually do not show characteristic resorption of distal digital tufts for several years66 and cutaneous calcinosis may not be present on x-ray examination for 7 to 10 years after onset. Approximately 20 per cent of patients have thickened periodontal membranes. This is not related to duration or severity of the disease and is rarely seen in other diseases. Two new antibody systems that have recently been found may become suitable for diagnostic confirmation in the future. Antibodies to a tissue extract from sclerodermatous skin56 have been found in 20 per cent of a group of patients with scleroderma. This antigen does not cross-react with autoantibodies in sera from patients with other rheumatic disease. In another study, all patients with progressive systemic sclerosis had uracil-specific antibodies to single-stranded RNA.! In the absence of definite findings or confirmatory serologic tests, the tentative diagnosis is usually supported by skin biopsy. Since skin thickness is quite variable, biopsies should be done on the hand or distal forearm for uniformity. Early in the disease they may be a mononuclear infiltrate around small arterioles and increased collagen replacing fat in the deeper layers of the dermis. As the cutaneous involvement progresses, there is atrophy of skin appendages with loss of hair follicles and sweat glands, thinning of the epidermis, and increased collagen bundles that are swollen and uniformly stained throughout the dermis. Among the patients with acrosclerosis, approximately 5 per cent have the CREST syndrome. 47 ,58 This acronym stands for calcinosis, Raynaud's, esophageal motility disorder, sclerodactyly, and telangiectasia. Patients with this form of the disease usually have cutaneous involvement distal to the metacarpalphalangeal joints. The skin about the mouth and on the dorsum of the hand may also be involved. The disease progresses very slowly and the prognosis is favorable. 47 At least a portion of the favorable prognosis is probably related to selection bias since calcinosis usually does not develop until the disease has been present for 7 to 10 years. Typical visceral involvement usually does not develop in these patients, but biliary cirrhosis or Sjogren's syndrome may be present.9 However, fulminant pulmonary fibrosis and hypertension have developed in some patients with this syndrome as late as 20 years after the onset of disease. Although the existence of this particular subgroup has been questioned, recent genetic evidence suggests that they constitute a different population from other patients with acrosclerosis. Twenty-six per cent of patients with CREST in one series were B27 positive, compared to a prevalence of 6 per cent in normals. 43 In contrast to the acrosclerotic form of progressive systemic sclero-
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sis, diffuse scleroderma affects males and females equally. Patients rarely have Raynaud's, and cutaneous involvement is predominantly truncal. These patients have a more aggressive form of the disease with severe, often fulminant visceral involvement. In one series the 5 year survival was 17 per cent.57
EFFECT OF VISCERAL INVOLVEMENT ON PROGNOSIS Since survival is closely related to the type and degree of visceral involvement, it seems appropriate to consider this in more detail. Overall survival rates vary from a 90 per cent 5 year survival for patients less than 40 to 70.358 to 73 per cent5 4 5 year survival among populations composed primarily of outpatients. This contrasts with a 50 per cent 5 year survival rate among patients hospitalized with a diagnosis of progressive systemic sclerosis. 39 The cumulative survival rate at 7 per years among hospitalized veterans was 35 per cent3~ as opposed to a civilian 10 year survival rate of 58.9 per cent among a referral, primarily outpatient population. 58 It seems clear that many patients can expect prolonged survival. Decreased survival is clearly related to renal, cardiac, and pulmonary involvement,38,39 and the risk of fulminant visceral involvement is greatest in the first 5 to 6 years of disease. In one series,6 early death occurred in patients with truncal involvement, blood urea nitrogen over 40, age over 40, pulmonary abnormalities on chest x-ray, and electrocardiographic abnormalities. In a study of 358 hospitalized male veterans, 17 with renal involvement manifest by elevated creatinine or BUN were dead within 10 months. 3s Cardiac involvement was second in significance to renal. Twenty-five per cent of patients with cardiac involvement alone survived for 5 years as opposed to an overall survival rate of 50 per cent.3S With pulmonary involvement without significant cardiac involvement, there was 45 per cent survival at 5 years and 34 per cent at 7 years. This was only slightly less than the overall rate of 50 per cent at 5 years and 44 per cent at 7 years in patients without significant involvement of these organs. 3S Gastrointestinal involvement did not affect the cumulative survival rate. The expected survival rate by life table analysis at 7 years was 91 per cent so that longevity is decreased even without demonstrable internal organ disease. In a study of hospitalized patients of both sexes, the overall 5 year survival rate was 50 per cent. 39 Men had a worse prognosis than women with 60 per cent of women surviving at 5 years as opposed to 40 per cent of men. 39 Also blacks had decreased survival, with 21 per cent alive at 7 years as opposed to 59 per cent for whites. 39 The different patterns of survival with disease of different organs naturally raises the question of the per cent of patients with various types of visceral involvement. In Table 2 the per cent of patients with disease in each organ is shown. This table was compiled from two sources. In the first large clinical series, data were obtained by studying patients clinically and at postmortem. 9 The second was from a controlled postmortem series and indicates the maximum organ involvemenU 5 In this discussion, we shall concentrate primarily on the kidney,
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Table 2.
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Systemic Involvement in Scleroderma IN VIVO
(%)
Raynaud's phenomenon Skin Esophagus Small BOWel} Colon Lung Pericardium Heart Kidney Muscle Joints
POST MORTEM
(%)
(N=261)
(N=58)
78 90 52
80 98 74 46 41 81 53 81 58 41
15 43 11
40 35 20 25
heart, and lungs since these affect survival. In each case, the pathogenesis of the visceral lesions is related to decreased nutritional blood flow secondary to myxomatous degeneration of the intima of small arteries. 9 • 41 Patients who have renal involvement may present with either fulminant, hypertensive, oliguric acute renal failure, or acute renal failure with normal blood pressure. 15 There has been considerable interest in defining the population at increased risk for renal involvement. Patients with large dilated capillaries with sluggish flow in both the nailfolds and dorsum of the fingers or hand appear to have increased incidence of renal as well as other internal organ involvement. 54 In one study, 83 per cent of patients with renal involvement had antecedent hypertension, proteinuria, or elevated blood urea nitrogen. IO This contrasted with 45 per cent of patients with scleroderma without renal disease. Sixty per cent with these markers died compared to 10 per cent of those without them during the 20 years of the study.IO Another harbinger of renal disease is chronic pericardial effusion with congestive failure. Six of 11 patients with chronic pericardial effusions and congestive failure developed renal failure within 6 months. 37 Analysis of pericardial fluid in one patient with acute pericarditis showed that it was an exudate with normal complement, elevated protein, and 400 white blood cells per cu mm.20 Also, all patients with microangiopathic hemolytic anemia in one study had renal arterial fibrin deposition and renal disease. 48 Studies of renal blood flow have documented that renal blood flow decreases significantly when peripheral Raynaud's is induced by cooling the hand. to A possible clinical correlate to this is that the incidence of renal involvement with scleroderma is increased in the winter months. 20 Two-thirds of patients who developed renal failure did so during the fall and winter months. The common factor in precipitating events such as cold weather or chronic pericardial effusion seems to be that these factors cause a decrease in pressure in small renal arteries. The compromised lumen may close completely with resultant fibrinoid necrosis. 9 It had been suggested that elevated plasma renin levels may be a mediator of renal injury.55 However, it seems more likely that renin increases
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after the onset of renal failure. '9 In one study, no relation was found between peripheral renin concentration and the vascular pathology. Four patients with early renal vascular changes had normal renin and renin substrate levels. Unfortunately, there is no specific treatment for the renallesion. 55 It is advisable to control hypertension when present to prevent renal vasoconstriction. Hemodialysis is the only recourse if the patient is a suitable candidate. A few patients have undergone successful renal transplantation3I but the natural history of the disease after renal failure is largely unknown. There are suggestions that the renal disease may not recur after transplantation3I and the skin may soften during hemodialysis. Patients with cardiac involvement may present with refractory congestive failure, arrhythmias, conduction disturbances or angina with normal coronary arteries. The incidence of sudden death due to arrhythmias is increased. Six of 8 patients studied post mortem had died suddenly.27 In another study, 45 per cent of scleroderma patients with patent coronary arteries had myocardial involvement ranging from "contraction band necrosis" to fibrosis. s "Contraction band necrosis" is recognizable as dense eosinophilic banding of the cytoplasma and occurs when myocardial blood flow has been interrupted and then resumed. Of the 13 patients with severe myocardial involvement, 10 had "contraction band necrosis," 11 had significant congestive failure, and 5 died suddenly. Presumably, in patients with cardiac disease, "contraction band necrosis" implies that the myocardial small arteries have undergone vasospasm with inadequate myocardial blood flow for a short period. This is similar to the decrease in renal blood flow with cold. Coronary arteries less than 1 mm in diameter had pathologic findings similar to renal arteries with intimal fibrosis and endothelial proliferationP Recent studies on pulmonary involvement in scleroderma suggests that the pulmonary vessels also have increased reactivity to cold. In patients with scleroderma who were followed during several seasons, the diffusion capacity increased from an average of 14 to 19 in 12 patients between winter and spring and decreased from 18 to 13 in 6 between a warm and cold season. IS There was no difference when patients were tested over two consecutive warm seasons. Other studies of serial pulmonary function in scleroderma suggest that the first abnormalities demonstrable are an increase in the average mid maximal flow rate and increased closing volumes. These are indicators of small airways disease. 22 Patients may be asymptomatic with normal chest x-ray films and otherwise normal on pulmonary function testing with these findings. Biopsy of a few patients with these early pulmonary function abnormalities has revealed small artery perivascular infiltrates without fibrosis. 34 A recent therapeutic study of the effect of prednisone and penicillamine on the lung disease did not demonstrate improvement but did show that the progression of the disease was not always uniform. '4 There seemed to be periods of high and low activity. The effect of environmental factors such as temperature was not considered in this study. However, it
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seems likely that some of the dramatic responses to therapy reported in the past may have been due to changes in ambient temperature. This information will be required in the future for interpretation of pulmonary function tests that appear to indicate improvement in patients with scleroderma. Since it is not possible to consider the functional and pathologic changes in each organ system, important considerations of other organ systems that relate to management will be discussed in the section on management.
