Southwestern Internal Medicine Conference: The Many Faces of Scleroderma J. DONALD SMILEY, MD
ABSTRACT: This review integrates the clinical aspects of systemic sclerosis (SSc; scleroderma) and scleroderma-like conditions with new knowledge of the control of blood vessel tone and the role of anoxia in the activation of connective tissues leading to fibrosis. Serologic tests, high resolution computed tomographic scanning, bronchoalveolar lavage, and physiologic assessment of pulmonary gas diffusion are compared as diagnostic tools and as means of quantitating internal organ involvement. Treatment of Raynaud's disease and phenomenon, management of scleroderma renal crisis, and new means for improving gastrointestinal function with octreotide, the somatostatin analogue, also are discussed. The relationship between idiopathic forms of SSc and eosinophilic fasciitis/eosinophilia-myalgia syndrome caused by L-tryptophan ingestion and the scleroderma-like disease associated with silicone breast implants also is discussed. KEY INDEXING TERMS: Bronchoalveolar lavage; Endothelial-derived-relaxing factor; Endothelin; Integrins; L-tryptophan; Octreotide; Raynaud's phenomenon; Scleroderma; Silicone breast implants. [Am J Med Sci 1992; 304(5):319-333.]
W
hen dealing with diseases of unknown cause, it is tempting to oversimplify based on one's narrow viewpoint like one of the five blind men describing an elephant. Each investigator explains the illness based on his own special interest area. Scleroderma, which probably represents more than one disease, possibly with more than one cause, affects multiple organ systems and is the proverbial elephant under discussion. It provides an opportunity to explore a wealth of new knowledge related to blood vessel funcFrom the Arthritis Consultation Center, Presbyterian Hospital of Dallas, Dallas, Texas. Correspondence: J. Donald Smiley, MD, Arthritis Consultation Center, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, Texas 75231. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
tion, inflammation of blood vessels and connective tissues, and the fibrosis that follows anoxic injury. It also permits discussion of two therapeutic "experiments" (L-tryptophan ingestion and silicone breast implants) that have induced changes that resemble features of idiopathic scleroderma. Finally, it allows speculation about possible new directions for the therapy of these serious diseases (Tables 1 and 2). Once permanent skin or internal organ changes begin to appear, several physical and laboratory differences separate SSe patients into useful groups, each with a separate clinical presentation and, often, a very different long-term prognosis. The degree of skin involvement is one of the most useful predictors. Clements et a14•5 devised an elaborate diagram to calculate a "Skin Score." This is very useful for research studies on scleroderma, but the practicing physician usually is able, within the first 1 or 2 years of observation, to determine whether involvement ofthe skin of the upper arms, face, or trunk is occurring, which suggests diffuse systemic sclerosis (DSSc). Limited cutaneous systemic sclerosis (LSSc) usually shows only limited cutaneous involvement of the fingers or hands. In rare cases, early in the course of the disease, no tightening of the skin is present in LSSc. However, in 93% of LSSc patients, rectangular telangiectases can be found on the fingers and palms.5 The "neck sign," elicited by having the patient raise his or her chin as high as possible and palpating the folds of the anterolateral neck for induration, is said to be positive in 90% of patients with DSSc at initial examination.6 Upon follow up of the 264 patients in the multicenter Scleroderma Criteria Cooperative Study in 1990, several interesting observations resulted. 7 On average, 3.8 years from the onset of symptoms elapsed for each patient before the diagnosis was made, suggesting that most physicians have considerable difficulty diagnosing early disease. The early symptoms probably were Raynaud's phenomenon or puffy swelling of hands and feet. Thus, diagnostic laboratory tests are needed that can sort early patients with primarily Raynaud's phenomenon into those likely to develop DSSc, LSSc, or overlap syndromes. The distribution of serologic findings among the three major variants of systemic sclerosis (SSe; sclero319
The Many Faces of Scleroderma
Table 3. Autoantibodies Useful in Differentiating Scleroderma Variants *
Table 1. Classification of Scleroderma and Scleroderma· Like Conditions Raynaud's disease and Raynaud's phenomenon Diffuse systemic sclerosis Limited cutaneous systemic sclerosis Overlap syndromes (sclerodermatomyositis, mixed connective tissue disease) Eosinophilic fasciitis/eosinophilia-myalgia syndrome (L-tryptophan) Responses to other substances (silicone implants)
derma) useful in diagnosis and prognosis is illustrated in Figure 1. Factors Regulating Vascular Tone
Most investigators of SSc believe that prolonged vasospasm causes anoxic injury that results in secondary fibrosis and scarring. Hundreds of publications, primarily in the cardiology literature during the last 5 years, have changed our view of the mediators of vascular tone in large and small blood vessels. Redundant, interacting systems that include neural mediators such as acetylcholine and norepinephrine, humoral mediators such as bradykinin, cell-membrane-derived mediators such as arachidonic acid derivatives, and inflammatory mediators such as cytokines all impinge on vascular endothelial cells to modify their function. Factors such as physical stress or trauma and hypoxia also change endothelial cell function and influence vascular tone. Finally, the secreted products of the endothelial cells themselves (relaxing factors and constricting factors) alter local vascular smooth muscle tone. 13 These complex interactions are illustrated in Figure 2. Endothelin 14 is the most potent vasoconstrictor peptide. It produces effective vasoconstriction at concentrations of 4 X 10-10 mol/I, and thus is 10 times more potent than angiotensin II or vasopressin on a molar basis. Endothelin likely plays an important role
% Positive Antinuclear antibody (HEp-2, K-B cells) Raynaud's phenomenon DSSc (80% female) LSSc (98% female) Overlap syndromes (90% female) Anti-topoisomerase I (Scl-70 kD kinetochore) Raynaud's phenomenon DSSc (white 17, black 37, latin ll)t LSSc Overlap syndromes Anti -centromere Raynaud's phenomenon DSSc LSSc Overlap syndromes Anti-nucleolar (PM-Scl, RNA polymerase I, U3 ribonucleoprotein -fibrillarin), anti-RNP Raynaud's phenomenon DSSc LSSc Overlap syndromes
25 58-70 98 98 2 23-75 2-18
o
14 0-1 43-80
o
6 8 14 80
* Composite data derived from references 8-12. t Illustrates racial variations in Houston, Texas. 9 Variable percentage reflects different values reported in the literature. DSSc = diffuse systemic sclerosis. LSSc = limited cutaneous systemic sclerosis.
