Usefulness of Low-dose Methotrexate Monotherapy for Treating Sarcoidosis

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1 ORIGINAL ARTICLE Usefulness of Low-dose Methotrexate Monotherapy for Treating Sarcoidosis Takuma Isshiki 1, Tetsuo Yamaguchi 1, Yoshihito Yamada 1, Keita Maemura 1, Kosuke Makita 1, Hideyuki Takeshima 1, Yasutaka Hirasawa 1, Yoko Yamaguchi 1, Keisuke Hosoki 1, Mika Suzuki 1, Chiyoko Kono 1, Jiro Terada 2 and Koichiro Tatsumi 2 Abstract Objective Methotrexate (MTX) is a cytotoxic agent that is commonly employed as an alternative to corticosteroids to treat sarcoidosis, although the proper use and efficacy of MTX as a single agent remain unclear. Methods The clinical records of patients newly diagnosed with sarcoidosis who were admitted to our institution between 2000 and 2009 were reviewed. Among these patients, 26 received 7.5 mg of MTX per week as a single agent, and the independent effects of MTX were analyzed. Results Six of the 26 patients (23%) exhibited an improvement of sarcoidosis-related lesions. The skin lesions demonstrated a relatively higher response rate (37%) than the pulmonary lesions (9%). Ten of the 26 patients (39%) experienced adverse effects, mostly mild hepatotoxicity. No severe adverse effects, including irreversible hepatotoxicity, were observed. Conclusion Although the efficacy of low-dose MTX monotherapy for sarcoidosis in this study was not high (23%), some patients exhibited definite improvements, and the drug proved to be safe, suggesting its possible benefits as a single agent for treating sarcoidosis. Key words: sarcoidosis, corticosteroids, methotrexate, alternative therapy, cytotoxic agent (Intern Med 52: , 2013) () Introduction Sarcoidosis is a multisystem granulomatous disorder whose optimal treatment remains undefined. Corticosteroids are recommended as the first choice of treatment (1). Although corticosteroids often benefit patients with sarcoidosis in the short term (2), the long-term use of corticosteroids is associated with toxic effects (3). Therefore, developing alternative agents to corticosteroids is necessary. In cases in which corticosteroid administration cannot be continued due to resistance, patient refusal or adverse effects, the use of alternative therapy is necessary. In the United States and Europe, cytotoxic agents are used in addition to oral corticosteroids as steroid-sparing agents to treat multisystem and chronic sarcoidosis (4). The safety and efficacy of methotrexate (MTX) has been demonstrated in patients with rheumatoid arthritis (5, 6), and the drug is now recommended as a first choice disease-modifying antirheumatic agent for the treatment of rheumatoid arthritis (7). The mechanisms underlying the effects of MTX in treating sarcoidosis remain unclear; however, anti-inflammatory pathways may be involved. Chan et al. reported that the antiinflammatory effects of MTX in RA patients are partly mediated by the release of adenosine (8). With respect to sarcoidosis, MTX has been found to decrease the release of hydrogen peroxide and tumor necrosis factor from alveolar macrophages (9). Similarly, in Japan, the immunosuppressive agent MTX has been used in cases in which the effects of oral steroids are minimal or the sarcoidosis is worsened or repeatedly relapses when the dose of steroids is reduced. Some patients Department of Chest Medicine, Japan Railway Tokyo General Hospital, Japan and Department of Respirology, Graduate School of Medicine, Chiba University, Japan Received for publication May 13, 2013; Accepted for publication July 25, 2013 Correspondence to Dr. Jiro Terada, jirotera@chiba-u.jp 2727

