Pathology
The distinguishing pathologic hallmark of SSc is the combination of widespread obliterative vasculopathy of small arteries and arterioles and fibrosis in the skin and internal organs. Whereas in established SSc these lesions occur in the absence of inflammation, in relatively early-stage disease, perivascular cellular infiltrates may be detected in multiple organs prior to the appearance of fibrosis. In the skin, infiltrates are located in the reticular dermis and are composed primarily of CD4+ T lymphocytes. In addition, CD8+ T cells, monocytes/macrophages, plasma cells, mast cells, and occasionally B cells may be detected. In the lungs the majority of infiltrating T cells are CD8+. Evidence of eosinophil degranulation in the absence of intact eosinophils may be found. The vascular lesion is characterized by intimal proliferation in the small and medium-sized arteries, resulting in luminal narrowing. Obliterative vasculopathy is a late finding most prominent in the heart, lungs, kidneys, and intestinal tract. Tissue fibrosis is found in the skin, lungs, gastrointestinal tract, heart, tendon sheath, perifascicular tissue surrounding skeletal muscle, and some endocrine organs. In these tissues, accumulation of connective tissue composed of collagens, fibronectin, proteoglycans, and other structural macromolecules leads to progressive replacement of normal tissue architecture, resulting in functional impairment of affected organs.
Skin
In the skin, fibrosis causes massive dermal expansion and obliteration of the hair follicles, sweat glands, and other appendages (Fig. 7-2A). Collagen fiber accumulation is prominent in the reticular dermis, and the fibrotic process invades the subjacent adipose layer with entrapment of fat cells. The epidermis is atrophic, and the rete pegs are effaced.
Lungs
Patchy infiltration of the alveolar walls with CD8+ lymphocytes, macrophages, and eosinophils occurs in early disease. With progression, interstitial fibrosis and vascular damage dominate the pathological picture, often coexisting within the same lesions in patients with dcSSc. Pulmonary fibrosis is characterized by expansion of the alveolar interstitium, with accumulation of collagen and other connective tissue proteins. The most common histologic pattern is nonspecific interstitial pneumonitis (Fig. 7-2B). Progressive thickening of the alveolar septae results in obliteration of the air spaces and honeycombing, as well as loss of pulmonary blood vessels. This process impairs gas exchange and contributes to worsening of pulmonary hypertension. Intimal thickening of the pulmonary arteries, best seen with elastin stain, underlies pulmonary hypertension (Fig. 7-2C) and, at autopsy, is often associated with multiple pulmonary emboli and evidence of myocardial fibrosis.
FIGURE 7-2
Pathologic findings in systemic sclerosis. A. Dermal sclerosis. The skin is thickened due to marked expansion of the dermis. Thick bundles of densely packed collagen replaces skin appendages. B. Early interstitial lung disease. Diffuse fibrosis of the alveolar septae and a chronic inflammatory cell infiltrate. Trichrome stain. C. Pulmonary arterial obliterative vasculopathy. Striking intimal hyperplasia and narrowing of the lumen of a small pulmonary artery, with minimal interstitial fibrosis, in a patient with limited cutaneous SSc.
Gastrointestinal Tract
Pathologic changes can be found at any level from the mouth to the rectum. The lower esophagus is frequently involved, with prominent fibrosis of the lamina propria and submucosa and atrophy of the muscular layers; striated muscle in the upper third of the esophagus is generally spared. Characteristic vascular lesions are often present. Replacement of the normal intestinal tract architecture results in disordered peristaltic activity, with gastroesophageal reflux, dysmotility, and small-bowel obstruction. Chronic reflux is associated with esophageal inflammation, ulcerations, and stricture formation and may lead to premalignant Barrett’s metaplasia.
Kidneys
In the kidneys, lesions in the interlobular arteries predominate, whereas glomerulonephritis is rare. Chronic renal ischemia is associated with shrunken glomeruli. Patients with scleroderma renal crisis show dramatic changes in small renal arteries with reduplication of elastic lamina, marked intimal proliferation, and narrowing of the lumen, often accompanied by thrombosis and microangiopathic hemolysis.
