Potential Pathogenesis and Clinical Aspects of
Pulmonary Fibrosis Associated with
Rheumatoid Arthritis
BERNADETTE R. GOCHUICO, MD
ABSTRACT: Pulmonary fibrosis is an extra-articular dis-
order that can occur in association with rheumatoid
arthritis. The differential diagnosis of this disorder is
similar to that of idiopathic pulmonary fibrosis, but
specific entities such as atypical pulmonary infections
and drug-induced interstitial lung disease must be con-
sidered as causes of pulmonary fibrosis in patients with
rheumatoid arthritis. Although the cause of lung fibrosis
in persons with rheumatoid arthritis is unknown, factors
that can potentially contribute to the pathogenesis of this
pulmonary disease include genetic susceptibility, devel-
P ulmonary fibrosis is an extra-articular disorder
that can occur in association with rheumatoid
arthritis.1,2 The differential diagnosis of this disor-
der is similar to that of idiopathic pulmonary fibro-
sis, but specific entities such as atypical pulmonary
infections and drug-induced interstitial lung disease
must be considered as causes of pulmonary fibrosis
in patients with rheumatoid arthritis.3–11 Although
the cause of lung fibrosis in persons with rheumatoid
arthritis is unknown, factors that can potentially con-
tribute to the pathogenesis of this pulmonary disease
include genetic susceptibility, development of an al-
tered immunologic response, and/or aberrant host re-
pair processes.12–18 The clinical course of patients with
pulmonary fibrosis and rheumatoid arthritis is heter-
ogeneous but is generally insidious, chronic, and pro-
gressive.1 These patients respond unpredictably to
available empiric therapeutic agents and, overall,
their prognosis is poor; limited data suggests that the
median survival time can be less than 4 years.1,2,19
Epidemiology
Rheumatoid arthritis is a systemic disorder affect-
ing 0.5 to 2% of the general population and can be
From the Pulmonary-Critical Care Medicine Branch, National
Heart, Lung, and Blood Institute, National Institutes of Health,
Bethesda, MD 20892.
Correspondence: PCCMB-NHLBI, NIH, Building 10, Room
6D03, 10 Center Drive MSC 1590, Bethesda, MD 20892-1590
(E-mail: gochuicb@nhlbi.nih.gov).
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
opment of an altered immunologic response, and/or
aberrant host repair processes. The clinical course of
patients with pulmonary fibrosis and rheumatoid arthri-
tis is heterogeneous but is generally insidious, chronic,
and progressive. These patients respond unpredictably
to available empiric therapeutic agents and, overall,
their prognosis is poor; limited data suggests that the
median survival time can be less than 4 years. KEY
INDEXING TERMS: Pulmonary fibrosis; Interstitial lung
disease; Lung; Rheumatoid arthritis; Collagen vascular
disease. [Am J Med Sci 2001;321(1):83–88.]
associated with various pulmonary abnormalities1,2.