2 do not improve with corticosteroids, while others cannot receive corticosteroids due to medical complications, reluctance to use corticosteroids or patient refusal. Although several reports have demonstrated the efficacy of MTX as a steroid-sparing agent for sarcoidosis (10-14), the efficacy of this drug as a single agent remains unclear. In this study, patients with sarcoidosis in whom low-dose MTX was administered as a single agent were retrospectively collected, and the independent effects of MTX were evaluated. This is the first clinical report to evaluate the use of MTX monotherapy in patients with sarcoidosis in Japan. Patients Materials and Methods Among the patients with histologically or clinically diagnosed sarcoidosis treated at our department between January 2000 and December 2009, the records of patients in whom MTX was administered as a single agent were reviewed. The diagnosis of sarcoidosis was made in accordance with the Diagnostic Standards and Guidelines for Sarcoidosis (15) published by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders. The diagnosis of sarcoidosis in Japan is made according to criteria that classify patients into a histologic diagnostic group and a clinical diagnostic group in the Japanese clinical setting. Because sarcoidosis can exhibit spontaneous improvement (16), only patients with no signs of improvement in organ lesions or whose organ lesions had worsened over the previous six months were included in this study. Since it was difficult to evaluate the efficacy of MTX for cardiac lesions, patients with cardiac lesions were excluded from the evaluation. MTX treatment The patients received oral MTX, in principal, at 7.5 mg per week as a single agent, and the independent effects of MTX were evaluated. In order to prevent adverse effects, folic acid was combined with MTX in all cases. The dose of MTX was reduced to 5 mg per week if intolerable or severe side effects occurred. If the side effects did not improve following dose reduction, the administration of MTX was discontinued. Evaluation of the response to MTX treatment All patients underwent physical and blood examinations and chest radiography at each visit, and pulmonary function tests were usually performed (except for chest radiographic stage 0-1 patients) every six months to evaluate the pulmonary lesions. The physical examinations included an evaluation of superficial lymph node swelling, if applicable. A judgment of the efficacy of the treatment was made by comparing each type of lesion before and after MTX use. Respiratory specialists (TI, TY and YY) compared the chest images obtained from the same patients. The specialists scored the chest imaging findings, including bilateral hilar lymphadenopathy (BHL) and the presence of lung infiltrates, on a scale of 1 to 5 (markedly worsened, worsened, unchanged, improved and markedly improved). A marked improvement was defined as the complete disappearance of all lesions and the occurrence of no new lesions. An improvement was defined as regression of the lung lesions of at least 50%. Progression, stability or regression of the lesions below 50% were considered to indicate a lack of response. If the parameters of the lung function, such as the % vital capacity (%VC), improved in association with the chest imaging findings, the respiratory specialists confirmed the improvement in the lungs. MRI images of the muscles were also assessed, if applicable. The findings of skin and ocular lesions were evaluated by a dermatologist and ophthalmologist, respectively. In principle, the same dermatologist evaluated the clinical response to MTX therapy according to the size and number of skin lesions. Similarly, the same ophthalmologist evaluated whether MTX was effective with regard to the ability to control all signs of inflammation in association with a reduction in the frequency of topical therapy with corticosteroids and the need for periocular steroid injections. The occurrence of adverse effects was evaluated at each visit with respect to subjective symptoms and physical examination and blood test results. The data are expressed as the mean ± SD. A univariate analysis was performed using the χ 2 test for categorical variables. Ethics This research was conducted in accordance with the guidelines of the Examination of the efficacy and safety of methotrexate, minocycline, doxycycline and inhaled steroids in sarcoidosis (Reference Number: H21-17, November 18, 2009) issued by the JR Tokyo General Hospital Research Ethics Committee. Patients Results The subjects included 26 patients (12 men and 14 women) whose ages ranged from 27 to 79 years (mean: 53± 13 years) at the time of the initiation of MTX administration. In patients with sarcoidosis affecting multiple organs, data were analyzed for each organ. The primary reasons for beginning MTX monotherapy were medical complications, a reluctance to use corticosteroids (n=12) and patient refusal to take corticosteroids (n=12). In addition, two of the 26 patients were treated with MTX because no signs of improvement were observed following the administration of corticosteroids (Table 1). MTX efficacy In total, 62 affected organs in 26 patients were evaluated 2728

