今日の臨床サポート

肺サルコイドーシス

著者: 乾直輝1) 浜松医科大学 臨床薬理学

著者: 須田隆文2) 浜松医科大学 第二内科

監修: 長瀬隆英 東京大学 内科学専攻器官病態内科学講座

著者校正/監修レビュー済:2021/10/13
患者向け説明資料

概要・推奨   

  1. サルコイドーシスの診断は除外診断である(推奨度1)
  1. サルコイドーシス病変はしばしば自然に軽快する(推奨度1)
  1. ステロイドはサルコイドーシスの肉芽腫病変に抑制的に作用する(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
乾直輝 : 研究費・助成金など(日本ベーリンガーインゲルハイム),奨学(奨励)寄付など(大鵬薬品,中外製薬)[2021年]
須田隆文 : 講演料(日本ベーリンガー,アストラゼネカ),研究費・助成金など(日本ベリンガー・インゲルハイム),奨学(奨励)寄付など(中外製薬,日本ベーリンガー,ノバルティス)[2021年]
監修:長瀬隆英 : 講演料(アストラゼネカ),研究費・助成金など(中外製薬)[2021年]

改訂のポイント
  1. 改定された「サルコイドーシス診療の手引き 2020 」に基づき、加筆・修正を行った(肺病変に関する大きな変更点はなし)。
  1. 線維化肺病変に対する治療薬ニンテダニブについて追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. サルコイドーシスは、種々の臓器に壊死を伴わない類上皮細胞肉芽腫ができる原因不明の全身性疾患である[1]
  1. わが国における有病率は人口10万人当たり1~2人程度で、欧米より低い。
  1. サルコイドーシスは、胸部画像の異常や呼吸器症状で発見されるほかに、霧視・羞明・飛蚊症・視力低下などの眼症状で発見されることが最も多く、次いで皮疹がある。まれに全身倦怠感や発熱などの全身症状で発見される。
  1. 診断時年齢は男女ともに若年のピークが減り全体に高齢化しており,50~60 歳代にピークがある。
  1. 健康診断の胸部画像の異常で発見される場合は、両側肺門リンパ節腫脹(bilateral hilar lymphadenopathy: BHL)によるものが大半で、その多くは無症状である。
  1. 肺サルコイドーシスを含むサルコイドーシスは、指定難病であり、重症度3以上などの場合は申請し認定されると医療費の自己負担分の一部が公費負担として助成される。(平成27年1月施行
  1. 難病法に基づく医療費助成制度
  1. サルコイドーシス(眼科)
  1. 心サルコイドーシス
 
  1. サルコイドーシスは免疫系の変調によって起こる疾患と考えられる(推奨度3)
  1. サルコイドーシスの発症には外因と体質の両因子の関与が想定され、後者の本態は細胞性免疫の異常と考えられる。
関節リウマチなどでTNFα阻害薬を投与したところ、サルコイド様の肉芽腫病変が発症し、投与中止後に肉芽腫が消退したとする報告がある。この場合の肉芽腫病変の発生はTNFα阻害薬に対する生体の一種の反跳現象によるものと思われる[2]
病歴・診察のポイント  
  1. 両側肺門リンパ節腫脹(bilateral hilar lymphadenopathy: BHL)を呈する症例ではサルコイドーシスを疑う。

