Interstitial Lung Disease in Polymyositis and Dermatomyositis

Transcription

1 Arthritis & Rheumatism (Arthritis Care & Research) Vol. 47, No. 6, December 15, 2002, pp DOI /art , American College of Rheumatology ORIGINAL ARTICLE Interstitial Lung Disease in Polymyositis and Dermatomyositis I. MARIE, 1 E. HACHULLA, 2 P. CHÉRIN, 3 S. DOMINIQUE, 4 P.-Y. HATRON, 2 M.-F. HELLOT, 4 B. DEVULDER, 2 S. HERSON, 3 H. LEVESQUE, 1 AND H. COURTOIS 1 Objectives. To assess prevalence, characteristics, and long-term outcome of interstitial lung disease (ILD) in polymyositis (PM) and dermatomyositis (DM). To determine predictive variables of ILD course in PM/DM, and to define both clinical and biochemical features associated with ILD onset in PM/DM. Methods. The medical records of 156 consecutive PM/DM patients in 3 medical centers were reviewed. Results. Thirty-six PM/DM patients (23.1%) developed ILD. We observed that 19.4% of patients with ILD had resolution of pulmonary disorders, whereas 25% experienced ILD deterioration. Morbidity and mortality rates were as high as 13.9% and 36.4%, respectively, in PM/DM patients with ILD. Parameters of PM/DM that related to ILD poor outcome were identified as follows: Hamman-Rich like pattern, initial diffusing capacity of carbon monoxide <45%, neutrophil alveolitis, and histologic usual interstitial pneumonia. Additionally, for the group with ILD, polyarthritis, higher values of erythrocyte sedimentation rate and C-reactive protein, presence of anti Jo-1 antibody, and characteristic microangiopathy were significantly more frequent. Conclusion. Our series underlines the high frequency of ILD in PM/DM patients, resulting in increased morbidity and mortality rates. It also indicates that PM/DM patients should routinely be screened for ILD, even those patients without anti Jo-1 antibody, because 69% of our ILD patients were seronegative for the anti Jo-1 antibody. Our findings further suggest that PM/DM patients presenting with factors predictive of ILD poor outcome may require more aggressive therapy. KEY WORDS. Polymyositis; Dermatomyositis; Interstitial lung disease; Anti Jo-1 antibody. INTRODUCTION Polymyositis (PM) and dermatomyositis (DM) are systemic inflammatory disorders affecting skeletal muscles and other organs, especially the lungs, either primarily or through complications of muscle weakness, resulting in interstitial lung disease (ILD), ventilatory insufficiency, and aspiration pneumonia (1 4). The prevalence of pulmonary involvement has been reported to be as high as 46% in PM/DM (1 9), and pulmonary disorders are still considered to be a common cause of morbidity in PM/DM. 1 I. Marie, MD, PhD, H. Levesque, MD, PhD, H. Courtois, MD, PhD: Centre Hospitalier Universitaire de Rouen-Boisguillaume, Rouen Cedex, France; 2 E. Hachulla, MD, PhD, P.-Y. Hatron, MD, PhD, B. Devulder, MD, PhD: Centre Hospitalier Universitaire de Lille, Lille Cedex, France; 3 P. Chérin, MD, PhD, S. Herson, MD, PhD: Groupe Hospitalier Pitié-Salpêtrière, Paris Cedex, France; 4 S. Dominique, MD, M.-F. Hellot, ScD: Centre Hospitalier Universitaire de Rouen, Rouen Cedex, France. Address correspondence to I. Marie, MD, PhD, Department of Internal Medicine, Centre Hospitalier Universitaire de Rouen-Boisguillaume, Rouen Cedex, France. Submitted for publication November 8, 2001; accepted in revised form March 10, ILD in particular may lead to life-threatening complications, i.e., ventilatory failure, secondary pulmonary arterial hypertension, or cor pulmonale (3,5 8,10 14). In a study cohort of PM/DM patients, Arsura and Greenberg (5) have noted a decreased survival in patients with ILD compared with those without ILD (60% at 31 months versus 76% at 60 months). The early detection of ILD is, therefore, a high priority in PM/DM patients. These findings prompted us to 1) assess prevalence, characteristics, and long-term outcome of ILD in 156 consecutive patients with PM/DM; 2) determine predictive variables of ILD course in PM/DM; and 3) define both clinical and biochemical features associated with ILD onset in PM/DM. PATIENTS AND METHODS One hundred fifty-six consecutive patients with a diagnosis of PM (n 90) and DM (n 66) were included in the study. Patients were seen at 3 university medical centers as either inpatients or outpatients between 1985 and No patient had other connective tissue disorders or myopathy. The diagnosis of PM/DM was based on Bohan and Peter criteria (15,16): 1) symmetric muscle weakness, 2) 614

