今日の臨床サポート

全身性強皮症

著者: 尾崎貴士 大分大学医学部 内分泌代謝・膠原病・腎臓内科学講座

監修: 金子礼志 国立国際医療研究センター 膠原病科

著者校正済:2020/06/19
現在監修レビュー中
患者向け説明資料

概要・推奨   

肺高血圧症治療
  1. ボセンタン肺高血圧症WHO機能分類classの患者への投与がおそらく推奨される(推奨度2)
  1. アンブリセンタンWHO機能分類の患者への投与がおそらく推奨される(推奨度2)
  1. マシテンタンWHO機能分類の患者への投与がおそらく推奨される(推奨度2)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
閲覧にはご契
閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
閲覧にはご契
閲覧にはご
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
閲覧にはご契
閲覧にはご
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となり
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
閲覧にはご契
閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
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:
尾崎貴士 : 未申告[2021年]
監修:金子礼志 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、間質性肺炎の治療内容にニンテダニブ(オフェブ)に関する内容を中心に加筆修正を行った。また、肺高血圧症の新基準に関して加筆修正した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. モルフェアなどの限局性強皮症や腎性全身性線維症などの他疾患を含め、広義の「強皮症」とすることもあるが、本稿ではいわゆる全身性強皮症(systemic sclerosis)を強皮症と呼び、解説する。
  1. 本症は皮膚や臓器の線維化および末梢循環障害を特徴とする疾患であり、厚生労働省特定疾患である。男女比は1:10程度と女性に多く、好発年齢は30~50歳である。
  1. 診断の際、レイノー(Raynaud)現象や抗核抗体などにおいて陽性率が高い項目のチェックも有用である。
 
Raynaud現象

Raynaud現象は、寒冷刺激や感情変化によって誘発される末梢動脈の攣縮がもたらす四肢末梢の虚血性変化である。比較的短時間のうちに蒼白⇒紫(チアノーゼ)⇒赤へと色調変化がみられるが、全患者で典型的な3相性の経過をたどるとは限らない。強皮症患者の90%程度でみられるとされている。

 
  1. 皮膚病変、肺高血圧症、間質性肺炎、心疾患、強皮症腎、消化管病変など、強皮症の障害は多岐にわたる可能性があり、臨床像や重症度は個々で大きく異なる。
  1. それぞれの臓器障害は経過中に出現してくることがあるため、初期評価とその後のフォローが重要である。
  1. 皮膚硬化が肘関節もしくは膝関節を越えて近位まで及ぶものをびまん皮膚硬化型(diffuse cutaneous SSc、dcSSc)、皮膚硬化が肘関節もしくは膝関節よりも遠位にとどまるものを限局皮膚硬化型(limited cutaneous SSc、lcSSc)としている。
 
強皮症(SSc)の病型分類と臨床的特徴

図は強皮症の病型分類とその臨床像のまとめである。初診時の病型分類、およびその後のフォローアップの際に参考となる。

 
  1. dcSScかlcSScかにより、合併しやすい臓器障害やその出現時期、皮膚硬化の進行に違いがあるとされており、患者をフォローしていくうえで参考となる。
  1. 全身性強皮症は、指定難病であり、①皮膚、②肺、③心、④腎、⑤消化管――のうち、最も重症度スコアの高いものがmoderate以上の場合などでは申請し認定されると保険料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 
病歴・診察のポイント  
問診:
  1. 以下の症状の有無を確認する。また、それぞれいつ頃からか、症状の増悪や寛解はあるかも聴取する。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

詳しくはクリック
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: Gérald Simonneau, David Montani, David S Celermajer, Christopher P Denton, Michael A Gatzoulis, Michael Krowka, Paul G Williams, Rogerio Souza
雑誌名: Eur Respir J. 2019 Jan;53(1). doi: 10.1183/13993003.01913-2018. Epub 2019 Jan 24.
Abstract/Text Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management.Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup "pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers", due to the specific prognostic and management of these patients, and a subgroup "PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement", due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.

Copyright ©ERS 2019.
PMID 30545968  Eur Respir J. 2019 Jan;53(1). doi: 10.1183/13993003.019・・・
著者: Donald P Tashkin, Robert Elashoff, Philip J Clements, Jonathan Goldin, Michael D Roth, Daniel E Furst, Edgar Arriola, Richard Silver, Charlie Strange, Marcy Bolster, James R Seibold, David J Riley, Vivien M Hsu, John Varga, Dean E Schraufnagel, Arthur Theodore, Robert Simms, Robert Wise, Fredrick Wigley, Barbara White, Virginia Steen, Charles Read, Maureen Mayes, Ed Parsley, Kamal Mubarak, M Kari Connolly, Jeffrey Golden, Mitchell Olman, Barri Fessler, Naomi Rothfield, Mark Metersky, Scleroderma Lung Study Research Group
雑誌名: N Engl J Med. 2006 Jun 22;354(25):2655-66. doi: 10.1056/NEJMoa055120.
Abstract/Text BACKGROUND: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease.
METHODS: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC.
RESULTS: Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant.
CONCLUSIONS: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