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文献 

著者: G W Hunninghake, U Costabel, M Ando, R Baughman, J F Cordier, R du Bois, A Eklund, M Kitaichi, J Lynch, G Rizzato, C Rose, O Selroos, G Semenzato, O P Sharma
雑誌名: Sarcoidosis Vasc Diffuse Lung Dis. 1999 Sep;16(2):149-73.
Abstract/Text
PMID 10560120  Sarcoidosis Vasc Diffuse Lung Dis. 1999 Sep;16(2):149-7・・・
著者: Claire Immediato Daïen, Agnes Monnier, Pascal Claudepierre, Arnaud Constantin, Jean-Paul Eschard, Eric Houvenagel, Mahtab Samimi, Stephan Pavy, Edouard Pertuiset, Eric Toussirot, Bernard Combe, Jacques Morel, Club Rhumatismes et Inflammation (CRI)
雑誌名: Rheumatology (Oxford). 2009 Aug;48(8):883-6. doi: 10.1093/rheumatology/kep046. Epub 2009 May 7.
Abstract/Text OBJECTIVE: TNF blockers have been recently evaluated for treating refractory sarcoidosis and could be efficient. However, several cases of sarcoidosis have been diagnosed during anti-TNF therapy. Here, we report the largest series of sarcoid-like granulomatosis following TNF blocker treatment.
METHODS: A call for observations of sarcoid-like granulomatosis following TNF blocker treatment was sent to the members of the French 'Club Rhumatismes et Inflammation'. Histological evidence of granulomatosis was required.
RESULTS: Observations of 10 patients [seven females; median age 50.5 (range 27-72) years] with sarcoid-like granulomatosis while on anti-TNF treatment were collected: five were treated with etanercept and five with monoclonal antibodies; four patients received TNF blockers for RA and six for SpA. The median delay between anti-TNF agent introduction and granulomatosis diagnosis was 18 (range 1-51) months. Clinical symptoms were mainly pulmonary and cutaneous. Angiotensin-converting enzyme activity was increased in six cases. Lymph-node and/or lung involvement were observed by CT scan of the chest for eight patients. The median delay between drug discontinuation and remission was 6 (range 1-11) months for clinical signs and 6 (range 2-12) months for biological and radiographic findings. Improvement was observed in all patients after drug discontinuation with or without steroids.
CONCLUSIONS: Sarcoid-like granulomatosis is rare but not exceptional in patients treated with TNF blockers (approximately 1/2800) and does not seem to be related to gender, rheumatic disease or in our series the type of anti-TNF drug used (monoclonal antibodies or soluble receptor). Discontinuation of anti-TNF usually leads to recovery.

PMID 19423648  Rheumatology (Oxford). 2009 Aug;48(8):883-6. doi: 10.10・・・
著者: G J Gibson, R J Prescott, M F Muers, W G Middleton, D N Mitchell, C K Connolly, B D Harrison
雑誌名: Thorax. 1996 Mar;51(3):238-47.
Abstract/Text BACKGROUND: Corticosteroids suppress disease activity in pulmonary sarcoidosis and their use produces symptomatic, radiographic, and functional improvement. There is, however, uncertainty regarding their effects on the overall natural history of the condition and long term benefit is unproven.
METHODS: Patients with pulmonary radiographic shadowing due to sarcoidosis were recruited in a multicentre study. Those who, in the first six months after entry to the study, neither required prednisolone for symptoms nor showed radiographic improvement were allocated at six months to receive either long term steroid treatment (group L) or selective treatment (group S), with regular assessment over the subsequent five years. Patients in group L were scheduled to receive steroid treatment for at least 18 months with the policy of achieving and maintaining maximal radiographic clearing, while in group S treatment was reserved for use only if warranted by later development of symptoms or deteriorating lung function. Symptoms, radiographic appearances, and respiratory function were assessed periodically during the study.
RESULTS: One hundred and forty nine patients were followed: 33 required prednisolone for troublesome symptoms within six months of entry and 58 showed radiographic improvement over this period. The remaining 58 patients were allocated to groups L (n = 27) and S (n = 31). Patients in group L showed greater improvements in symptoms, respiratory function, and radiographic appearances than those in group S, although the differences were not large. After adjusting for differences at the time of allocation, the average difference in vital capacity between groups L and S at final assessment was 9% of the predicted value. Side effects of treatment were frequent but usually mild, necessitating withdrawal in only two individuals.
CONCLUSIONS: After excluding those individuals who required steroids for control of symptoms, approximately half of the remaining patients with sarcoidosis and pulmonary shadowing showed spontaneous radiographic improvement during six months of observation. In those in whom the radiograph failed to improve, prolonged steroid treatment with the aim of optimising radiographic appearances resulted in a significantly better long term functional outcome.

