抗腫瘤壞死因子類藥品上市後使用與結核病感染風險評估

Anti-Tumor Necrosis Factor-alpha Therapy Utilization Patterns and Tuberculosis Infectious Risks Assessment

詹孟儒(Meng-Ju Chan)

指導教授 ： 溫燕霞

共同指導教授 ： 許茜甯(Chein-Ning Hsu)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2014年)

摘要

背景及目的：
抗腫瘤壞死因子類藥品 (anti-tumor necrosis factor-alpha agent, anti TNF-α)是中和前發炎性細胞激素作用的生物製劑產品，上市前臨床試驗結果顯示能有效改善病人的疾病進展與生活品質，然而接受anti TNF-α therapy治療的病人，可能因免疫調節降低而增加結核病、病毒性肝炎感染之風險。該類藥品是台灣藥政史上首例新藥上市初期即被要求執行上市後風險管理計畫 (risk management plan, RMP)之藥品，計畫目的為監測並預防病人使用該類藥品發生結核病、病毒性肝炎或病毒再活化等風險，建議病人在接受anti TNF-α治療前與療程中，應接受結核病與病毒性肝炎篩檢評估。
為了解RMP如何落實於臨床實務上與anti TNF-α agent上市後結核病感染風險的強度，本研究主要目的：一、分析anti TNF-α agent藥品使用型態及醫療機構對於RMP建議的配合度；二、評估罹患類風溼性關節炎、乾癬性關節炎或僵直性脊椎炎病人使用anti TNF-α agent，對於結核病感染風險之相關性。
方法：
(一) 以橫斷性研究設計，分析1/2005-11/2013期間曾處方任一項anti TNF-α agent病人之臨床特徵、藥品使用型態與新藥擴散情形。為了解對RMP的配合度，擷取1/2010-11/2013間之首次接受anti TNF-α治療病人醫療資料，依據RMP公布時間點 (1/1/2012)，區分為RMP執行前與執行後兩組，分別比較結核病與病毒性肝炎相關檢驗處置的開方率、並利用Logistic 迴歸模式探討影響檢驗處置開方之相關因素。
(二) 以回溯性世代研究設計，針對1/2005-11/2013間診斷為類風溼性關節炎、乾癬性關節炎或僵直性脊椎炎之病人進行分析。研究對象分成anti TNF-α agent新使用者與疾病調節抗風濕藥物(disease-modifying anti-rheumatic drugs , DMARDs)治療轉換者，進行兩組於開始用藥後的追蹤期間發生結核病感染風險比較，並按藥品使用組合將DMARDs治療轉換者分為嚴重與輕度疾病兩組。利用Cox迴歸模式分析可能干擾因素對感染風險的影響。
結果：
(一) 研究對象包括1,908位至少曾處方過一次anti TNF-α agent，平均年齡48.9歲，以女性(61.6%)及診斷類風濕性關節炎(61.1%)病人為主。年度新使用人數自2006年的7%逐年增加至11/2013年的23% (以每100病人-觀察月為單位)。共1,128位新使用者納入RMP配合度分析，含531位RMP執行前與597位RMP執行後的病人。結核病主要篩檢項目胸部X光檢查處方率自60%增加至執行後76%；B型肝炎表面抗原檢查自31%成長至51%；C型肝炎抗體檢查自32%成長至54%。RMP執行後病人顯著有較高機會接受胸部X光檢查(OR=2.8, 95% CI 2.1-3.7)、B型肝炎表面抗原檢查(OR=2.7, 95% CI 2.0-3.5)與C型肝炎抗體檢查(OR=2.7, 95% CI 2.0-3.5)。
(二) 研究對象為3,642位病人，含955位anti TNF-α agent新使用者與2,685位DMARDs治療轉換者。經Cox迴歸模式分析結果顯示，相較於DMARDs治療轉換者，anti TNF-α agent新使用者發生結核病之風險顯著增加(HR=2.4, 95% CI 1.2-4.9)。按藥品使用組合分層之結果顯示，anti TNF-α agent新使用者相較於輕度疾病之DMARDs治療轉換者，其結核病感染風險提高(HR=2.9, 95% CI 1.3-6.5)；而相較於嚴重疾病之DMARDs治療轉換者，其TB感染風險(HR=1.7, 95% CI 0.7-4.0)則不具統計學上顯著差異。
結論：
本研究結果顯示在RMP執行後，該醫療機構對首次接受anti TNF-α 治療之病人，其胸部X光、病毒性肝炎檢驗開方率顯著提升。類風溼性關節炎、乾癬性關節炎或僵直性脊椎炎診斷之病人接受anti TNF-α 治療，發生結核病感染之風險顯著高於未使用者，且風險隨疾病嚴重程度而有差異。

