Systemic sclerosis is an multisystem inflammatory autoimmune condition of unknown aetiology. It is associated with fibroblast proliferation and increased collagen deposition, causing damage to vasculature and fibrosis.

The term scleroderma is sometimes used interchangeably - this literally means 'hardening of the skin', one of the main characteristics of the condition. This causes the skin to have a classical shiny, tight appearance without normal skin folds. Patients generally initially present with tightening and thickening of the skin and Raynaud's phenomenon. This can progress to more widespread disease, including pulmonary and myocardial fibrosis, pulmonary arterial hypertension, and scleroderma renal crisis.

Systemic sclerosis is more common in women than men (3:1), and appears to occur more commonly in North America and Australia than in Europe, and more often in people of African origin. The peak age of onset is 40-50 years of age.

Systemic sclerosis is difficult to treat. Management generally involves systemic immunosuppressive therapy, monitoring for complications, and treating these if they arise.

Systemic sclerosis can be broadly differentiated into two types:

• Limited cutaneous systemic sclerosis (formally known as CREST syndrome).
  • Skin manifestations limited to face, forearms, hands, feet and lower legs
  • Usually milder with a more insidious onset
  • Clinical signs include calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia
  • Epidemiological studies are lacking but serum antibody studies suggest that 25% of cases of systemic sclerosis are limited
  • Most patients do not demonstrate systemic involvement but some develop pulmonary hypertension
• Diffuse cutaneous systemic sclerosis.
  • More rapid onset and poorer prognosis
  • Upper arms, thighs and trunk affected by skin manifestations
  • More widespread disease, which may cause pulmonary fibrosis, coronary artery disease or renal disease.

Rarer types of systemic sclerosis also exist, including a manifestation with internal organ involvement without skin changes.

The exact cause of systemic sclerosis is unknown, but there are a number of possible predisposing factors, including:

• Family history
• Vitamin D deficiency (a strong association has been documented)
• Radiotherapy

Possible triggers for onset of disease include

• Infection
  • CMV, EBV, parvovirus B19, hepatitis B
  • Helicobacter pylori, Chlamydia trachomatis
• Chemicals
  • Some pesticides
  • Hair dyes
  • Silica
• Drugs
  • Cocaine
  • Penicillamine
  • Bleomycin
  • Vitamin K

Systemic sclerosis is an autoimmune condition, the aetiology of which is unknown.

Many of the clinical and pathologic manifestations result from excessive and often progressive deposition of collagen in the skin and various internal organs. This process also affects the blood vessels, particularly small arterioles and arteries.

As with many autoimmune conditions, there is a genetic predisposition to systemic sclerosis, but it is likely an environmental trigger which leads to onset of the disease process. This environmental trigger causes endothelial cell abnormalities in small blood vessels, which leads to microvascular injury. Macrophages phagocytose fragments of these cells and present antigen to naïve T cells, which become T-helper cells. Studies have shown that patients with systemic sclerosis have an increased number of T-helper cells at sites of inflammation in the skin of their face and hands.

• T-helper cells secrete cytokines → this recruits more immune cells, including more macrophages, T and B lymphocytes, and neutrophils → this promotes a chronic inflammatory process.
• Cytokines attract fibrocytes alongside other inflammatory cells → fibrocytes, epithelial cells and endothelial cells differentiate into myofibroblasts, recruited for repair at sites of inflammation → these cells produce extracellular matrix (ECM) and lay down type I, III and VI collagen → this causes fibrosis, including the skin tightening association with scleroderma.

This inflammatory process also leads to a number of the other manifestations of systemic sclerosis:

• The inflammation can lead to tissue necrosis and an accumulation of dead cells → calcium binds to cytosol on the cell membranes of dead cells → calcium builds up in the skin, causing calcinosis.
• Inflammation damages blood vessels which causes telangiectasia.
• Damage to blood vessels can also initiate platelet aggregation → intravascular thrombosis → ischaemia → ischaemic ulcers → finger loss

One of the most important cytokines in this process is TGF-β

• It has potent extracellular matrix stimulatory effects.
• It induces generation of myofibroblasts.
• It decreases production of collagen-degrading metalloproteinases
• It stimulates production of protease inhibitors, which prevent ECM breakdown.

Systemic sclerosis is complex and heterogeneous and patients can therefore experience a wide range of different symptoms and patterns of organ involvement.

Limited Cutaneous Systemic Sclerosis

A typical patient may experience an insidious onset of initially mild symptoms such as finger swelling, pruritis, heartburn, and Raynaud's phenomenon. This progresses, with swallowing difficulties, calcinosis, and thickening, hardening and tightening of the skin of the fingers and hands, which can lead to ulceration and ischaemia.

