Pediatric Pulmonology 24:444–446 (1997)
Early Onset of Pulmonary Parenchymal Disease
Associated With Juvenile Rheumatoid Arthritis
Blakeslee E. Noyes, MD,1* Gary M. Albers, MD,1 Daphne E. deMello,
and Terry L. Moore, MD1
Key words: pulmonary disease; juvenile rheumatoid arthritis; complications.
INTRODUCTION
JRA is a chronic arthritic disease of childhood of un-
known etiology. Extraarticular manifestations of JRA
can include an erythematous skin rash, fever, iritis, hepa-
tosplenomegaly, and cardiovascular and pulmonary le-
sions, usually occurring in systemic-onset JRA.1 Pulmo-
nary parenchymal involvement is very uncommon. In
one series, 8 of 191 children (4%) who also had systemic
symptoms had pleural or parenchymal involvement, with
5 having pleural and only 3 of 191 having parenchymal
involvement.2 Pulmonary parenchymal abnormalities re-
ported to be directly associated with JRA include rheu-
matoid nodules, lymphoid hyperplasia, interstitial pneu-
monitis, obliterative bronchiolitis, and lymphoid bron-
chiolitis,2–5 and those associated with drug therapy for
JRA include methotrexate-induced pneumonitis6 and
bronchiolitis obliterans associated with gold therapy.7
Although these findings are rare, abnormalities in pul-
monary function, typically reflected by a decrease in the
diffusing capacity for carbon monoxide, occur in as
many as 30% of patients with JRA.8 Both restrictive and
obstructive patterns have been described in patients with
JRA2,8; patients with radiographic evidence of interstitial
lung disease appear to have pronounced restrictive de-
fects.2
Most reports of pulmonary disease associated with
JRA note the appearance of respiratory symptoms after
the onset of joint symptoms. In only rare instances does
pulmonary disease precede the joint manifestations of
JRA and then only by a few years.2,4 We describe a
13-year-old girl with histologic evidence of rheumatoid
lung disease as an infant who developed subcutaneous
nodules and joint symptoms typical of seropositive, poly-
articular-onset JRA at 12 years of age.
CASE REPORT
A 13-year-old white girl was referred to Cardinal
Glennon Children’s Hospital for evaluation of painful
subcutaneous nodules, which had first appeared 11⁄2
© 1997 Wiley-Liss, Inc.
MD,
2
Bruce K. Rubin, MD,1
years previously. These had been noticed at various times
to involve the elbows, fingers, and heels. Further ques-
tioning revealed a 11⁄2-year history of swelling of her
wrists, proximal interphalangeal, metacarpalphalangeal,
and knee joints, and a 1-year history of dyspnea on ex-
ertion, poor weight gain, and intermittent substernal
chest pain.
Her past history was significant for an evaluation at
another institution at 5 months of age with respiratory
distress, cyanosis, mild digital clubbing, and diffuse in-
terstitial infiltrates. At that time the pathologic changes in
the lung biopsy were interpreted as bird-breeders’ dis-
ease; she was subsequently treated with oral corticoste-
roids for 6 months and eventually had an uneventful
recovery with no further respiratory symptoms. She was
first seen at this hospital at 3 years of age for routine
medical care; her growth and the findings on her physical
examination, and chest radiograph were all within the
normal range. At 7 years of age she presented with cough
and fever, and a chest radiograph showed minimal peri-
hilar infiltrates. During the 2 years before her presenta-
tion, she reportedly had ‘‘pneumonia’’ on eight occa-
sions, which were treated on an outpatient basis.
On admission her physical examination was notable
for weight and height below the 5th percentile, tachypnea
and dyspnea at rest. Her chest examination showed mild
retractions with bilateral, diffuse, soft inspiratory crack-
les. She had mild to moderate digital clubbing, reduced
range of motion of her wrists, and metacarpophalangeal
and proximal interphalangeal joints of her first through
1
Department of Pediatrics, St. Louis University School of Medicine
and Cardinal Glennon Children’s Hospital, St. Louis, Missouri.
