Diagnoses: Cavitary rheumatoid nodules, multiple. Angiitis, necrotizing, muscular arteries and small veins. Nonspecific interstitial pneumonia, mild. Constrictive, cicatricial bronchiolitis obliterans, focal. Chronic fibrosing pleuritis

Comment: This man's major pulmonary findings were the cavitary rheumatoid nodules. Cancer and infection were excluded by histology and culture. Given the pattern of angiitis and granulomatosis (nodules), Wegener's granulomatosis (WG) could not be excluded histologically. The lack of upper respiratory and renal abnormalities, the negative ANCAs, and the presence of known rheumatoid arthritis, in which similar histologic findings occur, favored the diagnosis of rheumatoid angiitis and nodules. Further, the presence of early nodules in the pleura and the marked pleural thickening are not features of WG.

Although the interstitial pneumonia appeared mild and focal in the biopsies, it may account for the crackles heard at the left base. The low DLCO may be related to the vascular changes and the interstitial lung disease. Finally, mild bronchiectasis was present on the HRCT. Along with the constrictive, cicatricial bronchiolitis obliterans seen in the biopsies, it indicates that some degree of airway involvement may be contributing to the cough and dyspnea.


Pulmonary Manifestations of Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is a potentially crippling, systemic disease that affects about 2 million Americans, of whom about 75% are women. Revised criteria to distinguish it from other rheumatic diseases are listed in the table [1].

1987 Criteria for Classification of Rheumatoid Arthritis* [1]

  1. Morning stiffness of joints lasting > 1 hr
  2. Arthritis (soft tissue swelling or fluid) of 3 or more joint areas simultaneously (PIP, MCP, wrist, elbow, knee, ankle, MTP)
  3. Arthritis of hand joints
  4. Symmetric, simultaneous arthritis
  5. Rheumatoid nodules
  6. Serum rheumatoid factor
  7. Radiographic changes

*Rheumatoid arthritis is diagnosed if the patient has 4 or more criteria. Criteria 1-4 must be present for 6 or more weeks. The terms classic, definite, or probable are not used as modifiers.

Lung disease in RA: Several different patterns of disease, each having a different prognosis, occur. The diseases may be related to the rheumatologic disease itself, a medication, an interaction of dust and the rheumatologic disease, or an infection due to immunosuppression. Reasons for biopsy include symptoms or radiographic opacities unresponsive to therapy, acute clinical changes, nodules, and acute respiratory failure [2]. An open lung biopsy can be helpful in making a specific diagnosis (our patient and see below). Clinical and laboratory data do not predict the histologic patterns. HRCT can help to define the type and extent of lesions present.

Specific histologic patterns include [2]:

Note: Histologic examination may show a combination of these patterns, and elastic tissue stains are mandatory to identify airway and vascular abnormalities. Histologic diagnosis should specify type and severity of disease [2].

Pleural Disease

Non-specific, fibrous pleural thickening, effusions, or both may be found at autopsy in 1/2 of patients with rheumatoid arthritis [4]. Imaging methods yield a smaller fraction of patients with pleural disease. By HRCT, 22.5% of 40 outpatients with RA had pleural disease [5]. Plain radiographs showed sequelae of pleurisy in 18.8% of 309 patients with RA compared to 10.7% of a hospitalized, control population without rheumatic disease [6]. Histologically, the fibrosis is accompanied by a mild chronic inflammatory infiltrate and occasional lymphoid follicles. Rheumatoid nodules may also be present.

