Some environmentally associated sclerodermalike syndromes have been described as occurring after particular exposures, including to bleomycin, vinyl chloride, and silica dust.

No strong genetic associations have been recorded, but familial clusters have been recognized in some populations.

Microvascular injury with fibrosis and excess deposition of extracellular matrix, particularly collagen, is recognized. Endothelial injury has been hypothesized as the primary process, with resultant tissue ischemia and secondary fibrotic changes eventually resulting in the clinical phenotype of scleroderma. Vascular luminal narrowing secondary to intimal proliferation has been demonstrated.

Vasoactive mediators are abnormally expressed in patients with scleroderma. Elevated circulating levels of endothelin-1 and diminished levels of nitric oxide have been reported. These may ultimately be targets of therapeutic interventions.

Inflammation plays an important role, particularly early in the disease process. Inflammatory perivascular infiltrates with a T cell predominance, particularly at the border dividing the reticular dermis and subcutaneous fat, can be demonstrated.

Evidence of cellular immunity is supported by the predominance of T cells in the early tissue infiltrates, as well as by the correlations between interleukin-2 (IL-2) and soluble IL-2 receptor levels and disease activity.

There are similarities between scleroderma and graft versus host disease. Investigators have demonstrated cellular mosaicism in women with scleroderma, with retention of fetal cells in skin lesions and in the peripheral blood of women with systemic sclerosis. This suggests the possibility that a graft versus hostlike reaction induced by fetal cells contributes to the pathogenesis in these patients.

Autoantibodies are found in up to 95% of patients, although no direct pathogenic role has been demonstrated. These may be the epiphenomena of immune system activation and tissue injury.

Cytokines, including those of transforming growth β (β), IL-1, IL-2, and platelet-derived growth factor, have been implicated in fibroblast dysregulation and in excess collagen production.

Raynaud’s phenomenon occurs in 95% of patients, and its absence should caution the clinician to question the diagnosis. The typical changes are pallor and cyanosis followed by erythema in response to cold stimuli. Episodes can also be precipitated by stress and smoking or may occur spontaneously.

Intimal hyperplasia and adventitial fibrosis can result in attenuation of vessel lumen. Vasoconstriction in already compromised vessels can result in ischemia with digital ulcers, infarcts, and even autoamputation.

Visceral Raynaud’s phenomenon may occur in the heart and kidney.

An early edematous phase is characterized by puffy swelling of the hands and fingers.

With disease progression, the skin thickens and binds down, with loss of normal structures such as hair follicles. Spontaneous loosening of the skin can occur later in the course of the disease. Pruritus is a common complaint.

Skin discoloration is common, with areas of erythema early in the disease course and subsequent areas of hypopigmentation or hyperpigmentation.

Skin breakdown, particularly over the extensor surfaces of the joints of the hands, can result in ulcerations, which heal poorly and may become secondarily infected.

Skin changes often begin distally in the hands and progress more proximally to the trunk.

The pattern of skin involvement has allowed stratification into two distinct subgroups with differing serologic association, clinical course, and pattern of organ involvement (Table 34-1).

Symptoms include dyspnea and a nonproductive dry cough.

Pulmonary involvement can be complicated by secondary pulmonary hypertension in patients with advanced interstitial lung disease.

Pulmonary hypertension can occur early in patients with limited scleroderma in the absence of interstitial lung disease and can similarly present with dyspnea, particularly on exertion.

Hypertensive retinopathy, encephalopathy, and renal failure can occur if the syndrome is unrecognized and untreated.

The occurrence of the syndrome may be associated with corticosteroid use.

The syndrome can occur, uncommonly, in the absence of measurable arterial hypertension. Also, it may exist in patients with minimal or no sclerodermal skin changes (i.e., scleroderma sine scleroderma).

Early recognition is crucial because this complication of scleroderma is treatable.

Esophageal disease is the most common complaint, often related to lower esophageal sphincter incompetence and impaired esophageal motility. Dysphagia, odynophagia, pyrosis, erosive esophagitis, and strictures can occur.

Stomach involvement characterized by gastroparesis can cause bloating and early satiety. Gastric telangiectasias can be an important source of GI bleeding.

Small intestinal involvement can cause bloating, cramping abdominal pain, bacterial overgrowth, malabsorption, and diarrhea.