Clinical Differences Between Interstitial Lung Disease Associated With Clinically Amyopathic Dermatomyositis and Classic Dermatomyositis

CHEST Clinical Differences Between Interstitial Lung Disease Associated With Clinically Amyopathic Dermatomyositis and Classic Dermatomyositis Hiroshi Mukae, MD, PhD; Hiroshi Ishimoto, MD; Noriho Sakamoto, MD; Shintaro Hara, MD; Tomoyuki Kakugawa, MD; Seiko Nakayama, MD; Yuji Ishimatsu, MD; Atsushi Kawakami, MD; Katsumi Eguchi, MD; and Shigeru Kohno, MD, FCCP Original Research INTERSTITIAL LUNG DISEASE Background: Interstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM) is a potentially fatal condition in which the clinical features are not well understood. The aim of the present study was to clarify the differences in clinical characteristics and prognosis of patients with ILD associated with CADM (CADM-ILD) and classic dermatomyositis associated with ILD (DM-ILD). Methods: We retrospectively studied consecutive patients with CADM-ILD and classic DM-ILD who were hospitalized between 2001 and 2007 at Nagasaki University Hospital. The study group consisted of 11 patients with CADM-ILD and 16 patients with classic DM-ILD. We compared the clinical features and prognosis between the two forms. Results: The PaO 2 /FIO 2 ratio was significantly lower in patients with CADM-ILD than in patients with classic DM-ILD. The lymphocyte subsets ratio in the BAL fluid of patients with CADM-ILD was significantly higher than the corresponding ratio in patients with classic DM-ILD. ILD is classified as acute or chronic, and the acute subtype was more common in patients with CADM-ILD than in those with classic DM-ILD. The mortality rate for patients with CADM-ILD (45%) was much higher than that for patients with classic DM-ILD (6%), and all of the CADM deaths occurred in the group of patients with acute CADM-ILD. Conclusion: Our data suggest that the higher prevalence of the acute subtype of ILD in patients with CADM results in a higher mortality rate for patients with CADM-ILD. (CHEST 2009; 136:1341 1347) Abbreviations: CADM clinically amyopathic dermatomyositis; CADM-ILD clinically amyopathic dermatomyositis associated with interstitial lung disease; CTD-ILD interstitial lung disease associated with connective tissue disease; DM-ILD dermatomyositis associated with interstitial lung disease; ILD interstitial lung disease; PMX polymyxin B immobilized fiber Interstitial lung disease (ILD) frequently occurs in patients with connective tissue diseases such as dermatomyositis and polymyositis. 1,2 In patients with dermatomyositis and polymyositis, ILD is a complication with a prevalence of 5% to 65%. 3 Although Manuscript received November 22, 2008; revision accepted June 18, 2009. Affiliations: From the Second Department of Internal Medicine (Drs. Mukae, Ishimoto, Sakamoto, Hara, Kakugawa, Nakayama, Ishimatsu, and Kohno), the First Department of Internal Medicine (Drs. Kawakami and Eguchi), and the Department of General Medicine (Dr. Nakayama), Nagasaki University School of Medicine, Nagasaki, Japan. the clinical features of ILD associated with connective tissue disease (CTD-ILD) are similar to those of idiopathic interstitial pneumonias, the survival rate of patients with CTD-ILD is much greater, and Correspondence to: Hiroshi Mukae, MD, PhD, Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; e-mail: hmukae@nagasaki-u.ac.jp 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). DOI: 10.1378/chest.08-2740 www.chestjournal.org CHEST / 136 / 5/ NOVEMBER, 2009 1341

more than one-half of the patients have a chronic indolent course. 4 However, certain patients with CTD-ILD have a rapidly progressive and fatal form of ILD. In particular, a subset of patients with clinically amyopathic dermatomyositis (CADM), which is defined by the criteria of Sontheimer 5 and Sontheimer and Miyagawa, 6 experiences a fulminant and devastating course. 6 12 These patients are often resistant to intensive therapy, such as high-dose corticosteroids and immunosuppressive agents, resulting in fatal respiratory failure. As CADM associated with ILD (CADM-ILD) is a rare condition, its characteristics have not been fully clarified. In the present study, we examined a series of patients with CADM-ILD to determine its clinical features and prognosis compared with those of classic dermatomyositis associated with ILD (DM-ILD). Materials and Methods Patient and Diagnostic Criteria We retrospectively studied 27 consecutive Japanese patients with CADM and classic DM-ILD who were hospitalized at the Nagasaki University Hospital from 2001 to 2007. This hospital is a referral center in this area for ILD. All patients were referred to our hospital for the evaluation of dermatomyositisassociated ILD. Some patients were admitted to the hospital for diagnostic evaluation in the absence of clinical deterioration, whereas others were admitted for the evaluation of respiratory failure. Amyopathic dermatomyositis is characterized by Gottron rash or heliotrope rash, normal creatine kinase levels and muscle biopsy results, and no symptoms or signs of muscle weakness. Hypomyopathic dermatomyositis is characterized by Gottron rash or heliotrope rash, no symptoms of muscle weakness, and normal or only mildly reduced muscle strength consistent with age, sex, and severity of systemic illness. 