Rheumatoid Arthritis Hospitalized for

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1 Poor Prognosis in Patients with Rheumatoid Arthritis Hospitalized for Interstitial Lung Fibrosis* Markku Hakala, M.D. Fifty-seven patients with rheumatoid arthritis (RA) were treated in hospital for diffuse interstitial lung fibrosis. Although interstitial fibrosis (either on the basis of lung function tests or chest roentgenograms or both) is fairly common among patients with RA, according to this study interstitial fibrosis of sufficient extent or severity to warrant hospitalization was rare: incidence of hospitalization due to the lung disease in RA patients was one case per 3,500 patient-years. Eight patients had a largely reversible lung disease associated with drug treatment (gold, D-penicil- lamine or nitrofurantoin.) The remaining 49 had interstitial fibrosis of unknown cause. Causes for hospitalization were respiratory and general symptoms in 38, but infiltrations on routine chest roentgenographic examinations alone in eleven patients. Forty-five out of the 49 patients had crackles on auscultation. The most typical findings in lung function tests were restriction and a decreased diffusion capacity. These 49 patients showed a poor prognosis, with a median survival of 3.5 years and a five-year survival rate of 39 percent. Eliman and Ball' described diffuse interstitial lung disease, "chronic fibrosing pneumonitis" (ie, cryptogenic fibrosing alveolitis, interstitial pneumonia, interstitial lung fibrosis) in connection with rheumatoid arthritis (RA) in three patients and demonstrated poor prognosis for the lung disease. Although the association of RA and interstitial lung fibrosis has been controversial,'25 a higher prevalence of RA than expected has been found also in a patient series when the primary diagnosis has been cryptogenic fibrosing alveolitis. Slight pulmonary changes in association with RA are common,7 9 yet severe interstitial disease appears to be rare;"," hence, large series of patients with severe pulmonary fibrosis and RA are lacking. This study was designed, in particular, to describe a larger series of patients with RA who had been hospitalized for their lung disease, which by implication was severe. Clinical features of these patients are described and possible predisposing factors for lung disease are discussed. MATERIALS AND METHODS Patients All RA patients hospitalized for interstitial lung fibrosis (diagnostic code ') in the years , according to the Hospital Discharge Register which contains data on all hospitalizations in Finland, were included in the study. Twenty-one patients were excluded, eight who did not fulfill the criteria for classic or definite *From the Department of Medicine, Paivarinne Hospital, Jokirinne, Finland. This work was supported in part by a grant from the Finnish Anti- Tuberculosis Association, Helsinki, and the Rheumatism Research Foundation, Helsinki, Finland. Manuscript received July 17, 1986; revision accepted June 5. Reprint requests: Dr Hakala, Department of Medicine, Oulu University Central Hospital, SF Oulu, Finland 114 RA, '3 and 13 in whom the diagnosis of interstitial fibrosis had proved to be incorrect. Thereafter, the total number of patients included in the study was 57. The patients were divided into two categories: eight suffered from probable drug-induced, reversible lung disease,'4 and 49 had pulmonary fibrosis of unknown cause."1 Most of the latter showed lung disease with progressive course. Statistical Analysis Fisher's exact test and Mann-Whitney U-test were used in analysis of the data, as appropriate. RESULTS Drug-induced Lung Disease (Eight Patients) Eight patients were considered to have drug-induced lung disease based on the following criteria: 1) relatively acute onset of respiratory symptoms (cough, dyspnea and/or fever) and diffuse bilateral pulmonary infiltrates during drug therapy, 2) improvement after discontinuation of the drug (in a few cases after commencement of steroids), and 3) only moderate or slight interstitial infiltrations remaining on the chest roentgenograms as a sign of residual fibrosis. Five of the eight patients had a pulmonary reaction during sodium aurothiomalate therapy (total dose 450 to 1,100 mg), two of whom have been presented earlier.'6 Four of the patients also had an obvious gold-induced rash, with eosinophilia in two cases. One of the five died of acute myocardial infarction. One patient had a lung reaction during D-penicillamine treatment (450 mg daily for six months), and two during nitrofurantoin treatment (for two weeks and four months, respectively). All patients had also been treated with nonsteroidal anti-inflammatory drugs for their joint disease.