Copyright 2006 Massachusetts Medical Society.
PMID 16790698  N Engl J Med. 2006 Jun 22;354(25):2655-66. doi: 10.1056・・・
著者: Donald P Tashkin, Robert Elashoff, Philip J Clements, Michael D Roth, Daniel E Furst, Richard M Silver, Jonathan Goldin, Edgar Arriola, Charlie Strange, Marcy B Bolster, James R Seibold, David J Riley, Vivien M Hsu, John Varga, Dean Schraufnagel, Arthur Theodore, Robert Simms, Robert Wise, Fred Wigley, Barbara White, Virginia Steen, Charles Read, Maureen Mayes, Ed Parsley, Kamal Mubarak, M Kari Connolly, Jeffrey Golden, Mitchell Olman, Barri Fessler, Naomi Rothfield, Mark Metersky, Dinesh Khanna, Ning Li, Gang Li, Scleroderma Lung Study Research Group
雑誌名: Am J Respir Crit Care Med. 2007 Nov 15;176(10):1026-34. doi: 10.1164/rccm.200702-326OC. Epub 2007 Aug 23.
Abstract/Text RATIONALE: The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear.
OBJECTIVES: A second year of follow-up was performed to determine if these effects persisted after stopping treatment.
METHODS: A detailed analysis of data obtained over the two years of the study was performed.
MEASUREMENTS AND MAIN RESULTS: Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire-Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon.
CONCLUSIONS: One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered. Clinical trial registered with www.clinicaltrials.gov (NCT 000004563).

PMID 17717203  Am J Respir Crit Care Med. 2007 Nov 15;176(10):1026-34.・・・
著者: Rachel K Hoyles, Ross W Ellis, Jessica Wellsbury, Belinda Lees, Pauline Newlands, Nicole S L Goh, Christopher Roberts, Sujal Desai, Ariane L Herrick, Neil J McHugh, Noeleen M Foley, Stanley B Pearson, Paul Emery, Douglas J Veale, Christopher P Denton, Athol U Wells, Carol M Black, Roland M du Bois
雑誌名: Arthritis Rheum. 2006 Dec;54(12):3962-70. doi: 10.1002/art.22204.
Abstract/Text OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc.
METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed.
RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified.
CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

PMID 17133610  Arthritis Rheum. 2006 Dec;54(12):3962-70. doi: 10.1002/・・・
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・・・
著者: C Liu, J Chen
雑誌名: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004434. doi: 10.1002/14651858.CD004434.pub3. Epub 2006 Jul 19.
Abstract/Text BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease, which leads to right heart failure and premature death. Pulmonary arterial hypertension can be classified into five categories according to Venice classification: (1) Idiopathic PAH; (2) Familial PAH; (3) PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, drugs and toxins or other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy); (4) PAH associated with significant venous or capillary involvement, which includes pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH); (5) Persistent pulmonary hypertension of the newborn. PAH can also be secondary to chronic hypoxic lung disease as part of the "cor-pulmonale" syndrome, and also secondary to left sided heart disease, but these conditions are usually distinguished from those listed here.
OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.
SEARCH STRATEGY: A search was carried out using the CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of August 2005.
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials involving patients with pulmonary arterial hypertension (PAH) were selected by two reviewers.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies; assessed study quality; and extracted data. We analysed outcomes as continuous and dichotomous data.
MAIN RESULTS: In this updated version of the review, we added two RCTs. Altogether, five RCTs met the entry criteria of the review (reporting eight group comparisons). The studies were of short duration (12-16 weeks), recruiting a total of 482 participants. Three studies compared a non-selective ERA (bosentan) with placebo, one compared bosentan with sildenafil (a phosphodiesterase inhibitor) , and one compared a selective ERA (sitaxsentan) with placebo. Over a 12-16 week period ERAs improved exercise capacity, improve Borg dyspnoea score, some measures of cardiopulmonary haemodynamics (pulmonary artery pressure, pulmonary vascular resistance, and cardiac index) in symptomatic patients with mainly idiopathic PAH. The effect of ERAs on mortality was not significant. The most severe side effect, hepatic toxicity, was not common.
AUTHORS' CONCLUSIONS: ERAs in conjunction with conventional therapy over 12 to 16 weeks can improve exercise capacity, Borg dyspnoea scores and several cardiopulmonary haemodynamics variables in patients mainly with idiopathic PAH. The data on mortality do not currently show a benefit of this class of drugs on this endpoint. Additional assessment of this outcome is important in order to establish whether there is evidence that ERAs have an impact on the risk of death. Longer studies are required.