11 CADM is the combination of amyopathic and hypomyopathic dermatomyositis. 5,13 While the definition by Sontheimer 5 requires that skin disease be present for 6 months without the development of muscle disease, Sontheimer and Miyagawa 6 have also described a subset of patients with premyopathic dermatomyositis in whom fatal ILD developed within the first 6 months of their disease course. They included these patients in their review of CADM-ILD because the cases represented ILD occurring in a patient with dermatomyositis-specific skin disease in the absence of muscle disease. Our study population consisted of patients who fulfilled the traditional criteria of Sontheimer 5 and Bohan and Peter 14,15 and a group of patients who fit into the category of premyopathic dermatomyositis. ILD was diagnosed based on the presence of radiologic abnormalities in chest radiographs and helical CT scans. CADM and classic dermatomyositis were diagnosed by skin biopsy or by evaluation by a Japan College of Rheumatology-certified rheumatologist and a dermatologist (A.K. and K.E.), with consistent features found on examination. Clinical data, including history, treatment, laboratory findings, and BAL fluid findings, were obtained from the patients medical records. The Human Ethics Review Committees of Nagasaki University School of Medicine approved the study protocol, and all living participants provided written consent. Two patients in this study have already been described in a case report (case 3 8 and case 6 16 in patients with CADM-ILD). Scoring of Helical CT Scan Findings The helical CT findings were graded on a scale of 1 to 6 on the basis of the classification system previously reported by Ichikado and colleagues 17,18 as follows: (1) normal attenuation; (2) groundglass attenuation; (3) consolidation; (4) ground-glass attenuation with traction bronchiolectasis or bronchiectasis; (5) consolidation with traction bronchiolectasis or bronchiectasis; and (6) honeycombing. The presence of each of these six abnormalities was assessed independently in three zones (upper, middle, and lower) of each lung. The extent of each abnormality was determined by visually estimating the percentage (to the nearest 10%) of the affected lung parenchyma in each zone. The assessments of three observers were averaged. The abnormality score for each zone was calculated by multiplying the percentage area by the point value (score of 1 to 6). The six zone scores were averaged to determine the total score for each abnormality in each patient. The overall CT scan score for each patient was obtained by adding the six averaged scores. Statistical Analysis Values are expressed as the mean SD for continuous variables and as percentages for categorical variables. We performed statistical analyses with a computer software package (StatMate III for Macintosh, version 3.14; ATMS Co, Ltd; Tokyo, Japan). We used the Wilcoxon test to compare continuous variables, and the 2 test or Fisher exact test to compare categorical variables. Cumulative survival probabilities were estimated by using the Kaplan-Meier method. The log-rank test was used to compare the survival of groups of patients. A p value 0.05 was considered statistically significant, and all tests were two tailed. Results Clinical Features and Laboratory Findings Eleven patients (two men and nine women; mean [ SD] age, 60.4 10.7 years; current smokers, two patients; never-smokers, nine patients) were given a diagnosis of CADM-ILD, and 16 patients (one man and 15 women; mean age, 53.3 11.1 years; neversmokers, 16 patients) were given a diagnosis of classic DM-ILD. There were no statistically significant differences in the male/female ratio and the age distribution between CADM and classic dermatomyositis. No patients had any malignancies or pulmonary infection. Two patients with CADM (one patient treated with methotrexate and corticosteroid, and one patient treated with corticosteroid) and nine patients with dermatomyositis (seven patients treated with corticosteroid and cyclosporine, and two patients treated with corticosteroid) received treatment before hospital admission. Skin biopsies had been performed in 6 of the 11 patients with CADM and in 10 of the 16 patients with classic dermatomyositis; the pathologic findings were consistent with a diagnosis of dermatomyositis. 1342 Original Research

