Scleroderma and Related Diseases Part 1

Scleroderma

Definition and classification

Scleroderma, or systemic sclerosis, is a rare, slowly progressive rheumatic disease characterized by deposition of fibrous connective tissue in the skin and other tissues. It is accompanied by vascular lesions, especially in the skin, lungs, and kidneys. No cure is known.

Scleroderma may be either systemic or localized, with the systemic illness being either diffuse or limited. The limited form of systemic scleroderma, or CREST syndrome (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodacty-ly, and telangiectasias), involves internal organs less often than diffuse scleroderma. Except when pulmonary hypertension is present, patients with the limited form have a better prognosis than those with the diffuse form [see Table 1]. Systemic sclero-derma can be fatal.

Localized scleroderma is confined to the skin, subcutaneous tissue, and muscle and is not accompanied by the Raynaud phenomenon, acrosclerosis, or visceral involvement. There are two forms of localized scleroderma: morphea, which presents as variable-sized plaques of skin induration, and linear, which presents as bands of skin induration on the face or a single extremity. Linear scleroderma may be associated with muscle atrophy and involvement of the underlying bone. It usually afflicts children or young adults and may lead to significant growth impairment of the involved part. In the morphea version, the lesions may persist for months or years, after which improvement may occur [see Table 1]. Although there is a possibility of disfigurement, localized scleroderma is not a severe illness, and patients with the disease generally have a normal life span.


Epidemiology

The Raynaud phenomenon is associated with scleroderma [see Diagnosis, Clinical Manifestations, below]. Primary Ray-naud phenomenon (Raynaud phenomenon without underlying illness) is quite common, with up to 30% of young women having episodes. A meta-analysis showed that the transition rate to a defined inflammatory rheumatic disease (e.g., sclero-derma or lupus) is 3.2 per 100 patient-years of observation; the eventual development of an inflammatory rheumatic disease occurred in 12.6% of individuals. The best predictor of development of inflammatory disease is an abnormal nailfold capillary pattern, which has a predictive value of 47%; a positive an-tinuclear antibody test has a predictive value of 30%.1 Racial, genetic, and environmental factors have been proposed as influences of scleroderma risk and disease pattern.2

The overall global incidence of scleroderma is approximately 17 to 19 per one million population per year, with higher rates for women than for men. African Americans experience diffuse scleroderma more often than other ethnic groups; whites are more often diagnosed with the CREST variant.3 The prevalence in the United States is approximately 24 per 100,000 population3—fourfold to ninefold the prevalence in other countries. Mortality factors include diffuse disease, older age at onset, and internal organ involvement, particularly pulmonary and renal involvement. Some investigators have suggested that scleroderma is associated with various environmental expo-sures.4 For example, workers exposed to polyvinylchloride may experience the Raynaud phenomenon and scleroderma-like skin thickening.5 However, no substance has yet been convincingly linked with scleroderma.5 Silicone breast implants have not been found to be associated with scleroderma.6

Etiology

The etiology of scleroderma is largely unknown. The disease shows familial aggregation consistent with a genetic component, and family history is the strongest risk factor.3 In the United States, about 1.6% of relatives are affected, an over 60-fold higher prevalence than in the general population (0.026%).3 One etiologic factor may be a fibrillin defect. Fibrillin is a macromolecule that is a component of elastic fibers, and it is defective in Marfan syndrome. In an animal model (the tight-skin mouse, tskl), a scleroderma-like condition is caused by an insertion into the fibrillin gene that apparently encodes a latent binding region for the transforming growth factor-P (TGF-P) cytokine. One proposed explanation is that the abnormal fib-rillin binds an increased number of fibroblast growth factors that influence nearby fibroblasts. The current knowledge extends to Japanese and Oklahoma Choctaw scleroderma patients, who likely have a scleroderma-related genetic defect (e.g., secreted protein acidic and rich in cystein [SPARC]) in the fibrillin chromosomal region either in or near the gene.7 However, other genes (e.g., IL-1A, TGF-P, and IL-4) or environmental exposures may also be involved.