2 Table 1-Cause for Hospital Admission in 49 Patients with Pulmonary Fibrosis and Rheumatoid Arthritis Cause No. (%) Respiratory symptoms with fever and/or weight loss 23 (47) Exertional dyspnea 14 (29) Infiltrations in routine chest roentgenograms 11*(22) Hemoptysis 1 (2) *Three patients were free of symptoms Pulmonary Fibrosis of Unknown Cause (49 Patients) This group included 21 women and 28 men with permanent or progressive pulmonary fibrosis. Mean age at the time of diagnosis of the lung disease was 64 years (SD 8). Table 1 shows the causes for hospital admission in these patients. Five patients had a history of pleural effusion, which had been regarded as rheumatoid in four.'7 Forty-five patients (92 percent) had crackles on auscultation. The laboratory, roentgenographic and lung function findings are summarized in Table 2. When estimated as percentage of predicted value, women had a lower vital capacity (VC) and one second forced expiratory volume (FEV,) than men, means for VC being 60 and 80 percent (p = ) and for FEV, 63 and 81 percent (p = 0. 02), respectively. No difference in lung diffusion capacity (Dco) was found between the sexes (mean 53 percent for women and 52 percent for men). Representative lung biopsy specimens alone without a later autopsy were available in three patients (Table 3.) Sixteen of the 21 men and one of the 16 women in whom the smoking habits could be ascertained were smokers (current or ex-smokers.) The largest uniform occupational group consisted of farm- Table 2-Laboratory, Roentgenologic and Lung Function Findings in 49 Patients with Pulmonary Fibrosis and Rheumatoid Arthritis Serology Seropositive-42 patients Rheumatoid factor patients Seronegative-4 patients Data not available-3 patients Roentgenograms*t Diffuse bilateral reticular or reticulonodular shadowing-all patients Pulmonary function testing* Restrictive pattern;-21 patients Obstructive pattern -5 patientsl Diffusion defect-29 patients Normal spirometry/diffusion capacity-11/1 patients Spirometry/diffusion capacity not available-12/19 patients *On the first admission for lung disease. tin 20 (46.5 percent) ofthe 43 patients who had previous roentgenograms available, interstitial changes could be seen at least three years earlier. 1Restrictive pattern = vital capacity (VC) <80 percent of predicted value and one second forced expiratory volume (FEV,)/VC x 100 >70 percent. Obstructive pattern = FEVj/VC x 100 <70 percent. litwo patients with asthma. Table 3-Histopathologic Diagnoses in Lung Biopsies or at Autopsy in 17 Patients with Pulmonary Fibrosis and Rheumatoid Arthritis Biopsy only Autopsy Diagnosis (n = 3*) (n = 14) Chronic interstitial pneumonia 2t 14t Additional diagnosis: Diffuse alveolar damage - 4 Purulent bronchopneumonia 5 Granulomatous inflammation 1 *One open and two Tru-cut lung biopsies. t One patient with fatal outcome. tone patient with lymphoid interstitial pneumonia. ers and their wives (ten subjects). Only two patients had an occupation which could be associated with changes in lungs (a rock driller and a temperer). Mean age at the onset of joint disease was 52 years (SD 11). Arthritis was the first manifestation in 41 patients (84 percent), beginning from 3 to 44 (mean 15) years before the lung disease. Among the 41 patients, mean duration ofra until diagnosis oflung disease was longer in women than in men; 18 (SD 11) and 12 years (SD 6), respectively (p<o. 05). The pulmonary changes were primary manifestations in two women and simultaneous with arthritis in two women and four men. Twenty-eight of the 49 patients had received gold treatment and five had also received D-penicillamine. Seventeen (61 percent) of the former had suffered from obvious gold-induced side effects: seven withi dermatitis, six with proteinuria or other renal lesions, three with eosinophilia and one with fever. Of the five patients treated with D-penicillamine, two had experienced a rash and one, itching alone. The induction of interstitial fibrosis by sodium aurothiomalate was suspected in two patients (total dose of gold 450 and 3,000 mg) and by D-penicillamine