Limited cutaneous systemic sclerosis was formally known as CREST syndrome due to the following features:

• Calcinosis
  • Calcium deposits build up in the skin
  • Mostly on the fingers
• Raynaud's phenomenon
  • Painful discolouration of the skin of the fingers in response to certain triggers, most commonly exposure to the cold
  • Caused by vasospasm and vasoconstriction
  • Fingers generally go white (pallor), then blue (cyanosis), then red (hyperaemia)
• Esophageal dysmotility
  • Swallowing difficulties
  • Acid reflux
  • Oesophagitis
• Sclerodactyly
  • Skin tightening on the hands restricts the range of motion of the fingers and causes loss of fat pads
  • Swelling of the fingers or toes (dactylitis) may be an early sign
  • Eventually skin may crack and ulcerate
• Telangiectasia
  • Dilated capillaries at the skins surface
  • Often seen on the face
  • Fine, thready appearance
  • Blanches on palpation

Skin manifestations in limited systemic sclerosis are only seen on the face, hands, lower arms, lower legs and feet. Patients can experience tightening of the facial skin, especially around the mouth.
In some cases, limited systemic sclerosis may progress with development of pulmonary arterial hypertension.

Diffuse Cutaneous Systemic Sclerosis

Diffuse cutaneous systemic sclerosis causes more widespread disease with a poorer prognosis. It is generally more rapid in onset; patients may experience early signs of Raynaud's phenomenon and dactylitis which quickly progress to debilitating pulmonary or myocardial fibrosis, digital ischaemia, and renal disease.

Skin features

• Dry or itchy skin with reduced hair
• Raynaud's phenomenon - the most common symptom (>90% of cases). This is generally of more recent onset in diffuse disease, whereas patients with limited disease may have Raynaud's phenomenon for a number of years before developing other clinical signs.
• Sclerodactyly, dactylitis, calcinosis and telangiectasia as in limited disease
• Around half of patients suffer with digital ulceration

Musculoskeletal features

• Arthritis
• Myalgia
• Reduced range of movement at affected joints, both due to muscle atrophy and hardening and thickening of the skin

Gastrointestinal features

• Features of oesophageal dysmotility listed above
• Delayed gastric emptying
• Patients may experience faecal incontinence and rectal prolapse

Pulmonary features

• Fibrosis is clinically significant in a third of patients, and may be present in 80%. It presents with dry cough and dyspnoea with coarse crepitations on auscultation.
• Pulmonary arterial hypertension, a leading cause of death in systemic sclerosis. This presents with dyspnoea, syncope, and features of right ventricular strain.

Cardiac features (affect around 25% of patients)

• Coronary artery disease
• Myocardial fibrosis

Renal features (affect 15-20% of patients)

• Damage to vasculature can cause proteinuria and reduced glomerular filtration rate; this may worsen systemic hypertension

Patients can also experience genitourinary symptoms - men may have erectile dysfunction and women may suffer from dyspareunia.

Constitutional symptoms seen in other connective tissue diseases are common, including fatigue and weight loss.

Patients should be investigated with baseline investigations which may help to rule out more common causes for their specific symptoms. You could expect to see a raised ESR as a marker of long-term inflammation, and a patient with renal disease may also have deranged electrolytes, with an elevated urea and creatinine. Anaemia of chronic disease can also occur in patients with systemic sclerosis, so a normocytic anaemia may be evident on their bloods. An autoantibody screen is important for diagnosis, particular anti topoisomerase 1 and anti-centromere antibody, which are discussed in more detail below.

Various investigations are involved in the assessment and monitoring of different organ dysfunction, and a patient's initial presentation will guide you to which are most appropriate immediately

• Urine protein for renal disease
• Pro-BNP, ECG, echocardiography and cardiac MRI for heart disease
• Lung function tests for pulmonary fibrosis
• Oesophageal manometry to investigate dysmotility
• Hydrogen breath tests to investigate for small intestinal bacterial overgrowth
• Thermography and nail fold capillaroscopy to assess Raynaud's syndrome
• Hand X-ray may confirm calcinosis

Autoantibodies

Anti-nuclear antibody is present in most cases but is non-specific.

Anti-centromere antibody is associated with limited cutaneous systemic sclerosis, with a specificity of around 98%, although sensitivity is only around 60%. If disease progresses, it is more strongly associated with pulmonary hypertension than lung fibrosis or renal disease.

Anti-topoisomerase 1 (anti-Scl 70) is associated with diffuse cutaneous systemic sclerosis with a sensitivity of around 60%. It is associated with disease severity, and particularly associated with lung fibrosis and renal disease.

