Rheumatoid Arthritis-Associated Interstitial Lung Disease

Rheumatoid arthritis associated interstitial lung disease is fibrosing or inflammatory lung disease in patients with rheumatoid arthritis. Clinically significant disease affects about 5 to 10% of patients, and subclinical abnormalities on CT are seen in up to 30 to 40%.

It is a leading cause of death in rheumatoid arthritis. It often appears within 5 years of arthritis, and in some, lung disease comes first. Usual interstitial pneumonia is the commonest pattern (about 45 to 60%), followed by nonspecific interstitial pneumonia and organising pneumonia.

Pathophysiology. Citrullinated proteins in the lung, in a smoker or someone with the MUC5B promoter variant, trigger an autoimmune response against the lung, with fibroblast activation and collagen deposition. High titre rheumatoid factor and anti-CCP antibodies, male sex, smoking, older age and severe arthritis raise the risk.

Exertional dyspnoea and dry cough over months, which may be overlooked because of joint disease and reduced activity. Basal crackles and clubbing are frequent. Rheumatoid nodules, active synovitis and sicca symptoms may be present.

Rapid worsening, fever, hypoxaemia at rest or haemoptysis needs urgent assessment for infection, drug pneumonitis or acute exacerbation.

• High resolution CT: usual interstitial pneumonia (subpleural basal reticulation, honeycombing, traction bronchiectasis), or nonspecific interstitial pneumonia, or organising pneumonia pattern.
• Lung function: restrictive pattern with reduced FVC and DLCO. DLCO is the most sensitive for screening. Six minute walk test with oximetry.
• Serology: rheumatoid factor, anti-CCP antibody, antinuclear antibody, and inflammatory markers.
• Bronchoalveolar lavage to exclude infection, and biopsy rarely.
• Screening in high risk patients (male, smoker, high titre antibodies, long standing disease) with spirometry, DLCO, and CT in those with symptoms or crackles.
• Exclude drug pneumonitis (methotrexate, leflunomide), infection and heart failure.

Differential diagnosis.

• Drug induced pneumonitis (methotrexate, leflunomide, biologics)
• Infection, including Pneumocystis and tuberculosis in those on immunosuppression
• Rheumatoid nodules
• Bronchiectasis and follicular bronchiolitis
• Organising pneumonia
• Heart failure and pulmonary embolism
• Idiopathic pulmonary fibrosis

• Optimise treatment of arthritis with agents that do not worsen lung disease. Abatacept 125 mg subcutaneously weekly, rituximab 1 g intravenously on days 1 and 15 repeated every 6 months, and tocilizumab 162 mg subcutaneously weekly or every 2 weeks are preferred in established lung disease. TNF inhibitors are used with caution in those with existing interstitial disease. Methotrexate is generally continued unless pneumonitis is suspected, and leflunomide is avoided.
• Inflammatory or nonspecific interstitial pneumonia pattern: prednisolone 0.5 mg/kg daily (30 to 40 mg) for 4 to 8 weeks then tapered, with mycophenolate mofetil 500 mg twice daily increased to 1 to 1.5 g twice daily, or azathioprine 1 to 2 mg/kg daily.
• Progressive fibrosis: nintedanib 150 mg twice daily with food (100 mg twice daily in mild hepatic impairment), or pirfenidone 267 mg three times daily for 1 week, 534 mg three times daily for the second week, then 801 mg three times daily, with liver function checks and photoprotection. These slow the loss in FVC.
• Prophylaxis against Pneumocystis with co-trimoxazole 960 mg three times weekly in those on prednisolone 20 mg or more for over 4 weeks, or on rituximab or cyclophosphamide.
• Smoking cessation, vaccination against influenza, pneumococcus and COVID-19, pulmonary rehabilitation, oxygen when PaO2 is 7.3 kPa or less, and lung transplantation for suitable patients.
• Bone protection and a proton pump inhibitor while on steroids.

Complications and prognosis. Median survival is about 3 to 5 years after diagnosis for the usual interstitial pneumonia pattern, and better for nonspecific interstitial pneumonia. Acute exacerbation, pulmonary hypertension and lung cancer occur.

Monitoring. Spirometry, DLCO and walk test every 3 to 6 months, CT at 6 to 12 months or with change, and review of drug safety (full blood count and liver function every 1 to 3 months).

Referral and escalation. Refer to an interstitial lung disease service with rheumatology, and to a transplant centre for advanced disease.