in hemostasis after injury.15 It is increased in the serum after trauma 15 and is increased in the serum of patients with advanced atherosclerosis.16 Adnot et aP7 recently explored the role of chronic anoxia on vascular tone in an isolated rat lung preparation. Lungs from rats that had been maintained in AUTOANTIBODIES DIFFERENTIATING SCLERODERMA VARIANTS All Systemic Sc;lerosls (Scleroderma) Patients
Table 2. Incidence of Raynaud's, DSSc, LSSc, and Overlap Syndromes * No. Affected Raynaud's disease (no other identifiable connective tissue disease) Raynaud's phenomenon (associated with scleroderma or other connective tissue disease) DSSc (diffuse systemic sclerosis) LSSc (limited cutaneous systemic sclerosis) Overlap syndrome (mixed connective tissue disease, sclerodermatomyositis)
• Adapted from references 1-3.
320
1-5% of women 0.1% of men 150/100,000 women Rare in men 7-45/100,000 women 1-6/100,000 men 4-22/100,000 women Rare in men 0.4-3/100,000 women Rare in men
Anti-Cenlrcmere Antibody (ACA)
Antl·Scl·7Q
(ASci)
1Jiri9CI QitaDeo:Jls
Dlftus8
SVel9IliO 6clcr:lo!is
Systemic ScI8ro$~
Overlap Syndromes Sclerodermatomyositis MCTO
(C:'lCD'T)
Figure 1. Distribution of autoantibodies that may be useful in diagnosing and providing prognosis in the three major variants of SSc. November 1992 Volume 304 Number 5
Smiley
VASODILATORS
VASOCONSTRICTORS
Figure 2. Local endothelial cell regulation of vascular tone. Ach = acetylcholine. Bk = bradykinin. His = histamine. EDRF = endothelial relaxing factor. E-NO = nitric oxide from endothelium. Thromb(early) = early effect of local thrombin activation. AA = amino acids arginine, lysine, and ornithine. ADP, ATP = adenosine di-, triphosphate. Ser = serotonin. n-Epi = norepinephrine. TGF,8 = tissue growth factor beta. Stretch, shear = stress injuries. EDCF = endothelial constricting factor. Thromb(late) = delayed effect of local thrombin activation. Adapted from reference 13.
a simulated high altitude chamber (10-11% O2) for 1 or 3 weeks were compared to normal rat lungs and to 3-week-hypoxic rat lungs removed 48 hours after the rats had been returned to room air (20% O2). Perfusion with acetylcholine was used to induce endothelial relaxing factor (EDRF = E-NO) release. Vasodilation was reduced in the 1-week-hypoxic lungs, abolished in the 3-week-hypoxic lungs, and restored to the normal control level in the 3-week-hypoxic lungs returned for 48 hours to room air. Endothelin-induced vasoconstriction was greatest in the 3-week-hypoxic lungs and was not potentiated by E-NO antagonists, suggesting that no E-NO was released by the chronically hypoxic lung endothelial cells. In this model of pulmonary hypertension, pulmonary vasoconstriction appears to result, at least in part, from depletion of the counter balancing vasodilator EDRF (E-NO) from the pulmonary endothelial cells. Other factors that deplete or block the release of E-NO also could potentiate pulmonary hypertension, resulting in stretch-induced augmentation of vascular smooth muscle tone, cor pulmonale, and death in SSc patients.
formation, which chokes out organ function in the skin and elsewhere. 1.1S-20 Mast cells in the skin and other tissues are thought to playa pivotal role in the fibrosis of scleroderma. 21-25 Figure 3 summarizes this complex cascade, showing the role of T cells, macrophages, platelets, mast cells, fibroblasts, and endothelial cells, and the interacting cytokines and transforming cell growth factors in this phase of the pathogenesis of SSC. 21 Induction of a clinical remission in a patient with early scleroderma by ketotifen (Zaditen; Sandoz, East Hanover, NJ), a mast cell inhibitor, was reported recently.25 This emphasizes the need for further study of the central role of tissue mast cells in the pathogenesis of SSc. Raynaud's Disease and Raynaud's Phenomenon
Clinical Raynaud's phenomenon has been shown to be induced by gastrointestinal illnesses that involve bacterial infections. In 1964, Greisman, Hornick, and Woodward26 examined the role of gram-negative bacterial sepsis on cardiovascular function in nine healthy volunteers. They measured nailfold capillary blood flow using a dissecting microscope, then infused norepinephrine by drip intravenously and counted the number of drops per minute needed to cause sufficient vasoconstriction to obliterate nailbed blood flow. This was shown to be reproducible in each normal subject. They then infected each subject with Salmonella typhosa, and while each was ill with typhoid fever, the investigators repeated the nailbed blood flow experiment. The subject then was treated with chloramphenicol until fully recovered. One to five weeks later,
~~""':::::::?'--_ _ _...JI~
Collagen
Factors Initiating Fibrosis
Immunologic, chemical, or physical injury causes activation of fibroblasts, leading to collagen secretion and tissue scarring. T cells, macrophages, and platelets migrate into an area of injury and become activated, releasing a variety of cytokines that cause tissue mast cells and fibroblasts to proliferate and difi'erentiate. 1s-2o This process is accelerated in SSc, leading to the activation of genes for the production of intracellular matrix components (collagen-I, -III, -VI, fibronectin, and glycosaminoglycans) and resulting in dense scar THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 3. Endothelial cell, mast cell, and fibroblast interactions in SSc. From reference 22.