Pulmonary manifestations of rheumatoid arthritis
include pulmonary fibrosis, pleural disease, lung
nodules, Caplan syndrome, bronchiolitis obliterans
with or without organizing pneumonia, bronchiecta-
sis, and pulmonary vasculitis (Table 1).2 In addition,
lung disease in patients with rheumatoid arthritis
can be caused by infections or therapeutic agents
commonly used to treat rheumatoid arthritis, such
as methotrexate and gold salts.3–11 Although some of
these pulmonary disorders are benign and asymp-
tomatic, the development of fibrotic lung disease is
notable because it is one of the leading causes of
death in these patients, irrespective of therapy.2
Reports of epidemiologic studies have estimated
the prevalence of pulmonary fibrosis to be between 1
and 58% in patients with rheumatoid arthritis. This
wide variability is caused by the use of inconsistent
diagnostic criteria and detection methods for pulmo-
nary fibrosis in published studies. For example,
studies that based the diagnosis on chest roentgen-
ographic findings report an estimated prevalence of
fibrotic lung disease at 1 to 12%, whereas those that
established the diagnosis using reduced diffusion
capacity or other pulmonary physiology data report
an estimated prevalence of about 41% of patients
with rheumatoid arthritis.20,21 When multiple mea-
sures, such as bronchoalveolar lavage (BAL) cell
counts, chest radiographs, high-resolution computed
tomography (HRCT), and 99m-Technetium diethyl-
ene triamine pentaacetate (99m-TcDTPA) radionu-
83
Pulmonary Fibrosis Associated with Rheumatoid Arthritis
Table 1. Pulmonary Diseases Associated with Rheumatoid
Arthritis
Pulmonary fibrosis
Pleural disease
Pleural effusion
Pleural thickening
Lung nodules
Caplan syndrome
Bronchiolitis obliterans
Bronchiolitis obliterans with organizing pneumonia
Bronchiectasis
Pulmonary vasculitis
clide lung clearance scanning were used in evaluat-
ing persons newly diagnosed with rheumatoid
arthritis, abnormalities consistent with interstitial
lung disease were recognized in 58% of these pa-
tients.22 Thus, the prevalence of interstitial lung
disease in patients with rheumatoid arthritis may
have been historically underestimated by studies
that employed insensitive methods for detecting this
disorder.
Differential Diagnosis
The differential diagnosis of pulmonary fibrosis
with or without associated rheumatoid arthritis is
broad and includes fibrotic lung disease secondary to
other collagen vascular disorders, interstitial pul-
monary fibrosis mediated by infectious agents, med-
ication-induced pulmonary fibrosis, granulomatous
lung disease, chronic hypersensitivity pneumonitis,
asbestos- and other inhaled particle-induced fibro-
sis, radiation pneumonitis, recurrent aspiration
pneumonitis, amyloidosis, pulmonary renal syn-
drome, malignancy, and idiopathic pulmonary fibro-
sis (Table 2). Diagnoses of particular importance in
persons with underlying rheumatoid arthritis in-
clude atypical infections and interstitial lung dis-
ease induced by administration of therapeutic
agents such as methotrexate and gold.3–11 These
diseases must be considered and excluded in pa-
tients with rheumatoid arthritis and interstitial
lung disease.
Patients with rheumatoid arthritis are predis-
posed to the development of infection. In fact, this
complication is a leading cause of morbidity and
death of persons with rheumatoid arthritis.2,23 Spe-
cific infections include bacterial pneumonia caused
by Streptococcus pneumoniae and septic arthritis
caused by Staphylococcus aureus23. Although pneu-
monia caused by typical bacteria is usually easily
distinguishable from pulmonary fibrosis, infections
by certain microorganisms can closely resemble
rheumatoid arthritis-associated interstitial lung
disease; these include Mycobacteria species (espe-
cially M tuberculosis) and cytomegalovirus.3 Pneu-
mocystis carinii pneumonia has also been reported
in persons with rheumatoid arthritis. Although in-
84
Table 2. Differential Diagnosis of Pulmonary Fibrosis
Associated with Rheumatoid Arthritis
Pulmonary fibrosis secondary to other collagen vascular
disorders
Systemic sclerosis
Systemic lupus erythematosus
Polymyositis
Dermatomyositis
Sjogren syndrome
Mixed connective tissue disease
Pulmonary infections
Mycobacteria species (especially M tuberculosis)
Pneumocystis carinii
Cytomegalovirus
Medication-induced lung disease
Methotrexate
Gold compounds
Sulfasalazine
D-penicillamine
Granulomatous lung disease
Sarcoidosis
Langerhans cell granulomatosis
Chronic hypersensitivity pneumonitis
Inhaled particle-induced fibrosis
Asbestos
Silica
Beryllium
Coal
Radiation pneumonitis
Recurrent aspiration pneumonitis
Amyloidosis
Pulmonary renal syndrome
Malignancy
Idiopathic pulmonary fibrosis
fection occurs more commonly in those receiving
immunosuppressive agents, it can also occur in the
absence of such therapy.4 – 6 Infection caused by M
tuberculosis, cytomegalovirus, or P carinii must be
excluded before attributing interstitial changes to
rheumatoid arthritis, because the treatments for
these pulmonary conditions differ and the conse-
quences of misdiagnosis are grave. In particular, the
combination of failure to diagnose infection with M
tuberculosis and institution of corticosteroid therapy
for pulmonary fibrosis can permit the rapid, delete-
rious progression of tuberculosis.