Effusions accompany the pleural disease at some time during the course in about 5% of patients. The effusions are exudates with high protein (pleural fluid protein/serum protein >0.5) and LDH content (pleural fluid LDH/serum LDH > 0.6), low glucose (often <15 mg/dL), and PMNs and lymphoid cells [7,8]. Chronic effusions are frequently turbid or milky because of the presence of cholesterol crystals. These pseudochylous effusions can be distinguished from chylous effusions, which also have a milky appearance, by examination of a wet mount of fluid under the microscope [7]. In pseudochylous effusions, the distinguishing rhomboid crystals of cholesterol are seen best by polarized light. The triglyceride level in the fluid is not elevated, as it is in chylothorax. Cytologically, the presence of multinucleated giant cells and necrotic material, presumably derived from active nodules in the pleura, has been described as pathognomonic of effusions of RA [9]. However, the diagnosis is seldom made in this manner. Some effusions resolve spontaneously; others require simple removal of fluid, but some require pleurodesis or decortication [4].

Rheumatoid Nodules

Pulmonary rheumatoid nodules are immune-mediated granulomas with necrotic centers, palisaded histiocytes immediately adjacent to the necrosis, a layer of chronic inflammatory cells, and a fibrous capsule. In the early stages, the centers show numerous inflammatory cells undergoing necrosis. Histologically, pulmonary rheumatoid nodules are identical to subcutaneous nodules, which are more common. Nodules tend to be round, but as with infectious granulomas, they may become more irregular in outline as they enlarge. The term "necrobiotic nodule" is used to refer to the non-infectious nature of the granuloma.

Clinical aspects: Pulmonary rheumatoid nodules are more frequent in men than women, and occur especially in men with cutaneous nodules. In the lung, the nodules, either single or multiple, tend to be peripheral or pleural and range from millimeters up to 7 cm in diameter. They may increase in size or resolve spontaneously [3,10]. They do not usually interfere with pulmonary function unless they are large or cavitary [4]. Cough or hemoptysis may be associated with cavitary nodules [4]. By HRCT, they were found in 12.5% of 40 outpatients (28 men), about equally in 20 with pulmonary symptoms and 20 without [5]. Occasionally, they may calcify, and rarely they may cause a bronchopleural fistula, if they erode through the pleura [8,10]. Eosinophilia has been noted in two patients [11]. Nodules may be a complication of methotrexate therapy. In one report, 10 patients developed multiple nodules on the fingers, an unusual location, in association with methotrexate therapy, despite control of joint disease by the drug [12]. In another report, multiple, bilateral pulmonary nodules were found in a patient with progressive dyspnea. The dyspnea developed about 1 year after initiation of treatment with methotrexate, at which time there was improvement of his arthritis. The dyspnea subsided when the methotrexate was stopped, but the nodules, which were not biopsied, persisted [13]. The differential diagnosis includes lung cancer and infection [3], both of which were considered in our patient. Biopsy is often necessary for diagnosis [4].

Caplan's syndrome: In 1953, Caplan described a radiographic appearance characterized by variable numbers of radiographic nodules, 0.5 to 5 cm in diameter, distributed bilaterally throughout the lungs of coal workers with RA [14]. Just as in rheumatoid nodules in non-coal workers, they could enlarge, coalesce, cavitate, shrink, or calcify, The appearance differed from that of the pneumoconiosis alone and from progressive massive fibrosis (PMF) and was subsequently described in workers with silicosis or asbestosis, and workers with circulating rheumatoid factor, but without arthritis [15]. The arthritis may precede or occur after the development of the lung nodules, and the severity of arthritis is not related to the severity of the lung lesions [15]. Epidemiologically, the syndrome occurs in persons with low grade (category 0 or 1) as frequently as in those with high grade (category 3) pneumoconiosis, distinguishing it from PMF. Estimates of frequency, 2-6% of persons with coal workers' pneumoconiosis, are similar to the frequency of rheumatoid factor in the general population, suggesting that the presence of dust in persons with rheumatoid factor predisposes to the nodules. Histologically, the nodules must be distinguished from those of silicosis and coal workers [16].

Histologically, the nodules are similar to ordinary rheumatoid nodules except that Caplan's nodules in coal miners have accumulations of black pigment in layers within the region of central necrosis. In the setting of RA and dust exposure, the differential diagnosis of pulmonary nodules includes rheumatoid nodules (Caplan's syndrome), silicotic nodules, PMF, tuberculosis, and tumor [17].