321
The Many Faces of Scleroderma
the nailbed blood flow experiment was repeated. During the active typhoid fever illness and for many days after convalescence, all nine subjects remained 2 to 10 times more sensitive to norepinephrine than before their infection. Thus, a temporary supersensitivity to a vasoconstrictor stimulus had been induced. The investigators26 concluded that exposure to significant amounts of bacterial endotoxin over the several days of the typhoid illness had sensitized the vascular system to norepinephrine. They also concluded that systemic blood pressure and, to an even greater degree, the microvascular circulation had been temporarily altered. Years later, when the vogue of ileal-colonic bypass surgery for massive obesity was at its height, it was observed that about one-third of operated patients developed rheumatic disease complaints. In 1980, Utsinger27 collected 85 symptomatic bypass disease patients and found 82% had inflammatory arthritis and 17% had Raynaud's phenomenon. The symptoms had not been present prior to bypass surgery, and the arthritis and Raynaud's phenomenon disappeared within 1-2 weeks after the bowel was restored to a normal flow path. Utsinger27 was able to show elevated levels of immune complexes-cryoglobulins containing Escherichia coli and Bacteroides fragilis antigens-in the serum of 78 of the 85 patients studied. These observations suggest that bacterial endotoxin plays a role in the induction of Raynaud's phenomenon. Early Detection of SSc-Spectrum Disorders in Raynaud's Patients
Patients who eventually show clinical features of DSSc, LSSc, or overlap syndromes with scleroderma often give a history of many years of gradually worsening Raynaud's phenomenon before an accelerated phase of systemic involvement. 1.2 In the past, deciding which patient would progress to systemic involvement was difficult. However, new developments now make this task easier. The presence of biphasic (pallor, cyanosis), or triphasic (pallor, cyanosis, red flush) Raynaud's phenomenon, a positive antinuclear antibody (ANA), and changes in the nailfold capillary bed, including tortuous, dilated capillaries or areas of atrophy and scarring due to capillary loss, are strongly correlated with the presence of a variant of SSc. Takehara et aF8 thoroughly studied a group of 50 patients with severe Raynaud's phenomenon in 1990 and found three with visceral involvement compatible with early DSSc, 15 with a positive anti-centromere ANA compatible with LSSc, and six with a positive anti-ribonuclear protein (RNP) compatible with early overlap syndrome (mixed connective tissue disease or sclero-dermatomyositis). Treatment of Raynaud's Disease and Phenomenon
Whether linked to scleroderma or not, patients with severe Raynaud's often require treatment. 29 The role of emotional stress in modifying expression of vaso-
322
spasm cannot be underestimated. Biofeedback is said to improve many patients. 29 This is best viewed as a placebo effect, useful for patients with mild disease. This placebo effect enters into evaluation of any drug therapy of Raynaud's. For example, glowing reports of lasting benefit after intra-arterial reserpine persist. A sincere, persuasive physician can strongly influence the Raynaud's patient. A randomized, double-blind, crossover study that compared intra-arterial reserpine with intra-arterial saline gave evidence of subjective improvement in 48% of both groupS.30 Rate of digital ulcer healing is one of the better endpoints for assessing the efficacy of a given treatment. This has been used to claim benefit from prostaglandin E 1, a vasodilator and potent inhibitor of platelet aggregation, given at 6-10 ng/kg/min via a central venous catheter by continuous drip over a 72 hour period in single-blind, crossover studies.31 .32 The effect persisted for several weeks, and the treatment was well-tolerated with few side effects. Modification of prostaglandin production has been used to treat patients with Raynaud's. Omega-3-fatty acids from cold water fish oil compete with arachidonic acid and result in increased production of prostacyclin (PGI3; cyclooxygenase pathway) and decreased production of thromboxane A2 (5-lipoxygenase pathway) by forming the inert analogue thromboxane A 3 • When fish oil was given in a dose of 6.5 g/d and compared to the same amount of olive oil in a double-blind, controlled, prospective study,33 fish oil recipients with Raynaud's disease showed impressive improvement, but those with Raynaud's phenomenon due to SSc failed to improve. The best response in Raynaud's disease has been obtained with calcium channel blockers, which have been shown to block the action of endothelin. 14 In two recent double-blind, crossover studies,34.35 calcium channel blockers were shown to decrease the frequency and severity of Raynaud's attacks in Raynaud's disease, but not in Raynaud's associated with SSc. In contrast, prazosin, taken orally 0.1 mg three times daily, has been shown36.37 to decrease the frequency and severity of Raynaud's attacks in patients with SSc. Approximately half of the patients were able to tolerate the mild orthostatic hypotension and gain lasting benefit from prazosin treatment. A serotonin receptor antagonist, ketanserin, also has been reported to improve Raynaud's in 83% of patients with SSc, as measured by serial digital strain gauge plethysmography during controlled cold challenge. 38 Angiotensin converting enzyme inhibitors, such as capoten or enalapril, also have been recommended for patients with Raynaud's with SSc because they also improve renal blood flOW. 2.29 However, from my clinical experience, many SSc patients with Raynaud's phenomenon do not respond well to any vasodilator agent or combinations of agents. November 1992 Volume 304 Number 5
Smiley
Cold-Induced "Raynaud's of the Lungs and Heart"
There has been considerable debate about whether pulmonary or cardiac vasospasm occurs simultaneously with cold-induced peripheral Raynaud's phenomenon in SSc. A carefully done study of mean pulmonary artery pressures obtained before, during, and after cold exposure showed no change, suggesting that the pulmonary vasculature did not react to brief external cold exposure of the hands. 39 On the other hand, the development of reversible myocardial perfusion defects seen with thallium myocardial scintigraphy during cold-water hand immersion in SSc patients with Raynaud's suggests that coronary vasospasm may occur.40 Pregnancy in Patients with Raynaud's
Other workers have argued strongly that Raynaud's phenomenon can be generalized, causing vasoconstriction in organs such as the placenta during pregnancy.41,42 In patients with Raynaud's disease unassociated with other connective tissue disease and in Raynaud's associated with SSe, there was an increased frequency of premature births and decreased fetal birth weight, but no increase in fetal wastage compared to a matched control population. The authors concluded that an uneventful, healthy pregnancy is possible in women with Raynaud's with or without SSc, but advise against elective pregnancy in patients with rapidly progressive DSSc because of concern for renal crises and shortened overall life expectancy.42 Organ System Involvement in DSSc Affecting Prognosis Case 1. A 33-year-old woman was seen in 1975 with a 3 month history of severe Raynaud's phenomenon followed by puffy swelling of her hands and forearms. She had been living in Wisconsin and had moved to Dallas to escape the cold weather, which had worsened her Raynaud's. Three months before her visit, she had been entirely well with two normal pregnancies within three years of onset of her illness. During the three months after her initial visit, the skin involvement accelerated, with hidebound scarring extending to her face and trunk. Work-up showed her blood pressure at 90/60, a positive ANA 1:320 speckled, erythrocyte sedimentation rate 50 mm/ hr, and DLco 82% of predicted normal value. She refused cyclophosphamide therapy after hearing of its potentially toxic side effects, and she was unable to tolerate vasodilators because of induced orthostatic hypotension. Her hands became clawed, with loss of finger range of motion and absorption of distal phalanges. Ulcerations developed over her proximal interphalangeal joints and elbows. Over a weekend, she experienced severe headaches and dyspnea, and when seen in the emergency room, she was found to have blood pressure of 240/140 and retinal hemorrhages, exudates, and papilledema compatible with malignant hypertension. She then experienced complete renal shutdown. Despite heroic effort, not including angiotensin converting enzyme inhibitors, which were not available at that time, she died 7 days later. Her illness had occurred over S months.