P ATHOGENESIS Although the etiology of progressive systemic sclerosis is unknown and may be multifactorial, pathologic studies suggest that the vascular system is the earliest organ affected. 9 • 4l. 54, 63 Patients may have up to a 90 per cent decrease in capillaries per cu mm and abnormal, dilated loops with sluggish flow before Raynaud's phenomenon and cutaneous in duration develop.44 In addition to myxomatous degeneration and proliferation of small artery endothelial cells, there may be perivascular inflammation.63 In early cutaneous or visceral lesions, there may be considerable inflammation. There are currently two principal hypotheses relating to the pathogenesis of these abnormalities. The wide range of immunologic abnormalities suggests there may be a fundamental defect in this system. As mentioned previously, in one study all 40 patients with scleroderma had anti-single stranded RNA antibodies;' in another, approximately 20 per cent had antibodies to an extract of scleroderma skin. 56 These antibodies did not cross-react with other autoantibodies characteristic of other rheumatic diseases. In addition 50 to 70 per cent of patients with scleroderma have hypergammaglobulinemia as well as antinuclear antibodies, which are frequently nucleolar in pattern. A high percentage may have evidence for Sjogren's syndrome,2 another "autoimmune" disease, and the incidence of B27 histocompatibility antigen is increased in the CREST subgroup of scleroderma patients.43 The other hypothesis is that the lesions of progressive systemic sclerosis occurs as a result of a primary connective tissue abnormality with abnormal fibroblast proliferation and sclerosis of blood vessels. A wide variety of studies document that collagen biosynthesis is increased in affected skin. Prolyl hydroxylase, the enzyme that converts prolyl to hydroxyprolyl residues in collagen, is increased in activity in both affected and unaffected skin from scleroderma patients.32 The concentration of reducible aldimine collagen cross-links is increased in skin from active lesions. 25 These compounds are markers of collagen biosynthesis since they decrease as collagen fibrils age. Normally, there are very low levels in adult skin. Finally, fibroblasts derived from affected skin synthesized collagen and glycosaminoglycans as a significantly greater percentage of their total protein synthesis than controls.33 This abnormality persists in culture for at least 10 cell passages. These studies suggest that there are abnormalities in both the immune and connective tissue systems in scleroderma. Perhaps a primary abnormality in the immune
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system results in production of lymphokines which stimulate connective tissue synthesis and cause the typical connective tissue changes of scleroderma. 29
MANAGEMENT As indicated previously, progressive systemic sclerosis is a chronic, incurable disease of unknown etiology. Physicians should acknowledge this before accepting patients since a major problem in patient management is the tendency for patients to search from doctor to doctor for the "miracle cure" that is being withheld from them. When initially evaluating a patient with progressive systemic sclerosis, physicians should consider whether their patient's disease may actually be a different disease with sclerodermatous changes (Table 1). In particular, the diagnosis of mixed connective tissue disease and eosinophilic fasciitis should be considered with each case since they are both responsive to high dose prednisone. The absence of Raynaud's phenomenon, present in 90 per cent or more of patients, should increase one's suspicion of the diagnosis of scleroderma. Particularly in these cases, it is useful to do confirmatory tests such as skin biopsy, attempting to elicit an attack of Raynaud's phenomenon, nail fold capillaroscopy, and dental x-rays for periodontal membrane thickening. After the diagnosis of progressive systemic sclerosis is established, specific organ involvement should be ascertained. In particular, pulmonary function tests and esophageal manometry or cine esophagogram should be done in all patients. As many as 50 per cent of patients with esophageal reflux will be asymptomatic. 42 Since some patients will have abnormal manometry with normal cine esophagograms, manometry is preferable. The routine tests of cardiac and renal function such as electrocardiography, creatine clearance, and quantitative protein excretion are usually not particularly revealing but should be done early in the disease to establish a baseline. Handfilms and x-ray films of any cutaneous areas with chronic ulceration which may contain calcium should also be done. Following initial evaluation, the physician should decide whether the patient is mildly or severely affected since patients with renal or cardiac involvement will obviously require different treatment from those with limited cutaneous in duration. Treatment should be largely symptomatic and directed toward the specific organ system. Patients should be told to expect an average of one new therapeutic agent for progressive systemic sclerosis to be reported each year. They should be cautioned about using new agents until they have been shown to be effective for their particular problems.
SKIN Among the conservative measures which most patients require are skin and esophageal care. Fingers and hands should be protected, particularly in cold weather, with gloves and lanolin creams to prevent skin
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fissures and ulcers.64 The initial edematous phase of skin involvement may improve with low dose prednisone. If digital ulcers do develop, soaps to prevent crusting are necessary and debridement with topical fibrinolysin may be tried. It should be remembered that digital ulcers are a manifestation of compromised nutritional blood flow. The ulcer usually heals after sufficient atrophy has occurred that nutritional blood flow becomes adequate again. Oral reserpine in doses up to 1.0 mg will increase nutritional blood flow but is poorly toleratedP Intra-arterial reserpine also appears to increase digital blood floWS! but it is transient and the effect on frequency of Raynaud's or healing of digital ulcers is no better than injection of intra-arterial saline.53 Oral methyldopa (AIdomet) in doses up to 2 gm per day and oral guanethidine are also reported to be effective in treatment of disabling Raynaud's phenomenon. 2, 9. 48, 60 In addition, topical nitroglycerin paste applied to the area about the ulcer appears to promote healing.49 A wide variety of other agents such as griseofulvin, low molecular weight dextrans50 and vitamin E have also been reported effective for decreasing skin tightness and Raynaud's phenomenon. Sympathectomy should be avoided since the primary lesion is loss of arterioles. There may be no additional vessels available for increased flow after sympathectomy. Therapy of cutaneous calcinosis is quite unsatisfactory. Recently disodium etidronate was found to be ineffective in 3 patients. 40 Surgical excision is often the only therapy available. However, recent studies of the mechanism of calcification indicate that the initial step in calcification in bone is formation of ),-carboxy glutamic acid from glutamic acid by a vitamin K dependent enzyme system. This amino acid has also been found in areas of calcification in sclerodermatous skin. 35 Studies on the effect of inhibiting this enzyme system by vitamin K antagonists are in progress and may provide a new approach to treatment of calcification.
GASTROINTESTINAL TRACT Distal esophageal motility disorders are closely associated with Raynaud's phenomenon. In scleroderma, the lower esophageal sphincter pressure is less than normal. Esophageal reflux with esophagitis and resultant esophageal stricture can result. Up to 50 per cent of patients with evidence of reflux by radiographic testing may be asymptomatic. 42 All patients with evidence of esophageal reflux should be begun on a hiatus hernia regimen with small amounts of liquid with meals, small feedings,4 to 6 inch elevation of the head of the bed with blocks, sitting up for 2 to 3 hours after eating and antacids. Patients with hiatus hernia and reflux are at increased risk for developing esophageal stricture. 42 If an esophageal stricture should develop, dilatation is usually the treatment of choice. Patients with scleroderma frequently have decreased intestinal motility. This may be manifest on an upper gastrointestinal tract series by dilatation of the third portion of the duodenum and prolonged transit time. 42 This may lead to bacterial overgrowth and secondary malabsorp-
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tion because of deconjugation of bile salts. Malabsorption may not be clinically obvious with steatorrhea or frequent bowel movements. Since this condition responds promptly to treatment with oral tetracycline,30 patients with scleroderma who begin to lose weight or develop low calcium or increased prothrombin time should be evaluated for malabsorption with quantitative stool fats and then treated with oral tetracycline, 250 mg four times a day for 10 days, if the diagnosis is confirmed. The other principal gastrointestinal manifestation is colonic saccular diverticula. Although patients with scleroderma are frequently constipated, these diverticula rarely become infected or otherwise symptomatic. However, if constipation is a problem, it is advisable to give the patient stool softeners and agents to increase stool bulk and prevent fecal impaction. Although there is no specific treatment for renal or pulmonary involvement, patients should be cautioned about the possible detrimental effects of cold, since studies have documented effects on both renal blood flow lO and pulmonary diffusing capacity.18 Hypertension should be treated very aggressively since it may be the first indication of fulminant renal involvement. Patients with scleroderma in whom hypertension develops should be hospitalized and evaluated by renal function tests and intravenous pyelography. Renal arteriography may demonstrate the specific renal lesion of "scleroderma kidney" with obliteration of renal intralobular arteries and prolonged retention of the dye in renal arteries as occurs with acute hypertension. Therapy should be started immediately to minimize renal damage. If irreversible renal failure does develop, the patient should be evaluated for hemodialysis. The final decision as to chronic dialysis will be based upon multiple factors, but the degree of visceral involvement should be carefully considered, since significant cardiac compromise may prevent effective hemodialysis.