Interstitial Lung Disease

Diffuse alveolar damage: Two patients with this pattern on lung biopsy have been reported. In one with underlying diffuse interstitial fibrosis, there was recovery, and the fibrosing disease was stable at 4 years, but the second patient died at one month [2].

Bronchiolitis obliterans organizing pneumonia (BOOP): The clinical presentation of these patients is similar to that of patients with diffuse interstitial fibrosis (see below). In a review of 40 open lung biopsies from patients with rheumatoid arthritis, BOOP occurred in 6, and these patients had a more favorable outcome than 5 patients with diffuse interstitial fibrosis [2]. In another report of 3 patients with BOOP, whose symptoms improved on therapy, the similarity of the clinical picture to that of diffuse interstitial fibrosis was also noted, and the importance of open lung biopsy for diagnosis was emphasized [18]. The necessity of open biopsy might be debated, as both conditions are treated in the same way. In another patient, the acute episode improved, but restrictive disease persisted at one year [19].

Histologic changes: These lungs show granulation tissue in bronchiolar lumens, alveolar ducts, and proximal alveoli with sparing of more distal alveoli. Interstitial inflammation is confined to the areas with granulation tissue. Foamy alveolar macrophages are present at the margins. Lesions are all of the same age.

Diffuse interstitial pulmonary fibrosis (DIPF): Up to 40% of patients with RA may have interstitial lung disease [20,21]. However, the frequency depends on the tests used to define it (PFTs, chest radiographs, symptoms) and on the study population itself, as pulmonary disease is more likely in hospitalized patients than in outpatients with milder disease [4]. Severe, symptomatic DIPF is rare. A report from Finland estimated that its incidence was 1 case/3500 patient-years. Further, at least 14% of their 57 cases had drug-induced lung disease. Of 49 patients with severe disease that could not be related to therapy, the five-year survival was 39%, with a median survival of 3.5 years, similar to that for idiopathic pulmonary fibrosis. On the other hand, by PFTs or radiographs, 28% and 10%, respectively, of patients had DIPF, indicating that milder disease is very common in RA [22]. For example, in a group of 20 clinic patients with RA and no symptoms, signs, or radiographic manifestations of lung disease, HRCT showed interstitial disease in 4, bronchiectasis in 4, pleural disease in 7, and parenchymal nodules in 2. Even in the 20 clinic patients who had clinical evidence of interstitial disease, HRCT showed other changes including emphysema, bullae, bronchiectasis, pleural disease, and parenchymal nodules [5]. The outcome for those with less severe disease is unknown. It is probable that the histologic changes would now be classified as nonspecific interstitial pneumonia rather than usual interstitial pneumonia, and thus, outcomes might be more favorable than in those with UIP, as in patients with scleroderma-associated DIPF [23].

Clinical features: Interstitial disease usually follows the onset of arthritis by months to years, but occasionally may precede it [4,8,21]. In contrast with RA in general, men are more affected than women (2:1), subcutaneous nodules are often present, rheumatoid factor is present at high titer [4], and cigarette smoking may be an additional confounding or contributing factor [24]. Patients present with dyspnea and nonproductive cough. Fever, pleurisy, and hemoptysis may signify a coexisting type of lung disease. PFTs show a restrictive pattern and there may be hypoxemia that worsens with exercise. Diffusing capacity is reduced [4]. Eosinophilia has also been noted in patients with pulmonary fibrosis [25]. Several clinical studies are summarized below.

In a study of 155 patients with RA (2/3 of whom were hospitalized) and 95 controls without RA matched for age, sex, and smoking, it was found that 17% of the RA patients vs 5% of controls had chest crackles and 21% of RA patients vs 7% of controls had abnormal chest radiographs. These pulmonary abnormalities were associated with a restrictive ventilatory defect, smoking, active joint disease, cutaneous nodules, and gold therapy [24].

