Treatment with Methotrexate and Low-dose Corticosteroids in Sarcoidosis Patients with Cardiac Lesions

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1 ORIGINAL ARTICLE Treatment with Methotrexate and Low-dose Corticosteroids in Sarcoidosis Patients with Cardiac Lesions Sonoko Nagai 1, Takafumi Yokomatsu 2, Kiminobu Tanizawa 3, Kohei Ikezoe 3, Tomohiro Handa 3,YutakaIto 3, Shunpei Ogino 1 and Takateru Izumi 1 Abstract Objective Our objective was to evaluate the effectiveness of combination therapy consisting of low-dose corticosteroids with weekly methotrexate in patients with cardiac sarcoidosis in whom long-term therapy is required. Combination therapy was selected because long-term standard corticosteroid therapy tends to result in various adverse effects and the steroid-sparing effects of methotrexate have been reported. Methods This study was a small open-label study comparing long-term functional changes between patients who received combination therapy (5-15 mg/day of prednisolone and 6 mg/week of methotrexate) and patients who received corticosteroids alone. The comparative analysis was based on the following therapeutic indexes: ejection fraction (EF), left ventricular end-diastolic diameter (LVDd) on echocardiography, serum N- terminal fragment pro-brain natriuretic peptide (NT-proBNP) and cardiothoracic ratio (CTR) on plain chest radiographs. Patients Seventeen patients with cardiac sarcoidosis were examined in the sarcoidosis clinic. Cardiac sarcoidosis was diagnosed based on the Japanese diagnostic guidelines published in Results The EF was significantly stabilized in the combination therapy group but not in the corticosteroids alone group at three years after the first treatment. The CTR and NT-proBNP levels were significantly stabilized in the combination therapy group compared with those observed in the corticosteroids alone group at both three and five years after the first treatment. The LVDd values tended to be stable in the combination therapy group compared with those observed in the corticosteroids alone group. The combination therapy was associated with few adverse effects. Conclusion Weekly methotrexate therapy with daily small doses of corticosteroids stabilized the EF, CTR and NT-proBNP levels in the serum without eliciting adverse effects longitudinally. Key words: sarcoidosis, ejection fraction on echocardiography, cardiothoracic ratio on plain chest radiograph, N-terminal fragment pro-brain natriuretic peptide, methotrexate, corticosteroid (Intern Med 53: , 2014) () Introduction Sarcoidosis is fundamentally a chronic inflammatory disease. The pathological and clinical courses vary widely from spontaneous regression to fibrotic progression, leading to various patterns of organ dysfunction (1). The clinical phenotypes associated with different clinical courses have been proposed based on a review of 400 sarcoidosis cases collected worldwide (2). The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) Task Force classified nine phenotypes according to an evaluation of the clinical course up to five years after detection (2). According to the clinical phenotypes classified by the WASOG, 17% of cases spontaneously regress, 8% deteriorate, 34% manifest minimal remaining lesions with or without therapy and 34% progress to the chronic stage with or without treatment (2). Among patients who receive treatment, 40% reportedly re- Central Clinic, Clinical Research Center, Japan, Mitsubishi Kyoto Hospital, Japan and Department of Respiratory Medicine, Kyoto University Hospital, Japan Received for publication April 16, 2013; Accepted for publication September 18, 2013 Correspondence to Dr. Sonoko Nagai, nagai@chuo-c.jp 427

2 lapse after corticosteroids are tapered or discontinued altogether (3). In the A Case Controlled Etiologic Study of Sarcoidosis (ACCESS) trial, multiple lesion sites, lesion frequency according to the site and various associations between clinical characteristics and patient age, gender, number of lesions and population differences affect the prognosis (4). Although the frequency varies, functional deterioration has been reported in all affected organs. Among the lesions observed in various affected organs, cardiac lesions usually require corticosteroid therapy (5). Even under corticosteroid therapy, a substantial number of patients with cardiac sarcoidosis exhibit functional deterioration