B型肝炎病毒對自體免疫病人使用抗腫瘤壞死因子藥物者肝功能影響之研究

Study of the role of hepatitis B virus on liver function abnormality in patients with autoimmune disease using anti-tumor necrosis factor agents

邱瑩明(Ying-Ming Chiu)

指導教授 ： 賴美淑

共同指導教授 ： 陳建煒(Kin-Wei Chan)

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.01723

摘要

背景與目的：抗腫瘤壞死因子藥物為治療類風溼性關節炎、僵直性脊椎炎和乾癬/乾癬性關節炎等自體免疫疾病的新藥。此藥效果卓著，但因為抑制了腫瘤壞死因子使得感染過B型肝炎病毒（HBV）者，其體內HBV病毒容易不斷複製進而導致急性HBV肝炎，此情形不僅發生在HBsAg陽性者身上，HBsAg陰性/anti-HBc陽性者也可能發生。台灣為HBV感染之高盛行區，因此欲針對使用抗腫瘤壞死因子藥物之自體免疫病人：（1）比較不同HBV感染狀態下肝功能異常發生情形（2）了解肝功能異常病例的臨床特徵（3）分析不同HBV感染狀態引起肝功能異常之風險。
研究方法：第一部分為回溯性世代研究，收集2004~2013年間彰化基督教醫院過敏免疫風濕科使用抗腫瘤壞死因子藥物的自體免疫病人，並依照HBsAg陽性、HBsAg陰性/anti-HBc陽性和未感染三種不同感染狀態，比較用藥之後出現肝功能異常的發生率。同時瞭解肝功能異常發生的時間點，並針對發生肝功能異常的病例進行病歷回顧。此外也收集未曾使用過抗腫瘤壞死因子藥物的自體免疫病人，瞭解傳統免疫抑制藥物使用下在不同HBV感染狀態下肝功能異常之發生率。使用標準化率比及其95%信賴區間來檢定不同HBV感染狀態間的肝功能異常發生率是否具統計顯著性差異。第二部分為回溯性世代研究，使用前述研究所建立之抗腫瘤壞死因子藥物使用族群，並排除追蹤未滿一年以及第一年內無肝功能檢驗報告者。計算使用藥物後第一年內肝功能異常之發生率，並針對這些發生肝功能異常的病例，分析其HBV感染狀態分佈以及免疫抑制藥物使用情形，以探討可能影響肝功能異常發生之危險因素。第三部分為鑲嵌式病例對照研究，控制各種干擾因素後，瞭解不同HBV感染狀態對肝功能異常發生的風險。使用第二部分研究所建立之族群，此外凡是相同免疫疾病者及相同用藥年代者歸為同一次族群。在各別次族群中，若開始用藥後一年內有出現肝功能異常者定義為病例組，未出現肝功能異常者定義為對照組，並使用「1比all」的配對方式選取對照組。使用conditional logistic regression，以次族群做為分層變項，分析不同HBV感染狀態和肝功能異常發生之風險，並校正性別、年齡、肝功能異常之過去病史、各種免疫抑制藥物。
結果：（1）以肝功能超過正常值兩倍做為異常的定義下，HBsAg陽性者(n=35)的肝功能異常發生率高於未感染者(n=155)，年齡性別標準化發生率為19.6每百人年比上6.5每百人年(標準化率比 3.02，95%信賴區間1.23-7.46)，達統計顯著性差異；而HBsAg陰性/anti-HBc陽性者(n=282)的發生率和未感染的標準化發生率分別為6.8每百人年和6.5每百人年(標準化率比1.05，95%信賴區間0.49-2.25)，未達統計顯著性差異。有79%的病人其第一次肝功能異常出現的時間是在開始用藥的第一年內。（2）總共有390位抗腫瘤壞死因子藥物使用者納入分析，在使用藥物的第ㄧ年出現肝功能異常的病例有31位，發生率7.9%。這些病例中，女性佔64.5%(n=20)，平均年齡45.5歲；HBsAg陽性者(n=8)佔25.8%，HBsAg陰性/anti-HBc陽性者(n=14)佔45.2%，未感染者(n=9)佔29.0%。有肝功能異常的過去病史者佔25.8%(n=8)。有使用methotrexate者佔67.7%(n=21)，當中有併用葉酸和沒有併用葉酸者分別是36.7%(n=12)和29.0%(n=9)。（3）總共有368位病人納入分析。HBsAg陽性者出現肝功能異常的風險是未感染者的6.33倍 (95%信賴區間1.79-23.52)，達統計顯著性差異；HBsAg陰性/anti-HBc陽性是未感染者的0.88倍(95%信賴區間0.29-2.87)，未達統計顯著性差異。肝功能異常之過去病史和單獨使用methotrexate未併用葉酸，是影響肝功能異常發生的主要危險因素。
結論：本研究以醫院資料為基礎所做的回溯性世代研究發現，自體免疫病人使用抗腫瘤壞死因子藥物時，HBsAg陽性者出現肝功能異常的風險大約是未感染者的6倍，而HBsAg陰性/Anti-HBcAb陽性者則沒有顯著較高的肝功能異常風險。而肝功能異常的過去病史以及單獨使用MTX未併用葉酸，是影響肝功能異常發生的主要危險因素。