In a radiographic study of 309 patients with RA and an age and sex matched control group admitted to the hospital, diffuse reticulonodular fibrosis was found in 4.5% of those with RA. Only in females was the percentage increased over that in the control population (5.2% vs 0). Fibrosis did not occur until the fourth decade, and it was associated with subcutaneous nodules. In 6 patients, who were followed, there was no progression of lung disease after a mean of 5.2 years [6].

In an uncontrolled study of 41 patients with RA, 41.4% had an abnormal DLCO and accompanying restrictive abnormalities, but only about 1/2 of them had abnormal chest radiographs [26]. In another uncontrolled study of 129 patients with RA (84 hospitalized, 39 outpatients), abnormal chest radiographs or reduced VC or DLCO were found in 35%. Individually, radiographs were abnormal in 18%, VC or DLCO was reduced in 28%, and abnormalities in all three were found in 2%. The authors concluded that both chest radiographs and PFTs should be used to evaluate lung disease [27]. Many of the patients in both of these studies had no symptoms.

Diagnosis and Treatment: As in patients with other collagen-vascular disease and DIPF, open biopsy for diagnosis is seldom required, but bronchoscopy with transbronchial biopsy may be necessary to exclude infection. Discontinuing drugs known to cause lung disease may reverse the lung disease. In other cases, the use of steroids and cytotoxic agents, when necessary, has been associated with little success [22].

Airway Disease

Constrictive, follicular bronchitis/bronchiolitis: This reaction pattern tends to occur in middle-aged women, who present with progressive dyspnea, productive cough, and fever. Radiographs show reticulonodular opacities, but no bronchiectasis. PFTs show a restrictive, occasionally obstructive, or a mixed pattern [28-30]. Histologically, peribronchial/-iolar, mixed lymphoplasmacellular infiltrates with lymphoid follicle and germinal center formation surround and compress airway lumens. A mild alveolar wall infiltrate by similar cells and focal interstitial scar may be present. Airway lumens often contain a purulent exudate. Three patients followed for over 5 years became asymptomatic, but 2 others died of disease at 2.5 and 10 months, respectively. The histologic differential diagnosis includes viral pneumonia, hypersensitivity pneumonia, lymphoid interstitial pneumonia, and lymphoma [29].

Constrictive, cicatricial bronchiolitis: This rare complication also usually occurs in middle-aged women [31,32], but the disease has also been reported in a 12-year-old girl with juvenile RA [33]. Another report describes constrictive bronchiolitis as the only manifestation of disease in a 62-year-old man with a positive rheumatoid factor (1:1256), a family history of RA, but no arthritis [34]. Clinically, disease is characterized by a rapid (weeks to months) onset of dyspnea, dry cough, and a high-pitched mid-inspiratory squeak. PFTs show obstruction, and the chest radiograph shows hyperinflation. In one series, four of five patients died after 5 to 18 months [31]. This lesion has also been linked to both gold and penicillamine therapy, and these drugs should be stopped if this complication occurs [31-33,35].

More recently, clinical-pathologic correlations were described in 15 patients with bronchiolar disease and RA seen over a period of 15 years (1980-1994). Of the 15, 8 were female and 5 were smokers. The mean age was 57 years. Cough productive of yellowish sputum was present for a mean of about 5 years. Dyspnea was present in only 3. Late end-inspiratory crackles were common. Most had microorganisms (H. influenzae, P. aeruginosa) cultured from the sputum, repeatedly. There was mild airflow obstruction (FEV1/FVC <70% in 8), whereas DLCO was preserved. Based on histologic features, patients were divided into those with predominantly follicular bronchiolitis (FB) (N=8) and those with constrictive, cicatricial bronchiolitis obliterans (OB) (N=7). Interestingly, those with predominantly FB sometimes (3/8) had OB, in addition. Similarly 3/7 with OB also had FB. Most of the patients had chronic sinusitis. Treatment of 12 patients with erythromycin for a mean of 15 to 19 months produced improvement in cough, sputum, or dyspnea but no changes in the chest CT or PFTs. None died of respiratory failure over a follow-up period of about 2 years. The authors hypothesized that the continuous antigenic stimulation by microorganisms contributed to the airway disease [36]. In another study of PFTs in 100 patients with RA and normal chest radiographs and 84 control subjects matched for age, sex, and smoking habits, airway obstruction was found in at least 32% of those with RA. Values for FEV1/FVC and MMEF were significantly lower in the RA patients than in the control group, suggesting that the obstruction was not caused solely by cigarette smoking. The authors also speculated about the role of microorganisms in causing the airway disease [37].

