Background: Systemic sclerosis is a multisystem disease of connective tissue that is accompanied by vasculopathy. Scleroderma, its original name, means hard skin.

Clinically, progressive systemic sclerosis (PSS) is classified as diffuse or limited depending on the distribution of skin disease. PSS is considered limited when involvement is restricted to the distal extremities and face. The limited form is associated with a lower risk of visceral involvement, although pulmonary hypertension is more common.

Diffuse cutaneous systemic sclerosis (dcSSc) and limited cutaneous systemic sclerosis (lcSSc) scleroderma overlap the following syndromes:

1. CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, skin pigmentation, telangiectasias)

    

2. Mixed connective tissue disease (controversial whether this is a separate entity or an intermediate stage in the progression to connective tissue disease)

    

3. Scleromyositis (coexisting features of dermatomyositis without features of systemic lupus erythematosus)

    

4. Polymyositis synthetase (interstitial lung disease, myositis, Raynaud phenomenon, arthritis)

    

5. Morphea (focal cutaneous scleroderma)

Pathophysiology:

Immunopathogenesis

Recurrent ischemia with reperfusion in PSS generates reactive oxygen species that participate in intranuclear metal-ion catalyzed oxidation. These reactions are believed to alter the configuration of the autoantigenic components of intranuclear proteins, creating cryptic epitopes that stimulate self-reactive T cells.

Autoantibodies in PSS

A number of autoantibodies that recognize extracellular proteins have been identified, and evidence is increasing that these may be involved in disease pathogenesis. Two research groups have shown that one such protein, antiendothelial cell antibody, induces endothelial cell apoptosis.

Immunogenetics

The work of Fanning and colleagues supports the theory that the 3 main subtypes of PSS (ie, dcSSc, lcSSc, CREST syndrome) probably encompass 3 separate diseases, each having different pathogenic origins that influence autoantibody and disease expression.

The proportion of PSS subtypes within a population varies among racial groups. This may be related to differences in genes not susceptible to human leukocyte antigen (HLA), as hypothesized by Tan et al, or alternatively, this may reflect environmental influences differing among geographic locations, as hypothesized by Haustein and Anderegg.

The relative frequency of autoantibody expression and relative frequencies of specific HLA class I and class II alleles associated with PSS also vary among racial groups within a disease subtype. These trends may reflect racial differences in immunogenetic background, as hypothesized by Harvey et al.

Frequency:

• In the US: Annual incidence is 14 cases per million.

• Internationally: Estimated incidence is 20 cases per million, and the estimated prevalence is 500 cases per million.

Mortality/Morbidity: Visceral organ involvement is the primary cause of morbidity, while pulmonary disease is the most common cause of mortality.

• Mortality related to pulmonary and cardiac disease
  
  
  Pulmonary involvement is present in 60-100% of patients at autopsy, according to Veeraraghavan and Sharma.
  
  
  Interstitial fibrosis and pulmonary hypertension characterize pulmonary disease. The severity of pulmonary hypertension often is out of proportion to the degree of fibrosis and may be an isolated abnormality in as many as 10% of patients.
  
  
  Other complications include aspiration pneumonia, pneumothorax, lung cancer, pulmonary hemorrhage, and pleural disease.
  
  
  A higher incidence of ventricular late potentials is detected with high-resolution electrocardiography in patients with scleroderma with myocardial interstitial fibrosis. These are associated with hyperkinetic ventricular arrhythmias and sudden death.

• Morbidity related to visceral organ disease
  
  
  Gastrointestinal
  
  

  • The esophagus is involved in 50-90% of patients, according to Kahan and Menkes.
  • Pathophysiologically, a neuropathy of the enteric nerve plexus may be seen, with subsequent immune-mediated inflammation and fibrosis of smooth muscle.
  • Functional disturbances result in other complications, such as reflux esophagitis with risk of esophageal strictures, Barrett metaplasia, and carcinoma.
  • The same process causes small bowel pseudo-obstruction with complications of bacterial overgrowth and malabsorption.

  
  
  Renal
  
  

  • Renal disease manifests in 1 of the following 3 ways:
    
    
    • Malignant hypertension (scleroderma renal crisis)
    • Azotemia and proteinuria with a progressive chronic course
    • Rapidly progressive renal insufficiency in the setting of well-controlled blood pressure
    
    
  • Scleroderma renal crisis is precipitated by situations that compromise renal blood flow and tends to occur early in the disease.
  • Patients at highest risk are those with diffuse cutaneous scleroderma.

  
  
  Musculoskeletal and nervous systems
  
  

  • Musculoskeletal involvement is manifested by a chronic myopathy, nonerosive arthropathy, and soft tissue calcinosis, which is more common in lcSSc.
    
  • Peripheral nervous system symptoms may be an early feature of the disease, with cranial nerve dysfunction, polyneuropathy, and median nerve mononeuropathy (carpal tunnel syndrome).
    
  • Autonomic nervous system involvement is characterized by depressed parasympathetic activity and upregulated sympathetic activity. These alterations are believed to affect cardiac and GI function and may be an etiologic factor in the development of Raynaud phenomenon and microvascular disease.

Race: The proportion of PSS subtypes differs among racial groups. In black women, diffuse scleroderma is diagnosed at an earlier age and carries a poorer prognosis, as reported by Laing et al.