with adverse effects (6). There remains controversy regarding the clinical efficacy and optimal dose and duration of corticosteroid treatment for cardiac sarcoidosis (7). Based on the general consensus, alternative agents may be given to patients who do not respond to corticosteroids or who cannot tolerate their side effects. Methotrexate, an alternative therapeutic drug for sarcoidosis, the effects of which have been substantially reported, is prescribed primarily for chronic sarcoidosis and can be expected to confer both an immunomodulatory effect and steroid-sparing effect that prevents adverse corticosteroid responses during long-term therapy (8). In this study, we examined the therapeutic roles of methotrexate administered with low-dose corticosteroids in patients with cardiac lesions. As methotrexate exerts its effects slowly, we selected combination therapy consisting of low-dose corticosteroids, which can be expected to show therapeutic effects promptly and continuously, and weekly methotrexate, instead of methotrexate only. Materials and Methods Study population and methods Seventeen sarcoidosis patients with cardiac lesions treated at the Central Clinic/Clinical Research Center in Kyoto, Japan were enrolled in the study. Sarcoidosis was diagnosed clinically with or without a biopsy. Sites with lesions suggestive of sarcoidosis were surveyed clinically using interviews, chest radiographs (plain chest radiography and chest HRCT), abdominal CT, abdominal echography, bone density measurement, ECG, cardiac echography, pulmonary function tests, tuberculin skin tests, blood tests (ACE, 1,25-(OH)2 vitamin D, soluble IL2 receptor, WBC, alkaline phosphatase, gamma GTP, uric acid, creatinine, blood urea nitrogen, lysozyme), gallium scintiscan, myocardial scintiscan, FDG-PET and cardiac MRI. The study was approved by the Ethics Committee at the Central Clinic/Clinical Research Center. Diagnosis of cardiac sarcoidosis Cardiac sarcoidosis was diagnosed according to the diagnostic guidelines proposed by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2006 (9, 10). The following criteria for a definitive diagnosis and clinical diagnosis proposed under these guidelines were used: 1) Definitive diagnosis group, histological diagnosis using a cardiac biopsy; 2) Clinical diagnosis group, a negative biopsy with proven extracardiac sarcoidosis and fulfillment of two or more of four major criteria or one of four major criteria and two or more minor criteria. The major criteria included advanced atrioventricular (AV) block, basal thinning of the ventricular septum (11), a positive cardiac gallium uptake and a left ventricular ejection fraction of less than 50%. The minor criteria included abnormal ECG findings (ventricular tachycardia, frequent premature multifocal ventricular contractions, complete right bundle branch block, pathologic Q waves or abnormal axis deviation), ultrasonic echocardiography (UCG) abnormalities (regional wall motion abnormalities, ventricular aneurysms or unexplained increases in wall thickness), perfusion defects detected on myocardial scintigraphy, delayed gadolinium enhancement of the myocardium on cardiac MRI scanning and interstitial fibrosis or monocyte infiltration greater than moderate grade on an endomyocardial biopsy. Evaluation of disease severity and therapeutic effects Cardiac echocardiography was serially performed using an echocardiograph EUB-7500 (Hitachi-Medico, Japan). The ejection fraction (EF) was measured according to the M- mode method and/or Simpson method, the left ventricular end-diastolic diameter (LVDd), serum N-terminal fragment pro-brain natriuretic peptide (NT-proBNP) and cardiothoracic ratio (CTR) on plain chest radiography were used as therapeutic indexes in the cardiac sarcoidosis patients treated with corticosteroids alone or the combination therapy consisting of low-dose corticosteroids and weekly methotrexate. The duration was defined as the number of months from the detection of sarcoidosis lesions to the end of treatment in our clinic. The patients were followed up in our outpatient clinic at three-month intervals for more than five years after the start of treatment. In a small open-label comparative study, the EF and LVDd on echocardiography, NT-proBNP and the CTR on plain chest radiography were compared between the patients who received the combination therapy (5-15 mg/day of prednisolone and 6 mg/week of methotrexate: CS+MTX group) and the patients who received corticosteroids alone (30-60 mg/day as the initial dose) (CS group). The comparative evaluation was continued for one, three and five years after the start of treatment. The combination therapy group also received folic acid to prevent adverse side effects caused by methotrexate, and both groups received trimethoprim. The results were statistically compared using the nonparametric Wilcoxon test and x2 test. A p value of less than 0.05 was considered to be statistically significant. 428

