Types of systemic sclerosis^[1]

Systemic sclerosis is classified into two main types, according to the extent of skin involvement.

Limited cutaneous systemic sclerosis (lcSSc), or limited scleroderma

• 70% of systemic sclerosis cases.
• Affects only the face, forearms and lower legs up to the knee.
• CREST syndrome (= C alcinosis, R aynaud's disease, (O)E sophageal dysmotility, S clerodactyly, T elangiectasia) is an older term for limited scleroderma.

Diffuse cutaneous systemic sclerosis (dcSSc), or diffuse scleroderma

• 30% of systemic sclerosis cases.
• Involves also the upper arms, thighs or trunk.

Other types^[2]

There are rarer types, including systemic scleroderma sine scleroderma (internal organ involvement without the skin changes).

Epidemiology^[1]

Systemic sclerosis is present throughout the world and is represented in all ethnic groups. UK prevalence is 1:10,000 with a female: male ratio 4:1. The usual age of onset is 25-55 years, but it can affect any age group. It is rare in children.

Aetiology

The cardinal features of systemic sclerosis are excessive collagen production and deposition, vascular damage, and inflammation or autoimmunity.^[3]

The cause is unknown, although there is probably a genetic predisposition. Environmental factors may play a role in triggering the disease. These may include viruses such as cytomegalovirus and chemicals such as vinyl chloride, some pesticides, benzene derivatives and silica.^[3]

Clinical features^[1][4]

Patterns of disease

Common presenting symptoms are Raynaud's phenomenon (which may precede other symptoms by years), skin hardening in hands or face, and oesophageal symptoms. Early symptoms can also be nonspecific, eg fatigue, musculoskeletal pains and hand swelling. Both limited and diffuse scleroderma can involve internal organs, and the severity of skin changes does not necessarily reflect the severity of internal organ involvement.

• Limited cutaneous systemic sclerosis (lcSSc):
  • Generally a milder disease, with less skin involvement, slow onset and slow progression.
  • The slow onset may mean that symptoms are relatively unnoticed until internal complications occur.
• Diffuse cutaneous systemic sclerosis (dcSSc):
  • Usually a more rapid onset, with skin thickening and Raynaud's phenomenon occurring together or within a short interval. The skin changes may spread rapidly, within a few months of disease onset.
  • Skin changes can remit after several years, with softening of the skin and significant improvement in mobility.
  • Symptoms tend to be worst in the first 3 to 5 years of the disease, after which there is a stable phase and further deterioration is unlikely. The disease may then reverse to some extent, with softening of the skin and improved mobility.
  • Internal organ involvement is more common.

Symptoms and signs of systemic sclerosis

Note: the pattern and severity of disease vary for each individual.

General features

• Fatigue
• Weight loss

Skin features

• Signs in the hand:
  • Swelling (non-pitting oedema) of fingers and toes - a common early sign; digits may look sausage-like; hand movement may be limited.
  • Skin becomes hard and thickened - this may limit joint movement or cause joint contractures; in the fingers, this is known as sclerodactyly.
  • Swelling and sclerosis reduce hand movements, so patients may be unable to make a fist, or to place the palmar surfaces together - the 'prayer sign'.
  • Fingertips may have pitting, ulcers or loss of bulk from finger pads.
• Raynaud's phenomenon.
• Calcinosis - nodules or lumps of chalky material which may break through the skin.
• Face and mouth:
  • Tightening of facial skin.
  • Tight lips (microstomia) - can make dental hygiene difficult.
• Telangiectasia.
• 'Salt and pepper' appearance of skin, due to areas of hypopigmentation and hyperpigmentation.
• Dry or itchy skin; reduced hair over affected skin areas.

Musculoskeletal features

• Joint pain and swelling.
• Myalgia (due to inflammatory myopathy).
• Restriction of joint movement, contractures and muscle atrophy due to skin sclerosis.
• Tendon friction rubs - palpable/audible over the flexor/extensor tendons of the hands, knees and ankles (these are highly characteristic of dcSSc and should prompt early diagnosis and screening for complications).

Gastrointestinal (GI) features

• Heartburn and reflux oesophagitis.
• Oesophageal scarring and dysphagia.
• Delayed gastric emptying, eg fullness after meals.
• Reduced small bowel motility - can cause bacterial overgrowth, with bloating, malabsorption, diarrhoea and malnutrition.
• Constipation due to reduced colonic motility.

Investigations

Blood tests:^[4]

• FBC.
• ESR and CRP.
• Baseline biochemistry and renal function.
• Autoantibodies:
  • Antinuclear antibody - positive in 90-95% but not specific to systemic sclerosis.
  • Other autoantibodies (extractable nuclear antigens) - see box below.

