Rheumatoid arthritis (RA) is a systemic inflammatory disorder whose pulmonary effects can be grouped into eight categories: (1) pleural disease, (2) interstitial pneumonitis, (3) drug-related pulmonary disease, (4) pulmonary nodules, (5) airways disease, (6) pulmonary vascular disease, (7) apical fibrocavitary disease, and (8) miscellaneous effects. Although frequently present as distinct entities, more than one manifestation can occur simultaneously or in sequence in an individual with rheumatoid disease.
PLEURAL DISEASE
Pleural disease is the most frequent pulmonary manifestation; it occurs as pleurisy in 20% of cases or as pleural effusion in 3% to 5%. In addition, asymptomatic pleural involvement is probably common, because autopsy series show pleural fibrosis or pleural effusion in approximately 50% of patients with RA. Despite the fact that RA itself is more common among women, pleural disease has a striking predominance for middle-aged men. It can occur at any time during the course of the RA; in 20% of cases, however, it immediately precedes or occurs at the onset of arthritis. The presence of pleural disease appears to bear no definite relationship to the activity of the arthritis or to the titer of rheumatoid factor but correlates to some extent with the presence of subcutaneous nodules. Pathologically, the pleura shows chronic (mononuclear cell) inflammation; pleural or subpleural rheumatoid nodules may occasionally be seen.
Symptoms, which are usually minimal, are absent at least one-third of the time. When present, symptoms can include pleuritic pain or cough. Rarely, a large effusion causes dyspnea, especially in individuals with underlying parenchymal lung disease. Fever is uncommon. The chest roentgenogram reveals pleural thickening or effusion, which is unilateral in 80% of cases with a right-sided predominance.
A diagnostic thoracentesis is indicated to rule out other etiologies such as malignancy or infection. The pleural fluid is characteristically a yellow-green color, although long-standing effusions may have an opalescent or milky quality from cholesterol crystals. Rheumatoid effusions are exudative and have elevated protein levels and lactate dehydrogenase levels frequently above 1,000 U/L. The pH and glucose levels are low. The glucose is less than 50 mg/dL in 80% of cases and is less than 25 mg/dL in 66% of patients. The pleural fluid glucose fails to rise during intravenous infusions of glucose—a characteristic that distinguishes rheumatoid effusions from low glucose effusions caused by other diseases. The hyaluronidase level may be elevated. The differential cell count is usually lymphocytic, but granulocytes can predominate if the thoracentesis is done early on in the inflammatory process. Rheumatoid factor is present in higher concentrations than in the serum, but this is a nonspecific finding that occurs in effusions from other causes as well. Complement levels in pleural fluid can be sharply reduced in comparison with blood levels, a finding that distinguishes rheumatoid effusions and effusions secondary to systemic lupus erythematosus from those of other causes. A characteristic pleural fluid cytologic triad of elongated macrophages, giant multinucleated macrophages, and granular cell debris is felt to be diagnostic and should be sought. Mesothelial cells are nearly always absent. Pleural biopsy may be required to rule out malignancy or infection.
The pleural effusions in RA tend to resolve spontaneously over the course of several months and frequently leave residual pleural thickening. Rarely, such thickening is sufficient to cause significant lung restriction and lead to consideration of pleural decortication. If the pleural disease causes significant dyspnea or other symptoms, therapeutic options include (1) nonsteroidal anti-inflammatory drugs, (2) drainage by thoracentesis or chest tube, (3) a trial of oral or intrapleural corticosteroids if the effusion recurs, and (4) pleurodesis. Approximately 20% of RA-associated pleural effusions are persistent. Most of these, however, resolve within 1 to 5 years. Empyema has been reported to complicate rheumatoid pleural effusion, possibly because of impaired local defense mechanisms in conjunction with necrosis of a subpleural necrobiotic nodule. Systemic steroids, if used, could contribute to or mask the presence of an empyema, and those undergoing this treatment should be monitored carefully.
INTERSTITIAL PNEUMONITIS
Interstitial pneumonitis, historically and clinically indistinguishable from the idiopathic variety, occurs with greater-than-expected frequency in patients with RA. Conversely, 15% to 20% of patients with idiopathic interstitial pneumonitis either have a positive rheumatoid factor or develop symmetric polyarthritis consistent with RA during their clinical course. As with pleural disease, men are overrepresented. Interstitial pneumonitis precedes the onset of arthritis in 20% of patients. Patients are generally seropositive, but the activity of the arthritis bears no relationship to the occurrence or severity of the interstitial pneumonitis.