3 Table 1. Study Population and Clinical Profiles Table 2. Diagnostic Data Suggestive of Cardiac Lesions CS only CS+MTX p value No of the cases 7 10 Age (years old) 70.1 ± ± Man:Woman 1:6 2: duration (momths) 87.4 ± ± No of the lesion 3.29 ± ± on pace maker biopsy-proven I: II on chest X-p 6:1 8: %FVC (%) 98.5 ± ± FEV1 (L) 1.97 ± ± %DLCO (%) 80.1 ± ± serum ACE 23.1 ± ± Comorbidity Age: years old, duration: months from the detection of sarcoidosis to the introduction of therapy in this study, ACE: serum angiotensin converting enzyme (normal range: mu/ml) Chest X-p stage I: bilateral hilar lymphadenopathy (BHL), II: BHL and pulmonary opacities FVC: forced vital capacity, FEV1: forced expiratory volume one second, DLCO: diffusion capacity for carbon mono-oxide Numerical values express the means and standard deviations (SDs). CS: corticosteroid-treated group, CS+MTX: combination therapy Results Profiles of the patients with cardiac lesions As shown in Table 1, there were no significant differences in the gender distribution, duration after the detection of sarcoidosis, number of lesions, chest radiographic stages, pulmonary function results, serum angiotensin converting enzyme (ACE) activity or frequency of pacemaker implantation between the patients in the CS group and the patients in the CS+MTX group. Although the age of the examined patients was high (70.1±5.9 years in the CS group and 65.9± 7.7 years in the CS+MTX group), there were no differences in the rate of comorbidities (four patients in the CS group and three patients in the CS+MTX group). In addition, there were no differences in the type of comorbidity, such as diabetes mellitus, hypertension and hyperlipidemia, or the therapeutic drugs prescribed for several comorbidities between the two groups. Positive findings supportive of a diagnosis of cardiac lesions according to the Japanese guidelines are presented in Table 2. There were no significant differences between the groups in the major criteria or minor criteria for diagnosis. Cardiac sarcoidosis was diagnosed clinically in all patients, and the diagnosis was biopsy-proven in some patients. basal thinning of the septum positive Ga scinti scan AV (atrioventricular) Block EF (ejection fraction) <50% abnormality on echocardiogram myocardial scinti scan defect FGD-PET scan positive uptake Myocardial-biopsy positive Indexes in the left column: indexes proposed as major or minor diagnostic criteria in Japanese guidelines for the diagnosis of cardiac sarcoidosis (Ref. 8 ) FGD-PET:18F-fluorodeoxy glucose -positron emission tomography Cardiac muscle biopsy: positive finding of epithelioid cell granuloma Table 3. Comparison of the Ejection Fraction on Echocardiography between the CS-treated and CS+MTX-treated Groups 0* 52.3 ± ± ± ± ± ± ± ± EF: ejection fraction (%) on echocardiography, *years from the introduction of therapy Numerical values express the means and standard deviations (SDs). Features of the cardiac lesions The following abnormal findings were detected on electrocardiograms obtained at the introduction of therapy: atrial fibrillation, left branch bundle block, complete right bundle branch block and premature ventricular capture. There were no significant differences between the two groups in the spectrum of abnormal findings. Holter ECG was serially performed in all patients, and the incidence of abnormalities was similar between the two groups. Follow-up of the ejection fraction on UCG under treatment Based on the reliable diagnosis and matched study population, we evaluated the EF (%) and LVDd (mm) at one, three and five years after the introduction of therapy. The EF was stabilized in the CS+MTX group only at three years after the first treatment (Table 3). The EF values observed at three years were significantly lower in the CS group than in the CS+MTX group (44.5±13.8% versus 60.7±14.3% p= 429

