Systemic Sclerosis

Systemic sclerosis is a chronic disease characterized by: (1) chronic inflammation thought to be the result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs.^[90] Although the term scleroderma is ingrained in clinical medicine, this disease is better named systemic sclerosis because it is characterized by excessive fibrosis throughout the body. The skin is most commonly affected, but the gastrointestinal tract, kidneys, heart, muscles, and lungs also are frequently involved. In some patients the disease seems to remain confined to the skin for many years, but in the majority it progresses to visceral involvement with death from renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption. The clinical heterogeneity of systemic sclerosis has been recognized by classifying the disease into two major categories: diffuse scleroderma, characterized by widespread skin involvement at onset, with rapid progression and early visceral involvement; and limited scleroderma, in which the skin involvement is often confined to fingers, forearms, and face. Visceral involvement occurs late; hence, the clinical course is relatively benign. Some patents with the limited disease also develop a combination of calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, called the CREST syndrome. Several other variants and related conditions, such as eosinophilic fasciitis, occur far less frequently.

- The cause of systemic sclerosis is not known. Autoimmune responses, vascular damage, and collagen deposition all contribute to the ultimate tissue injur.

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It is proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that activate inflammatory cells and fibroblasts.^[92] Although inflammatory infiltrates are typically sparse in the skin of patients with systemic sclerosis, activated CD4+ T cells can be found in many patients, and T_H2 cells have been isolated from the skin. Several cytokines produced by these T cells, including TGF-β and IL-13, can stimulate transcription of genes that encode collagen and other extracellular matrix proteins (e.g., fibronectin) in fibroblasts. Other cytokines recruit leukocytes and propagate the chronic inflammation.
There is also evidence for inappropriate activation of humoral immunity, and the presence of various autoantibodies provides diagnostic and prognostic information.^[93] Virtually all patients have ANAs that react with a variety of nuclear antigens. Two ANAs strongly associated with systemic sclerosis have been described. One of these, directed against DNA topoisomerase I (anti-Scl 70), is highly specific. Depending on the ethnic group and the assay, it is present in 10% to 20% of patients with diffuse systemic sclerosis. Patients who have this antibody are more likely to have pulmonary fibrosis and peripheral vascular disease. The other, an anticentromere antibody, is found in 20% to 30% of patients, who tend to have the CREST syndrome or limited cutaneous systemic sclerosis. Only rarely does the same patient have both antibodies. The role of these ANAs in the pathogenesis of the disease is unclear; it has been postulated that some of these antibodies may stimulate fibrosis, but the evidence in support of this idea is not convincing.

-  Microvascular disease is consistently present early in the course of systemic sclerosis and may be the initial lesion. Intimal proliferation is evident in 100% of digital arteries of patients with systemic sclerosis. Capillary dilation with leaking, as well as destruction, is also common. Nailfold capillary loops are distorted early in the course of disease, and later they disappear. Thus, there is unmistakable morphologic evidence of microvascular injury. Telltale signs of endothelial activation and injury (e.g., increased levels of von Willebrand factor) and increased platelet activation (increased percentage of circulating platelet aggregates) have also been noted. However, what causes the vascular injury is not known; it could be the initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting damage on microvascular endothelium. Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger perivascular fibrosis. Activated or injured endothelial cells themselves may release PDGF and factors chemotactic for fibroblasts. Vascular smooth muscle cells also show abnormalities, such as increased expression of adrenergic receptors. Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring. Whether endothelial injury can also be initiated by toxic effects of environmental triggers remains uncertain but cannot be definitively excluded.

- The progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities, including the actions of fibrogenic cytokines produced by infiltrating leukocytes, hyperresponsiveness of fibroblasts to these cytokines, and scarring following upon ischemic damage caused by the vascular lesions. There is also evidence for a primary abnormality in collagen production. Consistent with this notion is the finding that a polymorphism in the gene encoding connective tissue growth factor is associated with systemic sclerosis.^[94] In mouse models of Marfan syndrome caused by mutations in the fibrillin-1 gene, some features of systemic sclerosis are also seen,^[95] suggesting again that connective tissue abnormalities may contribute to this disease.
- Virtually all organs can be involved in systemic sclerosis. Prominent changes occur in the skin, alimentary tract, musculoskeletal system, and kidney, but lesions also are often present in the blood vessels, heart, lungs, and peripheral nerves.

- A great majority of patients have diffuse, sclerotic atrophy of the skin, which usually begins in the fingers and distal regions of the upper extremities and extends proximally to involve the upper arms, shoulders, neck, and face. Histologically, there are edema and perivascular infiltrates containing CD4+ T cells, together with swelling and degeneration of collagen fibers, which become eosinophilic. Capillaries and small arteries (150 to 500 μm in diameter) may show thickening of the basal lamina, endothelial cell damage, and partial occlusion. With progression of the disease, there is increasing fibrosis of the dermis, which becomes tightly bound to the subcutaneous structures. There is marked increase of compact collagen in the dermis, usually with thinning of the epidermis, loss of rete pegs, atrophy of the dermal appendages, and hyaline thickening of the walls of dermal arterioles and capillaries. Focal and sometimes diffuse subcutaneous calcifications may develop, especially in patients with the CREST syndrome. In advanced stages the fingers take on a tapered, clawlike appearance with limitation of motion in the joints, and the face becomes a drawn mask. Loss of blood supply may lead to cutaneous ulcerations and to atrophic changes in the terminal phalanges. Sometimes the tips of the fingers undergo autoamputation.

