Scleroderma is a rare and complex autoimmune connective tissue disease that can potentially affect all organ systems. Technically, scleroderma is an aspect of systemic sclerosis, a systemic connective tissue disease that involves subcutaneous tissue, muscles, and internal organs. The cause of scleroderma is not known, so it is typically diagnosed by its clinical manifestations: skin thickening, vascular abnormalities, and other systemic effects most commonly affecting the lungs and kidneys. The limited cutaneous type of scleroderma affects the hands. Scleroderma is also associated with Raynaud’s phenomenon—which may precede the occurrence of scleroderma by months or even years. CREST syndrome is a limited cutaneous type of scleroderma that has a more indolent course and less visceral involvement than the diffuse type. CREST syndrome involves calcinosis, Raynaud's phenomenon, esophageal problems, sclerodactyly, and telangiectasias. Treatment may include vasodilating agents, corticosteroids, topical therapies, antiplatelet drugs, physical therapy, or covering the hands and feet if Raynaud’s phenomenon is present. Surgical intervention has specific limited, but sometimes very helpful, uses in scleroderma.1-6,9
Pathophysiology1-10
- Scleroderma symptoms result from non-inflammatory and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagen3
- The pathophysiology involves several cell lines, including the endothelium, fibroblasts, lymphocytes, and their soluble mediators, which account for the early vascular phase with an inflammatory infiltrate that eventually leads to fibrosis
- The vascular phase begins in the endothelium of small vessels throughout the body, but the primary event that triggers endothelial damage is unknown1
- In the endothelial phase, baseline hypoxia activates the overproduction of endothelin, which disturbs the balance of endothelin with nitric oxide and prostacyclins, and generates a potent vasoconstrictor action that is not countered; this starts a vicious cycle in which unresolved tissue ischemia leads to increased vasoconstriction, release of proinflammatory cytokines, and platelet aggregation, as well as stimulation of fibroblast activity1
- CREST syndrome is named after the 5 clinical features that may be present (Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasias), although not all patients display every symptom and the disease process varies greatly. CREST syndrome is thought to be an autoimmune disorder that results from abnormal fibroblast activity and increased collagen deposition, although the primary triggering mechanism is not known5 Silicone breast implants, toxic oil ingestion, exposure to silica dust and vinyl chloride, and administration of antineoplastic drugs are all environmental factors that have been linked to the development of scleroderma, CREST syndrome, and other connective tissue diseases5
Related Anatomy
- The two major forms of scleroderma are localized and systemic:
- Systemic scleroderma is further divided two subsets: limited (cutaneous) or diffuse2
- Localized scleroderma can be further divided into four basic types: limited, generalized, linear, and deep2
- CREST syndrome is one representation of the limited type of systemic scleroderma5
Incidence and Related Conditions
- Scleroderma is a rare disease, with an incidence of ~27 cases per million7,8
- The incidence of scleroderma is 4-9 times higher in women than men3
- CREST syndrome is relatively rare, but it affects women 3-4 times more often than men4
- Scleroderma has a higher incidence in African Americans than whites, and African Americans generally tend to have more severe symptoms and poorer outcomes3
- Calcinosis will occur in 22% of the patients with scleroderma in the first 10-15 years. Calcinosis seems to be triggered by microtrauma and it occurs in localized and diffuse patterns.9
- Raynaud’s phenomenon
- A transient reversible, vasospastic phenomenon induced by cold or stress occurring in the fingers, toes, and less frequently, the nose, ears, and nipples
- ~70% of individuals have Raynaud’s phenomenon when they initially present with scleroderma, and ~95% will eventually develop it at some point in the course of the disease
- Raynaud’s phenomenon may precede the clinical manifestations of scleroderma by months up to as long as 10 years1,9
Differential Diagnosis
- Amyloidosis
- Buschke’s disease
- Diabetic cheiroarthropathy
- Diabetic scleredema
- Eosinophilia-myalgia syndrome
- Eosinophilic fasciitis
- Generalized morphea
- Graft-versus-host disease
- Lupus
- Lyme disease
- Mixed connective tissue disease
- Morphea
- Nephrogenic systemic fibrosis
- Polymyositis
- Porphyria cutanea tarda
- Pseudoscleroderma
- Raynaud’s disease
- Reflex sympathetic dystrophy
- Rheumatoid arthritis
- Scleromyxedema
- Shulman’s syndrome
- Toxic oil syndrome