Table 1 Comparison of Clinical Characteristics Between With CADM-ILD and With Classic Dermatomyositis Characteristics CADM-ILD (n 11) Classic DM-ILD (n 16) p Value WBC count, cells/ L 6510 1820 9530 4840 0.048 C-reactive protein, 4.48 7.73 0.88 0.92 NS mg/dl Lactate 381 186 337 139 NS dehydrogenase, U/L Creatine kinase, 152 103 539 912 NS U/mL KL-6, U/mL 1460 1200 978 485 NS Pao 2 /Fio 2 ratio, mm Hg 258 111 385 40 0.0018 Data are presented as the mean SD, unless otherwise indicated. NS not significant. The mean duration of respiratory and/or skin symptoms before hospital admission was significantly shorter for CADM-ILD patients (4.6 4.6 months) than for classic DM-ILD patients (34.1 56.9 months; p 0.001). Skin symptoms preceded respiratory symptoms in 4 of 11 patients (36%) with CADM-ILD and in 7 of 16 patients (44%) with classic DM-ILD. The onset of pulmonary symptoms was concomitant with the onset of skin symptoms in 6 of the 11 patients (55%) with CADM-ILD and in 5 of 16 patients (31%) with classic DM-ILD. Solitary respiratory manifestations preceded any skin disease in one patient (9%) with CADM-ILD and in four patients (25%) with classic DM-ILD. with CADM-ILD and classic DM-ILD were classified as having the acute type or chronic type based on their clinical presentation. The acute type included patients in whom skin and respiratory symptoms developed within 2 months prior to admission to our hospital. Seven patients (64%) with CADM-ILD and three patients (19%) with classic DM-ILD were given a diagnosis of acute-type disease. Thus, a higher prevalence of acute-type disease was found in patients with CADM-ILD (p 0.05). Laboratory findings are summarized in Table 1. WBC counts were significantly greater in patients with classic dermatomyositis than in patients with CADM. Both groups had elevated levels of serum C-reactive protein, lactate dehydrogenase, and KL-6, but there were no significant differences between the two groups (Table 1). Antinuclear antibodies were present in 4 of 10 patients with CADM-ILD and in 11 of 13 patients with classic DM-ILD. Tests for anti-jo-1 antibody were negative in all patients with CADM-ILD; however, 5 of 16 patients with classic DM-ILD had positive results (Table 2). Pao 2 / Fio 2 ratio at hospital admission was significantly lower in patients with CADM-ILD than in patients with classic DM-ILD (Table 1). CT Scan Findings and the CT Scan Score CT scan images of the lung were available for all patients. Images from all patients showed groundglass opacities. Consolidation was more common in patients with CADM (Fig 1), as has been found in previous reports. 9,10 Helical CT scan images of the lung were available for 24 of 27 patients. We calculated the CT scan score in these 24 patients. The CT scan score is predictive of poor prognosis in patients with ARDS and acute interstitial pneumonia. 17,18 There was no significant difference in the CT scan score between patients with CADM-ILD (153 38) and patients with classic DM-ILD (133 24). However, in the CADM-ILD group, the CT scan score correlated inversely with Pao 2 /Fio 2 ratio (r 2 0.704; p 0.001) [Fig 2]. BAL Fluid Analysis BAL was performed in 7 patients with CADM and 11 patients with classic dermatomyositis. There were no significant differences in the number of total cells or the percentage of inflammatory cells between the two groups (Table 3). However, patients with CADM-ILD had a significantly higher lymphocyte subset (CD4 / CD8 ) ratio than patients with classic DM-ILD. Treatment All patients received therapy with corticosteroids. Seven patients with classic DM-ILD received therapy with corticosteroids alone, achieving a good effect, while therapy with corticosteroids alone did not provide improvement in any of the patients with CADM-ILD (Table 2). Immunosuppressive agents such as cyclosporine, methotrexate, cyclophosphamide, and tacrolimus were added to corticosteroid therapy in all patients with CADM-ILD and in eight patients with classic DM-ILD. Treatment with immunosuppressive agents and corticosteroids was effective in 5 of 11 patients with CADM-ILD and in 6 of 16 patients with classic DM-ILD. In addition, IV Ig agents were administered to two patients with classic DM-ILD. Three patients received leukocytapheresis, and two patients received treatment with a direct hemoperfusion column containing polymyxin B immobilized fibers (PMXs). Mortality and Survival During the observation period, 5 of the 11 patients (45%) with CADM-ILD died. These five patients www.chestjournal.org CHEST / 136 / 5/ NOVEMBER, 2009 1343