2 Interstitial Lung Disease in PM/DM 615 increased serum muscle enzymes, 3) myopathic changes on electromyography, 4) typical histologic findings on muscle biopsy, and 5) characteristic dermatologic manifestations (heliotrope rash, periungual erythema, Gottron s papules, and poikiloderma). All patients had an initial evaluation of organ involvement, which resulted in the detection of systemic complications, i.e., esophageal dysfunction, dysphonia, cardiac and pulmonary impairment. They were also examined for underlying malignancy. Moreover, patients underwent to biochemical assessment, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, leukocytosis, platelets, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), creatine kinase (CK), aldolase, and serum levels of protein and albumin. Autoantibody screen was also performed, i.e., antinuclear antibodies and anti Jo-1 antibody; other myositis-specific autoantibodies were not tested (other anti-synthetase antibodies, anti-signal recognition particle, anti Mi-2 antibodies), because detection of these antibodies is not yet available in our hospitals. Pulmonary involvement. Pulmonary involvement was systematically investigated initially in relation to clinical symptoms and by chest radiographs and pulmonary function tests (PFT). Pulmonary function tests. The following PFT parameters were assessed: vital capacity (VC), forced vital capacity (FVC), and diffusing capacity of carbon monoxide (DLCO). VC and FVC were measured by spirometry (using a water-sealed spirometer); the DLCO was obtained by the single-breath method. Data are expressed as percentages of predicted values. The predicted values for each subject, based on sex, age, height, and weight, were obtained from standard tables (17). High resolution computed tomography (HRCT). HRCT of the lungs was performed to investigate radiographic abnormalities consistent with ILD, i.e., parenchymal micronodules and nodules, linear, irregularity of the interfaces between peripheral pleura and aerated lung parenchyma, ground-glass, honeycombing, and traction bronchiectases or bronchiolectases (10,12, 14,18 20). During followup of PM/DM patients without ILD initially, lung investigations were also systematically carried out to detect ILD. Bronchoalveolar lavage (BAL). Twenty PM/DM patients with ILD underwent BAL, because this test is currently performed in 2 of our 3 investigative medical centers. Total and differential cell counts were evaluated. Patients were considered to have lymphocyte alveolitis if BAL lymphocytes were 18% and neutrophil alveolitis if BAL neutrophils were 4% whatever the percentage of alveolar lymphocytes. Lung biopsy. Eleven patients had lung biopsy, which was carried out in 2 of 3 investigative medical centers. Histologic analysis of lung biopsy specimens was carried out to detect the following abnormalities consistent with ILD: bronchiolitis obliterans organizing pneumonia (BOOP), usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and diffuse alveolar damage (10,12,14,21 26). Outcome of ILD. The functional course of all patients with ILD was assessed for clinical manifestations, PFT disturbances, and HRCT abnormalities. The outcomes were categorized as remission, improvement, or deterioration. Remission was defined as complete resolution of pulmonary symptoms associated with disappearance of radiographic signs of ILD and normalization of standard PFT values. Improvement was defined as when any of the former pulmonary alterations improved with therapy, without returning to normal values. was defined as when any of the former pulmonary conditions worsened despite therapy institution. Both survival and current status were based on hospital records (i.e., data obtained during routine followup visits). Finally, the cause of death was determined through hospital or physician records. Measurement of predictive factors. First, factors of poor outcome were determined at ILD diagnosis in PM/DM patients. Patients were divided into 2 groups: patients who deteriorated due to ILD and patients who did not; clinical and paraclinical data were compared between these 2 groups of patients. Second, ILD patients with and without anti Jo-1 antibody were compared regarding the characteristics of ILD, i.e., clinical data, course, and therapy. Third, PM/DM patients with and without ILD were compared to assess clinical, biochemical, and paraclinical features as predictive indicators of ILD. Statistical analysis. For group comparisons involving binary data, we used either the chi-square test or Fisher s exact test, depending on the sample size (n 5 and n 5, respectively). Comparisons involving continuous data were made using the Mann Whitney U test. The results were regarded as significant when the P value was Finally, cumulative survival rates were calculated in patients with and without ILD, using the Kaplan Meier test; the log-rank (Mantel Cox) test was also used to compare survival of patients with and without ILD. RESULTS The 156 consecutive patients with PM/DM consisted of 58 men and 98 women with a median age of 52 years at ILD diagnosis. The main characteristics of PM/DM patients are summarized in Table 1. Prevalence and characteristics of ILD. In this retrospective study, the prevalence of ILD was 23.1% (36 of 156). None of the patients had received drugs that might have led to pulmonary damage before ILD occurrence. As shown in Table 2, ILD onset preceded initial PM/DM clinical manifestations in 7 patients (range 3 16 months), was concurrently identified in association with PM/DM in 15 patients, and developed after PM/DM onset in 14 patients (range 2 96 months).