Factors that identified patients with DSSc who had a poor prognosis were reviewed in 1990,7 and the analysis of 484 demographic, clinical, and laboratory variables in 264 patients with definite SSc followed for more than 5 years is shown in Table 4. If renal disease had been present at the initial visit, 50% died within 3 months and 70% died within 5 years. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
The median survival for patients with significant cardiac involvement was 32 months, with 60% dead at 5 years; for pulmonary disease, 78 months, with 60% dead at 5 years; for gastrointestinal disease, 99 months, with 42% dead at 5 years; and for none of the above, 108 months, with 39% dead at 5 years. 7 Kidney Disease With and Without Hypertension Case 2. A 3S-year-old man had noted Raynaud's phenomenon and heartburn for IS months before he consulted his family physician in January 1975. A thorough evaluation showed normal SMA-IS values, normal complete blood count with hemoglobin of 16 gm/dL, and blood pressure of 100/60 with regular pulse and normal electrocardiogram findings. He had a positive ANA 1:640, speckled pattern. An anti-Scl-70 was unavailable at that time. He was noted to have extensive, puffy, nonpitting edema of his hands and feet and some skin tightness over his upper chest. There was increased skin pigmentation in the areas of edema and tightening. He was given a thiazide diuretic and was referred to a rheumatologist with a diagnosis of scleroderma. Five days later, when seen in the arthritis clinic, he was found to have blood pressure of 230/140, a rapid pulse of 10S/ min, increased respirations of 24/min and a severe, throbbing headache that was worse when he lay down. He was hospitalized and found to have retinal hemorrhages and papilledema, compatible with malignant hypertension. Laboratory examination showed blood urea nitrogen 32, creatine 2.1, white blood cell count lS,OOO, S3% polymorphonuclear leukocytes, and hemoglobin S.2 gm/dL. Blood smear showed burr cells, marked poikilocytosis, and numerous fragmented erythrocytes (helmet cells) compatible with microangiopathic hemolytic anemia. Blood and urine cultures were consistently negative. Platelet count was 10S,OOO/ILL. A direct Coombs' test was negative, and his reticulocyte count was 9%. A nephrology consultant was called, and the patient was begun on maximum doses of alpha-methyl dopa and hydralazine to control his rising blood pressure. His urine volume was 300-400 ml/24 hr, he had 4+ proteinuria, and 35-50 red blood cells/high-power field. Each day, his creatinine climbed approximately 3 mg/dL, suggesting essentially complete loss of renal function. His blood pressure was poorly controlled with a-methyl dopa (Aldomet) and hydralazine, but when he was begun on renal dialysis, his blood pressure hecame manageable. He was scheduled for renal transplantation when he was lost to follow up.
This is the only patient in whom I have observed the onset of "scleroderma kidney." He provides a powerful example of the devastation possible in this disease in a matter of a few days. Three points should be made about the course of his disease. First, those patients with rapid progression of skin involvement of the trunk are more likely to develop renal failure. Second, any process that results in abrupt changes in blood volume (increases or decreases) may precipitate renal failure. In this patient, the administration of a diuretic for edema may have triggered the renal change. Precipitation of scleroderma kidney failure may follow the administration of corticosteroids, perhaps because these agents modify vascular tone or increase blood volume, an association also noted in the multicenter Scleroderma Criteria Study 7 reviewed in Table 4. Third, this patient demonstrated a 50% fall in his hemoglobin level within a 5 day period with no evidence of bleeding and with large numbers of fragmented erythrocytes on his admitting blood smear. Heptinstall and colleagues43 noted evidence of intravascular hemolysis in 7 of 20 patients dying of scleroderma and autopsied at Johns Hopkins Hospital in Baltimore. Six
323
The Many Faces of Scleroderma
Table 4. Predictors of a Poor Prognosis in Systemic Sclerosis *
General factors Older age (average in yr) Digital pitting Proximal muscle weakness Taking prednisone Renal Proteinuria Increased blood urea nitrogen, creatinine Microangiopathic erythrocytes Pulmonary Dyspnea DLco (% of predicted normal value) Forced vito capacity (% of predicted normal value) Arterial P02 (mm Hg) Smoking tobacco Cardiovascular Heart rate (beats/min) Pedal edema Neck vein distention Abnormal EKG-PVCs, ST-T wave changes Left ventricular enlargement Laboratory findings D-Xylose absorption (g) ESR (mmjhr) Anti-topoisomerase I (Scl-70) Anti-centromere
Died 2 yr
p Value
53 53% 43% 31%
46 43% 15% 13%
ABSTRACT: This review integrates the clinical aspects of systemic sclerosis (SSc; scleroderma) and scleroderma-like conditions with new knowledge of the control of blood vessel tone and the role of anoxia in the activation of connective tissues leading to fibrosis. Serologic tests, high resolution computed tomographic scanning, bronchoalveolar lavage, and physiologic assessment of pulmonary gas diffusion are compared as diagnostic tools and as means of quantitating internal organ involvement. Treatment of Raynaud's disease and phenomenon, management of scleroderma renal crisis, and new means for improving gastrointestinal function with octreotide, the somatostatin analogue, also are discussed. The relationship between idiopathic forms of SSc and eosinophilic fasciitis/eosinophilia-myalgia syndrome caused by L-tryptophan ingestion and the scleroderma-like disease associated with silicone breast implants also is discussed. KEY INDEXING TERMS: Bronchoalveolar lavage; Endothelial-derived-relaxing factor; Endothelin; Integrins; L-tryptophan; Octreotide; Raynaud's phenomenon; Scleroderma; Silicone breast implants. [Am J Med Sci 1992; 304(5):319-333.]