The use of certain therapeutic agents for rheuma-
toid arthritis can also produce diffuse interstitial
changes. Methotrexate, gold compounds, sulfasala-
zine, and D-penicillamine have been associated with
the development of diffuse interstitial lung dis-
ease.7–11 Methotrexate, a folic acid analog commonly
used as an antitumor and immunosuppressive drug,
is well-known for its potential to cause potentially
life-threatening pulmonary disease.7 Methotrexate-
induced pneumonitis occurs in up to 5% of treated
persons with rheumatoid arthritis.7,8 Clinical man-
ifestations of methotrexate pulmonary toxicity in-
clude dyspnea, nonproductive cough, and fever.
These signs and symptoms can be observed in other
methotrexate-associated lung complications, includ-
January 2001 Volume 321 Number 1

Table 3. Potential Pathogenic Factors in Pulmonary Fibrosis
Associated with Rheumatoid Arthritis
Genetic factors
HLA-B40 antigen
␣1-protease inhibitor subtype
Pi M1M2
Pi MZ
Pi MS
Alteration in immunologic response
Aberrant host repair mechanisms
Pi, ␣1-protease inhibitor subtype.
ing hypersensitivity and nonhypersensitivity pneu-
monitis, P carinii infection, and cytomegalovirus
pneumonia.3,4,7,8 Risk factors identified as predis-
posing patients to methotrexate-induced pulmonary
toxicity include advanced age, preexisting intersti-
tial disease, and a prior adverse reaction to thera-
peutic agents for rheumatoid arthritis.8 Treatment
for methotrexate-induced pneumonitis involves dis-
continuation of drug administration, supportive
care, and possible use of systemic corticosteroids.
Gold compounds are pharmacologic agents that
can also be associated with the development of dif-
fuse lung disease. The presence of fever, skin rash,
lymphocytosis in BAL fluid, alveolar opacities dis-
tributed along bronchovascular bundles on chest
computed tomography images, and absence of sub-
cutaneous nodules or digital clubbing are features
that distinguish gold-induced pulmonary disease
from rheumatoid arthritis-associated lung disease.9
Predisposing factors that identify rheumatoid ar-
thritis patients at risk for developing gold-induced
lung disease are unknown. Therapy includes cessa-
tion of gold therapy, supportive care, and adminis-
tration of systemic corticosteroids (or steroid-spar-
ing medications) for severe toxicity.9
Pathogenesis
The etiology of pulmonary fibrosis in patients with
rheumatoid arthritis is unknown. Possible patho-
genic mechanisms include genetic factors, alteration
in immunologic response, and/or aberrant tissue re-
pair mechanisms (Table 3).