3 616 Marie et al Table 1. General characteristics of polymyositis/dermatomyositis patients Patient characteristics (n 156) n (%) Esophageal involvement 59 (37.8) Cardiac dysfunction 13 (8.3) Arthralgia/arthritis 43 (27.6) Pulmonary impairment Interstitial lung disease 36 (23.1) Ventilatory insufficiency due to 34 (21.8) PM/DM-related muscle weakness Aspiration pneumonia 27 (17.3) Malignancy 27 (17.3) Pulmonary symptoms were initially recorded in 27 patients with ILD, which mainly consisted of dyspnea (n 27), cough (n 5), and right heart insufficiency (n 1). Patients with ILD could be divided into 3 groups according to their presenting lung manifestations (Table 2): patients with acute lung disease (taking the form of antibioticresistant immunity-acquired pneumonia) similar to Hamman-Rich syndrome (n 6), patients with progressivecourse lung signs (n 21), and asymptomatic patients exhibiting abnormalities consistent with ILD on PFT and HRCT of the lungs (n 9). Antinuclear antibodies were reactive in 27 patients, and anti Jo-1 antibody in 11 cases. PFT results were consistent with ILD in all cases; median values of PFT parameters were as follows: FVC 69%, VC 72%, and DLCO 52%. Table 2. ILD characteristics of PM/DM patients* PM/DM with ILD (n 36) Presenting lung symptoms Hamman-Rich like syndrome 6 (16.7) Slowly progressive signs 21 (58.3) Asymptomatic 9 (25) Time onset Before PM/DM 7 (19.4) Concomitant with PM/DM 15 (41.7) After PM/DM 14 (38.9) BAL (n 20) Lymphocyte alveolitis 7 (35) 13 (65) Lung histology (n 11) NSIP 4 (36.4) UIP 5 (45.4) BOOP 2 (18.2) Course Resolution 7 (19.4) Improvement 20 (55.6) 9 (25) Mortality 5 (13.9) * Values are n (%). ILD interstitial lung disease; PM/DM polymyositis/dermatomyositis; BAL bronchoalveolar lavage; NSIP nonspecific interstitial pneumonia; UIP usual interstitial pneumonia; BOOP bronchiolitis obliterans organizing pneumonia. Moreover, spirometry showed severe impairment of lung parameters with DLCO values 45% at ILD diagnosis in 19.4% of patients. During initial evaluation of PM/DM patients with ILD, HRCT scanning of the lungs demonstrated the following abnormalities consistent with ILD: parenchymal micronodules or nodules in 11 patients (30.6%), linear in 27 patients (75%), irregularity of the interfaces in 30 patients (83.3%), ground-glass in 18 patients (50%), honeycombing in 2 patients (5.6%), and traction bronchiectases or bronchiolectases in 6 patients (16.7%). In these 36 patients, HRCT-related ILD changes were localized predominantly in pulmonary lower lobes (n 35). BAL cell profile was performed in 20 patients and revealed patterns such as lymphocyte (n 7) and neutrophil (n 13) alveolitis (Table 2). Finally, histologic analysis of pulmonary biopsy specimens was carried out in 11 patients (Table 2). This demonstrated histologic damage of NSIP and UIP in 4 and 5 patients, respectively. The 2 remaining patients had BOOP. Course of ILD. The median duration of ILD patients followup was 53 months. The outcome of our 36 PM/DM patients with ILD is summarized in Table 2. ILD resolution. ILD resolved in 7 patients (19.4%), i.e., lung symptoms completely healed and PFT returned to normal, associated with clearing of the HRCT within 48 to 120 months. BAL fluid analysis was performed in 3 of these patients, revealing lymphocyte (n 2) or neutrophil (n 1) alveolitis. Histologic lung analysis showed damage consistent with NSIP (n 2) and UIP (n 1). Control of ILD was obtained with steroids (n 7) and cyclophosphamide (n 3). ILD improvement. Twenty PM/DM patients experienced ILD improvement (55.6%). Lung symptoms disappeared in 16 patients (44.5%), although these patients had persistent abnormalities on PFT and HRCT. The 4 other patients (11.1%) had improvement in clinical pulmonary manifestations with ILD therapy; results of PFT and/or HRCT had also improved, without reaching normal patterns. BAL fluid analysis was performed in 8 of these patients, showing lymphocyte (n 5) and neutrophil (n 3) alveolitis. Two patients had pulmonary biopsies, revealing histologic evidence of NSIP (n 1) and BOOP (n 1). These patients received the following therapy for ILD: steroids (n 20), azathioprine (n 5), cyclophosphamide (n 2), and cyclosporine (n 1). ILD deterioration. In 9 patients (25%), the clinical pulmonary status worsened despite therapy initiation; ILD clinical deterioration was reflected in PFT and HRCT findings. Results of BAL fluid analysis showed an increased amount of neutrophils in all cases (n 9). Six of these patients underwent additional pulmonary biopsies, demonstrating histologic damage consistent with NSIP (n 1), UIP (n 4), and BOOP (n 1). Nine patients with ILD worsened. Five patients developed progressive respiratory failure within a median delay of 33.8 months, resulting in O 2 dependency and disability