TREATMENT WITH SYSTEMIC AGENTS In most studies the effectiveness of systemic agents is judged by improvement in cutaneous manifestations although this is not a significant factor in prognosis. This is a major problem in evaluating therapeutic potential. Cutaneous improvement has been reported with immunosuppressive agents such as prednisone,64 azathioprine,28 cytoxan,36 chlorambucil,36 estrogen preparations,24 D-penicillamine,4. 16. 17. 25. 59. 64 and recently colchicine.3 Documentation of improvement is often confined to clinical estimation of the degree of skin tethering. However, improvement in cutaneous involvement seems to be consistently reported with D-penicillamine. In one study, 5 of 10 improved64 and in another 25 of 34 improved, with 3 complete "cures."4 Obviously, treatment with potentially toxic agents is not justified if survival is not improved, and less potent agents will effect similar cutaneous improvement. The principal problem in evaluating therapeutic efficacy is that treatment is probably most effective early in the disease before fixed fibrotic changes occur. However, most patients will experience some cutaneous improvement after the initial inflammatory phase has subsided and some will have
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spontaneous, prolonged remissions. In this situation it seems mandatory to study new agents with objective measures of disease activity and to minimize physician bias. Aspirin is the first drug that should be considered among possible systemic agents for scleroderma. Therapeutic doses of salicylates will often relieve arthritis and reduce the inflammatory changes in the skin so that the patient may experience subjective improvement on this medication alone. Other, investigational agents should probably be reserved for patients in whom salicylates are ineffective. This may be quantitated by measurements of joint mobility such as the minimal distance between the third finger and the distal palmar crease and the interincisor distance. Also, the degree of cutaneous induration and joint stiffness and changes in the sedimentation rate may be used to follow activity of disease. Of agents currently being investigated, the two of most interest are penicillamine and colchicine. D-Penicillamine is an anti-inflammatory drug which also inhibits connective tissue biosynthesis. The mechanism of its anti-inflammatory action is unknown. There are several effects on connective tissue biosynthesis. It cleaves aldimine collagen cross-links and inhibits synthesis of collagen cross-links by forming a thiazolidine ring complex with the lysine-derived aldehydes that form cross-links.25 Patients with scleroderma who received penicillamine have noted softening of their skin lesions. The effect has also been correlated with biochemical alterations. In patients treated with Dpenicillamine the concentration of reducible aldimine cross-links in the skin decreased. 40 This is good evidence for decreased collagen biosynthesis. Penicillamine has usuaVy been given in doses of 1.5 to 3 gm per day. At this dose, toxic effects such as skin rash and proteinuria are frequent and there is a risk of aplastic anemia and membranous glomerulonephritis. Recently, studies with low dose D-penicillamine have been reportedP' 26 Since current evidence does not indicate that consistent visceral improvement results from high dose treatment, it seems reasonable to use low dose penicillamine in doses of 250 to 500 mg per day to minimize toxic effects and still obtain cutaneous benefits in patients with extensive skin lesions. Further studies are necessary to determine whether prolonged, low dose treatment early in the disease will affect progression of visceral lesions and prognosis. The second drug currently under investigation is colchicine. Colchicine is believed to stimulate collagenase activity and inhibit collagen biosynthesis by preventing collagen secretion from cells. Since it has recently been suggested that skin collagenase activity may be decreased in scleroderma7 and there is increased collagen biosynthesis, a trial of this agent seemed appropriate. Initial reports indicated that it was necessary to take the drug for several months as 0.6 mg two to three times a day, five days a week, for an effect on skin. 3 No data on visceral effects has been published. Some patients who have tried low dose colchicine have experienced nausea and vomiting and have refused to continue to take the drug. A recent study of the acute effect of colchicine in patients failed to document evidence of decreased collagen biosynthesis or increased collagen breakdown after colchicine infusion. 23 For these rea-
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sons, this drug has not been widely accepted. Additional controlled studies with documentation of improvement are required. In conclusion, when attempting to treat the patient with progressive systemic sclerosis, the physician should be aware that he is assuming a long term responsibility for a patient who may frequently become discouraged or depressed. Perhaps the best advice is "go slow and go low"26 in drug use. The most important aspects of therapy are those related to symptomatic therapy for each system involved. Only after this program of symptomatic therapy has been designed and accepted should the physician consider the use of systemic agents such as D-penicillamine. Since none of these is proven to affect visceral involvement, the potential benefits for each patient should be carefully weighed against the possible side effects and relative activity and stage of disease. Effective systemic therapy will not be possible without greater understanding of pathogenesis and recognition of the factors which identify patients at greatest risk and most likely to benefit.
REFERENCES 1. Alarc6n-Sergovia, D., and Fishbein, E.: Immunochemical characterization of the antiRNA antibodies found in scleroderma and systemic lupus erythematosus. J. Immunol., 115 :28-31, 1975. 2. Alarc6n-Sergovia, D., Ibaiiz, G., Hernandez-Ortiz, J., et aI.: Sjl'lgren' syndrome in progressive systemic sclerosis (scleroderma). Amer. J. Med., 57:78-85,1974. 3. Alarc6n-Segovia, D., IbMiez, G., Kershenobich, D., et aI.: Treatment of scleroderma. Lancet, 1 :1054-1055,1974. 4. Asboe-Hansen, G.: Treatment of generalized scleroderma with inhibitors of connective tissue formation. Acta Dermat. (Stockholm), 55 :461-465, 1975. 5. Ayers, S., Mihan, R., Levan, N. E., et al.: Raynaud's phenomenon, scleroderma and calcinosis cutis: Response to vitamin E. Cutis, 11 :54-62, 1973. 6. Bennett, R, Bluestone, R, Holt, P. J. L., etaI.: Survivalin scleroderma. Ann. Rheum. Dis., 30:581-588,1971. 7. Brady, A. H.: Collagenase in scleroderma. J. Clin. Invest., 56: 1175-1180, 1975. 8. Bulkley, B. H., Ridolfi, R. L., Salyer, W. R, et al.: Myocardial lesions of progressive systemic sclerosis. Circulation, 53 :483-490, 1976. 9. Campbell, P. M., and LeRoy, E. C.: Pathogenesis of systemic sclerosis: A vascular hypothesis. Sem. Arthrit. Rheum., 4:351-368,1975. 10. Cannon, P. J., Hassar, M., Case, D. B., et al.: The relationship of hypertension and renal failure in scleroderma (progressive systemic sclerosis) to structural and functional abnormalities of the renal cortical circulation. Medicine, 53: 1-46, 1974. 11. Capusan, I.: Curzio's case of scleroderma. Ann. Intern. Med., 76:146,1972. 12. Coffman, J. D., and Cohen, A. S.: Total and capillary fingertip blood flow in Raynaud's phenomenon. New Eng. J. Med., 285:259-263,1971. 13. Cohen, S., Fisher, R, Lipshutz, W., et al.: The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J. Clin. Invest., 51 :2663-2668, 1972. 14. Colp, C. R, Riker, J., and Williams, H.: Serial changes in scleroderma and idiopathic interstitiallung disease. Arch. Intern. Med., 132:506-515,1973. 15. D'Angelo, W. A., Fries, J. F., Masi, A. T., et al.: Pathologic observations in systemic sclerosis. Amer. J. Med., 46:428-440,1969. 16. Davis, P., and Bleehen, S. S.: D-Penicillamine in the treatment of rheumatoid arthritis and progressive systemic sclerosis. Brit. J. Derm., 94:705-711,1976. 17. Drug Ther. Bull., 12(9):75-76, 1974. 18. Emmannel, G., Saroja, D., Gopinathan, K., et al.: Environmental factors and the diffusing capacity of the lungs in progressive systemic sclerosis. Chest, 69 (SuppI.) 2:304-307, 1976. 19. Fleischmajer, R, and Gould, A. B.: Serum renin and renin substrate levels in scleroderma. Proc. Soc. Exper. BioI. Med., 150:374-379, 1975. 20. Gladman, D. D., Gordon, D. A., Urowitz, M. D., et aI.: Pericardial fluid analysis in scleroderma (systemic sclerosis). Amer. J. Med., 60:1064-1068,1976. 21. Greger, R. E.: Familial progressive systemic scleroderma. Arch. Derm., 111 :81-85, 1975.
