Rheumatoid arthritis is a systemic inflammatory disease predominantly
affecting the synovial membranes of the diarthrodial joints. The
disease affects all ethnicities, with an increasing prevalence between
the fourth and sixth decades. In North America, the annual incidence
is estimated to be 0.3–1.5%. The prevalence in
women is 2.5 times higher than in men. However, pulmonary manifestations
(Table 11–2) are more common in men, with a 3:1
ratio, and in those who develop disease later in life.
Pulmonary Manifestations in Rheumatoid Arthritis. |Favorite Table|Download (.pdf)
Pulmonary Manifestations in Rheumatoid Arthritis.
|Airflow limitation (obstruction)|
|Bronchiolitis obliterans (constrictive)|
|Empyema (aseptic or septic)|
|Pneumothorax secondary to a ruptured necrobiotic nodule|
|Rheumatoid nodules (necrobiotic nodules)|
|Interstitial lung disease|
|Interstitial pulmonary fibrosis|
|Bronchiolitis obliterans organizing pneumonia|
|Apical fibrobullous disease|
|Drug-induced lung disease|
|Thoracic cage immobility|
|Pulmonary vascular disease|
|Pulmonary artery hypertension|
|Reactivation of tuberculosis|
Rheumatoid arthritis appears to be a disease in which there is
an aberrant immunological response in genetically susceptible individuals.
Infectious agents, both bacterial and viral, have been implicated
in the development of RA, but the association remains tenuous despite
intense investigation. The immune response in RA is primarily centered
within the synovial membrane with an antigen-specific T lymphocyte
infiltration to a yet unidentified autoantigen. The resultant T
lymphocyte-mediated inflammatory response initiates a cytokine cascade
with subsequent immune complex deposition. Tumor necrosis factor-α (TNF-α)
appears to have a major role in the persistent inflammatory response
seen in RA, which leads to progressive articular destruction through
a variety of mechanisms. Whether TNF-α has a prominent
role in the pulmonary manifestations of the disease, is currently
being investigated. Experimental animal models do suggest that immune
complex-mediated lung injury is also responsible for the pulmonary
manifestations of RA. To date, an antigen has not been identified.
Symptomatic pulmonary disease most often occurs in individuals
with late-onset RA with the majority of patients presenting between
the ages of 50 and 60 years. Lung disease usually follows the articular
manifestations of RA, but does not necessarily correlate with the
extent of articular disease. Pulmonary involvement may also antedate
overt joint disease, as is the case in up to 20% of patients
who develop interstitial lung disease (ILD) complicating RA.
Dyspnea, a productive or nonproductive cough, and pleurisy are
the most common initial symptoms patients experience. However, incidental
radiographic abnormalities are commonly detected as necrobiotic
nodules, early interstitial lung disease, or small to moderate-sized
pleural effusions in otherwise asymptomatic patients.
Pleural disease is one of the more common pulmonary manifestations
of RA, with approximately 20% of RA patients reporting
a history of pleurisy. Autopsy studies document that 38–72% of patients
with RA have demonstrable pleural involvement at the time of death.
These findings range from pleural thickening, or small to moderate-sized
pleural effusions, to pyogenic or nonpyogenic empyema. Spontaneous
pneumothoraces complicating RA are rare but have been reported.
Pneumothoraces are thought to result from necrosis and cavitation
of subpleural necrobiotic nodules. Pleural effusions may be seen
concomitantly with necrobiotic nodules and/or interstitial
lung disease. Effusions are characteristically exudative, with glucose
concentrations < 30 mg/dL in up to 80% of patients.
Additionally, the pleural fluid rheumatoid factor is typically elevated
and is higher than that detected in the serum.
Airflow obstruction is another common pulmonary manifestation
of RA. Of all the connective tissue diseases, RA most commonly affects
the airways. Isolated airflow obstruction in the absence of prior
tobacco use, bronchiolitis obliterans (constrictive bronchiolitis),
follicular bronchiolitis with or without an underlying Sjögren’s
syndrome, bronchiectasis, bronchiolitis obliterans with obstructing
pneumonia (BOOP), and cricoarytenoid arthritis have all been reported
in RA. Cricoarytenoid arthritis is of particular concern as it occurs
in up to 25% of patients and predisposes patients to possibly
life-threatening acute laryngeal obstruction. Bronchiolitis obliterans
(BO) presents with an abrupt onset of dyspnea, nonproductive cough,
inspiratory crackles, and a mid-inspiratory squeak. Both d-penicillamine and secondary Sjögren’s
syndrome have been associated with bronchiolitis obliterans in RA.
In contrast to RA-associated ILD, which typically affects men more
often than women, BO is most often reported in middle-aged women.
Interstitial lung disease in RA is frequently insidious in onset
and is associated with progressive dyspnea on exertion and a chronic,
nonproductive cough. Bibasilar crackles, tachypnea, and exertional
hypoxia are frequently observed. Clubbing is present in up to 75% of
patients. Signs of pleural disease are commonly noted with concomitant
pleural-interstitial lung disease occurring in 20% of patients.
In the absence of overt articular disease, the clinical presentation
of RA-associated ILD is similar to that of idiopathic pulmonary
fibrosis (IPF). The notable difference between the two diseases
is the frequent pattern of clinical stability in the absence of
therapy in RA-associated ILD in distinct contrast to the progressive
course commonly characterizing IPF.
Bronchiolitis obliterans organizing pneumonia may also occur
in RA and presents with fever, cough, and patchy alveolar infiltrates.