4 Interstitial Lung Disease in PM/DM 617 Figure 1. Survival curves of polymyositis/dermatomyositis (PM/ DM) patients with (n 36) and without (n 120) interstitial lung disease (ILD). despite therapy with steroids (n 5), cyclophosphamide (n 3), and azathioprine (n 2). Three of these patients died within months; 1 of pulmonary arterial hypertension 3 years after occurrence of ILD and 2 of respiratory failure (n 2). Two other patients, who received steroids, developed bacterial aspiration bronchopneumonia within 6 39 months and died. The 2 remaining patients received steroids (n 2), cyclophosphamide (n 1), and azathioprine (n 1). Mortality and survival rates. Figure 1 shows the survival curve of PM/DM patients with ILD. Survival of our ILD patients was 94.4%, 90.4%, and 86.5% at 1, 3, and 5 years, respectively. The mortality rate, related to pulmonary complications, was 13.9% in ILD patients (n 5). As shown in Figure 1, survival was similar in PM/DM with ILD compared with those without (P 0.78). However, our analyses further revealed that ILD tended to be a negative risk factor for survival in PM/DM patients, after excluding paraneoplastic PM/DM (Figure 2). Factors associated with ILD deterioration. As shown in Table 3, only presenting lung manifestations such as Hamman-Rich like syndrome could be considered a predictive factor of ILD deterioration (P 0.024). Moreover, in paraclinical test findings, we observed that only BAL data were prognostic parameters of ILD course (Table 3); in turn, patients with ILD deterioration more often experienced neutrophil alveolitis than those without (100% versus 46.1%; P 0.018). Because only 11 patients with ILD underwent lung biopsies, ILD characteristics could not be statistically compared between patients with NSIP, UIP, and BOOP. However, ILD patients clinical features, BAL and HRCT data, and outcome, are presented according to histologic findings in Table 4. Parameters of ILD associated with anti Jo-1 antibody. Of the 15 patients with anti Jo-1 antibody, 11 presented Figure 2. Survival curves of polymyositis/dermatomyositis (PM/ DM) patients with (n 34) and without (n 95) interstitial lung disease (ILD), after excluding paraneoplastic cases. with ILD. We have demonstrated that the prevalence of ILD was as high as 73.3% in PM/DM patients with anti Jo-1 antibody. We concomitantly found that only the prevalence of Raynaud s phenomenon (54.6% versus 20.8%; P 0.046) and joint involvement (81.8% versus 58.3%; P 0.174) tended to be higher in ILD patients with anti Jo-1 antibody than in those without. As illustrated in Table 5, ILD time of onset was similar in patients with and without anti Jo-1 antibody. As regards the presenting pulmonary symptoms, patients with anti Jo-1 antibody less frequently experienced an asymptomatic form of ILD (0% versus 36%; P 0.034). We further failed to find any difference between data of BAL fluid analysis in ILD patients with and without anti Jo-1 antibody (Table 5). However, we have observed that the subgroup of patients with anti Jo-1 antibody more rarely developed BOOP (n 0) than those without (n 2). Finally, ILD course did not differ in patients with anti Jo-1 antibody compared with those without (Table 5). Predictive factors of ILD in PM/DM patients. General clinical data. We found no statistically significant difference between patients with and without ILD for median age (54 versus 50 years), sex, presence of muscle and dermatologic manifestations, esophageal dysfunction, or Raynaud s phenomenon (Table 6). Only the presence of joint involvement was more frequently found in the group of ILD patients (65.7% versus 18.2%; P ). On the other hand, cancer prevalence was lower among patients with ILD than in those without (5.6% versus 21.6%; P 0.028). Moreover, PM/DM course was similar in patients with and without ILD (Table 6), although the prevalence of PM/DM refractory to steroid therapy alone was higher in PM/DM patients with ILD (75% versus 55%; P 0.032). Laboratory and paraclinical findings. Comparison of both biochemical and immunologic variables was carried out in PM/DM patients with and without ILD (Table 7).

5 618 Marie et al Table 3. Clinical and paraclinical variables associated with ILD deterioration in PM/DM patients* Clinical and paraclinical variables With ILD deterioration, % (n 9) Without ILD deterioration, % (n 27) P Presenting pulmonary symptoms Hamman-Rich like syndrome Slowly progressive signs Asymptomatic Time onset Before PM/DM Concomitant diagnosis with PM/DM After PM/DM Initial DLCO 45% (without pulmonary arterial hypertension) BAL analysis (n 20) HRCT of the lungs Parenchymal micronodules/nodules Linear Irregularity of interfaces Ground-glass Honeycombing Bronchiectases PM/DM clinical features Raynaud s phenomenon Arthralgia/arthritis * ILD interstitial lung disease; PM/DM polymyositis/dermatomyositis; DLCO diffusing capacity of carbon monoxide; BAL bronchoalveolar lavage. HRCT high resolution computed tomography. Higher ESRs and CRP levels and lower hemoglobin levels were significantly more frequent in patients with ILD. We observed that the presence of antinuclear antibodies (P ) and anti Jo-1 antibody (P ) appeared to be correlated with ILD. Finally, the presence of characteristic nailfold capillaroscopic microangiopathy, showing enlarged capillary loops, was significantly more common in patients with ILD (65.4% versus 32.9%; P 0.003). DISCUSSION PM/DM-related ILD was initially described by Mills and Mathews in 1956 (27), and occurs in 5 64% of PM/DM patients (3,6 12,14,24,25,28 31). Our retrospective study included 156 consecutive PM/DM patients