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22. Guttadauria. M., Saroja, D., Gopinathan, P., et al.: Small airway disease in scleroderma. Arthritis Rheum., 18:283-284,1975. 23. Harris, K D., Jr., Hoffman, G. S., McGuire, J. L., et al: Colchicine: Effects upon urinary hydroxyproline excretion in patients with scleroderma. Metabolism, 24 :529-535, 1975. 24. Herbai, G.: Treatment of progressive systemic sclerosis with a synthetic weak estrogen cyclofenil (sexovid). Acta Med. Scand., 196:537-540,1974. 25. Herbert, C. M., Jayson, M. I. V., Lindberg, K. A., et al.: Biosynthesis and maturation of skin collagen in scleroderma and effect of D-penicillamine. Lancet, 1 :187-192,1974. 26. Jaffe, I. A.: The technique of penicillamine administration in rheumatoid arthritis. Arthritis Rheum., 18:513-514,1975. 27. James, T. N.: De subitaneis mortibus VIII coronary arteries and conduction system in scleroderma heart disease. Circulation, 50:844-856, 1974. 28. Jansen, G. T., Barraza, D. F., Ballard, J. L., et al.: Generalized scleroderma: Treatment with an immunosuppressive agent. Arch. Derm., 97:690-698, 1968. 29. Johnson, R. L., and Ziff, M.: Lymphokine stimulation of collagen accumulation. J. Clin. Invest., 58:240-252,1976. 30. Kahn, I. J., Jeffries, G. H., and Sleisinger, M. H.: Malabsorption in intestinal scleroderma. New Eng. J. Med., 274:1339-1344,1966. 31. Keane, W. F., Danielson, B., and Raij, L.: Successful renal transplantation in progressive systemic sclerosis. Ann. Intern. Med., 85:199-202,1976. 32. Keiser, H. R., Stein, H. D., and Sjoerdsma, H.: Increased protocollagen proline hydroxylase activity and sclerodermatous skin; Arch. Derm., 104:57-60, 1971. 33. LeRoy, K C.: Connective tissue synthesis by scleroderma skin fibroblasts in culture. J. Exper. Med., 135:1351-1362,1972. 34. LeRoy, K C.: Personal communication. 35. Lian, J. B.: Personal communication. 36. Mackenzie, A. H.: Prolonged alkylating drug therapy is beneficial in systemic scleroderma (PSS). Arthritis Rheum., 13:334, 1970. 37. McWhorter, J. K, and LeRoy, K C.: Pericardial disease in scleroderma. Amer. J. Med., 57:566-575,1974. 38. Medsger, T. A., and Masi, A. T.: Survival with scleroderma. 11: A life-table analysis of clinical and demographic factors in 358 male V.S. veteran patients. J. Chron. Dis., 26:647-660, 1973. 39. Medsger, T. A., Masi, A. T., Rodnan, G. P., et al.: Survival with systemic sclerosis (scleroderma). Ann. Intern. Med., 75:369-376,1971. 40. Metzger, A. L., Singer, F. R., Bluestone, R, et al.: Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. New Eng. J. Med., 291 :1294-1296, 1974. 41. Norton, W. L., and Nardo, J. M.: Vascular disease in progressive systemic sclerosis. Ann. Intern. Med., 73:317-324, 1970. 42. Poirer, T. ]., and Rankin, G. B.: Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Amer. J. Gastroent., 58:30-44,1972. 43. Rabin, B. S., Rodnan, G. P., Bassion, S., et al.: HLA antigens in progressive systemic sclerosis (scleroderma). Arthritis Rheum., 18 :381-382, 1975. 44. Redisch, W., Messina, K J., Hughes, G., et al.: Capillaroscopic observations in rheumatic diseases. Ann. Rheum. Dis., 29:244-253,1970. 45. Rodnan, G. P., and Benedek, T. G.: An historical account of the study of progressive systemic sclerosis. Ann. Intern. Med., 57:305-319,1962. 46. Rodnan, G. P., Di Bartolomeo, A. G., Medsger, T. A., et al.: Eosinophilic fasciitis-Report of seven cases of a newly recognized scleroderma-like syndrome. Arthritis Rheum., 18 :442-443, 1975. 47. Rodnan, G. P., Medsger, T. A., and Buckingham, R B.: Progressive systemic sclerosis-Crest syndrome: Observations on natural history and late complications in 96 patients. 48. Salyer, W. R., Salyer, D. C., and Heptinstall, R H.: Scleroderma and microangiopathic hemolytic anemia. Ann. Intern. Med., 78:895-897,1973. 49. Samuels, B.: Personal communication. 50. Schumacher, H. R: A scleroderma-like syndrome with fasciitis, myositis and eosinophilia. Ann. Intern. Med., 84:49-50, 1976. 51. Sharp, G. C., Irvin, W. S., Tan, K M., et al.: Mixed connective tissue disease. Amer. J. Med., 52:148-159,1972. 52. Shulman, L. K: Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? (abstract) J. Rheum., 1 (Suppl. 1): 46, 1974. 53. Siegel, R C., and Fries, J. F.: Intra-arterially administered reserpine and saline in scleroderma. Arch. Intern. Med., 134:515-518,1974. 54. Spencer-Green, G., Maricq, H. R, and LeRoy, K C.: Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis). In press.
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55. Stone, R. A., Tisher, C. C., Hawkins, H. K., et al.: Juxtaglomerular hyperplasia and hyperreninemia in progressive systemic sclerosis complicated by acute renal failure. Amer. J. Med., 56:119-123,1974. 56. Tan, E. M., and Rodnan, G. P.: Profile of antinuclear antibodies in progressive systemic sclerosis (PSS). Arthritis Rheum., 18 :430, 1975. 57. Tuffanelli, D. L., and Winkelmann, R. K.: Diffuse systemic scleroderma. Ann. Intern. Med., 57:198-203,1962. 58. Tuffanelli, D. L., and Winkelmann, R. K.: Systemic scleroderma. Arch. Derm., 84:359371, 1961. 59. Uitto, J., Helin, P., Rasmussen, 0., et al.: Skin collagen in patients with scleroderma: Biosynthesis and maturation in vitro and the effect of D-penicillamine. Ann. Clin. Res., 2:228-234, 1970. 60. Varadi, D. P., and Lawrence, A. M.: Suppression of Raynaud's phenomenon by methyldopa. Arch. Intern. Med., 124:13-18, 1969. 61. Willerson, J. T., Thompson, R. H., Hookman, P., et al.: Reserpine in Raynaud's disease and phenomenon. Ann. Intern. Med., 72:17-27,1970. 62. Wilson, R. H., McCormick, W. E., Tatum, C. F., et al.: Occupational acro-osteolysis: report of 31 cases. J,A.M.A., 201 :577-581, 1967. 63. Winkelmann, R. K.: Pathogenesis and staging of scleroderma. Acta Dermat. (Stockholm), 56:83-92. 1976. 64. Winkelmann, R. K., Kierland, R. R., Perry, H. 0., et al.: Management of scleroderma. Mayo Clin. Proc., 46:128-134,1971. 65. Wong, W. H., Freedman, R. 1., Rabens, S. F., et al.: Low molecular weight dextran therapy for scleroderma. Arch. Dermatol., 110:419-422,1964. 66. Yune, H. Y., Vix, V. A., and Klatte, E. C.: Early fingertip changes in scleroderma. J.A.M.A., 215:1113-1116,1971. Department of Medicine University of California School of Medicine 3rd Avenue and Parnassus Street San Francisco, California 94143
Scleroderma Robert C. Siegel, M.D. *
Progressive systemic sclerosis (scleroderma) is a multi system disease characterized by varying degrees of vascular change, fibrosis and inflammation in the skin and internal organs. Characteristically, the disease passes through stages of inflammation, fibrosis, and atrophy.9.63 The duration of these stages varies in different organs. The earliest recognizable alteration in affected organs seems to be endothelial cell proliferation and myxomatous degeneration in small arteries 150 to 500 microns in diameter.9 This may be accompanied by a periadventitial mononuclear infiltrate. As patients often estimate the gravity of a surgical procedure by the size of their scar, physicians in the past have often estimated the severity and prognosis of the disease by the extent of cutaneous induration and thickening. Although the cutaneous abnormalities may arrest the attention of the physician and cause the patient considerable discomfort, it is clear that prognosis is related to the type and degree of visceral involvement.3s . 39 Consequently, the principal goals in this article will be to describe the effect of visceral involvement on prognosis, to discuss the known risk factors which may suggest disease of a particular organ, and to show that treatment depends on a thorough assessment of organ involvement. Evaluation and management of the patient with progressive systemic sclerosis may be particularly challenging to the internist since patients develop problems relating to all facets of internal medicine.
DIAGNOSIS OF SCLERODERMA When considering the diagnosis of scleroderma, one should remember that patients with a wide variety of diseases may develop sclerodermatous skin changes. Many of the dramatic cures of scleroderma may actually have been spontaneous remissions of other, selflimited diseases. Ironically, this seems to be true for the first reported "Assistant Professor of Medicine and Orthopaedic Surgery. University of California, San Francisco This research was supported by National Institutes of Health Grant AM 18237, Dr. Siegel is the recipient of NIH Research Career Development Award 5 K04 AM00114.