The exact incidence of interstitial pneumonitis in RA is unclear. Characteristic roentgenographic findings of interstitial pneumonitis, a diffuse reticulonodular infiltrate with basilar predominance, occurred in 1.6% in a series of 516 patients with RA. Other series show characteristic plain chest film abnormalities in up to 6% of patients. High-resolution computed tomography (HRCT) is more sensitive than a plain chest roentgenogram in detecting interstitial disease. Various series report interstitial abnormalities in 10% to 60% of patients. Pulmonary function test abnormalities indicating characteristically restriction and reduced diffusing capacity abnormalities occur frequently. One report describes abnormal pulmonary function in 41% of an unselected series of patients with RA, the majority of whom had no pulmonary symptoms. The carbon monoxide diffusing capacity (DLCO) is believed to be more sensitive than spirometry and lung volume determination in detecting interstitial disease. A recent study concluded that a diffusing capacity less than 54% of predicted at presentation is a sensitive predictor of progressive interstitial lung disease.
With a combination of imaging techniques, physiologic testing, and bronchoalveolar lavage, abnormalities suggesting interstitial lung disease can be seen in up to 58% of patients with recent onset RA. In 14%, the changes are clinically significant. Cigarette smoking is an important risk factor in the development and progression of interstitial disease. Patients should be counseled regarding smoking cessation. Serologic testing for circulating levels of KL-6 (a MUC1 mucin) has been proposed as a sensitive marker for active rheumatoid interstitial pneumonitis as well as other forms of interstitial lung disease.
Nonproductive cough, exertional dyspnea, and easy fatigability are the most frequent symptoms. Clinical stability may be present for years, or, rarely, a rapid progression toward respiratory failure is seen. Examination reveals characteristic fine “Velcro” bibasilar crepitation. Subcutaneous nodules occur in most cases, and finger clubbing is quite common. Symptomatic individuals demonstrate hypoxemia (worsened by exercise), diminished DLCO, and reduced static lung volumes. The course of rheumatoid interstitial pneumonitis is variable.
The decision to treat rheumatoid-associated interstitial disease is based on the initial severity of symptoms and of physiologic impairment, as well as on the rate of deterioration over time. No controlled studies exist to guide treatment options. Initial treatment is usually with corticosteroids plus an immunosuppressive agent: cyclophosphamide or aziothioprine. Mycophenolate may have a role in treatment, although the series reporting a benefit had a small number of patients. Oxygen is given for hypoxemia. When appropriate, referral for lung transplantation may be considered. A poor prognosis for patients with RA hospitalized for evaluation or treatment of interstitial pneumonitis has been reported, with a median survival of 3.5 years and a 5-year survival of 39%.
DRUG-RELATED PULMONARY DISEASE
The possibility of drug-induced interstitial pneumonitis and of other pulmonary reactions to treatment must be kept in mind when evaluating patients with RA. Methotrexate causes pulmonary reactions in 1% to 5% of patients. An acute hypersensitivity interstitial pneumonitis is most common. Other reactions include pleuritis, hilar adenopathy, and nodules. Eosinophilia may be seen in up to 50%. Cough not associated with interstitial disease can occur, and which is thought felt to be an irritant effect of methotrexate. Risk factors for the development of methotrexate-associated pulmonary toxicity include advanced age, diabetes, low serum albumin, preexisting interstitial abnormalities, and previous adverse reactions to disease-modifying antirheumatic drugs. Low-dose methotrexate is not associated with the development of chronic interstitial lung disease. Opportunistic infections may occur.
Gold can produce interstitial pneumonitis. Factors that can help in distinguishing gold-induced interstitial pneumonitis from rheumatoid-associated interstitial disease are a female predominance, the presence of a skin rash or fever, low titers of rheumatoid factor, a lymphocytosis in bronchoalveolar lavage fluid, and gold-specific chest CT findings. With both methotrexate and gold, treatment of pulmonary toxicity involves withdrawal of the drug and administration of corticosteroids.
Ibuprofen has been associated with hypersensitivity pneumonitis, pleural effusions, and exacerbation of asthma. Corticosteroids are associated with opportunistic pulmonary infections that can resemble an interstitial pneumonitis.
Antitumor necrosis factor-α (anti-TNF-α) drugs, etanercept, infliximab, and adalimumab, have been associated with rapidly progressive, often fatal pulmonary fibrosis. They also raise the risk of opportunistic infections, particularly mycobacterial and fungal infections. Mycobacterium tuberculosis is more frequent. Infection may occur early in the treatment and present with extrapulmonary disease.
Leflunomide has been associated with fatal exacerbation of interstitial lung disease, pulmonary nodules, diffuse alveolar hemorrhage, and alveolar proteinosis.
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