Rheumatoid arthritis and the lung

See also separate Rheumatoid Arthritis article.

Lung disease is a well-recognised and important extra-articular manifestation of rheumatoid arthritis. A study in New Zealand of patients recently diagnosed with rheumatoid arthritis found that 30% of patients reported respiratory symptoms (dyspnoea, cough, wheeze), 20% of patients had physiological evidence of airflow obstruction and 40% had reduced gas transfer. The prevalence of abnormalities found with high-resolution CT was decreased attenuation in 67%, bronchiectasis in 35%, bronchial wall thickening in 50%, ground glass opacification in 18% and reticular changes in 12% of patients.¹

The range of pulmonary problems associated with rheumatoid arthritis includes:²

• Rheumatoid nodules:
  

  • The only pulmonary manifestation specific to rheumatoid arthritis.

  • They are typically benign but can lead to pleural effusion, pneumothorax, haemoptysis, secondary infection, and bronchopulmonary fistula.

• Caplan's syndrome:³
  

  • In 1953, Caplan described a characteristic radiographic pattern in coal miners with rheumatoid arthritis that was distinct from the typical progressive massive fibrosis pattern of coalworkers' pneumoconiosis.

  • CXRs show multiple well-defined rounded nodules, which are about 0.5-2 cm in diameter, distributed throughout the lungs but predominantly at the lung periphery.

• Interstitial lung disease (ILD):⁴

  • ILD and airways disease are the most common forms of rheumatoid arthritis-related lung disease.⁵

  • ILD can be present in most types of connective tissue disease, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome and mixed connective tissue disease.⁶

  • ILD most often occurs in middle-aged men. It is usually associated with severe arthritis and high serum levels of rheumatoid factor.

  • It presents with insidious onset of dyspnoea with occasional dry cough.

  • Associated pulmonary vasculitis may cause pulmonary hypertension.

• Bronchiolitis:
  

  • Bronchiolitis obliterans with organising pneumonia: clinical features include cough, shortness of breath, and bilateral crackles. The vital capacity is slightly decreased and the diffusing capacity is moderately to severely decreased. High-resolution chest CT scan shows bilateral ground-glass opacities with air bronchograms and triangular, pleura-based opacities. Steroids are the best treatment option. The prognosis is generally good, with resolution and cure for most patients.⁷

  • Obliterative bronchiolitis: a rare, usually fatal condition. Associated with penicillamine, gold, and sulfasalazine treatment. Presents with rapid-onset dyspnoea and dry cough. Fever is uncommon.

• Bronchiectasis:⁸
  

  • See also separate Bronchiectasis article.

  • Bronchiectasis co-existing with rheumatoid arthritis differs from the other types of bronchiectasis.

  • Patients with rheumatoid arthritis and bronchiectasis have worse obstructive airways disease, increased susceptibility to recurrent lower respiratory tract infections, faster lung function decline and higher mortality compared with subjects with bronchiectasis alone.

• Arteritis:
  

  • Arteritis of the pulmonary artery and lung is rare; signs of systemic vasculitis are usually present.

• Infection:
  

  • Respiratory infections account for 15-20% of deaths in rheumatoid patients.

• Drug toxicity:
  

  • Acute interstitial pneumonitis may occur in 1-5% of patients treated with methotrexate (see 'Methotrexate-associated lung disease in rheumatoid arthritis', below).

  • Penicillamine and gold may also cause pulmonary complications.⁹

• Pleural effusions:
  

  • See separate Pleural Effusion article.

  • Pleural effusions in rheumatoid arthritis are usually small, unilateral and asymptomatic.

  • Occasionally, an empyema may develop

• Lung cancer: is more common in patients with rheumatoid arthritis than in normal control subjects.

• Other diseases:
  

  • Rheumatoid arthritis patients can get apical fibro-bullous disease (apical fibrotic cavity lesions similar to ankylosing spondylitis).

  • Thoracic cage immobility causing restrictive lung disease.

  • Primary pulmonary hypertension (rare); secondary pulmonary hypertension (due to ILD) is more common.