Radiographic changes in bronchiolitis: Airway changes in RA were studied prospectively by HRCT and pulmonary function testing in 50 patients (9M: 41 F, mean age 58, 39 non-smokers), all without radiographic evidence of changes related to RA. HRCT was more sensitive (35 patients) than PFTs (13 patients) in detecting abnormalities. The airway changes were not related to the severity of rheumatologic findings or to smoking. The HRCT findings are summarized in the table [38].

HRCT Features of Airway Disease [38]

Histologic changes in bronchiolitis: The diagnosis is easily missed unless one looks specifically for airways next to each pulmonary artery. The airways can be completely replaced by non-specific scar, but usually some trace of airway elastic tissue can be found with an elastic van Gieson stain. In contrast to the frequent lesions of BOOP, constrictive bronchiolitis involves proximal, less numerous bronchioles. Only 1 or 2 may be found in several sections. Although scar tissue is usually present, in more active disease, granulation tissue can be found. The scar occupies just the bronchiole and not adjacent alveoli, as in BOOP.

Bronchiectasis: Bronchiectasis was described in 18 patients as a late complication of RA with an incidence of 0.6%. Females were represented more than males (14:4), and the mean age was 64 years. The mean duration of arthritis was 25 years before bronchiectasis developed, and productive cough, recurrent infections, hemoptysis, and dyspnea were present for an average of 4 more years before diagnosis. These patients probably represent the advanced stage of the more common, mild bronchiectasis noted on HRCT in the patients diagnosed with bronchiolitis described above, and as seen in the current patient [39] .

Vascular Changes

Medium-sized vessels: Angiitis in RA is associated with constitutional symptoms, subcutaneous nodules, neuropathies, rash or purpura, leg ulcers, and ischemic changes [40,41]. In 1953, Sokoloff, et al. described granulation tissue and associated inflamed vessels as precursors to the definitive cutaneous rheumatoid nodule [42]. This scenario accounts for the increased frequency of these nodules in patients with other manifestations of angiitis. Our histologic finding of angiitis in relation to nodules in the lung further supports this hypothesis. Other manifestations of angiitis in the lung, which occur in women, include both acute, diffuse angiitis with respiratory failure [43] and plexogenic angiopathy with pulmonary hypertension but little parenchymal fibrosis [44-46]. More common than these changes are the vascular changes that accompany interstitial lung disease--medial and intimal thickening and adventitial fibrosis without vasculitis--which may account for increases in pulmonary arterial pressure. Another cause of pulmonary hypertension reported in one patient is plasma hyperviscosity syndrome caused by a polyclonal gammopathy. It was reversed by plasmapheresis (mean PA pressure declining from 53 to 30) [47].

Alveolar hemorrhage/capillaritis: Five cases of RA and pulmonary-renal syndrome with alveolar hemorrhage have been reported [48,49]. One showed capillaritis on biopsy [49], and one had a positive p-ANCA test [48]. All recovered from the alveolar hemorrhage. Three other patients with RA, diffuse alveolar hemorrhage, and pulmonary capillaritis had no evidence of systemic angiitis or glomerulonephritis at the time of diagnosis. Two had pulmonary immune-complex deposition. Small pulmonary arteries were also involved in one patient. Tests for ANCAs were negative. All were treated with methylprednisolone ± cyclophosphamide. One died of a myocardial infarct, and the other two were alive without recurrence at 16 and 48 mo, respectively [50].