PMID 16856046  Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004434. d・・・
著者: R N Channick, G Simonneau, O Sitbon, I M Robbins, A Frost, V F Tapson, D B Badesch, S Roux, M Rainisio, F Bodin, L J Rubin
雑誌名: Lancet. 2001 Oct 6;358(9288):1119-23. doi: 10.1016/S0140-6736(01)06250-X.
Abstract/Text BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension.
METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.
FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups.
INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

PMID 11597664  Lancet. 2001 Oct 6;358(9288):1119-23. doi: 10.1016/S014・・・
著者: Lewis J Rubin, David B Badesch, Robyn J Barst, Nazzareno Galie, Carol M Black, Anne Keogh, Tomas Pulido, Adaani Frost, Sebastien Roux, Isabelle Leconte, Michael Landzberg, Gerald Simonneau
雑誌名: N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056/NEJMoa012212.
Abstract/Text BACKGROUND: Endothelin-1 is a potent vasoconstrictor and smooth-muscle mitogen. In a preliminary study, the orally administered dual endothelin-receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. The present trial investigated the effect of bosentan on exercise capacity in a larger number of patients and compared two doses.
METHODS: In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening.
RESULTS: At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening.
CONCLUSIONS: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension.

PMID 11907289  N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056・・・
著者: N Galiè, Lj Rubin, Mm Hoeper, P Jansa, H Al-Hiti, Gmb Meyer, E Chiossi, A Kusic-Pajic, G Simonneau
雑誌名: Lancet. 2008 Jun 21;371(9630):2093-100. doi: 10.1016/S0140-6736(08)60919-8.
Abstract/Text BACKGROUND: Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the effect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension.
METHODS: Patients with WHO FC II pulmonary arterial hypertension aged 12 years or over with 6-min walk distance of less than 80% of the normal predicted value or less than 500 m associated with a Borg dyspnoea index of 2 or greater were enrolled in this double-blind, placebo-controlled, multicentre trial. 185 patients were randomly assigned to receive bosentan (n=93) or placebo (n=92) for the 6-month double-blind treatment period via a centralised integrated voice recognition system. Primary endpoints were pulmonary vascular resistance at month 6 expressed as percentage of baseline and change from baseline to month 6 in 6-min walk distance. Analyses of the primary endpoints were done with all randomised patients who had a valid baseline assessment and an assessment or an imputed value for month 6. This trial was registered with ClinicalTrials.gov, number NCT00091715.
FINDINGS: Analyses were done with 168 patients (80 in the bosentan group, 88 in the placebo group) for pulmonary vascular resistance and with 177 (86 and 91) for 6-min walking distance. At month 6, geometric mean pulmonary vascular resistance was 83.2% (95% CI 73.8-93.7) of the baseline value in the bosentan group and 107.5% (97.6-118.4) of the baseline value in the placebo group (treatment effect -22.6%, 95% CI -33.5 to -10.0; p<0.0001). Mean 6-min walk distance increased from baseline in the bosentan group (11.2 m, 95% CI -4.6 to 27.0) and decreased in the placebo group (-7.9 m, -24.3 to 8.5), with a mean treatment effect of 19.1 m (95% CI 3.6-41.8; p=0.0758). 12 (13%) patients in the bosentan group and eight (9%) in the placebo group reported serious adverse events, the most common of which were syncope in the bosentan group and right ventricular failure in the placebo group.
INTERPRETATION: Bosentan treatment could be beneficial for patients with WHO FC II pulmonary arterial hypertension.

PMID 18572079  Lancet. 2008 Jun 21;371(9630):2093-100. doi: 10.1016/S0・・・
著者: Nazzareno Galiè, Horst Olschewski, Ronald J Oudiz, Fernando Torres, Adaani Frost, Hossein A Ghofrani, David B Badesch, Michael D McGoon, Vallerie V McLaughlin, Ellen B Roecker, Michael J Gerber, Christopher Dufton, Brian L Wiens, Lewis J Rubin, Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group
雑誌名: Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/CIRCULATIONAHA.107.742510. Epub 2008 May 27.
Abstract/Text BACKGROUND: Ambrisentan is a propanoic acid-based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.
METHODS AND RESULTS: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m.
CONCLUSIONS: Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

PMID 18506008  Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/C・・・
著者: Ronald J Oudiz, Nazzareno Galiè, Horst Olschewski, Fernando Torres, Adaani Frost, Hossein A Ghofrani, David B Badesch, Michael D McGoon, Vallerie V McLaughlin, Ellen B Roecker, Brooke C Harrison, Darrin Despain, Christopher Dufton, Lewis J Rubin, ARIES Study Group
雑誌名: J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81. doi: 10.1016/j.jacc.2009.07.033.
Abstract/Text OBJECTIVES: This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH).
BACKGROUND: Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH.
METHODS: In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data.
RESULTS: After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was approximately 2% per year; most of these events were mild and did not lead to discontinuation of drug.
CONCLUSIONS: Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).