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Table 1. Classification of Progressive Systemic Sclerosis and Diseases with "Scleroderma-Like" Syndromes "SCLERODERMA-LIKE" SYNDROMES
Mixed connective tissue disease Eosinophilic fasciitis Associated with other primary diseases Immunologic Systemic lupus erythematosus Dermatomyositis Scleromyxedema Bone marrow transplantation, graft versus host reaction Genetic Werner's syndrome Phenylketonuria Brandywine triracial isolate Tumor-associated Carcinoid Broncho-alveolar carcinoma En vironmental Vibration-induced Silicosis Polyvinyl chloride Metabolic Porphyria Amyloid Pos tinfectious Buschke's scleredema PROGRESSIVE SYSTEMIC SCLEROSIS
Acrosclerosis CREST syndrome Biliary Cirrhosis Sjogren's syndrome Diffuse scleroderma LOCALIZED FORMS
Linear scleroderma Morphea
case of "scleroderma." In this patient, a 19 year old girl, diffuse cutaneous induration developed and remitted after one year of treatment. Reported in 1659 by Curzio of Naples, this probably represents a case of Buschke's scleredemaP,45 Sclerodermatous skin changes represent one particular reaction to injury rather than a pathognomonic cutaneous finding. As noted in Table 1, indurated, fibrotic to hidebound skin may occur in a wide variety of inflammatory, metabolic, environmental, and genetic2! conditions. Of the "scleroderma-like" syndromes listed in the table, particular care should be taken to exclude the recently recognized conditions mixed connective tissue disease 5! and eosinophilic fasciitis. 52 Patients with mixed connective tissue disease have a high frequency of Raynaud's phenomenon, decreased or absent distal esophageal peristalsis, myositis, indurated skin, sausage-shaped or edematous digits, and polyserositis. They often have high titer, speckled pattern, antinuclear
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antibodies and antibody titers of 1:100,000 or greater to an extractable nuclear antigen (ENA) from calf thymus. 58 The RNA portion of the antigen is necessary for antigenicity since the antibody titer to ENA digested with ribonuclease is considerably decreased. These patients may resemble patients with systemic lupus erythematosus but they rarely have renal involvement and their disease may remit completely with high dose prednisone. Patients with eosinophilic fasciitis are predominantly middle-aged men who have a history of recent unusually heavy exercise. 46 , 50 They do not have Raynaud's phenomenon or arthritis but have indurated skin of the extremities and trunk and a peripheral eosinophilia as high as 35 per cent. They do not have antinuclear antibodies. On full-thickness biopsy of skin, fascia, and muscle, the deep fascia is characteristically infiltrated with eosinophils and thickened. There may be perivascular infiltration of histiocytes and lymphocytes in the dermis and subcutaneous fat as well,5° The natural history of the disease is not well known since only 10 cases have been described. However, in one series, 6 of 7 patients improved or had a complete remission with high dose prednisone. 46 Spontaneous remissions may also occur. Among other diseases with a sclerodermatous pattern of injury, there is particular confusion as to whether patients with systemic lupus erythematosus or dermatomyositis with Raynaud's phenomenon and skin changes represent overlap syndromes, two separate diseases, or the primary disease with a sclerodermatous cutaneous reaction. Examples of each possibility exist. However, it would seem most consistent to attempt to make a single diagnosis based on the spectrum of disease in the entire patient rather than diagnosing an "overlap" syndrome because of limited cutaneous findings. Of the other "sclerodermalike" syndromes in the table, there is particular interest currently in those related to the environment. Workers exposed to vinyl chloride have developed typical progressive systemic sclerosis with Raynaud's phenomenon and visceral involvement. 62 In addition, the incidence of progressive systemic sclerosis in coal miners and others chronically inhaling high concentrations of silica is much higher than in a control population.63 These facts suggest that this pattern of injury in certain patients may have developed as a result of exposure to other, unknown environmental factors. Among the conditions listed in Table 1 under the category of progressive systemic sclerosis, the most common form is acrosclerosis. Since 95 per cent of patients have acrosclerosis,58 most of the subsequent discussion will be concerned with this form. The incidence has been estimated at 2 to 12 per million per year with the peak onset in the third to fifth decade. 9 Over 75 per cent of patients have either Raynaud's phenomenon or skin tightening as their initial symptoms. 58 The rest usually present with a symmetric polyarthritis. Since the initial physical findings may be minimal, certain findings specific for progressive systemic sclerosis should be sought. If the patient does not have a history of Raynaud's phenomenon, an attempt should be made to provoke an attack with cold water. Although not all patients with Raynaud's phenomenon may develop typical changes, a positive test is extremely helpful. Early changes in the hands include loss of wrinkles over the knuckles,
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atrophy of distal digital pads so that they do not protrude beyond the fingernails, and loss of uniform pigmentation and sweat glands. With an ophthalmoscope at +40 or +20 plus immersion oil on the nail fold, it may be possible to observe decreased numbers of capillaries that are dilated and have very sluggish fiOW. 44 In addition, patients may have palpable or audible tendon friction rubs. Squared telangiectasias are usually not present for several years after onset of the disease. The initial laboratory evaluation may be nonspecific. Fifty per cent have hypergammaglobulinemia. Positive antinuclear antibodies occur in 50 to 60 per cent. This is often a nucleolar or speckled pattern.63 Hand x-rays usually do not show characteristic resorption of distal digital tufts for several years66 and cutaneous calcinosis may not be present on x-ray examination for 7 to 10 years after onset. Approximately 20 per cent of patients have thickened periodontal membranes. This is not related to duration or severity of the disease and is rarely seen in other diseases. Two new antibody systems that have recently been found may become suitable for diagnostic confirmation in the future. Antibodies to a tissue extract from sclerodermatous skin56 have been found in 20 per cent of a group of patients with scleroderma. This antigen does not cross-react with autoantibodies in sera from patients with other rheumatic disease. In another study, all patients with progressive systemic sclerosis had uracil-specific antibodies to single-stranded RNA.! In the absence of definite findings or confirmatory serologic tests, the tentative diagnosis is usually supported by skin biopsy. Since skin thickness is quite variable, biopsies should be done on the hand or distal forearm for uniformity. Early in the disease they may be a mononuclear infiltrate around small arterioles and increased collagen replacing fat in the deeper layers of the dermis. As the cutaneous involvement progresses, there is atrophy of skin appendages with loss of hair follicles and sweat glands, thinning of the epidermis, and increased collagen bundles that are swollen and uniformly stained throughout the dermis. Among the patients with acrosclerosis, approximately 5 per cent have the CREST syndrome. 47 ,58 This acronym stands for calcinosis, Raynaud's, esophageal motility disorder, sclerodactyly, and telangiectasia. Patients with this form of the disease usually have cutaneous involvement distal to the metacarpalphalangeal joints. The skin about the mouth and on the dorsum of the hand may also be involved. The disease progresses very slowly and the prognosis is favorable. 47 At least a portion of the favorable prognosis is probably related to selection bias since calcinosis usually does not develop until the disease has been present for 7 to 10 years. Typical visceral involvement usually does not develop in these patients, but biliary cirrhosis or Sjogren's syndrome may be present.9 However, fulminant pulmonary fibrosis and hypertension have developed in some patients with this syndrome as late as 20 years after the onset of disease. Although the existence of this particular subgroup has been questioned, recent genetic evidence suggests that they constitute a different population from other patients with acrosclerosis. Twenty-six per cent of patients with CREST in one series were B27 positive, compared to a prevalence of 6 per cent in normals. 43 In contrast to the acrosclerotic form of progressive systemic sclero-
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sis, diffuse scleroderma affects males and females equally. Patients rarely have Raynaud's, and cutaneous involvement is predominantly truncal. These patients have a more aggressive form of the disease with severe, often fulminant visceral involvement. In one series the 5 year survival was 17 per cent.57
EFFECT OF VISCERAL INVOLVEMENT ON PROGNOSIS Since survival is closely related to the type and degree of visceral involvement, it seems appropriate to consider this in more detail. Overall survival rates vary from a 90 per cent 5 year survival for patients less than 40 to 70.358 to 73 per cent5 4 5 year survival among populations composed primarily of outpatients. This contrasts with a 50 per cent 5 year survival rate among patients hospitalized with a diagnosis of progressive systemic sclerosis. 39 The cumulative survival rate at 7 per years among hospitalized veterans was 35 per cent3~ as opposed to a civilian 10 year survival rate of 58.9 per cent among a referral, primarily outpatient population. 58 It seems clear that many patients can expect prolonged survival. Decreased survival is clearly related to renal, cardiac, and pulmonary involvement,38,39 and the risk of fulminant visceral involvement is greatest in the first 5 to 6 years of disease. In one series,6 early death occurred in patients with truncal involvement, blood urea nitrogen over 40, age over 40, pulmonary abnormalities on chest x-ray, and electrocardiographic abnormalities. In a study of 358 hospitalized male veterans, 17 with renal involvement manifest by elevated creatinine or BUN were dead within 10 months. 3s Cardiac involvement was second in significance to renal. Twenty-five per cent of patients with cardiac involvement alone survived for 5 years as opposed to an overall survival rate of 50 per cent.3S With pulmonary involvement without significant cardiac involvement, there was 45 per cent survival at 5 years and 34 per cent at 7 years. This was only slightly less than the overall rate of 50 per cent at 5 years and 44 per cent at 7 years in patients without significant involvement of these organs. 3S Gastrointestinal involvement did not affect the cumulative survival rate. The expected survival rate by life table analysis at 7 years was 91 per cent so that longevity is decreased even without demonstrable internal organ disease. In a study of hospitalized patients of both sexes, the overall 5 year survival rate was 50 per cent. 39 Men had a worse prognosis than women with 60 per cent of women surviving at 5 years as opposed to 40 per cent of men. 39 Also blacks had decreased survival, with 21 per cent alive at 7 years as opposed to 59 per cent for whites. 39 The different patterns of survival with disease of different organs naturally raises the question of the per cent of patients with various types of visceral involvement. In Table 2 the per cent of patients with disease in each organ is shown. This table was compiled from two sources. In the first large clinical series, data were obtained by studying patients clinically and at postmortem. 9 The second was from a controlled postmortem series and indicates the maximum organ involvemenU 5 In this discussion, we shall concentrate primarily on the kidney,