Causes of Death in Autopsied Patients with Rheumatoid Arthritis, 1960-1990 (N=81)

The causes listed in the figure do not reflect the incidence of pulmonary fibrosis. For example, 7 of 8 who died of respiratory failure had pulmonary fibrosis, but pulmonary fibrosis was found in 28 patients (34.6%) overall, many of whom died of pneumonia. Two cases of pulmonary angiitis that were not associated with fibrosis occurred [51].

Pathogenesis and Treatment

RA is believed to be an immune-mediated disease that causes injury to the synovium and other tissues in persons with genetic susceptibility (HLA-DR4). The initiating event is unknown, but viral infection is a possibility. For example, the evidence for Epstein-Barr viral infection as a potential initiator of RA by means of molecular mimicry (antigenic sequence homologies of viral and human proteins) and defects in T-cell cytotoxic function has recently been reported [52]. In studies of the pathogenesis of lung disease, abnormal alpha-1-antitrypsin phenotypes (non-MM type) were found in 50% of 22 patients with RA and DIPF compared to 14% in 200 controls, suggesting that altered protease activity may play a role in lung disease [53].

In the past, a number of cytotoxic and immunosuppressive drugs have been used to treat the disease, but responses are often inadequate. Recently, attention has been turned to blocking inflammatory mediators of disease. Of all the mediators found in the rheumatoid joint, tumor necrosis factor-alfa (TNF-alfa) appears to play a key role in disease. Blocking its activity reduces symptoms of the disease. Currently, two blockers of TNF-alfa (infliximab and etanercept) are available. Each is being used, usually in combination with methotrexate, the main therapy of choice. Both gave rapid and sustained clinical improvement in a majority of patients treated in 6-month trials. In addition, depending on the study, titers of rheumatoid factor, levels of C-reactive protein, and ESR also fell. The drugs are contraindicated in patients with severe infections, in which decreased TNF might be detrimental [54,55]. Long-term results and cost effectiveness are still unknown, and there is no evidence that the anti-TNF therapy affects the lung disease.

References:

1. Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31:315-324.

2. Yousem S, Colby T, Carrington C. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 1985; 131:770-777.

3. Jolles H, Moseley P, Peterson M. Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma. Chest 1989; 96:1022-1025.

4. Hunninghake G, Fauci A. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 1979; 119:471-503.

5. McDonagh J, Greaves M, Wright A, Heycock C, Owen J, Kelly C. High resolution computed tomography of the lungs in patients with rheumatoid arthritis and interstitial lung disease. Br J Rheumatol 1994; 33:118-122.

6. Jurik A, Davidsen D, Graudal H. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol 1982; 11:217-224.

7. Case Records of the Massachusetts General Hospital. N Engl J Med 1994; 331:1642-1647.

8. Helmers R, Galvin J, Hunninghake G. Pulmonary manifestations associated with rheumatoid arthritis. Chest 1991; 100:235-238.

9. Naylor B. The pathognomonic cytologic picture of rheumatoid pleuritis. Acta Cytol 1990; 34:465-473.

10. Rubin E, Gordon M, Thelmo W. Nodular pleuropulmonary rheumatoid disease. Am J Med 1967; 42:567-581.

11. Portner M, Gracie Jr W. Rheumatoid lung disease with cavitary nodules, pneumothorax and eosinophilia. N Engl J Med 1966; 275:697-700.

12. Kerstens P, Boerbooms A, Jeurissen M, Fast J, Assmann K, van de Putte L. Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases. J Rheumatol 1992; 19:867-871.