3 Table 1. Characteristics of the Patients Treated with Methotrexate Age (onset of sarcoidosis, yrs, mean ± SD) 46 ± 15 Age (initiation of MTX, yrs, mean ± SD) 53 ± 13 Male/ Female (n) 12 / 14 Diagnosis Histological / Clinical (n) 18 / 8 Organ involved (%) Lung 22 (85%) Eye 16 (62%) Heart 13 (50%) Skin 11 (42%) Joint 6 (23%) Lymph node 4 (15%) Muscle 3 (12%) Years between onset and MTX administration (%) 0~4 years 10 (39%) 5~9 years 11 (42%) 10~19 years 3 (12%) 20~ years 2 (8%) Medication history of corticosteroid (yes / no) 10 / 16 Reason for administration of MTX as single agent Refractory to CS 2 Medical contraindication to CS 12 Patient refusal to take CS 12 MTX: methotrexate, CS: corticosteroids for MTX efficacy. Improvements were observed in six cases (23%) and 11 organs (18%). The clinical characteristics of the cases in which MTX was effective are shown in Table 2. Five of the six patients were women, and all cases were diagnosed histologically. The duration from the initiation of MTX to the confirmation of treatment efficacy was two to five months (median: three months). The total duration of MTX administration was between 16 and 80 months in this study, and if no adverse effects were observed, then the MTX treatment was continued. Comparing the response rate in each organ, the skin lesions tended to exhibit a high response rate compared with the pulmonary lesions; p=0.056 (Figure). Twenty-two of the 26 patients demonstrated involvement of the lungs. The chest radiograph stage in these 22 patients was 1, 2, 3 and 4 in 12, one, seven and two cases, respectively. MTX was effective with regard to treating pulmonary lesions in two cases only. Case 1 involved BHL and swelling of the superficial lymph nodes (Table 2). The BHL and swelling of the superficial lymph nodes regressed immediately after MTX was started. Since the patient in Case 6 developed diffuse infiltration in both lungs and corticosteroids did not exhibit any efficacy, these drugs were considered to be relatively contraindicated. Twenty-six months after the initiation of MTX, the lung infiltration exhibited regression and the % VC increased from 59% to 77% (Table 2). Additionally, 10 of the 26 patients had a medical history of corticosteroid use before starting MTX treatment in the present study. Four of these 10 patients had shown improvements with corticosteroid therapy in the past. Only one of these four patients showed a response to MTX. In contrast, the remaining six of the 10 patients showed no improvements with corticosteroids in the past. Among these patients, three showed a response to MTX. Therefore, even when the sarcoidosis responded to corticosteroids, not all patients exhibited a response to MTX. On the other hand, a portion of the patients who did not show an improvement with corticosteroid therapy responded to MTX treatment. Safety Among the 26 patients treated with MTX, side effects were observed in 10 cases (39%, four men and six women). Hepatotoxicity, digestive symptoms, hair loss and leukopenia were observed in six (21%), three (10%), one (3%) and one (3%) case, respectively. The average timing of the appearance of hepatotoxicity was two years. The degree of hepatotoxicity and leukopenia was mild, and all patients improved by reducing or discontinuing MTX. No cases of severe side effects or irreversible hepatotoxicity were observed, and no liver biopsies were performed in any case. Discussion Since the use of MTX for sarcoidosis was first reported in 1968 (17), multiple clinical trials of the drug as a steroidsparing agent have been published, especially since the 1990 s (10-14), and several case reports have been published in Japan (18, 19). Effective results of MTX treatment have been reported for lesions in the