Scleroderma

Scleroderma, primarily affecting middle-aged females, is a chronic connective tissue disease marked histologically by skin and visceral fibrosis and radiologically lower lobe pulmonary fibrosis and a patulous oesophagus.

Description

Scleroderma, or systemic sclerosis, is a heterogeneous connective tissue disorder characterised by alterations in the microvasculature, disturbances in the immune system, and excessive fibrosis in the skin and internal organs. The condition, more common in females, typically presents between 30-50 years of age and is the leading cause of major morbidity due to pulmonary arterial hypertension and interstitial lung disease.

Pathogenesis

The pathogenesis of scleroderma is complex, involving vascular damage, immune system activation, and connective tissue fibrosis. Key factors include a genetic predisposition, exposure to environmental triggers, and immune dysregulation, leading to inflammation and excessive collagen production. The resultant fibrosis affects the skin and various internal organs, causing their dysfunction.

The oesophagus is the most commonly affected location in the gastrointestinal tract, with the disease causing smooth muscle atrophy. This leads to diminished then absent peristalsis in the lower two-thirds, while the upper third, composed of skeletal muscle, remains unaffected. Such changes result in esophageal dysmotility, contributing to reflux and dysphagia, and may compromise the lower esophageal sphincter, exacerbating reflux-related complications.

The oesophagus is the most commonly involved location of the gastrointestinal tract. Smooth muscle atrophy causes hypoperistalsis and eventually aperistalsis in the lower two-thirds of the oesophagus. The upper third of the oesophagus contains skeletal muscle and is therefore unaffected.

Subtypes

Scleroderma has two primary subtypes:

1. Localised Scleroderma: Affects only the skin and underlying tissues, without systemic involvement. This is less common and typically less severe.
2. Systemic Sclerosis (SSc): Affects the skin and various internal organs, further divided into:
   • Limited cutaneous systemic sclerosis (lcSSc): Skin involvement is limited to the hands, arms, and face.
   • Diffuse cutaneous systemic sclerosis (dcSSc): Widespread skin involvement, including the torso and proximal extremities.

Epidemiology, Risk Factors & Associations

• Female sex (2-4 times more common than in males)
• Age between 30 and 50 years
• Certain occupational and environmental exposures, such as silica dust and organic solvents
• Association with other autoimmune and inflammatory conditions; CREST syndrome, systemic lupus erythematosus, polymyositis, dermatomyositis.

Clinical Features

Scleroderma typically manifests with Raynaud’s phenomenon, followed by progressive skin thickening and tightening. Other features include gastroesophageal reflux disease (GORD), pulmonary arterial hypertension, interstitial lung disease, and sclerodactyly.

The CREST syndrome (Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) is particularly associated with lcSSc.

Gastrointestinal Manifestations

Scleroderma frequently involves the gastrointestinal tract, with up to 90% of patients experiencing related symptoms. The entire gastrointestinal tract, from the mouth to the anus, can be affected.

• Oral: Microstomia (small mouth opening due to fibrosis), dental decay (due to dryness from secondary Sjogren’s syndrome), and dysphagia.
• Oesophagus: Dysphagia and gastroesophageal reflux disease (GORD) are common due to decreased oesophageal motility and lower oesophageal sphincter tone. Severe cases can lead to a condition known as scleroderma oesophagus (a dilated, poorly functioning oesophagus).
• Stomach: Gastroparesis (delayed gastric emptying) can cause bloating, early satiety, nausea, and vomiting. Gastric antral vascular ectasia (GAVE), also known as watermelon stomach, can cause chronic gastrointestinal blood loss and anaemia.
• Small intestine: Dysmotility of the small intestine may lead to bacterial overgrowth, malabsorption, and malnutrition. This can present with diarrhoea, bloating, and weight loss. Pseudo-obstruction may occur in severe cases.
• Large intestine: Decreased motility can lead to constipation. In severe cases, it can lead to pseudo-obstruction or even toxic megacolon. There’s an increased risk of diverticulum formation, which can lead to diverticulitis.
• Anorectal: Anal sphincter weakness can lead to faecal incontinence. Prolonged disease can lead to rectal prolapse due to chronic straining and weakened supporting structures.

Complications

Scleroderma is associated with significant morbidity, predominantly from pulmonary arterial hypertension, interstitial lung disease, and renal crisis.

Pathological Features

Histopathology

• Macroscopic: The skin appears tight, shiny, and sometimes pigmented due to melanin deposition.
• Microscopic: Dermal fibrosis with loss of adnexal structures, collagen bundle thickening, and perivascular lymphocytic infiltrates.

Serology

Presence of specific autoantibodies like anti-Scl-70 and anti-centromere antibodies which rarely coexist in the same patient, and their presence is indicative of the different disease subtypes.

• Anti-Scl-70 (anti-topoisomerase I) antibodies: These are present in about 20-40% of patients with systemic sclerosis, particularly those with diffuse cutaneous disease. These antibodies are highly specific (near 100%), but less sensitive (20-40%).
• Anti-centromere antibodies: These are present in about 20-30% of patients with systemic sclerosis, particularly those with limited cutaneous disease. Anti-centromere antibodies have a high specificity (around 98%) and a sensitivity of 20-30%.