13. Alarcón G, Koopman W, McCarty M. Nonperipheral accelerated nodulosis in a methotrexate-treated rheumatoid arthritis patient. Arthritis Rheum 1993; 36:132-133.

14. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953; 8:29-37.

15. Caplan A, Payne R, Withey J. A broader concept of Caplan's syndrome related to rheumatoid factors. Thorax 1962; 17:205-212.

16. Lindars D, Davies D. Rheumatoid pneumoconiosis. A study in colliery populations in the East Midlands coalfield. Thorax 1967; 22:525-532.

17. Williams W. Caplan's syndrome. Br J Clin Practice 1991; 45:285-288.

18. Rees J, Woodhead M, Sheppard M, du Bois R. Rheumatoid arthritis and cryptogenic organising pneumonitis. Respir Med 1991; 85:243-246.

19. van Thiel R, van der Burg S, Groote A, Nossent G, Wills S. Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Eur Respir J 1991; 4:905-911.

20. Shiel Jr W, Prete P. Pleuropulmonary manifestations of rheumatoid arthritis. Sem Arthritis Rheum 1984; 13:235-243.

21. Hakala M, Ruuska P, Hämeenkorpi R, Tiilikainen A, Ilonen J, Mäkitalo R. Diffuse interstitial lung disease in rheumatoid arthritis. Views on immunological and HLA findings. Scand J Rheumatol 1986; 15:368-376.

22. Hakala M. Poor prognosis in patients with rheumatoid arthritis hospitalized for interstitial lung fibrosis. Chest 1988; 93:114-118.

23. Wells A, Cullinan P, Hansell D, Rubens M, Black C, Newman-Taylor A, du Bois R. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1994; 149:1583-1590.

24. Hyland R, Gordon D, Broder I, Davies G, Russell M, Hutcheon M, Reid G, et al. A systematic controlled study of pulmonary abnormalities in rheumatoid arthritis. J Rheumatol 1983; 10:395-405.

25. Winchester R, Litwin S, Koffler D, Kunkel H. Observations on the eosinophilia of certain patients with rheumatoid arthritis. Arthritis Rheum 1971; 14:650-665.

26. Frank S, Weg J, Harkleroad L, Fitch R. Pulmonary dysfunction in rheumatoid disease. Chest 1973; 63:27-34.

27. Laitinen O, Nissilä M, Salorinne Y, Aalto P. Pulmonary involvement in patients with rheumatoid arthritis. Scand J Resp Dis 1975; 56:297-304.

28. Fortoul T, Cano-Valle F, Oliva E, Barrios R. Follicular bronchiolitis in association with connective tissue diseases. Lung 1985; 163:305-314.

29. Yousem S, Colby T, Carrington C. Follicular bronchitis/bronchiolitis. Hum Pathol 1985; 16:700-706.

30. Kinoshita M, Higashi T, Tanaka C, Tokunaga N, Ichikawa Y, Oizumi K. Follicular bronchiolitis associated with rheumatoid arthritis. Intern Med 1992; 31:674-677.

31. Geddes D, Corrin B, Brewerton D, Davies R, Turner-Warwick M. Progressive airway obliteration in adults and its association with rheumatoid disease. Quart J Med 1977; 46:427-444.

32. Murphy K, Atkins C, Offer R, Hogg J, Stein H. Obliterative bronchiolitis in two rheumatoid arthritis patients treated with penicillamine. Arthritis Rheum 1981; 24:557-560.

33. Pegg S, Lang B, Mikhail E, Hughes D. Fatal bronchiolitis obliterans in a patient with juvenile rheumatoid arthritis receiving chrysotherapy. J Rheumatol 1994; 21:549-551.

34. Schwarz M, Lynch D, Tuder R. Bronchiolitis obliterans: the lone manifestation of rheumatoid arthritis? Eur Respir J 1994; 7:817-820.

35. Epler G, Snider G, Gaensler E, Cathcart E, FitzGerald M, Carrington C. Bronchiolitis and bronchitis in connective tissue disease. A possible relationship to the use of penicillamine. JAMA 1979; 242:528-532.

