Lung Disease in Rheumatoid Arthritis

Carlotta Nannini; Jay H. Ryu; Eric L. Matteson


Curr Opin Rheumatol. 2008;20(3):340-346. 

In This Article

Forms of Lung Disease in Rheumatoid Arthritis

Pleural Disease

Pleural involvement is the most common manifestation of lung disease in RA. Although its prevalence has been estimated to be less than 5%, 20% of RA patients have symptoms related to pleural disease,[11] and a high frequency (40–75%) of pleural involvement is noted in autopsy reports.[39]

Treatment includes the drainage for recurrent symptomatic effusion, administration of oral corticosteroids, and treatment for the underlying RA.[40] Surgical decortication must to be considered if extensive pleural thickening results in restrictive lung disease.[41]

Rheumatoid Nodules

Rheumatoid lung nodules are more common in men than in women and are usually asymptomatic. They usually present more of a diagnostic than a therapeutic challenge. Rheumatoid lung nodules are detected on chest radiograph in about 0.2% of unselected patients with RA[42] and more frequently on HRCT (4%).[5]

The clinical course of pulmonary nodules is variable. The nodules may precede the clinical manifestation of RA or be concurrent. They may increase in size, resolve spontaneously, or appear at new sites as older nodules resolve.[43]

Interstitial Lung Disease

Idiopathic interstitial pneumonias are a heterogeneous group of nonneoplastic diseases resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis (84). These disorders affect not only the interstitium (space between endothelial and epithelial basement membranes) but also the adjacent airspaces, the peripheral airways, and the vessels.[44]

The main histologic patterns of ILD associated with RA are UIP, nonspecific interstitial pneumonia (NSIP), organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia), and diffuse alveolar damage.[5,39,45,46] These histologic patterns of interstitial pneumonias correlate with different radiological features ( Table 4 ). HRCT best depicts the underlying radiological pattern.

The presence of fibrosis determines the alteration of lung architecture ranging from coarse fibrotic changes (honeycombing fibrosis in UIP) or to relatively preserved architecture with mild-to-moderate interstitial chronic inflammation and fibrosis (NSIP). The most frequent histopathologic pattern found in RA-associated ILD is UIP followed by NSIP and organizing pneumonia combined with inflammatory airways disease.[46,47]

In general, UIP is associated with a significantly worse prognosis and a poor response to corticosteroid treatment.[48] The outcome of patients with fibrotic NSIP, however, may also be poor. Some of this apparent contradiction may be attributed to difficulties in making the histologic distinction between UIP and NSIP in advanced disease.[23,49] Occurrence of UIP in patients with RA appears to be associated with a better prognosis than to IPF, that is, idiopathic UIP.[43]

Airways Involvement

Studies in which RA patients and controls are matched for age, sex, and smoking habits reveal indices of airflow to be significantly lower in patients with RA, with a prevalence of pulmonary functional test abnormalities of 38%.[24] In a more recent study,[25] the prevalence of airways obstruction in 81 patients with RA who did not have smoking habit was 16%. This is significantly higher than prevalence in a comparison group of patients with non-RA joint disease who were matched for age and sex.

Cricoarytenoid arthritis and bronchiectasis are the major manifestations of large airways involvement. Direct or indirect laryngoscopy and computed tomography scanning reveal cricoarytenoid abnormalities in 75% of patients.[26] Clinical involvement is less frequent. HRCT has demonstrated that bronchiectasis is a common finding in RA, though symptomatic bronchiectasis is unusual. Radiologic findings of bronchiectasis or bronchiolectasis have been described in 30% of patients with RA who are undergoing HRCT.[50]

The pulmonary manifestations of RA also include bronchiolar disease such as follicular bronchiolitis and constrictive bronchiolitis (also called bronchiolitis obliterans). These diseases are usually seen in patients with positive rheumatoid factor and active joint disease. The symptoms are characterized by dyspnea and nonproductive cough.[39] Although chest radiograph is generally normal, computed tomography may show areas of air trapping, small nodular opacities in centrilobular distribution (follicular bronchiolitis and bronchiolitis obliterans), patchy areas of low attenuation (bronchiolitis obliterans), and peribronchial thickening (follicular bronchiolitis and bronchiolitis obliterans). PFTs reveal airflow obstruction.[51]

Pulmonary Hypertension

Isolated pulmonary hypertension with clinical manifestations is rare in patients with RA. The incidence of pulmonary artery systolic pressure higher than 30 mmHg suggests that pulmonary hypertension is significantly higher in patients with RA (26.7 versus 4.5% in controls; P = 0.03).[52•] Using Doppler echocardiography, pulmonary hypertension was found to be secondary to lung disease in 6% of an unselected population of patients with RA.[53]

Drug-induced Lung Disease

Several of the medications used to treat RA can be associated with lung injury (118). The incidence of pulmonary toxicity in patients treated with methotrexate for RA is 1–5%.[54] There appears to be no relationship between the occurrence of pulmonary toxicity and cumulative dosage. Toxicity is rare with doses less than 20 mg per week, although more recent studies have reported that methotrexate pneumonitis occurs with a dose of 5 mg per week.[55]

Interstitial pneumonia as an adverse reaction of leflunomide is rare. The incidence of such cases is reported to be 0.02% in Western countries. In Japan in 2003, 16 cases (0.48%) of ILD, including five fatal cases (0.15%), were associated with leflunomide therapy among 3360 registered patients.[56]

In recent years, a number of cases have been observed linking the use of the tumor necrosis factor-α (TNF-α) inhibitors, infliximab, etanercept, and adalimumab, to ILD.[57–61] The precise pathogenetic mechanism involved in the development or worsening of pulmonary fibrosis after TNF blockade remains elusive. Kuroki et al.[62] have demonstrated that TNF-α plays an important role in limiting pulmonary inflammation in mouse model of bleomycin-induced pneumopathy ( Table 5 ).


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