Cardiovascular and Pulmonary Pathology in Systemic Disease
Case 4 -
Nonspecific Interstitial Pneumonia (NSIP) Occurring in Association with Rheumatoid Arthritis.
Henry D. Tazelaar and Marie-Christine Aubry
PDF File (2.6 MB)
A 58-year-old man was noted to have a tender swollen proximal
interphalangeal joint of his right long finger on a routine physical examination. This was treated with
corticosteroids. He returned two months later complaining of pain and swelling in multiple joints. A
chest radiograph at the time showed bi-basilar infiltrates suggestive of pulmonary fibrosis. He
underwent open lung biopsy for diagnosis.
Slides illustrating Case 4 are in the accompanying PDF of the Powerpoint presentation.
Diagnosis: Nonspecific interstitial pneumonia (NSIP)
occurring in association with rheumatoid arthritis.
The patient was treated with various immunosuppressive agents
and prednisone. His lung function remained stable over the next six years allowing him to do those
activities he wished, given his physical limitations from the rheumatoid arthritis. He died of a
pulmonary embolus following treatment for lymphoma.
Sections show a wedge biopsy with fairly uniform changes
throughout. The interstitium is mildly widened, largely by a mononuclear cell infiltrate including
lymphocytes and plasma cells. Lymphoid aggregates are focally prominent and a rare germinal center is
present in some sections. Alveolar spaces vary from containing no cells to containing moderate numbers
of mononuclear cells and focally prominent edema fluid. Focal organizing pneumonia (bronchiolitis
obliterans organizing pneumonia, BOOP) is present on the majority of slides. There is minimal
architectural distortion, no significant interstitial fibrosis, and no honeycomb change. The features
are diagnostic of nonspecific interstitial pneumonia (NSIP), in this case occurring in a patient with a
newly diagnosed connective tissue disease, rheumatoid arthritis.
Lung involvement in patients with connective tissue disease (CTD) can be a source of significant
diagnostic difficulty for clinician and pathologist alike. Not only is the spectrum of pathology quite
broad, but with the exception of rheumatoid nodules, very few of the histologic lesions are unique. In
addition, the pathology in these patients may show overlap features between classic histologic
descriptions of entities, e.g. on a background of usual interstitial pneumonia, there may be superimposed
lymphoid hyperplasia. A further complicating factor is that lung involvement may precede the onset of
the full-blown disease by many months. Finally, the changes in the lung may be therapy related, either
as a direct effect of the drug e.g. methotrexate, or due to an opportunistic infection. Table 1
summarizes the pleuropulmonary changes which have been described in patients with rheumatoid arthritis.
Table 1 - Pleuropulmonary Manifestations of Rheumatoid Arthritis
| Pleural disease|
| Pleural effusion|
| Bronchopleural fistula|
| Necrobiotic nodules|
| Caplan's syndrome|
|Interstitial lung disease|
| Airway obstruction|
| Upper airway disease|
| Cricoarytenoid arthritis|
| Bronchiolitis obliterans with organizing pneumonia|
| Bronchiolitis obliterans|
|Pulmonary vascular disease|
| Primary or secondary pulmonary hypertension|
|Drug-related lung disease|
| Fibrobullous disease|
The largest study which assessed histopathologic findings in patients with RA is that of Yousem and
Colby (1985) who reviewed 40 open lung biopsies. A summary of their findings is found in Table 2.
Non-specific Interstitial Pneumonia
It is interesting to note that this manuscript was one of the first to characterize the histologic
findings of what is now recognized as NSIP, the category "chronic interstitial pneumonia:" a cellular
interstitial infiltrate of mononuclear cells, predominantly lymphocytes and plasma cells, without the
convincing interstitial scarring of UIP or DIP or the granulomatous reaction and bronchiolitis of
allergic alveolitis. This is almost the same description of histology as that utilized by Katzenstein
and Fiorelli in their landmark 1994 paper.