Heart
The heart is frequently affected, with prominent involvement of the myocardium and pericardium. The characteristic arteriolar lesions of intimal proliferation and luminal narrowing are accompanied by contraction band necrosis, reflecting ischemia-reperfusion injury, and patchy myocardial fibrosis that may also involve the conduction system.
Other Organs
Synovitis may be found in early SSc; however, with progression of the disease, the synovium becomes fibrotic. Fibrosis of tendon sheaths and fascia produces palpable and sometimes audible tendon friction rubs. Inflammatory myositis and, in later stages, muscle atrophy and fibrosis are common findings. Fibrosis of the thyroid gland and of the minor salivary glands may be seen.
Clinical Features
Overview
Systemic sclerosis can affect virtually every organ (Table 7-3).The disease shows a great deal of variability in its clinical expression from one patient to the next.
TABLE 7-3
INTERNAL ORGAN INVOLVEMENT: LIMITED CUTANEOUS AND DIFFUSE CUTANEOUS FORMS OF SYSTEMIC SCLEROSIS
|
FEATURES |
LIMITED CUTANEOUS SSc (%) |
DIFFUSE CUTANEOUS SSc (%) |
|
Skin involvement |
90a |
100 |
|
Raynaud’s phenomenon |
99 |
98 |
|
Esophageal involvement |
90 |
80 |
|
Pulmonary fibrosis |
35 |
65 |
|
Pulmonary arterial |
25 |
15 |
|
hypertension |
||
|
Myopathy |
11 |
23 |
|
Cardiac involvement |
9 |
12 |
|
Scleroderma renal crisis |
2 |
15 |
a10% of lcSSc patients have SSc sine scleroderma.
Patients can be classified into one of two major subsets defined by the degree of clinically involved skin (Table 7-2). In dcSSc, internal organ involvement occurs early and is often progressive. In contrast, lcSSc presents with long-standing Raynaud’s phenomenon, is associated with indolent skin and limited internal organ involvement, and carries a better prognosis. While classification of SSc into diffuse and limited cutaneous subsets is useful, disease expression is far more complex, and several distinct phenotypes are recognized within each subset. For example, 10-15% of patients with lcSSc develop severe pulmonary artery hypertension without significant interstitial lung disease (ILD). Other patients have systemic features of SSc without appreciable skin involvement (SSc sine scleroderma). Unique clinical phenotypes of SSc associate with specific autoantibodies (Table 7-4). Patients with “overlap” have typical SSc features coexisting with clinical and laboratory evidence of \ another autoimmune disease such as polymyositis, autoimmune thyroid disease, Sjögren’s syndrome, polyarthritis, autoimmune liver disease, or systemic lupus erythematosus.
TABLE 7-4
AUTOANTIBODIES IN SYSTEMIC SCLEROSIS (SSc)
|
TARGET ANTIGEN |
SSc SUBSET |
CHARACTERISTIC CLINICAL ASSOCIATION |
|
Topoisomerase-I |
dcSSc |
ILD, cardiac involvement, scleroderma renal crisis |
|
Centromere proteins |
lcSSc |
Digital ischemia, calcinosis, isolated PAH |
|
U3-RNP |
dcSSc |
PAH, ILD, scleroderma renal crisis, myositis |
|
Th/T0 |
lcSSc |
ILD, PAH |
|
PM/Scl |
lcSSc |
Calcinosis, myositis |
|
U1-RNP |
MCTD |
PAH |
|
RNA polymerase III |
dcSSc |
Extensive skin, scleroderma renal crisis |
Note: dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension.
The term scleroderma refers to localized scleroderma and is used to describe a group of localized fibrosing skin disorders that primarily affect children (Table 7-1).
In contrast to SSc, localized scleroderma is rarely associated with internal organ involvement. Morphea presents as solitary or multiple circular patches of thickened skin and, less commonly, widespread induration (generalized morphea); the fingers are spared. Linear scleroderma— streaks of thickened skin, typically in one or both lower extremities—may affect the subcutaneous tissues with fibrosis and atrophy of supporting structures, muscle, and bone. In children, the growth of affected long bones can be retarded.When linear scleroderma lesions cross joints, ■ significant contractures can develop.
