Systemic Sclerosis-Associated Interstitial Lung Disease

Systemic sclerosis associated interstitial lung disease is fibrosing or inflammatory lung disease in patients with systemic sclerosis. It occurs in about 40 to 50% on CT and is clinically significant in about a quarter to a third, and it is, with pulmonary arterial hypertension, the leading cause of death.

Risk factors are diffuse cutaneous disease, anti-topoisomerase I (anti-Scl-70) antibody, male sex and African ancestry, and early disease. Nonspecific interstitial pneumonia is the commonest pattern, and usual interstitial pneumonia is less common than in rheumatoid disease.

Pathophysiology. Vascular injury, immune activation and profibrotic cytokines (transforming growth factor beta) lead to fibroblast activation and collagen deposition in the lung. Chronic microaspiration from oesophageal dysmotility adds to injury.

Exertional dyspnoea and dry cough, often with few signs at first, then basal crackles. Features of systemic sclerosis include skin thickening, Raynaud phenomenon, digital ulcers, telangiectasia, dysphagia and reflux. Lung disease is most active in the first 3 to 5 years of the illness.

Rapid worsening, fever, new chest pain or haemoptysis needs urgent assessment. Hypertension with headache and renal impairment suggests scleroderma renal crisis, a medical emergency.

• High resolution CT at diagnosis in all patients: basal subpleural ground glass and reticulation (nonspecific interstitial pneumonia), or honeycombing (usual interstitial pneumonia), with a dilated oesophagus.
• Spirometry and DLCO every 3 to 6 months for the first 3 to 5 years. FVC of under 70% or a fall of 10% or more indicates progression.
• Autoantibodies: anti-topoisomerase I, anticentromere, anti-RNA polymerase III, and antinuclear antibody. Anti-Scl-70 predicts ILD.
• Echocardiography every year, with a DLCO to FVC ratio over 1.6 raising concern for pulmonary arterial hypertension, and right heart catheterisation when suspected.
• Bronchoalveolar lavage to exclude infection, and biopsy is not usually needed.
• Assess oesophageal disease and aspiration risk.

Differential diagnosis.

• Pulmonary arterial hypertension (low DLCO with normal CT)
• Chronic aspiration pneumonitis
• Respiratory muscle weakness (myopathy overlap)
• Drug toxicity
• Infection
• Heart failure
• Lung cancer

• First line immunosuppression for active or progressive disease: mycophenolate mofetil 500 mg twice daily, increased over 4 weeks to 1.5 g twice daily.
• Alternatives or additions: tocilizumab 162 mg subcutaneously weekly, rituximab 1 g intravenously on days 1 and 15, cyclophosphamide 600 mg/m2 intravenously monthly for 6 months (or oral 1 to 2 mg/kg daily for up to 12 months), and autologous stem cell transplantation in carefully selected young patients with rapidly progressive disease.
• Antifibrotic: nintedanib 150 mg twice daily with food (100 mg twice daily in mild hepatic impairment), either alone or with mycophenolate, for progressive fibrosis.
• Avoid high dose corticosteroid: prednisolone over 15 mg daily is linked to scleroderma renal crisis. Limit it to short, low dose courses, with regular blood pressure monitoring at home and an ACE inhibitor ready for any rise (captopril 6.25 to 12.5 mg three times daily, titrated).
• Treat reflux and aspiration: omeprazole 40 mg twice daily, head-of-bed elevation, small meals and prokinetic metoclopramide 10 mg three times daily before meals (limited course).
• Prophylaxis against Pneumocystis in those on cyclophosphamide, rituximab or higher dose steroid: co-trimoxazole 960 mg three times weekly.
• Pulmonary rehabilitation, oxygen when PaO2 is 7.3 kPa or less, vaccination against influenza, pneumococcus and COVID-19, and lung transplantation for suitable patients.
• Treat Raynaud and digital ulcers, and screen for pulmonary hypertension every year.

Complications and prognosis. Progressive fibrosis, pulmonary hypertension, and infection. Five year survival is about 70 to 80%, and lower in those with extensive disease or FVC under 50%.

Monitoring. Spirometry and DLCO every 3 to 6 months, CT at 6 to 12 months or when worsening, annual echocardiography, and blood count, liver and renal function on immunosuppressants.

Referral and escalation. Refer to a joint rheumatology and interstitial lung disease service, and to a transplant centre. Refer urgently for renal crisis.