Rheumatoid arthritis (RA) affects approximately 1% of the US population frequently has extra-articular manifestations. Most compartments of the lung are susceptible to disease. Interstitial lung disease (ILD) and airways disease are the most common forms of RA-related lung disease. RA-ILD carries the worst prognosis and most often manifests in a histologic pattern of usual interstitial pneumonia or nonspecific interstitial pneumonia. There have been no large, well-controlled prospective studies investigating therapies for RA-ILD. Treatment usually entails immunomodulatory agents. Further studies are needed to better understand pathogenic mechanisms of disease that lead to lung involvement in these patients.
Key points
- •
Rheumatoid arthritis commonly affects the lungs and can involve any compartment of the respiratory system.
- •
Usual interstitial pneumonia and nonspecific interstitial pneumonia are the most common patterns seen with interstitial involvement in rheumatoid arthritis.
- •
Treatment consists of long-term therapy with immunomodulatory agents.
- •
Further studies are needed to better characterize patients, predict progression, and determine optimal therapeutic regimens.
Introduction
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disorder characterized by articular and extra-articular manifestations. The lung is commonly a site of extra-articular disease. Within the lung, manifestations of RA vary and may include airways, parenchymal, vascular, and/or pleural disease ( Box 1 ). Manifestations of lung disease in RA typically follow the development of articular disease, but in some instances lung involvement is the first manifestation of RA and is the most aggressive feature of the disease. Clinicians should therefore remain alert to the possibility of lung disease in all patients with RA.
Interstitial lung disease
- •
Usual interstitial pneumonia
- •
Nonspecific interstitial pneumonia
- •
Organizing pneumonia
- •
Lymphocytic interstitial pneumonia
- •
Acute interstitial pneumonia
- •
Airways disease
- •
Follicular bronchiolitis
- •
Constrictive bronchiolitis (obliterative bronchiolitis)
- •
Bronchiectasis
- •
Cricoarytenoid arthritis
- •
Rheumatoid nodules
Pleural disease
- •
Pleuritis
- •
Pleural effusion
- •
Pneumothorax
- •
Empyema
- •
Vascular disease
- •
Pulmonary hypertension
- •
Vasculitis
- •
Rheumatoid pneumoconiosis (Caplan syndrome)
Drug toxicity
Infection
Amyloidosis
Fibrobullous disease
Introduction
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disorder characterized by articular and extra-articular manifestations. The lung is commonly a site of extra-articular disease. Within the lung, manifestations of RA vary and may include airways, parenchymal, vascular, and/or pleural disease ( Box 1 ). Manifestations of lung disease in RA typically follow the development of articular disease, but in some instances lung involvement is the first manifestation of RA and is the most aggressive feature of the disease. Clinicians should therefore remain alert to the possibility of lung disease in all patients with RA.
Interstitial lung disease
- •
Usual interstitial pneumonia
- •
Nonspecific interstitial pneumonia
- •
Organizing pneumonia
- •
Lymphocytic interstitial pneumonia
- •
Acute interstitial pneumonia
- •
Airways disease
- •
Follicular bronchiolitis
- •
Constrictive bronchiolitis (obliterative bronchiolitis)
- •
Bronchiectasis
- •
Cricoarytenoid arthritis
- •
Rheumatoid nodules
Pleural disease
- •
Pleuritis
- •
Pleural effusion
- •
Pneumothorax
- •
Empyema
- •
Vascular disease
- •
Pulmonary hypertension
- •
Vasculitis
- •
Rheumatoid pneumoconiosis (Caplan syndrome)
Drug toxicity
Infection
Amyloidosis
Fibrobullous disease
Epidemiology
RA is the most common connective tissue disease (CTD), with a prevalence of 0.5% to 2% in the general population. The disease occurs more frequently in women than in men with a ratio of 3:1. Extra-articular disease occurs in approximately 50% of patients, with the lung being a common site of involvement. Lung involvement may occur in as many as 67% of patients, although some reports indicate a lower incidence (around 10%–20%). This wide variation reflects differences in study design, study populations, and the way that lung disease in RA is defined. Many patients with RA have no clinical symptoms of respiratory disease despite radiographic or physiologic evidence of lung abnormalities, often leading to a misrepresentation of disease prevalence. In a study of 52 patients with RA, high-resolution computed tomography (HRCT) abnormalities were identified in 67.3% with only 40% of patients having respiratory symptoms. In addition to respiratory involvement from RA, medication toxicity and secondary pulmonary infections are important sources of lung disease that must be considered in patients with RA.