without any prior selection based on clinical presentation, including pulmonary manifestations, which tends to be representative of the entire PM/DM population. Therefore, a selection bias based on the severity of the disease with overt or subclinical signs could be excluded. In the present series, we have also shown the high frequency (23.1%) of ILD in PM/DM patients. ILD time of onset was variable in our patients, as previously mentioned (3,7 10,12,14,28 30,32). In essence, with respect to the onset of symptoms of PM/DM and ILD, the majority of our patients experienced simultaneous occurrence of both conditions (41.7%), although ILD preceded (19.4%) or developed after (38.9%) PM/DM in other patients. Time of onset of ILD could not be considered as a predictive parameter of lung outcome. In this instance, ILD often dominated the clinical course of PM/DM (75% of cases), masking the underlying muscle and skin manifestations (33). The clinical presenting characteristics of ILD in PM/DM patients were similar to those observed in idiopathic forms of ILD (10). Therefore, only a few patients had acute lung disease similar to the Hamman-Rich syndrome (16.7%), whereas other patients developed either a progressive or an asymptomatic pattern. Interestingly, we have further observed that patients with Hamman-Rich like syndrome had significantly less favorable outcome of ILD than those with the progressive or asymptomatic forms (66.7% versus 14.3% versus 22.2%). Different methods have been used for both initial assessment and followup of PM/DM patients with ILD. Our study confirms that both PFT and HRCT of the lungs are the methods of choice for diagnosis of ILD in PM/DM (9,12,14,34,35). PFT revealed restrictive changes with decreased DLCO in all patients. In particular, we have also noted that initial low values of DLCO ( 45%), without underlying pulmonary arterial hypertension (at echocardiography), were associated with poor prognosis of ILD; among our 7 PM/DM patients with an initial DLCO of 45%, only 1 patient experienced ILD resolution. HRCT scanning of the lungs was also a sensitive test, by accurately demonstrating evidence of ILD changes in all patients. These changes were localized predominantly in the pulmonary lower lobes, as reported by previous investigators (10,12,14,18 20). In our PM/DM patients with ILD, linear, irregularity of the interfaces, and ground-glass were the more common HRCT ab-

6 Interstitial Lung Disease in PM/DM 619 Table 4. Clinical and paraclinical characteristics of ILD, according to pulmonary histology* Patient number Lung biopsy Presenting lung signs ILD onset Initial DLCO <45% Initial HRCT abnormalities BAL analysis ILD course 1 NSIP Acute Before PM/DM Linear, irregularity of 2 NSIP Progressive After PM/DM Parenchymal micronodules, linear, irregularity of interfaces 3 UIP Progressive Before PM/DM Parenchymal micronodules, linear, irregularity of 4 NSIP Progressive With PM/DM Parenchymal micronodules, linear, irregularity of 5 BOOP Progressive Before PM/DM Linear, irregularity of 6 UIP Acute After PM/DM Irregularity of interfaces, honeycombing, bronchiectases 7 NSIP Acute Before PM/DM Parenchymal micronodules, linear, ground-glass 8 UIP Asymptomatic With PM/DM Linear, irregularity of interfaces 9 UIP Progressive With PM/DM Parenchymal micronodules, linear, irregularity of 10 BOOP Progressive Before PM/DM Linear, irregularity of 11 UIP Progressive Before PM/DM Linear, irregularity of interfaces Lymphocyte alveolitis Lymphocyte alveolitis Resolution Resolution Resolution Improvement Improvement * NSIP nonspecific interstitial pneumonia; UIP usual interstitial pneumonia; BOOP bronchiolitis obliterans organizing pneumonia; ILD interstitial lung disease; PM/DM polymyositis/dermatomyositis; DLCO diffusing capacity of carbon monoxide; HRCT high resolution computerized tomography. normalities (50% 83%), whereas honeycombing (5%) and bronchiectases/bronchiolectases (16%) tended to be more rare. Another main finding in our series was that HRCT of the lungs provides data concerning ILD stage, because only patients with linear, irregularity of the interfaces, or ground-glass had clearing of lung radiographic abnormalities. These changes were related to both active and reversible stages of ILD, i.e., histologic NSIP and BOOP (10,12,14,18 20). Our data confirm those of Mino et al (20) who noted in a series of 16 PM/DM patients that linear, irregularity of the interfaces, and parenchymal improved in 90% of cases at 23 months followup. Only a few reports have included data about the BAL cell profiles in PM/DM patients with ILD (3,5,6,11,34,36). As a guide to the severity and progress of alveolitis associated ILD, the significance of BAL differential cell count remains controversial in PM/DM (3,6,11,36). In our experience, patients with ILD had poor outcome when the initial BAL showed neutrophil alveolitis. We have indeed observed that all patients with ILD deterioration exhibited neutrophil alveolitis. In turn, our findings suggest that BAL cell profiles may be a helpful prognostic indicator in PM/DM patients with ILD. In addition, others have reported that histologic lung data are better indicators of survival than clinical or radiographic