PMID 8779124  Thorax. 1996 Mar;51(3):238-47.
著者: C Alberts, T W van der Mark, H M Jansen
雑誌名: Eur Respir J. 1995 May;8(5):682-8.
Abstract/Text In a double-blind, placebo-controlled study, we assessed the efficacy of inhaled budesonide on the course of newly diagnosed pulmonary sarcoidosis and whether budesonide treatment could postpone oral corticosteroid treatment. We evaluated: 1) symptoms; 2) chest radiography; 3) angiotensin-converting enzyme (ACE) in serum; and 4) lung function. Patients with histologically confirmed pulmonary sarcoidosis with chest radiographic stages I, II or III, and with an abnormal lung function (inspiratory vital capacity (IVC) < 79% of predicted or transfer factor of the lungs for carbon monoxide (TL,CO) < 77% pred) were included. Patients with radiographic stage II or III but with normal lung function were included when more than 20% of the total cell population in bronchoalveolar lavage fluid (BALF) was lymphocytes. Forty seven patients received placebo or budesonide (1.2 mg) once daily via a Nebuhaler for 6 months, followed by 6 months without treatment. Based on predetermined criteria, 11 patients were excluded during the blind treatment period as they needed oral prednisone: seven (28%) patients in the placebo group (n = 25) and four (18%) patients in the budesonide group (n = 22). Patient's Global Clinical Impression (GCI) score showed a significant difference in favour of budesonide. IVC showed a significant difference of 7.9% predicted between the two groups during the active treatment period. This difference persisted during follow-up, when the difference was 9.4% pred. TL,CO remained nearly unchanged over time, with no difference between the groups. Improvements in chest radiographic appearance and changes in serum ACE were similar for the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7656936  Eur Respir J. 1995 May;8(5):682-8.
著者: A Pietinalho, P Tukiainen, T Haahtela, T Persson, O Selroos
雑誌名: Chest. 1999 Aug;116(2):424-31.
Abstract/Text STUDY OBJECTIVE: To evaluate the efficacy of oral prednisolone, followed by inhaled budesonide, in patients with newly diagnosed (<3 months) stage I and stage II pulmonary sarcoidosis.
DESIGN: Double-blind, placebo-controlled, parallel-group, multicenter study.
SETTING: Twenty pulmonary medicine departments in Finland.
PATIENTS: One hundred eighty-nine adult patients were randomized to treatment. Patients with erythema nodosum or stage IV sarcoidosis (pulmonary fibrosis), and patients requiring immediate treatment with oral corticosteroids for extrapulmonary lesions or chronic illnesses were excluded.
TREATMENT: The patients received either oral prednisolone for 3 months (20 mg/d for 8 weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) followed by inhaled budesonide (Pulmicort Turbuhaler; Astra Draco; Lund, Sweden) for 15 months at 800 microg bid, or placebo tablets followed by placebo inhaler therapy.
MEASUREMENTS: Chest radiographs, lung volumes (FVC), diffusing capacity of the lung for carbon monoxide (D(LCO)), serum angiotensin-converting enzyme (SACE), and beta2-microglobulin at 3-month intervals.
RESULTS: After 3 months of treatment, radiographic improvements were seen in the active-treatment group when compared to the placebo-treatment group. At 6 months, the difference was still statistically significant. Later, no differences were found. In patients with initial stage I lesions, neither the FVC nor the D(LCO) (the percent predicted mean values) changed during the study, as they were normal from the beginning. In patients with initial stage II disease, the difference in the FVC mean values between the groups also remained unchanged throughout the study. In stage II patients treated for 18 months, but not earlier, the difference in D(LCO) became statistically significant; the largest differences were seen in patients with initial FVC values <80% of predicted and D(LCO) values <75% of predicted. The decrease in SACE in the active-treated stage II patients was significantly larger than in the placebo-treated patients. No difference was observed in adverse events between the active-treated patients and the placebo-treated patients.
CONCLUSION: Treatment is not required for patients with stage I disease. An initial treatment with prednisolone followed by long-term inhalation of budesonide is more effective than placebo in patients with stage II disease. Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for stage II sarcoidosis patients, rather than long-term oral corticosteroid therapy alone.