W
hen dealing with diseases of unknown cause, it is tempting to oversimplify based on one's narrow viewpoint like one of the five blind men describing an elephant. Each investigator explains the illness based on his own special interest area. Scleroderma, which probably represents more than one disease, possibly with more than one cause, affects multiple organ systems and is the proverbial elephant under discussion. It provides an opportunity to explore a wealth of new knowledge related to blood vessel funcFrom the Arthritis Consultation Center, Presbyterian Hospital of Dallas, Dallas, Texas. Correspondence: J. Donald Smiley, MD, Arthritis Consultation Center, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, Texas 75231. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
tion, inflammation of blood vessels and connective tissues, and the fibrosis that follows anoxic injury. It also permits discussion of two therapeutic "experiments" (L-tryptophan ingestion and silicone breast implants) that have induced changes that resemble features of idiopathic scleroderma. Finally, it allows speculation about possible new directions for the therapy of these serious diseases (Tables 1 and 2). Once permanent skin or internal organ changes begin to appear, several physical and laboratory differences separate SSe patients into useful groups, each with a separate clinical presentation and, often, a very different long-term prognosis. The degree of skin involvement is one of the most useful predictors. Clements et a14•5 devised an elaborate diagram to calculate a "Skin Score." This is very useful for research studies on scleroderma, but the practicing physician usually is able, within the first 1 or 2 years of observation, to determine whether involvement ofthe skin of the upper arms, face, or trunk is occurring, which suggests diffuse systemic sclerosis (DSSc). Limited cutaneous systemic sclerosis (LSSc) usually shows only limited cutaneous involvement of the fingers or hands. In rare cases, early in the course of the disease, no tightening of the skin is present in LSSc. However, in 93% of LSSc patients, rectangular telangiectases can be found on the fingers and palms.5 The "neck sign," elicited by having the patient raise his or her chin as high as possible and palpating the folds of the anterolateral neck for induration, is said to be positive in 90% of patients with DSSc at initial examination.6 Upon follow up of the 264 patients in the multicenter Scleroderma Criteria Cooperative Study in 1990, several interesting observations resulted. 7 On average, 3.8 years from the onset of symptoms elapsed for each patient before the diagnosis was made, suggesting that most physicians have considerable difficulty diagnosing early disease. The early symptoms probably were Raynaud's phenomenon or puffy swelling of hands and feet. Thus, diagnostic laboratory tests are needed that can sort early patients with primarily Raynaud's phenomenon into those likely to develop DSSc, LSSc, or overlap syndromes. The distribution of serologic findings among the three major variants of systemic sclerosis (SSe; sclero319
The Many Faces of Scleroderma
Table 3. Autoantibodies Useful in Differentiating Scleroderma Variants *
Table 1. Classification of Scleroderma and Scleroderma· Like Conditions Raynaud's disease and Raynaud's phenomenon Diffuse systemic sclerosis Limited cutaneous systemic sclerosis Overlap syndromes (sclerodermatomyositis, mixed connective tissue disease) Eosinophilic fasciitis/eosinophilia-myalgia syndrome (L-tryptophan) Responses to other substances (silicone implants)
derma) useful in diagnosis and prognosis is illustrated in Figure 1. Factors Regulating Vascular Tone
Most investigators of SSc believe that prolonged vasospasm causes anoxic injury that results in secondary fibrosis and scarring. Hundreds of publications, primarily in the cardiology literature during the last 5 years, have changed our view of the mediators of vascular tone in large and small blood vessels. Redundant, interacting systems that include neural mediators such as acetylcholine and norepinephrine, humoral mediators such as bradykinin, cell-membrane-derived mediators such as arachidonic acid derivatives, and inflammatory mediators such as cytokines all impinge on vascular endothelial cells to modify their function. Factors such as physical stress or trauma and hypoxia also change endothelial cell function and influence vascular tone. Finally, the secreted products of the endothelial cells themselves (relaxing factors and constricting factors) alter local vascular smooth muscle tone. 13 These complex interactions are illustrated in Figure 2. Endothelin 14 is the most potent vasoconstrictor peptide. It produces effective vasoconstriction at concentrations of 4 X 10-10 mol/I, and thus is 10 times more potent than angiotensin II or vasopressin on a molar basis. Endothelin likely plays an important role
% Positive Antinuclear antibody (HEp-2, K-B cells) Raynaud's phenomenon DSSc (80% female) LSSc (98% female) Overlap syndromes (90% female) Anti-topoisomerase I (Scl-70 kD kinetochore) Raynaud's phenomenon DSSc (white 17, black 37, latin ll)t LSSc Overlap syndromes Anti -centromere Raynaud's phenomenon DSSc LSSc Overlap syndromes Anti-nucleolar (PM-Scl, RNA polymerase I, U3 ribonucleoprotein -fibrillarin), anti-RNP Raynaud's phenomenon DSSc LSSc Overlap syndromes
25 58-70 98 98 2 23-75 2-18
o
14 0-1 43-80
o
6 8 14 80
* Composite data derived from references 8-12. t Illustrates racial variations in Houston, Texas. 9 Variable percentage reflects different values reported in the literature. DSSc = diffuse systemic sclerosis. LSSc = limited cutaneous systemic sclerosis.
