Scleroderma (also known as systemic sclerosis) is an uncommon, autoimmune connective tissue disease characterised by vascular abnormalities and fibrosis in the skin and a number of internal organs. Most forms lead to thickening of the skin but it is visceral complications that lead to a substantial disease-related mortality. Scleroderma primarily affects women aged 30 to 50 years. Patients with scleroderma are at high risk of developing pulmonary arterial hypertension (PAH).

Pathogenesis and pathophysiology
The pathogenesis of scleroderma involves immunological mechanisms, vascular damage, and fibrosis characterised by excessive accumulation of extracellular matrix components in the skin and internal organs.

There are two main types of scleroderma - ‘diffuse’ and ‘limited’: In diffuse scleroderma, there is progressive development of skin thickening starting with the hands and face, and extending to the arms and trunk. Internal organ involvement often develops early in the course of the disease. Gastrointestinal involvement may result in dysphagia, gastro-oesophageal reflux disease and bowel dysfunction while cardiac involvement is associated with arrhythmias, and heart failure. In the kidneys, scleroderma may lead to hypertension and renal failure and, in the liver, to primary biliary cirrhosis.

Limited scleroderma (also referred to as the CREST syndrome) has less skin involvement but may lead to any of the internal organ complications seen in the diffuse subset. Some of these, such as renal disease, occur less frequently in limited scleroderma but others such as isolated pulmonary hypertension are more frequent. However, PAH may develop as a serious complication from either type of scleroderma.

In diffuse scleroderma, PAH most often occurs in the context of interstitial lung fibrosis although it may also partly result from direct vascular injury.

In limited scleroderma, PAH is a leading cause of mortality which develops late in the disease. It most often occurs as a primary vasculopathy, complicating up to 15 percent of cases. It may also occur secondary to lung fibrosis in limited scleroderma.

Natural history of systemic sclerosis subsets
 

Due to the high prevalence of PAH in scleroderma patients, it is recommended that a transthoracic echocardiography is performed annually, even if the patients have no symptoms of PAH.

In patients with scleroderma developing breathlessness a number of causes must be entertained. The most common differential diagnosis is between lung fibrosis and PAH. In the former cough, interstitial lung field shadowing on chest radiograph, alveolitis on high resolution CT scan (HRCT) and a restrictive pattern on pulmonary function tests are diagnostic. There may be secondary PAH in established lung fibrosis which may be associated with typical findings on HRCT. Patients with isolated PAH in scleroderma are likely to have preserved lung volumes but diminished CO diffusing capacity on pulmonary function testing. Echo-Doppler examination is often abnormal. Peak pulmonary arterial systolic pressure can be elevated and indices of right ventricular function are generally altered. Right heart catheterization is the definitive investigation for diagnosis of PAH in scleroderma.

Experimental evidence suggests that endothelin-1 (ET-1) may be involved in the pathogenesis of the vascular fibrosis in the heart and kidney. The dermal fibrosis may also be a result of the actions of ET-1, which is released in vitro from the fibroblasts of scleroderma patients.

Epidemiology of PAH in patients with scleroderma
The frequency of PAH in patients with scleroderma is difficult to determine exactly, but the reported range has varied from nine percent to as much as 65 percent.

Diagnosis
The diagnosis of PAH is often overlooked because initial symptoms (such as dyspnoea on exertion) are non-specific and/or may be missed or ignored, particularly in patients with normal chest radiographs. (Diagnosing PAH) Due to the non-specific nature of early symptom manifestation, diagnosis is commonly not confirmed until up to three years from the initial symptom presentation, when the disease has progressed. If PAH is left untreated, the prognosis in scleroderma is poor – up to 60 percent of patients will die within two years of diagnosis.

PAH: High mortality

Screening
Although scleroderma patients overall are at higher risk of PAH than the general population, certain patient subgroups are particularly prone to the condition.

The advent of new therapies emphasises the need for early diagnosis and earlier treatment may lead ultimately to better outcomes. For the effective management of scleroderma patients a recommended Treatment Algorithm has been developed.

Due to the high prevalence of PAH in scleroderma patients, it is recommended that a transthoracic echocardiography is performed annually, even if the patients have no symptoms of PAH. Limited patients should be screened annually and patients with diffuse disease should be screened when symptoms occur.

Annual screening remains the recommendation – Echo-Doppler and PFT.

References

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