Scleroderma/systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease that affects multiple systems of the body. It is characterised by fibrosis of multiple organs, blood vessels and connective tissues. The term scleroderma is sometimes used interchangeably with SSc, but, strictly speaking, the term scleroderma refers to hardening and tightening of the skin as a result of excessive collagen deposition. It is an umbrella term that places emphasis on the skin involvement of the disease.

Scleroderma may be localised, as seen in the condition called morphoea (which is also known as localised scleroderma) or in linear scleroderma (affecting a line of skin on the limbs or face typically). However, it does not include internal organ involvement. SSc is a subtype of scleroderma that includes internal organ involvement (along with the dermatological features of course).

It affects women much more than men with a ratio of 5:1. It is more common in adulthood, most commonly in their 50s.

🔢 Classification

There are 2 main types of SSc. The way they are classified is dependent on the extent of dermatological involvement:

1. Limited cutaneous systemic sclerosis (LCSSc) - this is the more common form of SSc. It affects the skin of the face and distal limbs (forearms and lower limbs up until the knee). The autoantibodies associated are anti-centromere antibodies. It was previously known as CREST syndrome. The term CREST refers to the features present in LCSSc:
1. Calcinosis
2. Raynaud’s phenomenon - it is often the first sign of the disease.
3. Esophageal dysmotility
4. Sclerodactyly
5. Telangiectasia
2. Diffuse cutaneous systemic sclerosis (DCSSc) - this is the less common form of SSc. It involves more regions of the skin such as the proximal limbs and trunk as well. It has a poorer prognosis and is associated with a higher mortality rate. It has respiratory involvement in the form of insterstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). The autoantibodies associated are anti-Scl-70 antibodies.

Other, rarer forms of SSc include:

3. Overlap systemic sclerosis - this is when there is SSc with overlapping features of other autoimmune connective tissue diseases such as rheumatoid arthritis, SLE, myositis, Sjögren’s syndrome.
4. Sine scleroderma - this is when there is an absence of skin thickening (which is the hallmark feature of scleroderma) but there is still internal organ involvement.

⚠️ Risk factors

• Family history
• Antinuclear antibody (ANA) positivity
• Anti-centromere antibody positive
• Anti-RNA polymerase III antibody positive
• Anti-Scl-70 antibody positive
• Female sex

Pathophysiology

The aetiology and pathophysiology of SSc is yet to be fully understood. It seems to be an interplay of genetic, environmental, immunological and infectious factors.

• Genetic factors - a genetic predisposition has been suggested with prevalence increasing in first-degree relatives. HLA association as well as certain genes have been identified as potential links.
• Immunological factors - the strongest link is ANA positivity, with around 90% of patients being positive. The aforementioned ANA subtypes have been identified as links. However they are associated with different patterns of disease:
• Anti-centromere antibody - associated with limited skin involvement and a better prognosis.
• Anti-RNA polymerase III antibody - associated with kidney failure.
• Anti-Scl-70 antibody - associated with diffuse skin involvement and interstitial lung disease.
• Environmental factors - certain chemicals, drugs, radiotherapy, and vitamin deficiency have been associated with increased risk.

The 3 main components of SSc’s pathophysiology include:

1. Vascular damage
2. Fibrosis
3. Cell mediated and autoantibody autoimmunity

Immune activation, fibroblast activation and endothelial cell damage all occur. The fibroblasts produce an excess of collagen and the fibroblasts themselves over-proliferate. The immune activation results in cytokines being released (such as TGF-beta, IL-1, IL-4 and IL-6) that only perpetuate the cycle further. There is also a down-regulation of cytokines that inhibit such processes.

😷 Presentation

We will take a look at LCSSc and then DCSSc separately. The main difference between the two is the extent of cutaneous involvement. However, this does not always reflect the extent of internal organ involvement.

Often the presenting symptom across all forms:

• Secondary Raynaud’s phenomenon - this is where the fingertips change in response to mild cold triggers. The pattern is typically that the fingers change from white → blue → red. It corresponds with the following physiological changes that occur, which are vasoconstriction → cyanosis → hyperaemia. Primary Raynaud’s differs by having no associated systemic disease (idiopathic).