Biochemistry

• Increased markers of collagen turnover.

Biochemistry

Biochemical tests may demonstrate elevated levels of markers indicative of increased collagen turnover. For example, increased levels of the propeptides of type I and III procollagen can be seen in active disease. This is a reflection of the ongoing fibrotic process.

Radiological Features

General Features

• Characteristically demonstrates skin and subcutaneous tissue thickening and calcifications, particularly in the hands.
• Markedly dilated, atonic small bowel with thin, crowded circular folds and delayed barium transit time
• Pulmonary fibrosis, commonly in the lower lobes, with honeycombing and traction bronchiectasis.

CT

Non-contrast/HRCT

• Lungs: Interstitial lung disease is evident as reticulation, ground-glass opacities, honeycombing, and traction bronchiectasis. These features are typically worse in the lung bases and peripheral lung fields.
• Gastrointestinal tract:
  • May demonstrate mural thickening and luminal narrowing, particularly in the oesophagus, which could suggest reflux disease.
  • De
  • May demonstrate a markedly dilated 2nd portion of the duodenum which narrows abruptly as it crosses the midline (similar appearance to SMA syndrome)
  • May demonstrate a hidebound appearance of the duodenal and jejunal transverse folds – thin, rigid, closely-spaced and unchanging
• Heart: Pericardial effusion or fibrosis may be detected in some patients.
• Skin: Shows skin thickening, subcutaneous tissue fibrosis, and calcifications.

C+ Arterial & Venous: May demonstrate pulmonary artery enlargement in pulmonary arterial hypertension, as well as possible right heart enlargement.

• Oesophagus: Dilation of the oesophagus with a thinned wall can be observed due to loss of peristalsis. This is usually a late feature and is often associated with gastro-oesophageal reflux disease.
• Small and large bowel: Mural thickening, luminal dilation, or malabsorption can be identified in later stages due to smooth muscle atrophy and fibrosis.

XR

• May reveal features of interstitial lung disease such as reticular opacities, predominantly in the lung bases.
• Pulmonary arterial hypertension might be suggested by enlargement of the pulmonary arteries and right heart border.
• Oesophageal dilation might be seen as an air-filled structure in the mediastinum due to oesophageal dysmotility, a common complication of scleroderma.

FL

• Oesophagus:
  • There could be diffuse oesophageal dilation and dysmotility.
  • The lower oesophageal sphincter may appear relaxed, and the oesophageal wall may thin out due to atrophy and fibrosis. This can cause the oesophagus to appear dilated and featureless (rubber-hose oesophagus) on barium swallow studies.
• Small bowel: Hidebound bowel sign – narrow separation between the valvulae conniventes, which demonstrate normal fold thickness, with mild bowel dilatation
• Prolonged transit time with barium retention in duodenum and small bowel up to 24 hours

Grading and Staging

Scleroderma severity is typically graded by the extent of skin involvement (Rodnan skin score) and the degree of internal organ involvement.

Diagnosis

The diagnosis is primarily clinical, supported by serology and skin biopsy.

Differential Diagnosis

• Usual Interstitial Pneumonia (UIP)/Idiopathic Pulmonary Fibrosis (IPF): Typically shows subpleural and basilar predominant reticulation, honeycombing, and traction bronchiectasis. The absence of extrapulmonary manifestations and a clinical history devoid of rheumatologic symptoms can help distinguish UIP/IPF from scleroderma.
• Rheumatoid Arthritis (RA): Pulmonary involvement in RA can present as lower lobe fibrosis, similar to scleroderma. The presence of rheumatoid nodules, pleural effusions, and associated joint changes on imaging would favour RA. Serology showing rheumatoid factor and anti-CCP antibodies would further support the diagnosis.
• Systemic Lupus Erythematosus (SLE): Although more commonly associated with pleural disease, SLE can cause fibrosis that could be mistaken for scleroderma. Other associated findings like pleural effusions, lymphadenopathy, and serositis, along with positive ANA and anti-dsDNA antibodies, can aid in differentiating SLE from scleroderma.
• Asbestosis: A history of asbestos exposure and the presence of pleural plaques or diffuse pleural thickening on imaging could suggest asbestosis. Asbestosis-related fibrosis is also predominantly lower lobe and subpleural, similar to scleroderma.
• Drug Toxicity: Certain drugs, like amiodarone, bleomycin, and methotrexate, can induce pulmonary fibrosis. A careful medication history is crucial in these cases. While imaging findings can be nonspecific, a temporal relationship with the initiation of the offending drug can provide a diagnostic clue.

Prognosis

The prognosis of scleroderma is variable and largely depends on the extent of organ involvement. The 10-year survival rate is around 66%.

Management

Management is mainly symptomatic and involves multidisciplinary care. This includes immunosuppressive therapy, treatment of Raynaud’s phenomenon, skin care, and monitoring for complications.