in hemostasis after injury.15 It is increased in the serum after trauma 15 and is increased in the serum of patients with advanced atherosclerosis.16 Adnot et aP7 recently explored the role of chronic anoxia on vascular tone in an isolated rat lung preparation. Lungs from rats that had been maintained in AUTOANTIBODIES DIFFERENTIATING SCLERODERMA VARIANTS All Systemic Sc;lerosls (Scleroderma) Patients
Table 2. Incidence of Raynaud's, DSSc, LSSc, and Overlap Syndromes * No. Affected Raynaud's disease (no other identifiable connective tissue disease) Raynaud's phenomenon (associated with scleroderma or other connective tissue disease) DSSc (diffuse systemic sclerosis) LSSc (limited cutaneous systemic sclerosis) Overlap syndrome (mixed connective tissue disease, sclerodermatomyositis)
• Adapted from references 1-3.
320
1-5% of women 0.1% of men 150/100,000 women Rare in men 7-45/100,000 women 1-6/100,000 men 4-22/100,000 women Rare in men 0.4-3/100,000 women Rare in men
Anti-Cenlrcmere Antibody (ACA)
Antl·Scl·7Q
(ASci)
1Jiri9CI QitaDeo:Jls
Dlftus8
SVel9IliO 6clcr:lo!is
Systemic ScI8ro$~
Overlap Syndromes Sclerodermatomyositis MCTO
(C:'lCD'T)
Figure 1. Distribution of autoantibodies that may be useful in diagnosing and providing prognosis in the three major variants of SSc. November 1992 Volume 304 Number 5
Smiley
VASODILATORS
VASOCONSTRICTORS
Figure 2. Local endothelial cell regulation of vascular tone. Ach = acetylcholine. Bk = bradykinin. His = histamine. EDRF = endothelial relaxing factor. E-NO = nitric oxide from endothelium. Thromb(early) = early effect of local thrombin activation. AA = amino acids arginine, lysine, and ornithine. ADP, ATP = adenosine di-, triphosphate. Ser = serotonin. n-Epi = norepinephrine. TGF,8 = tissue growth factor beta. Stretch, shear = stress injuries. EDCF = endothelial constricting factor. Thromb(late) = delayed effect of local thrombin activation. Adapted from reference 13.
a simulated high altitude chamber (10-11% O2) for 1 or 3 weeks were compared to normal rat lungs and to 3-week-hypoxic rat lungs removed 48 hours after the rats had been returned to room air (20% O2). Perfusion with acetylcholine was used to induce endothelial relaxing factor (EDRF = E-NO) release. Vasodilation was reduced in the 1-week-hypoxic lungs, abolished in the 3-week-hypoxic lungs, and restored to the normal control level in the 3-week-hypoxic lungs returned for 48 hours to room air. Endothelin-induced vasoconstriction was greatest in the 3-week-hypoxic lungs and was not potentiated by E-NO antagonists, suggesting that no E-NO was released by the chronically hypoxic lung endothelial cells. In this model of pulmonary hypertension, pulmonary vasoconstriction appears to result, at least in part, from depletion of the counter balancing vasodilator EDRF (E-NO) from the pulmonary endothelial cells. Other factors that deplete or block the release of E-NO also could potentiate pulmonary hypertension, resulting in stretch-induced augmentation of vascular smooth muscle tone, cor pulmonale, and death in SSc patients.
formation, which chokes out organ function in the skin and elsewhere. 1.1S-20 Mast cells in the skin and other tissues are thought to playa pivotal role in the fibrosis of scleroderma. 21-25 Figure 3 summarizes this complex cascade, showing the role of T cells, macrophages, platelets, mast cells, fibroblasts, and endothelial cells, and the interacting cytokines and transforming cell growth factors in this phase of the pathogenesis of SSC. 21 Induction of a clinical remission in a patient with early scleroderma by ketotifen (Zaditen; Sandoz, East Hanover, NJ), a mast cell inhibitor, was reported recently.25 This emphasizes the need for further study of the central role of tissue mast cells in the pathogenesis of SSc. Raynaud's Disease and Raynaud's Phenomenon
Clinical Raynaud's phenomenon has been shown to be induced by gastrointestinal illnesses that involve bacterial infections. In 1964, Greisman, Hornick, and Woodward26 examined the role of gram-negative bacterial sepsis on cardiovascular function in nine healthy volunteers. They measured nailfold capillary blood flow using a dissecting microscope, then infused norepinephrine by drip intravenously and counted the number of drops per minute needed to cause sufficient vasoconstriction to obliterate nailbed blood flow. This was shown to be reproducible in each normal subject. They then infected each subject with Salmonella typhosa, and while each was ill with typhoid fever, the investigators repeated the nailbed blood flow experiment. The subject then was treated with chloramphenicol until fully recovered. One to five weeks later,
~~""':::::::?'--_ _ _...JI~
Collagen
Factors Initiating Fibrosis
Immunologic, chemical, or physical injury causes activation of fibroblasts, leading to collagen secretion and tissue scarring. T cells, macrophages, and platelets migrate into an area of injury and become activated, releasing a variety of cytokines that cause tissue mast cells and fibroblasts to proliferate and difi'erentiate. 1s-2o This process is accelerated in SSc, leading to the activation of genes for the production of intracellular matrix components (collagen-I, -III, -VI, fibronectin, and glycosaminoglycans) and resulting in dense scar THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 3. Endothelial cell, mast cell, and fibroblast interactions in SSc. From reference 22.
