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.
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
- Thickening and hardening of the skin: Skin appears smooth, shiny, and puffy.
- Sclerodactyly: fibrotic thickening and tightening of the skin of the fingers and hands
- 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)
- Vascular disease
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)
- E: Esophageal hypomotility; : smooth muscle atrophy and fibrosis → esophageal dysmotility and decreased 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
- Pulmonary disease: pulmonary hypertension and interstitial lung disease, increased risk of lung cancer
- Cardiac disease: fibrosis, myocarditis, pericarditis
- Abnormal collagen deposition → thickening of renal arteriolar walls → decreased renal blood flow → reduced kidney function
- Scleroderma renal crisis
- Auto-antibodies: Antinuclear antibodies (ANA) present in about 90% of cases
- 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).
Mixed connective tissue disease (MCTD, Sharp syndrome)
- Definition: overlapping symptoms of systemic sclerosis, systemic lupus erythematosus (SLE), and polymyositis
- Clinical presentation
The differential diagnoses listed here are not exhaustive.
Treatment focuses on organ-specific, symptomatic therapy. In the case of diffuse cutaneous disease or severe organ involvement, immunosuppressive therapy is indicated.
- General measures
- Progressive and diffuse skin involvement: methotrexate, mycophenolate mofetil, cyclophosphamide (for cases refractory to treatment with either MTX or MMF)
- Interstitial lung disease: mycophenolat mofetil (alternatives: e.g., cyclophosphamide or tocilizumab)
- Gastroesophageal reflux disease: PPIs
- Raynaud phenomenon: CCBs
- Renal involvement: ACE inhibitors
- Pulmonary hypertension: ambrisentan and tadalafil combination therapy