Pathophysiology and pathogenesis

The common pathologic features of tissues with scleroder-ma involvement are progressive fibrosis, vascular abnormalities, and inflammation. Fibrosis involves an accumulation of excessive collagen and other extracellular matrix constituents, such as glycosaminoglycans and fibronectin. The vascular abnormalities are intimal hyperplasia with collagen deposition and adventitial fibrosis, capillary dropout, dilatation, tortuosity, and fibrotic atherosclerosis. The inflammatory changes may include cellular infiltration. These pathologic characteristics are believed to be the result of three or more interacting components: autoimmunity, an endothelial abnormality, and a skin fi-broblast lesion. An alternative explanation is that these characteristics are the result of a disease process akin to graft versus host disease (GVHD).

Table 1 Classification of Scleroderma

Form

Syndrome

Scleroderma (systemic sclerosis)

Diffuse skin involvement Limited skin involvement (CREST syndrome) Overlapping features of mixed connective tissue disease

Localized scleroderma

Morphea: single or multiple plaques or generalized lesions Linear scleroderma

CREST—calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasias

Immune Cell and Cytokine Abnormalities

Activated thymus-derived lymphocytes predominate among the cells that infiltrate involved tissues; activated inflammatory cells are also present. Such immune and inflammatory cells release a plethora of cytokines and soluble mediators. Of particular note are cytokines influencing fibroblast function: inter-leukin-1 (IL-1), IL-4, IL-6, IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), tumor necrosis factor (TNF), and TGF-p. TNF and interferon gamma are antifi-brotic,8 but the action of TGF-P results in a pattern of tissue damage similar to the pattern seen in scleroderma. TGF-P stimulates fibroblasts and vascular smooth muscle cells to make collagen, and it stimulates endothelial cells to make endothelin-1, which, in turn, causes vasoconstriction and collagen production. B cells are also activated in patients with scleroderma, and some autoantibodies are relatively specific for scleroderma. Whether such humoral responses result in scleroderma tissue damage is under investigation.

Fibroblast Abnormalities

As with lymphocytes and macrophages showing activation in scleroderma, fibroblasts are also metabolically activated. Such activated cells overproduce collagen, other extracellular matrix molecules, and cellular adhesion molecules.9 The reasons why collagen gene expression is increased and sustained have not been fully explained. One possible explanation is that the presence of cytokines such as IL-4 and TGF-P strongly foster collagen production.8 TGF-P acts in large part through specific receptors that lead to activation of Smads, a family of second messenger/transcription factor proteins.10 Some genetic studies have supported the proposition that scleroderma is associated with TGF-P markers.11

Vascular Abnormalities

Vessels in involved tissues show disrupted pattern and function, characterized by altered endothelial permeability, adhesion of platelets and leukocytes to endothelium, and the presence of inflammatory cells. One current pathogenetic theory is that endothelial homeostasis is disrupted, leading to increased endothelin-1 production, reduced prostacyclin release, and enhanced coagulation.12 Endothelial cells express increased numbers of adhesion molecules necessary for inflammatory cell adhesion and extravasation. Capillaries become obliterated but are not replaced; involved tissues may become ischemic and then reperfused. The Raynaud phenomenon [see Diagnosis, Clinical Manifestations, below] is a hallmark vascular lesion that likely represents an exaggerated response of a stiff vessel wall to a typical environmental exposure. Microscopic analysis of the nailfolds of patients with scleroderma and Raynaud phenomenon reveals capillary disappearance and dilatation. In scleroderma, small arteries develop concentric intimal fibrosis and thus become narrow; this narrowing in turn greatly increases the vascular reactivity to alpha2-adrenergic agents.

Chimerism and Microchimerism

Chimerism denotes a state in which a person has cells derived from two or more other people. Male DNA consistent with microchimerism has been found more frequently and in higher concentrations in the circulation of women with sclero-derma who have had a previous male delivery than in women without scleroderma who have also had a male delivery. In addition, microchimerism has been found in tissues of mothers with scleroderma but not in the tissues of healthy mothers.13 However, cause and effect are not yet established,14 and parous women are reported to have a reduced scleroderma risk (odds ratio, 0.3).