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Systemic Involvement in Scleroderma IN VIVO
(%)
Raynaud's phenomenon Skin Esophagus Small BOWel} Colon Lung Pericardium Heart Kidney Muscle Joints
POST MORTEM
(%)
(N=261)
(N=58)
78 90 52
80 98 74 46 41 81 53 81 58 41
15 43 11
40 35 20 25
heart, and lungs since these affect survival. In each case, the pathogenesis of the visceral lesions is related to decreased nutritional blood flow secondary to myxomatous degeneration of the intima of small arteries. 9 • 41 Patients who have renal involvement may present with either fulminant, hypertensive, oliguric acute renal failure, or acute renal failure with normal blood pressure. 15 There has been considerable interest in defining the population at increased risk for renal involvement. Patients with large dilated capillaries with sluggish flow in both the nailfolds and dorsum of the fingers or hand appear to have increased incidence of renal as well as other internal organ involvement. 54 In one study, 83 per cent of patients with renal involvement had antecedent hypertension, proteinuria, or elevated blood urea nitrogen. IO This contrasted with 45 per cent of patients with scleroderma without renal disease. Sixty per cent with these markers died compared to 10 per cent of those without them during the 20 years of the study.IO Another harbinger of renal disease is chronic pericardial effusion with congestive failure. Six of 11 patients with chronic pericardial effusions and congestive failure developed renal failure within 6 months. 37 Analysis of pericardial fluid in one patient with acute pericarditis showed that it was an exudate with normal complement, elevated protein, and 400 white blood cells per cu mm.20 Also, all patients with microangiopathic hemolytic anemia in one study had renal arterial fibrin deposition and renal disease. 48 Studies of renal blood flow have documented that renal blood flow decreases significantly when peripheral Raynaud's is induced by cooling the hand. to A possible clinical correlate to this is that the incidence of renal involvement with scleroderma is increased in the winter months. 20 Two-thirds of patients who developed renal failure did so during the fall and winter months. The common factor in precipitating events such as cold weather or chronic pericardial effusion seems to be that these factors cause a decrease in pressure in small renal arteries. The compromised lumen may close completely with resultant fibrinoid necrosis. 9 It had been suggested that elevated plasma renin levels may be a mediator of renal injury.55 However, it seems more likely that renin increases
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after the onset of renal failure. '9 In one study, no relation was found between peripheral renin concentration and the vascular pathology. Four patients with early renal vascular changes had normal renin and renin substrate levels. Unfortunately, there is no specific treatment for the renallesion. 55 It is advisable to control hypertension when present to prevent renal vasoconstriction. Hemodialysis is the only recourse if the patient is a suitable candidate. A few patients have undergone successful renal transplantation3I but the natural history of the disease after renal failure is largely unknown. There are suggestions that the renal disease may not recur after transplantation3I and the skin may soften during hemodialysis. Patients with cardiac involvement may present with refractory congestive failure, arrhythmias, conduction disturbances or angina with normal coronary arteries. The incidence of sudden death due to arrhythmias is increased. Six of 8 patients studied post mortem had died suddenly.27 In another study, 45 per cent of scleroderma patients with patent coronary arteries had myocardial involvement ranging from "contraction band necrosis" to fibrosis. s "Contraction band necrosis" is recognizable as dense eosinophilic banding of the cytoplasma and occurs when myocardial blood flow has been interrupted and then resumed. Of the 13 patients with severe myocardial involvement, 10 had "contraction band necrosis," 11 had significant congestive failure, and 5 died suddenly. Presumably, in patients with cardiac disease, "contraction band necrosis" implies that the myocardial small arteries have undergone vasospasm with inadequate myocardial blood flow for a short period. This is similar to the decrease in renal blood flow with cold. Coronary arteries less than 1 mm in diameter had pathologic findings similar to renal arteries with intimal fibrosis and endothelial proliferationP Recent studies on pulmonary involvement in scleroderma suggests that the pulmonary vessels also have increased reactivity to cold. In patients with scleroderma who were followed during several seasons, the diffusion capacity increased from an average of 14 to 19 in 12 patients between winter and spring and decreased from 18 to 13 in 6 between a warm and cold season. IS There was no difference when patients were tested over two consecutive warm seasons. Other studies of serial pulmonary function in scleroderma suggest that the first abnormalities demonstrable are an increase in the average mid maximal flow rate and increased closing volumes. These are indicators of small airways disease. 22 Patients may be asymptomatic with normal chest x-ray films and otherwise normal on pulmonary function testing with these findings. Biopsy of a few patients with these early pulmonary function abnormalities has revealed small artery perivascular infiltrates without fibrosis. 34 A recent therapeutic study of the effect of prednisone and penicillamine on the lung disease did not demonstrate improvement but did show that the progression of the disease was not always uniform. '4 There seemed to be periods of high and low activity. The effect of environmental factors such as temperature was not considered in this study. However, it
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seems likely that some of the dramatic responses to therapy reported in the past may have been due to changes in ambient temperature. This information will be required in the future for interpretation of pulmonary function tests that appear to indicate improvement in patients with scleroderma. Since it is not possible to consider the functional and pathologic changes in each organ system, important considerations of other organ systems that relate to management will be discussed in the section on management.
P ATHOGENESIS Although the etiology of progressive systemic sclerosis is unknown and may be multifactorial, pathologic studies suggest that the vascular system is the earliest organ affected. 9 • 4l. 54, 63 Patients may have up to a 90 per cent decrease in capillaries per cu mm and abnormal, dilated loops with sluggish flow before Raynaud's phenomenon and cutaneous in duration develop.44 In addition to myxomatous degeneration and proliferation of small artery endothelial cells, there may be perivascular inflammation.63 In early cutaneous or visceral lesions, there may be considerable inflammation. There are currently two principal hypotheses relating to the pathogenesis of these abnormalities. The wide range of immunologic abnormalities suggests there may be a fundamental defect in this system. As mentioned previously, in one study all 40 patients with scleroderma had anti-single stranded RNA antibodies;' in another, approximately 20 per cent had antibodies to an extract of scleroderma skin. 56 These antibodies did not cross-react with other autoantibodies characteristic of other rheumatic diseases. In addition 50 to 70 per cent of patients with scleroderma have hypergammaglobulinemia as well as antinuclear antibodies, which are frequently nucleolar in pattern. A high percentage may have evidence for Sjogren's syndrome,2 another "autoimmune" disease, and the incidence of B27 histocompatibility antigen is increased in the CREST subgroup of scleroderma patients.43 The other hypothesis is that the lesions of progressive systemic sclerosis occurs as a result of a primary connective tissue abnormality with abnormal fibroblast proliferation and sclerosis of blood vessels. A wide variety of studies document that collagen biosynthesis is increased in affected skin. Prolyl hydroxylase, the enzyme that converts prolyl to hydroxyprolyl residues in collagen, is increased in activity in both affected and unaffected skin from scleroderma patients.32 The concentration of reducible aldimine collagen cross-links is increased in skin from active lesions. 25 These compounds are markers of collagen biosynthesis since they decrease as collagen fibrils age. Normally, there are very low levels in adult skin. Finally, fibroblasts derived from affected skin synthesized collagen and glycosaminoglycans as a significantly greater percentage of their total protein synthesis than controls.33 This abnormality persists in culture for at least 10 cell passages. These studies suggest that there are abnormalities in both the immune and connective tissue systems in scleroderma. Perhaps a primary abnormality in the immune
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system results in production of lymphokines which stimulate connective tissue synthesis and cause the typical connective tissue changes of scleroderma. 29
MANAGEMENT As indicated previously, progressive systemic sclerosis is a chronic, incurable disease of unknown etiology. Physicians should acknowledge this before accepting patients since a major problem in patient management is the tendency for patients to search from doctor to doctor for the "miracle cure" that is being withheld from them. When initially evaluating a patient with progressive systemic sclerosis, physicians should consider whether their patient's disease may actually be a different disease with sclerodermatous changes (Table 1). In particular, the diagnosis of mixed connective tissue disease and eosinophilic fasciitis should be considered with each case since they are both responsive to high dose prednisone. The absence of Raynaud's phenomenon, present in 90 per cent or more of patients, should increase one's suspicion of the diagnosis of scleroderma. Particularly in these cases, it is useful to do confirmatory tests such as skin biopsy, attempting to elicit an attack of Raynaud's phenomenon, nail fold capillaroscopy, and dental x-rays for periodontal membrane thickening. After the diagnosis of progressive systemic sclerosis is established, specific organ involvement should be ascertained. In particular, pulmonary function tests and esophageal manometry or cine esophagogram should be done in all patients. As many as 50 per cent of patients with esophageal reflux will be asymptomatic. 42 Since some patients will have abnormal manometry with normal cine esophagograms, manometry is preferable. The routine tests of cardiac and renal function such as electrocardiography, creatine clearance, and quantitative protein excretion are usually not particularly revealing but should be done early in the disease to establish a baseline. Handfilms and x-ray films of any cutaneous areas with chronic ulceration which may contain calcium should also be done. Following initial evaluation, the physician should decide whether the patient is mildly or severely affected since patients with renal or cardiac involvement will obviously require different treatment from those with limited cutaneous in duration. Treatment should be largely symptomatic and directed toward the specific organ system. Patients should be told to expect an average of one new therapeutic agent for progressive systemic sclerosis to be reported each year. They should be cautioned about using new agents until they have been shown to be effective for their particular problems.