PMID 10453872  Chest. 1999 Aug;116(2):424-31.
著者: Shanthi Paramothayan, Paul W Jones
雑誌名: JAMA. 2002 Mar 13;287(10):1301-7.
Abstract/Text CONTEXT: Corticosteroids are used in pulmonary sarcoidosis to reduce symptoms and minimize long-term damage. Spontaneous recovery is a common feature. Both the decision to initiate therapy and the treatment response may be influenced by disease severity, so trials need to use a randomized controlled design.
OBJECTIVE: To assess the effect of oral and inhaled corticosteroids on chest radiograph results, symptoms, pulmonary function, and long-term outcome in pulmonary sarcoidosis.
DATA SOURCES: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched all years through December 2001. Bibliographies of review articles and retrieved articles were searched, and pharmaceutical companies and authors of identified trials were contacted for other studies. There was no language restriction.
STUDY SELECTION: Trials were randomized and included a control group. Participants were adults with histologic evidence of pulmonary sarcoidosis. Treatments included the use of oral and inhaled corticosteroids for at least 8 weeks. The search identified 150 studies; 9 met the inclusion criteria, but only 8 provided usable data.
DATA EXTRACTION: Two reviewers assessed trial quality using the Jadad score, which evaluates the quality of randomization, blinding, and reasons for withdrawal. Data were extracted and sent to primary authors for verification.
DATA SYNTHESIS: In patients with stage 2 and 3 disease, oral corticosteroids improved findings on the chest radiograph after 6 to 24 months (Peto odds ratio, 2.54; 95% confidence interval [CI], 1.69-3.81; P<.001). Forced vital capacity improved with oral corticosteroids (weighted mean difference [WMD], 4.2% predicted; 95% CI, 0.4%-7.9% predicted) and diffusing capacity also improved (WMD, 5.7% predicted; 95% CI, 1.0%-10.5% predicted). In 2 small studies of inhaled corticosteroids, there was no effect on chest radiograph and inconsistent effects on lung function in one and only a small improvement in symptoms in the other. There were no data following corticosteroid withdrawal to assess any disease-modifying effect.
CONCLUSIONS: Oral corticosteroids improved results on the chest radiograph following 6 to 24 months of treatment and produced a small improvement in vital capacity and diffusing capacity. Trials of inhaled corticosteroids were small and results too inconsistent to make firm conclusions concerning their efficacy. There are no data to suggest that corticosteroid therapy alters long-term disease progression.

PMID 11886322  JAMA. 2002 Mar 13;287(10):1301-7.
著者: R P Baughman, D B Winget, E E Lower
雑誌名: Sarcoidosis Vasc Diffuse Lung Dis. 2000 Mar;17(1):60-6.
Abstract/Text BACKGROUND AND AIM OF THE WORK: Methotrexate has been steroid sparing for some patients with chronic sarcoidosis. We wished to determine whether methotrexate can be steroid sparing in the first year of corticosteroid therapy in sarcoidosis.
METHODS: Patients with new onset, symptomatic disease within four weeks of starting on prednisone were randomized to receive either methotrexate or placebo for the next year. They were seen monthly and prednisone dosage was tapered following a pre-determined schedule.
RESULTS: Of 24 patients enrolled, only 15 received at least six months of therapy. Since methotrexate appears to take six months to be effective, only patients who completed six or more months of therapy were evaluated. The amount of prednisone per day decreased for both groups: methotrexate (First 6 months: Median 26 (Range 15-37) mg/day); Second 6 months 8 (1-22) mg/day, p < 0.01) and placebo (First 6 Months 28 (24-33) mg/day; Second 6 months 16 (11-22) mg/day, p < 0.02), with less prednisone used for the methotrexate patients versus placebo in the last six months (p < 0.01). There was also less weight gain for those patients receiving methotrexate. There was no difference in toxicity between methotrexate and placebo. The difference between methotrexate versus placebo was not seen when all patients (including the dropouts) were analyzed.
CONCLUSIONS: Methotrexate can be a steroid sparing agent in acute sarcoidosis.

PMID 10746262  Sarcoidosis Vasc Diffuse Lung Dis. 2000 Mar;17(1):60-6.・・・
著者: Robert P Baughman, Marjolein Drent, Mani Kavuru, Marc A Judson, Ulrich Costabel, Roland du Bois, Carlo Albera, Martin Brutsche, Gerald Davis, James F Donohue, Joachim Müller-Quernheim, Rozsa Schlenker-Herceg, Susan Flavin, Kim Hung Lo, Barry Oemar, Elliot S Barnathan, Sarcoidosis Investigators
雑誌名: Am J Respir Crit Care Med. 2006 Oct 1;174(7):795-802. doi: 10.1164/rccm.200603-402OC. Epub 2006 Jul 13.
Abstract/Text RATIONALE: Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis.
OBJECTIVES: To assess the efficacy of infliximab in sarcoidosis.
METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52.
MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment.
CONCLUSIONS: Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.

PMID 16840744  Am J Respir Crit Care Med. 2006 Oct 1;174(7):795-802. d・・・
著者: Kevin R Flaherty, Athol U Wells, Vincent Cottin, Anand Devaraj, Simon L F Walsh, Yoshikazu Inoue, Luca Richeldi, Martin Kolb, Kay Tetzlaff, Susanne Stowasser, Carl Coeck, Emmanuelle Clerisme-Beaty, Bernd Rosenstock, Manuel Quaresma, Thomas Haeufel, Rainer-Georg Goeldner, Rozsa Schlenker-Herceg, Kevin K Brown, INBUILD Trial Investigators
雑誌名: N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.
Abstract/Text BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31566307  N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.10・・・

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