patterns in PM/DM patients with ILD (3,8 12,14,24,25,32,33,35). Patients with BOOP (66%) appeared to have a more favorable course than those with UIP (40%) or diffuse alveolar damage (0% 25%) (9,10,12 14,24,25,29,30,35). In our series, of the 11 PM/DM patients with ILD who underwent lung biopsies, 4 had NSIP, 5 had UIP, and 2 had BOOP; we have also observed a poorer course in patients with UIP compared with those with NSIP or BOOP. To date, only few investigators have assessed long-term outcome of ILD in PM/DM patients, although ILD is still considered to have a high morbidity due to decreased functional pulmonary status (3,5 14,25,28,29,34,35,37 40). In a recently reported series, survival of PM/DM patients with ILD was reported at 85.8%, 74.4%, and 60.4% at 1, 3 and 5 years, respectively (10). We have also observed roughly sim-

7 620 Marie et al Table 5. ILD features of PM/DM patients with and without anti Jo-1 antibody* ILD features With anti Jo-1 (n 11) Without anti Jo-1 (n 25) P Presenting pulmonary symptoms Hamman-Rich like syndrome, % Slowly progressive signs, % Asymptomatic, % Time onset Concomitant diagnosis with PM/DM, % BAL analysis (n 20) Lymphocyte alveolitis (n) 3/6 4/ (n) 3/6 10/ Lung histology (n 11) NSIP (n) 2/3 2/8 UIP (n) 1/3 4/8 BOOP (n) 0/3 2/8 ILD course Resolution, % Improvement, % , % * ILD interstitial lung disease; PM/DM polymyositis/dermatomyositis; BAL bronchoalveolar lavage; NSIP nonspecific interstitial pneumonia; UIP usual interstitial pneumonia; BOOP bronchiolitis obliterans organizing pneumonia. ilar survival rates in ILD patients, i.e., 94.4%, 90.4%, and 86.5% at 1, 3 and 5 years, respectively. Moreover, our findings underscore that ILD is a negative risk factor for survival in PM/DM patients, after excluding paraneoplastic PM/DM. In this instance, we have also shown that ILD related to PM/DM is associated with a decrease of patients functional status. Therefore, we have found that only 19.4% of PM/DM patients with ILD had resolution of pulmonary disorders; in contrast, 36.1% of PM/DM patients with ILD exhibited a marked reduction of activities due to ILD course, and 5 ILD patients further developed respiratory failure resulting in O 2 dependency. Finally, our retrospective study is, to our knowledge, the Table 6. Clinical features of PM/DM patients with and without ILD* Clinical features With ILD, % Without ILD, % (n 36) (n 120) P PM DM Sex Male Female Esophageal involvement Dysphonia Arthralgia/arthritis Malignancy PM/DM outcome Resolution PM/DM refractory to steroids * P values were obtained with chi-square or Fisher s exact tests. ILD interstitial lung disease; PM polymyositis; DM dermatomyositis. first to have investigated ILD outcome in PM/DM patients with anti Jo-1 antibody. Our results demonstrate that ILD patients with anti Jo-1 antibody less frequently developed an asymptomatic form of ILD compared with those without. Another relevant result was that no patient with anti Jo-1 antibody developed ILD with histologic lung damage consistent with BOOP. Interestingly, we have also observed that patients with anti Jo-1 antibody had similar ILD outcome, compared with those without, with respect to resolution, improvement, or deterioration of ILD and mortality rate related to ILD complications (18.2% versus 12%). Our findings suggest that patients with and without anti Jo-1 antibody may require similar management and followup of ILD. The specific therapy of ILD has not yet been clearly established in PM/DM patients. Corticosteroid therapy is considered the first-line therapy for PM/DM patients with ILD (3,6 14,24,25,28 30,35,39 41). Therapeutic response to steroids in patients with ILD depends on pulmonary histologic findings rather than clinical patterns (8 10,12,14,24,25,28,30,34,40,41); in turn, BOOP and NSIP are considered to produce the highest steroid response forms (8 10,12,14,24,25,28,30,34,40,41,42). Our series has also shown an improved response to steroid therapy in patients with NSIP and BOOP compared with those with UIP, suggesting that early control of alveolitis may be required before it causes irreversible damage to the alveolar-capillary membrane. Favorable outcome with immunosuppressive therapy in patients who failed to respond to steroids alone has been reported previously (3,5,8,9,10,12,14,28,34,35,39,43 45), and cyclophosphamide may improve the 5-year survival rate in these patients (34). In this instance, cyclophosphamide was used in 10 of 36 PM/DM patients with ILD; half of the patients who received cyclophosphamide have