PMID 19909879  J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81. doi: 10.・・・
著者: Tomás Pulido, Igor Adzerikho, Richard N Channick, Marion Delcroix, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Pavel Jansa, Zhi-Cheng Jing, Franck-Olivier Le Brun, Sanjay Mehta, Camilla M Mittelholzer, Loïc Perchenet, B K S Sastry, Olivier Sitbon, Rogério Souza, Adam Torbicki, Xiaofeng Zeng, Lewis J Rubin, Gérald Simonneau, SERAPHIN Investigators
雑誌名: N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917.
Abstract/Text BACKGROUND: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.
METHODS: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.
RESULTS: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.
CONCLUSIONS: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

PMID 23984728  N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/N・・・
著者: Richard N Channick, Marion Delcroix, Hossein-Ardeschir Ghofrani, Elke Hunsche, Pavel Jansa, Franck-Olivier Le Brun, Sanjay Mehta, Tomás Pulido, Lewis J Rubin, B K S Sastry, Gérald Simonneau, Olivier Sitbon, Rogério Souza, Adam Torbicki, Nazzareno Galiè
雑誌名: JACC Heart Fail. 2015 Jan;3(1):1-8. doi: 10.1016/j.jchf.2014.07.013. Epub 2014 Nov 11.
Abstract/Text OBJECTIVES: This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH).
BACKGROUND: PAH is a progressive, life-threatening disease often requiring hospitalization.
METHODS: In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated.
RESULTS: Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms.
CONCLUSIONS: Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179).

Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PMID 25457902  JACC Heart Fail. 2015 Jan;3(1):1-8. doi: 10.1016/j.jchf・・・
著者: Nazzareno Galiè, Hossein A Ghofrani, Adam Torbicki, Robyn J Barst, Lewis J Rubin, David Badesch, Thomas Fleming, Tamiza Parpia, Gary Burgess, Angelo Branzi, Friedrich Grimminger, Marcin Kurzyna, Gérald Simonneau, Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group
雑誌名: N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056/NEJMoa050010.
Abstract/Text BACKGROUND: Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.
METHODS: In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.
RESULTS: The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.
CONCLUSIONS: Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

Copyright 2005 Massachusetts Medical Society.
PMID 16291984  N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056・・・
著者: David B Badesch, Nicholas S Hill, Gary Burgess, Lewis J Rubin, Robyn J Barst, Nazzareno Galiè, Gerald Simonneau, SUPER Study Group
雑誌名: J Rheumatol. 2007 Dec;34(12):2417-22. Epub 2007 Nov 1.
Abstract/Text OBJECTIVE: Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD.
METHODS: In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed.
RESULTS: Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least 1 functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated.
CONCLUSION: In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.

PMID 17985403  J Rheumatol. 2007 Dec;34(12):2417-22. Epub 2007 Nov 1.
著者: Nazzareno Galiè, Bruce H Brundage, Hossein A Ghofrani, Ronald J Oudiz, Gerald Simonneau, Zeenat Safdar, Shelley Shapiro, R James White, Melanie Chan, Anthony Beardsworth, Lyn Frumkin, Robyn J Barst, Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group
雑誌名: Circulation. 2009 Jun 9;119(22):2894-903. doi: 10.1161/CIRCULATIONAHA.108.839274. Epub 2009 May 26.
Abstract/Text BACKGROUND: Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.
METHODS AND RESULTS: In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.
CONCLUSIONS: In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

PMID 19470885  Circulation. 2009 Jun 9;119(22):2894-903. doi: 10.1161/・・・
著者: D B Badesch, V F Tapson, M D McGoon, B H Brundage, L J Rubin, F M Wigley, S Rich, R J Barst, P S Barrett, K M Kral, M M Jöbsis, J E Loyd, S Murali, A Frost, R Girgis, R C Bourge, D D Ralph, C G Elliott, N S Hill, D Langleben, R J Schilz, V V McLaughlin, I M Robbins, B M Groves, S Shapiro, T A Medsger
雑誌名: Ann Intern Med. 2000 Mar 21;132(6):425-34.
Abstract/Text BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial.
OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease.
DESIGN: Randomized, open-label, controlled trial.
SETTING: 17 pulmonary hypertension referral centers.
PATIENTS: 111 patients with moderate to severe pulmonary hypertension.
INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone.
MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival.
RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition).
CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