BOOP differs from BO by the presence of infiltrates and alveolar
involvement. The course of BOOP in RA may be more recalcitrant and
less responsive to steroids than typically noted in other forms
of the disease in which prognosis is excellent.
Drug-induced lung disease secondary to methotrexate, d-penicillamine, or gold must be considered
in patients with pre-existing exposure to these medications. d-Penicillamine and gold have been associated
with BO whereas methotrexate has been reported to result in diffuse
pneumonitis, pleuritis, and noncardiogenic pulmonary edema. Drug-induced
lung diseases are discussed in further detail in Chapter 33: Drug-Induced Lung Disease.
Pulmonary vascular disease in the absence of overt fibrotic lung
disease is manifest less frequently in RA than in other connective
tissue diseases. Secondary pulmonary hypertension with cor pulmonale
may, however, complicate chronic fibrotic ILD from RA. Pulmonary
capillaritis causing diffuse alveolar hemorrhage, either isolated
or in association with systemic rheumatoid vasculitis, has been
The presence of rheumatoid factor (RF), which is autoantibody
to the Fc portion of immunoglobulin G, is the most common laboratory
abnormality in RA. The presence of RF, however, is not necessary
for the diagnosis of RA as only 85% of RA patients are
RF seropositive. RF can be detected in healthy volunteers as well
as others with chronic inflammatory diseases or viral or chronic
bacterial infections, and in organ transplant recipients. The presence
of RF, especially in high titers, is associated with the development
of extraarticular disease. Hypergammaglobulinemia, thrombocytosis,
eosinophilia, and hypocomplementemia may be observed. An elevated erythrocyte
sedimentation rate (ESR) or C-reactive protein (CRP) is noted during
periods of active inflammation and occurs more frequently with extraarticular
Pleural effusions are the most common radiographic abnormalities
in patients with RA. In up to 20% of patients, dense reticular
or reticulonodular opacities suggestive of ILD are present. Radiographic
honeycombing is usually a basilar, peripheral predominant process.
Upper lobe fibrosis or fibrobullous disease may occur but is less
common. Necrobiotic nodules, which frequently cavitate, are seen
in the lung periphery and may be several centimeters in diameter.
Airways disease may be evident with signs of basilar bronchiectasis
or air trapping from BO or follicular bronchiolitis. Patchy alveolar
opacities may represent RA-associated BOOP, however, infection must always
The pulmonary manifestations of RA must be distinguished from
medication-related side effects, infectious complications, or other
connective tissue disease that presents in a similar manner. Interstitial
lung disease secondary to RA mimics that seen in IPF. These diseases
must be distinguished from one another, as the rate of progression
in IPF is significantly faster without the variable course characterizing
Infectious complications are common in RA and respiratory infections
result in approximately 20% of patient deaths. Common bacterial
and viral pathogens as well as opportunistic agents should be considered
in all patients with new pulmonary disease, especially in those
who are receiving immunosuppressive therapy. An increased risk of
reactivation of latent tuberculosis has recently been reported in
patients receiving anti-TNF-α therapy. Gold, methotrexate,
cyclophosphamide, and d-penicillamine
all have pulmonary toxicities. Therefore, drug-related side effects
should be considered in all patients who develop pulmonary disease
while on therapy.
Disease-modifying antirheumatic drugs (DMARDs) such as corticosteroids
are commonly used to treat the pulmonary manifestations of RA. Both
objective physiological and radiographic improvements as well as
a subjective improvement in dyspnea have been reported with corticosteroid
therapy. There is less evidence to support the use of other agents
such as methotrexate, cyclophosphamide, azathioprine, or anti-TNF-α therapies.
In those who do respond to immunosuppressive therapy, either subjectively
or objectively, the addition of a cytolytic agent such as cyclophosphamide
or azothioprine may allow chronic immunosuppression with low-dose
prednisone and decreased corticosteroid-related side effects.
Pulmonary involvement, especially the presence of ILD, portends
a significantly reduced survival. In RA, the 5-year mortality in
patients with extraarticular involvement is twice that of patients
without extraarticular disease. However, a significant degree of
variation exists in disease progression. Some patients have a rapidly
progressive course whereas others progress slowly with long periods
of stability. Therefore, serial monitoring is essential to assess
disease progression for each patient.
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in rheumatoid arthritis-associated lung disease: CT patterns and
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(Useful diagnostic and prognostic information may be provided by
thin section CT scanning.)
Anaya JM et al: Pulmonary involvement in rheumatoid arthritis.
Semin Arthritis Rheum 1995;24(4):242.
(Detailed review of pathological findings.)
Gochuico BR: Potential pathogenesis and clinical aspects of
pulmonary fibrosis associated with rheumatoid arthritis. Am J Med
update on the pathophysiology of rheumatoid arthritis and the lung.)
Rajasekaran BA et al: Interstitial lung disease in patients
with rheumatoid arthritis: a comparison with cryptogenic fibrosing
alveolitis. Rheumatology (Oxford) 2001;40(9):1022.
(A comparison of clinical features and prognosis in rheumatoid ILD
and idiopathic pulmonary fibrosis.)
Rovere Querini P et al: Miliary tuberculosis after biological
therapy for rheumatoid arthritis. Rheumatology (Oxford) 2002;41(2):231.
Schwarz MI et al: Isolated pulmonary capillaritis and diffuse
alveolar hemorrhage in rheumatoid arthritis and mixed connective
tissue disease. Chest 1998;113(6):1609.
cause of capillaritis.)