8 Interstitial Lung Disease in PM/DM 621 Table 7. Laboratory findings and serologic, capillaroscopic data in PM/DM patients with and without ILD* With ILD (n 36) Without ILD (n 120) P Laboratory tests ESR, mm/hour 40 (2 140) 21 (1 105) C-reactive protein, mg/liter 12 (1 161) 6 (1 243) Hemoglobin, gm/dl 12.5 (8 16.2) 13.2 ( ) Leukocytosis, G/liter 8.1 ( ) 7.3 ( ) Platelets, mm 3 244,000 (60, ,000) 273,000 (72, ,000) Creatine kinase, units/liter 728 (13 25,231) 698 (10 27,356) Aldolase, units/liter 10.4 ( ) 9.6 ( ) Aspartate aminotransferase, units/liter 79.5 ( ) 47 (7 860) Alanine aminotransferase, units/liter 67 (20 259) 50 (5 1271) Serum total protein, gm/liter 67 (50 80) 69 (50 83) Serum albumin, gm/liter 35.6 (28 44) 38 ( ) Positive antinuclear antibodies, % Positive anti Jo-1 antibody, % Characteristic nailfold capillaroscopic microangiopathy, % * Except where indicated, values are median (range). P values were obtained with Mann-Whitney U test. ESR erythrocyte sedimentation rate; ILD interstitial lung disease; PM/DM polymyositis/dermatomyositis. either resolved (n 3) or improved (n 2) pulmonary status. Moreover, we have noted that cyclophosphamide was used at an earlier lung histologic stage in patients with improved pulmonary status. In our population, 8 patients with ILD were given azathioprine, resulting in improvement of lung impairment in 75% of cases. Our findings are in agreement with previously reported data (3,10,11,46). Cyclosporine may be an alternative therapy in patients with ILD resistant to high-dose steroids, alone or in combination with cytotoxic drugs, resulting in prolonged survival of patients (3,9 12,14,28,34,35,40,47,48). In our series, only 2 PM/DM patients with steroid-refractory ILD received cyclosporine, leading to improvement of lung parameters in 1. From a practical point of view, the knowledge of predictive indicators associated with ILD in PM/DM patients appears crucial to improve management at an early stage of the disease. Previous authors have described numerous variables of ILD in PM/DM (3,11). In the present series, neither age, sex, PM/DM, nor digestive features could be considered predictive factors in ILD, as described by other investigators (5,7,8,13). Of the systemic manifestations of PM/DM, only arthralgia/arthritis were found to be associated with ILD, confirming that these may be predictive factors of ILD (5,11,13). Moreover, we failed to observe a relationship between malignancy and ILD; in turn, our findings do not corroborate the hypothesis of paraneoplastic forms of ILD in PM/DM (37). In our experience, the prevalence of raised ESR and CRP levels was higher in PM/DM patients with ILD. Inflammatory anemia was also more commonly found in this subgroup of patients. The design of our study does not permit us to explain the reasons for these findings, although both inflammatory anemia and increased ESR and CRP could have been acute-phase reactants related to ILD. We have further noted that characteristic nailfold capillaroscopic microangiopathy is more frequent in patients with ILD; our findings suggest that the presence of capillaroscopic microangiopathy should encourage the investigation of ILD in PM/DM patients. If the relationship is confirmed, determination of microangiopathy may become an integral part of PM/DM evaluation for early detection of patients at risk for ILD. In conclusion, our series highlights the high frequency of ILD in PM/DM patients, resulting in increased morbidity and mortality rates. Our findings also indicate that ILD should be routinely searched in all PM/DM patients, with or without anti Jo-1 antibody, because frequency of ILD was as high as 73% in patients with anti Jo-1 antibody and because 69% of patients with ILD were seronegative for anti Jo-1 antibody. Our study further indicates that ILD assessment, including PFT and HRCT of the lungs, should be performed during both initial evaluation and followup of PM/DM patients. Finally, the following parameters could be considered as predictive of ILD poor outcome: Hamman-Rich like pattern, initial DLCO of 45%, neutrophil alveolitis, and histologic UIP; the presence of these factors may suggest more aggressive therapy of PM/DM patients with ILD. ACKNOWLEDGMENT The authors thank R. Medeiros for his advice in editing the manuscript. REFERENCES 1. Callen JP. Dermatomyositis. Lancet 2000;355: Marie I, Hachulla E, Hatron PY, Hellot MF, Levesque H, Courtois H, et al. Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 2001;28: Marie I, Hatron PY, Hachulla E, Wallaert B, Michon-Pasturel U, Devulder B. Pulmonary involvement in polymyositis and in dermatomyositis. J Rheumatol 1998;25: Marie I, Hatron PY, Levesque H, Hachulla E, Hellot MF, Michon-Pasturel U, et al. Influence of age on characteristics of polymyositis and dermatomyositis in adults. Medicine 1999; 78: Arsura EL, Greenberg AS. Adverse impact of interstitial pul-

9 622 Marie et al monary fibrosis on prognosis in polymyositis and dermatomyositis. Semin Arthritis Rheum 1988;18: Dickey BF, Myers AR. Pulmonary disease in polymyositis/ dermatomyositis. Semin Arthritis Rheum 1984;14: Frazier AR, Miller RD. Interstitial pneumonitis in association with polymyositis and dermatomyositis. Chest 1974;65: Schwarz MI, Matthay RA, Sahn SA, Stanford RE, Marmorstein BL, Scheinhorn DJ. Interstitial lung disease in polymyositis and dermatomyositis: analysis of six cases and review of the literature. Medicine 1976;55: Schwarz MI. The lung in polymyositis. Clin Chest Med 1998; 19: Douglas WW, Tazelaar HD, Hartman TE, Hartman RP, Decker PA, Schroeder DR, et al. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001;164: Grau JM, Miro O, Pedrol E, Casademont J, Masanes F, Herrero C, et al. Interstitial lung disease related to dermatomyositis: comparative study with patients without lung involvement. J Rheumatol 1996;23: Hirakata M, Nagai S. Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 2000;12: Lakhanpal S, Lie JT, Conn DL, Martin WJ II. Pulmonary disease in polymyositis/dermatomyositis: a clinicopathological analysis of 65 autopsy cases. Ann Rheum Dis 1987;46: Marie I, Dominique S, Remy-Jardin M, Hatron PY, Hachulla E. Pneumopathie interstitielle au cours des polymyosites et des dermatomyosites. Rev Méd Interne 2001;22: Bohan A, Peter JB. Polymyositis and dermatomyositis: first of two parts. N Engl J Med 1975;292: Bohan A, Peter JB. Polymyositis and dermatomyositis: second of two parts. N Engl J Med 1975;292: Quanjer PH. Clinical respiratory physiology: standardized lung function testing: working party report: standardization of lung function tests. Bull Eur Physiopathol Respir 1983;19 Suppl 5: Akira M, Hara H, Sakatani M. Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology 1999; 210: Ikezoe J, Johkoh T, Kohno N, Takeuchi N, Ichikado K, Nakamura H. High-resolution CT findings of lung disease in patients with polymyositis and dermatomyositis. J Thorac Imaging 1996;11: Mino M, Noma S, Taguchi Y, Tomii K, Kohri Y, Oida K. Pulmonary involvement in polymyositis and dermatomyositis: sequential evaluation with CT. AJR Am J Roentgenol 1997;169: Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157: Daniil ZD, Gilchrist FC, Nicholson AG, Hansell DM, Harris J, Colby TV, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160: Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J Surg Pathol 1994;18: Takizawa H, Shiga J, Moroi Y, Miyachi S, Nishiwaki M, Miyamoto T. Interstitial lung disease in dermatomyositis: clinicopathological study. J Rheumatol 1987;14: 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 1990;141: Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 2000;24: Mills ES, Matthews WH. Interstitial pneumonitis in dermatomyositis. JAMA 1956;160: Al-Janadi M, Smith CD, Karsh J. Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyositis/dermatomyositis. J Rheumatol 1989;16: Duncan PE, Griffin JP, Garcia A, Kaplan SB. Fibrosing alveolitis in polymyositis: a review of histologically confirmed cases. Am J Med 1974;57: Salmeron G, Greenberg D, Lidsky MD. Polymyositis and diffuse interstitial lung disease: a review of the pulmonary histopathologic findings. Arch Intern Med 1981;141: Songcharoen S, Raju SF, Pennebaker JB. Interstitial lung disease in polymyositis and dermatomyositis. J Rheumatol 1980; 7: Schwarz MI, Sutarik JM, Nick JA, Leff JA, Emlen JW, Tuder RM. Pulmonary capillaritis and diffuse alveolar hemorrhage: a primary manifestation of polymyositis. Am J Respir Crit Care Med 1995;151: Clawson K, Oddis CV. Adult respiratory distress syndrome in polymyositis patients with the anti Jo-1 antibody. Arthritis Rheum 1995;38: Maccioni FJ, Colebatch HJH. Management of fibrosing alveolitis with polymyositis dermatomyositis. Aust NZ J Med 1990;20: Schwarz MI. Pulmonary and cardiac manifestations of polymyositis-dermatomyositis. J Thorac Imaging 1992;7: Wallaert B, Hatron PY, Grosbois JM, Tonnel AB, Devulder B, Voisin C. Subclinical pulmonary involvement in collagenvascular diseases assessed by bronchoalveolar lavage. Am Rev Respir Dis 1986;133: Hochberg MC, Feldman D, Stevens MB. Adult onset polymyositis/dermatomyositis: an analysis of clinical and laboratory features and survival in 76 patients with a review of the literature. Semin Arthritis Rheum 1986;15: Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 1991;70: Marguerie C, Bunn CC, Beynon HLC, Bernstein RM, Hughes JMB, So AK, et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-trna synthetase enzymes.q J Med 1990;77: Nawata Y, Kurasawa K, Takabayashi K, Miike S, Watanabe N, Hiraguri M, et al. Corticosteroid resistant interstitial pneumonitis in polymyositis/dermatomyositis: prediction and treatment with cyclosporine. J Rheumatol 1999;26: Oddis CV. Current approach to the treatment of polymyositis and dermatomyositis. Curr Opin Rheumatol 2000;12: Yamanishi Y, Maeda H, Konishi F, Hiyama K, Yamana S, Ishioka S, et al. Dermatomyositis associated with rapidly progressive fatal interstitial pneumonitis and pneumomediastinum. Scand J Rheumatol 1999;28: Schnabel A, Reuter M, Gross WL. Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases. Arthritis Rheum 1998;41: Shinohara T, Kidaka T, Matsuki Y, Ishizuka T, Takamizawa M, Kawakami M, et al. Rapidly progressive interstitial lung disease associated with dermatomyositis responding to intravenous cyclophosphamide pulse therapy. Intern Med 1997; 36: Tanaka F, Origuchi T, Migita K, Tominaga M, Kawakami A, Kawabe Y, et al. Successful combined therapy of cyclophosphamide and cyclosporine for acute exacerbated interstitial pneumonia associated with dermatomyositis. Intern Med 2000;39: Rowen AJ, Reichel J. Dermatomyositis with lung involvement, successfully treated with azathioprine. Respiration 1983;44: Gruhn WB, Diaz-Buxo JA. Cyclosporine treatment of steroid resistant interstitial pneumonitis associated with dermatomyositis/polymyositis. J Rheumatol 1987;14: Maeda K, Kimura R, Komuta K, Igarashi T. Cyclosporine treatment for polymyositis/dermatomyositis: is it possible to rescue the deteriorating cases with interstitial pneumonitis? Scand J Rheumatol 1997;26:24 9.