A number of other autoantibodies are associated with systemic sclerosis, often with particular patterns of organ involvement. One of the most notable of these other antibodies in anti-RNA polymerase III, which is associated with diffuse systemic sclerosis and the development of scleroderma renal crisis. It is also associated with a relatively low rate of lung fibrosis.

Nail fold capillaroscopy
Nail fold capillaroscopy can be used to assess whether Raynaud's syndrome is associated with scleroderma or is due to another cause. It is a technique used to magnify and examine the area of the skin where the base of the fingernail meets the skin of the finger. This helps to examine the health of the peripheral capillaries. Microhaemorrhages, avascular areas and abnormal capillaries are signs of systemic sclerosis. Patients with primary Raynaud's have normal nail fold capillaries. Nail fold capillaroscopy can also be used as a prognosticator as it predicts risk of developing digital ulcers.

Diagnostic criteria
Diagnostic criteria for systemic sclerosis were developed in 2013 in collaboration between the American College of Rheumatology and the European League Against Rheumatism. These are mostly based on the clinical features of the disease and a score of 9 or above is diagnostic. Skin thickening extending proximal to the MCP joints gives a score of 9 and is therefore diagnostic in itself without the need for other features. Other features as part of the criteria include telangiectasia, Raynaud's phenomenon, abnormal nailfold capillaries, lung disease, and presence of autoantibodies.

A number of the signs and symptoms of systemic sclerosis are common with other connective tissue disorders, including mixed connective tissue disease and undifferentiated connective tissue disease. Similarities and differences are shown in the tables below:


Prognosis in MCTD is also much more favourable with 80% ten year survival; this may be partially due to the fact that renal disease is more severe in systemic sclerosis. UCTD can sometimes develop into a case with more specific clinical features, leading to a diagnosis of a specific connective tissue disease.

Pulmonary hypertension is not always associated with systemic sclerosis - a similar group of patients (women aged 40-50) present with pulmonary arterial hypertension, with symptoms of dyspnoea and right ventricular strain (oedema, fatigue). These patients would be less likely to present with thickening and hardening of the skin, calcinosis, or Raynaud's phenomenon.

A patient presenting with isolated Raynaud's phenomenon may be a first presentation of systemic sclerosis, but there are numerous other causes which would be more likely in an isolated case:

• Smoking
• Hypothyroidism
• Diabetes
• Malignancy
• Medications including beta blockers

There are of course numerous different causes of pulmonary fibrosis and various causes of kidney disease, so these should be considered when clinical features are isolated to one of these particular organs.

There are no high-quality studies on which to base advice on the management of systemic sclerosis given the uncommon and heterogenous nature of the disease. Early recognition, diagnosis and referral to specialist services is essential in diffuse disease due to the rapidly progressive nature of the condition. Immunosuppressive therapy can be considered in early disease, and regular monitoring is essential to ensure early detection and management of complications.

The British Society for Rheumatology guidelines suggest an early trial of systemic immunosuppressive therapy despite the limited evidence base.

• Mycophenolate mofetil and methotrexate are first line for skin involvement
• Cyclophosphamide and rituximab can also be considered
• Oral steroids may be used at the lowest dose possible to maintain remission
• Azathioprine and MMF can be used to maintain remission

Otherwise, management relies on effective monitoring and treatment of the different clinical features and complications.

Skin features

• Calcinosis
  • Managed pharmacologically with aluminium hydroxide, bisphosphonates, calcium-channel blockers, colchicine, or infliximab
  • Extracorporeal shock wave lithotripsy, intralesional steroid, laser therapy or surgical removal may also be used in specific circumstances.
• Raynaud's phenomenon
  • Managed conservatively with avoidance of triggers and use of gentle warming and massage during an attack.
  • If pharmacological treatment is required, nifedipine is first line
  • Losartan, alpha-blockers, statins, SSRIs and phosphodiesterase type-5 inhibitors may also be used
  • In severe cases, intravenous iloprost or digital sympathectomy may be required.
• Scleroderma
  • Gentle skin stretching
  • Use of emollients
  • Anti-histamines for pruritis
• Telangiectasia
  • Camouflage products
  • Laser therapy
• Ischaemic ulcers
  • Sildenafil is first line
  • Second line therapies are iloprost or bosentan
  • Analgesia may be required for pain control
  • Antibiotics if the ulcer is infected

Musculoskeletal features

• Physiotherapy
• Symptoms may be improved with immunosuppressive therapy.
• Non-steroidal anti-inflammatory drugs and other simple analgesics are often effective.

