Systemic Sclerosis

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Introduction

Systemic sclerosis (SSc) is an autoimmune disorder of the connective tissue, characterised by increased fibrosis and vascular changes. It commonly affects the skin (this is known as scleroderma, where the skin becomes hard and thickened), but can also affect the gastrointestinal, cardiac, respiratory, and renal systems.

SSc is a relatively rare disorder, affecting around 2.5 million people worldwide. As with many autoimmune disorders, women are more frequently affected than men, and the peak age of onset is between 35 and 55 years.1-3

There are two main types of SSc:2

  1. Limited cutaneous SSc (lcSSc): this is the most common type, involving the skin of the face and the skin below the elbows and knees (i.e. the hands and feet)
  2. Diffuse cutaneous SSc (dcSSc): skin changes are found in the same areas as in lcSSc, but also on the proximal limbs (upper arms and thighs) and the trunk. Patients with dcSSc have higher rates of internal organ involvement and subsequent mortality.

These forms of SSc should be distinguished from localised scleroderma (also known as morphoea) which only affects the skin.

This article will focus on systemic sclerosis (SSc) and will cover its effects on the skin and internal organs. Many patients with SSc cannot readily be classified into lcSSc or dcSSc.

You might also be interested in our medical flashcard collection which contains over 1000 flashcards that cover key medical topics.

Aetiology

The exact cause of SSc is unknown. It is believed that activation of fibroblasts after injury to endothelial cells lining the blood vessels results in excess collagen being produced and deposited within the skin and other organs. Additionally, there is widespread angiopathy and remodelling of blood vessels.4


Risk factors

SSc is suspected to be linked to both genetic and environmental factors. It can also overlap with other autoimmune conditions 2-5

Genetic factors

People with a family history of SSc have a higher risk of developing this condition. Certain gene variations involving the human leukocyte antigen (HLA) complex may also be involved.

Environmental factors

Exposure to chemicals, drugs and even some infectious diseases have been implicated.

Other associations

There may be a correlation between SSc and other autoimmune conditions involving the musculoskeletal system, as 20% of SSc cases overlap with systemic lupus erythematosus, myositis, Sjögren’s syndrome or rheumatoid arthritis.1,2


Clinical features

Limited cutaneous systemic sclerosis

Limited cutaneous systemic sclerosis was previously known as CREST syndrome due to its 5 cardinal features (see below).2,5 However, the acronym CREST is no longer used to distinguish limited SSc from the diffuse form, as these signs are also commonly seen in dcSSc.

It is featured here as the acronym can be a useful aide-memoire in remembering some of the key features of SSc:

  • C – Calcinosis: deposits of calcium in soft tissue – Figure 1
  • RRaynaud’s: characterised by colour change of the hands, initially white (ischaemic change), then purple (deoxygenated blood) then pink (reperfusion) – Figure 2
  • E – (o)Esophageal dysmotility: presents as dysphagia most often but there are other oesophageal symptoms
  • S Sclerodactyly: thickening and tightness of the skin of the fingers – Figure 3
  • T Telangiectasia: red spots around the mouth, nose and sometimes the palms, due to dilated capillaries

Patients with lcSSc generally have prominent vascular manifestations, which include the severe Raynaud’s phenomenon and mucocutaneous telangiectasia mentioned above. It has a slowly progressive course and can be followed by a later onset of pulmonary arterial hypertension (PAH).5

In lcSSC, Raynaud’s phenomenon usually precedes any other symptoms by years and even decades. Patients may complain of cold hands and/or feet and describe skin changing colour. In addition, swelling of the fingers (puffy fingers phase) may last for several months before sclerosis of the skin.1,2

Diffuse cutaneous systemic sclerosis

This has a rapid onset and Raynaud’s phenomenon can occur at the same time or after skin involvement. Internal organs are more likely to be involved, especially the lungs (pulmonary fibrosis) and kidneys (scleroderma renal crisis).2

History

For both lcSSc and dcSSc, typical symptoms include:

  • Tight, dry or itchy skin on the hands, feet, face or trunk
  • Fingers changing colour (Raynaud’s)
  • Puffy fingers
  • Oesophageal reflux or difficulty swallowing

If internal organs are involved, shortness of breath or palpitations may be the presenting complaint and so clinicians should enquire about symptoms linked to cardiovascular and respiratory systems 5,9

As some cases may overlap with other musculoskeletal disorders and connective tissue diseases it is important to take a comprehensive rheumatological history.10

Clinical examination

There is extensive individual variability in disease presentation.

