11/14/24, 10\:42 AM Systemic Sclerosis

Systemic Sclerosis

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Systemic sclerosis (SSc)\: autoimmune disorder of connective tissue; characterised by increased
changes; a
Types\:
Limited cutaneous SSc (lcSSc)\: skin involvement below elbows and knees, face; less internal organ involvement.
Di
Aetiology\: unknown; involves activation of
remodelling.
Risk factors\: genetic (family history, HLA complex variations), environmental (chemical exposure, drugs, infections),
overlaps with other autoimmune conditions.
Clinical features\:
lcSSc\: calcinosis, Raynaud’s phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (CREST syndrome);
severe Raynaud’s, mucocutaneous telangiectasia, pulmonary arterial hypertension.
dcSSc\: rapid onset; skin involvement, internal organ involvement (pulmonary
Investigations\:
Bedside\: blood pressure, ECG, urinalysis.
Laboratory\: ANA, anti-centromere antibodies, anti-Scl 70 antibodies, anti-RNA polymerase III antibodies, FBC, U&Es.
Imaging\: echocardiogram, HRCT, pulmonary function tests, X-rays of the hand.
Other\: endoscopy or barium swallow for dysphagia, further tests for suspected overlap with other conditions.
Diagnosis\: ACR/EULAR criteria; score of 9 required for diagnosis; criteria include skin tightening, sclerodactyly,
scars, Raynaud’s, speci
interstitial lung disease/pulmonary arterial hypertension.
Management\: no cure; symptom alleviation and prevention of deterioration.
Non-pharmacological\: patient education, smoking cessation, physiotherapy, occupational therapy, emollients for dry skin.
Pharmacological\:
Raynaud’s\: vasodilators (calcium channel blockers, phosphodiesterase inhibitors), prostacyclin analogues, endothelin
receptor antagonists.
Systemic agents\: methotrexate, cyclophosphamide, mycophenolate mofetil, biologics (rituximab).
Others\: proton pump inhibitors for re
ulcers.
Complications\:
Pulmonary\: pulmonary artery hypertension, interstitial lung disease.
Gastrointestinal\: oesophageal dysmotility, oesophagitis, Barrett’s oesophagus, strictures, gastroparesis, bleeding from
stomach telangiectasis, bowel motion changes.
Renal\: scleroderma renal crisis.
Cardiac\: arrhythmias, heart failure, pericarditis, endocarditis, pericardial e
Prognosis\: annual screening for pulmonary function tests, urinalysis, ECG, and echocardiogram to diagnose organ
involvement early and prevent complications.
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Introduction

Systemic sclerosis (SSc) is an autoimmune disorder of the connective tissue, characterised by increased
vascular changes. It commonly a
thickened), but can also a
SSc is a relatively rare disorder, a
women are more frequently a
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. Di
(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 a
skin.
This article will focus on systemic sclerosis (SSc) and will cover its e
with SSc cannot readily be classi

Aetiology

The exact cause of SSc is unknown. It is believed that activation of
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 di
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
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R - Raynaud’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
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
phase) may last for several months before sclerosis of the skin.
1,2
Figure 1. Digital calcinosis.
6
Figure 2. Raynaud’s phenomenon (white discolouration).
7
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Figure 3. Sclerodactyly of the
8

Di

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
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)
Pu
Oesophageal re
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
Shiny or discoloured skin on the hands sometimes with no skin folds
Thickened skin
Calcinosis (Figure 1)
Ulcers on the
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
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Di

Important di
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 di
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 su
crisis. A sudden rise in blood pressure or worsening of baseline hypertension can be the
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
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
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
Pulmonary function tests
X-rays of the hand\: may assess calcinosis (also helpful to exclude osteomyelitis if there is

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 speci
European League Against Rheumatism (ACR/EULAR) is designed to aid clinicians in making a
early disease (Table 1).
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Compared to previous classi
The speci
diagnosis of SSc.
11
Table 1. A table showing the ACR/EULAR criteria for diagnosis of systemic sclerosis
11
Criteria Score
Bilateral skin tightening close to
metacarpophalangeal joints
9
Sclerodactyly 4
Fingertip pitting scars 3
Raynaud’s 3
Presence of speci
Pu
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 sildena
receptor antagonists can be used to promote blood
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
in
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
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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-in
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/re
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 a
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 aInterstitial lung disease (pulmonary
dcSSC (50-80%). It presents as bibasilar pulmonary
These two conditions are the leading cause of death in people with SSc.
2,12

Gastrointestinal complications

Oesophageal dysmotility due to
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 e
1,2

References

Saracino A, Denton C, Oakley A. Systemic Sclerosis. Published in 2018 (updated in 2020). Available from\: [LINK]
Harding M, Cox J. Systemic Sclerosis. Published in 2016. Available from\: [LINK]
Scleroderma and Raynaud’s UK. Scleroderma. Published in 2021. Available from\: [LINK]
National Institute of Health. Systemic Scleroderma. Published in 2018. Available from\: [LINK]
Hughes M, Herrick AL. Systemic sclerosis. Published in 2019. Available from [LINK]
Heilman J. Calcinosis. Licence\: [CC BY-SA]. Available from\: [LINK]
Fletcher W. Raynaud’s phenomenon of right hand. Licence\: [CC BY-SA]. Available from\: [LINK]
Heilman J. Sclerodactyly. Licence\: [CC BY-SA]. Available from\: [LINK]
Adigun R et al. Systemic Sclerosis. Published in 2020. Available from\: [LINK]
Scherlinger M et al. Systemic sclerosis overlap and non-overlap syndromes share clinical characteristics but di
prognosis and treatments. Published in 2020. Available from\: [LINK]
https\://app.geekymedics.com/notebook/2679/ 7/811/14/24, 10\:42 AM Systemic Sclerosis
Van de Hoogan F et al. ClassiLINK]
Bellando-Randone S, Matucci-Cerinic M. Very early systemic sclerosis. Published in 2019. Available from\: [LINK]
Scleroderma and Raynaud’s UK. What causes Raynaud’s. Published in 2021. Available from\: [LINK]

Reviewer

Dr Claire Benson
Consultant Rheumatologist

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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
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