Severe involvement of the hands in a patient with longstanding scleroderma includes flexion contractures of the fingers related to fibrosis of the skin and of subcutaneous tissues. Increased pigmentation has occurred, and melanin loss (vitiligo) is evident in some areas. The distal aspects of the terminal phalanges in some fingers have undergone resorption or shortening. This process, termed autoamputation, usually occurs without ulceration of the terminal digit; the mechanism is unknown.

Figure 1 Severe involvement of the hands in a patient with longstanding scleroderma includes flexion contractures of the fingers related to fibrosis of the skin and of subcutaneous tissues. Increased pigmentation has occurred, and melanin loss (vitiligo) is evident in some areas. The distal aspects of the terminal phalanges in some fingers have undergone resorption or shortening. This process, termed autoamputation, usually occurs without ulceration of the terminal digit; the mechanism is unknown.

Diagnosis

Clinical Manifestations

Skin The first signs of scleroderma in the skin are swelling and thickening of the fingers and hands, with or without involvement of the face; later in the illness, other areas of skin may become thickened. Involvement of the trunk and arms proximal to the elbows is associated with visceral involvement and a poorer prognosis. The skin continues to thicken during the first 2 to 3 years after the onset of disease; the thickening then ceases and may recede, giving the impression that the skin is softening. In subsequent years, skin atrophy occurs, with con- comitant loss of hair, sebaceous glands, and sweat glands, as well as a loss of pliability. In addition, the skin becomes hide-bound—tightly drawn and bound to underlying structures.

Telangiectasias appear on the hands, face, and tongue in a patient with the CREST (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasias) variant of scleroderma. Thumbs are bandaged because of chronic ulcerations associated with the Raynaud phenomenon.

Figure 2 Telangiectasias appear on the hands, face, and tongue in a patient with the CREST (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasias) variant of scleroderma. Thumbs are bandaged because of chronic ulcerations associated with the Raynaud phenomenon.

In scleroderma, extensive calcinosis (hydroxyapatite crystal deposition) may be found in connective tissues and around joints. If extensive, calcinosis is usually associated with at least partial loss of joint motion.

Figure 3 In scleroderma, extensive calcinosis (hydroxyapatite crystal deposition) may be found in connective tissues and around joints. If extensive, calcinosis is usually associated with at least partial loss of joint motion.

Skin involvement is often most prominent in the hands and fingers (sclerodactyly); frequently, the face is also affected. A tightening of facial skin results in decreased skin lines, a pursed appearance, and a diminution in the oral aperture. The skin tightness may limit mobility, especially in the fingers. Flexion contractures may also develop in the fingers [see Figure 1]. Several other skin abnormalities may accompany these changes. Telangiectasias occur frequently and may be numerous [see Figure 2]. They are often most prominent on the face, hands, and oral mucosa. Calcinosis—the deposition of hydroxyapatite crystals in subcutaneous areas—may be limited or widespread and is usually located around joint capsules [see Figure 3]. Skin ulceration over calcific deposits may lead to drainage of a white material with a consistency resembling toothpaste. A diffuse increase in melanotic pigmentation may extend over the entire skin surface; areas of hypopigmentation are also commonly seen.

The Raynaud phenomenon is an episodic manifestation of numbness or pain accompanied by a two- or three-phase color change in the digits; these changes are triggered by cold temperatures or emotional stress and are relieved by warming the involved part. In severe cases, however, the relation to ambient temperature is sometimes less obvious. The episode typically begins with pallor, followed by cyanosis and, finally, by redness caused by reactive hyperemia [see Figure 4]. Prolonged ischemia may lead to painful digits, ulceration, and even gangrene. Almost all patients (95%) with diffuse or limited sclero-derma experience the Raynaud phenomenon. The Raynaud phenomenon is also seen in patients with other disorders, including other autoimmune diseases such as systemic lupus erythematosus (SLE), polymyositis, and several forms of vas-culitis; in patients who are receiving certain drugs, such as bleomycin, ergot derivatives, beta blockers, and methysergide; and after occupational exposure to vinyl chloride, cold temperatures, and vibrating tools.