Katzenstein and Fiorelli reported 64 patients with NSIP. There was a slight female predominance and
the mean age of this group was 46 years (range 9 to 78 years). This turns out to be significantly
younger than most patients with UIP. The patients presented with dyspnea, cough and fever, with a mean
duration of symptoms of eight months.
Table 2 - Primary Pattern of Pulmonary Pathology in 40 Wedge Lung Biopsies from
Patients with Rheumatoid Arthritis
| Rheumatoid nodules ||13|
|Lymphoid Hyperplasia (including follicular bronchiolitis) ||5|
|Chronic interstitial pneumonia NOS, (consistent with NSIP) ||5|
|Diffuse alveolar damage ||2|
|Granulomatous inflammation (? Drug Rxn) ||1|
|Eosinophilic pneumonia ||1|
|Hypersensitivity pneumonitis ||1|
|Desquamative interstitial pneumonia ||1|
Yousem SA, Colby TV. Am Rev Respir Dis 1985;131:770-77.
NSIP is characterized by the presence of chronic interstitial inflammation and/or fibrosis. In
contradistinction from UIP, NSIP is temporally uniform, and can be either patchy and bronchiolocentric or
diffuse. Rare granulomas were identified in 8% of Katzenstein's cases, as were focal areas of
bronchiolitis obliterations organizing pneumonia (50%).
NSIP lacks the spatial heterogeneity of UIP and the changes are less often accentuated in a
subpleural, paraseptal distribution. The interstitium is widened by chronic inflammatory cells:
lymphocytes, macrophages, and plasma cells. Some cases are associated with interstitial fibrosis, but it
tends to be all of the same age and more uniform on low-power appearance. In some cases, inflammation is
not present and fibrosis predominates.
What is most interesting, from the perspective of the current discussion is that patients with NSIP
may have a variety of associated diseases, especially CTD's, (rheumatoid arthritis, lupus,
dermatomyositis, scleroderma, and Sjögren's syndrome) were present in 16% of Katzenstein's cases. In a
recent Mayo study (Midthun et. al.), as many as 33% of 33 patients with NSIP had a CTD at the time of
diagnosis including polymyositis/dermatomyositis, progressive systemic sclerosis, and overlap syndrome.
There has been some debate in the literature about whether patients with pulmonary fibrosis
associated with a CTD have a better prognosis than those who have pulmonary fibrosis unassociated with
connective tissue disease. One of the most frequently quoted papers is by Wells, et al. Unfortunately,
the publication of this paper preceded the widespread recognition of NSIP as a subset of patients with
the clinical syndrome "idiopathic pulmonary fibrosis". Given the fact that patients with NSIP appear to
have a better prognosis than patients with UIP, and may present in a very similar fashion clinically,
this issue needs to be re-examined with this new category included. In the Midthun study, patients with
biopsy proven NSIP and connective tissue disease had a survival similar to that of patients with
There is also debate whether separating NSIP into histiologic subsets based on the degree of fibrosis
reveals further prognostic information. In Katzenstein and Fiorelli's original series, death occurred
among patients who had fibrosis and inflammation (30%) or fibrosis alone (50%) but no deaths were
reported in those patients with inflammation alone. Travis et al reported a 35% 10-year survival in a
combined group of patients with a fibrosing and cellular or fibrosing pattern and 100% for those with a
cellular pattern. In the Midthun study, we identified eight patients with cellular (group I), twenty-one
with cellular and fibrotic (group II), and four with a fibrotic histologic pattern (group III). Survival
did not differ between groups–nor was survival different when those within groups II and III were
combined and compared to group I. Histologic features of honeycombing were absent in our series.
