Systemic Sclerosis

A chronic autoimmune connective tissue disease characterised by widespread microvascular injury, immune activation and progressive fibrosis of the skin and internal organs, with substantial heterogeneity in extent and severity that determines prognosis and management.

Classification

Limited cutaneous systemic sclerosis involves skin thickening distal to the elbows and knees (and face), with the CREST features (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) and a relatively slower disease course, though pulmonary arterial hypertension remains a significant risk over time.

Diffuse cutaneous systemic sclerosis involves skin thickening extending proximal to the elbows and knees and the trunk. Progression is more rapid.

Internal organ involvement is earlier and more severe, including interstitial lung disease and scleroderma renal crisis. The interval between Raynaud phenomenon onset and skin involvement is shorter.

Systemic sclerosis sine scleroderma describes internal organ involvement characteristic of the disease without clinically evident skin thickening.

Pathophysiology

Endothelial injury triggers a cascade of immune activation, fibroblast stimulation and excessive collagen deposition. This produces progressive fibrosis of skin and internal organs.

A distinct vasculopathy affects small vessels throughout the body. It underlies both the Raynaud phenomenon and the risk of pulmonary arterial hypertension and scleroderma renal crisis.

Raynaud phenomenon is almost universal and frequently the earliest manifestation, often preceding skin changes by years in limited disease.

Skin involvement progresses through an early oedematous phase to sclerotic thickening and, later, atrophy, with sclerodactyly, digital pitting scars and ulceration, facial changes (microstomia, reduced oral aperture, telangiectasia, beak shaped nose), and calcinosis (subcutaneous calcium deposits, particularly over pressure points).

Gastrointestinal involvement is near universal and often underrecognised: oesophageal dysmotility causing dysphagia and severe reflux, gastric antral vascular ectasia (watermelon stomach) causing occult or overt bleeding, small intestinal dysmotility with bacterial overgrowth and malabsorption, and colonic involvement with constipation or, less commonly, wide mouthed diverticula.

Pulmonary involvement is the leading cause of death. It comprises two distinct processes requiring different surveillance and treatment.

• Interstitial lung disease is more common in diffuse disease, and presents with progressive dyspnoea and dry cough.
• Pulmonary arterial hypertension is more common in limited disease. It develops insidiously and requires active screening even in asymptomatic patients.

Cardiac involvement includes myocardial fibrosis, conduction abnormalities and pericardial disease.

Scleroderma renal crisis is a medical emergency. It presents with abrupt onset severe hypertension, rapidly progressive renal failure and microangiopathic haemolytic anaemia.

It occurs predominantly in early diffuse disease (typically within the first four years). It was historically associated with high mortality before the advent of angiotensin converting enzyme inhibitor treatment.

Musculoskeletal involvement includes arthralgia, tendon friction rubs (a specific finding in diffuse disease) and, occasionally, overlapping myositis.

Diagnosis is predominantly clinical, supported by classification criteria weighting skin thickening extent, Raynaud phenomenon, characteristic nailfold capillary changes, specific autoantibodies, digital ulceration or pitting scars, telangiectasia, pulmonary involvement and calcinosis.

• Anti centromere antibody is associated with limited disease and a higher risk of pulmonary arterial hypertension.
• Anti topoisomerase I (anti Scl 70) is associated with diffuse disease and interstitial lung disease.
• Anti RNA polymerase III is associated with diffuse skin involvement and a markedly increased risk of scleroderma renal crisis, so early identification of this antibody is clinically important.

Nailfold capillaroscopy shows characteristic capillary dilation, dropout and disorganisation, useful both diagnostically and for early identification before overt skin or organ involvement.

Baseline and regular surveillance pulmonary function testing (including diffusing capacity) and high resolution computed tomography of the chest screen for interstitial lung disease, with a fall in diffusing capacity disproportionate to lung volumes raising suspicion for evolving pulmonary arterial hypertension.

Annual echocardiography with estimated pulmonary artery pressure, alongside brain natriuretic peptide, forms part of routine screening for pulmonary arterial hypertension, with right heart catheterisation for definitive diagnosis where screening is abnormal.

Renal function and blood pressure monitoring, particularly closely in early diffuse disease and in anti RNA polymerase III positive patients, given scleroderma renal crisis risk.

Barium swallow, oesophageal manometry or endoscopy as indicated for gastrointestinal symptoms.

There is no disease modifying therapy that reverses established fibrosis, so management centres on organ specific treatment and, increasingly, immunosuppression to slow progression in early diffuse disease.

Raynaud phenomenon and digital ulceration are managed with calcium channel blockers, phosphodiesterase 5 inhibitors, endothelin receptor antagonists and intravenous prostacyclin analogues used according to severity.

Skin and early diffuse disease may benefit from immunosuppression with methotrexate, mycophenolate mofetil, or in more severe or progressive cases, cyclophosphamide or autologous haematopoietic stem cell transplantation in carefully selected patients.

Interstitial lung disease is treated with mycophenolate mofetil or cyclophosphamide as first line immunosuppression, with nintedanib (an antifibrotic) approved for progressive fibrosing disease, and tocilizumab showing benefit in preventing lung function decline in early diffuse disease with elevated inflammatory markers.

Pulmonary arterial hypertension is managed with pulmonary vasodilator therapy (endothelin receptor antagonists, phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin pathway agents) under specialist pulmonary hypertension service direction, often in combination regimens.

Gastro-oesophageal reflux is managed aggressively with high dose proton pump inhibitors given the severity typical in this disease, with prokinetics for dysmotility and antibiotics for small intestinal bacterial overgrowth.

Scleroderma renal crisis is a medical emergency requiring immediate initiation of an angiotensin converting enzyme inhibitor regardless of renal function, titrated aggressively to control blood pressure, with dialysis support as needed, since prompt treatment has transformed what was previously a near universally fatal complication.

General measures include regular skin care and emollients, physiotherapy to maintain joint mobility and prevent contracture, dental care given microstomia, and psychological support given the significant disease burden and disfigurement.

Multidisciplinary care (rheumatology, respiratory medicine, cardiology, gastroenterology, nephrology, dermatology) with structured annual surveillance for organ involvement underpins long term management given the unpredictable and organ specific progression of this disease.