關鍵字

抗腫瘤壞死因子類藥品 ； 上市後藥品風險管理計畫 ； 結核病 ； 病毒性肝炎 ； B型肝炎 ； C型肝炎 ； 上市後藥品安全監測

並列摘要

Purpose
To assess the utilization patterns of anti-tumor necrosis factor-alpha (TNF-α) therapy, extent of post-marketing risk management plan (RMP) adherence for anti TNF-α uses and tuberculosis (TB) infectious risk among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in the real practice setting.
Methods
(1) A cross-sectional study was designed for patients with at least one prescription of anti TNF-α agent during 1/2005-11/2013. Patient characteristics, treatment patterns and the annual diffusion rate of anti TNF-α new users were assessed. Based on the earliest date of their anti TNF-α therapy, anti TNF-α new users from 1/2010-11/2013 were identified to examine the extent of RMP adherence. New users were classified into the pre- and post-RMP groups (cut-point 1/1/2012) and compared with the relevant tests’ prescribing rate of TB and viral hepatitis between groups. A multivariate logistic regression model was performed to explore the factors influencing tests’ prescribing rate.
(2) Using the cohort study design, patients who diagnosed with RA, PsA or AS between 1/2005-11/2013 were analyzed. Anti TNF-α new users were identified and compared with diseases modifying ant-rheumatic drugs (DMARDs) treatment switchers on risk of active TB infection using Cox proportional hazard model. Further, we stratified the disease severity according to their DMARDs treatment combinations to ascertain whether the severity of disease are also associated the likelihoods of subsequent TB occurrence.
Results
(1) Overall 1,908 anti TNF-α prevalent users and 1,128 anti TNF-α new users were analyzed in the study. Mean age among anti TNF-α prevalent users were 48.9 years old, 61.6% were women and 61.1% were indicated for RA. A total of 418 (21.9%) patients were continuously on anti TNF-α treatment over 2 years. Annual anti TNF-α agent new user were increasing from 7% in 2006 to 23% / person-months in 2013. Of 1,128 new users (n=531 in pre- and 597 in post-RMP group), screening rates of chest X ray for TB screening increased from 60% in pre- to 76% in post-RMP, 31% to 51% for hepatitis B, and 32% to 54% for hepatitis C. RMP execution was significantly increased the prescription of chest X-ray (OR=2.8, 95% CI 2.1-3.7), hepatitis B surface antigen (OR=2.7, 95% CI 2.0-3.5) and hepatitis C antibody (OR=2.7, 95% CI 2.0-3.5).
(2) Of 3,642 patients (n=955 in anti TNF-α new user group and 2,685 in DMARDs switcher group) with RA, PsA or AS diagnosis were included in study. Patients on anti TNF-α therapy have a significantly greater risk of active TB than DMARDs switchers (HR=2.4, 95% CI 1.2-4.9). When compared with mild disease DMARDs switchers, TB risk will increase 2.9 times (95% CI 1.3-6.5); while compared with the severe disease DMARDs switchers, the risk (HR=1.7, 95% CI 0.7-4.0) was without the statistical difference.
Conclusion
After the introduction of RMP, screening rates of TB and viral hepatitis among anti TNF-α new user were increasing significantly in the study setting. Additional risk of TB was significantly associated with anti TNF-α use among patients with RA, PsA or AS and the susceptibility of risk further differ depending on each patient’s disease severity.

並列關鍵字

Tumor necrosis factor-alpha agent ； risk management plan ； tuberculosis ； viral hepatitis ； hepatitis B ； hepatitis C ； pharmacovigilance

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