Table 2 Clinical Characteristics of the CADM and Classic DM-ILD Cases Age, yr Sex Symptoms, mo Treatment Respiratory Skin Acute/ Chronic Anti-Jo1 Corticosteroids Cyclosporin A Others Outcome CADM-ILD 1 45 Female 1 1 Acute Cyclophosphamide Death 2 74 Female 1 1 Acute Cyclophosphamide Alive 3 49 Male 1 2 Acute Cyclophosphamide Death 4 74 Female 0.5 1 Acute Death 5 69 Female 2 2 Acute PMX, Leukocytapheresis Death 6 70 Male 6 6 Chronic PMX Alive 7 53 Female 0.3 10 Chronic Alive 8 67 Female 12 1 Chronic Cyclophosphamide Alive 9 57 Female 1 12 Chronic Tacrolimus, Cyclophosphamide Alive 10 57 Female 1 1 Acute Tacrolimus, Cyclophosphamide, Death Leukocytapheresis 11 49 Female 1 1 Acute Alive Classic DM-ILD 1 57 Female 29 3 Chronic IVIG Alive 2 63 Female 4 3 Chronic Alive 3 31 Female 2 9 Chronic Alive 4 52 Female 1 8 Chronic Tacrolimus Alive 5 62 Female 30 25 Chronic Alive 6 65 Female 1 1 Acute Alive 7 30 Female 2 5 Chronic Alive 8 59 Female 48 7 Chronic Death 9 45 Female 48 216 Chronic Leukocytapheresis Alive 10 63 Male 36 36 Chronic Alive 11 48 Female 60 120 Chronic Cyclophosphamide Alive 12 56 Female 10 10 Chronic Methotrexate Alive 13 47 Female 10 22 Chronic IVIG, Cyclophosphamide Alive 14 49 Female 2 4 Chronic Alive 15 66 Female 2 2 Acute Tacrolimus Alive 16 60 Female 1 1 Acute Alive IVIG IV high-dose Ig; negative; positive. had acute-type disease that followed a fulminant course with rapid progression of respiratory failure, and they died within 1 to 2 months (Table 2, Fig 3). The mortality rate for patients with the acute type of CADM-ILD was extremely high (5 of 7; 71%), while no patients with chronic-type CADM-ILD died. There were no significant differences in the male/ female ratio, age distribution, WBC counts, serum KL-6 levels, and CD4 /CD8 ratio in BAL fluid between survivors and nonsurvivors with CADM- ILD (data not shown). In contrast, 1 of the 16 patients (6%) with classic DM-ILD died; respiratory failure developed in this patient 4 years after disease presentation. Thus, the mortality rate for patients Figure 1. A representative CT scan of a patient with CADM- ILD (case 1) shows consolidation and ground-glass opacities predominantly in the subpleural region. Figure 2. Correlation between the CT scan score and Pao 2 /Fio 2 ratio in patients with CADM-ILD and classic DM-ILD. 1344 Original Research

Table 3 Comparison of BAL Fluid Findings Between With CADM-ILD and With Classic DM-ILD Variables CADM-ILD (n 7) with CADM-ILD was significantly higher than that for patients with classic DM-ILD (p 0.02). Discussion Classical DM-ILD (n 11) p Value Total cells, 10 5 cells/ml 5.4 2.6 3.5 2.4 NS Macrophages, % 55 15 46 25 NS Neutrophils, % 11 14 17 25 NS Eosinophils, % 1 1 4 3 NS Lymphocytes, % 33 17 33 24 NS CD4 /CD8 ratio 2.56 2.48 0.48 0.42 0.0024 Data are presented as the mean SD, unless otherwise indicated. See Table 1 for abbreviation not used in the text. Figure 3. Overall survival curves of patients with CADM-ILD and classic DM-ILD. Time indicates the number of months since the onset of respiratory or skin symptoms. CADM is a rare form of dermatomyositis that typically manifests with characteristic cutaneous lesions and mild or no muscle involvement. 5,13 Cottin et al 19 reported a favorable prognosis for patients with CADM-ILD, but there have been reports, 6 10 mainly from Asian regions, of several cases of fatal ILD associated with CADM. These observations suggest that CADM includes heterogeneous disease populations. The present study showed that the mortality rate of patients with CADM-ILD was significantly higher than that of patients with classic DM-ILD and that the acute type of ILD is more frequent in patients with CADM-ILD compared with those with classic DM-ILD. We also found that five of seven patients (71%) with acute type CADM- ILD died, while none of the patients with chronictype CADM-ILD died; these findings are consistent with previous reports. 