Honeycomb change was present in 20 of 22 biopsies showing fibrotic NSIP as reported by Travis et al., and
in 9 of 15 fibrotic NSIP by Nagai et al. The absence of honeycomb change in our series suggests that
what is called NSIP may differ between reported series and may account for the survival differences
Usual Interstitial Pneumonia
The frequency of usual interstitial pneumonia in open lung biopsies from patients with diffuse lung
abnormalities in connective tissue disease is between 20-30%. In the Yousem and Colby series, it was
present in 20% of patients with rheumatoid arthritis undergoing open lung biopsy. In a series of
patients with dermatomyositis(Douglas et. al.), it was identified in 81% of patients to undergo biopsy,
and in patients with the CREST syndrome, 30%.
On both high resolution CT scan and wedge biopsies, UIP tends to have a peripheral subpleural basilar
pattern of interstitial fibrosis and honeycomb change. The changes also tend to follow the interlobular
Histologically, the hallmark of UIP is heterogeneity. There are areas of normal lung, areas of old
fibrosis with dense collagen deposition and honeycomb change, and areas of more recent organization
called "fibroblast foci". In addition, there are usually varying degrees of interstitial chronic
inflammation. While characteristic, honeycomb change is non-specific, and also may not be seen on a
biopsy. If a biopsy only shows honeycomb change, attention to the clinical history may yield
clues that UIP is the most likely etiology.
Some literature suggests that patients with histologically proven UIP have a similar survival
regardless of whether they have an associated connective tissue disease. Bjoraker, et. al., report
mortality of 63% at two years for patients with lone UIP. Yousem, et. al., reported a 60% mortality in
patients with rheumatoid arthritis. A recent study by Utz, et. al., however, clearly showed superior
survival in patients with biopsy-proven UIP associated with a connective tissue disease.
The NSIP/UIP differential is summarized in Tables 3 & 4.
Table 3 - UIP and NSIP: Contrasting Features:
| ||UIP ||NSIP|
|Mean age ||57 ||49|
|Childhood ||No ||Occasional|
|Onset ||Insidious ||Subacute, insidious|
|Fever ||No ||Frequent|
|Mortality ||68% ||11%|
|(mean survival) ||(5-6-yrs) ||(17 mos)|
|Response to steroids ||Poor ||Good|
|Recovery possible ||No ||Yes|
Table 4 - UIP and NSIP: Contrasting Features:
| ||UIP ||NSIP|
|Temporal appearance ||Variegated ||Uniform|
|Inflammation ||Scant ||Prominent to scant|
|Collagen fibrosis ||Patchy ||None to diffuse|
|Fibroblast proliferation ||Focal ||Rare|
|BOOP ||No ||Focal|
|Honeycomb change ||Yes ||Rare (micro honeycomb)|
|Intraalveolar macrophages ||Focal ||Patchy|
|Hyaline membranes ||No ||No|
Lymphoid Interstitial Pneumonia
Lymphoid interstitial pneumonia (LIP) occurs most frequently in Sjögren's syndrome and rheumatoid
arthritis. The term lymphoid interstitial pneumonia also has some overlap with the histologic entity
follicular bronchiolitis (see below).
The majority of patients with LIP (unassociated with AIDS) are women, 2:1 female:male ratio. The
mean age at presentation is 50 years. Patients tend to present with dyspnea and cough, and more rarely,
with chest pain, fever, and weight loss. Ninety-two percent of these patients also have a
dysproteinemia, either hypergammaglobulinemia or hypogammaglobulinemia. A large proportion of patients
with LIP have some type of autoimmune disease (20%), Sjögren's syndrome, primary biliary cirrhosis, or
chronic active hepatitis. Chest x-rays tends to show bibasalar interstitial opacities and usually there
is no lymphadenopathy.
LIP is characterized histologically by dense diffuse interstitial lymphoid infiltrates comprised of
plasma cells and lymphocytes, as well as macrophages. In 20% of cases, germinal centers may be present
in the background. Small numbers of non-necrotizing granulomas may be seen 30% and, amyloid deposits
have been reported in about 10% of cases.
