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吸入型類固醇對於未使用過類固醇的中重度COPD病患可能有幫助
作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　October 27, 2009 — 根據一項於10月20日發表於內科學誌（Annals of Internal Medicine）的隨機分派安慰劑控制研究結果顯示，吸入型類固醇（ICS）治療，對於沒有使用過類固醇的中重度慢性肺阻塞疾病（COPD）病患可能是有幫助的。
　　
　　Therese S. Lapperre醫師與其來自GLUCOLD（Groningen Leiden大學肺阻塞疾病皮質類固醇）研究團隊的同事們寫到，ICS與長效β2-致效劑（LABAs）被用於治療中度到重度COPD。我們假設（1）以ICS作為長期維持療法可以提供抑制COPD病患氣管發炎作用（主要預後）；（2）這樣的作用與臨床改善有關；（3）停用ICS治療會誘發發炎與臨床狀況惡化；以及（4）ICS治療加上LABA並不能提供進一步的抗發炎作用。
　　
　　在荷蘭的兩家大學醫學中心，114位過去沒有使用過類固醇的中重度COPD、且目前或之前是吸菸病患被最小化隨機分派接受fluticasone propionate 500 mcg每天兩次持續6個月（共31位）或30個月（共26位）；fluticasone 500 mcg每天兩次，以及salmeterol 50 mcg每天兩次共30個月（單一吸入器；共28位）；或是使用安慰劑一天兩次（共29位）。
　　
　　主要試驗終點為支氣管切片與痰液中的細胞數目。次要試驗終點為試驗前、6與30個月時的乙醯甲膽鹼反應程度；以及每3個月評估一次的臨床預後。在114位受試者中，101位病患超過70%順從治療。
　　
　　相較於安慰劑，fluticasone治療與黏膜CD3+細胞（-55%；95%信賴區間[CI]為-74%~-22%；P=0.004）、CD4+細胞（-78%；95% CI為-88%~-60%；P<0.001）、CD8+細胞（-57%；95% CI為-77%~-18%；P=0.010），與巨大細胞（-38%；95% CI為-60%~-2%；P=0.039）。6個月時，相較於安慰劑，使用fluticasone的過度反應也是下降的（-38%；95% CI為-60%~-2%；P=0.036），且這些反應可以維持長達30個月。
　　
　　以fluticasone治療30個月，與巨大細胞數目減少及嗜伊紅性球數目、完整上皮百分比增加有關。這些改善可以以痰液中中性球、巨噬細胞、淋巴球數目下降，以及使力吐氣第一秒容積（FEV1）下降、呼吸困難次數減少、生活品質以及臨床症狀改善有關。
　　
　　在6個月時停止使用fluticasone治療的病患們，臨床預後變差且CD3+細胞數目（120%；95% CI為24%-289%；P=0.007）、巨大細胞數目（218%；95% CI為99%-407%；P<0.001）與漿細胞數目（118%；95% CI為9%-336%；P=0.028）增加有關。加上salmeterol與FEV1改善有關。
　　
　　研究作者寫到，ICS治療減少發炎反應，對過去沒有使用類固醇的中重度COPD患者們，可以減緩肺功能下降。加上LABA並不會加強這些效應。
　　
　　這項研究的限制是，這並未被設計以評估臨床預後，且24%病患並沒有在30個月時的主要預後數據，造成了可能的選擇性誤差。除此之外，僅使用可以順應治療的病患資料，且樣本數目太小，無法獲得對ICS治療相關不良反應的結論。
　　
　　研究作者們的結論是，我們的發現代表過去未使用類固醇、中度氣管阻塞、氣管過度敏感的COPD患者，對長期ICS治療是具有感受性的。這些對發炎反應與肺功能的長期效應並非暗指其因果關係，而是代表特定表現型的COPD病患可以達到修飾疾病的作用。
　　
　　荷蘭科學研究組織、荷蘭氣喘基金會、荷蘭格蘭素威康藥廠、Groningen大學醫學中心、以及Leiden大學醫學中心贊助這項研究。
　　
　　部分研究作者表示皆與Nycome、Chiesi、Boehringer Ingelheim、GlaxoSmithKline、AstraZeneca、Altana、Teva、Top Institute Pharma、Glaxo Wellcome、Novartis以及/或是Innovative Medicines Initiative有資金上的往來。