Other investigations:

• Urine protein - as baseline or if there are renal complications.
• Skin biopsy - may aid diagnosis.
• Nailfold capillaroscopy - helps to assess the likelihood of scleroderma in patients with Raynaud's phenomenon or swollen fingers.
• Hand X-ray may show calcinosis.
• Thermography with cold challenge helps to assess the severity of Raynaud's phenomenon.
• Endoscopy and/or barium studies, depending on gastrointestinal (GI) symptoms.

Regular monitoring for complications includes:^[4]

• Renal function.
• Lung function tests and chest CT scan.
• ECG and echocardiography.

Diagnosis

Diagnosis may be difficult, particularly in the early stages, as symptoms overlap with other connective tissue diseases. Diagnosis depends on the overall clinical picture rather than a specific test.

Diagnostic criteria for systemic sclerosis^[5]

Major criterion:

• The major criterion is symmetrical skin thickening, tightening or induration, occurring in the fingers AND proximal to the metacarpophalangeal or metatarsophalangeal joints.

Minor criteria:

• Sclerodactyly (symmetrical skin thickening, tightening or induration limited to the fingers).
• Digital pitting (depressed areas on fingertips) OR loss of substance from the finger pad.
• Bilateral, basilar lung fibrosis without another cause.

Systemic sclerosis is diagnosed when a patient has one major criterion OR at least two minor criteria.

Early diagnosis - the VEDOSS initiative^[1]

• There is a VEDOSS (= V ery E arly D iagnosis O f S ystemic S clerosis) initiative in Europe.
• Clinics aim for early diagnostic tests for systemic sclerosis in any patient with Raynaud's and finger swelling, using nailfold capillaroscopy and antinuclear antibody tests.

Differential diagnosis^[4]

Several other diseases can present in a similar way to systemic sclerosis, including:

• Raynaud's phenomenon from other causes.
• Vibration injury.
• Other connective tissue disease or mixed connective tissue disease, eg with features of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).
• Undifferentiated connective tissue disease.
• Amyloidosis.
• Chronic graft-versus-host disease.
• Paraneoplastic syndromes.

Management^[1][4]

Monitoring

Regular monitoring and reviews are aimed at early detection and treatment of complications. Monitoring includes a general review of symptoms, nutrition etc; and also:

• Blood pressure monitoring.
• Renal function monitoring.
• Lung function tests and chest CT scan.
• ECG and echocardiography.

Nondrug treatments

• Patient involvement and education:
  • 'Expert patient' programmes and the Scleroderma Society.
  • Awareness of urgent problems such as renal crisis or intestinal obstruction symptoms.
• Physiotherapy to promote joint mobility and muscle strength.
• Home exercises to maintain range of motion (such as gentle mouth, face and hand stretches).
• Avoid tobacco and maintain healthy weight.
• Nutritional advice, and supplements if needed.
• For Raynaud's phenomenon:
  • Prevention - avoid cold and trauma; use warm clothing or heated clothing.
  • For an attack - warm the body, hands and feet gently (the skin may be numb and unable to feel if the heat source is too hot); use gentle arm movements or gentle massage to help restore circulation.
• Occupational therapists - for adaptations to assist in daily living.
• Camouflage products - for cosmetic help with skin changes.

Immunotherapy^[6]

• Non-selective immunosuppressives - cyclophosphamide is the most commonly used and has been associated with improvements in both pulmonary function and skin involvement but efficacy may reduce beyond two years. Mycophenolate mofetil has also been used with improvements in lung function. Azathioprine and methotrexate alone may not be as beneficial as the aforementioned medications.
• T-cell targeted immunotherapy - T cells play a central role in much of the pathology of scleroderma, which probably explains why ciclosporin is effective. Other T-cell targeted therapy which is being tested includes sirolimus, antithymocyte globulin, and basiliximab.
• Other medical treatments - rituximab, intravenous immunoglobulins and anti-tumour necrosis factor alpha (anti-TNF-alpha) are also being investigated for the treatment of scleroderma.

Treatment of common symptoms and complications is also a major part of the management plan and is discussed below.

Management of skin and musculoskeletal symptoms

Raynaud's phenomenon symptoms and ulcers:

• Calcium-channel blockers (eg nifedipine) or angiotensin-II receptor antagonists (eg losartan).
• There are some reports that fluoxetine may help.
• Sympathectomy may relieve symptoms.
• For ischaemic ulcers:
  • Simple protective dressings.
  • Antibiotics if infected.
  • Vasodilators may help in some situations, eg bosentan may reduce the occurence of new ulcers.
  • New treatments for Raynaud's phenomenon are nitroglycerin (ointment) or sildenafil (currently recommended only if other treatments are not sufficient).^[3]

Skin dryness or itching:

• Emollients.
• Topical steroids (short course) or antihistamines.