in one patient (300 to 450 mg daily for 15 months), who were taking the drugs at the time of diagnosis of lung disease. Two of them also had a possible drug-induced rash, with eosinophilia in one, synchronous with the presentation of lung disease. Progress of the lung process did not, however, stop after discontinuation of the drugs, and all three patients had a fatal lung disease, with a mean survival from the first admission for lung disease of 2.3 years. Two of the 49 patients had long-term treatment with nitrofurantoin, a possible cause of interstitial fibrosis,'8 at the time of diagnosis of lung disease. One of them died of lung disease 34 months after the diagnosis. The other patient has marked, obviously stable pulmonary fibrosis and follow-up has lasted over five years. Treatment for Pulmonary Fibrosis of Unknown Cause Four patients treated with corticosteroids showed improvement in the lung function tests. All four were CHEST / 93 / 1 / JANUARY,

3 women, two with a seronegative and two with a seropositive disease. In one seronegative man, lung disease remained stable during prednisolone and azathioprine treatment. These five patients were the only responders among 34 (of 41 treated) patients in whom the effect of treatment could be evaluated. As only four seronegative patients were found among the patients with pulmonary fibrosis and RA, and three of them responded to treatment, the effect of treatment among seronegative patients was better compared to the 30 seropositive patients, of whom only two responded to therapy (p<0.05). The only seronegative nonresponder was a woman with fatal lymphoid interstitial pneumonia in whom the lung disease preceded seronegative arthritis. All five responders had respiratory symptoms when the treatment was begun, and in only one had the diagnosis been delayed (for at least four years). Follow-up lasted more than five years in four of the five patients. All 41 treated patients received corticosteroid therapy, with a mean starting dose of 35 mg prednisolone daily, and the treatment was continued in 25 patients without a break from diagnosis onward. No uniform criterion for commencement of corticosteroid therapy was found in the medical records. Four of these 41 patients had azathioprine treatment in addition, in three cases after corticosteroid therapy had proved ineffective. Two of the 41 patients received therapy with D-penicillamine combined with corticosteroids, and one had received D-penicillamine combined with both azathioprine and corticosteroids. Outcome in Pulmonary Fibrosis of Unknown Cause Thirty-five of the 49 patients have been followed to death. The remainder are alive and have been followed Table 4-Comparison of Clinical Features in Dead vs Alive Patients with Pulmonary Fibrosis and Rheumatoid Arthritis Dead Alive (n = 28*) (n = 14) No. of men 15 7 Mean age (yrs) on first admission Serologyt No. of seropositives No. of seronegatives 1 3 No. of cases with gold treatmentt 13 8 VC (mean) FEV, (mean) Dco (mean) *Seven deaths from other causes than interstitial fibrosis were excluded. tnot available in three cases. tthe four cases in whom the therapy has lasted less than one month were excluded. Results of lung function test given as percentage of predicted value on first admission for lung disease. Values of VC (vital capacity) were available in 20/13, FEV1 (one second forced expiratory volume) in 20/12 and Dco (lung diffusion capacity) in 13/13 of dead/alive patients. IIp<O for a minimum of four years. Mean survival from the first admission for lung disease in those followed to death was 3.0 years (SD 2.4). The 0.5, one-, two-, three- and five-year survival rates for the series were 90, 86, 71, 51 and 39 percent, respectively, and the median survival of the whole series was 3.5 years. Table 4 shows some clinical features of patients with regard to mortality. Causes of Death in Pulmonary Fibrosis of Unknown Cause Of the 35 fatalities, interstitial lung fibrosis was the main cause of death in 28 cases (80 percent). In the remaining patients, the main causes of death were: lung cancer (two