PMID 10733441  Ann Intern Med. 2000 Mar 21;132(6):425-34.
著者: Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiéry, Carmine Dario Vizza, Meinhard Kneussl, Alessandra Manes, Olivier Sitbon, Adam Torbicki, Marion Delcroix, Robert Naeije, Marius Hoeper, Ari Chaouat, Sophie Morand, Bruno Besse, Gerald Simonneau, Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group
雑誌名: J Am Coll Cardiol. 2002 May 1;39(9):1496-502.
Abstract/Text OBJECTIVES: The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH).
BACKGROUND: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system.
METHODS: In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class.
RESULTS: Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period.
CONCLUSIONS: Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.

PMID 11985913  J Am Coll Cardiol. 2002 May 1;39(9):1496-502.
著者: Robyn J Barst, Michael McGoon, Vallerie McLaughlin, Victor Tapson, Stuart Rich, Lewis Rubin, Karlman Wasserman, Ronald Oudiz, Shelley Shapiro, Ivan M Robbins, Richard Channick, David Badesch, Barry K Rayburn, Robin Flinchbaugh, Jeff Sigman, Carl Arneson, Roger Jeffs, Beraprost Study Group
雑誌名: J Am Coll Cardiol. 2003 Jun 18;41(12):2119-25.
Abstract/Text OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH).
BACKGROUND: Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available.
METHODS: A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life.
RESULTS: Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events.
CONCLUSIONS: These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.

PMID 12821234  J Am Coll Cardiol. 2003 Jun 18;41(12):2119-25.
著者: Ronald J Oudiz, Robert J Schilz, Robyn J Barst, Nazzareno Galié, Stuart Rich, Lewis J Rubin, Gérald Simonneau, Treprostinil Study Group
雑誌名: Chest. 2004 Aug;126(2):420-7. doi: 10.1378/chest.126.2.420.
Abstract/Text STUDY OBJECTIVES: To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD).
DESIGN: Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH.
PATIENTS: A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome.
INTERVENTIONS: Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min.
MEASUREMENTS: Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks.
RESULTS: At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 +/- 0.08 L/min/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients.
CONCLUSIONS: Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics.

PMID 15302727  Chest. 2004 Aug;126(2):420-7. doi: 10.1378/chest.126.2.・・・
著者: Hossein-Ardeschir Ghofrani, Nazzareno Galiè, Friedrich Grimminger, Ekkehard Grünig, Marc Humbert, Zhi-Cheng Jing, Anne M Keogh, David Langleben, Michael Ochan Kilama, Arno Fritsch, Dieter Neuser, Lewis J Rubin, PATENT-1 Study Group
雑誌名: N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655.
Abstract/Text BACKGROUND: Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.
METHODS: In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.
RESULTS: By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively).
CONCLUSIONS: Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).

PMID 23883378  N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/N・・・
著者: Olivier Sitbon, Richard Channick, Kelly M Chin, Aline Frey, Sean Gaine, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Irene M Lang, Ralph Preiss, Lewis J Rubin, Lilla Di Scala, Victor Tapson, Igor Adzerikho, Jinming Liu, Olga Moiseeva, Xiaofeng Zeng, Gérald Simonneau, Vallerie V McLaughlin, GRIPHON Investigators
雑誌名: N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056/NEJMoa1503184.
Abstract/Text BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.
METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).
RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.
CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

PMID 26699168  N Engl J Med. 2015 Dec 24;373(26):2522-33. doi: 10.1056・・・
著者: V D Steen, J P Costantino, A P Shapiro, T A Medsger
雑誌名: Ann Intern Med. 1990 Sep 1;113(5):352-7.
Abstract/Text OBJECTIVE: To determine the outcome of scleroderma renal crisis before and after the availability of angiotensin converting enzyme (ACE) inhibitors.
DESIGN: Evaluation of a large cohort of patients with systemic sclerosis and renal crisis who were followed prospectively.
SETTING: University scleroderma center.
PATIENTS: One hundred and eight patients who had scleroderma renal crisis between 1972 and 1987.
INTERVENTION: ACE inhibitors.
MEASUREMENTS AND MAIN RESULTS: Therapy with ACE inhibitors has dramatically improved the survival of patients with scleroderma renal crisis (1-year survival, 15% without and 76% with ACE inhibitors; P less than 0.001). However, 24 (44%) of 55 patients with scleroderma renal crisis who were treated with ACE inhibitors died early or required permanent dialysis. Older age, male sex, an initial serum creatinine level of more than 270 mumol/L, inadequately controlled blood pressure, and congestive heart failure were associated with these poor outcomes, but only older age and congestive heart failure were significant in a multivariate logistic regression analysis. Eleven of twenty patients (55%) who survived dialysis more than 3 months and continued to receive therapy with ACE inhibitors were able to discontinue dialysis after 3 to 15 months compared with 0 of 15 dialysis patients who did not receive ACE-inhibitor therapy (P = 0.002).
CONCLUSIONS: Patients with systemic sclerosis who develop hypertension should be treated with an ACE inhibitor. Improved survival and successful discontinuation of dialysis are possible when ACE inhibitors are used to treat scleroderma renal crisis.