Gastrointestinal features

• Reflux managed as in other circumstances
  • Conservative measures include sitting upright after food and not lying flat in bed, as well as reducing alcohol use and smoking of tobacco
  • Proton pump inhibitors, H2-receptor blockers and prokinetic agents are pharmacological options.
  • Prokinetic agents may also be useful for dysphagia
• Oesophageal strictures may require endoscopy and dilatation
• Gastric antral vascular ectasia may require endoscopy and laser coagulation at regular intervals.
• Bacterial overgrowth in the small bowel may require cyclical antibiotics, often ciprofloxacin or rifaxmin
• Issues with malabsorption may require nutritional advice and supplementation - rarely, total parenteral nutrition is required
• Dietary fibre, good fluid intake and laxatives for constipation
• Anti-diarrhoeal agents such as loperamide may be useful in chronic diarrhoea
• Surgical intervention may be required for rectal prolapse or bowel obstruction

Lung disease

• Extensive and progressive disease requires immunosuppressive therapy and cyclophosphamide is first line
• Prophylactic antibiotics may be required for repeated chest infections
• Pulmonary hypertension is managed with phosphodiesterase type-5 inhibitors, prostaglandin derivatives or endothelin receptor blockers

Scleroderma renal crisis

• Scleroderma renal crisis is managed initial with ACE inhibitors, although additional anti-hypertensives may be required, and some patients require dialysis.

Heart disease

• Systolic heart failure
  • ACE-inhibitors and carvedilol
  • Immunosuppressive therapy, with or without a pacemaker
  • An implantable cardioverter defibrillator may be useful
• Diuretics and calcium-channel blockers in diastolic heart failure

Erectile dysfunction

• As required sildenafil is not usually useful - patients may need regular or alternate day treatment

Autologous haematopoietic stem cell transplantation has been trialled in poor prognosis early diffuse disease and demonstrated a rapid clinical improvement, although there was evidence of treatment-related mortality.

There are various potential complications of systemic sclerosis dependent on specific organ involvement.

Skin features

• Digital ulcers can occur secondary to cracking of hardened, tight skin
  • Ulcers may become chronic and can become infected
  • This may eventually lead to critical digital ischaemia and finger loss

Gastrointestinal complications

• Watermelon stomach
  • Gastric antral vascular ectasia (GAVE)
  • This is when the lining of the stomach bleeds, giving the appearance of the skin of a watermelon with characteristic stripes of bleeding mucosa
  • This could present as an insidious upper GI bleed, causing malaena and anaemia
• Reduced small bowel motility can cause bacterial overgrowth and resultant bloating, malabsorption, diarrhoea and malnutrition
• Reduced gut motility may cause constipation and pseudo-obstruction

Respiratory complications

• Pulmonary fibrosis is clinically significant in a third of patients, and can lead to chronic dyspnoea and recurrent lower respiratory tract infection
• Pulmonary arterial hypertension is a leading cause of death in systemic sclerosis
• Aspiration pneumonia if reflux is severe
• Respiratory muscle weakness if there is severe myositis
• Pneumothorax

Cardiac complications

• Left ventricular systolic and diastolic dysfunction
• Pericarditis, sometimes with effusion
• Arrythmias
• Endocarditis

Scleroderma renal crisis

• Acute renal failure with severe hypertension, oliguria, oedema, proteinuria
• Associated with a poor prognosis
• Associated with anti-RNA polymerase III antibodies

There is also an increased rate of malignancy in patients with systemic sclerosis - particularly lung cancer, breast cancer and haematological malignancy.

Up to 50% of patients with systemic sclerosis also suffer with depression and 60% suffer with anxiety. Patients may also develop osteoporosis secondary to reduced blood flow and there appears to be an association with hypothyroidism.

Prognosis varies greatly dependent upon the pattern of organ involvement and severity of disease. Patients with limited systemic sclerosis may have a stable condition for many years, whereas diffuse disease can rapidly be fatal if it is left untreated.

• The most common cause of death used to be kidney disease but it is now thought to be pulmonary arterial hypertension, which causes 12% of deaths in patients with systemic sclerosis. Older patients with late onset disease are twice as likely to suffer from pulmonary hypertension, and hence have a higher mortality.
• Overall, five year survival is around 75% and ten year survival 62.5%.
  • This is consistent with the suggestion that some patients will have a remission in symptoms after a few years of severe disease.
• Cigarette smoking reduces overall survival.
• Following renal crisis, prognosis is generally poor, with around 70% one year survival and only 50% five year survival.

In a multicenter French cohort study, a number of poor prognosticators were identified

• Age over 60 years at diagnosis
• Diffuse cutaneous disease
• Scleroderma renal crisis (70% one year survival, 50% five year survival)
• <6-minute walking distance (due to dyspnoea)
• Forced vital capacity less than 70%
• Pulmonary arterial hypertension
• Valvular disease
• Malignancy
• Anaemia