In scleroderma, the Raynaud phenomenon is a manifestation of vasculopathy involving small arteries and capillaries; it occurs not only in the extremities but also in some involved viscera, such as the lungs and kidneys. Patients with scleroderma and the Raynaud phenomenon have characteristic capillary changes on nailfold microscopy. Nailfold microscopy consists of observation of the capillary structure of the periungual tissues with a handheld magnifying lens, such as that used in a standard ophthalmoscope. Patients with underlying scleroder-ma may exhibit loss of some capillaries and dilatation of capillaries in other nailfold areas. Such changes often occur in asso- ciation with internal organ involvement and may be used to predict the development of diffuse scleroderma when visceral involvement is not clinically apparent.

Vascular pathology usually manifests itself as the Raynaud phenomenon in patients with scleroderma. The cyanotic phase of the Raynaud phenomenon often involves the distal two thirds of the second and third fingers of both hands.

Figure 4 Vascular pathology usually manifests itself as the Raynaud phenomenon in patients with scleroderma. The cyanotic phase of the Raynaud phenomenon often involves the distal two thirds of the second and third fingers of both hands.

Table 2 Antinuclear Antibodies in Scleroderma

Immunofluorescent Pattern of Antinuclear Antibody Staining

Antigens

Clinical Pattern

Approximate Frequency (%)

Specificity

Nucleolar

Nuclear ribonucleoproteins (nRNPs)

Diffuse or limited scleroderma

50

Moderate

RNA polymerases I, II, and III

Diffuse scleroderma

23

High

Nuclear proteins PM-1 (PM-Scl) and Ku

Scleroderma-polymyositis overlap

< 5

High, for scleroderma and polymyositis

Centromeric (large speckles)*

Centromere proteins (CENP-A, CENP-B, and CENP-C)

Usually in limited scleroderma (CREST syndrome)

50 (of patients with CREST syndrome)

High

Diffuse (fine speckles)

Topoisomerase I (Scl-70)

Diffuse scleroderma

20-33

High

Homogeneous

Histones (mainly H1 and H3)

Localized scleroderma

50

Moderate

^Requires a human epithelial carcinoma cell line (HEp-2).

Proposed criteria for early diagnosis of scleroderma include either objective observation or measurement of cold-induced vasospasm, plus either abnormal nailfold microscopy, presence of antibodies directed toward characteristic autoantigens [see Table 2],16 or patient reports of Raynaud phenomenon and the presence of nailfold microscopic changes and autoantibodies.

Musculoskeletal system A mild, usually symmetrical, inflammatory arthritis can occur in scleroderma. Juxta-articular bone erosions occur frequently, especially in the distal inter-phalangeal joints, but the degree of destruction is usually less than that seen in rheumatoid arthritis. Flexion contractures of the fingers often develop and are most likely related to fibrosis of the tendons and joint capsules. Crepitus and friction rubs, detected by palpation or auscultation over tendons and bursas, are characteristic findings related to fibrotic changes of underlying tissues. Another skeletal complication is acral osteolysis, which is the resorption of the terminal phalanges and surrounding soft tissue with consequent shortening of the digits [see Figure 5]. It may occur without infection or ulceration. Patients with scleroderma may have one or more of a variety of muscle disorders,17 such as fatigue without objective evidence of muscle damage, a simple myopathy, or clear-cut inflammatory myositis.

