- 學位論文
中高累積劑量的甲氨蝶呤可能降低類風濕關節炎患者新發癌症的風險
MTX at middle and high accumulative doses might lower risk of new-onset cancers in patients with rheumatoid arthritis
摘要
研究目的 甲氨蝶呤（Methotrexate, MTX）是治療類風濕關節炎患者的“錨定藥物”，可能對罹癌風險具有雙重的作用；由於其抗代謝物特性，它可能具有抗癌作用，但由於其亦具有免疫抑製作用也可能促進癌症發生。因此，本研究旨在探討是否使用甲氨蝶呤可降低類風濕關節炎（Rheumatoid arthritis, RA）患者新生癌症的風險。 研究方法 我們使用以全國人口為基礎的全民健保資料庫（National Taiwan Insurance Research Database, NHIRD）百萬歸人檔，進行了全國為期12年的回溯性世代研究（retrospective cohort study）。在2000-2009年期間，本研究共有21,699位新診斷為類風濕關節炎的患者被納入，更進一步將此族群分類為使用甲氨蝶呤與非使用甲氨蝶呤兩組，並比較10,352位使用甲氨蝶呤的患者與其配對的11,347位非使用甲氨蝶呤患者的總體罹癌率。再依據世界衛生組織所制定的解剖治療化學分類轉換為每日定義劑量系統（defined daily dose, DDD）值為工具來評估藥物的曝露情形。在控制人口統計學變項和其他共同病症與聯合用藥後，使用Cox比例風險回歸模型來估算控制基線人口統計狀況及共同病症與聯合用藥後之罹癌風險危害比（Hazard ratio, HR）。 研究結果 經調整年齡、性別、癌症相關的共同病症及類風濕關節炎的聯合用藥後，使用甲氨蝶呤之患者相對於未使用者的罹癌風險危害比為0.87（95％信賴區間= 0.74-1.02）。非使用甲氨蝶呤患者組的罹癌累積發生率顯著高於使用甲氨蝶呤患者組（存活分析檢定p值<0.001）。在低累積劑量下（累計劑量<1125 mg，累積每日定義劑量系統值<450），相對於與非使用甲氨蝶呤患者組相比，使用甲氨蝶呤患者組的罹癌風險危害比為1.20（95％CI = 1.01-1.42）。然而，調整後的罹癌風險危害比在中累積劑量（累計劑量=1125-2250 mg，累積每日定義劑量系統值=450-899）及高累積劑量（累計劑量≥2250 mg，累積每日定義劑量系統值≥900）的甲氨蝶呤使用組，分別減少為0.66（95％信賴區間= 0.49-0.87）及0.33（95％信賴區間= 0.23-0.48）（趨勢分析p值< 0.0001）。 結論 藉由劑量依存性關係分析，中高累積劑量的甲氨蝶呤可能降低類風濕關節炎患者新發癌症的風險。
並列摘要
Background Methotrexate (MTX), the “anchor drug” in the treatment of Rheumatoid arthritis (RA), might have a dual effect on cancer; it probably has an anticancer effect due to its anti-metabolite property but may also promote cancer due to its immunosuppressive effects. Therefore, we investigated whether taking methotrexate (MTX) is associated with a lower risk of new-onset cancers in patients with rheumatoid arthritis (RA). Methods We conducted a 12-year retrospective cohort study from a population-based National Health Insurance Research Database in Taiwan. A total of 21,699 patients with newly diagnosed RA were enrolled during 2000–2009 and classified them into the MTX user group and the MTX non-user group. The overall cancer rate was compared between 10,352 new users of MTX and 11,347 non-users. We used the WHO Defined Daily Dose (DDD) as a tool to assess drug exposure. Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of disease after controlling for baseline demographics, other co-morbidities and RA-combined medication. Results After adjusting for age, sex, cancer-related comorbidities, and RA-combined medication, the HR of cancer risk was 0.87 (95% CI = 0.74–1.02) for the MTX user group compared with the MTX non-user group. The cumulative incidence of cancer in the MTX non-user group was significantly higher than that of the MTX-user group (log rank test p < 0.001). In the low accumulative dose group (cumulative dose < 1125 mg, cDDD < 450), the HR of cancer risk for MTX users was 1.20 (95% CI = 1.01–1.42) compared to the MTX-non-user group. However, the adjusted HR (aHR) of cancer risk was reduced to 0.66 (95% CI =0.49–0.87) in MTX middle dose users (cumulative dose 1125–2250 mg, cDDD: 450–899) and 0.33 (95% CI =0.23–0.48) for the MTX high dose group (cumulative dose ≥ 2250 mg, cDDD ≥ 900), respectively (p for trend < 0.0001). Conclusion MTX at middle and high accumulative doses might lower risk of new-onset cancers in patients with RA by a dose-dependent manner.