Currently, a case can be accepted as lymphoid interstitial pneumonia only after a diagnosis of
malignant lymphoma has been excluded by appropriate immunophenotypic and molecular genetic studies, as
many cases formerly classified as lymphoid interstitial pneumonia probably represent low grade lymphomas
in the lung.
Airway Disease: Follicular
As mentioned, there is some overlap between lymphoid interstitial pneumonia and follicular
bronchitis/bronchiolitis. The latter also tend to occur in women, with an age range of 15-77 years. The
underlying disease in this group of patients is again highly weighted towards patients with connective
tissue disease, including rheumatoid arthritis and Sjögren's syndrome. Patients with follicular
bronchiolitis present with dyspnea, cough, and fever and a chest radiograph often shows bilateral
reticular or reticular-nodular infiltrates, reflecting that this is generally a diffuse process.
Histologically, it is comprised of peribronchiolar (or peribronchial) lymphoid follicles with
secondary germinal centers, in the absence of primary large airway disease such as bronchiectasis. This
may be associated with scarring, but it tends to be focal, and associated with the airway alone.
Recently Hayakawa et al reported their experience with follicular bronchiolitis associated with
rheumatoid arthritis. Some of these patients had received gold alone or gold and Penicillamine. Their
main symptoms were productive cough and dyspnea. They tended to have inspiratory crackles and mild
obstruction on pulmonary function tests. Computed tomography showed centrilobular nodules with branching
structures, and airway wall thickening. The outcome of these patients was quite good with a survival of
88%. One died of malignant lymphoma. Interestingly, some of these patients appeared to respond to
Bronchiolitis Obliterans Organizing
BOOP has long been known to be associated with connective tissue diseases and in the now classic
paper by Epler et al, a connective tissue disease was present in about 10% of patients with BOOP. It
tends to be most commonly associated with rheumatoid arthritis and systemic lupus erythematosus, but has
also been reported in association with scleroderma and dermatomyositis/polymyositis.
BOOP tends to be patchy and in typical cases, areas of involvement are separated by relatively normal
lung. The characteristic feature is the polypoid-shaped mass of proliferating fibroblasts in terminal
bronchioles (bronchiolitis obliterans), and within alveolar ducts and alveolar sacs (organizing
pneumonia). In some biopsies, particularly transbronchial biopsies, only the organizing pneumonia
component may be present, but in the right clinical setting, the findings may be interpreted as
"consistent with BOOP".
Constrictive obliterative bronchiolitis tends to occur most commonly in rheumatoid arthritis. It has
also been reported in systemic lupus erythematosus.
The earliest observation of the association between constrictive bronchiolitis and rheumatoid
arthritis was made by Geddes in 1977. He reported on six women, five of whom had rheumatoid arthritis,
three of whom were on Penicillamine, and one of whom was on gold therapy. They presented with
progressive breathlessness, cough (usually non-productive), and on physical examination, they tended to
have signs of airway problems with inspiratory squeaks. The work-up revealed marked obstruction on
pulmonary function tests. In this particular study, the disease had a poor prognosis. Five out of the
six patients were dead within 18 months. A more recent evaluation of the outcome of patients with
constrictive obliterative bronchiolitis has been done by Hayakawa, et al. What is most interesting is
that in their group of patients, they had symptomatic improvement on antibiotics with 100% survival.
Histologically, the disease is characterized by intramural and peribronchiolar fibrosis with
narrowing of the terminal and respiratory bronchioles, or complete fibrous obliteration of the airway
lumen. This can be associated with smooth muscle hyperplasia. Bronchiolectasis and mucus stasis may be
seen as a secondary phenomenon. The changes may be very focal and surrounding parenchyma is usually
remarkably normal. The degree of airway-centered inflammation is variable, but in many cases, it is
non-existent. An elastic stain may be necessary to appreciate the extent of bronchiolar constriction or
even to recognize that an area of scarring represents a fibrotic bronchiole. In the absence of
bronchiolar scarring, the disease can be inferred by the presence of bronchiolar dilatation and mucus
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