Mortality is increased in patients with RA with extra-articular manifestations relative to those without extra-articular involvement, with cardiovascular disease, infection, and lung disease being the leading causes. Mortality in RA is greatest within the first 5 to 7 years after diagnosis and risk may be slightly higher in men than in women, with a mortality ratio of 2.07:1.97 respectively. Lung disease alone accounts for 10% to 20% of deaths in patients with RA, and most of these are attributed to interstitial lung disease (ILD).
Forms of lung disease in rheumatoid arthritis
Interstitial Lung Disease
ILD refers to heterogeneous group of parenchymal lung disorders classified by distinct clinical, pathologic, and radiographic features. The 2013 American Thoracic Society/European Respiratory Society official classification of the idiopathic interstitial pneumonias (IIPs) outlines the most recent histopathologic classifications of ILD, many of which may be seen in RA. The most common forms of ILD associated with RA are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP); however, organizing pneumonia (OP), desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, diffuse alveolar damage, and acute interstitial pneumonia have been reported. Smoking, advanced age, high-titer anticyclic citrullinated peptide antibodies, high-titer rheumatoid factor, family history of RA, and in some studies male gender are all risk factors for developing RA-ILD.
Pathophysiology
The pathophysiologic basis for development of ILD in patients with RA remains elusive. Available data suggest a role for both environmental and genetic factors. Specific human leukocyte antigen (HLA) variants including HLA-B54, HLA-DQB1*0601, HLA-B40, and HLA-DR4 have been associated with RA-ILD. Similarly, cigarette smoking has been linked with both RA and RA-ILD. Some speculate that the lungs may be a site of initial immune dysregulation that leads to the development of RA. Citrullinated proteins have been identified in bronchoalveolar lavage fluid from cigarette smokers without RA, and RA-related autoantibodies are detectable in the sputum of patients identified to be at risk for RA.
It is hoped that investigations of biomarkers for RA-ILD will identify key molecules and thus provide more insight into disease immunopathogenesis and avenues for early diagnosis. To date, serum autoantibodies against multiple citrullinated proteins and peptides including fibrinogen, vimentin, and citrullinated isoforms of heat shock protein 90 and matrix metalloproteinase-7 (MMP-7) and interferon-gamma inducible protein 10 have been associated with RA-ILD. The precise role of these proteins in tissue-specific disease manifestations is not known.
Prognosis and mortality
Information pertaining to the natural history of RA-ILD relies on data from a limited number of studies and more data are needed to confidently characterize prognosis and mortality within this population. The available studies indicate that patients with RA-ILD have a 3-fold increased risk of death relative to those without ILD. In addition, although overall mortality from RA seems to be decreasing, mortality from RA-ILD seems to be increasing, particularly in women and in older age groups. A study of 582 patients with RA identified a median survival of 2.6 years in those with ILD compared with 10 years in age-matched patients with RA without ILD. Within the category of RA-ILD, prognosis varies significantly depending on the precise histopathologic form of RA-ILD and from patient to patient. UIP is the most common subtype of RA-ILD and carries the worst prognosis, which differs from CTDs overall, in which the most common pattern of ILD is NSIP. High-quality studies of additional factors that influence prognosis are lacking. A recent systematic review of current literature investigating predictors of mortality in RA-ILD included 10 studies and found that male gender, older age, lower lung diffusion capacity for carbon monoxide (DLCO), a finding of UIP, and the extent of fibrosis were significant predictors of mortality.