4 Table 4. Comparison of the Left Ventricular Enddiastolic Diameter between the CS-treated and CS+MTX-treated Groups 0** 52.3 ±6.07* 49.7 ± ± ± ± ± ± ± mean ± SD, ** years from start of therapy left ventricular end-diastolic diameter (mm) was mesured serially 0,1,3,5 years after the introduction of the therapy. Table 5. Comparison of the Cardio-thoracic Ratio on Chest Radiograph between the CS-treated and CS+MTX-treated Groups 0** 0.54 ± 0.03* 0.52 ± ± ± ± ± ± ± mean ± SD, ** years from start of therapy Cardio-thoracic ratio (CTR) was mesured serially 0,1,3,5 years after the introduction of the therapy. CTR less than 0.5 is evaluated as absence of cardiac enlargement. CS treated 0 1 year 3 years 5 years CS+MTX treated 0 1 year 3 years 5 years Figure. Changes in the cardiac thoracic ratio (CR) on chest radiography before and after the combination therapy. (A patient treated with CS) 73 years old, woman, nonsmoker, duration 87 months, treatment: prednisolone 40 mg/day and tapering to 10 mg/day for four years. 0: at the time of combination therapy, 1 year: one year after therapy, 3 years: three years after therapy, 5 years: five years after therapy. CTR: at zero years, at one year, at three years, at five years. (A patient treated with CS+MTX) 78 years old, woman, nonsmoker, duration 48 months, treatment: prednisolone 10 mg/day and methotrexate 6 mg/week. 0: at the time of combination therapy, 1 year: one year after therapy, 3 years: three years after therapy, 5 years: five years after therapy. CTR: at zero years, at one year, at three years, at five years. 0.04). The LVDd values tended to be smaller in the CS+ MTX group than in the CS group three years after the first treatment (Table 4). The CS group exhibited cardiac enlargement on plain chest radiographs at three to five years after the start of therapy in association with decreased EF values (Figure). Mean- 430

5 Table 6. Comparison of Serum NT-proBNP Level between the CS-treated and CS+MTX-treated Groups 0** ± 551.9* ± ± ± ,865.4 ± 1, ± ,839.5 ± 3, ± mean ± SD, ** years from start of therapy NT-proBNP: N-terminal fragment pro Brain natriuretic peptide (normal range: less than 125 pg/ml) Serum NT-proBNP was mesured serially 0,1,3,5 years after the introduction of the therapy while, cardiac enlargement on plain chest radiographs was stabilized in the CS+MTX group over the same period (Figure). The CTR was significantly stabilized in the CS+MTX group, but not in the CS group, at both three and five years after the start of therapy (Table 5). The serum NT-proBNP levels were significantly lower in the CS+MTX group than in the CS group at three and five years after the first therapy (Table 6). Adverse effects of therapy There were no serious adverse effects, such as liver dysfunction, renal dysfunction, bone marrow suppression, opportunistic infections or drug-related pneumonia, in our series during long-term treatment with low-dose prednisolone and weekly methotrexate. Discussion This study was an open label study in which we longitudinally followed 17 cardiac sarcoidosis patients who received combination therapy consisting of low-dose corticosteroids (5-15 mg of prednisolone) and weekly low-dose methotrexate (6 mg/week) over a treatment period of five years. We selected patients with similar clinical features (age distribution, gender, duration of sarcoidosis, comorbidities, prescribed therapeutic drugs). Interestingly, the 17 patients had no pulmonary fibrotic lesions, and their pulmonary function test results were almost within the normal ranges. Therefore, the cardiac dysfunction observed in these patients reflected the presence of cardiac lesions due to sarcoidosis. Regarding this point, we evaluated whether the presence of pulmonary fibrosis significantly affects the prognosis of patients with cardiac sarcoidosis by reviewing the literature. One retrospective cohort showed that only one patient died of cardiac sarcoidosis among 142 sarcoidosis patients with radiographic stage IV disease (12). In this report, refractory pulmonary hypertension, chronic respiratory insufficiency and opportunistic infections, such as aspergilloma and nocardiosis, were the major causes of death. Based on the above-mentioned background, the cardiac function was stabilized in the CS+MTX group, but not in the CS group. There were few adverse effects