關鍵字

抗腫瘤壞死因子藥物 ； B型肝炎病毒 ； 自體免疫疾病 ； 回溯性世代研究 ； 鑲嵌式病例對照研究

並列摘要

Background and objective: Anti-tumor necrosis factor (anti-TNF) agents are new drugs for the treatment of autoimmune disease, such as rheumatoid arthritis, ankylosing spondylitis and psoriasis/psoriatic arthritis. Although anti-TNF agents have good efficacy, this class of drugs could suppress tumor necrosis factor which results in the duplication of hepatitis B virus (HBV) in patients with prior HBV infection, increasing the possibility of acute viral hepatitis. This happens not only in HBsAg-positive patients, but can also occur in HBsAg-negtive/anti-HBc-positive patients. As Taiwan is an endemic area for HBV infection, this study will focus on the analysis of autoimmune patients treated by anti-TNF agents to (1) compare the incidence of liver function abnormality in different HBV infection status, (2) understand the clinical characteristics of case with liver function abnormality, and (3) analyze the risk of liver function abnormality of each HBV infection status.
Method: The first part of the study was a retrospective cohort study which collected all autoimmune patients who were treated by anti-TNF agents in Department of Rheumatology of Changhua Christian Hospital from 2004 to 2013. The incidence of liver function abnormality was compared between patients tested HBsAg-positive, HBsAg-negtive/anti-HBc-positive, and uninfected, and the onset time of liver function abnormality were analyzed. In addition, chart review of those patients who developed liver function abnormality was performed. Autoimmune patients who only used traditional immunosuppressant were also collected, and the incidence of liver function abnormality of different HBV infection status was analyzed in these patients. Standardized rate ratio (SPR) and 95% confidence interval (95% CI) were used to test the statistically significant difference of liver function abnormality incidence between different HBV infection status groups.
The second part of the study was a retrospective cohort using the study population from the first part but excluding patients who were followed less than one year or lacked liver function data in the first year of treatment. The incidence of liver function abnormality in first year was calculated. Furthermore, HBV infection status and immunosuppressant use in the cases of liver function abnormality was analyzed to explore the possible risk factors of liver function abnormality.
The third part of the study was a nested case-control study which controlled all potential confounders to estimate the risk of liver function abnormality of each HBV infection status. Study group from the second part of the study was used. Patients were categorized in the same subgroup if they had the same underlying autoimmune disease and started anti-TNF agent therapy in the same calendar year. In each subgroup, those patients developed liver function abnormality in the first year of anti-TNF treatment were defined as case group, and those who did not were defined as control group. "1-to-all" matching was used to select the controls. With subgroup as the stratum variable in model analysis, conditional logistic regression was used to estimate the odds ratio for liver function abnormality of each HBV infection status after gender, age, past history of liver function abnormality, and immunosuppressant use were adjusted.
Result: (1) When the liver function abnormality was defined as >2-fold the upper limit of normal, HBsAg-positive patients (n=35) had significantly higher incidence of liver function abnormality than uninfected (n=155). The gender- and age-adjusted incidence rate were 19.6 per 100 person-year (PY) and 6.5 per 100 PY respectively, (SRR=3.02, 95% CI=1.23-7.46) and they were statistically different. On the other hand, incidence for HBsAg-negtive/anti-HBc-positive patients and uninfected were not significantly different from each other (6.8 per 100 PY and 6.5 per 100 PY respectively; SRR=1.05, 95% CI=0.49-2.25). 79% of the patients developed first incident of liver function abnormality during the first year of anti-TNF treatment.
(2) Among the 390 anti-TNF users who were included for the analysis, 31 developed liver function abnormality in the first year of anti-TNF treatment, an incidence rate of 7.9%. Among those cases with liver function abnormality, 64.5% were female (n=14), mean age was 45.5 years. Furthermore, 25.8% were HBsAg positive (n=8), 45.2% were HBsAg-negtive/anti-HBc-positive (n=14), and uninfected were 29.0% (n=9). 61.3% of the cases were rheumatoid arthritis (n=19), 45.2% of the cases started using anti-TNF agents in 2010~2012 (n=14). 25.8% of the cases had past history of liver function abnormality (n=8). 67.7% of the cases used methotrexate (n=21); of those, 36.7% of the cases combined with folic acid (n=12) and 29.0% of the cases did not combine with folic acid (n=9).
(3) A total of 368 patients were included for analysis. The HBsAg-positive patients had significantly higher risk of liver function abnormality than the uninfected (OR=6.33, 95% CI=1.79-23.52). However, the association of liver function abnormality between HBsAg-negtive/anti-HBc-positive and uninfected was statistically insignificant (OR=0.88, 95% CI=0.29-2.87). Past history of liver function abnormality and treatment with methotrexate alone without folic acid were the two major risk factors for liver function abnormality in those patients.
Conclusion: In this hospital-based retrospective cohort study of autoimmune patients treated by anti-TNF agents, the risk for liver function abnormality in HBsAg-positive patients was about 6-fold higher than uninfected, and HBsAg-negtive/anti-HBc-positive patients was not associated with higher risk of liver function abnormality. Past history of liver function abnormality and methotrexate only treatment without folic acid were the major risk factors for liver function abnormality.

並列關鍵字

anti-tumor necrosis factor (anti-TNF) agents ； hepatitis B virus (HBV) ； autoimmune disease ； retrospective cohort study ； nested case-control study

參考文獻

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