Systemic Sclerosis - Scleroderma

Includes dsSSc, lcSSc and CREST syndrome.

The name scleroderma is derived from the Greek for "hard skin" and emphasises the dermatological component of the disease. It was described by Hippocrates.The term systemic sclerosis emphasises that it is not confined to the skin but is a multi-system disease.

It is a group of autoimmune diseases in which there is increased fibroblast activity resulting in abnormal growth of connective tissue causing vascular damage and fibrosis. The process may be localised or systemic. The limited variety used to be called CREST syndrome but now it is called limited cutaneous systemic sclerosis, usually abbreviated to lcSSc whilst the systemic form, affecting the internal organs, is called diffuse cutaneous systemic sclerosis or dcSSc.

Scleroderma is present throughout the world and is represented in all ethnic groups. It affects approximately 2 per 100,000 per year. Prevalence is approximately 65-265 per million.¹ It has been reported in all age groups, but is rare in children. Females are affected more commonly than males with a ratio of 3:1.This female preponderance is much more marked for lcSSc than for dcSSc.

In Caucasians adults the dcSSc form is more common whilst in other races and in children lcSSc is the more usual.

The age of onset is usually about 30 to 40, being slightly later in men than in women. Around 85% develop between 20 and 60 years of age.

Risk Factors

A genetic predisposition has been described for scleroderma, but expression is unpredictable, and environmental factors are thought to play a role in triggering the disease. These environmental factors are thought to include, organic solvents, several synthetic adhesive or coating substances, viruses etc. It had been thought that breast implants might act as a trigger, but the current evidence does not support this theory.²

The presenting features are often non-specific (fatigue, musculoskeletal pains and hand swelling). Presentation of the localised and systemic forms of the disease may vary, but Raynaud's phenomena and skin changes in the form of hardened skin, are common to both. Raynaud's phenomenon is extremely common and may precede skin changes by a year. It is the presenting feature in 70%.

Symptoms and signs of lcSSc (formally CREST syndrome)

The E in CREST is from the American spelling of oesophagus.

• Calcinosis of skin (40%)
• Raynaud's phenomena (90-95%)
• oEsophageal involvement (90%) resulting in progressive dysphagia and dyspepsia
• Sclerodactyly (90%) tight shiny appearance of skin on fingers and toes, skin changes may also occur in bands giving the classic "coup de sabre" appearance.
• Telangiectasia (50%) on face, lips tongue, chest wall etc.

In addition several other features may be found:

• Non pitting oedema of the fingers
• A "salt and pepper"appearance due to areas of hypopigmentation and hyperpigmentation
• Dilated capillary loops at the base of the fingernails
• Microstomia from tightening of the skin produces "puckered lips"
• Ulceration of skin
• Involvement of internal organs may occur

Symptoms and signs of dcSSc

The symptoms and signs of dcSSc are at their worst in the first 3 to 5 years of the disease, after which patients enter a stable phase and further deterioration is unlikely. The disease often reverses to some extent with softening of the skin. Symptoms which occur include any of the signs associated with lcSSc but in addition:

• Pruritis is common
• Shortness of breath on exertion, progressing to dyspnoea at rest. Basal rales may indicate pulmonary fibrosis.
• Diffuse scleroderma rapidly progressing.
• Scleroderma affecting heart, kidneys, lungs, GI tract and other internal organs (<30%).
• Anorexia, fatigue, weight loss
• Joint pain, limitation of movement, joint swelling, and muscle pain may be present. SSc begins as joint pain in 15% of patients. It begins as inflammatory myopathy in 10% of patients.
• Weakness is a complaint in 80%

Diagnostic Criteria

Features of the disease are divided into 2 groups:

• Major features include centrally located skin sclerosis that affects the arms, face, and/or neck.
• Minor features include sclerodactyly, erosions, atrophia of the fingertips, and bilateral lung fibrosis.
• Diagnosis of systemic sclerosis is made when a patient has 1 major and 2 minor criteria.³

Sub-Groups

Systemic sclerosis is divided into 5 forms of which the first two represent the majority:

• Diffuse cutaneous systemic sclerosis or dcSSc
• Limited cutaneous systemic sclerosis or lcSS
• Transitory form (dcSSc/lsSSc).
• Systemic scleroderma sine scleroderma
• Malignant scleroderma

Several other diseases can present in a similar way to scleroderma including:-

• Eosinophilic fasciitis
• Undifferentiated connective tissue disease
• Vibration injury
• Buerger's disease
• Porphyria cutanea tarda
• Mycosis fungoides
• Connective tissue overlap syndromes
• Systemic lupus erythematosus

Routine blood tests may show:

• Elevated ESR
• Thrombocytopenia
• Hypergammaglobulinaemia
• Low haemoglobin due to microangiopathic haemolytic anaemia
• Increased creatine phosphokinase levels in patients with muscle involvement
• Increased urea and creatinine levels in patient with kidney involvement

Serology may show:

• Anti-centromere antibodies ( up to 90% of lcSSc)
• Anti-Scl-70 antibodies ( 40% of dcSSC)
• Anti-topoisomerase antibodies ( 40% of dcSSc)
• Although the type of antibodies found will give some indication as to the likely extent of the disease,⁴ regular follow up is required of both groups to determine those patients who may go on to develop internal organ involvement.

Skin biopsy may be useful.

Screening at regular intervals may include:

• Chest x-ray, chest CT scan and lung function tests (pulmonary fibrosis, bronchiectasis, pneumothorax, pulmonary hypertension)
• Especially in lcSSc, x-ray of the hands may show calcinosis, osteopenia and intra-articular calcification.
• ECG and echocardiogram. There may be pericarditis, myocarditis and symptomatic pericardial effusion.
• Endoscopy, colonoscopy, barium studies ( strictures )
• Renal ultrasound, (renal involvement)

Non-Drug

• Physiotherapy is useful in maintaining function in the joints.
• Heated clothing gives symptomatic relief for the pain of Raynaud's phenomena. Avoid cold, smoking and trauma.
• Counselling and advice on camouflage products may help with the appearance of the skin changes.
• Occupational therapists are able to suggest useful adaptations to assist in daily living, e.g. cutlery, clothing fasteners

Drugs

There is currently no drug treatment which has been shown to affect the progress of the disease process. Several agents have been used in the past with only limited success and thus treatment at present focuses on treating the symptoms or the consequences of the disease. Treatment for the vascular complications are most successful, especially in treating renal crises and pulmonary arterial hypertension.¹

• Calcium antagonists such as nifedipine may be useful in the treatment of Raynaud's phenomenon.
• Pruritis may respond to antihistamines, topical emollients and even PUVA.
• Anti-inflammatory agents may be used for myalgia and arthralgia.
• ACE inhibitors are used as soon as renal involvement is suspected.
• Acid suppression with PPIs can reduce symptoms of gastro-oesophageal reflux.
• Cyclophosphamide has been shown to increase the chances of survival from lung involvement and fibrosis if used early.^5,1Corticosteroids may also be beneficial.
• Endothelin antagonists improve morbidity and mortality in patients who develop pulmonary hypertension as a result of scleroderma.⁶

Trials using autologous stem cell transplantation and anti-fibrosis drugs (bosentan, interferon-gamma, relaxin) are being carried out.

Surgical

• Nodules of calcinosis may require surgical removal.
• Skin ulcers, if severe, may require skin grafts.
• Contractures may require surgical release.

The most severe complications occur in severe dcSSc and take the form of:

• Pulmonary hypertension with fibrosis or bronchiectasis is common and can be fatal.
• About 10% of patients with systemic sclerosis and 25% of those with diffuse, rapid skin involvement, will develop a renal crisis. This usually presents as accelerated hypertension, oliguria, headache, fatigue, oedema, and rapidly rising serum creatinine levels. However, 10% of cases of renal crisis occurs with normal blood pressure.
• Heart failure may result from myocardial disease, pericardial disease, conduction system disease, or arrhythmias.⁷
• Skin and joint complications include contractures and ulceration.
• GI problems include obstruction, malabsorption, incontinence, rarely perforation and peritonitis.

Pulmonary hypertension resulting from pulmonary fibrosis causes pulmonary hypertension and heart failure. The other major cause of death is renal involvement.

There may be an increased risk of several malignancies⁸ including breast carcinoma, multiple myeloma, lymphoma and cancer of the ovary, carcinoma of oesophagus, or colo-rectal carcinoma. The evidence is not overwhelming and there may be methodological difficulties.

Pregnancy in the disease carries a high risk of miscarriage, early delivery and complications of pregnancy.⁹ Risk is highest in the first 4 years after diagnosis. Aggressive therapy and careful monitoring may improve prognosis¹⁰ but certain drugs such as ACE inhibitors must be avoided.

The 10 years survival is 71% for the limited variety and 21% for the diffuse variety.¹¹
The most severe problems normally occur within 5 years of diagnosis. Modern management of pulmonary hypertension is improving the prognosis.¹²