during the long-term treatment. On average, the patients tended to have lesions at more than three sites outside of the heart and exhibited an increased serum ACE activity. Therefore, we diagnosed the cardiac sarcoidosis patients as having chronic, active disease. The diagnostic process was conducted according to the revised guidelines for the diagnosis of cardiac sarcoidosis proposed by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders in 2006 (9, 10). As the positive biopsy rate is lower in patients with cardiac sarcoidosis, the aforementioned guidelines are useful for diagnosing patients with proven noncardiac sarcoidosis and suspected cardiac involvement. All patients were reliably diagnosed as having cardiac lesions due to sarcoidosis. Cardiac lesions can be patchily distributed in the four chambers of the heart. The dysfunction caused by such lesions ranges from arrhythmia to right bundle block, left bundle block and complete atrioventricular (AV) block leading to cardiac failure or arrest (10). While the patients who progressed to complete AV block presented with roughly the same spectrum of ECG abnormalities when the therapy was introduced, 15 of 17 patients ultimately required pacemaker implantation. Regarding treatment, published data for several uncontrolled series of patients with cardiac sarcoidosis suggest that corticosteroid treatment is a valuable therapy for this condition. However, no randomized control data are available to support this hypothesis. In a retrospective series of 48 cardiac sarcoidosis cases in Japan, the response to highdose steroid therapy varied according to the ejection fraction at baseline: the patients with a pretreatment left ventricular ejection fraction of less than 30% responded poorly, whereas those with a pretreatment ejection fraction of between 30% and 55% showed improvements in the ejection fraction and decreases in the left ventricular end-diastolic volume (12). In a retrospective study of 195 Japanese patients with sarcoidosis, overall, a good clinical response to corticosteroids was observed in 70-80% of the treated patients; however, the response rate was only 48% in those with cardiac disease (13). In a retrospective study from France, corticosteroid therapy was found to improve abnormal echocardiographic parameters in 78% of cases and alleviated symptoms completely in nine of 17 patients presenting with congestive heart failure (14). In a retrospective study of cardiac sarcoidosis in 30 Japanese patients who received prednisone at a dose of 40 mg/day or more and 45 patients who received prednisone at a dose of less than 30 mg/day, no apparent survival benefits of high-dose over low-dose therapy were found (6). No data are currently available to support the efficacy of additional immunosuppressive therapy in patients with cardiac sarcoidosis treated with cyclophosphamide, 431

6 methotrexate or cyclosporine based on the results of controlled trials. Infliximab and etanercept, agents used to treat rheumatoid arthritis via their actions against tumor necrosis factor-α, have recently been proposed as treatments for some forms of chronic, refractory sarcoidosis (15). Among these various alternative drugs, methotrexate is primarily prescribed for chronic sarcoidosis and can be expected to confer both immunomodulatory and steroid-sparing effects (7). The combination of corticosteroids and other immunosuppressant agents, such as methotrexate and azathioprine, is initiated based on the patient s failure to respond to the initial treatment or the development of severe side effects from corticosteroids (16). Among immunosuppressant agents, therapeutic evidence of methotrexate has been accumulated based on several studies. Methotrexate is reported to be therapeutically effective primarily in cases of skin lesions (17, 18), ocular lesions (19) and neuromuscular lesions (20). In our clinical experience, the agent is therapeutically effective, albeit incompletely, for chronic sarcoidosis involving lesions of the lungs, heart and neuromuscular system. One study reported that 15 patients who suffered from advanced disease or experienced severe side effects with corticosteroids were treated with methotrexate for at least six months (21). In another study, 50 sarcoidosis patients with persistent symptoms who were eager to avoid or reduce corticosteroid therapy went on to complete at least