patients), lung tuberculosis, ischemic heart disease, stroke, rupture of the abdominal aorta and femoral fracture. Autopsies were performed on 14 of the 35 patients who died (Table 3). In one additional case, a forensic autopsy was performed but no tissue material from the lungs was obtained for histologic study. All 14 cases showed chronic interstitial lung fibrosis, advanced in most and with honey-combing in six. Right ventricular hypertrophy was found in five cases. DISCUSSION Some signs of interstitial lung involvement have been found in 28 and 10 percent of a Finnish RA population using lung function tests or roentgenologic methods of detection, respectively.'9 There are about 40,000 RA patients in Finland; hence, thousands of them have interstitial lung disease. It is clinically silent in the majority of patients,8 and during a five-year period only 57 patients were hospitalized because of lung disease, an incidence ofone case per 3,500 patient years, and at least eight (14 percent) of these had druginduced lung disease. The clinical spectrum of interstitial lung fibrosis in RA may be similar to that of idiopathic pulmonary fibrosis. While Hamman and Rich reported that fulminant pulmonary fibrosis led to death within six months,20 Sloper and Williams emphasized that a chronic course is much more common.2" Hospitalized patients represent the severe end of the spectrum, but even so, the outcome for RA patients with pulmonary fibrosis in the present series was poor. The median survival after diagnosis was only 3.5 years and the fiveyear survival rate 39 percent, corroborating the results Turner-Warwick and Evans6 reported in their review article. Why a common and usually benign lung fibrosis in some cases turns to a malignant disease cannot be answered on the basis of this study. Comparison of the dead with those who stayed alive did not show significant differences either. Male sex,4'5 smoking,58 high seropositivityll'14 and late onset ofra56 have been suggested as predisposing

4 factors for interstitial lung fibrosis in RA. Many ofthese correlations have been found in studies which have sought the association between lung disease and BA by chest roentgenographic examination or lung function tests,58 or have searched for the presence of lung disease in seropositive vs seronegative RA.222' Since the spectrum of interstitial fibrosis in RA is wide,2526 the correlations found in inactive or mild disease are not necessarily valid in active lung disease. The finding of no significant male predominance in the present study is similar to the findings in other studies which have reported progressive interstitial fibrosis in association with RA.",3'6 Seropositivity was a common feature among the patients of this study, in broad agreement with previously published series. Although smoking was common among the men of the present series, bronchial obstruction was rare, and men showed better results of spirometry than women. Instead, Dco was equally lowered in both sexes. The finding is in accordance with the suggestion that Dco-more accurately than spirometry-shows the real interstitial involvement in RA patients.9 Spirometry may be affected by the general musculoskeletal processes in RA;9'27 indeed, RA had lasted longer in the women than in the men of this study. The present finding that 61 percent of the goldtreated patients had side effects supports the impression that the frequency of gold-induced side effects is high in RA patients who also have pulmonary fibrosis.23 While genetic factors seem to modify gold tolerance,16'28 high-risk HLA antigens for gold-induced side effects were only marginally overrepresented in a patient series with interstitial fibrosis and RA.24 Gold and D-penicillamine therapy may give rise to reversible interstitial pneumonitis29'30 and, as demonstrated in the present series, only moderate or slight residual fibrosis on chest roentgenogram may remain if the treatment is stopped.30'32 Whether gold or D-penicillamine could give rise to more extensive pulmonary fibrosis, like chronic nitrofurantoin-induced reaction,18 is unclear3'34 