SKIN Among the conservative measures which most patients require are skin and esophageal care. Fingers and hands should be protected, particularly in cold weather, with gloves and lanolin creams to prevent skin
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fissures and ulcers.64 The initial edematous phase of skin involvement may improve with low dose prednisone. If digital ulcers do develop, soaps to prevent crusting are necessary and debridement with topical fibrinolysin may be tried. It should be remembered that digital ulcers are a manifestation of compromised nutritional blood flow. The ulcer usually heals after sufficient atrophy has occurred that nutritional blood flow becomes adequate again. Oral reserpine in doses up to 1.0 mg will increase nutritional blood flow but is poorly toleratedP Intra-arterial reserpine also appears to increase digital blood floWS! but it is transient and the effect on frequency of Raynaud's or healing of digital ulcers is no better than injection of intra-arterial saline.53 Oral methyldopa (AIdomet) in doses up to 2 gm per day and oral guanethidine are also reported to be effective in treatment of disabling Raynaud's phenomenon. 2, 9. 48, 60 In addition, topical nitroglycerin paste applied to the area about the ulcer appears to promote healing.49 A wide variety of other agents such as griseofulvin, low molecular weight dextrans50 and vitamin E have also been reported effective for decreasing skin tightness and Raynaud's phenomenon. Sympathectomy should be avoided since the primary lesion is loss of arterioles. There may be no additional vessels available for increased flow after sympathectomy. Therapy of cutaneous calcinosis is quite unsatisfactory. Recently disodium etidronate was found to be ineffective in 3 patients. 40 Surgical excision is often the only therapy available. However, recent studies of the mechanism of calcification indicate that the initial step in calcification in bone is formation of ),-carboxy glutamic acid from glutamic acid by a vitamin K dependent enzyme system. This amino acid has also been found in areas of calcification in sclerodermatous skin. 35 Studies on the effect of inhibiting this enzyme system by vitamin K antagonists are in progress and may provide a new approach to treatment of calcification.
GASTROINTESTINAL TRACT Distal esophageal motility disorders are closely associated with Raynaud's phenomenon. In scleroderma, the lower esophageal sphincter pressure is less than normal. Esophageal reflux with esophagitis and resultant esophageal stricture can result. Up to 50 per cent of patients with evidence of reflux by radiographic testing may be asymptomatic. 42 All patients with evidence of esophageal reflux should be begun on a hiatus hernia regimen with small amounts of liquid with meals, small feedings,4 to 6 inch elevation of the head of the bed with blocks, sitting up for 2 to 3 hours after eating and antacids. Patients with hiatus hernia and reflux are at increased risk for developing esophageal stricture. 42 If an esophageal stricture should develop, dilatation is usually the treatment of choice. Patients with scleroderma frequently have decreased intestinal motility. This may be manifest on an upper gastrointestinal tract series by dilatation of the third portion of the duodenum and prolonged transit time. 42 This may lead to bacterial overgrowth and secondary malabsorp-
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tion because of deconjugation of bile salts. Malabsorption may not be clinically obvious with steatorrhea or frequent bowel movements. Since this condition responds promptly to treatment with oral tetracycline,30 patients with scleroderma who begin to lose weight or develop low calcium or increased prothrombin time should be evaluated for malabsorption with quantitative stool fats and then treated with oral tetracycline, 250 mg four times a day for 10 days, if the diagnosis is confirmed. The other principal gastrointestinal manifestation is colonic saccular diverticula. Although patients with scleroderma are frequently constipated, these diverticula rarely become infected or otherwise symptomatic. However, if constipation is a problem, it is advisable to give the patient stool softeners and agents to increase stool bulk and prevent fecal impaction. Although there is no specific treatment for renal or pulmonary involvement, patients should be cautioned about the possible detrimental effects of cold, since studies have documented effects on both renal blood flow lO and pulmonary diffusing capacity.18 Hypertension should be treated very aggressively since it may be the first indication of fulminant renal involvement. Patients with scleroderma in whom hypertension develops should be hospitalized and evaluated by renal function tests and intravenous pyelography. Renal arteriography may demonstrate the specific renal lesion of "scleroderma kidney" with obliteration of renal intralobular arteries and prolonged retention of the dye in renal arteries as occurs with acute hypertension. Therapy should be started immediately to minimize renal damage. If irreversible renal failure does develop, the patient should be evaluated for hemodialysis. The final decision as to chronic dialysis will be based upon multiple factors, but the degree of visceral involvement should be carefully considered, since significant cardiac compromise may prevent effective hemodialysis.
TREATMENT WITH SYSTEMIC AGENTS In most studies the effectiveness of systemic agents is judged by improvement in cutaneous manifestations although this is not a significant factor in prognosis. This is a major problem in evaluating therapeutic potential. Cutaneous improvement has been reported with immunosuppressive agents such as prednisone,64 azathioprine,28 cytoxan,36 chlorambucil,36 estrogen preparations,24 D-penicillamine,4. 16. 17. 25. 59. 64 and recently colchicine.3 Documentation of improvement is often confined to clinical estimation of the degree of skin tethering. However, improvement in cutaneous involvement seems to be consistently reported with D-penicillamine. In one study, 5 of 10 improved64 and in another 25 of 34 improved, with 3 complete "cures."4 Obviously, treatment with potentially toxic agents is not justified if survival is not improved, and less potent agents will effect similar cutaneous improvement. The principal problem in evaluating therapeutic efficacy is that treatment is probably most effective early in the disease before fixed fibrotic changes occur. However, most patients will experience some cutaneous improvement after the initial inflammatory phase has subsided and some will have
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spontaneous, prolonged remissions. In this situation it seems mandatory to study new agents with objective measures of disease activity and to minimize physician bias. Aspirin is the first drug that should be considered among possible systemic agents for scleroderma. Therapeutic doses of salicylates will often relieve arthritis and reduce the inflammatory changes in the skin so that the patient may experience subjective improvement on this medication alone. Other, investigational agents should probably be reserved for patients in whom salicylates are ineffective. This may be quantitated by measurements of joint mobility such as the minimal distance between the third finger and the distal palmar crease and the interincisor distance. Also, the degree of cutaneous induration and joint stiffness and changes in the sedimentation rate may be used to follow activity of disease. Of agents currently being investigated, the two of most interest are penicillamine and colchicine. D-Penicillamine is an anti-inflammatory drug which also inhibits connective tissue biosynthesis. The mechanism of its anti-inflammatory action is unknown. There are several effects on connective tissue biosynthesis. It cleaves aldimine collagen cross-links and inhibits synthesis of collagen cross-links by forming a thiazolidine ring complex with the lysine-derived aldehydes that form cross-links.25 Patients with scleroderma who received penicillamine have noted softening of their skin lesions. The effect has also been correlated with biochemical alterations. In patients treated with Dpenicillamine the concentration of reducible aldimine cross-links in the skin decreased. 40 This is good evidence for decreased collagen biosynthesis. Penicillamine has usuaVy been given in doses of 1.5 to 3 gm per day. At this dose, toxic effects such as skin rash and proteinuria are frequent and there is a risk of aplastic anemia and membranous glomerulonephritis. Recently, studies with low dose D-penicillamine have been reportedP' 26 Since current evidence does not indicate that consistent visceral improvement results from high dose treatment, it seems reasonable to use low dose penicillamine in doses of 250 to 500 mg per day to minimize toxic effects and still obtain cutaneous benefits in patients with extensive skin lesions. Further studies are necessary to determine whether prolonged, low dose treatment early in the disease will affect progression of visceral lesions and prognosis. The second drug currently under investigation is colchicine. Colchicine is believed to stimulate collagenase activity and inhibit collagen biosynthesis by preventing collagen secretion from cells. Since it has recently been suggested that skin collagenase activity may be decreased in scleroderma7 and there is increased collagen biosynthesis, a trial of this agent seemed appropriate. Initial reports indicated that it was necessary to take the drug for several months as 0.6 mg two to three times a day, five days a week, for an effect on skin. 3 No data on visceral effects has been published. Some patients who have tried low dose colchicine have experienced nausea and vomiting and have refused to continue to take the drug. A recent study of the acute effect of colchicine in patients failed to document evidence of decreased collagen biosynthesis or increased collagen breakdown after colchicine infusion. 23 For these rea-
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sons, this drug has not been widely accepted. Additional controlled studies with documentation of improvement are required. In conclusion, when attempting to treat the patient with progressive systemic sclerosis, the physician should be aware that he is assuming a long term responsibility for a patient who may frequently become discouraged or depressed. Perhaps the best advice is "go slow and go low"26 in drug use. The most important aspects of therapy are those related to symptomatic therapy for each system involved. Only after this program of symptomatic therapy has been designed and accepted should the physician consider the use of systemic agents such as D-penicillamine. Since none of these is proven to affect visceral involvement, the potential benefits for each patient should be carefully weighed against the possible side effects and relative activity and stage of disease. Effective systemic therapy will not be possible without greater understanding of pathogenesis and recognition of the factors which identify patients at greatest risk and most likely to benefit.