The potential role of genetic factors in the patho-
genesis of pulmonary fibrosis in patients with rheu-
matoid arthritis has been investigated.12–14 Inher-
ited host susceptibility factors interacting with
single or multiple environmental exposures can po-
tentially initiate the development of the fibrotic pro-
cess in the lung. In support of this hypothesis, poly-
morphisms at several loci have been associated with
certain fibrotic lung diseases (eg, immunoglobulin
Gm with familial idiopathic pulmonary fibrosis, glu-
tamate 69 in human leukocyte antigen (HLA)-DP␤
with chronic beryllium disease and hard metal lung
disease, HLA-DR8 and tumor necrosis factor-␣ with
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Gochuico
coal worker’s pneumoconiosis, glutathione S-trans-
ferase class ␮ with asbestosis).24 –28 Also, an in-
creased frequency of polymorphisms at the HLA-
B40 antigen site has been observed in persons with
rheumatoid arthritis who have pulmonary fibrosis
or obliterative bronchiolitis.14 In patients with rheu-
matoid arthritis, the site that encodes for ␣1-pro-
tease inhibitor (␣1-Pi) has been reported to be asso-
ciated with the development of fibrotic lung
disease.12,13
The ␣1-Pi gene locus, located at 14q32.1, encodes
multiple allelic variations or subtypes of ␣1-Pi. ␣1-
Pi, a 56-kDa glycoprotein belonging to the serpin
family of serine protease inhibitors, is the major
protease inhibitor in human serum.29 Although
␣1-Pi is capable of interacting with a broad range of
proteases, its primary physiologic target is neutro-
phil elastase. Many ␣1-Pi subtypes, including the
five Pi M subtypes, are quantitatively and qualita-
tively “normal,” as determined by neutrophil elas-
tase inhibition. Several uncommon ␣1-Pi allelic vari-
ants, however, are associated with dysfunctional or
deficient ␣1-Pi that results from synthesis of cata-
lytically inactive enzyme or failure of an active pro-
tein to be delivered effectively from hepatocytes to
the circulation. Reduced levels of functional ␣1-Pi,
such as that observed in Pi ZZ variant homozygotes,
can cause a predisposition to the early development
of emphysema, especially in smokers.
In contrast to the association between ␣1-Pi phe-
notype and development of emphysema, a correla-
tion between ␣1-Pi subtype and the occurrence of
pulmonary fibrosis in patients with rheumatoid ar-
thritis is controversial. For example, one study did
not demonstrate a significant association between Pi
Z subtype and fibrotic lung disease in patients with
rheumatoid arthritis.30 However, studies involving
limited numbers of patients indicated that some
␣1-Pi heterozygotes (ie, Pi M1M2, Pi MZ, Pi MS)
were associated with fibrotic lung disease.12,13 Al-
though pathogenic mechanisms remain unknown,
␣1-Pi has been reported to reduce fibroblast prolif-
eration by inhibiting transferrin binding to its re-
ceptor.31 Because fibroblasts produce collagen and
other extracellular matrix proteins, this effect may
contribute to the regulation of fibroblast cell turn-
over and matrix protein synthesis. ␣1-Pi also con-
tributes to the regulation of immunity through its
modulation of monocyte and macrophage function,
lymphocyte proliferation and cytotoxicity.32 Consis-
tent with these data, ␣1-Pi administered to ham-
sters treated with bleomycin ameliorated the in-
flammation and fibrosis characteristic of this animal
model of pulmonary fibrosis.33 Thus, it is possible
that certain ␣1-Pi subtypes, previously character-
ized as functionally “normal” (with regard to their
ability to inhibit trypsin and elastase), are not func-
tionally normal in their ability to modulate fibro-
blast proliferation and immune cell function.
85
Pulmonary Fibrosis Associated with Rheumatoid Arthritis
Other pathogenetic processes that can potentially
contribute to the development of fibrotic lung dis-
ease in persons with rheumatoid arthritis include
immunologic dysregulation and alteration of tissue
repair mechanisms. Histologic findings of intersti-
tial infiltration by lymphocytes, accumulation of
mononuclear cells within the alveolar space, and
change in the distribution of T cell subsets suggest
that lymphocytes may be involved in the pathogen-
esis of this disorder.1 In addition, alveolar macro-
phages have the ability to produce matrix metallo-
proteinases, cytokines (eg, tumor necrosis factor-␣),
and growth factors (eg, platelet-derived growth fac-
tor, transforming growth factor-␣ and -␤, insulin-
like growth factor-I, and basic fibroblast growth
factor) that can promote fibroblast proliferation and
the accumulation of extracellular matrix pro-
teins.11,34 Furthermore, BAL specimens from per-
sons with rheumatoid arthritis and interstitial lung
disease can contain increased numbers of neutro-
phils with functional alterations, including elevated
myeloperoxidase activity and protease produc-
tion.16 –18 The proteases are believed to contribute to
the generation of fibrinopeptide A-reactive proteins
and collagenase within the lung, consistent with
potential effects of neutrophils on both synthesis
and degradation of matrix components in this
disease.