36. Hayakawa H, Sato A, Imokawa S, Toyoshima M, Chida K, Iwata M. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med 1996; 154:1531-1536.

37. Geddes D, Webley M, Emerson P. Airways obstruction in rheumatoid arthritis. Ann Rheum Dis 1979; 38:222-225.

38. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis. Clinical, functional, and HRCT findings. Am J Respir Crit Care Med 1998; 157:1658-1665.

39. Shadick N, Fanta C, Weinblatt M, O'Donnell W, Coblyn J. Bronchiectasis. A late feature of severe rheumatoid arthritis. Medicine 1994; 73:161-170.

40. Schneider H, Yonker R, Katz P, Longley S, Panush R. Rheumatoid vasculitis: experience with 13 patients and review of the literature. Sem Arthritis Rheum 1985; 14:280-286.

41. Vollertsen R, Conn D, Ballard D, Ilstrup D, Kazmar R, Silverfield J. Rheumatoid vasculitis: survival and associated risk factors. Medicine 1986; 65:365-375.

42. Sokoloff L, McCluskey R, Bunim J. Vascularity of the early subcutaneous nodule of rheumatoid arthritis. Arch Pathol 1953; 55:475-495

43. Baydur A, Mongan E, Slager U. Acute respiratory failure and pulmonary arteritis without parenchymal involvement. Demonstration in a patient with rheumatoid arthritis. Chest 1979; 75:518-520.

44. Kay J, Banik S. Unexplained pulmonary hypertension with pulmonary arteritis in rheumatoid disease. Br J Dis Chest 1977; 71:53-59.

45. Asherson R, Morgan S, Hackett D, Montanes P, Oakley C, Hughes G. Rheumatoid arthritis and pulmonary hypertension. A report of three cases. J Rheumatol 1985; 12:154-159.

46. Morikawa J, Kitamura K, Habuchi Y, Tsujimura Y, Minamikawa T, Takamatsu T. Pulmonary hypertension in a patient with rheumatoid arthritis. Chest 1988; 93:876-878.

47. Eaton A, Serota H, Kernodle Jr G, Uglietta J, Crawford J, Fulkerson W. Pulmonary hypertension secondary to serum hyperviscosity in a patient with rheumatoid arthritis. Am J Med 1987; 82:1039-1045.

48. Torralbo A, Herrero J, Portolés J, Barrientos A. Alveolar hemorrhage associated with antineutrophil cytoplasmic antibodies in rheumatoid arthritis. Chest 1994; 105:1590-1592.

49. Travis W, Colby T, Lombard C, Carpenter H. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 1990; 14:1112-1125.

50. Schwarz M, Zamora M, Hodges T, Chan E, Bowler R, Tuder R. Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease. Chest 1998; 113:1609-1615.

51. Suzuki A, Ohosone Y, Obana M, Mita S, Matsuoka Y, Irimajiri S, Fukuda J. Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol 1994; 21:33-36.

52. Blaschke S, Schwarz G, Moneke D, Binder L, Müller G, Reuss-Borst M. Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, and synovial membranes of patients with rheumatoid arthritis. J Rheumatol 2000; 27:866-873.

53. Geddes D, Webley M, Brewerton D, Turton C, Turner-Warwick M, Murphy A, Ward A. Alpha-1-antitrypsin phenotypes in fibrosing alveolitis and rheumatoid arthritis. Lancet 1977; 2:1049-1051.

54. Maini R, St Clair E, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J. et al. Infliximab (chimeric anti-tumour necrosis factor alfa monclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999: 354:1932-1939.

55. Weinblatt M, Kremer J, Bankhurst A, Bulpitt K, Fleischmann R, Fox R, Jackson C, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340:253-259.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Last revised 9/17/00

Copyright 2000 by Martha L. Warnock. All rights reserved.

Table of Contents