PMID 2382917  Ann Intern Med. 1990 Sep 1;113(5):352-7.
著者: V D Steen, T A Medsger
雑誌名: Ann Intern Med. 2000 Oct 17;133(8):600-3.
Abstract/Text BACKGROUND: Although scleroderma renal crisis, a complication of systemic sclerosis, can be treated with angiotensin-converting enzyme (ACE) inhibitors, its long-term outcomes are not known.
OBJECTIVE: To determine outcomes, natural history, and risk factors in patients with systemic sclerosis and scleroderma renal crisis.
DESIGN: Prospective observational cohort study.
SETTING: University program specializing in scleroderma.
PATIENTS: 145 patients with scleroderma renal crisis who received ACE inhibitors and 662 patients with scleroderma who did not have renal crisis.
MEASUREMENTS: Among patients with renal crisis, the four outcomes studied were no dialysis, temporary dialysis, permanent dialysis, and early death. Demographic, clinical, and laboratory data were compared to identify risk factors for specific outcomes. Follow-up was 5 to 10 years.
RESULTS: 61% of patients with renal crisis had good outcomes (55 received no dialysis, and 34 received temporary dialysis); only 4 of these (4%) progressed to chronic renal failure and permanent dialysis. More than half of the patients who initially required dialysis could discontinue it 3 to 18 months later. Survival of patients in the good outcome group was similar to that of patients with diffuse scleroderma who did not have renal crisis. Some patients (39%) had bad outcomes (permanent dialysis or early death).
CONCLUSIONS: Renal crisis can be effectively managed when hypertension is aggressively controlled with ACE inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hopes of discontinuing dialysis.

PMID 11033587  Ann Intern Med. 2000 Oct 17;133(8):600-3.
著者: Sule Apras, Ihsan Ertenli, Zeynep Ozbalkan, Sedat Kiraz, M Akif Ozturk, Ibrahim C Haznedaroglu, Veli Cobankara, Salih Pay, Meral Calguneri
雑誌名: Arthritis Rheum. 2003 Aug;48(8):2256-61. doi: 10.1002/art.11081.
Abstract/Text OBJECTIVE: The endothelial damage of microvascular structures in systemic sclerosis (SSc; scleroderma) is associated with increased levels of endothelial adhesion molecules and endothelium-associated cytokines, including E-selectin and thrombomodulin. Although there is still no ideal specific pharmacologic therapy for SSc, cyclophosphamide has resulted in clinical improvement in patients with SSc-related active alveolitis. This study was designed to assess the expression of E-selectin and thrombomodulin in patients with early diffuse SSc, and to investigate the effects of oral cyclophosphamide combined with prednisolone therapy on the levels of these endothelium-associated cytokines and on the patients' clinical outcomes.
METHODS: Thirteen patients with early diffuse SSc were treated with oral cyclophosphamide (2-2.5 mg/kg/day) and methylprednisolone (30 mg/every other day) for 1 year. The outcomes were determined as clinical (skin score) and laboratory parameters (including the erythrocyte sedimentation rate, complete blood cell count, levels of C-reactive protein, antinuclear antibody, anti-double-stranded DNA, rate of creatinine clearance, and findings on pulmonary function tests, esophageal manometry, and echocardiography). The concentrations of E-selectin and thrombomodulin were measured in the pretreatment and posttreatment serum samples from the SSc patients and from 12 healthy adults as controls.
RESULTS: In the patients with early diffuse SSc, pretreatment and posttreatment mean levels of E-selectin were 51 ng/ml (range 34.2-135.5) and 33.4 ng/ml (range 23-62.5), respectively (P = 0.01), and those of thrombomodulin were 82 ng/ml (range 35.8-120.5) and 74.6 ng/ml (range 23.3-91.3), respectively (P = 0.016). Clinical and laboratory parameters (the skin score and measures of pulmonary function [forced vital capacity and diffusing capacity for carbon monoxide]) were also improved (P < 0.05 for each) at the end of the followup period.
CONCLUSION: Combination therapy with cylophosphamide plus prednisolone is effective in the treatment of early diffuse SSc. Circulating levels of E-selectin and thrombomodulin not only demonstrate the extent of endothelial injury and/or activation, but also could be a useful marker to monitor the disease activity in SSc.