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The Many Faces of Scleroderma
the nailbed blood flow experiment was repeated. During the active typhoid fever illness and for many days after convalescence, all nine subjects remained 2 to 10 times more sensitive to norepinephrine than before their infection. Thus, a temporary supersensitivity to a vasoconstrictor stimulus had been induced. The investigators26 concluded that exposure to significant amounts of bacterial endotoxin over the several days of the typhoid illness had sensitized the vascular system to norepinephrine. They also concluded that systemic blood pressure and, to an even greater degree, the microvascular circulation had been temporarily altered. Years later, when the vogue of ileal-colonic bypass surgery for massive obesity was at its height, it was observed that about one-third of operated patients developed rheumatic disease complaints. In 1980, Utsinger27 collected 85 symptomatic bypass disease patients and found 82% had inflammatory arthritis and 17% had Raynaud's phenomenon. The symptoms had not been present prior to bypass surgery, and the arthritis and Raynaud's phenomenon disappeared within 1-2 weeks after the bowel was restored to a normal flow path. Utsinger27 was able to show elevated levels of immune complexes-cryoglobulins containing Escherichia coli and Bacteroides fragilis antigens-in the serum of 78 of the 85 patients studied. These observations suggest that bacterial endotoxin plays a role in the induction of Raynaud's phenomenon. Early Detection of SSc-Spectrum Disorders in Raynaud's Patients
Patients who eventually show clinical features of DSSc, LSSc, or overlap syndromes with scleroderma often give a history of many years of gradually worsening Raynaud's phenomenon before an accelerated phase of systemic involvement. 1.2 In the past, deciding which patient would progress to systemic involvement was difficult. However, new developments now make this task easier. The presence of biphasic (pallor, cyanosis), or triphasic (pallor, cyanosis, red flush) Raynaud's phenomenon, a positive antinuclear antibody (ANA), and changes in the nailfold capillary bed, including tortuous, dilated capillaries or areas of atrophy and scarring due to capillary loss, are strongly correlated with the presence of a variant of SSc. Takehara et aF8 thoroughly studied a group of 50 patients with severe Raynaud's phenomenon in 1990 and found three with visceral involvement compatible with early DSSc, 15 with a positive anti-centromere ANA compatible with LSSc, and six with a positive anti-ribonuclear protein (RNP) compatible with early overlap syndrome (mixed connective tissue disease or sclero-dermatomyositis). Treatment of Raynaud's Disease and Phenomenon
Whether linked to scleroderma or not, patients with severe Raynaud's often require treatment. 29 The role of emotional stress in modifying expression of vaso-
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spasm cannot be underestimated. Biofeedback is said to improve many patients. 29 This is best viewed as a placebo effect, useful for patients with mild disease. This placebo effect enters into evaluation of any drug therapy of Raynaud's. For example, glowing reports of lasting benefit after intra-arterial reserpine persist. A sincere, persuasive physician can strongly influence the Raynaud's patient. A randomized, double-blind, crossover study that compared intra-arterial reserpine with intra-arterial saline gave evidence of subjective improvement in 48% of both groupS.30 Rate of digital ulcer healing is one of the better endpoints for assessing the efficacy of a given treatment. This has been used to claim benefit from prostaglandin E 1, a vasodilator and potent inhibitor of platelet aggregation, given at 6-10 ng/kg/min via a central venous catheter by continuous drip over a 72 hour period in single-blind, crossover studies.31 .32 The effect persisted for several weeks, and the treatment was well-tolerated with few side effects. Modification of prostaglandin production has been used to treat patients with Raynaud's. Omega-3-fatty acids from cold water fish oil compete with arachidonic acid and result in increased production of prostacyclin (PGI3; cyclooxygenase pathway) and decreased production of thromboxane A2 (5-lipoxygenase pathway) by forming the inert analogue thromboxane A 3 • When fish oil was given in a dose of 6.5 g/d and compared to the same amount of olive oil in a double-blind, controlled, prospective study,33 fish oil recipients with Raynaud's disease showed impressive improvement, but those with Raynaud's phenomenon due to SSc failed to improve. The best response in Raynaud's disease has been obtained with calcium channel blockers, which have been shown to block the action of endothelin. 14 In two recent double-blind, crossover studies,34.35 calcium channel blockers were shown to decrease the frequency and severity of Raynaud's attacks in Raynaud's disease, but not in Raynaud's associated with SSc. In contrast, prazosin, taken orally 0.1 mg three times daily, has been shown36.37 to decrease the frequency and severity of Raynaud's attacks in patients with SSc. Approximately half of the patients were able to tolerate the mild orthostatic hypotension and gain lasting benefit from prazosin treatment. A serotonin receptor antagonist, ketanserin, also has been reported to improve Raynaud's in 83% of patients with SSc, as measured by serial digital strain gauge plethysmography during controlled cold challenge. 38 Angiotensin converting enzyme inhibitors, such as capoten or enalapril, also have been recommended for patients with Raynaud's with SSc because they also improve renal blood flOW. 2.29 However, from my clinical experience, many SSc patients with Raynaud's phenomenon do not respond well to any vasodilator agent or combinations of agents. November 1992 Volume 304 Number 5
Smiley
Cold-Induced "Raynaud's of the Lungs and Heart"
There has been considerable debate about whether pulmonary or cardiac vasospasm occurs simultaneously with cold-induced peripheral Raynaud's phenomenon in SSc. A carefully done study of mean pulmonary artery pressures obtained before, during, and after cold exposure showed no change, suggesting that the pulmonary vasculature did not react to brief external cold exposure of the hands. 39 On the other hand, the development of reversible myocardial perfusion defects seen with thallium myocardial scintigraphy during cold-water hand immersion in SSc patients with Raynaud's suggests that coronary vasospasm may occur.40 Pregnancy in Patients with Raynaud's
Other workers have argued strongly that Raynaud's phenomenon can be generalized, causing vasoconstriction in organs such as the placenta during pregnancy.41,42 In patients with Raynaud's disease unassociated with other connective tissue disease and in Raynaud's associated with SSe, there was an increased frequency of premature births and decreased fetal birth weight, but no increase in fetal wastage compared to a matched control population. The authors concluded that an uneventful, healthy pregnancy is possible in women with Raynaud's with or without SSc, but advise against elective pregnancy in patients with rapidly progressive DSSc because of concern for renal crises and shortened overall life expectancy.42 Organ System Involvement in DSSc Affecting Prognosis Case 1. A 33-year-old woman was seen in 1975 with a 3 month history of severe Raynaud's phenomenon followed by puffy swelling of her hands and forearms. She had been living in Wisconsin and had moved to Dallas to escape the cold weather, which had worsened her Raynaud's. Three months before her visit, she had been entirely well with two normal pregnancies within three years of onset of her illness. During the three months after her initial visit, the skin involvement accelerated, with hidebound scarring extending to her face and trunk. Work-up showed her blood pressure at 90/60, a positive ANA 1:320 speckled, erythrocyte sedimentation rate 50 mm/ hr, and DLco 82% of predicted normal value. She refused cyclophosphamide therapy after hearing of its potentially toxic side effects, and she was unable to tolerate vasodilators because of induced orthostatic hypotension. Her hands became clawed, with loss of finger range of motion and absorption of distal phalanges. Ulcerations developed over her proximal interphalangeal joints and elbows. Over a weekend, she experienced severe headaches and dyspnea, and when seen in the emergency room, she was found to have blood pressure of 240/140 and retinal hemorrhages, exudates, and papilledema compatible with malignant hypertension. She then experienced complete renal shutdown. Despite heroic effort, not including angiotensin converting enzyme inhibitors, which were not available at that time, she died 7 days later. Her illness had occurred over S months.