Initial Clinical Presentation
The initial clinical presentation is quite different in the diffuse and the limited cutaneous forms of the disease.
In dcSSc, the interval between Raynaud’s phenomenon and appearance of other manifestations is generally brief (weeks to months). Soft tissue swelling and intense pru- _ ritus are signs of the early inflammatory “edematous” phase of dcSSc. The skin on the fingers, hands, distal limbs, and face is usually affected first. Patients may note diffuse hyperpigmentation. Carpal tunnel syndrome can occur. Arthralgias are common and may be associated with muscle weakness and decreased joint mobility. During the ensuing weeks to months, the inflammatory edematous phase evolves into the “fibrotic” phase. Fibrosis starts in the dermis and is associated with loss of body hair, reduced production of skin oils, and a decline in sweating capacity. The subcutaneous tissue becomes affected, with fat atrophy and fibrosis of underlying fascia, muscle, and other soft tissue structures. Progressive flexion contractures of the fingers ensue. The wrists, elbows, shoulders, hip girdles, knees, and ankles are also affected due to fibrosis of the supporting joint structures. While advancing skin involvement is the most visible manifestation of early active dcSSc, progressive internal organ involvement occurs during this stage. The initial 4 years of the disease is the period of rapidly evolving systemic involvement; if organ failure does not occur during this period, the systemic process may then stabilize without further progression.
The course of the disease in lcSSc is more indolent and relatively benign. The period between the onset of Raynaud’s phenomenon and additional manifestations such as gastroesophageal reflux, telangiectasia, or calcinosis is commonly several years. Raynaud’s phenomenon tends to be more severe in lcSSc and is frequently associated with critical digital ischemia, ulcerations, and autoamputation.
Although significant renal involvement or pulmonary fibrosis is uncommon, isolated pulmonary artery hypertension develops in 10-15% of patients with lcSSc. Overlap of SSc with other autoimmune syndromes, including the sicca complex, polyarthritis, cutaneous vasculitis, and biliary cirrhosis, occurs primarily in the lcSSc subset.
Organ Involvement
Raynaud’s Phenomenon
Raynaud’s phenomenon, defined as episodic vasoconstriction in the fingers and toes, develops in virtually every patient with SSc. In some, episodes may also affect the tip of the nose and earlobes. Attacks are triggered by exposure to cold, a decrease in temperature, emotional stress, and vibration. In colder climates, patients commonly experience an increase in the frequency and severity of episodes during the winter months. Typical attacks start with pallor, followed by cyanosis of variable duration. Eventually erythema develops spontaneously or with rewarming of the digit. The progression of the three color phases reflects the underlying pathogenic mechanisms of vasoconstriction, ischemia, and reperfusion. Some patients with Raynaud’s phenomenon may experience only pallor or cyanosis.
As much as 3-5% of the general population has Raynaud’s phenomenon, and it is more frequent in women. In the absence of associated signs or symptoms of an underlying condition, Raynaud’s phenomenon is classified as primary, and represents an exaggerated physiological response to cold. Secondary Raynaud’s phenomenon occurs as a complication of SSc and other connective tissue diseases, hematological and endocrine conditions, and occupational disorders, as well as in association with the use of beta blockers such as atenolol, anticancer drugs such as cisplatin and bleomycin, and a variety of other medications. Distinguishing primary versus secondary Raynaud’s phenomenon can present a diagnostic challenge. The lack of an underlying cause for Raynaud’s phenomenon on the basis of the history and physical examination; a positive family history of Raynaud’s phenomenon; absence of digital tissue necrosis, ulceration, or gangrene; and a negative test for antinuclear antibodies support the diagnosis of primary Raynaud’s phenomenon. Secondary Raynaud’s phenomenon tends to develop at an older age (>30 years), is clinically more severe (episodes more frequent, prolonged, and painful), and is frequently associated with ischemic lesions and infarction in the digits (Fig. 7-3).The cutaneous capillaries at the nailbed can be viewed under a drop of grade B immersion oil using a low-power stereoscopic microscope. Nailfold microscopy may be helpful in Raynaud’s phenomenon; patients with primary Raynaud’s phenomenon have normal capillaries that appear as regularly spaced parallel vascular loops, whereas in SSc and other connective tissue diseases, nailfold capillaries are distorted with widened and irregular loops, dilated lumen, and areas of vascular “dropout.” In patients with SSc, Raynaud’s-like abnormal vascular reactivity may involve multiple vascular beds, and cold-induced episodic vasospasm has been documented in the pulmonary, renal, gastrointestinal, and coronary circulations.
