Case 4 -

Nonspecific Interstitial Pneumonia (NSIP) Occurring in Association with Rheumatoid Arthritis. Henry D. Tazelaar and Marie-Christine Aubry

PDF File (2.6 MB) Clinical History 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. Follow-up 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. Discussion 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 Pleuritis Pleural effusion Pneumothorax Bronchopleural fistula Empyema Rheumatoid nodules Necrobiotic nodules Caplan's syndrome Interstitial lung disease Airway involvement Airway obstruction Upper airway disease Cricoarytenoid arthritis Bronchiectasis Bronchiolitis obliterans with organizing pneumonia Bronchiolitis obliterans Pulmonary vascular disease Vasculitis Primary or secondary pulmonary hypertension Drug-related lung disease Miscellaneous Infection Fibrobullous disease Amyloidosis 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 BOOP 6 UIP 5 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 idiopathic NSIP. 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 between series. 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 septa. 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 bronchitis/bronchiolitis. 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 antibiotic therapy. Bronchiolitis Obliterans Organizing Pneumonia 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". Obliterative (Constrictive) Bronchiolitis 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 stasis. References Colby, T.V., Pulmonary pathology in patients with systemic autoimmune diseases. Clin Chest Med, 1998. 19(4):587-612, vii. Despaux, J., et al., Rheumatoid arthritis and bronchiectasis. A retrospective study of fourteen cases . Rev Rhum Engl Ed, 1996. 63(11): p. 801-8. Douglas WW, Tazelaar HD,Hartman TE, Hartman RP, Decker PA, Schroeder DR, and Ryu JH. Polymyositis—Dermatomyositis-associated Interstitial Lung Disease. Am J Respir Crit Care Med. 164;1182-1185:2001. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Eng J of Med 312:152-158, 1985. Flaherty KR, Colby TV, Travis WD et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Resp Crit Care Med 2003;167:1410-1415. Geddes DM, Corrin B, Brewerton DA, Davies RJ, Turner-Warwick M. Progressive airway obliteration in adults and its association with rheumatoid disease. Quarterly J of Med, New Series XLVI, 184:427-444, 1977. Hayakawa H, Sato A, Imokawa S, Toyoshima M, Chida K, Iwata M. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med 154:1531-1536, 1996. Helmers, R., J. Galvin, and G.W. Hunninghake, Pulmonary manifestations associatedwith rheumatoid arthritis . Chest,. 100(1): p. 235-8, 1991. Hubbard R, Venn A. The impact of coexisting connective tissue disease on survival in patients with fibrosing alveolitis. Rheumatology 2002; 41:676-679. Katzenstein A-L, Fiorelli RF. Non-specific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 18(2):136-147, 1994. Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease, Third Edition, Published by W. B. Saunders Company, 1997. Lynch JP III, Belperio J, Flint A, Martinez F. Bronchiolar Complications of Connective Tissue Disorders. Seminars in Resp and Crit Care Med 20:149-68;1999. Morgan C, Knight C, Lunt M et al. Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis 2003;62:146-150. Muir TE, Tazelaar HD, Colby RV, Myers, JL. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc 72:639-642, 1997. Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clinics in Chest Medicine 14:611-622, 1993. Shadick, N.A., et al., Bronchiectasis. A late feature of severe rheumatoid arthritis. Medicine (Baltimore), 1994. 73(3): p. 161-70. Tanaka N, Kim JS, Newell JD, Brown KK, Cool CD, Meehan R, Emoto T, Matsumoto T, Lynch DA. Rheumatoid arthritis-related lung diseases: CT findings. Radiology 2004; 232:81-91. Tanoue, L.T., Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med, 1998. 19(4): p. 667-85, viii. Tansey et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology 2004; 44:585-596. Tazelaar HD, Viggiano RW, Pickersgill J, Colby TV. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 141:727-733, 1990. Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 14:1112-1125, 1990. Utz JP, Ryu JH, Douglas WW, Hartman TE, Tazelaar HD, Myers JL, Allen MS, Schroeder D. High short-term mortality following lung biopsy for usual interstitial pneumonia. Eur Respir J. 2001 Feb;17(2)175-9. Wells AU, Cullinan P, Hansell DM, Rubens MB, Black CM, Newman-Taylor AJ, Du Bois RM. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 149:1583-1590, 1994. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol 16:700-706, 1985. Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 21:467-474, 1990. Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 131:770-777, 1985