The majority of respiratory manifestations occur within the first 5 years of disease, although respiratory symptoms may precede the onset of articular symptoms in 10–20% of cases.¹⁰

How common is lung disease in rheumatoid arthritis? (Epidemiology)¹⁰

• Interstitial lung disease is the most common pulmonary manifestation of rheumatoid arthritis lung disease, being detected in up to 60% of patients with rheumatoid arthritis on high-resolution computed tomography, clinically significant in 10% of cases, and is a leading cause of illness and death in patients with RA.

• Although rheumatoid arthritis is more common in females, rheumatoid arthritis-interstitial lung disease occurs more frequently in males, with a male-to-female ratio as high as 2:1 in some studies.

• The onset of lung disease typically occurs in the fifth to sixth decade of life.

• Additional risk factors associated with rheumatoid arthritis-interstitial lung disease include smoking history, seropositivity for rheumatoid factor or anti-CCP antibodies, as well as rheumatoid arthritis disease activity.

• The prevalence of airway disease in rheumatoid arthritis is high and can occur in 39–60% of patients. Both the large (upper and lower) and distal small airways can be involved. The most common manifestations are bronchiectasis, bronchiolitis, airway hyperreactivity and cricoarytenoid arthritis.

Differential diagnosis

The association of rheumatoid arthritis with lung disease may be due to:

• Rheumatoid-associated lung disease.

• Drug-related lung disease secondary to drugs used to treat rheumatoid arthritis.

• Infection secondary to immunosuppression.

• Co-existent medical conditions - eg, chronic obstructive pulmonary disease.

Diagnosing lung disease in rheumatoid arthritis (investigations)¹⁰

• Blood tests for evaluation of rheumatoid arthritis, including serology.

• Respiratory function tests, including spirometry.

• CXR.

• Aspiration of pleural fluid.

• High resolution CT.

• Lung biopsy.

Management of lung disease in rheumatoid arthritis

There are several management guidelines for rheumatoid arthritis, including those from the National Institute for Health and Care Excellence (NICE). ¹¹ However, they do not include details of the management of lung disease in rheumatoid arthritis.

The management issues relevant to rheumatoid interstitial lung disease include:¹⁰

• Treatment with immunosuppressive agents is generally used regardless of the pattern of fibrosis, though research is much needed to address whether this is the best strategy. Corticosteroids are the mainstay of therapy in rheumatoid interstitial lung disease. Cyclophosphamide and mycophenolate mofetil have been used with varying success.

• Many of the therapeutic options for rheumatoid arthritis such as DMARDs and biologic agents have been linked to pulmonary toxicity (although rare). While DMARDs and biologic agents are widely used for the joint manifestations of rheumatoid arthritis, the potential treatment benefits for rheumatoid interstitial lung disease are unknown.

• Due to the potential of pulmonary toxicity associated with methotrexate use, it is seldom used as a treatment of rheumatoid interstitial lung disease.

• Pirfenidone reduces levels of IL-6 and TNF-α, both key cytokines in rheumatoid arthritis pathogenesis. It may reduce disease progression in rheumatoid interstitial lung disease.

• Other treatment considerations include cessation of cigarette smoking, pulmonary rehabilitation, oxygen supplementation, treatment of associated pulmonary hypertension as well as other comorbidities including abnormal gastro-oesophageal reflux, and lung transplant consideration when appropriate.

Prognosis¹²

• ILD associated with rheumatoid arthritis causes significant morbidity and mortality.

• Better means of identifying and treating rheumatoid interstitial lung disease are needed to improve the prognosis, with a median survival of only 3-7 years after diagnosis.

• Mortality is particularly high in patients who develop ILD and pulmonary hypertension.

Methotrexate-associated lung disease in rheumatoid arthritis¹³

• Methotrexate pneumonitis is an unpredictable and life-threatening side-effect of methotrexate therapy.

• Presentation is often subacute with symptoms often present for several weeks or months before diagnosis.

• It presents most often with cough, dyspnoea and fever. It may progress rapidly to respiratory failure.

• Methotrexate should be discontinued immediately. Often treatment with steroids is required. Other immunosuppressive drugs, such as cyclophosphamide have also been used successfully. Tocilizumab has also been reported to be beneficial.