Lung Disease in
Rheumatoid Arthritis
Zulma X. Yunt, MD, Joshua J. Solomon, MD*
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.1 Clinicians should therefore remain alert to the possibility of
lung disease in all patients with RA.
EPIDEMIOLOGY
RA is the most common connective tissue disease (CTD), with a prevalence of 0.5% to
2% in the general population.2 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.3 Lung involvement may
Disclosure: NIH Diversity Supplement 3R01 HL109517–01A1S1.
Autoimmune Lung Center, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
* Corresponding author.
E-mail address: solomonj@njhealth.org
KEYWORDS
Rheumatoid arthritis Extra-articular disease Pulmonary Interstitial lung disease
Interstitial pneumonia Bronchiolitis Pleural effusion Drug-induced lung disease
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.
Rheum Dis Clin N Am - (2015) -–-
http://dx.doi.org/10.1016/j.rdc.2014.12.004 rheumatic.theclinics.com
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occur in as many as 67% of patients, although some reports indicate a lower incidence (around 10%–20%).4–6 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.4 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
Box 1
Pulmonary manifestation of 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
2 Yunt & Solomon
a mortality ratio of 2.07:1.97 respectively.7,8 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).9–11
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.12 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.13,14 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.15
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.16–19 Similarly, cigarette
smoking has been linked with both RA and RA-ILD.20,21 Some speculate that the lungs
may be a site of initial immune dysregulation that leads to the development of RA.22
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.23,24
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 1025–27 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.28,29 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.29 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,1,14,30 which differs from CTDs overall, in
which the most common pattern of ILD is NSIP.1 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
Lung Disease in Rheumatoid Arthritis 3
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.31
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.20 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).14,32
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%.6 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
Fig. 1. UIP in RA. The UIP pattern consists of peripheral basilar predominant reticular abnormalities, honeycombing, traction bronchiectasis, and minimal to no ground-glass
opacification.
4 Yunt & Solomon
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.6,33 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).
Treatment
No randomized placebo-controlled therapeutic trials have been performed to date in
RA-ILD. As such, no consensus therapeutic guidelines have been established. Our
practice is to monitor these patients closely for progression of disease and initiate
treatment when clinical symptoms manifest or when there is physiologic evidence
of progressive disease. In all cases, risk of therapy must be weighed against threat
of disease.
Current treatment regimens usually involve corticosteroid therapy with or without a
cytotoxic agent; most commonly azathioprine, mycophenolate mofetil (MMF), or
cyclophosphamide. Recent retrospective analyses centered on treatment of RA-ILD
with MMF and rituximab have shown promising results. In a study of 125 patients
with CTD-related ILD treated with MMF, subgroup analysis of 18 patients with RAILD identified a trend toward improved forced vital capacity following initiation of therapy.34 Further, this drug has shown good patient tolerability and safety in patients with
CTD-ILD.34,35 Retrospective studies with rituximab have recently shown success in
cases of refractory CTD-ILD,36,37 although larger prospective studies are needed to
validate these findings in patients with RA-ILD. Limited reports also exist for treatment
with cyclosporine, methotrexate, and tumor necrosis factor (TNF) alpha inhibitors.36–41
Response to therapy in RA-ILD seems to correlate with histopathologic form of disease. As in IIPs, NSIP shows better response to therapy and prognosis than a UIP
Fig. 2. Nonspecific interstitial pneumonia in RA. The nonspecific interstitial pneumonia
pattern consists of reticulation and ground-glass with little or no architectural distortion
or honeycombing.
Lung Disease in Rheumatoid Arthritis 5
pattern.1,14 Note that control of joint disease does not translate to control of lung disease, and optimal management requires a coordinated approach between an experienced pulmonologist and rheumatologist.
All patients with RA-ILD should be encouraged to abstain from smoking. Smokingrelated lung disease should be treated if present. Oxygenation should be evaluated
during rest, ambulation, and sleep and supplemental oxygen should be prescribed
as indicated. Vaccinations for influenza and pneumococcal pneumonia are recommended for all patients. We also recommend prophylaxis against Pneumocystis jiroveci pneumonia for all patients on immunosuppressive therapy. In managing the
articular manifestations in patients with RA-ILD, methotrexate use should generally
be avoided because of well-documented pulmonary toxicity. TNF-alpha inhibitors
should be used with caution in these patients following reports of increased rates of
lung toxicity with these agents.42,43 In spite of these reports, a prospective observational study of 367 patients with RA-ILD showed no increase in mortality following
treatment with anti-TNF agents compared with standard immunomodulatory
Table 1
Lung toxicity of rheumatoid therapies
Medication Symptoms Radiopathologic Findings Incidence
Methotrexate Dyspnea, cough,
fever62
Common: bilateral interstitial
granulomatous infiltrates
with ground-glass
opacification on chest CT62
Uncommon: unilateral
infiltrates, pleural
effusions, reticulonodular
disease, hilar
lymphadenopathy63–66
0.3%–11.6%67
Most cases occur within 2 y of
drug initiation and may
occur after a single dose68
Anti-TNF Dyspnea Aseptic granulomatous
pulmonary nodules, both
noncaseating and
necrotizing69,70
Accelerated interstitial lung
infiltrates42,43
Bronchospasm71
ILD, 0.5%–3%72
Leflunomide Dyspnea, fever,
cough73
Diffuse or patchy
ground-glass opacities.