-  The alimentary tract is affected in approximately 90% of patients. Progressive atrophy and collagenous fibrous replacement of the muscularis may develop at any level of the gut but are most severe in the esophagus. The lower two thirds of the esophagus often develops a rubber-hose inflexibility. The associated dysfunction of the lower esophageal sphincter gives rise to gastroesophageal reflux and its complications, including Barrett metaplasia ( Chapter 17 ) and strictures. The mucosa is thinned and may be ulcerated, and there is excessive collagenization of the lamina propria and submucosa. Loss of villi and microvilli in the small bowel is the anatomic basis for the malabsorption syndrome sometimes encountered.

-  Inflammation of the synovium, associated with hypertrophy and hyperplasia of the synovial soft tissues, is common in the early stages; fibrosis later ensues. These changes are reminiscent of rheumatoid arthritis, but joint destruction is not common in systemic sclerosis. In a small subset of patients (approximately 10%), inflammatory myositis indistinguishable from polymyositis may develop.

-  Renal abnormalities occur in two thirds of patients with systemic sclerosis. The most prominent are the vascular lesions. Interlobular arteries show intimal thickening as a result of deposition of mucinous or finely collagenous material, which stains histochemically for glycoprotein and acid mucopolysaccharides. There is also concentric proliferation of intimal cells. These changes may resemble those seen in malignant hypertension, but in scleroderma the alterations are restricted to vessels 150 to 500 μm in diameter and are not always associated with hypertension. Hypertension, however, does occur in 30% of patients with scleroderma, and in 20% it takes an ominously rapid, downhill course (malignant hypertension). In hypertensive patients, vascular alterations are more pronounced and are often associated with fibrinoid necrosis involving the arterioles together with thrombosis and infarction. Such patients often die of renal failure, which accounts for about 50% of deaths in persons with this disease. There are no specific glomerular changes.

-  The lungs are involved in more than 50% of individuals with systemic sclerosis. This involvement may manifest as pulmonary hypertension and interstitial fibrosis. Pulmonary vasospasm, secondary to pulmonary vascular endothelial dysfunction, is considered important in the pathogenesis of pulmonary hypertension. Pulmonary fibrosis, when present, is indistinguishable from that seen in idiopathic pulmonary fibrosis

-  Pericarditis with effusion and myocardial fibrosis, along with thickening of intramyocardial arterioles, occurs in one third of the patients. Clinical myocardial involvement, however, is less common.

- Systemic sclerosis has a female-to-male ratio of 3 : 1, with a peak incidence in the 50- to 60-year age group. Although systemic sclerosis shares many features with SLE, rheumatoid arthritis ( Chapter 26 ), and polymyositis ( Chapter 27 ), its distinctive features are the striking cutaneous changes, notably skin thickening. Raynaud's phenomenon, manifested as episodic vasoconstriction of the arteries and arterioles of the extremities, is seen in virtually all patients and precedes other symptoms in 70% of cases. Dysphagia attributable to esophageal fibrosis and its resultant hypomotility are present in more than 50% of patients. Eventually, destruction of the esophageal wall leads to atony and dilation, especially at its lower end. Abdominal pain, intestinal obstruction, or malabsorption syndrome with weight loss and anemia reflect involvement of the small intestine. Respiratory difficulties caused by the pulmonary fibrosis may result in right-sided cardiac dysfunction, and myocardial fibrosis may cause either arrhythmias or cardiac failure. Mild proteinuria occurs in as many as 30% of patients, but rarely is the proteinuria severe enough to cause a nephrotic syndrome. The most ominous manifestation is malignant hypertension, with the subsequent development of fatal renal failure, but in its absence progression of the disease may be slow. The disease tends to be more severe in blacks, especially black women. As treatment of the renal crises has improved, pulmonary disease has become the major cause of death in systemic sclerosis.

- As mentioned earlier, the CREST syndrome is seen in some patients with limited systemic sclerosis. It is characterized by calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia, and the presence of anticentromere antibodies. Patients with the CREST syndrome have relatively limited involvement of skin, often confined to fingers, forearms, and face, and calcification of the subcutaneous tissues. Involvement of the viscera, including esophageal lesions, pulmonary hypertension, and biliary cirrhosis, may not occur at all or occur late. In general the patients live longer than those with systemic sclerosis with diffuse visceral involvement at the outset.

References:
1. Kumar, Raminder et al.  Robbins and Cotran Pathologic Basis of Disease 8th Ed.  Sander Elsevier. 2010.