Clinical features
Exertional dyspnea and cough of insidious onset are the predominant clinical symptoms of RA-ILD. Fatigue and generalized weakness are also frequently seen. Radiographic evidence of ILD on HRCT precedes the development of respiratory symptoms in a significant number of patients with RA and time to development of symptoms for patients with subclinical ILD is not known. Given the prevalence of lung involvement in RA, clinicians should have a low threshold to pursue evaluation of new respiratory complaints in this population. Once present, symptoms usually progress over time; however, the rate of progression is variable from patient to patient and within the different histopathologic forms of ILD. Studies indicate that patients with UIP may progress faster than other subtypes of ILD in RA and at rates similar to those reported for idiopathic pulmonary fibrosis (IPF).
Radiographic features
HRCT has increased the diagnostic sensitivity and accuracy for RA-ILD greatly compared with chest radiograph alone. In a study of 150 consecutive individuals with RA, HRCT evidence of ILD was seen in 19% of patients; however, bilateral interstitial infiltrates were seen on chest radiograph in less than 3%. The most common radiographic finding is a UIP pattern, which is characterized on HRCT by peripheral basilar predominant reticular abnormalities, honeycombing, traction bronchiectasis, and minimal to no ground-glass opacification ( Fig. 1 ). NSIP is the other common pattern in RA-ILD and is characterized by reticulation and ground-glass with little or no architectural distortion or honeycombing ( Fig. 2 ).
Diagnostic evaluation
Early symptoms of respiratory disease, particularly dyspnea on exertion, may be difficult to ascertain in patients with exercise-limiting joint disease. Clinicians should therefore remain alert to subtle symptoms, including new cough, change in activity level, or low resting oxygen levels. The initial diagnostic evaluation for patients with RA with respiratory symptoms includes an assessment of lung physiology with pulmonary function tests (PFTs), radiographic imaging with HRCT, and assessment of the patient’s oxygenation both at rest and with activity. Initial PFTs should include components of lung volume, airflow with bronchodilator challenge, and DLCO measurements. For initial imaging, HRCT imaging is recommended rather than chest radiograph for its superior sensitivity in detecting early parenchymal disease and small airways disease. Lung biopsy is not indicated in most cases of RA-ILD; however, if the diagnosis is uncertain or computed tomography findings are atypical, surgical lung biopsy may be useful. Transbronchial biopsies have low yield and are generally not performed, although they may be helpful for the purpose of ruling out drug-related disease or infection. For all patients with diffuse parenchymal disease, infection and drug-induced disease must be ruled out before making a diagnosis of ILD. Numerous medications used in the treatment of RA have reported pulmonary toxicities ( Table 1 ).
| Medication | Symptoms | Radiopathologic Findings | Incidence |
|---|---|---|---|
| Methotrexate | Dyspnea, cough, fever | Common: bilateral interstitial granulomatous infiltrates with ground-glass opacification on chest CT Uncommon: unilateral infiltrates, pleural effusions, reticulonodular disease, hilar lymphadenopathy | 0.3%–11.6% Most cases occur within 2 y of drug initiation and may occur after a single dose |
| Anti-TNF | Dyspnea | Aseptic granulomatous pulmonary nodules, both noncaseating and necrotizing Accelerated interstitial lung infiltrates Bronchospasm | ILD, 0.5%–3% |
| Leflunomide | Dyspnea, fever, cough | Diffuse or patchy ground-glass opacities. Often with septal thickening | ILD, <1% 2-fold increased risk of new ILD seen in those with prior methotrexate use |
| Rituximab | Dyspnea | Acute/subacute OP Acute respiratory distress syndrome | Unknown |
| Sulfasalazine | Dyspnea, cough | Variable. Most commonly, eosinophilic pneumonia and peripheral eosinophilia Interstitial fibrosis | Unknown |
| Tocilizumab | — | OP Exacerbation of ILD Allergic pneumonitis | Unknown |
Related posts:
Lung Disease in Rheumatic Diseases
Demystifying Lung Disease in the Rheumatic Diseases
Determining Respiratory Impairment in Connective Tissue Disease–Associated Interstitial Lung Disease
Interstitial Lung Disease in Scleroderma
Pulmonary Complications of Inflammatory Myopathy
Management of Connective Tissue Disease–associated Interstitial Lung Disease
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