and no answer can be given on the grounds of this study either. If both the drug and RA can induce lung disease, it may be impossible to resolve which is the primary cause, and at least one experimental study has shown that intravenous rheumatoid factor will accentuate or potentiate an ongoing inflammatory process in the lung.35 Results of steroid and immunosuppressive therapy in cases of interstitial fibrosis in association with RA have been poor, and only sporadic remissions have been reported.6 In the present series, seronegative patients had a better response to therapy than seropositive patients, but therapy had been started at an early phase in the lung disease in the former. The natural history of interstitial fibrosis in RA patients is variable, and at least two different varieties ofinterstitial lung disease may exist. One is benign and sometimes discovered only in its affect on lung function tests. The other is a more malignant, progressive disorder leading to death in a few years. Whether these two varieties are two distinct disorders or only the two poles of the same process must at present remain undecided. ACKNOWLEDGMENT: I thank Dr. Paavo Paakko, Department of Pathology, University of Oulu, for re-evaluating the autopsy material; and Dr. Esko Huhti, Department of Medicine, University of Oulu, Oulu and Professor Heikki Isomaki, Rheumatism Foundation Hospital, Heinola for helpful criticisms of the manuscript. REFERENCES 1 Ellman P, Ball RE. "Rheumatoid disease" with joint and pulmonary manifestations. Br Med J 1948; ii: Aronoff A, Bywaters EGL, Fearnley GR. Lung lesions in rheumatoid arthritis. Br Med J 1955; ii: Cruickshank B. Interstitial pneumonia and its consequences in rheumatoid disease. Br J Dis Chest 1959; 53: Stack BHR, Grant IWB. Rheumatoid interstitial lung disease. Br J Dis Chest 1965; 59: Walker WC, Wright V. Diffuse interstitial pulmonary fibrosis and rheumatoid arthritis. Ann Rheum Dis 1969; 28: Turner-Warwick M, Evans RC. 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5 21 Sloper JC, Williams E. Diffuse interstitial fibrosis. Hamman- Rich syndrome. Lancet 1955; ii: Tomasi TB Jr, Fudenberg HH, Finby N. Possible relationship of rheumatoid factors and pulmonary disease. Am J Med 1962; 33: Sievers K, Aho K, Hurri L, Perttala Y Studies of rheumatoid pulmonary disease. A comparison of roentgenological findings among patients with high rheumatoid factor titers and with completely negative reactions. Acta Tuberc Scand 1964; 35: Hakala M, Ruuska P, Hameenkorpi R, Tiilikainen A, Ilonen J, Makitalo R. Diffuse interstitial lung disease in rheumatoid arthritis. Views on immunological and HLA findings. Scand J Rheumatol 1986; 15: Patterson CD, Harville WE, Pierce JA. Rheumatoid lung disease. Ann Intern Med 1965; 62: Walker WC, Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore) 1968; 47: Turner-Warwick M. Immunology ofthe lung. London: E Arnold, 1978; Panayi GS, Wooley P, Batchelor JR. Genetic basis of rheumatoid disease: HLA antigens, disease manifestations, and toxic reactions to drugs. Br Med J 1978; ii: Winterbauer RH, Wilske KR, Wheelis RE Diffuse pulmonary injury associated with gold treatment. N Engl J Med 1976; 294: Eastmond CJ. Diffuse alveolitis as complication of penicillamine treatment for rheumatoid arthritis. Br Med J 1976; i: Hakala M, van Assendelft AHW, Ilonen J, Jalava S, Tiilikainen A. Association of different HLA antigens with various toxic effects of gold salts in rheumatoid arthritis. Ann Rheum Dis 1986; 45: Smith W, Ball GV. Lung injury due to gold treatment. Arthritis Rheum 1980; 23: Geddes DM, Brostoff J. Pulmonary fibrosis associated with hypersensitivity to gold salts. Br Med J 1976; i: Scott DL, Bradby GVH, Aitman TJ, Zaphiropoulos GC, Hawkins CE Relationship of gold and penicillamine therapy to diffuse interstitial lung disease. Ann Rheum Dis 1981; 40: DeHoratius RJ, Williams RC Jr. Rheumatoid factor accentuation of pulmonary lesions associated with experimental diffuse proliferative lung disease. Arthritis Rheum 1972; 15: Plan to Attend 54th Annual Scientific Assembly Anaheim October 3-7,