Scleroderma

Contributed by Dr Sandeep Bawa, specialist registrar in rheumatology and Dr Joel David, consultant rheumatologist, Department of Rheumatology, Nuffield Orthopaedic Centre, Oxford

1. Epidemiology and aetiology

Scleroderma is an uncommon autoimmune connective tissue disease affecting blood vessels and skin.

In the UK, it has an incidence rate of four cases per million per year with a prevalence of 30 cases per million, and a female predominance of 4:1. All age groups may be affected, but it is common between 30 to 50 years. Rates are higher in black Afro-Caribbean women, who have a tendency for diffuse disease and hence a worse prognosis.

Aetiology

An activated immune system, vascular damage and excessive synthesis of the extracellular matrix are the main pathological mechanisms thought to be involved in the the illness.

Fibroblast proliferation causes excessive production of collagen type I and  III and endothelial disruption causes platelet activation. Autoantibodies, such as anti-nuclear factors, Scl-70 and anti-centromere antibodies are frequent. However, it is not clear if these represent a direct causal link. Environmental triggers including chemical exposure, mechanical stimuli and viruses such as CMV and HSV5 have been implicated.

Scleroderma cannot be directly inherited. Some studies have shown a linkage with genetic markers, but environmental triggers are thought to play an initiating role.

Classification

Scleroderma is classified into groups and subtypes (see box above). Patients with limited systemic sclerosis have prominent vascular manifestations with telangiectasia and early onset of Raynaud’s syndrome. CREST syndrome is a subtype of limited systemic sclerosis characterised by calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly and telangiectasia.

CLASSIFICATION OF SCLERODERMA

Localised scleroderma

  • More common in children.
  • Morphea — circumscribed patches of thickened skin.
  • Linear scleroderma — skin, muscle, bone affected.
  • En coup de sabre — scalp lesion.

Systemic sclerosis

  • Limited systemic sclerosis — face, neck, forearm, hands and lower leg skin involvement, prominent vascular manifestations.
  • Diffuse systemic sclerosis — skin changes can affect the whole body. Major organ involvement.

Overlap syndromes (SLE, MCTD)

Scleroderma sine scleroderma

  • No skin involvement. Gastric, pulmonary, renal or cardiac involvement.

Environmentally induced scleroderma

Scleroderma-like diseases

  • Graft versus host disease, scleredema.

2. Clinical features

Skin involvement

There is thickened sclerotic skin involvement with varying amounts of tethering. Tightening of the skin may cause contractures of joints, a small mouth (microstomia), dryness and irritation. The vascular abnormalities may result in digital ulcers, calcinosis and telangiectasia.

Patients in the limited subtype have skin involvement restricted to hands, forearm, face and neck. The diffuse subtype may involve the chest, abdomen, upper arms and shoulders. Skin pigment changes may also occur.

Raynaud’s phenomenon

Characteristically in Raynaud’s phenomenon, the digits change colour from white (pallor), to blue (cyanosis) and finally red (reperfusion) — a triple-phase colour change. Symptoms maybe precipitated by a drop in temperature. Severe episodes can be complicated by digital ulceration and infarction.

Other organ involvement

Cutaneous disease activity does not correlate with organ involvement.

Pulmonary fibrosis (PF) occurs most commonly in the diffuse subtype. Reduced exercise tolerance, cough and shortness of breath are recognised symptoms. Progression can lead to pulmonary hypertension. The onset of PF is usually within the first three years of diagnosis, associated with the greatest loss of lung volume. These patients have a five-fold increase in the risk of lung cancer.

Pulmonary hypertension primarily due to vascular disease is more common in the limited subtype (15 per cent). It is usually a late manifestation of the disease. It can be complicated by right heart failure and pulmonary thrombosis. Renal involvement can be seen in up to 50 per cent of patients, usually in the diffuse subtype. Hypertension can be accelerated and is usually a marker of poor outcome.

Gastrointestinal involvement manifests through neural involvement which leads to oesophageal dysmotility, and later in incompetence of the lower oesophageal sphincter. Symptoms experienced include reflux, cough, dysphagia secondary to impaired motility and stricture formation. Constipation, diarrhoea, abdominal pain secondary to pseudo-obstruction and malabsorption due to small bowel bacterial overgrowth can manifest as a result of lower gastrointestinal involvement.

Other features include myocarditis, pericardial effusion and cardiac conduction disturbances. Musculoskeletal symptoms manifest as arthralgia, myalgia and tendon friction rubs.

Investigations and diagnosis

Diagnosis is based on the history and examination. Skin biopsy is not necessary. Establishing the antibody profile can be helpful in confirming systemic sclerosis, but its absence does not rule out the diagnosis.

Antinuclear antibody is positive in up to 95 per cent of patients but is not specific. Anti-centromere antibody is more commonly associated with the limited form of the disease. Anti-DNA topoisomerase I (Scl-70) antibody is commonly seen in the diffuse subtype. Anti RNA polymerase I & III are also very specific to systemic sclerosis but are seen in only a fifth of patients. Anti-PM-Scl autoantibody is associated with myositis and anti U3-RNP with pulmonary hypertension.

MAIN CLINICAL FEATURES
 Limited systemic sclerosis
Diffuse systemic sclerosis
Skin
Forearm, hands, feet, head, neck Generalised
Raynaud's phenomenon
Precedes skin involvement Coincides with/develops later 
Pulmonary fibrosis
Less common/non-progressiveEarly/progressive

3. Management

Management depends on the type of scleroderma diagnosed. Patients should be managed in collaboration with the rheumatologist.

There is no cure. It is important to screen for complications and  these should then be aggressively treated. Risk factors that increase morbidity should be addressed.

Patients should be advised on lifestyle modification such as weight control, smoking cessation, cholesterol and  stress reduction. If Raynaud’s phenomenon is present, patients should be advised to avoid cold, stress, caffeine, smoking and beta-blockers; to use gloves, calcium channel blockers or ACE inhibitors. Specialist referral is required for prostacyclin infusion.

Complications

In the case of pulmonary hypertension, look for characteristic signs in history and examination such as parasternal heave, loud P2, raised JVP and swelling ankles. Yearly echocardiogram and specialist referral for heart catheterisation may be necessary. Treatment involves endothelin receptor antagonist, phosphodiesterase-5 inhibitor and  prostacyclin analogue.

In patients with pulmonary fibrosis (PF), look for characteristic signs in history and examination including fine inspiratory crepitations and perform yearly pulmonary function tests.

Specialist referral should be required for chest X-ray and HRCT immunosuppression. Patients with renal disease require tight control of BP, six monthly U+E  and regular urinalysis. ACE inhibitor is the treatment of choice. Refer to a specialist if the patient’s condition is uncontrolled or deteriorating.

Multi-disciplinary approach

Proton pump inhibitors should be used to prevent reflux/stricture formation. Antibiotics could be prescribed if malabsorption syndrome or bacterial overgrowth  is present. Specialist referral is recommended for imaging and motility studies if complications occur.

Patients who have normal pulmonary function tests at the time of presentation are unlikely to develop severe PF. Renal disease usually occurs within the first five years of diagnosis. A multidisciplinary approach should be adopted in order to provide patient education and a self-management plan. Patients should report any changes in their condition.  Self-help groups provide an invaluable source of support.

Prognosis is associated with the extent of skin and organ involvement. Young age, African-Caribbean ethnicity, anaemia, elevated ESR, anti-Scl-70 and pulmonary and renal involvement indicate a more severe prognosis. Survival rates over 10 years are 71 per cent for LCS, and 21 per cent for the diffuse subtype.

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