Inhaled Corticosteroids May Be Helpful in Steroid-Naive Patients With Moderate to Severe COPD

By Laurie Barclay, MD
Medscape Medical News

October 27, 2009 — Inhaled corticosteroid (ICS) therapy may be helpful in steroid-naive patients with moderate to severe chronic obstructive pulmonary disease (COPD), according to the results of a randomized, placebo-controlled trial reported in the October 20 issue of the Annals of Internal Medicine.

"...ICSs and long-acting β2-agonists (LABAs) are used to treat moderate to severe...COPD," write Therese S. Lapperre, MD, and colleagues from the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) Study Group. "We hypothesized that 1) long-term maintenance therapy with ICS provides anti-inflammatory effects (primary outcome) in the airways of patients with COPD; 2) such effects are associated with clinical improvements; 3) discontinuing ICS therapy induces a flare-up of inflammation and clinical deterioration; and 4) adding a LABA to ICS therapy provides no further anti-inflammatory effects."

At 2 university medical centers in the Netherlands, 114 steroid-naive patients with moderate to severe COPD who were current or former smokers were randomly selected by the minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).

The primary endpoint of the study was cell counts in bronchial biopsies and sputum. Secondary endpoints were methacholine responsiveness determined at baseline, 6, and 30 months; and clinical outcomes evaluated every 3 months. Of the 114 participants, 101 patients were more than 70% adherent to therapy.

Compared with placebo, fluticasone treatment was associated with lower counts of mucosal CD3+ cells (–55%; 95% confidence interval [CI], –74% to –22%; P = .004), CD4+ cells (–78%; 95% CI, –88% to –60%; P < .001), CD8+ cells (–57%; 95% CI, –77% to –18%; P = .010), and mast cells (–38%; 95% CI, –60% to –2%; P = .039). Hyperresponsiveness was also reduced with fluticasone vs placebo at 6 months (P = .036), and these effects were maintained after 30 months.

Treatment with fluticasone for 30 months was associated with lower mast cell count and increased eosinophil count and percentage of intact epithelium. These improvements were mirrored by reductions in sputum neutrophil, macrophage, and lymphocyte counts as well as in improvements in decline of forced expiratory volume in 1 second (FEV1), reduced dyspnea, improved quality of life, and clinical improvements.

Patients who discontinued fluticasone therapy at 6 months had worsened clinical outcome and increased CD3+ cell counts (120%; 95% CI, 24% to 289%; P = .007), mast cell counts (218%; 95% CI, 99% to 407%; P < .001), and plasma cell counts (118%; 95% CI, 9% to 336%; P = .028). The addition of salmeterol was associated with improvement in FEV1.

"ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD," the study authors write. "Adding LABAs does not enhance these effects."

Limitations of this study were that it was not designed to assess clinical outcomes and that 24% of patients did not have primary outcome data at 30 months, creating possible selection bias. In addition, only data from adherent patients were used, and sample size was too small to draw conclusions about adverse events associated with ICS use.

"Our findings indicate that a subphenotype of patients with COPD who are steroid-naive and have moderate airway obstruction and airway hyperresponsiveness are sensitive to long-term ICS therapy," the study authors conclude. "These prolonged effects on inflammation and lung function do not imply causality but suggest that disease modification can be achieved in particular phenotypes of patients with COPD."

Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of the Netherlands, University Medical Center Groningen, and Leiden University Medical Center supported this study.

Some of the study authors have disclosed various financial relationships with Nycomed, Chiesi, Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Altana, Teva, Top Institute Pharma, Glaxo Wellcome, Novartis, and/or Innovative Medicines Initiative.

Ann Intern Med. 2009;151:517-527.