lungs (11, 12), skin (11), musculoskeletal system (13) and nerves (14). It has been reported that MTX is effective in up to two-thirds of all cases (11) and may be a therapeutic option for treating the chronic progression or recurrence of sarcoidosis. Lynch (20, 21) reported that the use of MTX treatment for sarcoidosis should be limited to steroid-resistant cases. However, in the general clinical setting, there are steroidintolerant patients who have had to discontinue steroids due to adverse effects, and a proportion of patients refuse to use steroids. In the present study, the major reasons for administering MTX as a single agent were: 1) the existence of medical complications that prevented the patient from receiving corticosteroids and 2) patient refusal to take corticosteroids. The steroid-sparing, rather than direct, effects of MTX on sarcoidosis have been previously emphasized. Although the steroid-sparing effects of MTX have been elucidated, the positive effects of MTX as a single agent have not been clarified. However, in the present study, 23% of the patients who received MTX monotherapy exhibited some degree of regression of organ lesions. Skin lesions tended to show a higher response rate than pulmonary lesions. Although this tendency is similar to the findings of a past report (11), the response rate was lower than that reported in previous studies. One reason for this may be that previous reports evaluated the steroid-sparing effects of MTX and, from the viewpoint of steroid dose reduction, MTX was deemed to be responsive. In the present study, we evaluated the independent effects of MTX, and an improvement in objective findings was judged to represent a positive response. The second rea- 2729

4 Table 2. Clinical Characteristics of the Cases in which MTX was Effective No. Age Age Sex Affected organs Diagnostic organs Responsive organs Stage Period Reason for switching MTX (onset) (initiation of MTX) (histology) (chest radiograph) from steroid therapy F Eye, Lung, LN Skin Lung, LN I 3 M (7.5mg/week) patient refusal F Eye, Skin TBLB Skin none 2 M (7.5mg/week) medical contraindication F Eye, Lung, Skin Skin Skin I 5 M (7.5mg/week) medical contraindication F Eye, Lung, Skin, M Skin Skin, M III 2 M (7.5mg/week) medical contraindication F Eye, Lung, Skin Skin Eye, Skin I 3 M (7.5mg/week) medical complication M Eye, Lung, Skin Skin Lung III 26 M (7.5mg/week) refractory to steroid therapy Affected organs: LN: lymph node, M: muscle, Period: Period from administration to improvement Response rate (%) Lung (n=22) Eyes (n=16) Skin (n=11) Joints (n=6) Organ Involved Lymph nodes (n=4) Muscle (n=3) Total (n=62) Figure. Response rate to methotrexate in each organ. Table 3. Summary of the Case Reports on Japanese Sarcoidosis Patients Treated with MTX Case Age Sex Affected organs Responsive organs Treatment dose of MTX Period References Language 1 46 M Lung, Skin Lung, Skin mono 7.5 mg/week 2-3 weeks (18) English 2 48 M Eye, Lung Lung mono 5 mg/week 2 month (24) Japanese 3 52 F Lung, LN, Heart Heart PSL 30 mg 7.5 mg/week 3 month (25) Japanese 4 70 F Eye, Lung, Heart Heart PSL 5 mg/week 4 month (26) Japanese 5 23 M Eye, Lung Eye PSL NA NA (27) Japanese 6 69 F Eye, Lung, LN, Heart no response mono 7.5 mg/week NA (28) Japanese 7 53 F M, Heart no response mono 7.5 mg/week NA (28) Japanese 8 66 F Lung, M, Heart no response mono 5 mg/week NA (28) Japanese 9 63 F Lung, Heart no response mono 5 mg/week NA (28) Japanese F Eye Eye mono NA NA (29) Japanese M Lung, CNS CNS PSL 30 mg 10 mg/week NA (30) Japanese M Eye, Skin Skin PSL 6 mg 6 mg/week 1 month (31) Japanese M Eye, Lung Lung PSL 10 mg 6 mg/week NA (32) Japanese F Lung, Skin, M Skin PSL NA NA (33) Japanese F Eye, Lung, LN Lung, LN mono 7.5 mg/week 3 month (19) Japanese M Eye, Lung, Skin Lung mono 7.5 mg/week 26 month (19) Japanese Period: Period from administration to improvement son is that the dose of MTX employed in this study was lower than that used in previous reports. In the majority of past reports, the MTX dose was 10 mg per week. Because we conducted this study according to the Japanese guidelines for the treatment of rheumatoid arthritis, the dose of MTX was 7.5 mg per week. Although the response rate was lower than that observed in previous reports, it may be that a lower dose of MTX therapy results in a higher level of safety. With regard to safety, no severe adverse effects were observed in the 26 patients who received MTX. Although the incidence of hepatotoxicity was relatively high, the side effects were mild and resolved after stopping the medication. Previous reports have shown that severe liver dysfunction is 2730

