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EBM Journal Club Rheumatoid Arthritis : Is Tripterygium wilfordii Hook F a remedy?

Aquire Appraisal Apply Audit 2 BACKGROUND 類風濕性關節炎 (rheumatoid arthritis, RA) 是一種慢性全身進展性的自體免疫疾病

8% 女性發生率約為男性的三倍, 好發於 35-50 歲成年人常見有骨頭關節發炎疼痛和受傷, 可能會侵犯內臟血管神經等而導致全身疲倦體重減輕食慾不振等症狀 Clinical

1 EBM Journal Club Rheumatoid Arthritis : Is Tripterygium wilfordii Hook F a remedy? 報告者 :R2 劉書毓指導醫師 : 陳星諭醫師時間地點 :2015/10/21 PM12:30 台北中醫門診 B1 會議室 OUTLINE Background Scenario Ask(PICO) Aquire Appraisal Apply Audit 2 BACKGROUND 類風濕性關節炎 (rheumatoid arthritis, RA) 是一種慢性全身進展性的自體免疫疾病不同種族有不同的盛行率, 美國盛行率約 0.6%, 台灣盛行率約 0.8% 女性發生率約為男性的三倍, 好發於歲成年人常見有骨頭關節發炎疼痛和受傷, 可能會侵犯內臟血管神經等而導致全身疲倦體重減輕食慾不振等症狀 Clinical manifestation of RA 3 4 Note: For classification purposes, a patient has RA if at least four of these criteria are satisfied (the first four must have been present for at least six weeks)

2010 年 ACR/EULAR(American College Of Rheumatology/European League against Rheumatism) 關節發炎的數量與部位 2-10 個大關節 ( 從肩肘髖膝踝的關節 ) 1 分 1-3 個小關節 ( 從掌指關節之間近端指間關節第二至第五蹠趾關節拇指手腕間關節 ) 2 分 4-10 個小關節 3 分大於 10 個關節

或 ESR 於正常值的上限 1 分症狀持續六週以上 1 分若病人總分達到 6 分以上 ( 總分 10 分 ), 即可確診為類風濕性關節炎疾病嚴重度評估工具 :ACR Responses criteria & DAS28 ACR Responses criteria : 美國風濕病學會所製定的標準, 分為 ACR20 ACR50 ACR70 ACR20 定義為病人腫脹及觸痛關節數 (28 個

2 2010 年 ACR/EULAR(American College Of Rheumatology/European League against Rheumatism) 關節發炎的數量與部位 2-10 個大關節 ( 從肩肘髖膝踝的關節 ) 1 分 1-3 個小關節 ( 從掌指關節之間近端指間關節第二至第五蹠趾關節拇指手腕間關節 ) 2 分 4-10 個小關節 3 分大於 10 個關節 ( 至少要有 1 個小關節 ) 5 分血清學異常 -Rheumatoid factor (RF) 或 anti-citrullinated peptide/protein antibody (ACPA) RF 或 ACPA 兩項中有一項高於正常值, 但數值低於正常值的 3 倍 2 分 RF 或 ACPA 兩項中有一項高於正常值, 且數值高於正常值的 3 倍 3 分抽血檢驗發炎指數 :CRP 或 ESR 於正常值的上限 1 分症狀持續六週以上 1 分若病人總分達到 6 分以上 ( 總分 10 分 ), 即可確診為類風濕性關節炎疾病嚴重度評估工具 :ACR Responses criteria & DAS28 ACR Responses criteria : 美國風濕病學會所製定的標準, 分為 ACR20 ACR50 ACR70 ACR20 定義為病人腫脹及觸痛關節數 (28 個 ) 有 20% 改善, 以及下列五項中至少有三項改善 20% 以上 : 患者對疼痛的評估患者的綜合評估醫生的綜合評估患者對活動能力的自我評估發炎指數 (CRP 或 ESR) DAS 28 (Disease Activity Score 28): 主要是評估 28 處關節疾病活動度, 主要是依據四項指標來決定 DAS28 的數值下列為四項指標 : TJC28 (Tender Joint count):28 個關節中有觸痛關節數 SJC28 (Swollen Joint count):28 個關節中有腫脹關節數 ESR: 紅血球沉降速率 GH (general health): 整體健康狀態評估 7 8 SCENARIO 一位 60 歲女性患者, 具類風溼性關節炎病史, 持續門診追蹤治療已 20 年, 她曾接受 DMARDS,Immunotherapy, 與 Steroid 等治療方式, 但病情反覆, 效果不如預期患者來到中醫就診, 詢問醫師 : 雷公藤對於類風溼性關節炎是否有療效? 要吃到多少才會改善類風濕性關節炎的症狀呢? 9 10 應該要念 EBM 的... 醫生啊 ~ 我的關節炎吃了一堆類固醇也打針了, 可是還是會痛, 隔壁鄰居介紹我吃雷公藤, 甘嗚效?