A close inspection of the skin is required. Typical findings may include:

  • Shiny or discoloured skin on the hands sometimes with no skin folds
  • Thickened skin
  • Calcinosis (Figure 1)
  • Ulcers on the fingers
  • Telangiectasia on the face, hands or mucosal surfaces
  • Microstomia: a small mouth
  • Joint contractures
  • Depigmentation or hyperpigmentation of skin (salt-and-pepper skin)2,5

Nailfold capillaroscopy is sometimes performed in patients presenting with Raynaud’s to distinguish between primary and secondary Raynaud’s phenomenon. It inspects the capillaries close to the nail fold which normally have a ‘hair-pin’ like appearance. People with SSc have dilated capillary loops, micro-haemorrhages or avascular areas, associated with a worse prognosis.5


Differential diagnoses

Important differential diagnoses for systemic sclerosis include:

  • Localised scleroderma: patches of thickened skin, but not involving internal organs. Raynaud’s phenomenon is not associated with it.
  • Primary Raynaud’s: some patients may present with Raynaud’s but have no underlying disease causing it. Nailfold capillaroscopy is helpful in differentiating primary from secondary.
  • Secondary Raynaud’s: additional autoimmune conditions that can cause Raynaud’s are rheumatoid arthritis, Sjogren’s and systemic lupus erythematosus. Consider these possibilities especially when the patient presents with general symptoms such as joint pain and fatigue. The aforementioned conditions can also present concomitantly with SSc.1,12,13

Investigations

Bedside investigations

Relevant bedside investigations include:

  • Blood pressure: this should be measured as people with a recent diagnosis of dcSSc may suffer a scleroderma renal crisis. A sudden rise in blood pressure or worsening of baseline hypertension can be the first signs of this condition.
  • ECG: to check for any cardiac involvement (for example arrhythmias). Right ventricular hypertrophy may suggest pulmonary artery hypertension
  • Urinalysis: to look for evidence of proteinuria or haematuria in renal disease

Laboratory investigations

Diagnosis of SSc is based on clinical findings and specific autoantibodies:9

  • Antinuclear antibodies (ANA): these are positive in over 95% of patients with SSc but are also raised in other conditions
  • Anti-centromere antibodies: these are more likely to be positive in lcSSc
  • Anti-Scl 70 antibodies (Anti-topoisomerase I): linked to an increased risk of lung fibrosis. These are more likely to be positive in dcSSc
  • Anti-RNA polymerase III antibodies: these are associated with rapidly progressive skin disease and scleroderma renal crisis.  These are more likely to be positive in dcSSc.

Other relevant laboratory investigations include:

  • Full blood count (FBC): looking for signs of anaemia (gastrointestinal bleeding may occur)
  • Urea and electrolytes (U&Es): to check renal function

Imaging

Relevant imaging investigations include:1,9

  • Echocardiogram: may be performed if there are any cardiovascular or respiratory symptoms
  • High-resolution CT scan (HRCT): lung fibrosis may be visible
  • Pulmonary function tests
  • X-rays of the hand: may assess calcinosis (also helpful to exclude osteomyelitis if there is finger ulceration)

Other investigations

Depending on the patient’s symptoms, endoscopy or barium swallow (for dysphagia) may be performed, followed by oesophageal manometry.

If overlap with other connective tissue diseases is suspected, further investigations are warranted (e.g. measurement of creatinine kinase if myositis is suspected).9


Diagnosis

There are no specific diagnostic criteria, but the classification proposed by the American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) is designed to aid clinicians in making a final diagnosis and recognise early disease (Table 1).

Compared to previous classifications, the ACR/EULAR criteria includes vascular changes as well as skin manifestations. The specific features are outlined below, together with their allocated scores. A score of 9 is necessary to make a definite diagnosis of SSc.11

Table 1. A table showing the ACR/EULAR criteria for diagnosis of systemic sclerosis11

Criteria Score

Bilateral skin tightening close to metacarpophalangeal joints

9

Sclerodactyly

4

Fingertip pitting scars

3

Raynaud’s

3

Presence of specific antibodies

3

Puffy fingers

2

Digital ulcers

2

Telangiectasia

2

Abnormal nail fold capillaroscopy

2

Interstitial lung disease/pulmonary arterial hypertension

2

 


Management

There is currently no cure for SSc. Management is focused on alleviating symptoms and preventing further deterioration and organ involvement.

Non-pharmacological management

To aid with symptom control and avoid complications, non-pharmacological management of systemic sclerosis can include:2

  • Patient education: giving advice on how to avoid triggers for Raynaud’s phenomenon (for example, keeping hands warm by wearing gloves and warm clothes, use of hand warmers) and how to manage an episode (slowly warm up hands/feet and massage to promote circulation)
  • Encourage smoking cessation
  • Physiotherapy and exercise to prevent contractures
  • Occupational therapy if the function of hands or legs are impaired
  • Emollients for dry skin

Pharmacological management

Management of Raynaud’s 

Most of the time, Raynaud’s is treated conservatively. If severe episodes are recurrent, vasodilators (calcium channel blockers such as nifedipine or phosphodiesterase inhibitors such as sildenafil), prostacyclin analogues or endothelin receptor antagonists can be used to promote blood flow and prevent ulcers and ischaemia of the fingers.