2
Department of Pathology, St. Louis University School of Medicine
and Cardinal Glennon Children’s Hospital, St. Louis, Missouri.
*Correspondence to: Dr. Noyes, Director, Division of Pulmonary
Medicine, Cardinal Glennon Children’s Hospital, 1465 South Grand
Blvd, St. Louis MO 63104-1095. E-mail: Noyes@slu.edu
Received 11 May 1997; accepted 23 August 1997.
 Pulmonary Disease in Juvenile Rheumatoid Arthritis
Fig. 1. Chest radiograph taken when the patient was 13 years of
age, showing extensive bilateral patchy infiltrates involving all
segments of the lung.
fourth digits on the right hand, and painful nodules over
the extensor surfaces of both elbows, both heels, and the
right patella. A chest radiograph (Fig. 1) demonstrated
diffuse interstitial infiltrates with no evidence of honey-
combing. Sweat chloride testing, blood gases analysis,
and echocardiographic studies were normal. Her com-
plete blood count showed hemoglobin concentration and
hematocrit of 12.5/g/dl and 38.4% respectively, and the
leukocyte count was 6.5 × 103 cells/mm3 with a normal
differential count. The erythrocyte sedimentation rate
was 42 mm/h. Her RF titer was positive at 1:5120, and
the antinuclear antibody was positive at 1:40, diffuse
pattern. Antibodies for double-stranded DNA and anti-
Smith antibody were negative. Immunoglobulins, C3,
C4, and CH100 were quantitatively normal, and the re-
sult of testing for HIV antibody was negative. Urine and
serum calcium values, liver function tests, and the level
of angiotensin-1-converting enzyme were also normal. A
skeletal survey was normal, and an ophthalmologic ex-
amination revealed no evidence of uveitis or retinitis.
Abbreviations
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
JRA Juvenile rheumatoid arthritis
PFT Pulmonary function testing
RF Rheumatoid factor
SLE Systemic lupus erythematosis
445
Fig. 2. Necrobiotic nodule from left elbow shows central fibri-
noid necrosis (arrowheads), surrounded by a palisade of epi-
thelioid histiocytes (arrows).
Pulmonary function studies showed a restrictive pattern
with a total lung capacity of 1.51 L (49% predicted),
FVC 0.81 l (34% predicted), and an FEV1 of 0.70 L
(30%). Biopsy of a left elbow nodule showed a necrobi-
otic granuloma consistent with a rheumatoid nodule (Fig.
2). A lung biopsy was considered but rejected in the face
of overwhelming clinical evidence of JRA, including
polyarthritis, a serological titer positive for RF, and JRA-
associated interstitial lung disease.
A review of the lung biopsy performed at 6 months of
age revealed a histologic pattern consistent with rheu-
matoid lung disease (Fig. 3). Three years since her diag-
nosis, her RF titer remains elevated, and the patient
has been treated with a variety of agents, including cor-
ticosteroids, methotrexate, hydroxychloroquine, and
naproxen. She has had worsening dyspnea, radiographic
infiltrates, and progressive restrictive lung disease [total
lung capacity: 1.38 L (36% predicted), FVC: 0.80 L
(27%), FEV1: 0.74 L (26%)], but her joint disease has
improved with no active synovitis.
DISCUSSION
Our 13-year-girl presented with rheumatoid lung dis-
ease as an infant. The lung disease preceded the devel-
opment of the articular manifestations of JRA by many
years. The apparent response of her rheumatoid lung dis-
ease to corticosteroids when she was an infant with an
interim asymptomatic period of 8–10 years before the
onset of joint symptoms and a recurrence of dyspnea and
interstitial infiltrates is even more striking for JRA.
The marked and persistent elevation of this patient’s
RF titer, the presence of a biopsy-proven rheumatoid
nodule, and the radiographic and lung function findings
of interstitial lung disease makes the diagnosis of JRA-
associated lung disease nearly certain. Similarly, sarcoid-
446 Noyes et al.
Fig. 3. The lung biopsy at 5 months of age reveals interstitial
pneumonitis. Note the thickened alveolar septa (arrows), con-
taining a mononuclear cell inflammatory infiltrate.
osis can produce arthritis, parenchymal infiltrates, and a
restrictive pattern on lung function testing; however, hi-
lar adenopathy is typically observed in sarcoidosis, but
was not seen in this case. Further, the Caucasian race of
this child, the normal values for angiotensin-1-converting
enzyme, serum and urine calcium, and the absence of
noncaseating granulomas and of ocular findings of uve-
itis or iritis makes sarcoidosis very unlikely. SLE can
also produce arthritis and pulmonary involvement, but
this patient had no rash or renal involvement typical of
SLE, and specific serology was negative for this disor-
der. The clinical features in this case and the absence of
vasculitis in her biopsy specimen makes other vascular
disorders producing joint abnormalities and lung disease,
such as polyarteritis nodosa, Wegener granulomatosis,
and Churg-Strauss syndrome, very unlikely.
The overall prevalence of pulmonary disease associ-
ated with JRA has been estimated to be 4–8% with more
patients having pleural than parenchymal manifestations;
pulmonary disease is usually observed only in systemic
onset disease.1,2,8 In the series reported by Athreya and
coworkers,2 six of seven patients with either pleural or
parenchymal abnormalities had evidence of lung disease
at the time of or after the diagnosis of JRA was made, but
again, all in systemic-onset patients. To our knowledge,
there are no reports of JRA-associated pulmonary disease
occurring in infancy with apparently complete resolution
induced by corticosteroid treatment and a subsequent
prolonged remission for several years before the onset of
typical joint symptoms of polyarticular-onset JRA. There
are only two reports of pulmonary parenchymal lesions
occurring before joint abnormalities2,3 and none in a se-
ropositive, polyarticular-onset JRA patient. In one,
Athreya and coworkers2 reported a 6-year-old in whom a
diagnosis of idiopathic pulmonary hemosiderosis was
made at 11 months of age and JRA developed at 21⁄2
years of age. In another, lymphoid interstitial pneumoni-
tis was diagnosed by lung biopsy 21⁄2 years before the
diagnosis of JRA.3 This patient had an excellent clinical
and radiographic response to erythromycin and predni-
sone with improvement in respiratory rate, exercise tol-
erance, and a clearing of her radiographic infiltrates.3
Similarly, our patient had an excellent response to corti-
costeroids at 6 months of age when her tachypnea and
oxygen dependence disappeared. By 3 years of age, she
had a normal chest radiograph and examination, and no
evidence of digital clubbing. However, when she was 10
years of age recurrent pneumonia developed, which, in
retrospect, was probably indicative of the onset of the
pulmonary parenchymal disease associated with her
JRA. Unlike other patients reported with JRA-associated
lung disease, our patient has had progressive respiratory
compromise with worsening dyspnea, radiographic infil-
trates, and pulmonary function abnormalities despite an-
tiinflammatory therapy. The onset of pulmonary symp-
toms 1–2 years before her presentation, the severe degree
of lung impairment as measured by PFTs, and the pres-
ence of digital clubbing suggests that a substantial degree
of established lung disease was present at the time of
diagnosis; this probably explains the poor response of her
lung disease to corticosteroids.
In summary, we have described a patient with an un-
usually early presentation of JRA who had biopsy-
proven pulmonary disease at 6 months of age and in
whom seropositive, polyarticular-onset JRA developed
many years later, accompanied by typical pulmonary
manifestations of JRA-associated lung disease including
dyspnea, digital clubbing, and a severe restrictive defect.
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