ASK(PICO)- Asking an Answerable Clinical Question ACQUIRE- Searching The Best Evidence

Tripterygium wilfordii Hook F Standard pharmacological treatment (ST) swollen joint

erythrocyte sedimentation rate(esr) 13 14 Model of Organization of EBM Information Study 15

words: Rheumatoid Arthritis, Tripterygium wilfordii Hook F Various herbal preparations have

3 ASK(PICO)- Asking an Answerable Clinical Question ACQUIRE- Searching The Best Evidence Problem 病人問題 Intervention 介入處置 Comparison 對照處置 Outcome 臨床結果 PICO Rheumatoid Arthritis Tripterygium wilfordii Hook F Standard pharmacological treatment (ST) swollen joint count(sjc); duration of morning stiffness(dms); grip strength(gs); rheumatoid factor(rf); erythrocyte sedimentation rate(esr) Model of Organization of EBM Information Study UptoDate Key words: Rheumatoid Arthritis, Tripterygium wilfordii Hook F Dynamed Key words: Rheumatoid Arthritis, Tripterygium wilfordii Hook F Various herbal preparations have been, and continue to be, examined for possible benefit for arthritis and musculoskeletal diseases. A good example is a Chinese herbal remedy (an alcohol extract of Tripterygium wilfordii Hook F, TwHF 雷公藤 ) for rheumatoid arthritis (RA), with suggestive immunosuppressive properties. RESULT: 無相關的文獻摘要

19 20 No PDF file Only chinese RCTs 21 22

Applicability Oxford CEBM Critical Appraisal

是否此篇回顧的搜尋策略可能有遺漏可能合適的臨床試驗? 3-1. 研究收錄標準是否有明確的界定?

所收錄的研究是否是有效力 (valid) 的研究 (randomization,

4 PubMed Key words: Rheumatoid Arthritis, Tripterygium wilfordii Hook F RESULT: 三篇符合主題 No PDF file Only chinese RCTs APPRAISAL VIP Validity Impact Practice Applicability Oxford CEBM Critical Appraisal Sheets 1. 此篇系統回顧是否提出明確定義的問題? 2. 是否此篇回顧的搜尋策略可能有遺漏可能合適的臨床試驗? 3-1. 研究收錄標準是否有明確的界定? 3-2. 關於研究族群涉入治療比較分組及結果評估是否適切? 4. 所收錄的研究是否是有效力 (valid) 的研究 (randomization, blinding and completeness of follow-up )? 5. 如果有 meta-analysis, 所收錄的研究是否有足夠的一致性以產生合併的資料?

5 1. 此篇系統回顧是否提出明確定義的問題?(PICO) Problem 病人問題,Intervention 介入處置,Comparison 對照處置,Outcome 臨床結果 Title Intervention Extracts of Tripterygium wilfordii Hook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials Problem Abstract Comparison Randomised controlled trials (RCTs) comparing the effects of Tripterygium wilfordii Hook F (TwHF) extracts (TEs) and placebo (PBO) or diseasemodifying antirheumatic drugs (DMARDs) in patients with RA were included. Compared with DMARDs, TEs alone produced a mild increase in grip strength (GS). Outcome 此篇回顧的搜尋策略是否可能遺漏可能合適的臨床試驗? 明確指出搜尋方式及關鍵字, 且未受到語言限制, 有明確 Mesh term 研究收錄標準是否有明確的界定? 有註明回顧論文總數量及排除數量及原因

Inclusion Criteria Exclusion Criteria Randomised controlled trials (RCTs) were (1) studies using any TwHF-containing included regardless of blinding, herbs or other herbal extracts publication

were selected for analysis if they satisfied (2) Case reports, reviews, retrospective the following criteria: studies, or studies without control groups (1) the subjects took extracts of TwHF were