Clinical Manifestations
The clinical manifestations of pulmonary fibrosis
associated with rheumatoid arthritis are indistin-
guishable from those observed in patients with other
chronic fibrotic lung diseases.1,2 The age of onset is
variable, with a mean reportedly in the fifth to sixth
decade of life. Symptoms are insidious, and can
include dyspnea, nonproductive cough, and chest
pain. Physical exam can reveal inspiratory crackles
and digital clubbing. Findings associated with rheu-
matoid arthritis such as subcutaneous nodules can
be observed in up to 52%, whereas rheumatoid fac-
tor is detectable in 70 to 80% of these patients.35
Notably, although the majority of persons with
rheumatoid arthritis present with pulmonary dis-
ease either after or concurrent with the onset of
arthritis, approximately 10% of patients develop
symptomatic lung disease before the development of
joint disease.1,2
Radiologic Characteristics
Roentgenographic features of rheumatoid arthri-
tis-associated pulmonary fibrosis are variable and
include early patchy basilar alveolar opacities, pro-
gressive reticulonodular interstitial densities with
loss of lung volume, and end-stage honeycombing
(Table 4).36 Although these findings are nonspecific,
the coexistence of rheumatoid nodules or pleural
86
Table 4. Radiologic Characteristics of Pulmonary Fibrosis
Associated with Rheumatoid Arthritis
Chest roentgenogram
Basilar alveolar opacities
Reticulonodular interstitial densities
Loss of lung volume
Honeycombing
High-resolution computed tomography
Ground-glass opacification
Basal honeycombing
Bronchiectasis
Coexistent emphysema or pleural disease
Findings suggestive of underlying rheumatoid arthritis
Rheumatoid nodules
Pleural disease
abnormalities with basilar interstitial changes is
suggestive of rheumatoid arthritis-associated fi-
brotic lung disease.
HRCT of the chest is an important modality that
should be used to assess patients with fibrotic lung
disease. A correlation between thin-section HRCT
and pathologic fibrosis scores in patients with idio-
pathic pulmonary fibrosis has been reported.37 Al-
though similar histologic correlations are not avail-
able for patients with rheumatoid arthritis-related
pulmonary fibrosis, HRCT scans of the chest in 44%
of patients with rheumatoid arthritis and suspected
interstitial lung disease demonstrated ground-glass
opacification or basal honeycombing.38 Other com-
monly observed findings include bronchiectasis, em-
physema, and pleural disease.
Limited data are available regarding the assess-
ment of these patients with radionuclide examina-
tions such as 99m-TcDTPA lung clearance scanning
and J001X scintigraphy.39,40 In a small group of
patients with a variety of diffuse infiltrative lung
diseases, alveolar permeability as measured by
99m-TcDTPA lung clearance scanning was similar
in both early- and late-stage disease.39 Because the
utility of 99m-TcDTPA lung clearance scans in pa-
tients with rheumatoid arthritis and pulmonary fi-
brosis was not specifically assessed, its application
in the management of such patients is unclear.
Pulmonary Physiology Characteristics
As in other fibrotic lung disorders, pulmonary
fibrosis in patients with rheumatoid arthritis is
characterized by a restrictive pattern of ventilatory
function and reduced diffusion capacity.35 Such abnor-
malities can be observed in patients with rheumatoid
arthritis who have normal chest roentgenograms. In a
cross-sectional study, 10% of nonsmoking patients
with rheumatoid arthritis had a mild reduction of
forced vital capacity and 15% had a diffusion capacity
of less than 80% of predicted values; only 5% had
detectable interstitial abnormalities on chest films.
