Scleroderma (systemic sclerosis) is a complex disease in which extensive
fibrosis, vascular alterations, and autoantibodies against various cellular
antigens are among the principal features (Fig. 1 and 2).1 There are two major
subgroups in the commonly accepted classification of scleroderma: limited cutaneous
scleroderma and diffuse cutaneous scleroderma.2 In limited cutaneous scleroderma,
fibrosis is mainly restricted to the hands, arms, and face. Raynaud’s phenomenon
is present for several years before fibrosis appears, pulmonary hypertension
is frequent, and anticentromere antibodies occur in 50 to 90% of patients. Diffuse
cutaneous scleroderma is a rapidly progressing disorder that affects a large area of
the skin and compromises one or more internal organs.
We believe that the acronym CREST (calcinosis, Raynaud’s phenomenon, esophageal
motility dysfunction, sclerodactyly, and telangiectasia) is obsolete, since it cannot
be assigned to only one subgroup of patients with the disease and does not
sufficiently indicate the burden of internal-organ involvement. In rare cases, patients
with scleroderma have no obvious skin involvement. Patients with scleroderma plus
evidence of systemic lupus erythematosus, rheumatoid arthritis, polymyositis, or
Sjögren’s syndrome are considered to have an overlap syndrome. This classification
can be useful, but none of the proposed classifications sufficiently reflect the
heterogeneity of the clinical manifestations of scleroderma.
Scleroderma can lead to severe dysfunction and failure of almost any internal
organ. Here, too, there is considerable heterogeneity (Table 1). Involvement of
visceral organs is a major factor in determining the prognosis. The kidneys, esophagus,
heart, and lungs are the most frequent targets. Renal involvement can be
controlled by angiotensin-converting–enzyme inhibitors. Severely debilitating esophageal
dysfunction is the most common visceral complication, and lung involvement
is the leading cause of death.
The mechanisms underlying visceral involvement in scleroderma are unclear,
despite progress in the treatment of these complications. Relevant data on mechanisms
are limited, since most of the available information is derived from crosssectional
studies and from patients in various stages of the disease, often after
treatment; moreover, there are no satisfactory animal models of scleroderma. Nevertheless,
a critical evaluation of the available experimental and clinical data will help
reduce ambiguity and may provide the basis for future studies of scleroderma