6 Inclusion Criteria Exclusion Criteria Randomised controlled trials (RCTs) were (1) studies using any TwHF-containing included regardless of blinding, herbs or other herbal extracts publication status, or language. Studies were excluded. were selected for analysis if they satisfied (2) Case reports, reviews, retrospective the following criteria: studies, or studies without control groups (1) the subjects took extracts of TwHF were also excluded. alone or with other DMARDs for at least 4 (3) Studies were also excluded if the dose weeks of TEs was not available. (2) the study was an RCT with a parallel or (4) RCTs that lacked sufficient data to crossover design allow for the calculation of the net (3) TEs were used as an active treatment changes in outcomes and their variances intervention from the baseline to the endpoint were (4) people enrolled were diagnosed with also eliminated fro more analysis. RA, according to the 1987 guidelines of the American Rheumatology Association 關於研究族群涉入治療比較分組及結果評估是否適切? Study Groups 10RCTs(9 in China, 1 in USA) Intervention TEs compared with a placebo(pbo); TEs compared with DMARDs; and TEs with DMARDs compared with DMARDs alone. Groups comparisons Two studies compared TEs with a PBO. Six studies randomised the participants to receive TEs alone versus a control of DMARDs. Two trials compared a cointervention of TEs and DMARDs (methotrexate, or sulfasalazine) with a control of DMARDs alone. Outcomes The primary outcomes were tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), and grip strength (GS). The secondary outcomes consisted of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) 所收錄的研究是否為有效力 (valid) 的研究? There are four trials that were of high quality, most of the included trials were of low quality (Jadad score < 3) because of unclear randomization, deficient allocation concealment, inadequate blinding, and undescribed withdrawals and dropouts. An adequate double blind was also performed in two of the four trials. Meanwhile, withdrawals and dropouts were described in four trials 如果有 meta-analysis, 所收錄的研究是否有足夠的一致性以產生合併的資料? TEs compared with a PBO 顯著差異, 同質性高顯著差異, 中度異質性

The significant difference was identified between TEs and PBO in terms of the SJC, DMS, and ESR. 顯著差異, 高度異質性 A small but significant increase in GS was also found.

顯著差異, 同質性高 37 38 TEs compared with DMRDs 顯著差異, 高度異質性 39 40 The pooled results displayed no significant differences between TEtreated group and the DMARDs group, aside from GS.

7 The significant difference was identified between TEs and PBO in terms of the SJC, DMS, and ESR. 顯著差異, 高度異質性 A small but significant increase in GS was also found. 無顯著差異, 低度異質性 TEs were superior to PBO in improving joint function and reducing disease activity in RA. 顯著差異, 同質性高 TEs compared with DMRDs 顯著差異, 高度異質性 The pooled results displayed no significant differences between TEtreated group and the DMARDs group, aside from GS. However, no effects were found for TJC, SJC, DMS, RF, ESR,or CRP. Only one trial described the results, which were a 20% improvement in RA as defined by ACR (ACR 20), ACR50, and ACR70, so we did not pool these results. There were no beneficial effects on SJC,DMS,or ESR when comparing Tes with DMARDs. Furthermore, the TE group had increased GS compared with the DMARDs group

TEs with DMARDs compared with DMARDs 無顯著差異, 同質性高 Z P The statistical heterogeneity among the studies was found to be significant regarding the results for ESR(P= 0.05).

8 TEs with DMARDs compared with DMARDs 無顯著差異, 同質性高 Z P The statistical heterogeneity among the studies was found to be significant regarding the results for ESR(P= 0.05). The pooled results showed no significant differences between the two groups in terms of ESR or CRP. Unfortunately, none of the included trials reported its results: ACR 20, ACR 50, or ACR70. TEs plus DMARDs had the same effects as those of two synthetic DMARDs alone in terms of lowering disease activity in RA Egger spublication bias plots and Begg s test showed that there were no significant publication biases for three outcomes in which the numbers of the included trials were not less than 5. However, these results cannot be considered convincing because there were fewer than ten trials. AEs 7 reported mild to moderate gastro-intestinal events in a few of the participants who received TEs. Menstruation disorders or amenorrhea was reported in 6 trials in the TE group. 3 trials reported mild liver function abnormalities in a few patients caused by the intake of TEs. Due to different interventions,limited data, and the lowquality of the included studies,the Aes were not ultimately combined APPLY 3E.. evidence, experience, expectation 我們的病人是否與研究中差異很大同樣是 RA 患者您期望您的病人從研究結果中獲得多大的好處? 還有哪些替代方案? 研究結果適用於您的病人嗎? 病人可服用雷公藤使類風濕性關節炎獲得改善 Glucocorticoids, DMARDs, Biologic DMARDs 不一定我們的病人如何看待此治療的結果可參考 AUDIT 依據研究, 雷公藤的療效跟 DMARDs 效果差不多, 但是雷公藤的服用劑量與副作用仍須審慎評估, 應該在醫師指示下使用哦! 是! 謝謝醫生 ~

9 THANKS FOR Ur ATTENTION 49 9

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