Sex: Male-to-female ratio is 1:3.

Age: Symptoms manifest in the fourth to sixth decades, although a juvenile form exists.

Clinical Details: Clinical diagnosis of PSS

Serologic markers: A well-defined antinuclear antibody profile is available for scleroderma. Three main mutually exclusive serologic subgroups are recognized as follows, as reported by Harvey and McHugh:

• Anti-DNA topoisomerase (anti-Topo) I, with a frequency of 22%

   

• Antibodies to centromere proteins, with a frequency of 26%

   

• Anti-RNA polymerase (RNAP) III antibodies, with a frequency of 18%.

These autoantibodies may not be involved directly in disease pathogenesis; however, they are reliable markers of disease-specific pathology. For example, anti-RNAP III antibodies are associated with a higher risk of diffuse PSS, a greater likelihood of renal involvement, and the shortest cumulative survival times.

Anti-Topo I positive patients have the greatest risk of interstitial lung fibrosis, with intermediate cumulative survival times and risk of renal disease. Anticentromere antibody is present in a high proportion of patients with the limited form of PSS. This serum profile has the longest cumulative survival times and is associated with the lowest risk of pulmonary fibrosis and renal disease.

Skin biopsy: A skin biopsy is performed to confirm clinical suspicion. Biopsy does not provide a reliable distinction of localized scleroderma (morphea) from systemic scleroderma.

Intravital capillaroscopy: Almost all patients with dcSSc or lcSSC present with Raynaud phenomenon. This can be distinguished from the Raynaud syndrome of idiopathic vasospasm by demonstrating the presence of cutaneous microangiopathy. Microscopic evaluation of epilluminated capillaries in the nail bed of patients with PSS reveals a chaotic distribution of focally aneurysmally enlarged capillaries. The combination of this pattern and leaky capillaries has a diagnostic sensitivity of greater than 80%.

Clinical diagnosis of pulmonary disease in PSS

Physiology: Diffusing capacity for carbon monoxide (DLCO) is sensitive for pulmonary disease, since findings are abnormal in 90% of symptomatic patients. Marked reductions in the mean DLCO are suggestive of the predominant vascular disease observed in overlap syndromes. In the absence of pulmonary hypertension, reductions in the DLCO correlate highly with the extent of fibrosing alveolitis, as seen on CT. Exercise pulmonary function tests (PFTs) are more sensitive to early disease than static PFTs. The dominant ventilatory defect is restrictive.

Bronchoalveolar lavage: Bronchoalveolar lavage (BAL) fluid cell counts are used to assess the degree of inflammatory activity and to guide treatment. Abnormalities may be present early in the disease and precede radiographic changes (subclinical alveolitis).

Echocardiography: Echocardiographic measurements of systolic pulmonary arterial pressure correlate well with right-sided heart catheterization values.

Lung biopsy: Transbronchial biopsy is nondiagnostic. Open lung biopsy may be performed to confirm active alveolitis when considering aggressive immunosuppressive therapy.

Preferred Examination: Chest radiograph is insensitive, since findings are abnormal in only two thirds of patients with pulmonary disease.

High-resolution CT (HRCT) is the best imaging test for assessing the extent and severity of pulmonary disease. Reported detection of fibrosis with HRCT is 60-90% compared to 60-100% at autopsy.

Limitations of Techniques: HRCT findings are abnormal in most patients with functional impairment. False-negative HRCT imaging studies have occurred in the setting of alveolitis, as documented by Remy-Jardin et al using BAL in patients with normal PFTs.

DIFFERENTIALS

Asbestosis
Idiopathic Pulmonary Fibrosis

Other Problems to be Considered:

Other diagnostic considerations with the usual interstitial pneumonitis (UIP) pattern of basal predominant fibrosis include other collagen vascular diseases, particularly rheumatoid arthritis and chronic hypersensitivity pneumonitis (can mimic idiopathic pulmonary fibrosis [IPF]).

X-RAY

Findings:
Early findings - Subpleural reticular or reticulonodular opacity in a basal predominant distribution

Late findings

• Fibrotic changes involving the lower two thirds of the lung, with associated volume loss and honeycombing

   

• Pulmonary artery enlargement and cardiomegaly

Ancillary findings - Diffuse esophageal dilation with resultant "air esophagram sign" (useful when present to differentiate PSS from IPF, asbestosis, and rheumatoid arthritis)

Degree of Confidence: Chest radiograph is relatively insensitive in early disease, and findings may be minimal even in advanced disease; however, chest radiographic findings are observed in as many as two thirds of symptomatic patients, with findings suggestive of fibrosis demonstrated in 25-45% of patients.

False Positives/Negatives: Interstitial lung disease with a predominant lower lobe distribution on chest radiograph may be due to numerous etiologies including PSS. Clinical history and esophageal dilatation on radiograph suggests PSS. Any phase of IPF, asbestosis, interstitial pulmonary edema, lymphangitic metastases, pulmonary hemorrhage, and other diffuse lung diseases may mimic PSS on chest radiograph. On the posteroanterior (PA) view, the breast shadows can mimic increased markings over the lower lung zones. Lateral view is critical to obtain a less obscured view of the lower lobes.