Factors that identified patients with DSSc who had a poor prognosis were reviewed in 1990,7 and the analysis of 484 demographic, clinical, and laboratory variables in 264 patients with definite SSc followed for more than 5 years is shown in Table 4. If renal disease had been present at the initial visit, 50% died within 3 months and 70% died within 5 years. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
The median survival for patients with significant cardiac involvement was 32 months, with 60% dead at 5 years; for pulmonary disease, 78 months, with 60% dead at 5 years; for gastrointestinal disease, 99 months, with 42% dead at 5 years; and for none of the above, 108 months, with 39% dead at 5 years. 7 Kidney Disease With and Without Hypertension Case 2. A 3S-year-old man had noted Raynaud's phenomenon and heartburn for IS months before he consulted his family physician in January 1975. A thorough evaluation showed normal SMA-IS values, normal complete blood count with hemoglobin of 16 gm/dL, and blood pressure of 100/60 with regular pulse and normal electrocardiogram findings. He had a positive ANA 1:640, speckled pattern. An anti-Scl-70 was unavailable at that time. He was noted to have extensive, puffy, nonpitting edema of his hands and feet and some skin tightness over his upper chest. There was increased skin pigmentation in the areas of edema and tightening. He was given a thiazide diuretic and was referred to a rheumatologist with a diagnosis of scleroderma. Five days later, when seen in the arthritis clinic, he was found to have blood pressure of 230/140, a rapid pulse of 10S/ min, increased respirations of 24/min and a severe, throbbing headache that was worse when he lay down. He was hospitalized and found to have retinal hemorrhages and papilledema, compatible with malignant hypertension. Laboratory examination showed blood urea nitrogen 32, creatine 2.1, white blood cell count lS,OOO, S3% polymorphonuclear leukocytes, and hemoglobin S.2 gm/dL. Blood smear showed burr cells, marked poikilocytosis, and numerous fragmented erythrocytes (helmet cells) compatible with microangiopathic hemolytic anemia. Blood and urine cultures were consistently negative. Platelet count was 10S,OOO/ILL. A direct Coombs' test was negative, and his reticulocyte count was 9%. A nephrology consultant was called, and the patient was begun on maximum doses of alpha-methyl dopa and hydralazine to control his rising blood pressure. His urine volume was 300-400 ml/24 hr, he had 4+ proteinuria, and 35-50 red blood cells/high-power field. Each day, his creatinine climbed approximately 3 mg/dL, suggesting essentially complete loss of renal function. His blood pressure was poorly controlled with a-methyl dopa (Aldomet) and hydralazine, but when he was begun on renal dialysis, his blood pressure hecame manageable. He was scheduled for renal transplantation when he was lost to follow up.
This is the only patient in whom I have observed the onset of "scleroderma kidney." He provides a powerful example of the devastation possible in this disease in a matter of a few days. Three points should be made about the course of his disease. First, those patients with rapid progression of skin involvement of the trunk are more likely to develop renal failure. Second, any process that results in abrupt changes in blood volume (increases or decreases) may precipitate renal failure. In this patient, the administration of a diuretic for edema may have triggered the renal change. Precipitation of scleroderma kidney failure may follow the administration of corticosteroids, perhaps because these agents modify vascular tone or increase blood volume, an association also noted in the multicenter Scleroderma Criteria Study 7 reviewed in Table 4. Third, this patient demonstrated a 50% fall in his hemoglobin level within a 5 day period with no evidence of bleeding and with large numbers of fragmented erythrocytes on his admitting blood smear. Heptinstall and colleagues43 noted evidence of intravascular hemolysis in 7 of 20 patients dying of scleroderma and autopsied at Johns Hopkins Hospital in Baltimore. Six
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The Many Faces of Scleroderma
Table 4. Predictors of a Poor Prognosis in Systemic Sclerosis *
General factors Older age (average in yr) Digital pitting Proximal muscle weakness Taking prednisone Renal Proteinuria Increased blood urea nitrogen, creatinine Microangiopathic erythrocytes Pulmonary Dyspnea DLco (% of predicted normal value) Forced vito capacity (% of predicted normal value) Arterial P02 (mm Hg) Smoking tobacco Cardiovascular Heart rate (beats/min) Pedal edema Neck vein distention Abnormal EKG-PVCs, ST-T wave changes Left ventricular enlargement Laboratory findings D-Xylose absorption (g) ESR (mmjhr) Anti-topoisomerase I (Scl-70) Anti-centromere
Died 2 yr
p Value
53 53% 43% 31%
46 43% 15% 13%