two years of methotrexate therapy (22). In these 50 patients, methotrexate was found to be a well-tolerated therapeutic drug with significant steroid-sparing actions and efficacy for the treatment of chronic symptomatic sarcoidosis (22). The administration of long-term therapy is mandatory for chronic cardiac sarcoidosis, especially to prevent functional declines that can lead to congestive cardiac failure or sudden death in patients with cardiac lesions. Corticosteroid therapy may fail to prevent functional deterioration longitudinally (6). The Delphi study offered no precise guidance on how to treat sarcoidosis with corticosteroids or alternative agents (23, 24). Based on the above-described background, we evaluated the therapeutic effects of combination therapy (5-15 mg of prednisolone/day and 6 mg of methotrexate/week) from the start of treatment, because the therapy must be maintained longitudinally in order to prevent various adverse effects caused by corticosteroid therapy by reducing the dose of the medications. As methotrexate exerts its therapeutic effects slowly, we selected combination therapy consisting of methotrexate with low-dose corticosteroids. This type of treatment has not yet been reported. Therefore, we attempted to identify a feasible treatment option for patients with chronic, active sarcoidosis with cardiac lesions who should be treated longitudinally. The therapeutic indexes used in the present study included the EF, LVDd on echocardiography, CTR on chest radiography and the serum NT-proBNP level. These indexes appeared to be compatible with the patients symptoms and activities of daily living. There were no significant differences in the EF values obtained using the M-mode method and Simpson method. Measuring the CTR and serum NTproBNP levels was feasible, in light of the simple methodology and significant results observed in our patients at both three and five years after therapy. The dose of methotrexate was fixed at 6 mg/week, a dose unlikely to elicit adverse effects. While our patients exhibited few adverse effects caused by methotrexate, another report found that toxic reactions to methotrexate eventually occurred in more than 10% of sarcoidosis patients who received the agent for more than two years (25). Regarding the prognosis of cardiac sarcoidosis, treatment with both corticosteroids and our combination therapy may not support patients whose cardiac function has deteriorated severely at the time of treatment introduction. A Japanese group reported that the incidence of ECG abnormalities in a total of 963 sarcoidosis patients was 22.1%, which was more frequent than that observed in the sex- and agematched healthy control subjects (17.9%, p<0.025). Providing careful follow-up and early treatment may prevent the progression of the disease. In accordance with this view point, our combination therapy may stabilize the clinical course of cardiac sarcoidosis patients with cardiac dysfunction who do not yet suffer from cardiac failure and may prevent the various adverse effects caused by corticosteroids. A large-scale, controlled, prospective study to assess this approach is, of course, warranted. Conclusion In 17 patients with cardiac sarcoidosis (particularly those with pacemakers due to complete AV block), the administration of combination therapy consisting of low-dose prednisolone and weekly methotrexate as the initial treatment following long-term maintenance therapy stabilized the cardiac function with few adverse effects. The authors state that they have no Conflict of Interest (COI). Acknowledgement We thank Mr. Seigen Ueda, Ms. Megumi Hiramatsu, Ms. Miki Matsumoto, Mr. Kazuhiko Taira, Mr. Yusuke Nakagawa and Ms. Nana Matsuzaki in the clinic for carefully performing echocardiography and the other medical examinations. We also thank Ms Tomoko Kita, Ms. Masako Yokota, Ms. Sachi Nakajima and Ms. Kimie Hashizume for managing all patients carefully. We thank all other staff who continue to help our clinical practice and study in the Clinic. We thank Mr. Simon Johnson for editing the manuscript. References 1. Nagai S, Handa T, Ito Y, Ohta K, Tamaya M, Izumi T. Outcome of sarcoidosis. Clin Chest Med 29: , Baughman RP, Nagai S, Balter M, et al. Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force. Sarcoidosis Vasc Diffuse Lung Dis 28: 56-64,

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