PMID 12905480  Arthritis Rheum. 2003 Aug;48(8):2256-61. doi: 10.1002/a・・・
著者: M Calguneri, S Apras, Z Ozbalkan, I Ertenli, S Kiraz, M A Ozturk, I Celik
雑誌名: Clin Rheumatol. 2003 Oct;22(4-5):289-94. doi: 10.1007/s10067-003-0733-2.
Abstract/Text Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1-2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion index, predicted forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group. No life-threatening or irreversible adverse reaction was observed. This open study supports the use of oral cyclophosphamide plus prednisolone therapy to prevent fibrosis and its complications in the early stages of diffuse SSc.

PMID 14579158  Clin Rheumatol. 2003 Oct;22(4-5):289-94. doi: 10.1007/s・・・
著者: G Valentini, C Paone, G La Montagna, I Chiarolanza, M Menegozzo, E Colutta, L Ruocco
雑誌名: Scand J Rheumatol. 2006 Jan-Feb;35(1):35-8. doi: 10.1080/03009740510026896.
Abstract/Text OBJECTIVE: To investigate the efficacy of a treatment with low-dose intravenous cyclophosphamide (CYC) and low-dose prednisone in early diffuse cutaneous systemic sclerosis (dcSSc).
METHODS: Patients with dcSSc and a disease duration <24 months consecutively admitted to a tertiary centre underwent a prospective 1-year study. They were treated with i.v. CYC 500 mg/pulses, 10 mg prednisone equivalent, and supportive therapy. Modified Rodnan skin score (mRss), Health Assessment Questionnaire-Disability Index (HAQ-DI), forced vital capacity (FVC), and diffusing lung capacity for CO (DLCO) were assessed as outcome measures. In addition, the nine Medsger severity scale scores were evaluated.
RESULTS: mRss and DLCO significantly improved at both 6 (p = 0.002 and 0.012, respectively) and 12 months (p = 0.002 and 0.003, respectively). HAQ-DI showed a nearly significant reduction at 12 months (p = 0.06). Medsger's severity scores also improved for general condition (p = 0.001), peripheral vascular (p = 0.05), skin (p = 0.02), joint/tendon (p = 0.001), muscle (p = 0.05), and lung (p = 0.02). No treatment interruption was needed.
CONCLUSIONS: This preliminary study suggests a role for low-dose i.v. CYC in the treatment of early dcSSc. Controlled studies are warranted.

PMID 16467039  Scand J Rheumatol. 2006 Jan-Feb;35(1):35-8. doi: 10.108・・・
著者: Ioannis Pakas, John P A Ioannidis, Katerina Malagari, Fotini N Skopouli, Haralampos M Moutsopoulos, Panayiotis G Vlachoyiannopoulos
雑誌名: J Rheumatol. 2002 Feb;29(2):298-304.
Abstract/Text OBJECTIVE: To evaluate the safety and efficacy of monthly intravenous pulses of cyclophosphamide (CP) in combination with low or high doses of prednisolone in patients with systemic sclerosis (SSc) related interstitial lung disease (ILD) with FVC < 70% of predicted.
METHODS: An open label, non-parallel arm study, performed in the rheumatology outpatient clinic of a university hospital. Twenty-eight patients with SSc related ILD were evaluated. Endpoint evaluations included the evolution of high resolution computed tomography, pulmonary function tests, skin involvement and dyspnea over 12 months. Patients were treated with monthly IV CP in combination with prednisolone at low (< 10 mg/day; n = 12) or high doses (1 mg/kg/day for 4 weeks, then reducing the prednisolone by 5 mg/day on alternating days each 2 weeks; n = 16).
RESULTS: In the low dose steroid group, no improvement was seen for any endpoint at 6 and 12 months of followup. In the high dose steroid group, at 12 months there was significant improvement in the percentage of "ground glass" parenchymal lung involvement (-5.7%; p = 0.003), as well as in the percentage of predicted FVC (12.4%; p < 0.001), the percentage of predicted DLCO (7.3%; p = 0.029), the percentage of skin involvement (-5.4%; p = 0.01), and the severity of dyspnea (p = 0.012). Substantial improvement was seen as early as 6 months. One patient (low dose group) died from ILD.
CONCLUSION: A combination of IV pulse CP with high doses of prednisolone shows promising efficacy in improving the clinical, physiological, and radiological evolution of SSc related ILD with reversal of the underlying alveolitis.

