Systemic Sclerosis (Scleroderma)

Overview

Systemic Sclerosis, also called Scleroderma, is a chronic multi-system disease that is characterized by an early inflammatory phase followed by progressive fibrosis and small-vessel vasculopathy. Two clinical subtypes, Limited and Diffuse have been described, differing the geography of affected tissues.

Etiology and Pathogenesis

The underlying defect that drives pathology in sclerderma is still unknown. However, the disease appears to result as a consequence of derangements in three basic areas: 1) Hyperactivation of collagen synthesis by fibroblasts, 2) Small-vessel vasculopathy characterized by intimal proliferation and luminal narrowing, and 3) Inappropriate immune activation. How these derangements interact and amplify one another is poorly understood and going beyond this cursory explanation is sadly beyond the scope of this resource.

Morphology

Regardless of the organ involved, the primary morphological features of scleroderma are progressive fibrosis and a vasculopathy of capillaries and small arterioles. These changes are typically preceded by inflammation of the affected structures with a perivascular infiltrate of lymphocytes. The vasculopathy is characterized by intimal proliferation and endothelial injury, often leading to luminal narrowing and ultimately obliteration of the vessel. While the progressive fibrosis will often lead to mechanical dysfunction of the affected organ, the progressive loss of small vasculature and consequent chronic ischemia may result in its atrophy.

Clinical Consequences

Systemic Sclerosis can be thought to occur in two basic patterns depending on the extent of tissues involved: Limited and Diffuse. Limited Scleroderma is characterized by a relatively restricted geography of sclerosis, primarily limited to the skin of the distal upper extremities and the face with late involvement of the visceral organs. In addition, these patients tend to display a prototypical array of symptoms termed "CREST Syndrome", characterized by Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. In contrast, Diffuse Scleroderma is characterized by widespread sclerosis of the skin and early involvement of the visceral organs. Whatever the subtype, scleroderma tends to develop in late adulthood, between the third and fifth decades, with a predominance in women. The clinical course is highly variable with a slow downward decline in some with the potential for clinical plateau or even gradual regression.

Skin involvement is typically bilateral, begins in the fingers and advances proximally to include the face, and in the case of diffuse sclerosis spreads to the trunk. During the early inflammatory phase of disease the skin may look erythematous and edematous but over time the dermis becomes progressively fibrotic and thickened, termed "Sclerodactyly" when affecting the fingers. These changes are typically accompanied by progressive thinning of the overlying epidermis, obliteration of the dermal appendages, and in some cases ulcerations. Over time, the skin can become so contracted and fibrotic that the hands assume an immobile claw-like position. When affecting the face, patients may look much younger than their age in early stages due to elimination of wrinkles but with further time develop contracted, mask-like features.
In a subset of patients, especially those with CREST Syndrome, deposits of calcium may form within the skin, termed Calcinosis Cutis. These chalk-like deposits are typically appear as painless subcutaneous nodules, but may cause ulceration of the overlying skin. Patients with CREST Syndrome also often display telangiectasias, especially on the upper extremities and face.

Pulmonary involvement occurs in the majority of patients with the Diffuse subtype of scleroderma and is the leading cause of death. Pulmonary hypertension and pulmonary fibrosis are the two basic sequelae and are heralded by progressive dyspnea on exertion and a dry cough.

Both the upper and lower GI system can be affected in scleroderma, although involvement is limited to the upper tract in the Limited subtype. In the upper GI, fibrosis typically involves the esophagus with progressive collagenization of the muscularis propria and lamina propria. These changes lead to dysmotility of the esophagus and dysfunction of the lower esophageal sphincter, resulting in dysphagia, GERD, and a propensity for Barrett Esophagus.
Similar changes affect the small and large intestines in the Diffuse Scleroderma subtype, generating intestinal dysmotility. The resultant bacterial overgrowth, combined with atrophy of the intestinal mucosa and loss of intestinal villi, together contribute to a potentially profound Malabsorption Syndrome.

In a small subset of patients with Diffuse Scleroderma renal vascular changes can precipitate malignant hypertension. It appears that these patients develop intimal proliferation and luminal narrowing of their renal interlobular and arcuate arteries, reducing glomerular blood flow which in turn activates the renin-angiotensin-aldosteron system and consequently triggers hypertension. As blood pressure increases, the renal arterial narrowing is compounded by the necrosis and thrombosis characteristic of malignant hypertension, further promoting rising arterial pressures. Before modern interventions these scleroderma renal crises were almost universally fatal.

Patients with diffuse scleroderma display patchy fibrosis of potentially all layers of the heart as well as intimal proliferation and liminal narrowing of the intraepicardial arteries. These changes often lead to conduction abnormalities with attendant arrhythmias, valvular heart disease, and potentially heart failure. The pulmonary hypertension described above likely contributes to some of the cardiac pathology and may yield right heart failure and ultimately cor pulmonale in some.

In early stages, patients may complain of arthralgias although true joint inflammation is rare. Over time, the synovium and tendons become fibrosed, leading to progressive joint immobility. Muscle weakness and atrophy are likely secondary to the consequent disuse although in some patients a myositis indistinguishable from polymyositis may develop.

Raynaud Phenomenon (see page) is often the presenting symptom of the Limited subtype of scleroderma although it can be observed in the diffuse subtype as well.

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