Over an 8-year period, radiographs taken of the hand of a patient with scleroderma demonstrate a progressive, terminal resorption of the digits. The earlier film (left) shows a loss of the spherical terminal portion of the distal phalanx of the thumb and a small, dense calcific deposit at the terminal aspect of the thumb. After an 8-year period, dramatic changes can be seen (right). An almost complete loss of the terminal phalanx of the thumb and a partial loss of the distal phalanges of the remaining fingers are observed. In addition, the entire distal phalanx of the third finger is lost along with part of the middle phalanx. Loss of the middle phalanx is less common than loss of the distal phalanges. A generalized osteopenia is present in the later stage, which is probably related to osteoporosis of disuse, and a calcific deposit has formed in the ulnar aspect of the wrist. The apparent narrowing of interphalangeal joint spaces may be associated with flexion contractures of the fingers, which are caused by the fibrous thickening of the connective tissues of the hand.

Figure 5 Over an 8-year period, radiographs taken of the hand of a patient with scleroderma demonstrate a progressive, terminal resorption of the digits. The earlier film (left) shows a loss of the spherical terminal portion of the distal phalanx of the thumb and a small, dense calcific deposit at the terminal aspect of the thumb. After an 8-year period, dramatic changes can be seen (right). An almost complete loss of the terminal phalanx of the thumb and a partial loss of the distal phalanges of the remaining fingers are observed. In addition, the entire distal phalanx of the third finger is lost along with part of the middle phalanx. Loss of the middle phalanx is less common than loss of the distal phalanges. A generalized osteopenia is present in the later stage, which is probably related to osteoporosis of disuse, and a calcific deposit has formed in the ulnar aspect of the wrist. The apparent narrowing of interphalangeal joint spaces may be associated with flexion contractures of the fingers, which are caused by the fibrous thickening of the connective tissues of the hand. 

GI tract Almost every part of the GI tract may be involved in scleroderma.18 Sjogren syndrome, which causes dry eyes and dry mouth, occurs in about one third of patients with sclero-derma. Esophageal hypomotility, which is demonstrated by cinefluoroscopic examination and manometric studies, occurs in more than 90% of patients with scleroderma, many of whom are asymptomatic [see Figure 6]. The absence of normal peristaltic waves in the lower two thirds of the esophagus may cause dysphagia; incompetence of the gastroesophageal sphincter leads to reflux esophagitis and sometimes may result in esophageal stricture. Barrett esophagus, esophageal carcinoma, and candidal esophagitis may ensue. Similarly, hypomotil-ity of the stomach, small intestine, colon, and anorectal area may occur, possibly causing gastroparesis, pseudo-obstruction, colonic impaction, or impaired anorectal function. Telangiec-tasias may be present in the gastric mucosa and the mucosa of the small intestine and colon. Gas may dissect into the intestinal wall (pneumatosis intestinalis) and leak into the peritoneal cavity, simulating a perforated viscus. Characteristic wide-mouthed diverticula of the colon may develop; these are pathognomonic of scleroderma. The early lesions of the GI tract may be caused by autonomic nerve dysfunction; auto-nomic nerve dysfunction may in time lead to smooth muscle atrophy and irreversible muscle fibrosis of the gut. Primary biliary cirrhosis and drug-induced hepatitis may also be associated with scleroderma.

Lungs Pulmonary involvement represents an important cause of scleroderma-related morbidity and mortality19; lung disease is the most frequent cause of scleroderma-related death. Although scleroderma-related findings may range from associated malignancy and silicosis to calcinosis and hemorrhage, the most common findings are pulmonary vascular disease and interstitial inflammation and fibrosis. Isolated pulmonary hypertension is typically found in the CREST syndrome (prevalence is 50% to 65% in the limited cutaneous subset and up to 35% in the diffuse subset)20; interstitial pulmonary fibrosis may be found in both limited and diffuse scleroderma (at postmortem examination, the frequency is about 75%).