FIGURE 7-3
Digital necrosis. Sharply demarcated necrosis of the fingertip in a patient with limited cutaneous SSc.
Skin Features
Clinically evident skin thickening is the hallmark of SSc that distinguishes it from other connective tissue diseases. The distribution of skin thickening is invariably symmetrical and bilateral. In the early stages of dcSSc, edema is gradually replaced by skin thickening that characteristically advances from distal to proximal extremities in an ascending centripetal fashion. In the affected areas, the skin is firm, coarse, and thickened. The extremities and trunk may be darkly pigmented. In some patients, diffuse tanning in the absence of sun exposure is a very early manifestation of skin involvement. In dark-skinned patients, vitiligo-like hypopig-mentation may occur. Because pigment loss spares the perifollicular areas, a “salt-and-pepper” appearance of the skin may be seen; this pattern is most common on the scalp, upper back, and chest. Dermal sclerosis due to collagen accumulation causes obliteration of hair follicles, sweat glands, and sebaceous glands, resulting in hair loss, decreased sweating, and dry skin. Transverse creases on the dorsum of the fingers disappear (Fig. 7-4).The fingers develop fixed flexion contractures, causing reduced hand mobility and muscle atrophy. Skin thickening in combination with fibrosis of the subjacent tendons accounts for contractures of the wrists, elbows, and knees. Thick ridges at the neck due to firm adherence of skin to the underlying platysma muscle interfere with neck extension. The face assumes a characteristic “mauskopf” appearance with taut and shiny skin, loss of wrinkles, and occasionally an expressionless facies due to reduced mobility of the eyelids, cheeks, and mouth. Thinning of the lips with accentuation of the central incisor teeth and fine wrinkles (radial furrowing) around the mouth complete the picture. The oral aperture may be dramatically reduced; microstomia interferes with eating and oral hygiene.The nose assumes apinched,beak-like appearance.
FIGURE 7-4
Sclerodactyly. Note skin induration and fixed flexion contractures at the proximal interphalangeal joints in a patient with limited cutaneous SSc.
In established SSc of long duration, the affected skin is firmly bound to the subcutaneous fat (tethering) and undergoes thinning and atrophy. Macular telangiectasia 2-20 mm in diameter occur frequently, particularly in lcSSc. These skin lesions, which resemble the telangiectasia seen in hereditary hemorrhagic telangiectasia, are prominent on the face, hands, lips, and oral cavity. Breakdown of atrophic skin leads to slow-healing ulcerations that are most common at the extensor surfaces of the proximal interphalangeal joints. Other sites for skin ulcerations include the volar pads of the fingertips and bony prominences such as the elbows and malleoli. Chronic ulcers are painful and may become secondarily infected, resulting in osteomyelitis. Healing of ischemic fingertip ulcerations leaves characteristic digital “pits.” Soft tissue loss at the fingertips due to ischemia is frequent and may be associated with striking resorption of the terminal phalanges (acro-osteolysis) (Fig. 7-5).
Calcium deposits occur in the skin and soft tissues, particularly in patients with lcSSc who are positive for anticentromere antibodies. The deposits, varying in size from tiny punctate lesions to large conglomerate masses, are composed ofcalcium hydroxyapatite crystals and can be readily visualized on plain x-rays. Frequent locations include the finger pads, palms, extensor surfaces ofthe forearms, and the olecranon and prepatellar bursae (Fig. 7-6). Paraspinal calcifications may cause neurological complications. Calcific deposits are generally noted as persistent firm, nontender subcutaneous lumps and may occasionally ulcerate through the overlying skin, producing drainage of chalky white material, pain, and local inflammation.
FIGURE 7-5
Acro-osteolysis. Note dissolution of terminal phalanges in a patient with long-standing limited cutaneous SSc.