5 not associated with the administration of MTX for < two years or a total dose of <1,500 mg (22). Baughman (23) recommended that, in cases of recurrence of sarcoidosis following the administration of MTX, liver biopsies should be performed if liver impairment is observed. Since the dose of MTX used in the United States and Europe is higher than that administered in Japan, it is possible that the occurrence of hepatotoxicity will increase due to long-term administration in the United States and Europe. In the present study, no severe adverse effects were observed in association with low-dose MTX, even with long-term administration. However, it is necessary to be cautious regarding adverse effects in patients treated with long-term MTX administration. The present study is associated with several limitations. First, this study was a retrospective analysis and not a randomized controlled prospective trial. In sarcoidosis patients, spontaneous improvements are occasionally observed; therefore, comparisons of MTX versus a placebo are needed to accurately assess the effects of MTX. In order to exclude the effects of spontaneous improvement, we included only patients who had exhibited no signs of improvement in organ lesions over the previous six months. However, further investigations are required to verify our hypothesis. Second, not all patients evaluated in the present study were histologically diagnosed. In this study, the diagnosis of sarcoidosis was made in accordance with the Diagnostic Standards and Guidelines for Sarcoidosis (15), and most cases were histologically confirmed; however, some patients were diagnosed clinically. Although a portion of the patients were not histologically diagnosed, the cases in which MTX was effective were histologically confirmed cases (Table 2). Third, the efficacy of MTX in Japanese patients may differ from that observed in other countries, as the clinical manifestations of sarcoidosis vary among ethnic groups. A total of 16 case reports of sarcoidosis in Japanese patients treated with MTX are summarized in Table 3. MTX therapy was effective in 12 of the 16 cases described in these reports. Therefore, the use of MTX in Japanese sarcoidosis patients may be more effective than that observed in other countries. Fourth, this study did not demonstrate any indications for MTX monotherapy due to the patient selection bias described in the Methods section. It remains unclear whether medical complications or reluctance to use corticosteroids are applicable to MTX monotherapy. Conclusion This is the first clinical report to evaluate the use of MTX monotherapy in patients with sarcoidosis in Japan. We administered MTX in sarcoidosis patients as a single agent and evaluated the independent effects of the drug. Efficacy was observed in six of 26 patients (23%) and 18% of all target organs. Our results indicate that, even as a single agent, MTX is effective for treating sarcoidosis in some cases. Although it is not yet clear which patients will benefit, if the dose is small, MTX can be safely used with routine clinical monitoring. The authors state that they have no Conflict of Interest (COI). Acknowledgement The present study was supported in part by a grant to the Research of Diffusive Lung Disease and Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare of Japan. References 1. ATS/ERS/WASOG statement on sarcoidosis. Am J Respir Crit Care Med 160: , James DG, Carstairs LS, Trowell J, et al. Treatment of sarcoidosis. Lancet 2: , Sharma OP. Pulmonoary sarcoidosis and corticosteroids. Am Rev Respir Dis 147: , Paramothayan S, Lasserson T. Treatment for pulmonary sacroidosis. Respir Med 102: 1-9, Williams HJ, Willkens RF, Samuelson CO, et al. 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