9,10 The mortality rate for patients with chronic CADM-ILD has been shown to be similar to that of patients with classic DM-ILD. We tried to use laboratory results to find a better way of characterizing patients with CADM-ILD, especially patients with acute-type disease. However, there were no significant differences between patients with CADM-ILD and those with classic DM- ILD, except for high WBC counts, low Pao 2 /Fio 2 ratio (Table 1), and the absence of anti-jo-1 antibody (Table 2) in CADM-ILD compared with patients with classic DM-ILD. Although KL-6 was previously reported to be a useful marker for ILD in patients with dermatomyositis and polymyositis, 20 it did not have prognostic significance in the present study. We next examined characteristics of chest CT scan features of CADM-ILD. This is the first report to describe quantitative CT scan scores in patients with CADM-ILD compared with those of patients with classic DM-ILD. The few previous studies of CT scan findings from patients with CADM-ILD 9,10 have often reported ground-glass opacities, consolidation, and reticular opacities in these patients; these characteristics have also been found in patients with classic DM-ILD. 21,22 The CT scan findings in the present study are consistent with these reports; the CT scan score was inversely correlated with Pao 2 / Fio 2 ratio only in patients with CADM-ILD (Fig 2), suggesting that it may be useful in patients with CADM-ILD. The BAL results indicate that the CD4 /CD8 ratio is greater in CADM patients than in those with classic dermatomyositis. An increased percentage of CD8 lymphocytes (cytotoxic T cells) was previously found in BAL fluid from patients with DM- ILD. 23 Kurasawa et al 24 reported that the number of CD25 CD4 and CD25 CD8 T cells in the BAL fluid of patients with dermatomyositis was significantly greater in patients with corticosteroidresistant interstitial pneumonia than in patients with corticosteroid-sensitive interstitial pneumonia. While little is known about the BAL findings of patients with CADM-ILD, Suda et al 9 demonstrated that the CD4 /CD8 ratio in BAL fluid tended to be higher in patients with acute-type CADM-ILD. Ito et al 25 found a higher CD4 /CD8 ratio in the peripheral blood and BAL fluid of patients with dermatomyositis with rapidly progressive ILD. The findings of these previous reports were consistent with our present data, which suggests a different immune reaction in the lung between CADM-ILD and classic DM-ILD patients. In this study, all patients received corticosteroids, and seven patients with classic DM-ILD who received corticosteroids alone achieved a good re- www.chestjournal.org CHEST / 136 / 5/ NOVEMBER, 2009 1345

sponse. However, corticosteroids alone did not improve the condition of any patients with CADM- ILD. Immunosuppressive agents, such as cyclosporine, were needed in all patients with CADM-ILD and 8 of the 16 patients with classic DM-ILD. However, five of seven patients with acute-type CADM-ILD died despite the treatment; this high mortality rate suggests that the current therapy is not sufficient for acute-type CADM-ILD. Miyazaki et al 12 reported a case of diffuse alveolar damage in a patient with rapidly progressive CADM-ILD that was successfully treated with an early intervention of corticosteroids, cyclosporine, and pulse cyclophosphamide. In addition to immunosuppressants, PMX treatment has been reported 26,27 to improve oxygenation in patients with ARDS and acute exacerbation of idiopathic pulmonary fibrosis. We encountered a patient with CADM-ILD (case 6) who was successfully treated with PMX. 16 Future studies are needed to elucidate a new effective therapy for acutetype CADM-ILD. In conclusion, our data suggest that the higher prevalence of the acute subtype of ILD in patients with CADM results in a higher mortality rate for patients with CADM-ILD. However, our present study is limited by the small number of patients. In addition, there is ascertainment bias toward patients who are sick enough to warrant referral to our hospital, and milder or subclinical cases are unlikely to be included. Acknowledgments Author contributions: Dr. Mukae designed the article, acquired the data, analyzed and interpreted the data, and drafted the article. Drs. Ishimoto, Sakamoto, Hara, Kakugawa, Nakayama, Ishimatsu, and Kawakami acquired the data, interpreted the data, and helped draft the article. Drs. Eguchi and Kohno interpreted the data and helped draft the article. Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. References 1 Tazelaar HD, Viggiano RW, Pickersgill J, et al. Interstitial lung disease in polymyositis and dermatomyositis: clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990; 141:727 733 2 Marie I, Hachulla E, Cherin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2002; 47:614 622 3 Fathi M, Lundberg IE. Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 2005; 17: 701 706 4 Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007; 175:705 711 5 Sontheimer RD. 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