Summary
Systemic sclerosis (SSc) is a chronic disease caused by abnormal growth of connective tissue, which leads to diffuse thickening and hardening of the skin and often the inner organs. SSc is categorized into limited SSc and diffuse SSc. The more common, limited form of SSc begins with sclerosis of the fingers, hands, and face, which then progresses to the center of the body. Limited SSc is often associated with symptoms of CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) and may be followed by internal organ involvement as the disease progresses. Diffuse SSc is less common but more aggressive, with early organ system involvement that may be life-threatening if damage to the heart, lungs, or kidneys occurs. Treatment is symptomatic and based on the extent of skin and organ system involvement. In the case of diffuse inflammation of the skin and/or organs, immunosuppressive drugs (e.g., methotrexate) should be administered. The prognosis varies depending on which organs are involved, with pulmonary arterial hypertension, interstitial lung disease, and cardiac disease significantly increasing the mortality rate.
Epidemiology
Epidemiological data refers to the US, unless otherwise specified.
Pathophysiology
The pathophysiology of SSc is not completely understood, but several factors play role in the development of the disease.
- Autoimmunologic component (see “Diagnostics”)
- Inflammatory synthesis of extracellular matrix: fibroblast proliferation and increased synthesis of normal collagen leading to fibrosis
- Noninflammatory vasculopathy: underlying mechanism of many of the more severe disease features, e.g., CAD, pulmonary artery hypertension, and renal crisis
References:[4]
Clinical features
Common symptoms
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Cutaneous findings
- Thickening and hardening of the skin: Skin appears smooth, shiny, and puffy.
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Sclerodactyly: fibrotic thickening and tightening of the skin of the fingers and hands
- Initially edema, followed by fibrosis with waxy appearance of the skin
- Red-blue discoloration of the fingers
- Limited range of motion and possibly flexure contractures and clawing of the digits
- Multiple, painful ischemic digital ulcers with atrophy and necrotic spots
- Digital pitting: hyperkeratotic scarring, most commonly affecting the fingertips
- Lesions on the proximal nail fold
- Depigmentation of the skin with sparing of perifollicular pigmentation (salt-and-pepper appearance)
- Face
- Loss of expression (mask-like facies)
- No wrinkles
- Shortened frenulum
- Microstomia accompanied with characteristic perioral wrinkles
- Vascular disease
- Other
Limited cutaneous systemic sclerosis
- Skin manifestations are usually restricted to the hands, fingers, and face.
- Disease progression is slower compared to diffuse cutaneous systemic sclerosis.
- In 90% of cases, Raynaud phenomenon precedes the onset of other symptoms.
- Extracutaneous organ involvement may occur.
- Often manifests as CREST syndrome
- C: Calcinosis cutis (small white calcium deposits on the pressure points of the extremities such as the elbows, knees, fingertips, and, to a lesser extent, face and neck)
- R: Raynaud phenomenon
- E: Esophageal hypomotility; : smooth muscle atrophy and fibrosis → esophageal dysmotility and decreased LES pressure → dysphagia, gastroesophageal reflux, heartburn → aspiration, Barrett esophagus, stricture
- S: Sclerodactyly
- T: Telangiectasia
Diffuse cutaneous systemic sclerosis
- Skin manifestations are widespread and typically spread from the trunk to the elbow.
- Disease progression is rapid.
- Raynaud phenomenon often coincides with or follows the onset of other symptoms.
-
Extracutaneous organ manifestations are common.
- Arthralgia and myalgia: can result in contractures
-
Gastrointestinal tract
- Esophageal dysmotility → dysphagia and reflux
- Small bowel dysmotility → bloating, gas, constipation, and cramping
- Pulmonary disease: pulmonary hypertension and interstitial lung disease; , increased risk of lung cancer
- Cardiac disease: fibrosis, myocarditis, pericarditis
-
Renal disease
- Abnormal collagen deposition → thickening of renal arteriolar walls → decreased renal blood flow → reduced kidney function
-
Scleroderma renal crisis
- Occurs in 10–15% of cases of diffuse SSc
- Life-threatening complication, e.g.:
- Treatment: ACE inhibitors [5]
References:[6][7][8][9][10][11][12][13]
Diagnostics
-
Auto-antibodies: Antinuclear antibodies (ANA) present in about 90% of cases
- Limited SSc: anticentromere antibodies (ACA)
-
Diffuse SSc
- Anti-Scl-70 (anti-topoisomerase I antibody)
- Anti-RNA polymerase III
- See “Antibody diagnosis of autoimmune diseases.”
- Serum protein electrophoresis: ↑ γ-globulins
- Chest x-ray: detects possible pulmonary involvement
- Other tests: may be indicated based on organ-specific symptoms (e.g., signs of renal crisis).
References:[14][15]
Differential diagnoses
Mixed connective tissue disease (MCTD, Sharp syndrome)
- Definition: overlapping symptoms of systemic sclerosis, systemic lupus erythematosus (SLE), and polymyositis
-
Clinical presentation
- Myositis
- Arthritis
- Acrosclerosis
- Raynaud phenomenon
- Pulmonary hypertension
- The course is usually milder than that of other connective tissue diseases (CTD) but may progress into another CTD.
-
Diagnosis
- Most patients are positive for ANAs and anti-U1 RNP (see “Antibody diagnosis of autoimmune disease”).
- ANAs have a speckled pattern on immunofluorescence.
References:[16]
The differential diagnoses listed here are not exhaustive.
Treatment
Treatment focuses on organ-specific, symptomatic therapy. In the case of diffuse cutaneous disease or severe organ involvement, immunosuppressive therapy is indicated.
-
General measures
- Physical therapy, massage
- Prevent dry skin
- Warm oil and paraffin baths
- Avoid soap
- Phototherapy
- Immunosuppressive therapy: : e.g., methotrexate
-
Organ-specific therapy
- PPIs in cases of gastroesophageal reflux disease
- CCBs for Raynaud phenomenon
- D-penicillamine for skin and visceral complications