Reduced pulmonary function was more commonly ob-
January 2001 Volume 321 Number 1

served in rheumatoid arthritis patients who had evi-
dence of severe disease (ie, circulating rheumatoid
factor, rheumatoid nodules, bony erosions), pulmonary
symptoms (ie, cough, dyspnea, pedal edema, pleurisy),
or cumulative treatment with methotrexate for
greater than 1 year. Longitudinal evaluation of these
patients and pathologic confirmation of pulmonary
fibrosis were not performed.
BAL Fluid and Pathology Findings
The cellular constituents in BAL fluid and the
pulmonary pathology in patients with rheumatoid
arthritis and pulmonary fibrosis have been exam-
ined. The reported BAL fluid findings of patients
with rheumatoid arthritis have been generally in-
consistent and nonspecific. This variability is possi-
bly related to differences in patients’ disease activ-
ity, quantity of cigarettes smoked, and exposure to
certain disease-modifying drugs, including metho-
trexate, gold compounds, and penicillamine.16,41 Un-
til further information demonstrating diagnostic or
prognostic utility of BAL analysis in defined popu-
lations with rheumatoid arthritis become available,
routine evaluation of BAL cells in all patients with
rheumatoid arthritis is not clinically indicated.
The pathologic features of pulmonary fibrosis in
patients with rheumatoid arthritis include (in the
early stages), accumulation of lymphocytes, plasma
cells, and macrophages within arterioles, bronchi-
oles, and interalveolar septa as well as the later
findings of fibrosis, bronchiolar dilation, parenchy-
mal cyst formation with epithelial hyperplasia, and
honeycombing.42,43 Although these features are also
present in other fibrotic lung diseases, the concom-
itant identification of rheumatoid nodules in lung
tissue is specific for and diagnostic of rheumatoid
arthritis-associated lung disease.
Therapeutic Considerations and Prognosis
Despite the absence of controlled studies to eval-
uate medical therapy for this disease, several case
reports describe clinical responses to systemic corti-
costeroids, azathioprine, cyclophosphamide, metho-
trexate, and D-penicillamine.1 Administration of
therapeutic agents for this disease, therefore, is
based largely on anecdotal experience, and clinical
criteria that guide medication selection are unavail-
able. Drugs that have been used to treat patients
with pulmonary fibrosis and rheumatoid arthritis
are noted in Table 5.
Although pulmonary fibrosis is known to be a
leading cause of death in these patients, their prog-
nosis is still poorly defined and difficult to assess
because of the heterogeneous nature of the disease.2
A small, retrospective analysis of hospitalized per-
sons with rheumatoid arthritis and lung fibrosis
reported a median survival of less than 4 years and
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Gochuico
Table 5. Therapeutic Considerations for Pulmonary Fibrosis
Associated with Rheumatoid Arthritis
Systemic corticosteroids
Azathioprine
Cyclophosphamide
Cyclosporine
Methotrexate
Penicillamine
Hydroxychloroquine sulfate
a 5-year survival rate of 39%.19 The prognosis of
patients with less severe disease remains unknown.
Conclusion
Pulmonary fibrosis in persons with rheumatoid
arthritis is an uncommon lung disorder that may
affect more patients than has been recognized thus
far. Atypical infections and drug-induced lung dis-
ease are important conditions to exclude in these
patients. The pathogenesis of the lung fibrosis is
unknown and may involve genetic host susceptibil-
ity, immune cell dysregulation, and/or aberrant tis-
sue repair mechanisms. The clinical features, heter-
ogeneous disease course, and unfavorable prognosis
seem to resemble those that characterize idiopathic
pulmonary fibrosis. Therapeutic options include em-
piric trials of systemic corticosteroids and/or steroid-
sparing agents.
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January 2001 Volume 321 Number 1