Isolated pulmonary hypertension usually results in cough, dyspnea, and syncope; it has a severe prognostic outlook (5-year survival < 10%). Pulmonary hypertension is defined by a resting mean pulmonary arterial pressure greater than 25 mm Hg or an exercise-induced mean pulmonary arterial pressure greater than 30 mm Hg; in addition, pulmonary hypertension is often associated with abnormal diffusing capacity for carbon monoxide. In persons with limited cutaneous involvement, decreasing diffusing capacity of the lung for carbon monoxide (Dlco) is an excellent predictor of subsequent pulmonary hypertension; one study of 106 patients reported that at baseline, patients who subsequently developed pulmonary hypertension had a mean pulmonary arterial pressure only slightly higher than patients who did not, but the Dlco in patients with pulmonary hypertension declined from a mean of 80% to a mean of 35%. The early clinical features associated with subsequent pulmonary hypertension included more severe Raynaud phenomenon and digital tip ulcers, as well as positivity for serum autoantibodies directed toward nucleoli.21

Hypomotility of the esophagus in scleroderma, which is demonstrated by the lack of peristaltic waves in the barium column, is frequently an asymptomatic finding, but it may be associated with dysphagia and incompetence of the gastric sphincter, which results in reflux esophagitis.

Figure 6 Hypomotility of the esophagus in scleroderma, which is demonstrated by the lack of peristaltic waves in the barium column, is frequently an asymptomatic finding, but it may be associated with dysphagia and incompetence of the gastric sphincter, which results in reflux esophagitis.

Interstitial fibrosis is typically accompanied by dyspnea and cough, and the 5-year survival is about 45%. Although chest roentgenograms may show linear and reticular abnormalities, high-resolution CT scanning is favored for the detection of early disease; on CT scans, alveolitis appears as patchy areas with a ground-glass appearance. Interstitial fibrosis appears to result from inflammatory alveolitis: the release of various cy-tokines and chemokines in the course of the inflammatory process results in fibroblast activation and extracellular matrix remodeling. Association between severe esophageal involvement and interstitial fibrosis suggests that gastroesophageal reflux may contribute to fibrotic changes.22

Heart Patients with clinically evident scleroderma-relat-ed heart disease have a poor prognosis.23 The myocardium is involved in approximately 20% to 25% of clinical cases of systemic scleroderma. Scleroderma-associated myocardial disease is typically characterized by patchy areas of myocardial fibrosis replacing normal muscle; this may cause hypertrophy and diminished cardiac output, particularly with exercise. Di-astolic dysfunction24 and atherosclerotic coronary artery disease are common. Myocardial infarctions may develop in patients with scleroderma who have normal findings on coronary artery catheterization. Myocarditis may also occur in patients with scleroderma-associated inflammatory myositis. The patchy myocardial fibrosis and conduction system involvement may result in various arrhythmias and sudden death. Pericardial disease is common at autopsy, but clinically evident pericardial manifestations occur in only 5% to 16% of cases. Such pericardial disease may cause acute pericarditis, arrhythmias, pericardial effusions, or sudden death. In limited cutaneous scleroderma, apart from a similar frequency of cardiac arrhythmias and conduction defects, heart involvement is generally less frequent and less severe than in diffuse scleroderma.

Kidneys Chronic mild proteinuria and mild hypertension are common effects of scleroderma but typically do not result in significant renal dysfunction. The most significant disease process associated with scleroderma is renal crisis,25 which consists of the rapid development of malignant hypertension, hy-perreninemia, microangiopathic hemolytic anemia, and oligu-ric renal failure. Renal crisis typically occurs in the scleroderma subset characterized by rapidly progressive diffuse skin disease. Renal crisis was formerly the most common cause of death in patients with scleroderma, but aggressive treatment with angiotensin-converting enzyme (ACE) inhibitors early in the course of disease has greatly improved outcome.

Other organ systems Although scleroderma rarely involves the central nervous system, peripheral neuropathy may occur. The most frequent form is unilateral or bilateral trigemi-nal neuropathy of one or more of the three trigeminal branches; this neuropathy presents as progressive numbness and pain. Widespread autonomic nervous system dysfunction underlies the propensity for the Raynaud phenomenon and intestinal involvement. Hematopoietic consequences of scleroderma are uncommon.

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