Often with septal
thickening74
ILD, <1%73
2-fold increased risk of new
ILD seen in those with prior
methotrexate use75
Rituximab Dyspnea Acute/subacute OP76
Acute respiratory distress
syndrome76
Unknown
Sulfasalazine Dyspnea, cough Variable. Most commonly,
eosinophilic pneumonia
and peripheral
eosinophilia77
Interstitial fibrosis78
Unknown
Tocilizumab — OP79
Exacerbation of ILD80
Allergic pneumonitis81
Unknown
Abbreviations: CT, computed tomography; TNF, tumor necrosis factor.
6 Yunt & Solomon
agents.44 Patients with progressive disease should be considered for lung transplant
evaluation. Survival rates after transplant for RA-ILD are similar to those for IPF and
with significant improvements in quality-of-life scores following transplantation.45
Airways Involvement (Bronchiolitis, Bronchiectasis, and Cricoarytenoid Disease)
Prevalence of airways disease in RA is high; it occurs in 39% to 60% of patients.46–48
Any part of the airway may be involved, including the large airways (upper and lower)
and distal small airways. The most common manifestations are bronchiectasis, bronchiolitis, airway hyperreactivity, and cricoarytenoid arthritis. PFTs and HRCT obtained
with expiratory images are useful in making a diagnosis of airways involvement with
HRCT, showing greater sensitivity for detection of small airways disease relative to
PFTs.34
Cricoarytenoid arthritis and bronchiectasis are the most common forms of large
airway involvement. Cricoarytenoid abnormalities occur in as many as 75% of patients,
although fewer have clinically significant symptoms.49 Arthritis of the cricoarytenoid
joints leads to midline adduction of the vocal cords with resultant hoarseness and in
some cases inspiratory stridor. Bronchiectasis, defined as destruction and widening
of the large airways, occurs in 16% to 58% of patients with RA.50,51 Most cases are
not clinically significant but, when present, symptoms include cough and sputum production. Treatment of RA patients with known bronchiectasis using a biologic agent
has been reported as an independent risk factor for lower respiratory tract infection.52
Small airways disease refers to disease involving the distal airways (2 mm in diameter or less). Two forms of small airways disease (follicular bronchiolitis and constrictive bronchiolitis) have been described in association with RA. Follicular bronchiolitis is
identified pathologically by the presence of hyperplastic lymphoid follicles with reactive germ cell centers within bronchiole walls. Constrictive bronchiolitis (also referred
to as obliterative bronchiolitis) is identified by concentric narrowing of membranous
and respiratory bronchioles caused by peribronchiolar inflammation and fibrosis
without evidence of lymphoid hyperplasia.53 There are limited reports regarding disease course and prognosis for RA-associated follicular and constrictive bronchiolitis.
Prognosis is thought to be poor; however, in a recent prospective study in CTDassociated bronchiolitis (in which 50% of patients had RA), the forced expiratory volume in 1 second showed stability over time in both forms, suggesting that bronchiolitis
associated with CTD may have a less aggressive course than idiopathic disease.54,55
Rheumatoid Nodules
Rheumatoid necrobiotic nodules are pulmonary lesions histologically composed of a
central fibrinoid necrotic region surrounded by mononuclear cells, granulation tissue,
lymphocytes, plasma cells, and fibroblasts. The nodules may be single or multiple and
are typically found in pleural or subpleural regions, occasionally with cavitation.56,57
Rheumatoid nodules carry good prognosis and may come and go over time.
Neoplasm and infection should be ruled out, but once a diagnosis is made no specific
therapy is typically required.
Vascular Disease
Pulmonary arterial hypertension is exceedingly rare in RA. It is more commonly seen in
other CTDs such as scleroderma and systemic lupus erythematosis.58 The most common form of vascular involvement in RA is rheumatoid vasculitis, which is characterized pathologically by the presence of a destructive inflammatory infiltrate within small
and medium-sized blood vessel walls. This condition carries significant morbidity and
mortality, but primary involvement of the lung is rare.59
Lung Disease in Rheumatoid Arthritis 7
Pleural Involvement
Pleuritis and pleural effusions are the most common forms of pleural disease in RA. RA
effusions are exudative and sterile, often with low glucose (80%) and low pH
(71.4%).60 A cytologic finding of elongated macrophages and multinucleated giant
cells alongside granulomatous debris is pathognomonic for rheumatoid effusions.61
These findings mirror those in rheumatoid synovitis or rheumatoid nodules. Occasionally, pleural involvement may precede joint disease. Pleural effusions often resolve
spontaneously over time. As with rheumatoid lung nodules, infection and malignancy
should be considered and ruled out, if appropriate.
FUTURE CONSIDERATIONS/SUMMARY
RA is a common disorder with a myriad of pulmonary manifestations. Although any
compartment of the respiratory system is at risk, the ILDs cause the greatest concern.
In its most severe form, affected patients can develop a fibrotic ILD with progression
similar to that seen in IPF. Treatment is based on expert opinion and there are no
placebo-controlled trials. In order to effectively care for these patients, a better understanding is needed of the link between synovitis and pulmonary disease. Predictors of
lung involvement, biomarkers to clinically phenotype patients, and well-designed
treatment trials are urgently needed.
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