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22. Guttadauria. M., Saroja, D., Gopinathan, P., et al.: Small airway disease in scleroderma. Arthritis Rheum., 18:283-284,1975. 23. Harris, K D., Jr., Hoffman, G. S., McGuire, J. L., et al: Colchicine: Effects upon urinary hydroxyproline excretion in patients with scleroderma. Metabolism, 24 :529-535, 1975. 24. Herbai, G.: Treatment of progressive systemic sclerosis with a synthetic weak estrogen cyclofenil (sexovid). Acta Med. Scand., 196:537-540,1974. 25. Herbert, C. M., Jayson, M. I. V., Lindberg, K. A., et al.: Biosynthesis and maturation of skin collagen in scleroderma and effect of D-penicillamine. Lancet, 1 :187-192,1974. 26. Jaffe, I. A.: The technique of penicillamine administration in rheumatoid arthritis. Arthritis Rheum., 18:513-514,1975. 27. James, T. N.: De subitaneis mortibus VIII coronary arteries and conduction system in scleroderma heart disease. Circulation, 50:844-856, 1974. 28. Jansen, G. T., Barraza, D. F., Ballard, J. L., et al.: Generalized scleroderma: Treatment with an immunosuppressive agent. Arch. Derm., 97:690-698, 1968. 29. Johnson, R. L., and Ziff, M.: Lymphokine stimulation of collagen accumulation. J. Clin. Invest., 58:240-252,1976. 30. Kahn, I. J., Jeffries, G. H., and Sleisinger, M. H.: Malabsorption in intestinal scleroderma. New Eng. J. Med., 274:1339-1344,1966. 31. Keane, W. F., Danielson, B., and Raij, L.: Successful renal transplantation in progressive systemic sclerosis. Ann. Intern. Med., 85:199-202,1976. 32. Keiser, H. R., Stein, H. D., and Sjoerdsma, H.: Increased protocollagen proline hydroxylase activity and sclerodermatous skin; Arch. Derm., 104:57-60, 1971. 33. LeRoy, K C.: Connective tissue synthesis by scleroderma skin fibroblasts in culture. J. Exper. Med., 135:1351-1362,1972. 34. LeRoy, K C.: Personal communication. 35. Lian, J. B.: Personal communication. 36. Mackenzie, A. H.: Prolonged alkylating drug therapy is beneficial in systemic scleroderma (PSS). Arthritis Rheum., 13:334, 1970. 37. McWhorter, J. K, and LeRoy, K C.: Pericardial disease in scleroderma. Amer. J. Med., 57:566-575,1974. 38. Medsger, T. A., and Masi, A. T.: Survival with scleroderma. 11: A life-table analysis of clinical and demographic factors in 358 male V.S. veteran patients. J. Chron. Dis., 26:647-660, 1973. 39. Medsger, T. A., Masi, A. T., Rodnan, G. P., et al.: Survival with systemic sclerosis (scleroderma). Ann. Intern. Med., 75:369-376,1971. 40. Metzger, A. L., Singer, F. R., Bluestone, R, et al.: Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. New Eng. J. Med., 291 :1294-1296, 1974. 41. Norton, W. L., and Nardo, J. M.: Vascular disease in progressive systemic sclerosis. Ann. Intern. Med., 73:317-324, 1970. 42. Poirer, T. ]., and Rankin, G. B.: Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Amer. J. Gastroent., 58:30-44,1972. 43. Rabin, B. S., Rodnan, G. P., Bassion, S., et al.: HLA antigens in progressive systemic sclerosis (scleroderma). Arthritis Rheum., 18 :381-382, 1975. 44. Redisch, W., Messina, K J., Hughes, G., et al.: Capillaroscopic observations in rheumatic diseases. Ann. Rheum. Dis., 29:244-253,1970. 45. Rodnan, G. P., and Benedek, T. G.: An historical account of the study of progressive systemic sclerosis. Ann. Intern. Med., 57:305-319,1962. 46. Rodnan, G. P., Di Bartolomeo, A. G., Medsger, T. A., et al.: Eosinophilic fasciitis-Report of seven cases of a newly recognized scleroderma-like syndrome. Arthritis Rheum., 18 :442-443, 1975. 47. Rodnan, G. P., Medsger, T. A., and Buckingham, R B.: Progressive systemic sclerosis-Crest syndrome: Observations on natural history and late complications in 96 patients. 48. Salyer, W. R., Salyer, D. C., and Heptinstall, R H.: Scleroderma and microangiopathic hemolytic anemia. Ann. Intern. Med., 78:895-897,1973. 49. Samuels, B.: Personal communication. 50. Schumacher, H. R: A scleroderma-like syndrome with fasciitis, myositis and eosinophilia. Ann. Intern. Med., 84:49-50, 1976. 51. Sharp, G. C., Irvin, W. S., Tan, K M., et al.: Mixed connective tissue disease. Amer. J. Med., 52:148-159,1972. 52. Shulman, L. K: Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? (abstract) J. Rheum., 1 (Suppl. 1): 46, 1974. 53. Siegel, R C., and Fries, J. F.: Intra-arterially administered reserpine and saline in scleroderma. Arch. Intern. Med., 134:515-518,1974. 54. Spencer-Green, G., Maricq, H. R, and LeRoy, K C.: Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis). In press.
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55. Stone, R. A., Tisher, C. C., Hawkins, H. K., et al.: Juxtaglomerular hyperplasia and hyperreninemia in progressive systemic sclerosis complicated by acute renal failure. Amer. J. Med., 56:119-123,1974. 56. Tan, E. M., and Rodnan, G. P.: Profile of antinuclear antibodies in progressive systemic sclerosis (PSS). Arthritis Rheum., 18 :430, 1975. 57. Tuffanelli, D. L., and Winkelmann, R. K.: Diffuse systemic scleroderma. Ann. Intern. Med., 57:198-203,1962. 58. Tuffanelli, D. L., and Winkelmann, R. K.: Systemic scleroderma. Arch. Derm., 84:359371, 1961. 59. Uitto, J., Helin, P., Rasmussen, 0., et al.: Skin collagen in patients with scleroderma: Biosynthesis and maturation in vitro and the effect of D-penicillamine. Ann. Clin. Res., 2:228-234, 1970. 60. Varadi, D. P., and Lawrence, A. M.: Suppression of Raynaud's phenomenon by methyldopa. Arch. Intern. Med., 124:13-18, 1969. 61. Willerson, J. T., Thompson, R. H., Hookman, P., et al.: Reserpine in Raynaud's disease and phenomenon. Ann. Intern. Med., 72:17-27,1970. 62. Wilson, R. H., McCormick, W. E., Tatum, C. F., et al.: Occupational acro-osteolysis: report of 31 cases. J,A.M.A., 201 :577-581, 1967. 63. Winkelmann, R. K.: Pathogenesis and staging of scleroderma. Acta Dermat. (Stockholm), 56:83-92. 1976. 64. Winkelmann, R. K., Kierland, R. R., Perry, H. 0., et al.: Management of scleroderma. Mayo Clin. Proc., 46:128-134,1971. 65. Wong, W. H., Freedman, R. 1., Rabens, S. F., et al.: Low molecular weight dextran therapy for scleroderma. Arch. Dermatol., 110:419-422,1964. 66. Yune, H. Y., Vix, V. A., and Klatte, E. C.: Early fingertip changes in scleroderma. J.A.M.A., 215:1113-1116,1971. Department of Medicine University of California School of Medicine 3rd Avenue and Parnassus Street San Francisco, California 94143