Systemic agents

Systemic agents are used for the management of skin disease, as well as internal organ involvement:1,9

  • Methotrexate: this is a disease-modifying agent, which may help to improve skin disease and any associated inflammatory arthritis or myositis
  • Cyclophosphamide and mycophenolate mofetil: may be used for skin and lung disease
  • Biologics: such as rituximab may be used for patients with SSc refractory to other treatments

Usage of corticosteroids in high doses or long-term could precipitate a scleroderma renal crisis. They are still used in certain scenarios when rapid anti-inflammatory effects are required (e.g. flare-up of inflammatory arthritis, myositis or alveolitis).

Additional medications

Depending on the patients’ symptoms, other medications that may be considered include:1,2,5

  • Proton pump inhibitors: can be prescribed for patients with heartburn/reflux
  • Angiotensin-converting enzyme (ACE) inhibitors: are given to patients admitted with scleroderma renal crisis
  • Anti-arrhythmic agents: may be needed for the management of conduction problems of the heart due to sclerosis. If the person develops heart failure secondary to lung disease, this should be managed accordingly.
  • Antibiotics: if any ulcers are infected

Complications

As internal organs can be affected, there are a plethora of complications. In order to diagnose organ involvement early and to prevent these complications, patients are monitored closely in secondary care. Annual screening should include pulmonary function tests, urinalysis, ECG and echocardiogram.2,5

Pulmonary complications

Pulmonary artery hypertension (PAH), especially in patients with lcSSC. It occurs quite late after SSc onset (approx.10 years) but affects up to 30-50% of people. Interstitial lung disease (pulmonary fibrosis) is more common in patients with dcSSC (50-80%). It presents as bibasilar pulmonary fibrosis which can be asymptomatic in some.

These two conditions are the leading cause of death in people with SSc.2,12

Gastrointestinal complications

Oesophageal dysmotility due to fibrosis is common. In addition, oesophagitis, Barrett’s oesophagus and oesophageal strictures can develop. Gastroparesis may lead to nausea and early satiety and contributes to malnutrition and weight loss. Bleeding can occur from telangiectasis of the stomach (‘watermelon stomach’) and intestinal dysmotility can alter bowel motions.2

Renal complications

Scleroderma renal crisis is the most severe complication and is more common in patients with dcSSc.2

Cardiac complications

Besides arrhythmias and heart failure secondary to pulmonary arterial hypertension, other cardiovascular conditions that can occur include pericarditis, endocarditis and pericardial effusion.1,2


Key points

  • Systemic sclerosis is an autoimmune disease affecting collagen production in the body
  • It can be limited (skin changes below the elbows and knees) or diffuse (more involvement of internal organs and wider distribution of skin changes)
  • Common symptoms of systemic sclerosis are tightness and itchiness of the skin, Raynaud’s phenomenon and oesophageal symptoms
  • Typical examination findings include calcinosis, Raynaud’s, sclerodactyly and telangiectasia
  • Primary investigations include autoantibodies: antinuclear antibodies, anticentromere antibodies, anti-Scl-70 antibodies and anti RNA polymerase III antibodies
  • Management is mainly supportive, treating symptoms of organ involvement
  • The most important complications include interstitial lung disease, pulmonary arterial hypertension and scleroderma renal crisis

Reviewer

Dr Claire Benson

Consultant Rheumatologist


Editors

Dr Sherrie Samuels

Dr Chris Jefferies


References

  1. Saracino A, Denton C, Oakley A. Systemic Sclerosis. Published in 2018 (updated in 2020). Available from: [LINK]
  2. Harding M, Cox J. Systemic Sclerosis. Published in 2016. Available from: [LINK]
  3. Scleroderma and Raynaud’s UK. Scleroderma. Published in 2021. Available from: [LINK]
  4. National Institute of Health. Systemic Scleroderma. Published in 2018. Available from: [LINK]
  5. Hughes M, Herrick AL. Systemic sclerosis. Published in 2019. Available from [LINK]
  6. Heilman J. Calcinosis. Licence: [CC BY-SA]. Available from: [LINK]
  7. Fletcher W. Raynaud’s phenomenon of right hand. Licence: [CC BY-SA]. Available from: [LINK]
  8. Heilman J. Sclerodactyly. Licence: [CC BY-SA]. Available from: [LINK]
  9. Adigun R et al. Systemic Sclerosis. Published in 2020. Available from: [LINK]
  10. Scherlinger M et al. Systemic sclerosis overlap and non-overlap syndromes share clinical characteristics but differ in prognosis and treatments. Published in 2020. Available from: [LINK]
  11. Van de Hoogan F et al. Classification Criteria for Systemic Sclerosis. Published in 2013. Available from: [LINK]
  12. Bellando-Randone S, Matucci-Cerinic M. Very early systemic sclerosis. Published in 2019. Available from: [LINK]
  13. Scleroderma and Raynaud’s UK. What causes Raynaud’s. Published in 2021. Available from: [LINK]

 

 

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