In SSc there are changes seen on nailfold capillaroscopy that indicate secondary Raynaud’s phenomenon as opposed to primary Raynaud’s disease:

1. Abnormal capillaries
2. Avascular areas
3. Micro-haemorrhages
4. Ischaemic ulcerations
• Skin hardening/thickening
• Oesophageal dysmotility

Other general features of the disease include: fatigue and weight loss.

😷

Limited cutaneous systemic sclerosis (LCSSc):

As the name implies, there may be less skin involvement with the distal limbs predominantly affected. It typically has a slower onset as compared to DCSSc.

It was previously referred to as CREST syndrome as a mnemonic for the features present:

• Calcinosis - calcium deposits found predominantly at the fingertips.
• Raynaud’s phenomenon - as described above.
• Esophageal dysmotility - it is in fact heartburn and dysphagia that are the most common symptoms described. This is due to dysmotility and incompetence of the lowere oesophageal sphincter. It occurs due to atrophy and smooth muscle dysfunction.
• Sclerodactyly - this is when the skin of the fingers becomes thickened. The skin becomes tightened around the joints and begins to contract, thus reducing range of motion and reducing function of the hands.
• Telangiectasia - dilation of blood vessels <1mm in diameter. It most commonly occurs on the hands, face, palms and mucous membranes. It can also occur in the antrum of the stomach, leading to watermelon stomach (gastric natural vascular ectasia) which may result in chronic GI bleeding and anaemia.

Let’s now take a look at some of the system specific features of SSc:

• Skin features
• Raynaud’s phenomenon
• Swelling of the fingers and toes
• Thickening and hardening of skin
• Pitting of the digits
• Digital ulceration
• Calcinosis
• Tightening of the skin - especially of the lips and face
• Telangiectasia
• Hypopoigmentation and hyperpigmentation - leading to salt and pepper appearance.
• Dry skin
• Musculoskeletal features
• Arthritis
• Myalgia
• Restriction of joints and contractures
• Tendon friction rub
• Gastrointestinal features
• Heartburn
• Reflux oesophagitis
• Watermelon stomach
• Delayed gastric emptying and reduced motility (leading to constipation)
• Faecal incontinence or rectal prolapse
• Pulmonary features
• Interstitial lung disease (pulmonary fibrosis) - which presents with dyspnoea (especially on exertion), coarse crackles, cough.
• Pulmonary arterial hypertension - which presents with dyspnoea, syncope, and signs of right cardiac failure.
• Cardiac features
• Myocardial fibrosis
• Microvascular coronary artery disease
• Accelerated atherosclerosis and coronary artery disease
• Renal features
• ANCA-associated glomerulonephritis
• Scleroderma renal crisis
• Genitourinary features
• Erectile dysfunction - occurs in most men with the disease.

🔍 Investigations and criteria

The American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) outlined a criteria which helps in diagnosing the disease. A score of 9 or more equates to a diagnosis of SSc:

1. Skin thickening extending proximal to the MCP joints - 9 points.
2. Sclerodactyly - 4 points.
3. Fingertip pitting scars - 3 points.
4. Raynaud’s phenomenon - 3 points.
5. SSc-related antibody positive - 3 points.
6. Skin thickening of fingers - 2 points.
7. Ulcerated fingertips - 2 points.
8. Telangiectasia - 2 points.
9. Abnormal nailfold capillaries - 2 points.
10. Pulmonary arterial hypertension/interstitial lung disease - 2 points.

What investigations can aid the criteria scoring?

• Serum ANA autoantibodies
• Anti-centromere antibody positive
• Anti-RNA polymerase III antibody positive
• Anti-Scl-70 antibody positive
• High-resolution CT chest - to assess for ILD (ground glass opacities and interstitial fibrosis)
• Barium swallow - to assess for oesophageal dysmotility.
• Echocardiogram - to assess for right ventricular systolic dysfunction as a result of pulmonary arterial hypertension.
• Pulmonary function tests
• Nailfold capillaroscopy

🧰 Management

There is no definitive management for SSc. As the disease has a lot of heterogeneity in its course and presentation, it is difficult to treat the disease. Regular monitoring and reviews

🚨 Complications

• Depression
• Malignancy - SSc has shown to increase risk of lung cancer, breast cancer and haematological cancers as well. Reflux oesophagitis increases the risk of Barrett’s oesophagus and subsequent oesohpageal cancer.
• Osteomyelitis - associated with skin ulcers.
• Hashimoto’s thyroiditis - linked with the disease.
• Malabsorption
• Cardiac arrhythmias