Skin thickening:

• For patients with rapidly progressing diffuse scleroderma, consider a trial of immunosuppressant treatment, eg mycophenolate or cyclophosphamide.

Surgical procedures for specific indications such as:

• Release of contractures
• Removal of troublesome calcinosis

Myalgia, arthralgia and painful oedema:

• Non-steroidal anti-inflammatory drugs (NSAIDs), if tolerated.
• Simple analgesics.

Gastrointestinal (GI) symptom management

For upper GI symptoms:

• Maintain upright posture after meals; raise the head of the bed; limit alcohol.
• Proton pump inhibitors.
• May also need H₂-receptor antagonists and pro-motility agents (metoclopramide or domperidone).
• Dilatation of oesophageal strictures if required.

For intestinal bacterial overgrowth and malabsorption:

• Cyclical antibiotics.
• Nutritional advice and nutritional supplements; rarely, parenteral nutrition is required.

For constipation:

• Dietary fibre and good fluid intake.
• Softening laxatives (such as lactulose) and/or soluble fibre (such as ispaghula).^[1][7]

Complications (internal organ involvement) and their treatment^[1][4]

Gastrointestinal (GI) complications

See also specific GI sections under 'Clinical features' (symptoms) and 'Management' headings.

Stomach:

• 'Watermelon stomach' (gastric antral vascular ectasia):
  • May cause anaemia and GI bleeding.
  • May need endoscopic laser coagulation to prevent bleeding.

Obstruction and pseudo-obstruction:

• Can occur due to reduced motility and bacterial overgrowth.
• Can be complicated by perforation and peritonitis.
• Pseudo-obstruction is treated initially by bowel rest and antibiotics.
• Laparotomy may be needed.

Anorectal:

• In some cases, the rectum and anus are involved, causing faecal incontinence.
• This may require surgery.

Scleroderma renal crisis

• A serious complication with features of accelerated hypertension.
• Can lead to renal failure if not treated promptly.
• Occurs in up to 20% of patients with diffuse scleroderma, usually in the first four years of the disease.
• Occurs in about 5% of patients with limited scleroderma.
• Presentation:
  • Usually presents as accelerated hypertension with oliguria, headache, fatigue, oedema, rapidly rising serum creatinine levels, proteinuria and microscopic haematuria.
  • 10% of scleroderma renal crises occur with apparently normal blood pressure, but the blood pressure is higher than baseline values - hence the importance of regular blood pressure monitoring.
• Treatment is with angiotensin-converting enzyme (ACE) inhibitors, plus dialysis if necessary.

Pulmonary complications

Pulmonary fibrosis (interstitial lung disease):

• Occurs in about 30% of scleroderma patients.
• Causes restrictive lung disease.
• Symptoms and signs: exertional dyspnoea, cough, coarse basal crackles.
• Treatment:
  • Some trials suggest benefit from cyclophosphamide, which may be followed by azathioprine and prednisolone; benefits must be weighed against side-effects.
  • Supportive treatment: prompt treatment of chest infections - oxygen if needed.

Pulmonary arterial hypertension (PAH):

• Occurs in about 15% of patients with diffuse scleroderma and 5% with limited scleroderma.
• Symptoms and signs: exertional dyspnoea, syncope, right ventricular strain features.
• Treatment:
  • Drug treatment of PAH has improved recently and includes: endothelin receptor antagonists, eg bosentan or sitaxsentan; vasodilators, eg sildenafil; prostaglandin derivatives, eg iloprost (nebulised) or epoprostenol (infusion).
  • Supportive treatment, eg oxygen.

Other respiratory problems:

• Aspiration pneumonia from severe reflux.
• Respiratory muscle weakness if there is severe myositis or extensive skin disease involving the chest.

Cardiac complications

• Occur in about 10% of patients with diffuse scleroderma, and 5% of those with limited scleroderma:
  • Myocardial disease, pericarditis or pericardial effusion; these may cause cardiac impairment or congestive cardiac failure.
  • Arrhythmias and conduction defects.
• Treat according to the clinical features.

Sjögren's syndrome

• This may occur in patients with an 'overlap syndrome', where there are both scleroderma and Sjögren's syndrome features.
• Common symptoms are dry eyes and mouth; other mucous membranes, eg vagina, may be symptomatic.
• Can cause eye irritation, dysphagia, dysphonia and increased dental decay.
• Treat with lubricants, eg artificial tears and saliva, and dental care.

Pregnancy^[8]

Successful pregnancy is possible. It should be planned when the disease is stable to avoid complications. Close monitoring, multidisciplinary care and individually tailored treatment are needed.

Prognosis^[4]

The disease course varies with each individual. The prognosis depends on the extent of complications. For example, one study found the 9-year survival rate was 38% in patients with severe organ involvement, but 72% in patients without such involvement.^[3]