Systemic scleroderma (or sclerosis)

Systemic scleroderma is a disease that primarily affects the small-calibre blood vessels (arterioles and capillaries) throughout the body and is accompanied by widespread fibrosis.
The involvement of the blood vessels explains an early symptom present in almost all patients: Raynaud’s phenomenon.

This very painful phenomenon is characterised by whitening of the fingers when exposed to cold (or to other factors such as stress or cigarette smoking), often followed by a phase during which the fingers become very red or even purple. It may sometimes lead to necrosis (death) of the skin at the fingertips (known as digital ulcers). Fibrosis consists of excessive deposition of collagen, a protein found throughout the body that provides structure to tissues and organs.

Immune dysregulation, particularly inflammation and autoimmunity, is also involved in this disease. This is why certain autoantibodies are tested for when establishing the diagnosis of systemic scleroderma.

The cause of the disease remains unknown, but it probably involves both a particular genetic predisposition and certain environmental factors. A body of evidence suggests that there is a low genetic predisposition to systemic scleroderma.

Analysis of familial risk in several groups of patients has shown that the risk of developing this disease among first-degree relatives (first generation) was 13 times higher than in the general population (15 times higher for the siblings of a patient with scleroderma).
Although these results demonstrate a familial risk and support the search for genetic factors, the risk of transmission remains very low for any given individual, and families in which one parent has this disease should be reassured.

Which tissues and organs are affected by this disease? 

Systemic scleroderma affects various tissues and organs, including the skin, lungs, digestive tract, kidneys and heart. The fibrosis observed in systemic scleroderma corresponds to an exaggerated and poorly controlled tissue-repair process. The relationship between vascular abnormalities and the fibrotic process is poorly understood. 

The disease was called systemic scleroderma because of the frequency and appearance of the skin lesions (“-derma”), but the term systemic sclerosis (also used) better reflects the extension of the fibrotic process to other organs, which characterises this disease. 
Systemic sclerosis must be distinguished from localised scleroderma, in which only the skin is affected by fibrosis/sclerosis; this is also referred to as morphoea. 

Conversely, in some cases of systemic scleroderma, the skin may be unaffected even though organs are involved; this is referred to as scleroderma sine scleroderma.
The extent of skin involvement assessed at its maximum extent (when the involvement was most severe) appears to be associated with the risk of developing deep-organ lesions. Assessing the severity of skin fibrosis is therefore important in guiding monitoring and treatment.

Epidemiology of systemic scleroderma

Systemic scleroderma is a rare, so-called “orphan” disease. An orphan disease is defined as having a prevalence (the number of people living with the disease) of fewer than one person in 2,000 (proposed European legislation on orphan medicines). The prevalence of systemic scleroderma is still poorly understood and varies considerably between regions and countries. In Europe, the prevalence is approximately 100 to 200 per million inhabitants.
In most cases, the first signs of systemic scleroderma appear at around 40–50 years of age, most often in women (four women for every one man). 

What are the clinical manifestations of systemic scleroderma?

The symptoms and signs present at onset vary according to the two main subtypes of the disease: 

• In the diffuse cutaneous form, all the signs usually appear at the same time, generally combining Raynaud’s syndrome, skin fibrosis that progressively extends towards the thighs and arms, and often joint and tendon pain.
• In the limited cutaneous form, Raynaud’s syndrome most often predates the disease by several years, and disease onset is often marked by its worsening, associated with thickening of the skin of the fingers (sclerodactyly) and, possibly, of the face and/or the appearance of telangiectasias (small dilations of the blood vessels). Oesophageal involvement is common in this form and is characterised by heartburn and gastro-oesophageal reflux.

While the onset of the disease is easy to date in the diffuse cutaneous form, this is often more difficult in the limited cutaneous form. The first sign other than Raynaud’s syndrome is usually used to date the onset of the disease. 

Progression varies according to the two subtypes of skin involvement, although there are individual exceptions to the following:

• In the diffuse cutaneous form, the disease progresses rapidly and may lead to more or less significant organ damage, which must be sought from the outset. Studies have shown that after 3 to 5 years, the inflammatory process of the disease often stops or stabilises, with only the damage already established persisting. After several years, some abnormalities may even improve, particularly skin fibrosis, which tends to become more flexible. This is crucial, as it determines patient follow-up (which is particularly close during the first few years) and treatment. Disease-modifying treatments should primarily be evaluated during the active phase of the disease, that is, during the first 3 to 5 years, when fibrosis develops.
• In the limited cutaneous form, disease progression is slower. The main risk associated with the progression of this form is the development of pulmonary arterial hypertension, which generally occurs after 10–15 years of disease progression. Regular monitoring must therefore be continued to detect this serious complication, which can go unnoticed if the necessary tests are not performed, as it only causes symptoms relatively late.

The diagnosis of systemic scleroderma is based on a clinical examination, blood tests and capillaroscopy. In addition, other tests are carried out to assess the extent of the disease (that is, to determine which organs are affected besides the skin).

• Clinical signs: mainly Raynaud’s phenomenon and skin thickening; the clinical examination also looks for digestive manifestations (acid reflux, etc.), pulmonary manifestations (shortness of breath, cough, etc.), and others.
• Blood tests: these look for the presence of antinuclear factors (detectable in 98% of cases), such as anti-Scl-70 antibodies and anticentromere antibodies.
• Capillaroscopy: the base of the nail is simply examined under a microscope to look for signs of microcirculatory involvement: the presence of dilated capillaries (megacapillaries) and areas where the capillaries have disappeared (avascular areas).
• Assessment of the extent of the disease may include other tests, such as a chest CT scan, pulmonary function tests, a six-minute walk test, an echocardiogram, an electrocardiogram, right heart catheterisation, a gastroscopy and an X-ray of the hands.

There is currently no treatment that cures the disease.

The treatments currently available aim to relieve the symptoms (symptomatic treatment) and slow the progression of the disease (disease-modifying treatment).

Symptomatic treatment is primarily aimed at reducing the discomfort caused by Raynaud’s phenomenon and gastro-oesophageal reflux. It consists of taking medicines that dilate the blood vessels and reduce acid secretion by the stomach.

Disease-modifying treatment is mainly indicated when the inflammatory component is significant, particularly if it extends to the skin and/or affects organs such as the lungs. In such cases, low doses of oral corticosteroids are used, together with an immunosuppressant medicine (which reduces the activity of the immune system).

Some examples of conventional immunosuppressants include azathioprine, mycophenolate mofetil, cyclophosphamide and methotrexate. Newer, more targeted treatments are also available and are still under investigation, including rituximab and tocilizumab.

Systemic sclerosis is managed within the Multidisciplinary Centre for Systemic Scleroderma.

www.sclérodermie.be

www.eustar.org

www.fesca-scleroderma.eu

The Multidisciplinary Systemic Sclerosis Centre provides care for systemic sclerosis, a rare autoimmune disease affecting the tissue that supports the organs (connective tissue) and the small arteries (arterioles), whose main characteristic is hardening of the skin. Physicians from different specialties work together to diagnose and treat the disease.

Coordination of the Multidisciplinary Systemic Sclerosis Centre

• Tel: 02 555 3650
• Fax: 02 555 8247
• Email: msoyfoo [at] ulb [dot] ac [dot] be (msoyfoo[at]erasme[dot]ulb[dot]ac[dot]be)