PMID 11842824  J Rheumatol. 2002 Feb;29(2):298-304.
著者: Bridget Griffiths, Sarah Miles, Hilary Moss, Rod Robertson, Douglas Veale, Paul Emery
雑誌名: J Rheumatol. 2002 Nov;29(11):2371-8.
Abstract/Text OBJECTIVE: To document the effectiveness, including the longterm effect, of a course of intravenous (IV) pulses of methylprednisolone (MP) and cyclophosphamide (CYC) in patients with scleroderma (SSc) who had evidence of lung inflammation on high resolution computer tomographic (HRCT) scan of the chest.
METHODS: Fourteen consecutive patients with SSc and lung involvement were treated with 6 pulses of IV MP (10 mg/kg) and IV CYC (15 mg/kg) given at 3-4 weekly intervals. HRCT scans and lung function tests were performed at baseline and after the 6th pulse. Further lung function tests were repeated at 12 months and annually thereafter.
RESULTS: Modified Rodnan skin scores improved significantly by 35% from a median baseline score of 17 (IQR 14-26.5) to a posttreatment score of 13 (IQR 10.5-18.5; p = 0.0058). HRCT scan scores improved significantly (p = 0.04). Twelve of 13 patients experienced either improvement or stabilization of the HRCT score. Median DLCO and lung volumes remained stable during the first 12 months. After a median followup of 26 months (IQR 19-43), 67% of patients experienced deterioration in DLCO. Median deterioration was 23% (IQR 44-0.6), with the median rate of deterioration of the predicted value of the DLCO/month being 0.87% (IQR 1.24-0.02). The treatment was safe and well tolerated.
CONCLUSION: This IV regimen stabilized lung disease in patients with SSc. When treatment was stopped, or reduced in intensity, a deterioration in lung function occurred in the majority of patients. Rate of deterioration of DLCO may be a useful marker for determining the intensity of treatment. These findings have implications for treating lung disease and designing clinical trials in patients with SSc.

PMID 12415594  J Rheumatol. 2002 Nov;29(11):2371-8.
著者: J Pope, D Fenlon, A Thompson, B Shea, D Furst, G Wells, A Silman
雑誌名: Cochrane Database Syst Rev. 2000;(2):CD000953. doi: 10.1002/14651858.CD000953.
Abstract/Text OBJECTIVES: To assess the effects and toxicity of the following agents:Prostaglandin analogues together with other agents proposed for the treatment of Raynaud's phenomenom (RP) in scleroderma.
SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages.
SELECTION CRITERIA: All randomized controlled trials comparing prostaglandin analogues versus placebo were eligible if they reported clinical outcomes within the start of therapy, and if the dropout rate was less than 35%.
DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers (DF, AT). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous, respectively.
MAIN RESULTS: Seven randomized trials and 332 patients were included. Five of the seven trials were of parallel design. Five trials compared I.V. Iloprost and one trial studied p.o. Iloprost and another p.o. Cisaprost. Some trials were dose finding trials so various doses of Iloprost were used. Due to different efficacies of I.V. Iloprost, oral Iloprost and oral Cisaprost, the overall efficacy of these drugs was somewhat diluted. Intravenous Iloprost appears to be effective in the treatment of secondary Raynaud's phenomenon.
REVIEWER'S CONCLUSIONS: Intravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.

PMID 10796395  Cochrane Database Syst Rev. 2000;(2):CD000953. doi: 10.・・・
著者: Donald P Tashkin, Michael D Roth, Philip J Clements, Daniel E Furst, Dinesh Khanna, Eric C Kleerup, Jonathan Goldin, Edgar Arriola, Elizabeth R Volkmann, Suzanne Kafaja, Richard Silver, Virginia Steen, Charlie Strange, Robert Wise, Fredrick Wigley, Maureen Mayes, David J Riley, Sabiha Hussain, Shervin Assassi, Vivien M Hsu, Bela Patel, Kristine Phillips, Fernando Martinez, Jeffrey Golden, M Kari Connolly, John Varga, Jane Dematte, Monique E Hinchcliff, Aryeh Fischer, Jeffrey Swigris, Richard Meehan, Arthur Theodore, Robert Simms, Suncica Volkov, Dean E Schraufnagel, Mary Beth Scholand, Tracy Frech, Jerry A Molitor, Kristin Highland, Charles A Read, Marvin J Fritzler, Grace Hyun J Kim, Chi-Hong Tseng, Robert M Elashoff, Sclerodema Lung Study II Investigators
雑誌名: Lancet Respir Med. 2016 Sep;4(9):708-719. doi: 10.1016/S2213-2600(16)30152-7. Epub 2016 Jul 25.
Abstract/Text BACKGROUND: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide.
METHODS: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129.
FINDINGS: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019).
INTERPRETATION: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile.
FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27469583  Lancet Respir Med. 2016 Sep;4(9):708-719. doi: 10.1016/・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから