Formosan Journal of Rheumatology (formerly Journal of Rheumatology, R.O.C.) Vol. 27, No. 2, December, 2013 Contents Guideline Taiwan guideline for the management of gout and hyperuricemia Original Articles The clinical characters and outcome of antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective single-center study Cheng-Hsun Lu, Chieh-Yu Shen, Cheng-Han Wu, Chia-Li Yu A retrospective investigation of ultrasound findings in patients with shoulder pain from one center in northern Taiwan Min-chung shen, Deh-Ming Chang, Tsung-Yun Hou, Feng-Cheng Liu, Hsiang-Cheng Cen, Shi-Jye Chu, San-Yuan Kuo, Chen-Hung Chen, Chi-Ching Chang Analysis of sources, purposes and presentations of soft-tissue masses referred for ultrasonography Wei-Jhe Hong, Ying-Ming Chiu Relationship between the level of anti-double strand DNA antibody and lupus renal diseases in patients with systemic lupus erythematosus Ching-Hui Hsu, Ming-Han Chen, Wei-Sheng Chen, Chien-Chih Lai, Hsiao-Yi Lin Pain survey in rheumatology outpatient clinics in Taiwan Xiu-Cheng Yeh, Kuang-Yun Huang, Shu-Fen Lo, Chun-Ming Huang, Tien-Tsai Cheng, Hsin-Hua Chen, Li-Hsin Lin, Shih-Chang Lin, Chung-Tei Chou The risk of serious infections in patients with rheumatoid arthritis treated with different tumor necrosis factor α inhibitors Yen-Ning Cheng, Yi-Ming Chen, Tsu-Yi Hsieh, Yi-Hsing Chen, Der-Yuan Chen 1 27 37 44 51 59 67 Clinical Images Left shoulder cystic mass with rice bodies formation Jia-Feng, Chen Fulminant sarcoidosis with hemophagocytic lymphohistiocytosis Fu-Chiang Yeh 75 76 Cover Image Left shoulder cystic mass with rice bodies formation Musculoskeletal sonography revealed subcutaneous cystic mass with synovial membrane hyperplasia, and multiple digit or oval-like rice bodies, which were characterized by hypoechoic cores and hyperechoic rims (Figure A). Synovectomy (Figure B), and tissue culture developed candida spp.
中華民國風濕病雜誌 第 2 7 卷第 2 期民國 1 0 2 年 1 2 月 目 錄 Guideline 台灣痛風與高尿酸血症 2013 診治指引 1 中華民國風濕病醫學會痛風與高尿酸血症診治指引發展團隊蔡嘉哲余光輝林孝義梁統華陳峙仰陳俊宏許秉寧鄭添財謝祖怡魏正宗 原著 抗嗜中性球細胞質抗體相關血管炎患者之臨床表現與治療反應 : 單一醫學中心之回顧性研究 27 呂政勳沈玠妤吳政翰余家利 骨骼肌肉超音波於病人肩關節疼痛的診斷 北台灣一家醫學中心的病歷回溯性調查 37 沈明忠張德明侯宗昀劉峰誠陳相成朱士傑郭三元陳政宏張棋楨 針對軟組織腫塊被轉介施行超音波評估之回溯性分析 44 洪偉哲邱瑩明 斑性狼瘡患者抗雙股 DNA 抗體的變化和狼瘡性腎病變的相關性 51 許敬暉陳明翰陳瑋昇賴建志林孝義 台灣風濕科門診疼痛調查 59 葉修誠黃光永羅淑芬黃春明鄭添財陳信華林理信林世昌周昌德 類風濕性關節炎患者經不同抗腫瘤壞死因子藥物治療後比較其產生嚴重性感染的風險 67 鄭硯寧陳一銘謝祖怡陳怡行陳得源 臨床影像 左肩囊腫內含米體 75 陳嘉夆 猛爆性類肉瘤合併噬血細胞淋巴組織細胞增生 76 葉富強 封面圖片 左肩囊腫內含米體
Formosan Journal of Rheumatology 2013;27:1-26 Guideline 台灣痛風與高尿酸血症 2013 診治指引 Taiwan guideline for the management of gout and hyperuricemia 中華民國風濕病醫學會 痛風與高尿酸血症診治指引發展團隊名單 依姓氏筆劃順序 痛風診治指引發展委員長 : 蔡嘉哲中山醫學大學附設醫院風濕免疫過敏科 指引發展委員 : 余光輝林口長庚醫院風濕過敏免疫科林孝義台北榮民總醫院過敏免疫風濕科梁統華台北和平醫院過敏免疫風濕科陳峙仰台北宏恩綜合醫院痛風科陳俊宏中國醫藥大學附設醫院風濕免疫科許秉寧台大醫院過免疫風濕過敏科鄭添財高雄長庚醫院風濕過敏免疫科謝祖怡台中榮民總醫院過敏免疫風濕科魏正宗中山醫學大學附設醫院風濕免疫過敏科 中華民國內分泌學會中華民國糖尿病學會台灣內科醫學會台灣家庭醫學醫學會 共同推薦 1
理事長的話 2013 年, 第二版的台灣痛風與高尿酸血症診治指引終於出版了 第一版由中華民國國家衛生研究院委託出版, 由蔡嘉哲醫師 余光輝醫師 梁統華醫師 蔡文展醫師 魏正宗醫師及謝祖怡醫師等於 2007 年撰寫完成 有鑑於最近痛風及高尿酸血症有新的進展, 尤其是新藥之問世改變了治療策略, 痛風引起發炎之機轉也有新的發現, 且痛風及高尿酸血症對心臟血管 腎臟 及代謝症候群皆有影響, 所以促成了新版指引之產生 感謝各位編輯委員, 包括余光輝醫師 林孝義醫師 梁統華醫師 陳峙仰醫師 陳俊宏醫師 許秉寧醫師 鄭添財醫師 謝祖怡醫師 魏正宗醫師及本人之努力, 每一章節都經過逐條討論, 都是大家有共識之結晶, 終於完成新版指引, 造福廣大之痛風病人, 值得慶賀 中華民國風濕病醫學會理事長蔡嘉哲 2
第一章 摘要 痛風是現代人的文明病, 它是因尿酸排泄減少或尿酸產生增加所造成的疾病 臨床表現上, 痛風是血尿酸濃度過高, 引起尿酸鈉鹽結晶沉積於關節 軟骨 滑囊液 肌腱或軟組織中的一種發炎性疾病 痛風好發於中年男性及停經後的女性, 主要是以男性佔 90-95% 居多 急性痛風突然發作時可見關節處紅 腫 熱 痛等現象, 好發處為下肢的關節 高尿酸血症是導致痛風的最重要因素, 血尿酸值 >7.0 mg/dl 為高尿酸血症, 血尿酸濃度越高, 持續的時間越久, 發生痛風的機會越大, 但絕大多數 (90%) 高尿酸血症的人沒有任何症狀終身不發病, 只有約 10% 的人最終會成為痛風患者 急性痛風發作時, 約有三分之一患者的血中尿酸值是落在正常範圍內, 因此必須加上過去的病史 臨床表現 病程及誘發因子等來做鑑別診斷, 確定診斷可在急性發作時抽取關節液, 在顯微鏡下發現有被白血球吞噬的針狀尿酸鈉鹽結晶 高尿酸血症及痛風的病因分類, 可分為產生過多型 (10%) 與排泄不良型 (90%) 痛風患者的自然病程及臨床表現大致可以分為下列四個階段 : 無症狀高尿酸血症 急性痛風性關節炎 不發作間歇期 慢性痛風石關節炎 不同的階段, 其治療方式亦不同, 無症狀高尿酸血症通常不需要藥物治療 急性痛風關節炎疼痛時, 常使用口服非類固醇消炎藥物和 / 或秋水仙素, 必要時可使用口服或注射類固醇 不發作間歇期和慢性痛風石病變時, 應使用降尿酸藥物 ( 包括促進尿酸排泄和抑制尿酸產生二大類, 依病情不同使用不同藥物 ), 這些藥物通常相當安全, 但少數人可能會有極罕見的嚴重副作用, 因此使用時宜由小劑量開始, 再逐漸增加到每個人最適合的最低劑量 痛風是無法治癒的疾病, 大多數病患需要長期服藥控制血尿酸, 治療的目標是使血中尿酸值控制在 6.0 mg/dl 以下 治療上可簡單遵守下列原則 : 從未有過關節炎發作的無症狀血尿酸值高於 7.0 mg/dl 者, 即應注意調整生活型態及飲食, 減少啤酒 烈酒 內臟 海產的攝取, 使血尿酸值小於正常值 7.0 mg/dl 以下 ; 而已經罹患痛風之患者, 一般建議曾急性痛風性關節炎發作者, 宜開始接受長期的藥物治療, 這樣一來既可使痛風不會再發作, 更可避免痛風併發症的產生 當由醫師與患者共同決定需要開始藥物治療時, 降尿酸藥物治療的目標是要使血尿酸值長期控制在 <6.0 mg/dl, 對已有痛風結石患者, 宜將血尿酸值控制在 5.0 mg/dl 以下, 以加速痛風石溶解速度, 只靠食物控制通常無法達到治療的目標 第二章 本文 第一節台灣之痛風與高尿酸血症流行病學痛風是一種常見的慢性關節炎 臨床上表現以高尿酸血症, 關節與關節週邊痛風石沉積, 間歇 反覆的急性關節炎發作為表現 [1] 流行病學報告顯示自從 1980 年代開始 [2,3], 全世界痛風的盛行率與發生率都有逐漸增加的趨勢 [4,5] 英國的痛風的盛行率在 1990 年代約為 0.95%( 男性 1.64%, 女性 0.29%)[5] 1990-1999 年英國 United Kingdom 家庭醫師研究資料庫 (UK General Practice Research Database) 報告更顯示痛風的盛行率增加到 1.4%, 男性約為女性的 3.6 倍 [6] 德國在 2000 到 2005 年報 3
告的痛風盛行率也是 1.4%, 此數據與英國大致相近 [7] 痛風的發生率就英國而言相對穩定, 約略 1991 年的每千人 1.19 人年 (per 1,000 personyears) 逐漸增加至 1994 年的每千人 1.8 人年 (per 1,000 person-years)[6] 美國的諾瑪蒂夫老化研究 (Normative Aging Study) 的報告則顯示每千人約有 2.8 人年 (per 1,000 personyears) 的痛風發生率 [4]; 此數據與美國佛蘭明罕心臟病世代研究 (Framingham Heart Study Cohort) 的每千人 2.4 人年 (per 1,000 person-years) 相近 [8] 根據 1993 至 1996 年潘文涵教授的台灣營養與健康調查 (Nutrition and Health Study in Taiwan [NAHSIT]) 報告 [9], 台灣人的平均血尿酸濃度男性約為 6.63 mg/dl, 而女性則約莫 5.62 mg/dl 高尿酸血症( 男性血尿酸濃度 >7.70 mg/dl, 女性 >6.60 mg/dl) 的盛行率在男性則約為 42.1%, 女性則約為 27.4% 較諸於世界其他的國家與種族高尿酸血症( 血尿酸濃度 >6.0 mg/dl) 的盛行率確實偏高 ( 圖一 )[10,11] 在此 NAHSIT 的報告也顯示痛風的盛行率在男性約為 3.3%, 女性則約為 1.1%[9] 同時間 1996-97 年, 周碧瑟教授在金門的痛風田野調查研究也顯示, 痛風在高尿酸血症病人中的盛行率估計大約是 1.7%[12] 這些數據均稍微高於周昌德教授 1994 年, 在台灣鄉間 近郊, 與城市三個區域所調查的痛風盛行率 ( 分別是 0.16 0.67 0.67%)[13] 陳俊宏醫師 2012 年根據台灣健保資料庫所作的推估, 痛風的盛行率約為 1.2%, 痛風病人的平均年齡約為 49.5 ± 14.8 歲,85% 為男性 [14] 就痛風的發生率而言, 男性的估計大約是每千人 3.09 人年 (per 1,000 person-years), 女性則大約是每千人 0.53 人年 (per 1,000 person-years) 男性的發生率約為女性的六倍, 女性在停經後的痛風發生率則略為增加至每千人 1.29 人年 (per 1,000 person-years) 最近 NAHSIT 的報告 [4], 又比較 1993-1996 與 2005-2008 兩個年代台灣高尿酸血症與痛風的盛行率, 發現男性的高尿酸血症盛行率從之前的 25.3% 降低至 22.0%, 女性的高尿酸血症盛行率也從之前的 16.7% 降低至 9.7%(p 均 <0.0001) 但是在病人的自我報告痛風 4 圖一 我國高尿酸血症的盛行率與各國盛行率之比較 [9,10,65-67]
(self-reported gout) 盛行率方面, 男性則從 4.74% 增加至 8.21%, 女性也從 2.19% 增加至 2.33% (p 均 <0.0001) 高尿酸血症是造成痛風的最主要危險因子 美國的諾瑪蒂夫老化研究 (Normative Aging Study) 就曾報告血尿酸與痛風盛行率之間的關係 [4]: 當血尿酸濃度 <7.0 mg/dl, 痛風的盛行率約為 0.1%; 當血尿酸濃度增至 7.0-8.9 mg/dl, 痛風的盛行率則約增加至 0.5%; 當血尿酸濃度增至 9.0 mg/dl, 痛風的盛行率則約增加至 4.9% 再者, 根據英國與德國的回溯性研究報告顯示, 以血尿酸濃度 <6.0 mg/dl 做基準, 當血尿酸濃度為 6.0-7.0 mg/dl, 則痛風復發的相對危險性約 1.33; 當血尿酸濃度增至 7.0-8.0 mg/dl, 痛風復發的相對危險性則約增加至 1.49; 當血尿酸濃度為 8.0-9.0 mg/dl, 則痛風復發的相對危險性又增加至 1.71; 當血尿酸濃度 9.0 mg/dl, 則痛風復發的相對危險性則約增加至 2.15[7] 急性痛風發作的誘發因子包括最近大量飲酒 ( 尤其是啤酒或是高酒精濃度烈酒的攝取 ), 動物性高嘌呤飲食如紅肉 海產的攝取, 急性創傷 手術 利尿劑使用 以及體重增加有關 [15] 但是過去痛風的報告都以男性痛風為主, 有關女性發生痛風的情形則較少描述 [16] 根據台灣健保資料庫所做的分析, 不同性別間痛風發生的危險因子有一點差異 ( 表一 ) [14] 經多變項因子校正後, 高尿酸血症相關痛風的風險比 (Hazard ratio) 在男性為 9.65 (95% 信賴區間 8.53-10.9), 之後依次為高血壓的 1.32(95% 信賴區間 1.17-1.48), 肥胖的 1.30(95% 信賴區間 1.15-1.47), 以及高血脂的 1.12(95% 信賴區間 0.99-1.26); 女性的痛風風險比 (Hazard ratio) 則依次為高尿酸血症的 9.28(95% 信賴區間 7.00-12.3), 肥胖的 2.15 (95% 信賴區間 1.67-2.76), 高血脂的 1.70(95% 信賴區間 1.32-2.19) 與高血壓的 1.34 (95% 信賴區間 1.02-1.77) 近年來高尿酸血症與痛風盛行率的增加, 可能與近數十年來肥胖與代謝症候群的增加有關 [7] 美國第三次全國健康與營養調查(Third National Health and Nutrition Examination Survey [NHANES III]) 報告顯示高尿酸血症與痛風的病人當中, 代謝症候群的盛行率顯著地升高 [17,18] 雖然高尿酸血症是造成痛風的最主要危險因子, 但是臨床上觀察, 具有高尿酸血症的病人僅有十分之一會發展出痛風性關節炎 [19,20] 同時病人在急性痛風發作時, 血尿酸也不一定升高 所以除了高尿酸血症以外, 可能有其他的代謝因子參與而誘發急性痛風的發作 最近 2013 年台灣的一篇報告顯示高尿酸血症如果合併某些代謝異常的共病症, 如高血 表一 不同危險因子造成台灣民眾發生痛風的風險比 (hazard ratio) [14] Sex (n/n) Men (1,341/60,181) Women (265/72,375) Post-menopause (213/22,783) person-years 436,852.7 P-Y 531,625.3 P-Y 165,382.0 P-Y Incidence 3.09 x 10-3 PYs 0.53 x 10-3 PYs 1.29 x 10-3 PYs HR (95% CI) Age-adjusted Multi-adjusted Age-adjusted Multi-adjusted Age-adjusted Multi-adjusted Age - 1.03 (1.02-1.03) - 1.05 (1.04-1.06) - 1.02 (1.00-1.04) Hyperuricemia 10.5 (9.27-11.8) 9.65 (8.53-10.9) 12.3 (9.33-16.1) 9.28 (7.00-12.3) 9.54 (7.08-12.9) 7.68 (5.66-10.4) Obesity 2.13 (1.88-2.40) 1.30 (1.15-1.47) 3.70 (2.90-4.72) 2.15 (1.67-2.76) 2.97 (2.27-3.88) 1.90 (1.44-2.51) Hypertension 1.74 (1.54-1.95) 1.32 (1.17-1.48) 2.11 (1.59-2.79) 1.34 (1.02-1.77) 1.76 (1.32-2.34) 1.23 (0.92-1.65) Hyperlipidemia 1.81 (1.61-2.04) 1.12 (0.99-1.26) 2.77 (2.16-3.57) 1.70 (1.32-2.19) 2.36 (1.80-3.09) 1.59 (1.20-2.09) Diabetes 0.82 (0.65-1.03) 0.85 (0.67-1.07) 1.62 (1.17-2.24) 1.15 (0.83-1.60) 1.65 (1.18-2.30) 1.27 (0.90-1.79) 5
壓 肥胖 以及高血脂等, 發生痛風的危險性, 與代謝症候群的危險因子有關 [21] 尤其是肥胖 ( 包括過重與一般性肥胖 ) 的女性病人, 以及具有高三酸甘油酯的男性病人, 雖然血尿酸值仍在正常值以下, 但是仍然有痛風發作的可能 ( 圖二 三 四 ) 至於代謝症候群則與全世界一致, 此症候群在男性病人仍然是預測痛風發作的良好指標 倘若男性病人具有代謝症候群的話, 縱使血尿酸值仍在正常值以下, 痛風關節炎發作的風險仍然較高, 約增加 37% 的風險比 (Hazard ratio: 1.37; 95% 信賴區間 1.01-1.87) 但是代謝症候群在女性病人的指標意義較不明顯 [21] 陳俊宏醫師在 2009 年曾報告高尿酸血症為全死亡 (all-cause) 與心血管 (CVD) 死亡的獨立危險因子 隨著血尿酸的增加, 全死亡與心血管死亡成劑量效應的增加趨勢 ( 圖五 圖六 ), 這關係在心血管死亡上尤為明顯 [20,21] 血尿酸濃度每增加 1.0 mg/dl, 全死亡與心血管死亡的危險性約增加 8-13% 這篇報告與美國克里夫蘭的世代研究報告一致, 都顯示在高風險病人如高血壓與糖尿病的病人可以使用血尿酸濃度來預測死亡風險, 這現象在女性身上尤其明顯 [23] 這些報告也提供一個檢視無症狀高尿酸血症與全死亡或心血管死亡之間的關聯性 最近溫啟邦教授使用大型美兆健診資料庫作分析, 也再次確認高尿酸血症為全死亡或心血管死亡的獨立危險因子 這個現象甚至在低危險的族群人口中, 尤其是不具任何代謝症候群成分, 而僅有高尿酸血症的病人, 尿酸值仍然是一個獨立危險因子 ( 表二 )[23] 6 圖二 高尿酸血症與一般性肥胖 (general obesity) 中央型肥胖 (central obesity) 或體重過重對於男性痛風發作風險的合併影響 [21] n= 痛風發作人數 ;N= 總人數
圖三 高尿酸血症與一般性肥胖 中央型肥胖或體重過重對於女性痛風發作風險的合併影響 [21] n= 痛風發作人數 ;N= 總人數 圖四 不同血尿酸值者若合併有高三酸甘油酯血症及一般性肥胖, 對於痛風發作風險的影響 [21] 根據這些台灣的研究報告, 血尿酸在預測全死亡或心血管的死亡上呈一個 U 字型的劑量效應關係 [22,24] 以血尿酸濃度 5.0-5.9 mg/dl 做基準, 當血尿酸濃度為 >7.0 mg/dl, 則增加 10% 全死亡,38% 心血管死亡的危險性 ; 當血尿酸濃度 9.0 mg/dl, 則全死亡的危險性增 7
圖五 血尿酸濃度與全死亡的相關性 [22] 圖六 血尿酸濃度與心血管死亡的相關性 [22] 8 加 38%, 心血管死亡的危險性則增加 82% 反之, 在族群人口中, 倘若沒有明顯的心血管危險因子, 或是沒有任何前心血管危險因子, 高尿酸血症的病人, 其血尿酸濃度 >8.0 mg/ dl, 發生全死亡及心血管死亡的風險比 (Hazard ratio) 分別是 1.39 與 2.38 而當血尿酸濃度 >9.0 mg/dl 時, 其發生全死亡及心血管死亡的風險比 (Hazard ratio) 則分別是 1.37 與 3.37 但是相對於目前仍具有爭議的無症狀高尿酸血症的風險 [25], 痛風與全死亡或心血
表二 血尿酸值對於全死因致死率 (all-cause mortality) 及心血管疾病致死率 (CVD mortality) 的影響 [23] 全死因致死率 心血管疾病致死率 尿酸 (mg\dl) 總人數 死亡人數 HR a (95% CI) HR b (95% CI) HR c (95% CI) 死亡人數 HR a (95% CI) HR b (95% CI) Total 484,568 16,246 3,265 0.1-3.9 40,401 982 1.17 d 1.13 d 1.17 d 151 1.03 1.12 (1.09-1.26) (1.03-1.24) (1.06-1.29) (0.86-1.23) (0.87-1.43) 4.0-4.9 96,909 2,318 1.02 1.04 1.06 341 0.86 d 0.98 (0.97-1.08) (0.97-1.11) (0.99-1.14) (0.75-0.98) (0.82-1.18) 5.0-5.9 117,970 3,554 1.00 ( 參考值 ) 6.0-6.9 102,231 3,671 1.04 (0.99-1.09) 7.0-7.9 68,470 2,629 1.06 d (1.01-1.12) 8.0-8.9 35,052 1,589 1.20 d (1.13-1.27) 9.0 23,535 1,503 1.54 d (1.45-1.64) 7.0 127,057 5,721 1.20 d (1.15-1.25) 每增加 1.0 mg\dl 1.06 d (1.05-1.07) CI: 信賴區間 HR: 風險比 (hazard ratio) a 依年齡調整 1.00 ( 參考值 ) 1.05 (0.99-1.12) 1.06 (0.99-1.14) 1.22 d (1.13-1.33) 1.58 d (1.45-1.71) 1.21 d (1.14-1.28) 1.06 d (1.05-1.08) 1.00 ( 參考值 ) 1.02 (0.96-1.08) 1.01 (0.94-1.08) 1.11 d (1.02-1.20) 1.35 d (1.24-1.47) 1.10 d (1.04-1.17) 1.03 d (1.02-1.05) 618 1.00 ( 參考值 ) 764 1.27 d (1.14-1.41) 620 1.48 d (1.32-1.66) 368 1.64 d (1.44-1.87) 403 2.39 d (2.10-2.71) 1,391 1.71 d (1.55-1.88) 1.18 d (1.16-1.21) 1.00 ( 參考值 ) 1.23 d (1.06-1.43) 1.29 d (1.11-1.51) 1.51 d (1.27-1.80) 2.13 d (1.79-2.53) 1.52 d (1.33-1.74) 1.14 d (1.11-1.17) HR c (95% CI) 1.17 (0.92-1.50) 1.02 (0.85-1.22) 1.00 ( 參考值 ) 1.20 d (1.03-1.39) 1.23 d (1.05-1.44) 1.36 d (1.14-1.63) 1.82 d (1.52-2.18) 1.38 d (1.20-1.58) 1.10 d (1.07-1.14) b 依年齡 吸菸與否 教育程度 血壓 空腹血糖 身體質量指數 (BMI) 三酸甘油酯 總膽固醇 心血管疾病史 高血壓病史 糖尿病史 不同診所差異 c 依年齡 吸菸與否 教育程度 血壓 空腹血糖 身體質量指數 (BMI) 三酸甘油酯 總膽固醇 心血管疾病史 高血壓病史 糖尿病史 不同診所差異 尿蛋白及腎絲球過濾率 (GFR) d P<0.05 管死亡之間的風險關係則較為確立 [26,27] 美國佛蘭明罕心臟病世代研究(Framingham Heart Study Cohort) 報告指出, 男性痛風病人約增加 60% 發生冠心病, 和增加兩倍發生心絞痛的風險 [19] 美國國家醫療照護專家追蹤研究(National Health Professional Follow-up Study) 報告顯示, 男性痛風病人相對於非痛風病人發生全死亡或心血管死亡的風險分別增加 28% 與 55% 此風險比(Hazard ratio) 與慢性冠心症的患者相近 [28] 類似的研究結果也出現在美國的 MRFIT 研究 (Multiple Risk Factor Intervention Trial)[29] 這些研究顯示緩慢而持續的關節發炎促使血管硬化, 與血栓形成, 從而加速心血管疾病的風險 [25,30] 但是痛風與全死亡或心血管死亡之間的風險關係, 也有可能間接來自痛風與代謝症候群的關係 因為痛風與肥胖, 高血壓, 以及糖尿病之間有強烈的相關性 [17] 所以最近在台灣的報告, 指出五十歲以上非糖尿病的痛風病人與其後所發生的心血管死亡之間的相對危險性 (relative risk) 為 1.71(95% 信賴區間 1.66-1.75), 但其風險經過代謝因子的校正後降低為 1.10(95% 信賴區間 1.07-1.13) [31] 這些估計較諸之前其他國家的計算是低很多 這偏低的估計也有可能來自痛風病人同時服用如 allopurinol 等降尿酸藥物所致 日本的觀察性研究顯示, 使用降尿酸藥物將尿酸降至 6 mg/dl 以下, 可以預防 86% 的痛風復發 [32] 這份報告也與 2006 年歐洲風濕病聯盟 (EULAR) 對於痛風治療的建議 [27] 以及 2012 年美國風濕病學院 (American College of Rheumatology) 的痛風治療指引 [26,33] 若 9
合符節 美國 2008 年對於發生早發性高血壓與高尿酸血症的青少年所進行 allopurinol 的雙盲研究 [34], 指出 allopurinol 具有降低這群青少年血壓與血尿酸的療效 同時期依據美國榮民患有高尿酸血症的病人使用 allopurinol 的觀察性研究, 也顯示使用藥物降低血尿酸對於降低全死亡率的益處 [30] 因此治療慢性痛風的方式中, 使用降尿酸藥物固然已為全世界所接受, 但是未來是否也可以使用降尿酸藥物在無症狀高尿酸血症的病人身上, 以降低全死亡或心血管死亡之間的風險, 目前仍需要更多的證據以作進一步的評估與審視 [25] 第二節高尿酸血症的定義及原因高尿酸血症是指血尿酸濃度過高, 其定義分為二種, 其一是流行病學上的定義, 指血尿酸濃度比正常人的平均值加上二個標準差還高, 便稱為高尿酸血症 另一則是生理化學上的定義, 是指血中每 100 毫升血液中的尿酸濃度大於 6.8 或 7.0 毫克 (mg/dl)[35] 正確地來說, 血尿酸濃度的正常值, 應以生理化學的定義為準, 即成年人血尿酸值 >7.0 mg/dl 為高尿酸血症 人體內的血尿酸濃度會受種族 遺傳基因 性別 年齡的影響, 如女性在停經前血尿酸值較男性低, 但停經後血尿酸會增高 ; 青春期前血尿酸濃度較低, 但青春期後則會逐漸增加到接近成年人水準 血尿酸值在 7.0-8.0 mg/dl 之間者, 即需注意檢查是否合併有痛風 高血壓 糖尿病 肥胖 代謝症候群等相關疾病 ( 表三 ) 研究報告顯示健康男性血尿酸值 >9.0 mg/dl 時痛風性關節炎的每年發生率為 4.9%, 血尿酸值為 7.0-8.9 mg/dl 時, 其每年發生率為 0.5% 血尿酸值低於 7.0 mg/dl 時, 其每年 表三 高尿酸血症及痛風的相關疾病和原因 1. 相關疾病 (Clinical Disorders) 肥胖 Obesity 慢性腎衰竭 Chronic renal failure 鉛中毒 Lead poisoning 惡性腫瘤 Malignant diseases 溶血性疾病 Hemolytic disorders 鐮狀細胞性貧血 Sickle cell anemia 乾癬 Psoriasis 高血壓 Hypertension 代謝症候群 Metabolic syndrome 組織缺氧 Tissue hypoxia 限鹽 Salt restriction 脫水 Dehydration 飢餓 Starvation 乳酸酸血症 Lactic acidosis 糖尿病酮酸血症 Diabetic ketosis 副甲狀腺機能亢進 Hyperparathyroidism 甲狀腺機能低下 Hypothyroidism 尿崩症 Diabetes insipidus 妊娠毒血症 Toxemia of pregnancy 家族性幼年型高尿酸腎病變 Familial juvenile hyperuricemic nephropathy 多囊性腎疾病 Polycystic kidney disease 髓質囊狀腎臟病 Medullary cystic kidney disease 慢性鈹疾病 Chronic beryllium disease 類肉瘤病 Sarcoidosis 巴特氏症候群 Bartter s syndrome 唐氏症 Down syndrome 次黃嘌呤 - 鳥嘌呤磷醣基核甘轉換酵素缺乏 HGPRT deficiency 磷酸核糖焦磷酸合成酶活性過強 PPRP synthetase overactivity 糖原貯積病第 I, III, V, VII 型 Glycogenosis I, III, V, VII 2. 藥物及飲食 (Drug and Diet) Low dose aspirin ( 低劑量阿斯匹靈 <2 gm/day) Diuretics ( 利尿劑 thiazide and loop diuretics) Pyrazinamide ( 抗結核藥物 ) Ethambutol ( 抗結核藥物 ) Cyclosporine ( 環孢靈 ) Nicotinic acid ( 菸鹼酸 ) Levodopa ( 治療帕金森氏症藥物 ) Cytotoxic drugs ( 化學治療藥物 ) Laxative abuse (alkalosis) ( 不當使用瀉藥 ) Methoxyflurane ( 麻醉藥 ) Tacrolimus ( 免疫抑制藥物 ) Fructose ( 果糖 ) Pancreatic extracts ( 胰臟萃取物 ) Excessive purine intake: meat, seafood ( 肉類 海產 ) High alcohol (ethanol) intake: beer, spirit ( 啤酒 烈酒 ) 10
發生率為 0.1% [36] 尿酸是嘌呤 (purine, 也有人譯為普林 ) 在人體代謝的最終產物, 體內嘌呤在肝臟代謝形成尿酸, 最後由腎臟將尿酸隨尿液排出體外, 如果體內產生過多或腎臟排泄尿酸不良, 就會形成尿酸過高 一般而言, 體內尿酸約三分之一是來自飲食, 另三分之二是來自身體內細胞核的核酸嘌呤新陳代謝產生 正常人每日製造的尿酸約有三分之二由腎臟經尿液排出, 約三分之一由腸內細菌分解代謝隨大腸糞便排出, 另有極少量由汗腺排泄 但腎臟功能異常的病人由腎臟排泄的量減少, 相對地由腸道排泄的量會增加 正常人每天約產生 750 mg 尿酸, 其中 500 mg 由腎臟排出, 其餘則經由大腸排出體外, 因此可能造成高尿酸血症的原因如下 :(1) 攝取富含嘌呤或導致嘌呤合成增加的食物,(2) 尿酸的合成代謝增加 ( 內源性過量產生 ),(3) 腎臟排泄尿酸受阻 第三節痛風的臨床表現及自然病程分期痛風好發於成年高尿酸血症男性及停經後的高尿酸血症女性 痛風性關節炎好發於下肢關節, 痛風發作時, 會在關節處局部發生紅腫熱痛的現象, 嚴重者可能會痛得無法走路 無法穿鞋 急性痛風經常在半夜或一大早突然發作, 有超過 50% 的病人首次發作的部位在腳大拇趾的第一個關節 ( 第一蹠趾間關節 ), 有時候也發生在其他關節, 如足背 踝 膝 腕 肘 手指間關節都可能發生, 而發病的前幾年通常是單側發作, 隨著病情的進展之後可能同時侵犯多處關節, 演變至上肢或較近端大關節的發作, 甚至合併發燒, 這一種突然的發作通常在數天到兩週內自然消退, 可能一年發生數次, 也可能幾年才發生一次 發病的誘因可因飲酒 受傷 手術 某些藥物 攝食過多高嘌呤食物 疲勞 或感染等而誘發 急性痛風關節炎常發生於半夜, 發作部位出現紅腫熱痛, 輕微的碰觸都可能會加劇疼痛, 少數患者甚至會合併發燒及畏寒的現象, 但合併發燒畏寒時, 須由醫師診查排除合併致命性感染或潛在疾病的可能 [37,38] 痛風的臨床病程可以分為四個階段 : 一 無症狀高尿酸血症 ( a s y m p t o m a t i c hyperuricemia), 二 急性痛風關節炎 (acute gouty arthritis), 三 不發作間歇期 (interval gout), 四 慢性痛風石關節炎 (chronic tophaceous gout) 一 無症狀高尿酸血症 : 無症狀的高尿酸血症通常需要經過一段很長的時間, 才會有第一次痛風關節炎的發作, 這時候才開始稱之為痛風 (gout), 從未有過關節炎發作者, 只能稱為無症狀的高尿酸血症 (asymptomatic hyperuricemia), 它只是一種生化上的異常, 注意飲食及找出原因並矯正, 血尿酸值可能會回復正常 此時雖然血尿酸濃度高, 但臨床上無症狀, 必須由驗血才能發現 罹患痛風的機率, 隨著血液中尿酸濃度的升高而顯著增加, 但大多數患者 (90%) 可能終身都不會痛風發作 除血尿酸濃度高以外, 包括肥胖 體重增加 喝酒 高血壓 使用利尿劑 腎功能不全 或家族成員中曾有罹患痛風的人也是發生痛風的高危險群 [12,39], 近年以臺灣族群進行的研究顯示基因因素亦為重要因素, 腫瘤壞死因子 (TNF) 基因 863C/A 多型性及位於染色體 4q21 的第二環 GMP- 依賴性蛋白激酶基因與臺灣族群罹患痛風疾病相關 [40,41], 而轉型生長因子 -β1 11
(TGF-β1) 基因 869T/C 和 -509C/T 多型性與痛風石性痛風也呈現顯著相關 [42], 而臺灣原住民位於染色體 4q25 的標記 D4S2623 及單胺氧化酶之多型性, 亦與痛風的發作相關 [43,44] 無症狀的高尿酸血症不需要立即使用降尿酸藥物治療, 但並非不需處理, 必須找出潛在引起高尿酸血症的原因 ( 表三 ), 並控制相關問題和疾病, 尤其是未來可能惡化心血管風險的代謝症候群相關疾病 藥物如阿斯匹靈 酒精 利尿劑 抗結核藥 環孢靈 [45] 化學治療藥物等會導致血尿酸增加, 少數使用者可能會引起高尿酸血症而造成痛風 二 急性痛風性關節炎 : 急性痛風關節炎, 大多為單一關節炎, 主要的臨床表現為劇烈的關節疼痛, 關節及周圍軟組織出現紅腫熱痛, 但後期可多處關節炎發作和發燒 大多是突然發作, 常在午夜或凌晨發病, 有些病人可有輕微疼痛或刺痛為痛風發作的先兆 急性痛風性關節炎主要侵犯下肢遠端關節, 初發時受累的關節的頻率依序為第一腳趾關節 足背 踝 膝 腕 指和肘關節等 若尿酸值持續過高, 經過一段時間產生結晶在關節腔內沈積, 急性痛風關節炎的發作頻率大多會隨時間增加 三 不發作間歇期 : 是指兩次急性痛風關節炎中間的無症狀不痛期間 急性發作後可自然緩解, 不留任何後遺症而完全復原, 此時無症狀期稱為不發作間歇期 病人在第一次和第二次急性痛風發作之間隔時間差異頗大, 根據研究, 約有 4% 的患者終身不再發作, 大約 61% 在一年內復發, 約 88% 在兩年內復發, 有些人甚至十幾年後再復發, 但一半以上患者發作的頻率會隨時間經過而增加, 不發作間歇的期間越來越短 [46] 四 慢性痛風石關節炎 : 長期沒有治療時, 痛風病人的皮下及關節產生痛風石結節 ( 尿酸鈉鹽的結晶 ), 有些會導致關節變形, 嚴重時關節喪失活動能力 痛風石結節可能在耳朵 皮下 關節 軟骨等發生, 也可能沉積在腎臟影響腎臟的功能 此種痛風石出現距離第一次痛風發作的時間自 3 至 42 年不等, 平均為 11.6 年, 但近年來報告已經縮短到平均 5 到 6 年即出現痛風石 痛風石雖然可能不痛, 卻會引起該關節的僵硬 破壞 變形 切記要注意痛風石如果有表面傷口破皮, 應注意有無細菌感染馬上就醫, 以避免細菌擴散造成敗血症引起死亡或感染蔓延造成須截肢的併發後遺症 [37,38] 12 第四節痛風的診斷正確的診斷與適當的治療是極為重要的 痛風關節炎較常見於大腳趾關節 踝關節或膝關節等 高尿酸血症是痛風最重要的生化基礎, 但並不是痛風的同義詞 根據研究, 高尿酸血症者終其一生, 大約只有 10% 的人會發展成為痛風 確定診斷是在急性發作時抽取關節液, 在顯微鏡下發現有被嗜中性白血球吞噬的針狀尿酸鈉鹽結晶, 它在偏光顯微鏡下呈現負雙折光 目前大多採用 1977 年美國風濕病學會制訂的急性痛風診斷分類標準 [47], 該標準強調關節液和痛風石結節中找到尿酸鈉鹽結晶, 作為確定的痛風診斷 但當抽取關節液困難或不便時, 根據 12 項臨床特徵中具備 6 項或 6 項以上, 並排除其它疾病後, 也能
優先考慮痛風的診斷 該診斷標準如下 : 表四 1977 美國風濕病醫學會痛風的診斷標準 [15] 一 關節液中有尿酸鈉鹽結晶, 二 用化 A. 尿酸鈉鹽結晶存在於關節液中學方法或偏光顯微鏡證實痛風石結節中含 B. 痛風石結節抽取液中證實有尿酸鈉鹽結晶尿酸鈉鹽結晶, 三 符合以下 12 項臨床條 C. 以下的 12 個項目中有 6 個或 6 個項目以上 (1) 反覆發作病史 ( 超過 1 次以上急性關節炎的發件中 6 項或 6 項以上者 :(1) 超過 1 次以上急作 ) 性關節炎發作的病史 ;(2) 發炎症狀在 1 天 (2) 一天以內達到極限的發炎症狀內達到高峰 ;(3) 急性單側關節炎發作 ;(4) (3) 急性單關節炎 (4) 關節發紅現象患部關節皮膚呈暗紅或紅色 ;(5) 第一蹠趾 (5) 第一近端腳趾關節的疼痛或腫脹關節疼痛或腫脹 ;(6) 單側第一蹠趾關節炎 (6) 單側的第一近端腳趾關節炎發作發作 ;(7) 單側跗骨 ( 足踝 ) 關節炎發作 ; (7) 單側的跗骨 ( 足踝 ) 關節炎發作 (8) 疑似痛風石結節 (8) 有可疑的痛風石結節 ;(9) 高尿酸血 (9) 高尿酸血症症 ;(10) X 光片檢查顯示不對稱關節腫脹 ; (10) X 光片呈現非對稱性的關節腫脹 (11) X 光片檢查顯示不伴侵蝕的骨皮質下囊 (11) X 光片呈現皮下囊腫而無侵蝕腫 ;(12) 關節炎發作時抽取之關節液微生 (12) 無菌性關節液物培養呈無菌狀態 符合以上一 二 三中任何一個條件者 ( 表四 ), 可考慮診斷為痛風, 但須排除其它關節疾病 痛風最確定的診斷是從關節液中看到白血球吞噬尿酸結晶現象的存在, 但因在痛風發作的不同時期會影響尿酸結晶的存在而使關節液鏡檢成為診斷敏感性低但診斷專一性極高的檢驗方式 但即使關節液之偏光顯微鏡鏡檢出現尿酸結晶, 仍須考量痛風和敗血性關節炎可能合併出現的可能, 因此若臨床上懷疑病患關節具有細菌感染, 仍應進行關節液的革蘭氏染色檢查以及細菌培養 也因為如此, 痛風的診斷有時候仍必須綜合臨床經驗 過去病史 發作病史 臨床表徵 病程及誘發因子等來做鑑別診斷 另外要注意的是, 血中的尿酸值絕對不宜做為診斷的唯一依據, 約有 30% 發生急性痛風關節炎之病患, 關節炎發作時血尿酸值是 <7.0 mg/dl, 但只要繼續抽血追蹤, 血尿酸值都會超過 8.0 mg/dl[48], 相反地, 高尿酸血症患者亦有相當比例在長期追蹤中都未發生痛風發作 影像學的檢查在痛風診斷的角色正快速進展中, 部分慢性期痛風患者在一般 X 光檢查即可能發現在病變關節的骨緣有被痛風石侵蝕的缺損, 或腎臟超音波可發現腎臟在皮髓質交界的髓質部超音波出現痛風性腎病變, 但這些影像學發現都只能增加診斷的可能性而非用以確定診斷, 傳統影像學檢查對排除痛風關節炎以外的關節病變成因的角色或許更形重要 關節高解析度超音波 關節電腦斷層掃描 關節雙能電腦斷層 (dual-energy CT) 可幫助診斷痛風, 當尿酸沉積在關節部位, 關節高解析度超音波可觀察到 double contour sign 的現象 另外高解析度超音波亦可偵測身體檢查不易發現的痛風石 關節超音波也對提高關節液抽取的成功率有很好的幫助 然而 double contour sign 本身並不足以作為使用降尿酸治療之依據, 其他結晶性關節病變或代謝性疾病也可能出現類似表現 對臨床未曾出現症狀的關節出現超音波下符合痛風關節炎表現等發現時, 仍應積極進行關節病變成因之鑑 13
別診斷 至目前為止沒有單一的影像學檢查可以用以確定診斷痛風, 只能用於排除其他診斷或作為診斷參考, 因此在足夠的臨床懷疑下對病患進行合適的影像學檢查或追蹤檢查都是獲得正確診斷的合理臨床作為 第五節鑑別診斷尿酸和痛風雖然有密切的關係, 但血尿酸高合併關節炎不見得就是痛風, 而且急性發作時約有三分之一患者血尿酸值是在正常範圍內, 因此要正確地診斷痛風, 是要根據詳細的病史 理學檢查並配合血液生化檢查來做正確的判斷及鑑別診斷 確定痛風必須靠關節液檢查, 在偏光顯微鏡下看到針狀尿酸結晶為白血球吞噬可確定診斷 蜂窩性組織炎 反覆性風濕症 ( 遊走性關節炎 ) 細菌性關節炎 假性痛風 血清陰性脊椎關節炎 類風濕性關節炎 退化性關節炎等都應當列入鑑別診斷 關節炎的病因很多, 發作時卻有共同的症狀, 也就是紅 腫 熱 或痛, 因此鑑別診斷很重要, 即使是典型的痛風發作, 有時候還是需要醫師來做鑑別診斷, 尤其是治療效果不理想或是病程過久不符合常態的時候 若在診斷上有疑問, 應該轉診風濕病專科醫師作進一步的確定診斷 蜂窩性組織炎是真皮及皮下組織被細菌感染的疾病 反覆性風濕症在台灣很常見, 因其症狀酷似痛風, 是最常被誤診為痛風的一種關節炎, 少數反覆性風濕症可能是類風濕性關節炎或紅斑性狼瘡的前兆, 須注意鑑別診斷 反覆性風濕症好發於二十到四十歲的男女性, 可能侵犯四肢任何關節或關節周圍組織, 其中以手指及腳趾 腕 膝及踝關節最常發作, 也可能侵犯足底和手掌面 大多數的細菌性關節炎是單一關節炎, 多發性的細菌性關節炎不常見, 常發生在免疫力低的病人身上 假性痛風好發於六十歲以上老人的膝 肘 肩等大關節 血清陰性脊椎關節炎包括僵直性脊椎炎 乾癬性關節炎 潰瘍性結腸炎 克隆氏症 及反應性關節炎, 特點包括薦腸關節炎 脊椎炎下背疼痛, 及週邊不對稱性的二到四個關節炎, 典型的是在下肢大關節 ( 膝 踝關節 ), 及軸心關節 ( 肩 臗關節 ) 發生腫痛, 常伴隨著肌腱骨骼附著部病變的發生 類風濕性關節炎為多發性且對稱性地侵犯多個手指關節 退化性關節炎除膝關節與手部遠端指間關節外, 有時會侵犯腳的大拇趾的第一個關節 ( 稱為 bunion), 需做鑑別診斷 14 第六節治療目的與治療計畫藥物治療又可分為急性發作期和慢性期兩大類, 兩者使用的藥物不同, 所以一定要讓病患分清楚什麼時候該服用哪類藥物 例如 : 急性疼痛時應使用消炎止痛藥物和 / 或秋水仙素, 此時使用降尿酸藥物並沒有幫助 ; 相反地來說, 在不痛的痛風間歇期和慢性期, 應該使用降尿酸藥物, 使血尿酸值持續維持在 6.0 mg/dl 以下, 可以讓痛風較不易再發作, 痛風石也應可逐漸消失 ( 表五 ) 另外應對病患進行充分的衛教, 改變生活型態, 並告知遵循醫囑以及服用藥物的益處 而且不要用其他療效未經證實之輔助療法 1. 無症狀高尿酸血症的治療對於從沒有過症狀的高尿酸血症, 基本目標是藉以發掘潛在的疾病 毒性物質作
表五 痛風及高尿酸血症的治療方針 用 或藥物副作用, 尤其是患者潛在相關的代謝症候群, 然後儘早調整生活型態或予以治療 而降尿酸藥物的投予與否則未有全球一致的定論, 需要由醫師及患者依據病患個人發展為痛風的風險因子及相關疾病 ( 如進行性慢性腎功能不全 ) 情形, 共同達成臨床決定, 除非合併有 HGPRT 酵素 (Hypoxanthine-Guanine Phosphoribosyl Transferase) 缺乏等經確定的基因異常 或血液疾病或癌症將接受化學治療 或器官移植患者使用環孢靈造成尿酸值升高, 否則通常不一定必須用藥物降低血尿酸 但仍應充份告知患者血尿酸值越高, 未來產生痛風性關節炎的危險性越高, 及即使血尿酸值持續偏高也不意謂著一定會產生痛風的正反雙面事實, 因此無併發症風險的單純無症狀高尿酸血症並非長期使用降尿酸藥物治療的適應症 但對無症狀的高尿酸血症患者, 建議每 6 個月追蹤檢驗一次血尿酸值 15
2. 急性痛風關節炎的藥物治療急性痛風關節炎通常是一種疼痛會自行好轉的關節炎, 若沒有服用消炎止痛藥物治療, 急性的疼痛通常會在一週內自行痊癒好轉, 一次發作很少超過兩星期, 但提早使用消炎止痛藥物治療可以迅速緩解疼痛 因此當發作初期有疼痛預兆時, 愈早給予消炎止痛藥物, 則止痛效果愈好, 並可減少急性痛風關節炎發作的總天數及藥物服用量, 所以病患應居家隨時準備數天消炎止痛藥物, 以備不時之需時緊急使用 另外, 急性關節疼痛時可用局部冰敷以減少部分的疼痛 治療急性痛風關節炎時, 主要使用的消炎止痛藥物有三種包括 : 非類固醇消炎止痛藥 (NSAID, nonsteroidal antiinflammatory drug) 秋水仙素 (colchicine) 類固醇(corticosteroid), 這三種藥物的選擇應依照病人是否合併其他內外科疾病而定 ( 表六 ) 至於降尿酸藥物在急性期時, 如果原來還沒有使用, 就不要用, 若原本就有使用, 則繼續使用, 且不應增減劑量 ; 因為血尿酸濃度急速變化升降時, 反而可能引發急性痛風關節炎的發作 非類固醇消炎止痛藥 (NSAID): 口服或注射非類固醇消炎止痛藥在治療急性痛風方面有很好的效果, 如果沒有使用上的相對禁忌, 它常被當作第一線藥物使用 NSAID( 包含 COX-2 抑制劑 ) 在以下情況應小心使用 : 高血壓, 心血管疾病, 嚴重腎功能不全, 消化性潰瘍, 及其他共病症 且應使用在急性痛風關節炎治療時所建議之最高劑量, 並持續使用到症狀緩解, 但對於老年人及腎功能受損的病人使用要特別小心, 要減低劑量及監測腎功能 非類固醇消炎止痛藥物的可能副作用是腸胃不適 胃或十二指腸潰瘍伴隨出血或穿孔 週邊水腫 頭痛 頭暈 凝血功能不全 或皮疹藥物過敏等 若有消化道潰瘍病史者, 則可考慮使用新一代的選擇性抑制環氧化酶 (COX-2) 非類固醇消炎止痛藥, 也有相同的止痛效果, 但對合併有急性心血管阻塞 16 表六 急性痛風關節炎的藥物治療 藥物名稱 建議參考劑量 臨床上考慮 非類固醇消炎止痛藥 (NSAID) 秋水仙素 (Colchicine) 類固醇 (Corticosteroid) 1. 非選擇性環氧化酶抑制劑 (Non-selective COX-2 inhibitors) 2. 選擇性環氧化酶抑制劑 (Selective COX-2 inhibitors) 1. 秋水仙素 0.5 mg 早晚一粒, 同時合併使用非類固醇消炎止痛藥 2. 有發作預感時, 在前 3 個小時每小時給 0.5 mg, 總共 3 到 6 粒為止 3. 70 歲以上老人之建議劑量皆需要減半使用 1. Prednisolone 口服 20-40 mg/day 2. 大單一關節內注射類固醇 (triamcinolone acetonide 40 mg) 3. Methylprednisolone i.v. 100-150 mg/day for 1-2 days 4. ACTH 40 USP units i.m. or i.v. 1. 急性發作時, 愈早給消炎止痛藥物, 效果愈好 2. 以下狀況應小心使用 : 高血壓, 心血管疾病, 嚴重腎功能不全, 消化性潰瘍, 及其他共病症 1. 急性關節炎發作時, 若發作超過 48 小時才使用秋水仙素, 效果較差 2. 預防發作的劑量 CCr >50: 1# qd-bid CCr 35-49: 1# qd CCr 10-34: 1# q2-3d CCr <10 避免使用病人不能使用非類固醇消炎止痛藥和秋水仙素時, 改用類固醇來作為短期急性治療是一個選擇 COX: Cyclooxygenase, ACTH: Adrenocorticotropic hormone, i.m.: 肌肉注射, i.v.: 靜脈注射, CCr: creatinine clearance ml/ min 肌酸酐清除率
疾病患者應衡量使用非類固醇消炎止痛藥之利弊 一般使用非類固醇消炎止痛藥物在 24 小時內, 疼痛症狀可以很明顯地獲得減緩 秋水仙素 (colchicine): 秋水仙素在治療痛風上是一個古老的藥物, 在治療過程中有時會出現胃腸道副作用, 例如噁心 腹瀉等, 因而限制了秋水仙素的使用 對於急性痛風的患者而言, 秋水仙素愈早使用愈好, 在關節炎發作後的前 24-48 小時內儘快使用秋水仙素來治療, 其中有 2/3 的病人在數小時後可獲得緩解 許多臨床醫師使用秋水仙素 0.5 mg 早晚各一粒加上非類固醇消炎止痛藥物合併使用 ; 或有發作預感時, 在前 3 個小時每小時給 0.5 mg, 總共 3 到 6 粒為止 也有醫師給予低劑量秋水仙素 (1.0 mg), 一小時後再給予 0.5 mg, 之後每 12 小時持續用藥 ( 最多一天三次 ), 直到症狀緩解 急性痛風發作時, 秋水仙素不宜作為單一藥物使用, 除非病人為急性發作有預感時, 才可單一使用 合併痛風石的慢性痛風患者在使用降尿酸藥物時, 為了預防反覆發作, 可長期併用低劑量秋水仙素 避免使用秋水仙素靜脈注射 ( 目前國內無此製劑 ), 因為它可能會產生危險致死的併發症, 其它罕見的副作用包括骨髓抑制, 尤其是對於患有腎功能不全及肝膽道閉塞的病人 目前, 臨床上秋水仙素常被用來作為預防急性痛風復發 [49], 在使用降尿酸藥物治療的前三到六個月可以合併使用低劑量口服秋水仙素 ( 腎功能正常的病人一天一次或兩次, 每次一顆 0.5 mg), 對於腎功能不全的病人及老年人秋水仙素的使用需降低劑量, 並注意極少數可能的副作用包括肌肉病變及骨髓抑制 Colchicine 與 P-glycoprotein 抑制劑或 CYP3A4 抑制劑 (clarithromycin erythromycin cyclosporine ketoconazole fluconazole verapamil 萄柚汁 atorvastatin disulfiram pravastatin simvastatin) 合併使用時, 副作用產生的機會可能會較高 類固醇 (corticosteroid): 若病人不能使用非類固醇消炎止痛藥和秋水仙素時, 改用類固醇來作為急性短期治療是一個選擇 若只有一至二個大關節發作, 可在關節內注射類固醇以緩解關節發作, 特別是不適合或不能使用非類固醇消炎止痛藥和秋水仙素的時候 在關節內注射類固醇前先抽取出關節液可減輕疼痛及腫脹 口服 prednisolone 通常的劑量可從每日總量 20-30 毫克開始, 分次使用, 症狀緩解即開始減低劑量, 使用天數依醫師臨床判斷, 儘量以不超過七天為原則 無法口服藥物的病人有需要時可使用靜脈注射類固醇, 但應小心停用後疼痛再度反彈出現 糖尿病的患者在使用類固醇時必須小心 3. 不發作間歇期及慢性痛風石關節炎的治療目前痛風患者高尿酸血症的治療是以藥物為主 至於痛風患者何時該開始長期使用降尿酸藥物作為終身之預防治療, 尚未有一致的共識 [3,27,50-53], 有些專家建議在早期即開始採取藥物治療 [51,53], 建議有高尿酸血症, 且曾急性發作痛風關節炎者, 宜開始接受長期降尿酸藥物治療, 以預防急性關節炎發作和併發症 不過有些專家支持若每年超過 2 次以上之急性痛風發作, 才考慮使用降尿酸藥物作為預防療法 [52] 一般建議終身長期服用, 降尿酸藥物治療的目標應設在控制血尿酸值 <6.0 mg/ 17
dl [35,50] 合併痛風石病患, 初期的目標可設在 <5.0 mg/dl [27], 以加速痛風石的溶解 使用降尿酸藥物的前 3 到 6 個月, 可合併每日口服小劑量秋水仙素, 能有效地預防急性發作, 不發作之後再嘗試停用秋水仙素 此外, 高尿酸血症可能是藥物引起的, 如利尿劑 (loop or thiazide diuretics) 低劑量阿斯匹林( 每日小於 2 公克 ) 菸鹼酸 抗結核藥物 (pyrazinamide, ethambutol) 器官移植抗排斥藥物環孢靈 (cyclosporine) 及酒精等, 因此在採取降尿酸藥物治療前, 必須先評估其高尿酸產生之原因, 如果懷疑高尿酸血症是藥物所引起的, 應先考慮是否要停用藥物或以其它藥物替代 利尿劑是可能造成痛風的因子, 所以應和醫師討論用藥, 權衡利弊決定是否繼續使用利尿劑, 如有需要仍應使用利尿劑 降尿酸藥物中,xanthine oxidase 抑制劑 (XOI) 為首選, 包含 allopurinol 及 febuxostat [54] 另外亦可用促進尿酸排泄的藥物 benzbromarone probenecid 及 sulfinpyrazone 投予降尿酸藥物之前, 應根據患者之肝腎功能及其他背景疾病因素決定最適當之用藥選擇 Allopurinol 100, 300 mg/ 錠劑 : 是一種尿酸合成抑制劑, 它會抑制黃嘌呤氧化酶 (xanthine oxidase), 從而抑制嘌呤 (purine) 轉化為尿酸, 降低血液及尿液中的尿酸濃度, 一般用於預防痛風 腎結石 及化療藥物導致的高尿酸血症 對於尿酸製造過多者, 或有腎結石或腎衰竭者, 使用 allopurinol 常見副作用紅疹過敏 腸胃不適等 Allopurinol 之半衰期雖僅一到三小時, 而主要代謝產物 oxypurinol 之半衰期則長達十七至四十小時, 故一天只需服用一次, 而使用劑量需隨著腎功能 ( 肌酸酐廓清率 CCr) 來調整 Allopurinol 為尿酸製造過多者之合理用藥, 因它同時對排泄過低及製造過多之情況有效, 故為常被處方之降尿酸藥物 Allopurinol 一般有相當好的耐受性, 其副作用的發生率低, 但是 allopurinol 過敏症候群 (allopurinol hypersensitivity syndrome, AHS) 之嚴重度可從輕微之紅疹進展至嚴重藥物過敏, 包括皮膚及黏膜的壞死 Stevens-Johnson syndrome 毒性表皮溶解症 肝壞死 腎功能不良等 嚴重藥物過敏發生的時間變異相當大, 使用後的 1 至 728 天 ( 平均 47 天 ) 均可能發生, 死亡率約為 20-25 %, 腎功能不全及年紀大於六十歲似乎是導致嚴重過敏的重要因素 因此建議 allopurinol 宜較保守使用於以下適應症 :(1) 痛風石 (tophaceous gout),(2) 尿酸製造過多 ( 在一般飲食狀況下,24 小時尿液之尿酸排泄量大於 800 mg),(3) 病患不適合使用促進尿酸排泄藥物治療, 如 : 無法耐受其副作用 或缺乏效用或腎功能不好者,(4) 尿酸成分尿路結石病史,(5) 接受化學治療之癌症病患用以預防急性尿酸引起腎病變 對於腎功能正常的病患,allopurinol 的劑量範圍在每日 100-800 mg, 建議口服由每日 100 mg 開始, 一個月後如果沒有過敏再增加劑量, 一般的常用劑量為每日 300 mg 但在腎功能不佳的病患, 經由腎臟排除之代謝物 oxypurinol 可能會蓄積, 應依病患之腎功能來調整劑量 帶有 HLA-B*5801 基因的人使用後會有較高機率產生嚴重過敏, 建議醫師在處方 allopurinol 之前, 得先檢測 HLA-B*5801 基因 然而未帶此基因者也有可能對此藥產生嚴重過敏, 不論有無帶此基因皆宜小心使用 藥物交互作用 :Allopurinol 與其他藥物併用時, 應特別謹慎, 因可能會增加過敏症候群的發生 例如 allopurinol 與 18
ampicillin thiazide 類利尿劑 ACEI 合併使用, 可能是產生過敏症候群之危險因子 Allopurinol 藥物過敏者, 建議轉診至風濕過敏免疫科專科醫師評估治療 在服用抗凝血劑 warfarin 者應注意出血 合併使用 azathioprine mercaptopurine 時要調降劑量 Febuxostat 80 mg/ 膜衣錠 : 是一種黃嘌呤氧化酶選擇性抑制劑 (XOI), 與別嘌呤醇 (allopurinol) 構造不同, 為非嘌呤化學結構, 因此不會影響嘌呤與嘧啶的代謝, 但也屬 XOI Febuxostat 主要由肝臟代謝, 因此輕度至中度的腎功能受損者無須調整劑量, 衛生福利部核准對輕中度肝腎功能不全患者不需要調整劑量 起始劑量為每日 40 mg, 二週後可增加至 80 mg, 直到達到治療目標為止 ( 血尿酸 <6.0 mg/dl), 最高劑量可考慮增加至每日劑量 120 mg( 註 : 我國 febuxostat 仿單建議起始劑量為 40 mg 每天一次, 二週後尿酸未低於 6.0 mg/dl 的患者, 建議使用 80 mg 每天一次 ) 副作用比例不高, 常見的有噁心 嘔吐 腹瀉 腹痛等腸胃症狀, 少數肝功能指數異常, 頭痛, 或關節痛 建議觀察心血管疾病徵象及檢測肝功能指數 由於結構不同, febuxostat 在至今的文獻報告中很少發生嚴重皮膚過敏反應 促尿酸排泄藥物 (uricosuric agent) 有 benzbromarone( 苯溴香豆酮 ) probenecid ( 丙磺舒 ) 及 sulfinpyrazone( 苯磺唑酮 ) 三種, 三者都可有效控制尿酸 然而此類藥物對尿酸之製造無影響, 而僅是增加其排除, 因此不適用於下列病患 :(1) 製造過多引起的高尿酸血症,(2) 腎功能降低時, 此類藥物會失去效用, 尤其是 sulfinpyrazone probenecid 在 CCr <30 ml/min 時無效, 應避免使用,(3) 有尿酸成分尿路結石者為禁忌, 因易增加尿路結石及尿酸腎病變危險 促進尿酸排泄藥物通常要從小劑量開始, 且喝水要充足, 以預防尿路尿酸結石的副作用 Benzbromarone 50, 100 mg / 錠劑或膠囊 : 一般 benzbromarone 的口服劑量為一天一次, 一般常用的劑量為每日 50 mg, 最大劑量為每日 100 mg,ccr <20 ml/min 時, 因缺乏效果應避免使用 Benzbromarone 近幾年在國外有少數猛爆性肝炎案例報告, 衛生福利部要求廠商需加註肝功能不良之警語, 並在最初給藥六個月內, 應定期進行肝功能檢查, 在使用期間如有肝臟不良反應之症狀如食慾不振 全身倦怠發生時, 應立即停止使用並就醫檢查, 但目前台灣尚未有嚴重肝炎病例報告 Probenecid 500 mg / 錠劑 : 藥物半衰期為 6 到 12 小時, 通常每次口服 250-500 mg 開始, 一天兩次 每日使用總量 1 公克時, 約一半患者可控制血尿酸在正常範圍 最大劑量為每日 3 公克, 分為 2 到 3 次口服 副作用為腸胃不適 食慾下降 皮膚出疹, 尿路尿酸結石等 由於 probenecid 在腎小管抑制許多弱有機酸的排泄, 所以引起了許多藥物交互作用 例如, 抑制 penicillins cephalosporins nalidixic acid rifampicin 以及 nitrofurantoin 分泌, 使得抗生素在血中的濃度增加, 延長作用時間 Sulfinpyrazone 100 mg / 錠劑或膠囊 : 是一種兼具抗血小板作用的促尿酸排泄藥物, 一般起始劑量為每次 50-100 mg, 一天口服兩次 一般常用劑量為每日總量 300-400 mg, 最大劑量為每日總量 800 mg, 分為 2 到 3 次口服 副作用為腸胃不適 皮膚出疹, 尿路尿酸結石等 雖然貧血 白血球減少 血小板減少以及顆粒性白血球缺乏症的副作用很少發生, 但使用 sulfinpyrazone 期間還是建議血液常規檢查 Sulfinpyrazone 19
可能抑制 sulfonylurea 類降血糖藥物的代謝而造成低血糖 可能抑制血小板, 在服用抗 凝血劑 warfarin 者應注意出血現象 第七節痛風合併症的治療尿酸鈉鹽 ( 痛風石 ) 長期沉積於關節及皮下組織導致 (1) 關節破壞變形, 或沉積於腎臟而引起 (2) 泌尿道尿酸結石 (uric acid urolithiasis) (3) 痛風性腎髓質病變 (gouty urate nephropathy) 或 (4) 急性阻塞性尿酸腎病變 (acute uric acid nephropathy) 痛風病人併發泌尿道結石的比率較常人高出 2 到 3 倍, 其發生機會隨著尿中尿酸排泄量增多而增加, 病人應多喝水以預防泌尿道結石 另外, 少數患者必要時可合併使用小蘇打 ( 碳酸氫鈉 ) 或檸檬酸鉀使尿液鹼化, 使尿液酸鹼 ph 值維持在 6.0-7.0, 以預防尿酸沉積於腎臟或腎小管內形成泌尿道結石 ; 但因兩者皆含有高單位電解質, 在腎臟功能不佳者應謹慎使用 痛風腎病變的治療和慢性痛風的治療並沒有什麼不同, 包括限制高嘌呤飲食, 維持正常血尿酸值, 避免脫水及利尿劑, 及使用適當的降尿酸藥物, 但要注意調整減少藥物的使用劑量 Rasburicase 可治療及預防具有高腫瘤負擔和在化學治療時可能會引發快速腫瘤溶解危險的血癌患者之急性高尿酸血症 ; 預防急性阻塞性尿酸腎病變 (acute uric acid nephropathy) 可使用 allopurinol 減少尿酸產生, 但是當惡性腫瘤細胞快速溶解造成腫瘤溶解症候群 (Tumor Lysis Syndrome, TLS) 合併急性阻塞性尿酸腎病變時,rasburicase 的建議劑量是 0.2 mg/kg, 每天一次, 每次靜脈輸注時間需三十分鐘以上 健保給付規定為限用於血液腫瘤 ( 急性白血病和 high grade 淋巴瘤 ) 患者之下列情形 :(1) 治療前或療程開始後, 血尿酸值成人高於 10.0 mg/dl; 兒童高於 8.0 mg/dl 者 (2) 有心臟或腎臟衰竭, 無法忍受大量靜脈輸液者 (3) 對 allopurinol 過敏者 使用以每日一至二劑並以三日為限 Rasburicase 不 表七 口服降尿酸藥物 ( 治療目標是使血尿酸值控制在 < 6.0 mg/dl) 藥物名稱 Allopurinol 別嘌呤醇 Febuxostat 福避痛 Benzbromarone 苯溴香豆酮 Sulfinpyrazone 苯磺唑酮 Form 100 mg/tab 80 mg/tab 50, 100 mg/tab, cap Probenecid 丙磺舒 100 mg/tab, cap 500 mg/tab Half-life oxypurinol 17-40 hr 1.3 to 15.8 hr 12-18 hr 1-3 hr 6-12 hr Initial dose 100 mg QD 40 mg QD 50 mg QD 100 mg BID 250-500 mg BID Usual dose 300 mg/day 40-80 mg/day 50 mg/day 300-400 mg/day 1-1.5 gm/day Maximal dose 800 mg/day 80 mg/day 100 mg/day 800 mg/day 3 gm/day Side effects Drug interaction Severe allopurinol hypersensitivity syndrome, rash, dyspepsia Azathioprine, mercaptopurine, warfarin GI upset, headache, abnormal liver function test Azathioprine, mercaptopurine Liver toxicity, allergy, GI upset, abnormal liver function test, urolithiasis GI upset, rash, marrow depression, abnormal liver function test, urolithiasis GI upset, rash, headache, abnormal liver function test, urolithiasis warfarin warfarin Ampicillin, salicylates, penicillin, heparin, dapsone, rifampicin, azathioprine 20
可用於對其成分或賦形劑過敏者 G6PD 缺乏症患者或使用 rasburicase 曾發生溶血性貧血或變性血紅素血症的病人 必須密切觀察病人是否發生過敏, 尤其是皮膚部位的過敏反應或支氣管痙攣 痛風病人方面,uricase 可針對一些複雜難以治療的痛風病人, 但台灣尚未進口核准使用 長期尿酸過高可能在手腳等形成痛風石, 造成關節變形, 行動不便及困難, 有時痛風石表面的皮膚磨破而成為流出白色尿酸結晶的傷口, 容易發生續發性傷口細菌感染 此外, 痛風石尿酸結晶常卡在組織內, 與肌腱 韌帶還有皮下組織糾結在一起, 外科手術清除痛風石的同時, 對其表面皮膚血液循環的破壞很大, 若表皮變薄時傷口不易縫合, 有時會術後皮膚壞死, 而造成長期傷口不易癒合 對痛風石患者, 初期宜口服降尿酸藥物將血尿酸值控制在 5.0 mg/dl 以下, 以加速痛風石溶解速度 第八節痛風的預防痛風的預防, 首要的是生活型態的調節及使用降尿酸藥物, 生活型態的調整包括 : 肥胖者減輕體重, 戒酒 ( 尤其是啤酒 ), 減少動物性高嘌呤食物攝取, 另外需維持血尿酸值在 6.0 mg/dl 以下, 然而對某些嚴重痛風結石患者, 將血尿酸值控制在 5.0 mg/dl 以下, 可加速結石的溶解速度 使用降尿酸藥物的初期, 因血尿酸值急速降低, 有可能誘發痛風之發作 故開始使用降尿酸藥物至少一兩週內, 應合併使用預防痛風發作之藥物 預防痛風發作藥物之首選為低劑量秋水仙素 (colchicine) 秋水仙素預防痛風之建議劑量為每天 0.5-1 mg, 使用期間需至少三個月, 相較於安慰劑, 可有效預防痛風復發 (7/21 vs. 17/22, NNT=2), 不過此劑量之秋水仙素導致腹瀉的機率為安慰劑之 8.38 倍, 但另一個研究指出, 每日 0.5 mg 秋水仙素, 使用六個月, 可以有效預防痛風復發, 且無副作用 秋水仙素在腎功能不佳的病患 (CCr <50 ml/min) 劑量應減半 若血尿酸值已達治療目標, 且無痛風症狀至少 3 至 6 個月, 則可考慮停止預防痛風發作藥物 痛風病人若合併高血壓, 則首選降壓藥物為 Losartan, 儘量不要使用 thiazide 類利尿劑 利尿劑會增加痛風發作機率 72%(95%CI = 1.67-1.76) 若病人合併高血脂, 則首選降血脂藥物為 fenofibrate, 可降低血尿酸值 20% 第九節痛風日常生活指導與飲食建議痛風病人或高尿酸血症的人常合併有高血壓 糖尿病 肥胖 高脂血症 代謝症候群 心血管疾病 和少數腎功能不佳及腎衰竭, 因此應抽血檢查相關疾病, 定期追蹤測量體重 血壓 血糖 膽固醇 三酸甘油酯 腎功能肌酸酐, 不要只注意血中的尿酸值, 如有相關疾病如高血壓 糖尿病 肥胖 高脂血症 腎功能不佳等也應加以一起治療, 並給予飲食及生活指導 [27] 根據研究, 無症狀高尿酸血症民眾的血尿酸值 肥胖 體重增加 飲酒 使用利尿劑和高血壓等, 是得到痛風的主要危險因子 [12,39], 如果控制得宜, 可以減少痛風發生的機會 另外, 急性痛風關節炎發作可能由於外傷 喝酒 疲勞 藥物 外科手術或急性內外科疾病而誘發, 痛風病人應注意避免發生 根據一項調查 47,150 21
表八 痛風的預防 22 名介於 40 到 75 歲的男性, 追蹤 12 年期間發現 730 名新的痛風患者, 研究者將食物攝取份量的多寡分成五等分, 結果發現攝食較多肉類的人比攝食較少肉類的人高出約 41% 罹患痛風的機會 (1.41 倍 ); 攝食較多海鮮的人比攝食較少海鮮的人高出約 51% 罹患痛風的機會 (1.51 倍 ); 習慣攝取乳製品的人罹患痛風的風險減少了 44% 的機會 (0.56 倍 ); 但食用蔬菜類, 包括黃豆 豆類 蕈菇類等, 並不會提高發生痛風的風險 [4,55] 另一研究指出[56], 跟不喝酒的人比較起來, 每天喝 12 盎司 (355 C.C.) 啤酒的人罹患痛風的風險增加 49%( 相對風險 1.49 倍 ), 每天喝 1 小杯 (44 C.C.) 烈酒的人罹患痛風的風險增加 15%( 相對風險 1.15 倍 ), 而每天喝 4 盎司 (118 C.C.) 葡萄酒的人罹患痛風的風險並沒有增加 ( 相對風險 1.04 倍 ) 另一個 14,809 位 20 歲以上美國男女性一般民眾的橫斷性研究指出, 攝食較多肉類的人比攝食較少肉類的人, 血尿酸平均高出 0.48 mg/dl; 吃較多海鮮的人比吃較少海鮮的人, 血尿酸平均高出 0.16 mg/dl; 每天喝牛乳較多的人比喝牛乳較少的人, 血尿酸平均低了 0.21 mg/dl; 每兩天至少吃一次優格的人比不吃優格的人, 血尿酸平均低了 0.26 mg/
dl; 至於總蛋白質的攝取量, 則與尿酸無關 [57]; 同一研究也指出 [58], 每天每多喝 12 盎司 (355 C.C.) 啤酒的人, 血尿酸平均增加 0.46 mg/dl, 每天每多喝 1 小杯 (44 C.C.) 烈酒的人, 血尿酸平均增加 0.29 mg/dl; 而每天每多喝 4 盎司 (118 C.C.) 葡萄酒的人, 血尿酸值平均減少 0.04 mg/dl 至於痛風病人是否要進行嚴格的低嘌呤飲食控制呢? 根據研究發現, 飲食控制約只能使血尿酸下降約 1.0-2.0 mg/dl 左右, 通常無法使血尿酸值 <6.0 mg/dl, 因此若要把血尿酸值降下來, 大多需服用藥物來達成, 若能合併低嘌呤飲食控制, 將可減少藥物使用劑量 另外飲食控制對於痛風常合併的疾病如高血壓 糖尿病 高血脂 肥胖則是很重要 當然, 飲酒尤其是啤酒對痛風病人而言是應該節制的 根據研究 [59], 食物中蔬果類 乳製品的嘌呤含量都不高, 醣類的五穀根莖也都可食, 比較需要節制的是曬乾的香菇與紫菜 ; 蛋白質中內臟 海產類的嘌呤都偏高, 海產中只有嘌呤低的海參與海蜇皮適合食用 油脂類並不會導致尿酸升高, 但卻會造成膽固醇過高 黃豆類製品的嘌呤含量其實不高, 對血尿酸並無太大影響 一般而言, 含高嘌呤的食物如動物內臟 海產及酒精尤其是啤酒, 宜避免大量食用 根據統計發現, 約一半痛風患者在急性痛風發作前沒有誘發因素存在, 另外一半的急性痛風發作前有誘因存在, 其中以啤酒為最常見原因 ( 佔百分之六十 ), 其次為海產 ( 百分之十八 ), 內臟食物 ( 百分之十四 ), 而豆類製品則幾乎很少引起發作 [48], 同時根據台灣 日本及美國學者測量各種豆類的嘌呤含量也不太高, 因此可以推翻民間誤傳痛風不可以吃豆類的說法 另一個間接證據是, 常吃豆製品的出家人也很少得到痛風 總而言之, 啤酒 內臟及海鮮最好不要攝取, 至於豆類根據各方面研究顯示是可以適量食用, 除非它確曾引起個別病人的痛風發作 最後在痛風日常生活指導與飲食建議為 : 1. 維持標準的體重 : 若體重過重應慢慢減重, 不宜快速減肥或斷食, 以免因細胞大量崩解產生尿酸而導致痛風發作, 減重以每月減輕一公斤以內為宜 2. 維持適當水分補充 : 水分缺乏不足時可能誘發痛風的發作 [39,60,61], 且在適當和適量的補充水分後 3-4 天, 血尿酸值常可回復到正常值 [62] 適當和適量的補充水分是一般痛風發作, 或者惡性腫瘤化療後引起急性痛風發作以及減少尿酸結石形成中一項很重要的預防及治療方式 [62] 多補充水分則可以促進尿酸排泄及預防尿路結石 3. 醣類方面 : 所有五穀根莖類皆可食用, 蔬菜類除曬乾香菇和紫菜不宜大量食用外, 如豆芽 豆苗皆可食用, 水果則無禁忌 4. 蛋白質方面 : 對含有高嘌呤的食物如內臟, 海鮮類 ( 海參 海蜇皮除外 ), 即宜減少攝取 5. 乳製品方面 : 文獻指出每日攝取超過兩杯玻璃杯量的牛奶可以降低 50% 的痛風發生率 [55] 另外一個為期四週時間之 randomized clinical trial 發現, 完全無乳製品的飲食 (dairy-free diet), 會使血尿酸值往上增加 [63] 6. 油脂方面 : 由於高脂肪食物會抑制尿酸排泄, 在急性痛風發作期需避免大量食用 7. 酒精及含糖飲料 : 酒精及含糖飲料在體內會代謝為乳酸影響尿酸排泄, 並且本身會 23
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Formosan Journal of Rheumatology 2013;27:27-36 Original Article The Clinical Characters and Outcome of Antineutrophil Cytoplasmic Antibody-associated Vasculitis: A Retrospective Single-Center Study Cheng-Hsun Lu, Chieh-Yu Shen, Cheng-Han Wu, and Chia-Li Yu Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Objective: To retrospectively review the classification, clinical course, treatment response and investigated prognostic factors. of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Patients with positive ANCA that received treatment at the National Taiwan University Hospital (NTUH) between January 1, 2007 and March 31, 2013 were enrolled. The range of involved organs was based on medical records, images and laboratory data. The Birmingham vasculitis activity score (BVAS) was evaluated for each patient. The treatments, clinical outcome and disease recurrences were recorded for statistical analyses. Results: Nineteen myeloperoxidase (MPO)-ANCA-positive patients and seven proteinase 3 (PR3)-ANCApositive patients had newly diagnosed AAV during the study period. Microscopic polyangiitis (MPA) was the most common classification (42% overall). Kidneys and lungs were the most frequently involved organs, with an incidence rate of 73% and 69%, respectively. Moreover, 53% of patients with MPO-AAV had chronic kidney disease before diagnosis. In addition, the all-cause mortality rate in this study was 26% and infection was the most common cause of death. Of the six expired patients, 5 died due to infectious complications. The higher BVAS, Japanese vasculitis activity score (JVAS) for patients with renal vasculitis, or involvement of both lung and kidney, has the higher all-cause mortality. Conclusions: AAV is not common, but does cause considerable morbidity and mortality. MPO-AAV was more common than PR3-AAV in this study, and the majority of the diagnoses were MPA. Both BVAS and JVAS predicted survival outcome. Early diagnosis combined with adequate treatment, and measures to prevent, reduce or monitor infection, may help with overall survival. Key words: Antineutrophil cytoplasmic antibodies (ANCA); vasculitis; Taiwan; ANCA. Introduction The systemic vasculitis represents heterogeneous conditions resulting in inflammation of blood vessels. Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis are characterized by the presence of ANCAs, including microscopic polyangitis (MPA), Corresponding author: Chia-Li Yu, M.D., Ph.D. Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital. #7, Chung Shan South Rd., Taipei 100, Taiwan. Tel: +886-2-2312-3456 ext. 65011; Fax: +886-2-2321-9837 E-mail: chialiyu@ntu.edu.tw Received: June 30, 2013 Revised: July 25, 2013 Accepted: August 19, 2013 granulomatosis with polyangitis (GPA) (Wegener's granulomatosis), and Churg-Strauss syndrome (CSS) [1-3]. ANCA-associated vasculitis (AAV) has an annual incidence of 20 per million. Its outcome is often poor. Renal involvement is frequently seen and is strongly associated with outcome [4]. AAV also represents the most common cause of pulmonary vasculitis, and is characterized by inflammation and necrosis of the pulmonary blood vessels, most commonly affecting the pulmonary capillaries [5]. The current standard assessment tool used currently for scoring disease activity in the systemic vasculitis is the Birmingham vasculitis activity score (BVAS) developed for evaluation of activity of systemic vasculitis in 1994. The BVAS was recently modified to the current version: 27
Clinical characters and outcome of AAV BVAS v. 3, which contains 56 items [2]. Other tools for evaluating disease severity and death in AAV have also been developed. Koike et al demonstrated a simpler measure for predicting death in patients with MPO- ANCA-associated vasculitis with renal involvement by using the Japanese vasculitis activity score (JVAS) [6]. The introduction of immunosuppression with alkylating agents and glucocorticoids, and renal replacement therapy has reduced the mortality of AAV [7-9]. Rituximab, an anti-cd20 monoclonal antibody, was found to be effective for induction of remission in severe ANCA-associated vasculitis, and evidence for the role of rituximab as a remission maintenance agent has been published in two open-label studies of long-term control of the disease [10-13]. ANCA can be detected by indirect immunofluorescence using ethanol-fixed neutrophils. Two staining patterns, the perinuclear (P-ANCA) and the cytoplasmic (C-ANCA), are known. The major target antigen of P-ANCA associated with vasculitis is myeloperoxidase (MPO), while that of C-ANCA is proteinase 3 (PR3). MPO-ANCA-associated vasculitis is more frequent in Japan, China and Hong Kong, whereas RP3-ANCAassociated vasculitis is more common in Europe and USA [14-17]. Thus, racial differences in AAV patients may exist between Asians and Caucasians. There is a preponderance of MPA, constituting about 80% of Chinese patients with AAV [17,18], and MPO-ANCA appeared frequently even in Chinese patients with a clinical picture of GPA [19]. Age and pulmonary infection were found to be independent predictors of death [20]. Older age and pulmonary hemorrhage also appear to be the risk for all-cause death in severe ANCA-associated glomerulonephritis patients, who were dialysis-dependent at presentation [21]. In Taiwan, Hung et al examined clinical and pathological predictors in ANCA-seropositive Taiwanese patients, and found chronic glomerular lesions in renal biopsy predicting poor renal outcome [22]. However, their study was limited to biopsy proven pauci-immune necrotizing crescentic glomerulonephritis. Genetic factors such as DRB1*1101 or DRB1*1202 had been shown to affect susceptibility of Chinese patients with AAV [18,23]. Differences in HLA gene and antigen frequencies have been observed between various ethnic groups of the Chinese population in Taiwan [24]. Clearly, it is important to have further studies evaluating the clinical features and treatment response in AAV among Taiwanese people. ANCA-associated vasculitis could also associate with interstitial lung disease (ILD) [25-27]. The association between ILD and AAV, particularly MPA, has been described in a number of case reports and series. Ando et al disclosed a high incidence of groundglass attenuation and consolidation in the peripheral lung on chest computer tomography in patients with MPO- ANCA [28]. The association between ILD and AAV is unlikely to be a coincidence. According the report by Arulkumaran et al, ILD was observed in 2.7% of ANCAassociated vasculitis patients, and all the patients had MPO-ANCA and a clinical diagnosis of MPA, giving them a prevalence rate of 7.2% in patients with MPA [26]. However, PR3-ANCA-positive interstitial lung disease has also been reported [29]. In this retrospective study, we reviewed the classifications, clinical course and treatment response of patients with ANCA-associated vasculitis (AAV), and secondly, investigated the prognostic factors for patient survival. Material and Methods Patient selection and inclusion criteria Patients over 20 years old who had positive ANCAs in their serum at the National Taiwan University Hospital (NTUH), Taipei, Taiwan between January 1, 2007 and March 31, 2013 were enrolled into this retrospective study. The titers of ANCAs were measured by the automated enzyme fluoroimmunoassay (EliA PR3 S and EliA MPO S, Pharmacia Diagnostics GmbH & Co.). Their clinical features, preexisting diseases, laboratory findings at diagnosis, and the outcomes of the ANCA-positive patients were reviewed. The date of their onset of the first symptom that made clinicians suspect AAV and check their ANCA titer was defined as the start date for entry into the present study. Only patients with newly diagnosed AVV after January 1, 2007 were included in this study. Exclusion criteria are patients who were previously diagnosed as AAV and receive therapy before January 1, 2007, who lost of follow up before or within 1 month after the initiation of therapy, who received induction therapy in other hospital, or who underwent chemotherapy for known malignancy or known hematological disorder. Drug-induced ANCA-associated vasculitis [18, 22], vasculitis secondary to infection, or systemic autoimmune diseases were also excluded. Organ involvement The incidence of involved organ was based on their medical records, image studies and laboratory data during their first admission or clinic visit due to AAV. 28
Lu et al Definition of involved organ was according to the BVAS [2], which includes nine domains: general, cutaneous, mucous membranes/eyes, ears/nose/throat, chest/lungs, cardiovascular, abdominal, renal, and nervous system. Based on the BVAS, patients with new developed or worsened hypertension, proteinuria, hematuria, or rise in serum creatinine that was attributable to active vasculitis were considered to have renal involvement. Similarly, lung involvement included the development of wheeze, lung nodules and cavities, pleural effusion/ pleurisy infiltrate, endobronchial involvement, alveolar hemorrhage, and respiratory failure due to the activity of AAV. Interstitial lung involvement was based on evidence found by a high-resolution computer tomography (HRCT) of chest, or pulmonary function test with an impaired carbon monoxide diffusion capacity (DL CO ). Eosinophilia was defined as an eosinophil count over 1500 per micro liter or more than 10% in white blood cells [1]. Clinical diagnosis and disease activity scoring The disease classification was mainly based on the clinical diagnosis given by their attending physician. If no classification of AAV was given clinically, we would review their medical records and classify their AAV according to the American College of Rheumatology (ACR) and Chapel Hill Consensus Conference (CHCC) criteria [1, 30]. Missing data was assumed to be negative. The disease activity was accessed with the BVAS in all enrolled patients. The Japanese vasculitis activity score (JVAS), which was designed to evaluate disease severity of rapidly progressive glomerulonephritis and also shown to predict death in AAV patients, could evaluate disease activity with a sum score of 4 clinical parameters, including age, serum creatinine and C-reactive protein (CRP) levels, and pulmonary lesions [6,31], was also accessed in our patients with renal involvement. Treatment, Outcome and Disease Recurrence Patients were followed-up until May 31, 2013. Those lost to follow-up before May 2013 was excluded for survival analysis. Initial phase treatments were studied. The dose of corticosteroids and, the administration of cyclophosphamide, plasma exchange, plasmapheresis, intravenous immunoglobulin (IVIG), rituximab, and disease-modifying antirheumatic drugs (DMARDs) during induction therapy are recorded. The primary endpoint was all-cause death. The recurred disease was defined as new or worsened manifestations of AAV that were also believed to require a change in therapy [8]. Statistical analysis Categorical variables were presented as percentages and continuous variables were presented as the mean with standard deviation. Data were analyzed by using the Mann-Whitney U test or Fisher s exact test, depending on the type of variables. Patient survival was assessed using the Kaplan-Meier method and Breslow test to identify independent risk factors. All the statistical analyses were performed by SPSS (IBM SPSS Statistics version 20.0). Association with p<0.05 was considered to be statistical significant. Results Patient characteristics and clinical features During Jan. 2007 to Mar. 2013, there were 104 patients having positive ANCA. Among them, 75 patients (72%) were positive for MPO-ANCA, and 26 patients (25%) positive for PR3-ANCA. Two patients with SLE and one patient with head-and-neck cancer have low-titer of the both ANCA. Nineteen MPO-ANCA-associated vasculitis patients and seven PR3-ANCA-associated vasculitis patients were taken into further analysis. Their characteristics were summarized in Table 1. In the MPO-AAV patients, 58 % were female, and their average age was 61.0 ± 17.7 years (range from 27.9 to 80.4). In the PR3-AAV patients, 43% were female, and their average age was 57.2 ± 23.2 years (range from 26.6 to 91.7). The mean observation period was 23.1 ± 23.6 (range from 0.1 to 72.2) months in MPO- AAV patients, and 24.1 ± 16.1 (range from 3.6 to 42.2) months in PR3-AAV patients. There was no significant difference in age, gender, and observation period between MPO-AAV and PR3-AAV patients. Overall, 11 (42%) of the 26 patients were diagnosed as MPA, 4 (15%) were diagnosed as GPA, and one had CSS. MPA was the most common classification, while there were 10 (38%) patients diagnosed as unclassified AAV. Only one MPA patient had PR3-ANCA, and no GPA patient had positive MPO-ANCA. Most (53%) MPO-AAV patients had preexisting chronic kidney disease (CKD) before diagnosis; however, in the PR3- AAV patients, no preexisting CKD was recorded. Kidneys and lungs were the most frequent involved organs, with an incidence of 73% and 69%, respectively. Hemoptysis was common, with 37% of the MPO- AAV patients and 57% of the PR3-AAV patients had 29
Clinical characters and outcome of AAV Table 1. Characters of ANCA-associated vasculitis patients at diagnosis. Patient Characters MPO-ANCA (n = 19) PR3-ANCA (n = 7) p Overal (n = 26) Gender (F:M) 11:8 3:4 0.665 14:12 Age at diagnosis (year) 61.0 ± 17.7 57.2 ± 23.2 0.651 60.0 ± 18.9 observation period (months) 23.1 ± 23.6 24.1 ± 16.1 0.543 23.3 ± 21.6 Baseline disease Diabetes 1 (5%) 2 (29%) 0.167 3 (12%) Hypertension 10 (53%) 4 (57%) 1.000 14 (54%) Pre-existing CKD 10 (53%) 0 0.023 10 (38%) RRT before diagnosis 0 0 0 Disease category MPA 10 (53%) 1 (14%) 0.178 11 (42%) GPA 0 4 (57%) 0.002 4 (15%) CCS 1 (5%) 0 1.000 1 (4%) Unclassified 8 (42%) 2 (29%) 0.668 10 (38%) Fever >38 C 6 (32%) 6 (86%) 0.026 12 (27%) Arthritis 4 (21%) 3 (43%) 0.340 7 (27%) HBV 1 (5%) 2 (29%) 0.167 3 (12%) HCV 1 (5%) 0 1.000 1 (4%) AKI 12 (63%) 2 (29%) 0.190 14 (54%) Renal Biopsy 7 (37%) 0 0.462 7 (27%) ILD 8 (42%) 3 (43%) 1.000 11 (42%) Hemoptysis 7 (37%) 4 (57%) 0.407 11 (42%) Intubation due to AAV 3 (16%) 2 (29%) 0.588 5 (19%) Blood test at diagnosis Hemoglobin (g/dl) 9.5 ± 1.9 11.0 ± 1.8 0.070 9.9 ± 2 Platelet (k/μl) 307.2 ± 120.6 324.6 ± 197.3 0.964 311.8 ± 141 Creatinine (mg/dl) 3 ± 2.4 1.6 ± 1.2 0.248 2.6 ± 2.2 Albumin (g/dl) 3.4 ± 0.7 3.4 ± 0.6 0.989 3.4 ± 0.6 CRP (mg/dl) 8 ± 6.7 12.9 ± 11.5 0.364 9.3 ± 8.3 ANCA titer (IU/mL) 210.2 ± 209.0 81.0 ± 92.9 BVAS 17.1 ± 4.9 18.6 ± 9.2 0.682 17.5 ± 6.2 Immunosuppressive therapy 17 (89%) 7 (100%) 1.000 24 (92%) Categorical variables were presented as percentages, and continuous variables were presented as the mean ± standard deviation. Abbreviations: CKD, chronic kidney disease; RRT, renal replacement therapy; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; CCS, Churg-Strauss syndrome; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; AKI, acute kidney injury; ILD, interstitial lung disease; AAV, ANCA-associated vasculitis; CRP, C-reactive protein; BVAS, Birmingham vasculitis activity score. hemoptysis at diagnosis (42% overall) in patients with lung involvement. Seven patients (27%) received renal biopsy for evaluation of renal disease, and another one patient received skin biopsy. The renal biopsy usually showed pauci-immune crescentic glomerulonephritis. One had reported focal and segmental glomerular necrosis with immune complex. Only one renal biopsy specimen showed tubulointerstitial nephritis. Most patients showed no pathology with regards to the involved organ. Besides the lungs and kidneys, the frequently involved systems were in order, the nervous system (35%), the skin (27%), and the ears, nose and throat (ENT) (23%). Incidences of affected organs are shown in Figure 1. Treatment and outcome Total two patients did not receive any immunosuppressive therapy because of old age and due to the fact this they had signed do not resuscitate orders. Moreover, another patient was lost to follow-up after receiving only 2 months of treatment. All 3 patients were not taken into consideration for the outcome analysis. All patients received steroid treatment. Patients with major organ involvement received either steroid pulse (MTP pulse) or cyclophosphamide pulse (CYC pulse) therapy. Most patients with renal involvement had received either plasmapheresis or plasma exchange. One patient with cutaneous vasculitis was simply treated with oral steroids. Three patients had been supported by 30
Lu et al Table 2. The clinical features of the survivors and nonsurvivors. Figure 1. The incidence of organ involvement according to antibody group. The solid bars denote the patients with MPO-ANCA; the hollow bars denote the patients with PR3-ANCA. No significant difference was found in the frequency of involved organ between the antibody groups. Abbreviations: ENT, ear, nose, and throat; CV, cardiovascular; GI, gastrointestinal. extracorporeal membrane oxygenation (ECMO), and two of them eventually died. Intravenous immunoglobulin had been used in one patient supported on ECMO for uncontrolled disease. Two patients received rituximab for induction with a combination of cyclophosphamide pulse therapy, and both of them successfully tapered steroids to low dose after six months of receiving treatment. In the 19 patients with renal involvement, 5 received induction therapy with MTP pulse, and 12 received CYC pulse (with or without plasmapheresis or plasma exchange). There was no significant difference with regards to their mean creatinine levels on Day 0 and Day 30 after different treatments. One MPO-ANCA positive patient and three PR3- ANCA positive patients had disease recurrence during the observation period; two of them received MTP pulse therapy, and the other 2 received CYC pulse therapy for induction therapy. Six patients died and the all-cause mortality rate in this study was 26%. Infection was the most common cause of death among 5 patients. The clinical features of the survivors and non-survivors are shown in Table 2. Regarding the survivors, 65 % were female, 65% had MPO-ANCA, 35% had PR3 ANCA, and their average age was 55.0±17.5 years (range from 26.6 to 83.3). Regarding the non-survivors, 33% were female, 83% had MPO-ANCA, 17% had PR3-ANCA, and their Character Survivor (n = 17) Non-survivor (n = 6) p Gender (F:M) 11:6 2:4 0.341 Mean age (years) 55.0 ± 17.5 65.0 ± 22.4 0.256 ANCA type (MPO:PR3) 11:6 5:1 0.621 Baseline disease Diabetes 3 (18%) 0 0.539 Hypertension 8 (47%) 5 (83%) 0.179 Preexisting CKD 5 (29%) 4 (67%) 0.162 Renal involvement 10 (59%) 6 (100%) 0.124 AKI 8 (47%) 4 (67%) 0.640 Hematuria 7 (41%) 4 (67%) 0.058 Proteinuria 9 (53%) 6 (100%) 0.371 Chest involvement 10 (59%) 6 (100%) 0.124 Hemoptysis 5 (29%) 5 (83%) 0.052 Ventilator support 3 (18%) 2 (33%) 0.576 ECMO support 1 (6%) 2 (33%) 0.155 Concurrent renal and 6 (35%) 6 (100%) 0.014 lung involvement Concurrent hemoptysis 4 (24%) 5 (83%) 0.018 and hematuria Laboratory data Hemoglobin 10.1 ± 1.9 9.7 ± 1.9 0.746 Creatinine 2.5 ± 2.4 2.4 ± 1.4 0.720 Albumin 3.6 ± 0.6 3.4 ± 0.5 0.382 CRP 8.9 ± 9.6 10.5 ± 6.3 0.354 BVAS at diagnosis 16 ± 6.7 21.5 ± 3.1 0.016 Induction treatment PP or PE 4 (24%) 3 (50%) 0.318 MTP pulse 7 (41%) 0 0.124 CYC pulse 9 (53%) 6 (100%) 0.058 Abbreviations: ECMO, extracorporeal membrane oxygenation; P P, p l a s m a p h e r e s i s ; P E, p l a s m a e x c h a n g e ; M T P, methylprednisolone; CYC, cyclophosphamide. average age was 65.0±22.4 years (range from 32.5 to 91.7). Regarding the survivors, 3 (18%) had diabetes, 8 (47%) had hypertension, and 5 (29%) had preexisting CKD. Regarding the non-survivors, none had diabetes, 5 (83%) had hypertension, and 4 (67%) had preexisting CKD. There was no significant difference in age, gender, ANCA type, and baseline disease between the survivors and non-survivors. On the contrary, concurrent involvement of lung and kidneys, and the pulmonary renal syndrome were significantly associated with mortality. BVAS clearly showed a significant difference between survival (16 ± 6.7) and non-survival (21.5 ± 3.1) patients with a p-value of 0.016. Correlations among patient survival and ANCA type, BVAS, JVAS, ILD and preexisting CKD are 31
Clinical characters and outcome of AAV Figure 2. Relationship between patient survival and ANCA type, Birmingham vasculitis activity score (BVAS), Japanese vasculitis activity score (JVAS), interstitial lung disease (ILD), and preexisting chronic kidney disease (CKD). Kaplan-Meier curve of patient survival according to (A) MPO-ANCA (solid line) and PR3-ANCA (dashed line), p=0.213, (B) BVAS 20 (solid line) or <20 (dashed line), p= 0.021, (C) JVAS 6 (dashed line) or <6 (solid line), p= 0.019, (D) with ILD (dashed line) and without ILD (solid line), p=0.699, and (E) with preexisting CKD (dashed line) and without preexisting CKD (solid line), p=0.053. shown in Figure 2. BVAS could predict patient survival (p-value=0.021), and the JVAS could predict renal-involved patient survival (p-value=0.019). No significant difference was noted in ANCA type or ILD. Although preexisting CKD tended to have a poor patient survival, but no statistical significance was observed (p-value=0.053). 32
Lu et al Discussion In the present study, we demonstrated the clinical features, treatment response and outcomes of AAV patients in a single medical center. Similar to reports in the related literature [17, 32-34], the most frequently involved organs in AAV patients were the kidneys. According to a report from China, the prevalence of organ involvement was 87.1% in kidneys, 61% in lungs, 43% in gastrointestinal tract (GI), and 15.7% in nervous systems, which showed higher GI involvement and lower nervous system involvement [17] as compared to our data. According to a Japanese study of MPO-AAV patients, the leading systems involved were the kidneys, lungs, and nervous systems [32]. In our MPA patients, lung involvement was common (73%), and hemoptysis was a main pulmonary manifestation. This result is similar to the Japanese study, and is different from the European patient cohorts [35-37]. We also showed that elderly people were susceptible to this disease. It was observed that 46% of AAV patients were older than 65 years old at diagnosis in our study, and this is similar to a related report in China [17]. Only one patient had ischemic chest pain during disease attack in this study. In similar studies, the incidence of cardiovascular involvement was also less than ten percent [37, 38]. The prevalence of ANCA in patients with ILD is suggested as 8-36% in the published reports in the related literature [39, 40], and the prevalence of clinical ILD in AAV was 2.7% [26]. However, 42% of patients had ILD noted by HRCT or PFT in this study, which was much higher than published reports in the related literature. Moreover, three of our PR3-ANCA-positive patients had ILD on their chest CT scan, but ILD has been rarely reported in PR3-ANCA-associated vasculitis [29]. However, ILD can be hard to distinguish from vasculitic infiltrates on imaging at the time of diagnosis, and repeated imaging and pulmonary function test with DLCO may therefore be required to confirm the diagnosis. Preexisting CKD affected 53% of the MPO-AAV patients in this study. In a Japanese study including 74 MPO-ANCA-related nephritis patients [38], preexisting CKD was reported in 27% of the patients. In 10 MPO- ANCA-positive patients who had preexisting CKD in our study, only one of them had known diabetes mellitus. Most of them did not have a definite etiology of preexisting CKD, and AAV-related kidney disease could be suspected. In contrast, none of the PR3-AAV patients in our study had preexisting CKD. This may be due to the relatively small patient number in our study, but we also found that PR3-AAV patients had more extensive involvement regarding ENT, skin, and nervous system, and had a significantly higher incidence of fever, which would cause patients to seek medical assistance at an early stage of their disease before chronicity developed. Patients with renal disease usually came to our medical department after edema developed. An earlier diagnosis may be possible in the MPO-AAV patients with preexisting CKD to improve their outcome. The ANCA-associated vasculitis was not a common disease, but had a considerable morbidity and mortality rate. Over the past 50 years we have witnessed extraordinary progress in the treatment of AAV. GPA and MPA are no longer routinely fatal within weeks to months, as was often the case in earlier eras [3]. Treatment of severe AAV with cyclophosphamide and glucocorticoids has substantially reduced the high mortality rate previously associated with these diseases [9, 41]. Rituximab has been shown to not be inferior to cyclophosphamide for remission induction in the Rituximab in AAV (RAVE) trial, a randomized, double-blind, placebo-controlled investigation [11]. RAVE employed the most rapid glucocorticoid taper studied in an AAV trial to date [3]. Two of our patients, one with MPO-AAV and the other with PR3-AAV, received rituximab for induction with a combination of cyclophosphamide, and both of them tapered steroid to a low dose (no more than 10 mg per day) within 6 months of receiving treatment. Another two PR3-AAV patients received rituximab for disease flare and one of them had a good response, although the other later died due to infection. As seen in prior reports, ANCA titers failed to predict survival in our patients. Patients with pulmonary renal syndrome had higher mortality. The BAVS showed significant correlation to all-cause death. A simpler scoring system, the JVAS, could also correlate to mortality in patients with renal involvement. Due to the high incidence of renal involvement in our patients, the JVAS which includes only 4 parameters may be more easily used to clinically to evaluate disease activity and predict survival. Severe flares occurring preferentially in PR3-ANCA-positive patients was reported in a recent study [3]. In our study, 3 of 7 PR3-AAV patients had relapse of disease within 1 year; though not statistically significant, this was more than 1 of 19 MPO-AAV patients who had flare-ups 5 years after induction therapy. This finding might be compatible with the concept that PR3-AAV and MPO-AAV are distinct autoimmune syndromes [42]. 33
Clinical characters and outcome of AAV In the present study, steroid pulse therapy was only given in the survivors, which may be due to the fear of steroid pulse therapy clinically in patients with critical conditions and high disease activity. Overall, the influence of treatment on mortality and relapses has to be interpreted with caution because this study was retrospective, and therapeutic regimens were heterogeneous. ECMO was used in 3 of our patients, and one successful weaning from ECMO and ventilator after cyclophosphamide pulse therapy. Though the incidence of AAV was not high, clinicians still should still be very alert to these diseases due to the considerable mortality. Similar to most studies, the majority of mortalities were due to infectious complications [4, 18, 38, 43]. In the five non-survivors, their fatal infections were hospital acquired pneumonia, catheter related infections, Pneumocystis jiroveci pneumonia, Aspergilus infection, and cytomegalovirus infection, which are generally related to prolonged hospitalization and compromised immunity. Measures to prevent, reduce or monitor potential infections might help to diminish potentially fatal infection complications [44]. To the best of our knowledge, published English investigations to demonstrate the clinical features of AAV and factors predicting survival of such patients in Taiwan are rare. Since the patient number in this study was small, further multi-center studies with larger sample sizes are required. Conclusions AAV is not a common disease, but is known to have considerable morbidity and a high mortality rate. MPO- AAV was more common than PR3-AAV in this study, and the majority of diagnoses were MPA. Both BVAS and JVAS predicted survival outcome. Early diagnosis combined with adequate treatment, and measures to prevent, reduce or monitor infection may help with overall survival. References 1. Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007 Feb;66(2):222-7. 2. Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 2009 Dec;68(12):1827-32. 3. Miloslavsky E, Specks U, Merkel P, Seo P, Spiera R, Langford C, et al. Clinical outcomes of remission induction therapy for severe ANCA-Associated vasculitis. Arthritis Rheum. 2013 Jun 10. 4. Furuta S, Jayne DR. Antineutrophil cytoplasm antibodyassociated vasculitis: recent developments. Kidney Int. 2013 Feb 20. 5. Krause ML, Cartin-Ceba R, Specks U, Peikert T. Update on diffuse alveolar hemorrhage and pulmonary vasculitis. Immunol Allergy Clin North Am. 2012 Nov;32(4):587-600. 6. Koike K, Fukami K, Yonemoto K, Iwatani R, Obata R, Ueda K, et al. A new vasculitis activity score for predicting death in myeloperoxidase-antineutrophil cytoplasmic antibodyassociated vasculitis patients. Am J Nephrol. 2012;35(1):1-6. 7. Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med. 1967 Jul;43(1):8-14. 8. Walsh M, Flossmann O, Berden A, Westman K, Hoglund P, Stegeman C, et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Feb;64(2):542-8. 9. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med. 1979 Aug 2;301(5):235-8. 10. Luqmani R. Maintenance of clinical remission in ANCAassociated vasculitis. Nat Rev Rheumatol. 2013 Feb;9(2):127-32. 11. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. 12. Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Nov;64(11):3760-9. 13. Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sanchez- Menendez M, Ytterberg SR, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. Arthritis Rheum. 2012 Nov;64(11):3770-8. 14. Ozaki S. ANCA-associated vasculitis: diagnostic and therapeutic strategy. Allergol Int. 2007 Jun;56(2):87-96. 15. Lee S, Lawton JW. Heterogeneity of anti-pr3 associated disease in Hong Kong. Postgrad Med J. 2000 May;76(895):287-8. 16. Hattori M, Kurayama H, Koitabashi Y. Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children. J Am Soc Nephrol. 2001 Jul;12(7):1493-500. 17. Chen M, Yu F, Zhang Y, Zhao MH. Clinical [corrected] and pathological characteristics of Chinese patients with antineutrophil cytoplasmic autoantibody associated systemic 34
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Clinical characters and outcome of AAV 抗嗜中性球細胞質抗體相關血管炎患者之臨床表現與治療反應 : 單一醫學中心之回顧性研究 呂政勳沈玠妤吳政翰余家利 國立台灣大學附設醫院內科部過敏免疫風濕科 目的 : 探討北部一家醫學中心之抗嗜中性球細胞質抗體相關血管炎患者之臨床表現 治療反應與預後 方法 : 蒐集 2007 年 1 月至 2013 年 3 月間, 利用酵素免疫分析法檢驗抗嗜中性球細胞質抗體陽性, 並於國立台灣大學附設醫院接受治療之患者 以病例回顧方式記錄患者臨床表現 侵犯器官範圍 相關檢驗結果, 且評估患者之伯明翰血管炎活動指數 並統計分析患者之治療方式與成果, 以及疾病復發 結果 : 本研究總共納入了 26 例新診斷抗嗜中性球細胞質抗體相關血管炎患者, 當中 19 位為白血細胞髓過氧化酶抗體陽性,7 位為蛋白酶 3 抗體陽性 其中百分之 42 為顯微型多血管炎, 是最常見之診斷 本研究的患者中, 腎臟與肺部是最常被侵犯的器官, 分別占了百分之 73 與百分之 69 白血細胞髓過氧化酶抗體陽性之患者中, 百分之 53 在確診血管炎之前已有慢性腎病變 在追蹤期間共有 6 位患者於接受免疫調節治療後死亡 (26%), 感染是最常見之死因, 共有五名患者死於感染併發症 而肺腎症候群 較高之伯明翰血管炎活動指數或腎臟受侵犯患者之日本血管炎活動指數, 皆與患者之存活有關 結論 : 與過去東亞族群之研究相似, 在本研究中, 白血細胞髓過氧化酶抗體陽性血管炎比蛋白酶 3 抗體陽性血管炎更為常見, 疾病分類則以顯微型多血管炎為最常見 肺腎症候群 伯明翰血管炎活動指數與日本血管炎活動指數皆可預測患者存活 及早診斷與治療, 以及減少感染應可改善預後 關鍵詞 : 抗嗜中性球細胞質抗體 (ANCA) 血管炎 台灣 ANCA 36
Formosan Journal of Rheumatology 2013;27:37-43 Original Article A retrospective investigation of ultrasound findings in patients with shoulder pain from one center in northern Taiwan Min-chung Shen 1,2, Deh-Ming Chang 2, Tsung-Yun Hou 2, Feng-Cheng Liu 2, Hsiang-Cheng Cen 2, Shi-Jye Chu 2, San-Yuan Kuo 2, Chen-Hung Chen 2, Chi-Ching Chang 3 1 Division of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan 2 Division of Rheumatology, Immunology and Allergy, Department of Internal medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 3 Division of Rheumatology, Immunology and Allergy, Taipei Medical University Hospital, Taipei, Taiwan Objective: Research has shown that 15 30% of adults experience shoulder pain at some point during the course of their lives. The sensitivity and specificity of musculoskeletal ultrasound (MSUS) have been validated, showing that this tool can complement surgical findings and magnetic resonance imaging. We report ultrasound findings of patients with shoulder pain in rheumatological daily practice. Methods: The subject population for this retrospective study included 240 patients complaining of shoulder pain at the MSUS department of our rheumatology service between January 2010 and December 2012. The ultrasound examination included views of the rotator cuff, the long head of the biceps tendon, the subacromial-subdeltoid bursa, the acromioclavicular joint, and the glenohumeral joint. Results: Of the 240 patients, 140 were women and 100 were men, with ages ranging from 17 to 89 years and a mean age of 54.31 ± 14.64 years. Alterations of shoulder structures were detected in the supraspinatus tendon (76.2%), biceps tendon (62.4%), subscapularis tendon (22.9%), glenohumeral joint (20.4%), acromioclavicular joint (15.3%), subacromial-subdeltoid bursa (13.3%), and infraspinatous tendon (9.2%). Impingement (14.1%) and calcifications (8.2%) were also detected. Eight patients (3.3%) exhibited no sonographic evidence of any alteration. The sensitivity of the technique was confirmed by the finding of alterations in 96.7% of the cases. Conclusion: Although physical examination allows for a diagnostic approach in the treatment of shoulder pain, the technique is typically not accurate enough to ensure that the correct diagnosis is made. MSUS offered the precision necessary to detect the underlying pathology in 97% of the cases. Key words: Musculoskeletal ultrasound, painful shoulder Introduction Shoulder pain is one of the most common complaints Corresponding author: Chi-Ching Chang M.D. Division of Rheumatology, Immunology, Allergy, Department of Medicine, Taipei Medical University Hospital. No.252, Wu-Hsing Street, Taipei, Taiwan. Tel: +886-2-27372181 ext 3903; Fax: +886-2-27363051 E-mail: ccchang@tmu.edu.tw Received: September 16, 2013 Revised: October 6, 2013 Accepted: October 10, 2013 among those presenting at rheumatology clinics and often leads to considerable disability. Shoulder pain may be caused by various intra-articular, peri-articular and/or extra-articular mechanisms. The most common causes are rotator cuff disorders, acromioclavicular joint disease, and glenohumeral joint disorders [1], with classification of these disorders based primarily upon the results of clinical tests [2-7]. However, physical examination is often insufficient for a comprehensive understanding of the underlying pathology [8]. Among the alternate techniques available, 37
Musculoskeletal ultrasound, shoulder pain musculoskeletal ultrasound (MSUS) is the most accurate [9]. MSUS is regarded as the method of choice for noninvasive procedures and is expected to serve as an important tool in the evaluation of shoulder pain. The purpose of this study was to determine the likelihood that a given patient complaining of shoulder pain could be evaluated using MSUS. Patients and Methods Medical records and imaging studies were reviewed over a period of 2 years (01/01/2010 12/31/2012). The study group included 240 patients presenting with complaints of shoulder pain and referrals for MSUS at our rheumatology service. All patients were examined with commercially available equipment, including a 7.5 12 MHz linear phased-array transducer. A standardized scanning technique was used [10,11]. Investigations included the following: the rotator cuff and the tendons of the long head of the biceps brachii muscle, the subacromialsubdeltoid bursa, the acromioclavicular joint, and the glenohumeral joint. Each image was assessed for evidence of subacromial impingement. The MSUS diagnostic criteria for shoulder abnormalities were as follows. A full-thickness tear was defined as non-visualization of the tendon or fiber discontinuity from the humeral head to the subacromialsubdeltoid bursa. A partial-thickness tear was defined as a partial tear of the tendon fibers involving either the bursal or the articular surface that appears as a focal hypoechoic or anechoic defect not traversing the entire tendon thickness. Tendinosis was defined as abnormal echogenicity or tendon thickening with or without internal hypo or hyperechoic foci. Biceps tendon subluxation was defined as an empty bicipital groove and identification of the displaced tendon. A biceps tendon tear was defined as interruption of the tendon fibers, separation of the ends, and hypoechoic fluid filling the defect. Biceps sheath effusion was defined as a thickness of the hypoechoic halo of fluid surrounding the biceps tendon greater than 2cm. Calcification was defined as hyperechoic foci or a line with or without posterior acoustic shadowing. Subacromial impingement was defined as a buckling of the cuff effect as the cuff passes beneath the coracoacromial arch or fluid distending the subacromial-subdeltoid bursa or thickened bursa in front of the acromion while the arm is abducted. Subacromialsubdeltoid bursitis was defined as a hypoechoic fluidfilled bursa greater than 2 mm thick. Acromioclavicular Table 1. Baseline characteristics of the patients (n = 240) Sex (men/women) 100/140 Age 54.31 ± 11.3 (range 17 89) Rheumatologic diagnosis (%) Osteoarthritis 144 (60%) Rheumatoid arthritis 20 (8.3%) Sjögren s syndrome 6 (2.5%) Adult-onset Still s disease 2 (0.83%) None 68 (28.3%) degenerative changes were defined as the presence of osteophytes with associated articular surface irregularity with or without joint effusion or capsular thickening. Glenohumeral joint effusion was defined as a distance from the posterior infraspinatus tendon greater than 2 mm [9]. Results Table 1 shows the baseline demographic characteristics of the subjects. The study group consisted of 140 women and 100 men (mean age, 54.31 ± 14.64 years; range, 17 89 years). Table 2 presents the MSUS findings for patients presenting with complaints of Table 2. Sonographic findings with the spectrum of the specific alterations among the various anatomic structures of the shoulder. (n = 240) Finding Prevalence (%) Supraspinatus Full-thickness tear 30 (12.5) Partial-thickness tear 120 (50) Tendinosis 33 (13.7) Infraspinatus Tendinosis 22 (9.1) Subscapularis Tendinosis 28 (11.6) Partial-thickness tear 27 (11.2) Biceps brachii Tendinosis 62 (25.8) Full-thickness tear 52 (21.6) Partial-thickness tear 36 (15) Subluxation 0 (0.0) Subacromial-subdeltoid bursitis 32 (13.3) Glenohumeral joint effusion 49 (20.4) Impingement 34 (14.1) Acromioclavicular joint Effusion 7 (2.9) Degeneration 9 (3.7) Degeneration and fluid 21 (8.7) All tendons calcifications 20 (8.3) 38
Shen et al shoulder pain. MSUS revealed abnormalities in 232 (96.7%) patients. Rotator Cuff Supraspinatus tendon abnormalities were found in 76.2% (183/240) of patients. Full-thickness tears (Fig. 1) were detected in 30 patients (12.5%), partialthickness tears (Fig. 2) were seen in 120 (50%) patients, and tendinosis was detected in 33 (13.7%) patients. Alterations of the subscapularis tendon were observed in 55 (22.9%) patients, tendinosis in 28 (11.6%) and partialthickness tears in 27 (11.2%). Only 22 (9.1%) patients exhibited signs of infraspinatus tendinosis. Calcifications (Fig. 3) were observed in a total of 20 (8.3%) patients. Biceps tendon Alterations of the long head of the biceps tendon were found in 150 (62.4%) patients. Evidence of tendinosis (Fig. 4) was seen in 62 (25.8%) patients. Partial-thickness tears were seen in 36 (15%) patients and full-thickness tears were seen in 52 (21.6%) patients. No patient showed any sign of subluxation. Acromioclavicular joint (ACJ) ACJ abnormalities were found in 37 (15.4%) patients. Degenerative changes (osteophytes and Figure 3. 55 year-old man with painful shoulder, longitudinal scan of subscapularis tendon (SUB), calcified lesion (arrow) with acoustic shadow (star) in tendon. LT = lesser tuberosity. Figure 1. 61 year-old man with painful shoulder, transverse scan of supraspinatus tendon (SST), fullthickness tear of the supraspinatus tendon (arrow). GT = greater tuberosity. Figure 2. 75 year-old woman with painful shoulder, longitudinal scan of supraspinatus tendon (SST), partialthickness tear of the supraspinatus tendon (circle). GT = greater tuberosity. Figure 4. 80 year-old man with painful shoulder, transverse scan of biceps tendon, anechoic tendon sheath widening of the long head of biceps tendon with synovial proliferation, power doppler sonography showed increased vascularity (box). 39
Musculoskeletal ultrasound, shoulder pain capsular hypertrophy) alone were seen in 9 patients (3.7%). Presence of fluid in the joint alone was seen in only 7 (2.9%) patients (Fig. 5). Both degenerative changes and presence of fluid in the joint were seen in 21 (8.7%) patients. Glenohumeral joint Fluid in the glenohumeral joint cavity was detected in 49 (20.4%) patients (Fig. 6). Patients with fluid in the joint cavity were also more likely to have rotator cuff Figure 5. 72-year-old man with painful shoulder, transverse scan of the acromio-clavicular joint, effusion within joint with distension of the joint capsule. A = acromion, C = clavicle, E = effusion. tears. Subacromial-subdeltoid bursa (SASD bursa) Fluid in the SASD bursa was seen in 32 (13.3%) patients (Fig. 7). Subacromial impingement was found in 34 (14.1%) patients. Discussion Painful shoulder is a very common rheumatological condition. The accuracy of any investigation of shoulder abnormalities is important because it can impact treatment decisions. Physical examinations and conventional radiography, currently the most widely used approaches, have shown low accuracy as lesion diagnostic tools [9]. MSUS is a noninvasive, dynamic, inexpensive, and extensively available imaging technique for the assessment of painful shoulder [11, 12]. MSUS can differentiate among various primary pathologies or several entities of similar clinical picture. The spectrum of abnormal ultrasonographic findings in the present study were as follows. Rotator cuff disease We found that the rotator cuff tendon was the structure most likely to be affected in this group of Figure 6. 75-year-old woman with painful swelling shoulder, transverse scan of shoulder, fluid collection in the gleno-humeral joint. E = effusion, G = glenoid edge, H = humeral head. Figure 7. 28-year-old man of adult Still s disease with painful shoulder, longitudinal scan of supraspinatus tendon (SST), subacromial-subdeltoid bursitis with evidence of effusion (arrow) and synovial proliferation (star). GT = greater tuberosity. 40
Shen et al patients. In particular, the supraspinatus tendon most commonly exhibited abnormalities that could be detected by ultrasound (76.2%). Similarly, Iagnocco et al. [13] and Naredo et al. [9] reported the supraspinatus to be the most commonly involved tendon. The reason for frequent involvement of the supraspinatus tendon is its anatomical location between 2 bones (the head of the humerus and the acromion). The tendon is compressed during forward flexion of the shoulder joint. This leads to ischemia and later to degeneration of the tendon. In the present study, partial-thickness tears were more common than full-thickness tears. These findings are in accordance with those reported by Brennke et al. [14]. Iagnocco et al. [13] and Naredo et al. [9] reported infraspinatus involvement to be more common than supraspinatus involvement. However, our results suggest that the subscapularis was more likely than the infraspinatus to exhibit an abnormality. This variability may reflect differences in sample size. Impingement Impingement is rarely an isolated finding. There are usually secondary changes within the supraspinatus tendon or the subacromial bursa. We observed such changes to be more common in our study than in the findings reported by Naredo el al. This discrepancy may be due to differences in the study populations, particularly in patient age. Biceps tendon pathology The abnormalities of the bicep tendons is an important cause of shoulder pain, and is commonly associated with rotator cuff pathology [15]. We found the biceps tendon exhibited alterations, including tendinosis, partial-thickness tears, and full-thickness tears. These findings are in accordance with the results reported by Iagnocco et al. and Naredo et al. The biceps tendon is subject to mechanical forces that contribute to cuff impingement because of its anterior position. Further, the synovial sheath of the biceps is an extension of the glenohumeral synovial membrane. Hence, the frequent association of cuff tears with biceps tendon abnormalities. Acromioclavicular joint abnormality Alterations in the ACJ were often found in association with both inflammatory and degenerative changes. The pathological findings detected most commonly by MSUS in the ACJ include irregular bone surfaces, osteophytes, effusions, erosions, acromioclavicular cysts, and dislocation [10,16,17]. Degenerative changes (osteophytes and capsular hypertrophy) alone were seen in 9 (3.7%) painful shoulders. Presence of fluid in the joint alone was seen in only 7 (2.9%) painful shoulders. Both degenerative changes and presence of fluid in the joint were seen in only 21 (8.7%) painful shoulders. These findings are in accordance with those reported by Iagnocco et al. Glenohumeral joint effusion In our study, only 49 (20.4%) patients had fluid in the glenohumeral joint cavity. Fluid in the joint cavity was associated with a torn rotator cuff. The less frequent involvement of the glenohumeral joint could be attributed to the limited number of subjects with synovitis. Subacromial-subdeltoid bursa We found SASD bursal fluid, which is associated with numerous causes of shoulder pain, in 32 (13.3%) of examined patients. SASD bursitis often accompanies rotator cuff lesions and impingement syndrome [18]. Fluid within both the bursa and the joint in the presence of a full-thickness tear of the rotator cuff is due to direct communication between the 2 compartments through the defect, akin to positive findings during a single-contrast arthrogram. In a partial-thickness tear, the presence of fluid is more likely due to direct mechanical irritation of the bursa by impingement or fenestrations within the partially torn cuff, which allow for communication. The volume of fluid seen within the bursa is far greater in full-thickness tears than in partial-thickness tears or impingement. Calcific tendonitis The etiology and pathogenesis of calcific tendonitis of the rotator cuff are still unknown [19-22]. It is very important to distinguish a particular case of shoulder pain as resulting from calcific tendonitis alone or from a rotator cuff tear. Tendon calcifications were observed in 20 (8.3%) patients in our study, in whom complaints of shoulder pain had been mistakenly attributed to rotator cuff tears. We recognize several possible limitations of this study. First, it is the retrospective investigation of the accuracy of ultrasound findings in patients with shoulder pain. There was no analysis of physical examinations or other images. To compensate for these limitations, only obvious abnormal ultrasound findings were included. From above discussion, we observe that MSUS 41
Musculoskeletal ultrasound, shoulder pain offered the valuable and the precision necessary to detect the underlying pathology of shoulder pain in 97% of the cases presented here. In conclusion, MSUS is recognized to be a useful and important tool for the assessment of patients with painful shoulder. References 1. Mitchell C, Adebajo A, Hay E, Carr A. Shoulder pain: diagnosis and management in primary care. Br Med J 2005; 331:1124-8. 2. van der Windt DA, Koes BW, De Jong BA, Bouter LM. Shoulder disorders in general practice: Incidence, patient characteristics, and management. Ann Rheum Dis 1995; 54:959-64. 3. Bot SD, Van der Waal JM, Terwee CB, Van der Windt DA, Schellevis FG, Bouter LM, et al. Incidence and prevalence of complaints of the neck and upper extremity in general practice. Ann Rheum Dis 2005; 64:118-23. 4. Chakravarty KK, Webley M. Disorders of the shoulder: an often unrecognised cause of disability in elderly people. Br Med J 1990; 300:848-9. 5. Chard MD, Hazelman R, Hazelman BL, King RH, Reiss BB. Shoulder disorders in the elderly: a community survey. Arthritis Rheum 1990; 34:766-9. 6. Feleus A, Bierma-Zeinstra SM, Miedema HS, Bernsen RM, Berhaar JA, Koes BW. Incidence of non-traumatic complaints of arm, neck and shoulder in general practice. Man Ther 2008; 13:426-33. 7. Ostor AJK, Richards CA, Prevost AT, Speed CA, Hazleman BL. Diagnosis and relation to general health of shoulder disorders presenting to primary care. Rheumatology 2005; 44:800-5. 8. Tytherleigh-Strong G, Hirahara A, Miniaci A. Rotator cuff disease. Curr Opin Rheumatol 2001; 13:135-45. 9. Naredo E, Aguado P, De Miguel E, Uson J, Mayordomo L, Gijon-Banos J, et al. Painful shoulder: comparison of physical examination and ultrasonographic findings. Ann Rheum Dis 2002; 61:132-6. 10. Backhaus M, Burmester GR, Gerber T, Grassi W, Machold KP, Swen WA, et al. Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 2001; 60: 641 9. 11. van Holsbeeck MT, Introcasso J. Sonography of the shoulder. Musculoskeletal ultrasound, 2nd ed. St Louis, Mo: Mosby, 2001: 463 516. 12. Bureau NJ, Beauchamp M, Cardinal E, Brassard P. Dynamic sonography evaluation of shoulder impingement syndrome. AJR Am J Roentgenol 2006; 187: 216 20. 13. Iagnocco A, Coai G, Leone A, Valesini G. Sonographic study of painful shoulder. Clinical and Experimental Rheum 2003; 21:355-8. 14. Beall DP, Williamson EE, Ly JQ, Adkins MC, Emery RL, Jones TP, et al. Association of biceps tendon tears with rotator cuff abnormalities: degree of correlation with tearsof the anterior and superior portions of the rotator cuff. Am J Roentgenol 2003; 180: 633 9. 15. Brenneke SL, Morgan CJ: Evaluation of ultrasonography in the assessment of rotator cuff tendon tears. Am J Sports Med 1992; 20:287-9. 16. Hodler J, Resnick D. Current status of imaging of articular cartilage. Skeletal Radiol 1996; 25:703-9. 17. Naredo E, Iagnocco A, Valesini G, Uson J, Beneyto P, Crespo M. Ultrasonographic study of painful shoulder. Ann Rheum Dis 2003; 62: 1026-7. 18. Petersson CJ. Spontaneous medial dislocation of the tendon of the long biceps brachii. An anatomic study of prevalence and pathomechanics. Clin Orthop 1986; 211:224 7. 19. Rathbun JB, Macnab I. The microvascular pattern of the rotator cuff. J Bone Joint Surg Br 1970; 52:540 53. 20. Booth RE Jr, Marvel JR Jr. Differential diagnosis of shoulder pain. Orthop Clin North Am 1975; 6:353 79. 21. Chard MD, Cawston TE, Riley GP, Gresham GA, Hazleman BL. Rotator cuff degeneration and lateral epicondylitis: a comparative histological study. Ann Rheum Dis 1994; 53: 30 4. 22. Uhthoff HK, Sarkar K, Maynard JA. Calcifying tendinitis: a new concept of its pathogenesis. Clin Orthop 1976; 118:164 8. 42
Shen et al 骨骼肌肉超音波於病人肩關節疼痛的診斷 北台灣一家醫學中心的病歷回溯性調查 1,2 沈明忠 2 張德明 2 侯宗昀 2 劉峰誠 2 陳相成 2 朱士傑 2 郭三元 2 陳政宏 3 張棋楨 1 國軍桃園總醫院內科部 2 三軍總醫院風濕免疫過敏科 3 台北醫學大學附設醫院風濕免疫過敏科 目的 : 研究報告顯示在一般成人中, 約有 15-30% 於生活過程中會經歷肩部疼痛 骨骼肌肉超音波的敏感性和特異性已獲得證實, 成為外科手術發現及核磁共振檢查之外的替代工具 針對病患肩部疼痛, 我們發表了日常風濕科超音波檢查結果 方法 : 我們在 2010 年 1 月及 2012 年 12 月之間於本院風濕科超音波室, 回溯性調查共 240 位病人抱怨肩部疼痛 超音波檢查包含了旋轉肌群 二頭肌腱的長頭 三角肌下 - 肩峰下滑囊 肩峰鎖骨關節, 和肩窩肱骨關節 結果 :240 位病人中, 有 140 位女性和 100 位男性, 年齡為 17 歲至 89 歲, 平均為 54.31 ± 14.64 歲 肩部結構發生病變率分別是脊上肌腱為 76.2% 二頭肌肌腱為 62.4% 肩胛下肌腱為 22.9% 肩窩肱骨關節為 20.4% 肩峰鎖骨關節為 15.3% 三角肌下- 肩峰下滑囊炎為 13.3%, 及脊下肌腱為 9.1% 同時也檢查到夾擠現象為 14.1% 以及鈣化現象為 8.2% 有 8 位病人超音波顯示無病變產生 此檢查方式的精確率達 96.7% 結論 : 雖然理學檢查可作為診斷和治療肩部疼痛的方法, 然而此方式並無法提供診斷的正確性 骨骼肌肉超音波對於肩膀疼痛的病人約 97% 可提供病變處 關鍵詞 : 骨骼關節超音波 肩膀疼痛 43
Formosan Journal of Rheumatology 2013;27:44-50 Original Article Analysis of Sources, Purposes and Presentations of Soft-Tissue Masses referred for Ultrasonography Wei-Jhe Hong, Ying-Ming Chiu Division of Allergy, Immunology, and Rheumatology Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan Objective: Soft-tissue masses are common and difficult to accurately diagnosis initially. Therefore, many patients are referred for sonographic study and clinical follow-up. Here, we aimed to analyze the sources, purposes and presentations of those referred. Methods: We analyzed 187 patients referred for evaluation of soft-tissue masses using high-resolution ultrasonography between January 2009 and June 2013. All electronic medical records, reasons for referral, and ultrasonographic reports were reviewed. Results: The study comprised 100 female and 87 male patients aged from 0.25 to 94 years old (mean age, 44.29 years old). Dermatology department referred the majority of the patients, followed by rheumatology. The mean size of lesions was 2.41 cm with a range of 0.30 to 7.70 cm. Lesions (n=187) were usually located on the back (n=36) and lower limbs (n=36). Lipoma was the most commonly diagnosed lesion (n=73), followed by ganglion cyst (n=18) and epidermoid inclusion cyst (n=14). The epidemiology of lesions in this study (age, sex, size, proportion and distribution) resembled with that of a large population study conducted without ultrasonographic intervention. Benefits of ultrasound intervention were also discussed in this study. Conclusion: This study describes the benefit of ultrasonography in soft-tissue masses detection and describes the presentation of soft-tissue masses related in a single medical center in Taiwan. Key words: ultrasonography, imaging, soft-tissue masses, soft tissue Introduction Soft-tissue masses are common in terms of both the global and Taiwanese population. This term encompasses a range of both benign and malignant processes. Studies have shown that the majority of soft-tissue masses are benign. In the United States, the incidence of soft-tissue tumors is approximately 3 cases Corresponding author: Ying-Ming Chiu Division of Allergy, Immunology, and Rheumatology Department of Internal Medicine, Changhua Christian Hospital. No.135, Nanxiao St., Changhua City, Changhua County 500, Taiwan (R.O.C.) Tel: +886-4-7238595#1031; Fax: +886-4-7228289 E-mail: 129273@cch.org.tw Received: September 16, 2013 Revised: September 30, 2013 Accepted: October 1, 2013 per 1,000 people, and only 0.67% of these are malignant [1]. In Taiwan, patients with soft-tissue masses often visit a Dermatologist, surgeon, rheumatologist or another medical professional ( such as general practitioner and geriatrician ). However, it is difficult to accurately diagnose the patient upon initial presentation and biopsy may be essential in order to to confirm the diagnosis on a few occasions. The number of patients being referred for imaging analysis and characterization of soft-tissue masses rather than for short-term clinical follow-up or biopsy is increasing [2]. Several imaging modalities have been used to assess these masses, including plain radiography, nuclear medicine, high-resolution ultrasonography (HRUS), computed tomography (CT), magnetic resonance imaging (MRI), angiography and positron emission tomography (PET). 44
Hong et al Of the above mentioned imaging studies, HRUS appears to be favored by medical practitioners for several reasons, including wide availability, relative inexpensiveness, no ionizing radiation exposure, and capable of demonstrating the relationship of the lesion to the underlying soft-tissue structures by dynamic realtime examination [3]. The sonographic appearance of superficial masses or tumors has been described by multiple authors [4 7]. In Changhua Christian Hospital, many patients are referred by primary and secondary care clinicians for the assessment of soft-tissue masses using HRUS which is useful for acquiring information about the echogenicity, vascularity, size, and depth of the lesions as well as their relationship to adjacent structures [8]. Several previous papers have discussed the indications of ultrasound use for soft-tissue masses detection [9]. In summary, this study aimed to analyze the sources, purposes and presentations of those referred for sonographic survey in a single medical center in Taiwan. Materials and Methods Patients In this retrospective study, the medical records of 187 patients referred for evaluation of soft- tissue masses using HRUS performed by rheumatologists between January 2009 and June 2013 in Changhua Christian Hospital were analyzed. All patients electronic medical records and ultrasonographic reports were reviewed. Furthermore, we also analyzed referral divisions. Imaging All soft-tissue masses were checked using Grayscale US and Power Doppler US or Color Doppler US. Diagnostic criteria for specific lesions using ultrasound, which have previously been described, were followed in this study. The 3 most common types of lesions detected in this study are listed below. First, the typical characteristics of lipoma such as (1) elongated isoechoic or echogenic mass in subcutaneous tissues [10], (2) existence of striated echoes in the tumor corresponding to the septa [11], (3) well-defined margins, and (4) avascularity or low vascularity on Power Doppler. Second, the typical characteristics of ganglion cyst such as (1) cystic anechoic mass with posterior acoustic enhancement that arises from a tendon sheath or joint capsule, (2) exhibits lobulation and contain internal septations or dependent debris [12], (3) well-defined margins, and (4) avascularity on Power Doppler. Finally, the typical characteristic epidermoid inclusion cyst such as (1) round to oval structure along with the phenomena of dorsal acoustic amplification and lateral shadowing [13-16], (2) homogeneous hypoechoic segment or plaque-like material disseminated within the lesion is possibly because of clustered cholesterol material or oil-droplets [17], (3) well-defined margins, and (4) avascularity on Power Doppler. Ultrasonography was performed with a highfrequency probe (> 10 MHz) for small superficial lesions and a 5 10 MHz probe for larger lesions as advised [18]. Shape, size, depth, echogenicity, composition, sound transmission, margin, and vascularity were recorded. We collected the above mentioned information by recording the comments of the initial ultrasonographer, and there is, therefore, no reason to discuss intraobserver or interobserver variability. Statistical analysis This was a descriptive study. Data analysis was performed according to the study objectives. Patient s characteristics are reported as simple descriptive statistics. Results As mentioned previously, we collected data on 187 patients who were referred for the assessment of softtissue masses using ultrasound between January 2009 and June 2013 at Changhua Christian Hospital, Taiwan. Purposes of referral included (1) confidence about the presence of suspected soft-tissue masses, (2) assessment of the characteristics of soft tissue masses, (3) evaluation of the relationship of the lesion to adjacent tissues, and (4) provision of more information, regarding requirement of invasive procedures or real-time interventions. Patient s characteristics and sites of lesions are summarized in Table 1. The sample included 100 female and 87 male patients aged from 0.25 to 94 years (mean age, 44.29 years). Mean lesion size was 2.41 cm ranging from 0.30 to 7.70 cm. Depth varied but only superficially, therefore, it has not been described here. The physical distribution of lesions was recorded as follows: back (n=36), lower Limbs (n=36), face (n=23), upper Limbs (n=21), hand/wrist (n=16), neck (n=14), scalp (n=13), foot/ankle (n=13), abdomen (n=9), and chest (n=6). We also analyzed the distribution of referral divisions (Table 2). The majority of referees were dermatologists (n=121) followed by rheumatologists (n=24), and then 45
Soft-Tissue Masses and sonography Table 1. Patient Characteristics and Site of Lesions Characteristic Value Age, mean [range], y 44.3 [0.25-93] Male to female ratio 87:100 Size of lesions, mm 24 ± 6 Site of lesions Siteh Scalp Face Neck Chest Abd Back Hand/ Wrist Upper Limbs Lower Limbs Foot/ Ankle N 13 23 14 6 9 36 16 21 36 13 187 Tatal Table 2. Distribution of Referral Sources for Sonography Referral Sources Dermatology Rheumatology Hematology Infection Surgeon General medicine Others Total = 187, Dermatology = 121, Rheumatology = 24, Hematology = 15, Infection = 9, Surgeon = 6, General medicine = 5, Others (Pediatrics 3, Neurology 1, Nephrology 1, Gastroenterology 1, ENT 1) = 7 hematologists (n=15), infection specialists (n= 9), surgeon (n= 6), general practitioners (n=5), pediatricians (n=3), neurologist (n=1), nephrologist (n=1), gastroenterologist (n=1), and ENT specialist (n=1). We noted that lipoma was the most commonly diagnosed lesion (n=73), followed by ganglion cyst (n=18), and epidermoid inclusion cyst (n=14). There were 46 patients who could not be definitively diagnosed based on ultrasound and the remaining 36 patients were diagnosed with other conditions (Table 3). Among 73 lipoma patients, 30 patients underwent biopsy and histological proof in 25 patients was detected. In addition, 10 patients with epidermoid inclusion cysts underwent biopsy and histological proof in 8 patients was detected. Among the lipomas diagnosed in the sample, 43 (59%) were homogeneous, 40 (55%) were isoechoic, and 24 were hypoechoic (33%). Sixty-three (86%) of them had well-defined margins and 65 (90%) were ovoid in shape. Furthermore, all lipomas (100%) were solid and only 3 (4%) showed mildly increase in vascularity. All diagnosed ganglion cysts (100%) were homogeneous, hypoechoic, cystic and had well-defined margins. Seventeen (94%) were round in shape and 1 (6%) had mildly increase in vascularity. Seven (50%) epidermoid inclusion cysts were homogeneous and all (100%) were hypoechoic. Thirteen (93%) had well-defined margins and 11 were ovoid (79%) in shape. All (100%) of them were solid and 6 (43%) showed presence of vascularity ( Figure 1 ). We noted that 34 (74%) unknown lesions were heterogeneous and 26 (57%) were isoechoic. Thirtyeight (83%) of them showed ill-defined margins. Seventeen (37%) were ovoid in shape and 15 (33%) were scalloped. Twenty-five (54%) were solid and 13 (28%) were cystic. In addition, 17 (37%) showed the presence of vascularity. It is interesting to review the distribution of the specific types of lesions. For example, lipomas (n=73) were usually noted on the back (n=24), upper limbs (n=13), head/neck (n=12), and then lower limbs (n=10). Ganglion Cysts (n=18) were usually noted on the hand/wrist (n=12) and foot/ankle (n=4). Furthermore, epidermoid inclusion cysts (n=14) were usually noted Table 3. Nature of Specific Masses and Patient Demographics Mass Masses, n Female Male Mean Age, y Mean Size, cm Lipoma 73 32 41 44.3 (3-72) 3.1 ± 0.7 G.C. 18 13 5 47.4 (9-72) 1.1 ± 0.2 EIC 14 7 7 39.6 (12-79) 2.6 ± 0.6 Unknown 46 29 17 48.9 (1-94) 2.0 ± 0.4 Others 36 19 17 38.7 (0.25-79) 2.1 ± 0.4 46
Hong et al Figure 1. An 18-year-old male patient had facial mass on the left side for months. On ultrasound investigation, it presented as a cutaneous ovoid lesion over the left pre-auricle area. It was heterogeneous and hypoechoic with welldefined margins and a solid composition. The mass showed dimensions of 2.25*1.77*1.22 cm in size with a depth of 0.37 cm. In addition, no vascularity was detected on Doppler. A diagnosis of epidermoid inclusion cyst was favored and was later confirmed with skin biopsy. on the head/neck (n=10) (Table 4-1). The distribution of other lesions are summarized at Table 4-2. In addition, we noted that the proportion and distribution of lesions referred by dermatologists for sonography were similar according to the results obtained from the cases (Table 5). Such conditions were also noted in those who were Table 4-1. Distribution of Specific Lesion Table 5. Distribution of Specific Lesion (referred from Lipoma Ganglion Cyst EIC Unknown Dermatology) (n=121) Scalp 2 0 2 3 Lipoma Ganglion Cyst EIC Unknown Others Face 3 0 3 13 Scalp 2 0 2 3 4 Neck 7 0 5 2 Face 2 0 3 12 3 Chest 5 0 0 0 Neck 3 0 5 2 0 Abdomen 3 0 2 4 Chest 4 0 0 0 1 Back 24 1 1 6 Abdomen 2 0 1 2 0 Hand/Wrist 1 12 0 1 Back 18 0 0 3 3 Upper Limbs 13 1 0 4 Hand/Wrist 0 7 0 1 2 Lower Limbs 10 0 0 13 Upper Limbs 8 1 0 1 2 Foot/Ankle 5 4 1 0 Lower Limbs 7 0 0 5 3 Total 73 18 14 46 Foot/Ankle 4 3 1 0 1 Total 50 11 12 29 19 Table 4-2. Distribution of Specific Lesion Hematoma Bone Hemangioma Panniculitis Pilomatricoma Lymph node Calcification Baker cyst Others Scalp 0 2 1 0 0 2 0 0 1 Face 1 0 1 0 2 0 0 0 0 Neck 0 0 0 0 0 0 0 0 0 Chest 0 0 0 0 0 0 0 0 1 Abdomen 0 0 0 0 0 0 0 0 0 Back 0 1 1 0 0 0 0 0 2 Hand/Wrist 2 0 0 0 0 0 0 0 0 Upper Limbs 0 0 2 0 1 0 0 0 0 Lower Limbs 4 0 0 4 0 0 2 2 1 Foot/Ankle 0 2 0 0 0 0 0 0 1 Total 7 5 5 4 3 2 2 2 6 *Others: scalp-furuncle; chest-furuncle; back, one case of dermatofibrosarcoma and another described as a muscular component; lower limbs-neurofibromatosis; foot/ankle-fatty component. 47
Soft-Tissue Masses and sonography referred by rheumatologists ( Lipoma : back = 4, head/ neck = 3, limbs = 2 ; ganglion cyst : hand/wrist = 5, foot/ ankle = 1 ; epidermoid inclusion cyst : 0 ; Unknown : limbs = 4, abdomen = 1 ; Others : 4). Discussion Soft tissues are defined as the subcutaneous and cutaneous tissues or compartments, muscles and tendons, fatty tissue, the soft parts of the joints (joint capsule, synovium, and ligaments) and peripheral neurovascular bundles [19]. Soft-tissue masses are common in the general population. Most are benign [1] and could be caused by other structural abnormality such as bony protrusions. These lesions involve a number of pathologies and are difficult to diagnose accurately only by history taking or physical examination. Imaging modalities including plain radiography, nuclear medicine, HRUS, CT, MRI, angiography and PET can all increase the accuracy of diagnosis. Among these tools, HRUS is an appropriate, noninvasive and could even be the first-line modality to evaluate soft-tissue masses. Several published studies have found that sonography is effective in the evaluation of soft-tissue masses. Kuwano et al [8] noted that sonography is useful for the pre-operative examination of subcutaneous lesions, increasing the sensitivity of the diagnosis of lipoma from 55% to 88% and the specificity of the diagnosis of epidermal cyst from 94% to 99% compared with palpation alone. Furthermore, in a retrospective study of 818 patients (693 benign and 125 malignant masses) published by Chiou et al [20], the most predictive sonographic features of malignancy were infiltrated margin, scalloped shape, and size greater than 5 cm. Therefore, we thought ultrasound could offer useful clues to clinicians. In this retrospective study, we analyzed 187 patients referred for evaluation of soft-tissue masses using HRUS for the duration of 4.5 years. The dermatology department referred majority of the cases followed by rheumatology. Original purposes for referral varied. These lesions (n=187) were generally located on the back (n=36) and lower limbs (n=36) (Table 1). A review of the distribution of lesions was conducted in a large population by Kransdorf in 1995 [21]. In this study, lipoma was the most common type of lesions, was most prevalent in patients aged between 40 and 50 years and tended to occur on the trunk or head/neck. The findings of our study are similar. Kransdorf also noted that ganglion cysts had a tendency to occur on the hand/wrist, and our observation had similar result. Other specific lesions referred for sonographic exam also resembled the above mentioned theories (Table 4 and 5). The necessary of ultrasonography is debatable because the possibility and proportion of the detecting these lesions and distribution these lesions were similar whether or not if ultrasonography or not was performed. However, changing the point of view, our database and collection were reliable that may reflect the clinical epidemiology. Second, recalling the purposes for referring, including (1) confidence about the presence of suspected soft-tissue masses, (2) assessment of the characteristics of soft tissue masses, (3) evaluation of the relationship of the lesion to adjacent tissues, and (4) provision of more information, regarding requirement of invasive procedures or real-time interventions, therefore, we concluded that ultrasonography can help clinician to diagnose the cause of soft-tissue masses and to plan treatment. In conclusion, this study describes the application of ultrasonography in soft-tissue masses and the general characteristics of their presentation in a single medical center in Taiwan. References 1. Damron TA, Beauchamp CP, Rougraff BT, Ward WG. Softtissue lumps and bumps. J Bone Joint Surg 2003;85A:1142 55. 2. Wagner JM, Lee KS, Rosas H, MD, Kliewer MA. Accuracy of Sonographic Diagnosis of Superficial Masses. J UltrasoundMed 2013; 32:1443 1450. 3. Lin CS, Wang TG, Shieh JY, Chen WS. Accuracy of Sonography in the Diagnosis of Superficial Ganglion Cyst and Lipoma. J Med Ultrasound 2009;17(2):107 113. 4. Widmann G, Riedl A, Schoepf D, Glodny B, Peer S, Gruber H. State-of the-art HR-US imaging findings of the most frequent musculoskeletal soft-tissue tumors. Skeletal Radiol 2009; 38:637 649. 5. Ahuja AT, King AD, Kew J, King W, Metreweli C. Head and neck lipomas: sonographic appearance. AJNR Am J Neuroradiol 1998; 19:505 508. 6. Inampudi P, Jacobson JA, Fessell DP, et al. Soft-tissue lipomas: accuracy of sonography in diagnosis with pathologic correlation. Radiology 2004; 233:763 767. 7. Choong KKL. Sonographic appearance of subcutaneous angiolipomas. J Ultrasound Med 2004; 23:715 717. 8. Kuwano Y; Ishizaki K; Watanabe R; Nanko H. Efficacy of Diagnostic Ultrasonography of Lipomas, Epidermal cysts, and Ganglions. Arch Dermatol. 2009; 145(7): 761-764. 9. Hwang S and Adler RS. Sonographic Evaluation of the Musculoskeletal Soft Tissue Masses. Ultrasound Quarterly 48
Hong et al 2005; 21:259 270. 10. Fornage BD, Tassin GB. Sonographic appearances of superficial soft tissue lipomas. J Clin Ultrasound. 1991;19 (4): 215-220. 11. Fornage B. Soft tissue masses: the underutilization of sonography. Semin Musculoskelet Radiol. 1999; 3:115 133. 12. Ortega R, Fessell DP, Jacobson JA, et al. Sonography of ankle ganglia with pathologic correlation in 10 pediatric and adult patients. AJNR Am J Roentgenol 2002;178:1445 9. 13. Ulrich J, Voit C. Ultrasound in dermatology, II: ultrasound of regional lymph node basins and subcutaneous tumours. Eur J Dermatol. 2001; 11(1): 73-79. 14. Ulrich J, Gollnick H. Differential diagnosis of cutaneous and subcutaneous tumours assessed by 7.5 MHz ultrasonography. J Eur Acad Dermatol Venereol. 1999; 12(2): 187-189. 15. Takemura N, Fujii N, Tanaka T. Epidermal cysts: the best surgicalmethod can be determined by ultrasonographic imaging. Clin Exp Dermatol. 2007; 32(4): 445-447. 16. Lee HS, Joo KB, Song HT, et al. Relationship between sonographic and pathologic findings in epidermal inclusion cysts. J Clin Ultrasound. 2001; 29(7):374-383. 17. Reynolds JH, Wolinski AP. Sonographic appearance of branchial cysts. Clin Radiol 1993;48:109 10. 18. Chiou HJ, Chou YH, Chiou SY, Wang HK. Ultrasonography in Superficial Soft Tissue Tumors. J Med Ultrasound 2007;15(3):152 174. 19. Gielen JLMA, De Schepper AM, Vanhoenacker F, Parizel PM, Wang XL, Sciot R, Weyler J. Accuracy of MRI in characterization of soft tissue tumors and tumor-like lesions. A prospective study in 548 patients. Eur Radiol (2004) 14:2320 2330. 20. Chiou HJ, Chou YH, Chiu SY, et al. Differentiation of benign and malignant superficial soft-tissue masses using grayscale and color Doppler ultrasonography. J Chin Med Assoc 2009; 72:307 315. 21. Kransdorf MJ. Benign Soft Tissue Tumors in a Large Referral Population: Distribution of Specific Diagnoses by Age, Sex, and Location. AJR 1995; 164:395-402. 49
Soft-Tissue Masses and sonography 針對軟組織腫塊被轉介施行超音波評估之回溯性分析 洪偉哲邱瑩明 彰化基督教醫院內科部過敏免疫風濕科 目的 : 軟組織腫塊於臨床上並不少見, 但是常無法第一時間就得到適當的診斷 因此, 不少患者會被轉介安排超音波做進一步評估與追蹤 本研究的立意是希望瞭解開單科別的來源與目的以及針對這些病灶做基本的分析 方法 : 自 2009 年 1 月至 2013 年 6 月期間, 總共有 187 名患者接受檢查 所有相關的病歷內容 轉介目的與超音波報告均被完整地瀏覽和紀錄 結果 : 於這 187 名患者, 女性佔 100 位而男性則為 87 位 平均年齡為 44.29 歲, 年紀最小的為 3 個月大, 最年長的則為 94 歲 病灶平均的大小為 2.41 公分, 分佈小至 0.30 公分而最大達 7.70 公分 結果顯示以背部與下肢的病灶數最多 脂肪瘤為最常見超音波確診病灶, 其次為腱鞘與表皮囊腫 整體以及個別病灶的流行病學分析 ( 好發年紀, 性別, 比例與分佈情形 ) 均與先前其他大規模而未經超音波介入的研究相仿 此外, 我們亦瀏覽曾探討軟組織超音波應用以及可信度的文章 結論 : 本篇研究描述在台灣單一醫學中心其超音波檢查於軟組織腫塊應用的情況, 以及對檢查結果的基本分析 關鍵詞 : 超音波 影像學 軟組織腫塊 軟組織 50
Formosan Journal of Rheumatology 2013;27:51-58 Original Article Relationship between the level of anti-double strand DNA antibody and lupus renal diseases in patients with systemic lupus erythematosus Ching-Hui Hsu, Ming-Han Chen, Wei-Sheng Chen, Chien-Chih Lai, and Hsiao-Yi Lin Department of medicine, Division of Allergy, Immunology, Rheumatology, Taipei Veteran General Hospital, Taipei, Taiwan. Objective: The goal of this study was to investigate the development of acute lupus nephritis or end stage renal disease in patients who had persistently high or variant levels of anti-dsdna. Methods: Patients who fulfilled the diagnostic criteria for SLE were placed into one of three groups: persistent high levels, variant levels, and persistent normal levels of anti-dsdna. Clinical renal diseases were based on the present of acute lupus nephritis, and the development of end stage renal disease (ESRD). Results: A total of 257 patients were enrolled in the study. Among them, 86 patients never have an elevation of anti-dsdna during the follow-up period, 46 patients had variant levels of anti-dsdna, and 125 patients had persistently high levels of anti-dsdna. We compared the lupus nephritis flares and ESRD between normal anti-dsdna group with high anti-dsdna group or variant anti-dsdna group, and the results showed significantly statistics different in acute lupus nephritis between the comparisons (p< 0.001, p<0.001 respectively). However, there were no statistics different in ESRD (p=0.539, p=0.061 respectively). Conclusion: Patients who consistently showed a high anti-dsdna level would have higher rate of acute lupus nephritis. Besides, if their serum elevated level of anti-dsdna could not back and consistently within normal range, these patients also have less favorable renal outcome. Therefore, more intensive follow up and aggressive medical treatments are needed for these patients. Key words: systemic lupus erythematosus(sle), anti-dsdna, lupus nephritis Introduction Systemic lupus erythematosus (SLE) is a connective disease that can involve multiple organs, including the skin, musculoskeletal system, central nervous system, etc, and lupus nephritis is one of the most serious manifestations of SLE. Lupus nephritis will Corresponding author: Hsiao-Yi Lin Department of medicine, Division of Allergy, Immunology, Rheumatology, Taipei Veteran General Hospital. No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City, Taiwan 11217, R.O.C. Tel: +886-2-28712121 ext 7521 E-mail: hylin@vghtpe.gov.tw Received: August 16, 2013 Revised: September 5, 2013 Accepted: September 30, 2013 cause deterioration of renal function and mortality, including an increased absolute annual mortality rate or cumulative risk of death overtime [1]. The development of lupus nephritis is related to several demographic characteristics such as age, races, and gender. The age of onset and disease duration will affect the probability of developing lupus nephritis. A greater percentage of patients with juvenile-onset SLE (diagnosed at age <18 years) show renal involvement compared to patients with adult-onset SLE [2]. Furthermore, only 5% of patients who are diagnosed with SLE at an age >50 years show renal involvement [3]. Ethnicity can also affect the development and prognosis of the disease. Lupus nephritis is more likely to occur in certain ethnic groups such as African Americans, Asians, and Hispanics [4, 5]. Furthermore, Asian males are more susceptible to lupus 51
anti-dsdna in lupus nephritis nephritis, and have a worse renal outcome [6]. Lupus nephritis is considered to be an immune complex mediated glomerular disease, but tubular and vascular damage are also involved. Vascular damage may result from vessel wall necrosis, or thrombotic microangiopathy. The World Health organization(who) first defined lupus nephritis in 1982, and verified its pathology in 1995 [7]. The International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) further modified the classification criteria in 2004 [8,9]. Despite the use of immunosuppressive agents can control or produce a complete remission of lupus nephritis; the disease still flares sometime during the lifespan of 27-66% of patients [10]. Nevertheless, proper treatment can strongly affect the renal outcome of lupus nephritis and the risk for developing end stage renal disease (ESRD). A previous study with long term follow-up of patients disclosed that the median time to renal flare was 36 months in patients who had completed treatment, but 18 months in partially treated patients [11]. Renal biopsy is the gold standard for diagnosing lupus nephritis; however, this is an invasive procedure and the use of serial biopsies to monitor the status of SLE is almost impractical. Additionally, the use of serial biopsies in special groups of patients, such as patients with coagulopathy, may also be impractical. Anti-dsDNA was first detected in mice and humans in 1957 [12]. While anti-dsdna is found in only 70-80% in SLE patients, it has a high specificity for SLE. That is, only 0.5% of a normal population will test positive for the presence of anti-dsdna. Anti-dsDNA can be detected in serologic examinations, and is deposited on the glomeruli, causing the onset or worsening of glomerulonephritis [13]. It is widely accepted that the level of anti-dsdna in serum can reflect disease activity, and is used as a marker during clinical follow-up of SLE patients. However, among the patients followed up in the outpatient department in this study, we discovered that there were patients who had persistently high levels of anti-dsdna in their serum, and it was difficult to evaluate the disease activity in these patients by only using anti-dsdna levels. Additionally, there were still some patients who showed varying levels of antidsdna, but not all of these patients suffered from flares of lupus nephritis. Therefore, this cross-sectional observational study was conducted to identify the association between changes in the levels of anti-dsdna in a patient, and the presence of renal diseases. Materials and Methods Patient selection Patients with SLE were recruited from the outpatient department of Taipei Veteran General Hospital in Taiwan between February 1, 2011 and February 1, 2013. These patients were well informed, and the whole process fit the Institutional Review Board (IRB) certification. All enrolled patients met the ACR diagnostic criteria for the diagnosis of SLE in 1997, and were regularly followed up during this period without mortality. Newly diagnosed patients were subjected to a variety of laboratory tests and physical examinations, and only patients diagnosed as having SLE were accepted for enrollment. The exclusion criteria including: patients who had recently received a renal transplantation, and patients who might have a renal comorbidity such as diabetes mellitus or polycystic kidney disease. The diagnosis of lupus nephritis was made according to the ACR classification criteria that persistent proteinuria (> 0.5 g/day on more than 2 occasions); the presence of urinary cellular casts (red cell, granular case, or mixed); or the existence of hematuria which could not be attributed to other causes such as infection or renal stone formation [14]. Some studies defined that the level of serum creatinine level should be within normal range to maintain a remission status [15], but some studies suggested that serum creatinine rise within 30% is defined as stable status [16]. In our study, we followed the definition that patients who had proteinuria (> 0.5 g/day on more than 2 occasions), presence of urinary cellular casts, or increasing serum creatinine ( 25%) due to active disease [17]. End stage renal disease (ESRD) was diagnosed according to ISN/RPS guidelines, and defined as a glomerular filtration rate < 15 ml/min (ie, stage V chronic kidney disease). An event of disease was recorded any time during the study period when a patient met the diagnostic criteria described above. The duration of disease was calculated as the number of years, and the medications used by the patients were also evaluated. The primary goal of this study was to check for different renal outcomes in relation to different anti-dsdna levels; and therefore, we divided patients into 3 groups: patients who had persistent positive of anti-dsdna (high anti-dsdna level), patients who had variant levels of anti-dsdna (variant anti-dsdna levels between negative and positive), and patients who consistently had normal levels of anti-dsdna (normal anti-dsdna). 52
Hsu et al Anti-dsDNA evaluation The level of anti-dsdna was detected by using QUANTA Lite dsdna ELISA kit (INOVA Diagnostics, Inc., San Diego, Ca, USA). In brief, a patient s serum was collected, and prepared as a 1:100 dilution. Then 100 μl of the diluted serum sample, a positive control, and a negative control were added into assay wells. After incubation for 30 minutes at room temperature, the culture medium was removed, and washed 3 times with 200 μl of washing buffer. The washing buffer was then completely removed and 100 μl of the IgG conjugate was added to each well, followed by incubation for at least 30 minutes. The reaction mixtures were washed 3 times and then 100 μl of TMB Chromogen was added to each well, followed by another 30 min incubation. Finally, 100 μl of Stop Solution was added to each well, and the wells were read by ELISA at 450 nm. The results of the assays were classified as negative: 0-92.6 units/ml, equivocal: 92.7-138.9 units/ml, moderately positive: 139-370.4 units/ml, or strongly positive: > 370.5 units/ml. The clinic at Taipei Veteran General Hospital interpreted a result > 92.7 units/ml as a positive finding. Statistical evaluation The renal outcomes were classified as being either a lupus nephritis flare-up or end stage renal disease (ESRD). We used the chi-squared test to compare differences between study groups, and a p value < 0.05 was used to indicate statistical significance. All data were analyzed using SPSS software (SPSS, Chicago, IL, USA). Results A total of two hundred and fifty seven patients were enrolled in this study, and all patients fulfilled at least 4 of the ACR criteria for SLE. No patient mortality occurred during the study. As showed in table 1, a total of 125 patients were included in the high antidsdna group, 46 patients were included in the variant anti-dsdna group, and 86 patients were included in the normal anti-dsdna group. The group of patients with normal anti-dsdna levels had a lower rate in azathioprine use, when compared with the high antidsdna group, and variant anti-dsdna group. When analyzing the data, we initially compared with acute lupus nephritis and ESRD between negative antidsdna group, and positive anti-dsdna group (Table 2), to meet the present studies. Previous studies proved that positive finding of anti-dsdna had relationship with lupus nephritis, and we checked our collected data in this viewpoint. We combined the variant anti-dsdna group with the high anti-dsdna group, for comparison with the normal anti-dsdna group. The results showed that 90/171 patients had lupus nephritis in positive antidsdna group, while 21/86 patients had lupus nephritis in negative anti-dsdna group (p < 0.001). The result is compatible with previous studies. Additionally, 18/171 patients in positive anti-dsdna group had ESRD, while 5/86 patients in normal anti-dsdna group had ESRD (p = 0.197). We then further compared the high anti-dsdna group with the normal anti-dsdna group, and the variant anti-dsdna group with the normal anti-dsdna group (Table 3). The results showed that 65/125 patients in high anti-dsdna group suffered from lupus nephritis, and this finding was significantly different when compared to results in the normal anti-dsdna group (p < 0.01). The results also showed that in the persistently high anti-dsdna group, 10/125 patients suffered from ESRD, and 5/86 patients had ESRD in the normal antidsdna group (p= 0.539). There was no significant difference in the incidence of ESRD between the high anti-dsdna group and the normal anti-dsdna group. We also compared the variant anti-dsdna group, and normal anti-dsdna group for the occurrence of lupus nephritis and ESRD (Table 3). The results disclosed that 25/46 (54%) patients in the variant anti-dsdna group suffered from lupus nephritis during the followup period, which was statistically different from results in the normal anti-dsdna group (p < 0.001). Furthermore, 8/46 (17%) patients in the variant anti-dsdna group had ESRD, compared to 5/86 patients in normal anti-dsdna group (P = 0.061), but this difference was not statistically significant. Finally, we compared the renal outcomes in the high anti-dsdna group with those in the variant anti-dsdna group (data not shown). The results showed there was no significant difference between these 2 groups regarding the incidence of lupus nephritis flare (p = 0.785), or ESRD (p = 0.093). Discussion Investigations have focused on the development of new biomarkers to detect lupus nephritis flare-ups during patient follow up. As mentioned above, it is difficult to use routine renal biopsies to monitor the status of patients during follow up; therefore, the development of 53
anti-dsdna in lupus nephritis Table 1. Characteristic of three groups Normal anti-dsdna n = 86 Variant level anti-dsdna n = 46 Persistent high anti-dsdna n = 125 Gender Male 0 4 (9%) 10 (8%) Female 86 (100%) 42 (91%) 115 (92%) Age at diagnosis, yrs Mean ± SD 29.4 ± 11 23.6 ± 8 25 ± 8 Median 27 23 26 Range 12-58 12-51 10-52 Disease duration, yrs Mean ± SD 14.4 ± 8 14 ± 7 14.5 ± 7 Median 14 14 13 Range 2-37 2-36 2-34 anti-dsdna level Mean ± SD 40 ±11.7 123 ± 52.8 308 ± 55.8 Median 40 101 276 *Initial serum creatinine Mean ± SD 0.7 ± 0.41 0.67 ± 0.3 0.67 ± 0.25 Median 0.6 0.6 0.6 Initial serum C3 level Mean ± SD 84.3 ± 21.2 69.3 ± 23.1 67.5 ± 21.5 Median 87.2 62 64 Initial serum C4 level Mean ± SD 18.3 ± 7.6 15.4 ± 8.8 13.7 ±6.8 Median 16.4 13.6 13 SLEDAI score at inclusion Median (Q1-Q3) 0 (0-4) 4 (0-6) 4 (1.5-6) Hypertension 13 (15%) 5 (11%) 14 (11%) Medicatin of ACEI/ARB 6 (6%) 7 (15%) 13 (10%) Medication for SLE Hydroxychloroquine 63 (73%) 24 (52%) 100 (80%) Azathioprine 24 (27%) 22 (47%) 55 (44%) Mycophenolate mofetil 12 (13%) 5 (11%) 3 (2%) Oral steroid 73 (84%) 40 (87%) 117 (93%) Methylprednisolone(IV) 5 (6%) 10(21%) 22 (18%) Cyclophosphamide(IV) 0 (0%) 2 (4%) 3 (2%) Rituximab 2 (2%) 1 (2%) 4 (3%) Continuous variables showed as mean ± SD, median; categorical variables showed as number (%). * Patients under hemodialysis did not receive regularly serum creatinine followup SLEDAI: SLE Disease Activity Index. The variable was not normal distribution, so the data was presented as median, quartile rather than mean ± SD ACEI/ARB: angiotensin-converting-enzyme inhibitor / angiotensin II Receptor Blockers assays based on the presence of autoantibodies is a main topic of research in SLE. Autoantibodies associated with kidney diseases have been developed, including antidsdna, anti-nucleosomes, anti-α-actinin, and C1q, etc [18]. Additional serum biomarkers such as anti-crp antibody, serum IL-12 levels, serum apolipoprotein (apo) CIII levels, anti-endothelial cell antibody, etc are also under investigation [19]. In addition to serum biomarkers, several urine biomarkers such as vascular cell adhesion molecule-1 (VCAM-1), urinary neutrophil gelatinase associated lipocalin (NGAL), P-selectin, and tumor necrosis factor receptor-1 (TNFR-1), etc are also under investigation [20]. In addition to the development of new biomarkers for lupus nephritis, biomarkers currently in clinical examination may also have additional uses, and this is especially true for anti-dsdna. Anti-dsDNA itself is not just a biomarker for lupus nephritis, but also has a role in the pathogenesis of lupus nephritis. There are two main theories regarding the pathogenic role of anti-dsdna. 54
Hsu et al Table 2. Compare the never high group with other two groups negative anti-dsdna group n=86 positive anti-dsdna group n = 171 Lupus 21 (24%) 90 (52%) P < 0.001 nephritis ESRD 5 (5%) 18 (11%) P = 0.197 The positive anti-dsdna group consisted of the variant antidsdna group and the high anti-dsdna group. Patients whose serum level of anti-dsdna was within normal range throughout the period of follow-up were grouped into negative anti-dsdna group. The first theory is that nucleosome, the fragment of chromatin spread from the apoptotic cells, enters the bloodstream, and induces autoreactive B cells to secret anti-dsdna [21]. Then, the anti-dsdna nucleosome complex settles onto the renal basement membrane and activates the complement system to induce nephritis. The second theory is that the anti-dsdna, anti-nucleosome directly attacks the structure of the kidney, such as the isoforms of α-actinin, a group of microfilament protein. It is proved that multiple isoforms of α-actinin can act as a cross-reactive renal target for pathogenic anti-dsdna [22-23]. In this study, patients were categorized into three groups depending on their levels of serum anti-dsdna. Results showed that patients who tested positive for the presence of anti-dsdna had a greater possibility of developing lupus nephritis. We combined the variant anti-dsdna group with the persistently high antidsdna group, and then compared this combined group with the normal anti-dsdna group. Results of this comparison showed a significant difference in the occurrence of lupus nephritis, and proved that antidsdna is associated with lupus nephritis. These results are compatible with those from other similar studies. However, there was no difference between the groups for the occurrence of ESRD, and this might be due to the small number of ESRD patients. In the outpatient department of our hospital, patients are often found to have persistent high serum levels of anti-dsdna. Some of these patients are experiencing a lupus nephritis flare-up, while others are not. In this study, our data demonstrated that patients who had persistent high levels of anti-dsdna had a significantly greater incidence of occurrence of lupus nephritis flareup when compared to patients with normal anti-dsdna levels. However, the possibility of a patient in either group having ESRD was similar. Therefore, our results showed that patients who had persistent high levels of anti-dsdna had a higher possibility of lupus nephritis, but the rate of ESRD was not significantly different. Patients who had variant levels of anti-dsdna had a significantly greater number of lupus nephritis flareups compared to patients with normal anti-dsdna levels; however, the difference in occurrence of ESRD between these 2 groups was not statistically significant, even though there was a trend toward significance. Further studies with larger numbers of patients who are followed for long time periods might provide additional information relevant to this finding. Newly diagnosed patients were excluded from this study; therefore, the possibility that anti-dsdna levels might return to normal after treatment was excluded. This means that variant patients indeed had varying levels of antidsdna during the two years of follow up. However, we cannot simply assume that the elevation of antidsdna was accompanied by lupus nephritis, because some of these patients experienced a lupus flare-up while their anti-dsdna was in a normal range, or they had normal renal function while their anti-dsdna was elevated. Therefore, patients with variant anti-dsdna levels, results from other associated examinations such as changes in complement, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or additional newly developed biomarkers should be combined to give a proper evaluation. Decrease serum level of complements also had role in disease activation evaluation, and our data also disclosed that the variant anti-dsdna group, and persist high anti-dsdna group had hypocomplementemia. The results may also give us more evidence that these two groups of patients had relatively higher relapsing rate of lupus nephritis. Table 3. Comparing renal flare-up and ESRD between groups Norma anti-dsdna group n = 86 Variant anti-dsdna group n = 46 Persistent high anti-dsdna group n = 125 p value Normal group v.s. variant group p value Normal group v.s. persistent high group Lupus nephritis 21 (24%) 25 (54%) 65 (52%) p < 0.001 p < 0.001 ESRD 5 (5%) 8 (17%) 10 (8%) p < 0.061 p =0.539 Data was represents as the total patient number, and the chi-squared test is selected to compare differences between groups. The chisquared test is selected to compare differences between groups. p value < 0.05 indicates statistical significance. 55
anti-dsdna in lupus nephritis For patients with lupus nephritis, treatments rely on induction therapy and maintenance therapy. Previous data has shown that patients receiving mycophenolate mofetil (MMF) or oral cyclophosphamide experienced similar rates of remission, partial remission, or relapse [24, 25]. Maintenance therapy has relied on the use of different treatment medications. Azathioprine and MMF were equally effective for reducing the risk of renal disease, and were superior to the prolonged use of intravenous cyclophosphamide [26]. However, other similar studies showed that maintenance therapy using azathioprine could reduce, but not completely prevent flare-up of lupus nephritis. In our study, the group of patients with normal anti-dsdna levels had a lower rate in azathioprine use, when compared with the high antidsdna group. This finding could have been due to the normal anti-dsdna group having a more stable disease, and therefore, the dose of medication was tapered down. There were no significant differences in the occurrence of ESRD among the 3 groups of patients. Approximately 10-15% of all SLE patients will develop ESRD, and > 20 independent risk factors have been associated with poor renal outcomes [27]. These risk factors can be divided into several categories including: a patient s demographic characteristics (male gender, young age, and race, such as being African American or Asian); the presence of other comorbidity diseases such as hypertension; pathologic results (crescent lupus nephritis, high chronicity index); the availability of adequate medication; and treatment results (complete or partial remission). The reason that there was no significant difference of three groups in our study might be due to the small sample size, and short length of patient follow up. The cross section study may also mislead the outcome presentation. The limited of this study is that we only included two years data of anti-dsdna, and patients level of antidsdna would have other variant change beyond these two years. For example, patients who belong to normal anti-dsdna group might have abnormal elevation of anti-dsdna beyond this period, and should be joints into the variant anti-dsdna group. There are many risk factors have relationship with renal outcome, and these data should also be taken into considered. We did not further subclass the study groups according to other risk factors such as previous treatment outcome (complete remission or partial remission), previous renal pathologic change, etc. Besides, the flare of other condition such as hematologic change (hemolysis, leucopenia, thrombocytopenia), vasculitis, CNS involvement, etc will let us to change the medical therapeutics, and then had effect on the development of renal diseases. Besides, due to the limited of retrospective study, it would cause the incomplete of collection data. For instance, not all of our selected patients received the renal biopsy, so it was unable to read the definite pathologic renal injury of these patients. Stepwise regression will have better results, but our collected data could not meet the test requirement. We selected the chisquare test for the statisctics analysis in this study, and it could not give us the information about the strength of the relationship. Besides, the sample size would also affect the analysis of chi-square test. The gender of the patients may have also affected the results of our study. In this study, the ratio of males to females in the variant anti-dsdna group vs. the high anti-dsdna group was ~1:9, which is similar to the gender distributions reported in other studies. However, there were no male patients in the normal anti-dsdna group, and this might have affected the outcome. Therefore, it may be necessary to increase the sample size of the 3 groups, or even to design a head-to-head cohort study to provide more detailed and precise results. In conclusion, this study suggests that patients with persistently high or variant levels of anti-dsdna indeed have a higher possibility of having acute lupus nephritis. Therefore, it is important to provide more intensive follow up and arrange for additional examinations of these patients in the future. Acknowledgments The authors gratefully thank Ms. Virginia Chen for the assistance in the data collection. References 1. Mok CC, Tang SS. Incidence and predictors of renal disease in Chinese patients with systemic lupus erythematosus. Am J Med 2004; 117:791-5 2. Hoffman IE, Lauwerys BR, De Keyser F, et al. Juvenileonset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis 2009; 68:412-5 3. Cameron JS. Lupus nephritis. J Am Soc Nephrol 1999; 10:413-24 4. Bastian HM, Roseman JM, McGwin G Jr, et al; LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus 2002; 11:152-60 5. Austin HA 3rd, Boumpas DT, Vaughan EM, et al. Highrisk features of lupus nephritis: importance of race and 56
Hsu et al clinical and histological factors in 166 patients. Nephrol Dial Transplant 1995; 10:1620-8. 6. Seligman VA, Lum RF, Olson JL, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002; 112:726-9. 7. Churg J, Bernstein J, Glassock RJ: Renal Disease: Classification and Atlas of Glomerular Diseases, 2nd Ed., New York, Igaky-Shoin, 1995. 8. Weening JJ, D Agati VD, Schwartz MM, et al. Classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65:521 30. 9. Hiramatsu N, Kuroiwa T, Ikeuchi H, et al. Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions. Rheumatology (Oxford). 2008; 47:702-7. 10. Sidiropoulos PI, Kritikos HD, Boumpas DT. Lupus nephritis flares. Lupus 2005; 14:49-52. 11. Illei GG, Takada K, Parkin D, et al. Renal flare are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 2002; 46:995-1002. 12. Ceppellini R, Polli E, Celada F. A DNA-reacting factor in serum of a patient with lupus erythematosus diffusus. Proc Soc Exp Biol Med 1957; 96:572-4. 13. Vlahakos DV, Foster MH, Adams S, et al. Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. Kidney Int 1992; 41:1690 700. 14. Mok CC, Kwok RC, Yip PS. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum 2013; 65:2154-60. 15. Moroni G, Quaglini S, Maccario M, Banfi G, Ponticelli C: Nephritic flares are predictors of bad long-term renal outcome in lupus nephritis. Kidney Int 1996; 50: 2047 53. 16. Ciruelo E, de la Cruz J, Lopez I, Gomez-Reino JJ: Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide. Arthritis Rheum 1996; 39: 2028 34. 17. Fischer-Betz R, Chehab G, Sander O, et al. Renal outcome in patients with lupus nephritis using a steroid-free regimen of monthly intravenous cyclophosphamide: a prospective observational study. J Rheumatol 2012; 39:2111-7. 18. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358:929-39. 19. Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Bio med Biotechnol. 2010; 2010:638413. 20. Wu T, Xie C, Wang HW, Zhou XJ, et al. Elevated urinary VCAM-1, P-selectin, soluble TNF receptor-1, and CXC chemokine ligand 16 in multiple murine lupus strains and human lupus nephritis. J Immunol 2007; 179:7166-75. 21. Berden JH, Licht R, van Bruggen MC, Tax WJ. Role of nucleosomes for induction and glomerular binding of autoantibodies in lupus nephritis. Curr Opin Nephrol Hypertens 1999; 8: 299-306. 22. Conquefers S, Renaudineau Y, Jousse S, et al. The anti-alpha actinin test completes anti-dna determination in systemic lupus erythematosus. Ann NY Acad Sci 2005; 1050:170-75 23. Renaudineau Y, Croquefer S, Jousse S, et al. Association of alpha-actinin-binding anti-double-stranded DNA antibodies with lupus nephritis. Arthritis Rheum 2006; 54:2523-32. 24. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343:1156-62. 25. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005; 353:2219-28 26. Houssiau FA, Jadoul M. Cytotoxic therapy of lupus nephritis: recent developments. Nephrol Dial Transplant 2002; 17:955-7. 27. Ortega LM, Schultz DR, Lenz O, Pardo V, Contreras GN. Review: Lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus 2010; 19:557-74. 57
anti-dsdna in lupus nephritis 紅斑性狼瘡患者抗雙股 DNA 抗體的變化和狼瘡性腎病變的相關性 許敬暉陳明翰陳瑋昇賴建志林孝義 台北榮民總醫院過敏免疫風濕科 目的 : 此篇研究的目的為探討紅斑性狼瘡患者在長期的追蹤時, 其急性腎病變或慢性腎衰竭與抗雙股 DNA 抗體持續追蹤數值的相關性 方法 : 將符合紅斑性狼瘡診斷之患者, 將其分組為 : 血清抗雙股 DNA 持續陽性反應 反覆變化 以及持續陰性反應三組, 比較三組間急性狼瘡性腎炎以及接受血液透析的比例差異 結果 : 總共 257 位患者納入研究討論, 其中有 86 位患者為持續陰性反應組 46 位患者為反覆變化組, 而有 126 位患者為持續陽性組 將持續陰性組和持續陽性組以及反覆變化組比較, 其狼瘡性腎炎復發有統計上顯著之差異 (p<0.001, p<0.001); 但是, 在接受血液透析的患者比例則沒有統計學上之意義 (p=0.539, p=0.061) 結論 : 患者在其罹病過程中, 若是其抗雙股 DNA 抗體持續處於陽性反應則其狼瘡性腎炎較易復發 ; 此外, 患者之抗雙股 DNA 抗體即使回到正常值, 但是不能持續處於陰性反應則其狼瘡性腎炎的復發也較為頻繁 因此, 臨床上需要更密集以及更多相關性的檢查來追蹤此類患者 關鍵詞 : 紅斑性狼瘡 抗雙股 DNA 抗體 狼瘡性腎炎 58
Formosan Journal of Rheumatology 2013;27:59-66 Original Article Pain Survey in Rheumatology Outpatient Clinics in Taiwan Xiu-Cheng Yeh 1,2, Kuang-Yun Huang 3, Shu-Fen Lo 4, Chun-Ming Huang 5, Tien-Tsai Cheng 6, Hsin-Hua Chen 7, Li-Hsin Lin 8, Shih-Chang Lin 9, Chung-Tei Chou 1 Division of Allergy/Immunology/Rheumatology, Department of Internal Medicine, 1 Taipei Veterans General Hospital, Taipei, Taiwan, 2 National Yang-Ming University Hospital, Yilan, Taiwan, 3 Buddhist Tzu Chi General Hospital at DaLin, Chiayi, Taiwan, 4 Chang Gung Memorial Hospital at Linkou, New Taipei City, Taiwan, 5 China Medical University Hospital, Taichung, Taiwan, 6 Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, 7 Taichung Veterans General Hospital, Taichung, Taiwan, 8 National Cheng Kung University Hospital, Tainan, Taiwan. 9 Cathay General Hospital, Taipei, Taiwan Objective: For this study, a pain survey was conducted in the rheumatology outpatient department (OPD) of eight medical centers in Taiwan to determine the prevalence and characteristics of pain in a Taiwanese rheumatology patient population. Methods: Multi-center pain survey was conducted among Taiwanese patients in rheumatology OPDs. Eight medical centers in Taiwan were enrolled from July to September in 2009 to recruit participants. Using a well-designed and validated pain survey questionnaire that was uploaded to touch-screen computers, all questions were answered by the patients themselves and checked by physicians. Results: In all, 8,549 patients were recruited from 8 medical centers in the northern, central and southern regions; 62% (5,316)) of patients had pain, and among them, more than 70% were suffering from moderate to severe pain (VAS >4). Chronic pain with duration of more than three months was found in 64% of the with-pain patients. The most common diseases in this pain survey were rheumatoid arthritis (RA, 24.2%), osteoarthritis (OA, 11.2%), systemic lupus erythematosus (SLE, 15.3%), gout (11.9%), ankylosing spondylitis (AS, 8.2%) and other autoimmune diseases (AID, 12.6%). Of the 5,316 patients with pain, females were predominant (64%). The overall average visual analogue scale (VAS) score was 4.76. The prevalence of pain was increased with age. In Taiwan, the highest pain prevalence (68%), but lowest average VAS (4.5), was observed in the central region. In contrast, the highest average VAS (5.33) was found in the southern region. Severe pain was significant in inflammatory and non-inflammatory joint diseases and in fibromyalgia syndrome, compared with SLE or AID. Conclusion: The pain survey revealed that 62% of Taiwanese patients had chronic rheumatic pain and most of them with moderate to severe pain had received pain management. The pain might have resulted from the inadequate or insufficient treatment. The reason for the differences in pain prevalence and severity in different areas of Taiwan remains unknown and further study is needed. Key words: Pain, prevalence, rheumatic diseases, Taiwanese, VAS Corresponding author: Chung-Tei Chou, M.D. Division of Allergy, Immunology and Rheumatology, Taipei Veterans General Hospital. No.201, Sec.2, Shipai Rd., Beitou Dist., Taipei, Taiwan 112 Tel: +886-2-28757130; Fax: +886-2-28721874 E-mail: ctchou@vghtpe.gov.tw Received: July 9, 2013 Revised: July 20, 2013 Accepted: September 30, 2013 Introduction Pain is a major health problem and one of the most common reasons for seeking medical care. Pain should be considered an independent disease entity requiring proper and adequate treatment. Chronic pain affects 10% 50% of individuals worldwide [1-8] with 59
Pain survey in Rheumatology OPD musculoskeletal conditions being the most common causes of nonmalignant chronic pain[1]. Arthritis affects at least 50% of individuals aged 65 years, and up to 40% of the general population will be affected by musculoskeletal disorders. Ever since a 2-year national survey was conducted by the National Institutes of Health of the United States in 1998 and revealed that more than 9% of the adult population suffers from high levels of chronic pain, the increased social burden of medical resources being wasted on ineffective treatment has drawn attention to chronic pain as a medical and public health issue [2]. A Swedish population study in 2001 revealed that chronic musculoskeletal pain is common in the general population [1]. Later, a large-scale computer-assisted telephone survey in 15 European countries and Israel reported that chronic pain of moderate to severe intensity occurred in 19% of adult Europeans [3]. In 2010, an internet survey in the US reported that the prevalence of chronic pain was 30.7% and that it was higher for females (34.3%) than males (26.7%) and increased with age [4]. Pain is the primary complaint of individuals with chronic musculoskeletal disorders. Pain is not just a symptom, for its impact on the patient's quality of life, independence and social participation, and on the national economy is enormous and is second only to that of cardiovascular disease [9]. Pain management is commonly dealt with by physicians, and it is a challenging task because it requires a more complex approach for the diagnosis and treatment. In Asia, the epidemiology of pain in the field of rheumatic disease is limited. A Hong Kong survey of common pain in 2002 reported the prevalence of chronic pain was 10.8%, and that it significantly affected work and daily life [10]. A Singapore survey in 2009 found the prevalence of chronic pain was 8.7%, with a higher prevalence among females (10.9%) and in those with increasing age [11]. In 2011, another crosssectional study of a Japanese adult population revealed the prevalence of chronic pain was 15.4% (males, 13.6%; females, 16.8%), the duration of treatment was prolonged, and more than 30% of patients reported unchanged or aggravated symptoms and dissatisfaction with treatment. Pain adversely affects daily life and both physical and mental health [12]. One survey of neck/ shoulder pain (NSP) and low back pain (LBP) among school teachers in China found the prevalence of NSP and LBP was 48.7% and 45.6%, respectively [13]. In this study, a large-scale pain survey was carried out in the rheumatology outpatient department (OPD) of eight medical centers in Taiwan in order to understand the prevalence and characteristics of pain in a Taiwanese population. Materials and Methods Participants and procedures Eight medical centers from different areas in Taiwan were enrolled. These included in northern Taiwan: Taipei Veterans General Hospital, Chang Gung Memorial Hospital at Linkou, and Cathay General Hospital; in central Taiwan: Taichung Veterans General Hospital, China Medical University Hospital, and Buddhist Tzu Chi General Hospital at DaLin; and in southern Taiwan: National Cheng Kung University Hospital and Kaohsiung Chang Gung Memorial Hospital. All consecutive patients visiting rheumatology clinics were recruited from July to September in 2009. We used well-designed and validated pain survey questionnaires uploaded to touch-screen computers and let the participants answer the questions by themselves. Study nurses would assist participants if they had problems completing the questionnaire, in order that the procedure would run smoothly. The contents of the questionnaire included demographic data, the prevalence of pain and its characteristics as VAS (visual analogue score) pain scale scores, body areas affected by pain and the duration of pain; the diagnosis and previously used medication(s) sections were completed by rheumatologists in each hospital. The diagnosis/diagnoses and medications were recorded using a multi-select model in order to facilitate completing the answers for the questionnaires. The completed questionnaires were collected by the study nurses. Data analysis Data from the eight medical centers was collected and brought into the same form. The entire body of data was integrated and summarized as a descriptive statistical table describing clinical variables (Table 1). Results Pain Prevalence and severity Within three months (from July to September, 2009), we recruited a total of 8549 patients at rheumatology clinics exclusively. The population was female-dominant (68%) and the female-to-male ratio was 2:1 (Fig. 1b); 62% (5,316/8549) of patients had pain at the time of the pain survey (Fig. 1a), and among them, about 70% had either moderate (VAS 4-6) or severe (VAS 7-10) pain 60
Yeh et al Table 1. Demographic characteristics of participants N % N % Total Study Sample 8,549 100 Pain location (in 5,316 p't) Age Groups Head 321 6 <35 1,571 18.3 Neck & shoulder 1,523 28.6 35-64 5,082 59.4 Chest 197 3.7 >65 1,896 22.2 Back 1,482 27.8 Gender Upper limb 3,171 59.6 Males 2,708 31.6 Hip 633 11.9 Females 5,841 68.3 Lower limb 2,601 48.9 OPD visit Others 342 6.4 First visit 937 10.9 Diagnosis distribution (8,549 p't) Follow-up 7,612 89 Rheumatoid arthritis 2,069 24.2 Current pain 5,316 62.1 Osteoarthritis 957 11.2 VAS 1-3 (in 5,316 p't) 1,555 29.2 Ankylosing spondylitis 705 8.2 VAS 4-6 (in 5,316 p't) 2,624 49.3 Psoriatic arthritis 201 2.3 VAS 7-10 (in 5,316 p't) 1,137 21.3 Systemic lupus erythematous 1,308 15.3 Pain duration (in 5,316 p't) Fibromyalgia 107 1.2 <1wk 589 11.1 Gout 1,017 11.9 1wk-1mon 684 12.9 Osteoporosis 282 3.3 1mon-3mon 594 11.2 Autoimmune diseases 1,077 12.6 >3mon 3,449 64.9 Others 1,308 15.3 Figure 1. (a) Prevalence: percentage of the presence or absence of pain. (b) percentage of gender in total 8,549 patients. (c) percentage of three groups in different pain severity among 5,316 patients with pain. (d) distribution of 5,316 patients with pain by VAS pain scale scores. 61
Pain survey in Rheumatology OPD (Fig. 1c). Chronic pain with duration of more than three months was experienced by 65% of all pain sufferers. The pain locations varied, but over half of the patients had pain in the upper extremities and/or the lower extremities. The pain prevalence increased with age. Only 35% of those aged below 25 had pain, but more than 70% of those aged up to 65 complained of pain. A higher pain score was found in elderly people (aged >65) than in the younger population (4.9 vs. 4.7) (Fig. 2b). The diagnosis of rheumatic diseases and VAS during the pain survey In this study, rheumatoid arthritis (RA) was confirmed in 24.2%, osteoarthritis (OA) in 11.2%, systemic lupus erythematous (SLE) in 15.3%, gout in 11.9%, ankylosing spondylitis (AS) in 8.2%, psoriatic arthritis in 1%, fibromyalgia syndrome in 1% and other autoimmune diseases (AID) in 12.6% (Fig. 2a). For gender differences, RA and SLE were female-dominant, and AS and gout were male-dominant. In a further evaluation of the pain scale for different rheumatic diseases, the highest VAS was found in OA patients (5), and followed by gout patients (4.7) and RA patients (4.5) (Fig. 2d). Regional differences in rheumatic diseases and pain score Taiwan is a relatively small island, and can be divided into northern, central, and southern regions. Taipei, the capital, is located in the north, which is an area with a high living standard and highly educated population. In contrast, Kaohsiung, the harbor city, is located in the south, which is an area with a relatively low living standard and low income. The prevalence of RA, OA and gout are significantly higher in the south than in the north. However, AS and SLE were less frequently seen in the south (Table 2). Severity of pain was classified into mild (VAS 1-3), moderate (VAS 4-6) and severe (VAS 7-10). As a whole, people living in the south had higher pain scores, both moderate and severe, than people living in the north or central regions (Fig. 3). The average VAS was 5.3 in the south, which was significantly higher than in the north (4.7) and the central (4.5) regions (p=0.001). 62 Figure 2. (a) Diagnosis distribution in percentage among 8,549 patients. (b) Pain prevalence in different age groups. (c) Percentage of medication usage among 8,549 patients. (d) Average VAS in different rheumatic diseases.
Yeh et al Table 2. Diagnosis distribution in three different areas in Taiwan Pain management by medications For pain treatment, nearly 50% of patients took nonsteroid anti-inflammatory drugs (NSAIDs), followed by disease-modifying anti-rheumatic drugs (DMARDs) (43%). Approximately one-third of patients received steroid treatment. Analgesic, ultracet, and biologic therapy was administered to only a small percentage of our patients (Fig. 2c). Discussion North (%) Central (%) South (%) RA 18.9 24.0 28.4 OA 6.4 9.9 21.3 AS 7.0 8.3 5.5 SLE 19.9 9.5 8.8 Fibromyalgia 1.6 0.4 0.1 PsA 1.1 1.0 0.6 Gout 8.9 9.2 18.2 Osteoporosis 3.0 0.7 7.6 AID 9.9 16.8 5.3 Others 13.6 15.7 9.6 Pain was the main complaint of patients in rheumatology OPDs. Various diseases are associated with acute/subacute/chronic inflammation usually involving the joints. Osteoporosis is common in aged females and may cause bone loss or fracture, leading to musculoskeletal pain. In 2003, the WHO s Global Burden of Disease study and the Bone and Joint Monitoring Project conducted a large-scale survey on the burden of musculoskeletal (MSK) disorders including OA, RA, osteoporosis, and LBP. From this report, it is clear that the burden of these major MSK conditions increases with age [14]. Besides, in the 2010 Brazilian National Household Survey, around 80% of Brazilians aged 60 years or more reported having at least one chronic non-communicable disease, with chronic musculoskeletal disorders being the most prevalent diseases (including spinal problems, OA and RA) [9]. The purpose of conducting a pain survey is to try to understand the pain problem of OPD patients, realize the pain severity, measure the treatment outcome, manage the pain early and enhance the relationship between the physicians and patients. The pain survey in this study revealed a high prevalence of pain, which was 62.1% overall among patients in rheumatology OPDs in Taiwan, similar to other reports, and the pain increased with age. More than 70% of patients had moderate or severe pain, and most were under treatment. A previous community study of an elderly population reported that 69% of Taiwanese patients complained of pain even after treatment [15]. In Canada, 64% of chronic pain sufferers complained they were under-treated and 68% of physicians admitted their patients were not treated properly [16]. The reasons for under-treatment of pain are multiple, including the Figure 3. Pain severity distribution in three different areas in Taiwan 63
Pain survey in Rheumatology OPD failure to assess the pain, inadequate knowledge about pain assessment and management by primary care physicians, a misperception that pain is a natural and expected consequence of aging, and concern about the use of analgesics or NSAIDs with cognitive dysfunction or other comorbid illnesses (cardiovascular or renal risk). In our rheumatology clinic survey, 24% of patients were identified with RA, which is the disease that causes more pain and that may lead to a disability. Most RA patients received DMARDs, NSAIDs and even biologic therapy. However, the mean VAS score was 4.5, which indicated many RA patients still had moderate pain. Inadequate treatment, including poor compliance, stopping medicines when shifting to Chinese medicines, inability to get anti-tnf alpha therapy, and osteoporosis with fracture, as well as other comorbid illnesses (fibromyalgia syndrome) with chronic pain, can make the pain persistent. The interesting finding in this study was the significantly higher VAS in OA (5), compared to RA (4.5) or gout (4.6). Symptoms of OA are variable, but in general, are mild. More pain appears in inflammatory OA and requires NSAIDS to stop the inflammation and pain [17]. Many OA patients in Taiwan visit orthopedic doctors or herb doctors, or take glucosamine over-the-counter by themselves. When the symptoms worsen, they go to the rheumatology clinic, and that is why the pain score was so high among OA patients. As a matter of fact, a high score was also found in gout patients. Life-long use of an anti-hyperuricemic agent seems impossible to most patients, and frequent attacks of gouty arthritis in chronic gout may lead to a high VAS score [18,19]. Another important finding in the national survey is the different rheumatic disease patterns in different regions of Taiwan. The prevalence of OA and gout were much higher in the south than in the north and central regions. Since southern Taiwan has many factories and industrial parks with a large proportion of laborers and heavy workers, there is a higher risk of overloading the knee or trauma. Trauma or overuse is one contributing factor to developing knee OA [17]. This might be the reason for the high prevalence of OA in the south, but further study is needed to confirm this. Risk factors for gout, including trauma, and high alcohol consumption and seafood intake, are common among residents in the south. This is why there is a two-fold difference in the prevalence of gout between the south and the north. The high VAS score in the south is perhaps associated with more gout, OA and under-treatment for those laborers who are still working, even with pain. Our study demonstrated that older age, female gender and specific diseases increased the chances of pain, mostly in a chronic status. All the samples were limited to the population of rheumatology patients in OPDs of medical centers, and correlation to the general population in Taiwan may not be suitable due to the selective nature of the study population. In conclusion, this national survey shows that pain is common, chronic and under- or inappropriately treated in Taiwanese patients with rheumatic diseases. Pain is a multi-factorial disease and should be managed as early as possible. The causes of regional differences in rheumatic diseases and pain severity are unknown and further study is needed. References 1. Eriksen J, Jensen MK, Sjøgren P, Ekholm O, Rasmussen NK. Epidemiology of chronic non-malignant pain in Denmark. Pain 2003;106(3):221-8. 2. NIH guide: new directions in pain research: I [Internet]. National Institutes of Health (Internet). 1998. 3. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. 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Yeh et al and characteristics of chronic musculoskeletal pain in Japan. J Orthop Sci 2011;16(4):424-32. 13. Yue P, Liu F, Li L. Neck/shoulder pain and low back pain among school teachers in China, prevalence and risk factors. BMC public health 2012;12:789. 14. René Fejer, Ruhe A. What is the prevalence of musculoskeletal problems in the elderly population in developed countries? A systematic critical literature review. Chiropr Man Therap 2012;24:Sect. 1. 15. Yu HY, Tang FI, Kuo BI, Yu S. Prevalence, interference, and risk factors for chronic pain among Taiwanese community older people. Pain Manag Nurs 2006;7(1):2-11. 16. Moulin DE, Clark AJ, Speechley M, Morley-Forster PK. Chronic pain in Canada--prevalence, treatment, impact and the role of opioid analgesia. Pain Res Manag 2002;7(4):179-84. 17. Das SK, Farooqi A. Osteoarthritis. Best Pract Res Clin Rheumatol 2008;22(4):657-75. 18. Dalbeth N, Lindsay K. The patient's experience of gout: new insights to optimize management. Curr Rheumatol Rep 2012;14(2):173-8. 19. Schlesinger N. Treatment of chronic gouty arthritis: it is not just about urate-lowering therapy. Semin Arthritis Rheum 2012;42(2):155-65. 20. Can G, Solmaz D, Binicier O, Akar S, Birlik M, Soysal O, et al. High frequency of inflammatory back pain and other features of spondyloarthritis in patients with rheumatoid arthritis. Rheumatol Int 2013;33(5):1289-93. 21. Hagen K, Linde M, Heuch I, Stovner LJ, Zwart JA. Increasing prevalence of chronic musculoskeletal complaints. A large 11-year follow-up in the general population (HUNT 2 and 3). Pain Med 2011;12(11):1657-66. 22. Hiller CE, Nightingale EJ, Raymond J, Kilbreath SL, Burns J, Black DA, et al. Prevalence and impact of chronic musculoskeletal ankle disorders in the community. Arch Phys Med Rehabil 2012;93(10):1801-7. 23. Reich K, Kruger K, Mossner R, Augustin M. Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaque-type psoriasis. Br J Dermatol 2009;160(5):1040-7. 24. Smith BH, Elliott AM, Chambers WA, Smith WC, Hannaford PC, Penny K. The impact of chronic pain in the community. Fam Pract 2001;18(3):292-9. 65
Pain survey in Rheumatology OPD 台灣風濕科門診疼痛調查 1,2 葉修誠 3 黃光永 4 羅淑芬 5 黃春明 6 鄭添財 7 陳信華 8 林理信 9 林世昌 1 周昌德 1 台北榮民總醫院內科部過敏免疫風濕科 2 陽明大學附設醫院內科部過敏免疫風濕科 3 大林慈濟醫院內科部過敏免疫風濕科 4 林口長庚醫院內科部過敏免疫風濕科 5 中國醫藥大學附設醫院內科部過敏免疫風濕科 6 高雄長庚醫院內科部過敏免疫風濕科 7 台中榮民總醫院內科部過敏免疫風濕科 8 成功大學附設醫院內科部過敏免疫風濕科 9 國泰醫院內科部過敏免疫風濕科 目的 : 於臺灣不同地區的八個醫療中心風濕科門診進行調查, 以瞭解台灣人口疼痛之盛行率及特性 方法 : 在多個醫學中心的風濕科門診對患者進行調查 自 2009 年 7 月至 9 月, 臺灣八個醫學中心參與並招募參加者 使用了經設計及驗證 載入到有觸控面板之電腦的調查問卷, 由病人自己回答所有問題, 再由醫生檢查 結果 : 自北 中和南地區的八個醫療中心招募總共 8,549 病人 62%( 共 5,316 人 ) 的患者有疼痛, 其中 70% 以上具中度至重度疼痛 (VAS > 4) 64% 的疼痛患者發現慢性疼痛的持續時間超過三個月 調查中最常見的疾病是類風濕性關節炎 (RA,24.2%) 退化性關節炎(OA,11.2%) 紅斑性狼瘡 (SLE,15.3%) 痛風(11.9%) 僵直性脊椎炎(AS,8.2%) 和其他自身免疫性疾病 (AID,12.6%) 在 5,316 位有疼痛的患者, 以女性為主 (64%) 疼痛量表(visual analogue scale, VAS) 的整體平均為 4.76 疼痛的盛行率隨年齡增長而增加 在臺灣, 中部地區的疼痛盛行率最高 (68%), 但有著最低的平均疼痛量表值 (4.5) 相較之下, 南部地區發現有最高的平均疼痛量表值 (5.33) 相對於紅斑性狼瘡或自身免疫性疾病, 我們注意到在發炎性及非發炎性關節疾病 (inflammatory and non-inflammatory joint diseases) 和纖維肌痛症 (fibromyalgia) 明顯有嚴重的疼痛 結論 : 在疼痛的調查中, 即使接受了疼痛的處置,62% 的台灣人患者有慢性風濕性疼痛, 其中大部分為中至重度疼痛 這可能是由於不適當或不足夠的治療 造成台灣不同地區的疼痛盛行率及嚴重度不同之原因仍未明, 應需要進一步的研究 關鍵詞 : 疼痛 盛行率 風濕疾病 台灣人 疼痛量表 66
Formosan Journal of Rheumatology 2013;27:67-74 Original Article The risk of serious infections in patients with rheumatoid arthritis treated with different tumor necrosis factor α inhibitors Yen-Ning Cheng 1, Yi-Ming Chen 1,2, Tsu-Yi Hsieh 1,2, Yi-Hsing Chen 1,2, Der-Yuan Chen 1,2 1 Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei, Taiwan Objective: To evaluate the risk of serious infection in patients with rheumatoid arthritis (RA) treated with etanercept or adalimumab between 2007 and 2012 in a single medical center. Methods: We retrospectively collected the demographic data, clinical characteristics, laboratory findings, and all episodes of serious infection during anti-tumor necrosis factor (TNF)-α therapy. The incidence rate was calculated from the observed number of serious infections and patient-years of follow-up. Univariate and multivariate logistic regression analyses were made to identify the independent predictors of serious infection. Results: A total of 595 patients were included in the analyses: 319 (54%) treated with etanercept and 276 (46%) treated with adalimumab. The overall incidence rate was 6.45/100 patient-years: 5.05/100 patient-years for etanercept and 8.28/100 patient-years for adalimumab. The risk of serious infection was significantly higher in adalimumab than in etanercept (adjusted OR: 2.01, 95% CI: 1.15-3.49, p=0.014). Advanced age at the start of TNF-α inhibitor therapy and chronic pulmonary diseases were associated with significantly higher independent risks for serious infection. Conclusion: The risk of serious infection in RA patients treated with adalimumab was significantly higher than that in RA patients treated with etanercept in this cohort. Key words: Rheumatoid arthritis, tumor necrosis factor-α, infection Introduction Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and it can lead to substantial societal effects in terms of cost, disability, and lost productivity [1]. It is associated with significantly increased mortality and morbidity, and infection is one of Corresponding author: Tsu-Yi Hsieh, M.D., Ph.D. Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital. No 1650, Sec 4, Taiwan Boulevard, Taichung City, 40705, Taiwan. Tel: +886-4-23592525 ext 3354; Fax: +88604023503285 E-mail: zuyihsieh@gmail.com Received: October 7, 2013 Revised: October 20, 2013 Accepted: October 30, 2013 the major causes that hampers proper management of the disease and influences the prognosis [2]. Patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-ra controls [3], and this may be related to the disease itself, comorbidities, or therapies including corticosteroids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and biologic drugs [4]. Tumor necrosis factor (TNF)-α inhibitors are effective in reducing inflammation in patients with early or longstanding RA and significantly improve the signs and symptoms, function, radiographic progression and quality of life [5-6]. However, TNF-α plays an essential part in the host defense system, and inhibition of TNF-α may lead to an increased risk of infections in RA patients [7]. A number of studies and meta-analyses, including some conducted in Japan [13-14], showed an increased 67
serious infections in RA on anti-tnf risk of serious infections during anti-tnf-α therapy, compared to treatment with conventional DMARDs [3, 7-14]. Etanercept and adalimumab were the first two TNF-α inhibitors to be approved in Taiwan. They have different modes of action, and perhaps that is why the differences in infection risk were observed in previous studies [15-17]. The aim of this study was to evaluate the risk of serious infection in RA patients treated with etanercept or adalimumab between 2007 and 2012 in a single medical center. Materials and Methods Patients We retrospectively reviewed the medical records for all patients who had been diagnosed by a rheumatologist as having RA according to the 1987 American College of Rheumatology (ACR) classification criteria, and who had received at least one infusion of etanercept or adalimumab, in Taichung Veterans General Hospital between September 2007 and December 2012. All patients were treated in line with the regulations of the national health insurance for anti-tnf-α therapy: (1) fulfilled the ACR classification criteria for RA; (2) 28-joint disease activity score (DAS28) > 5.1; (3) failure to respond to at least two DMARDs including methotrexate (MTX) unless contraindicated; and (4) no contraindication for TNF-α inhibitor therapy. The present study was approved by the Ethics Committee for Clinical Research, Taichung Veterans General Hospital. Data collection Information on demographic characteristics including age at the start of TNF-α inhibitor therapy, gender, positivity of rheumatoid factor (RF) or anticyclic citrullinated peptide (anti-ccp) status, presence of bone erosions, use of corticosteroids and MTX, and total number of DMARDs at the start of anti-tnf-α therapy were collected. Disease activities (assessed by DAS28), disease duration, extra-articular manifestations and comorbidities before starting anti-tnf-α therapy, and treatment information were also obtained. Felty s syndrome, rheumatoid noduli, pericarditis, pleuritis and rheumatoid vasculitis were regarded as extra-articular manifestations. Presence of chronic pulmonary disease, diabetes mellitus and leukopenia were regarded as comorbidities, possibly relevant to the occurrence of serious infections. All episodes of serious infection that occurred during the period of anti-tnf-α therapy plus five times the half-life of the specific TNF-α inhibitor (15 days for etanercept and 70 days for adalimumab) were recorded. After five times the half-life less than 5% of the working metabolites are circulating in the blood [17]. Serious infection was defined as life-threatening, requiring hospitalization and/or intravenous antibiotic therapy, or leading to persistent or significant disability/ incapacity or a comparable significant risk [18]. All serious infections were categorized by infection site: upper respiratory tract, lower respiratory tract, skin and soft tissue, musculoskeletal, cardiovascular, intraabdominal, urinary tract, ear nose and throat, central nervous system, bacteremia, and miscellaneous serious infections, and by causative pathogens: bacterium, virus, fungus, Mycobacterium tuberculosis (TB), nontuberculous mycobacterium (NTM), and other pathogens. Statistical analyses The incidence rates for serious infections were calculated from the observed number of events divided by the number of patient-years of exposure to anti- TNF-α therapy. Baseline differences between the two groups in patient, disease, and treatment characteristics were analyzed using independent sample t test or chi-square test. We also analyzed the differences in demographic characteristics and the type of TNF-α inhibitors between the patients with and those without infection. Independent risk factors for serious infections were identified by univariate and multivariate logistic regression. All of the analyses were performed using the Statistical Package for the Social Sciences, (SPSS) version 18.0, and a 5% level of significance (two-sided) was adopted. Results Patient characteristics As illustrated in Table 1, a total of 595 patients (mean age ± SD, 53.3±13.5 years) were included in this analysis: 319 (54%) patients treated with etanercept and 276 (46%) patients treated with adalimumab. Most patients were female (82%), and all patients had high disease activity (mean DAS28±SD: 6.59±0.8). Etanercept-treated patients had small but significantly greater disease activity, a higher percentage of positive anti-ccp, more DMARDs used, a larger dosage of corticosteroids, and a shorter disease duration than adalimumab-treated patients. There were 2 etanercepttreated and 24 adalimumab-treated patients had 68
Cheng et al Table 1. Baseline demographic data, clinical characteristics, and laboratory findings in patient with rheumatoid arthritis receiving therapy with etanercept or adalimumab a All patients (n=595) Etanercept (n=319) Adalimumab (n=276) p Value Age at the start of TNF-α inhibitor, years 53.3±13.5 53.9±13.7 52.7±13.3 0.286 Female (%) 488 (82.0%) 253 (79.3%) 235 (85.1%) 0.082 DAS28 (%) 6.6±0.8 6.7±0.8 6.5±0.9** 0.006 RF positivity (%) 524 (88.1%) 289 (90.6%) 235 (85.1%) 0.055 Anti-CCP positivity (%) 339 (87.8%) 150 (92.0%) 189 (84.8%)* 0.045 Presence of bone erosions (%) 384 (65.3%) 199 (63.6%) 185 (67.3%) 0.385 Disease duration, years 8.9±7.3 8.3±7.1 9.5±7.5* 0.049 DMARDs at baseline, number 2.8±0.9 3.0±0.8 2.6±0.9*** 0.000 MTX use (%) 463 (77.8%) 252 (79.0%) 211 (76.4%) 0.518 MTX dose, mg/wk 11.0±6.2 11.3±6.1 10.6±6.2 0.179 Corticosteroid use (%) 576 (96.8%) 309 (96.9%) 267 (96.7%) 1.000 Prednisolone dose, mg/day 8.3±3.5 8.7±3.5 8.0±3.4* 0.027 Medical history (%) Extra-articular manifestations 65 (11.0%) 36 (11.3%) 29 (10.5%) 0.864 Chronic pulmonary disease b 80 (13.4%) 36 (11.3%) 44 (15.9%) 0.124 Leucopenia 16 (2.7%) 5 (1.6%) 11 (4.0%) 0.118 Diabetes mellitus 57 (9.6%) 35 (11.0%) 22 (8.0%) 0.271 Abbreviation: TNF = tumor necrosis factor; DAS 28 = 28-joint disease activity score; RF = rheumatoid factor; CCP = cyclic citrullinated peptide; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate a Data presented as mean ± standard deviation or number (percentage) b Including interstitial pneumonia, chronic obstructive pulmonary disease, bronchial asthma, and bronchiectasis *p < 0.05, **p < 0.01, ***p < 0.001, versus Etanercept-treated group, as detected by independent sample t test or chi-square test ACEI/ARB: angiotensin-converting-enzyme inhibitor / angiotensin II Receptor Blockers previously used with another TNF-α inhibitor, but none of them experienced serious infection during the period of anti-tnf-α therapy plus five times the half-life of the previous TNF-α inhibitor. Occurrence of serious infections Among all patients treated with TNF-α inhibitors (1643.3 patient-years), 92 (15.5%) patients had experienced at least one of the 106 serious infection. The overall incidence rate was 6.45/100 patient-years of follow-up: 5.05/100 patient-years for etanercept (patientyears of exposure: 931.2 years), and 8.28/100 patientyears for adalimumab (patient-years of exposure: 712.2 years). The incidence rate of serious infection among patients treated with adalimumab were significantly higher than those treated with etanercept (incidence rate ratio [IRR]: 1.83, 95% CI: 1.22-2.75). The risk was higher during the first year of treatment (51/106, 48.1%) than during the second year (22/106, 20.8%). The most common sites of serious infection were the lower respiratory tract (34.0%), skin and soft tissue (23.6%), and urinary tract (21.7%) (Table 2). Bacteria accounted for 64.2% of the causative pathogens in serious infectious events, fungi for 6.6%, viruses for 4.7%, TB for 9.4%, and NTM for 2.8%. In 17% of cases the pathogen was not identified. Difference between the etanercept and adalimumab treatment Table 3 shows the difference in the clinical characteristics of patients with and without serious infections. The mean age of patients with serious infection was 60.6 years, the mean disease duration was 10.4 years, and the mean DAS28 was 6.75. Nearly 90% were positive for RF or anti-ccp, 12% had extraarticular manifestations, 28.3% had chronic pulmonary disease, 4.3% had leukopenia, and 16.3% had diabetes mellitus. Univariate analysis showed the age at the start of TNF-α inhibitor therapy (p<0.001), disease duration (p=0.036), comorbidities including chronic pulmonary disease (p<0.001) and diabetes mellitus (p=0.019), and use of adalimumab (p=0.011) were associated with a higher risk of serious infection. Multivariate models confirmed that age at the start of TNF-α inhibitor therapy (adjusted odds ratio [aor] 1.04, 95% CI: 1.02-1.07, p<0.001), chronic pulmonary disease (aor 2.55, 95% CI: 1.32-4.91, p=0.005), and use of adalimumab (aor: 2.01, 95% CI: 1.15-3.49, p=0.014) were statistically independent predictors of serious infections (Table 4) 69
serious infections in RA on anti-tnf Table 2. Number of serious infections by site of infection and kind of pathogen in patient with rheumatoid arthritis receiving therapy with etanercept or adalimumab Site of infection a All patients (n=106) Etanercept (n=47) Adalimumab (n=59) Lower respiratory tract 36 (34.0%) 15 (31.9%) 21 (35.6%) Skin and soft tissue 25 (23.6%) 13 (27.7%) 12 (25.5%) Urinary tract 23 (21.7%) 10 (21.3%) 13 (27.7%) Bacteremia 8 (7.5%) 2 (4.3%) 6 (12.8%) Musculoskeletal 7 (6.6%) 2 (4.3%) 5 (10.6%) Central nervous system 4 (3.8%) 1 (2.1%) 3 (6.4%) Intra-abdominal 3 (2.8%) 3 (6.4%) 0 (0%) Fever of unknown origin 2 (1.9%) 1 (2.1%) 1 (2.1%) Upper respiratory tract 1 (0.9%) 1 (2.1%) 0 (0%) Other 1 (0.9%) 0 (0%) 1 (2.1%) Kind of pathogen b Bacteria 68 (64.2%) 31 (66.0%) 37 (62.7%) Fungus 7 (6.6%) 5 (10.6%) 2 (4.3%) Virus 5 (4.7%) 2 (4.3%) 3 (6.4%) TB 10 (9.4%) 3 (6.4%) 7 (14.9%) NTM 3 (2.8%) 1 (2.1%) 2 (4.3%) Abbreviation: TB = mycobacterium tuberculosis; NTM = nontuberculous mycobacterium a One in etanercept-treated group and 4 in adalimumab-treated group had more than one site of infection in a single episode of serious infection b Two in etanercept-treated group and 3 in adalimumab-treated group had more than one kind of pathogen in a single episode of serious infection; 17% the pathogen was not ldentified 70 Table 3. Comparison between subjects with and without serious infection in patient with rheumatoid arthritis receiving therapy with etanercept or adalimumab a Factors Without infection (n=503) With infection (n=92) p Value Age at the start of TNF-α inhibitor, years 52.0±13.4 60.6±12.0** 0.000 Female (%) 417 (82.9%) 71 (77.2%) 0.243 DAS28 (%) 6.6±0.8 6.8±0.9 0.069 RF positivity (%) 440 (87.5%) 84 (91.3%) 0.386 Anti-CCP positivity (%) 280 (87.5%) 59 (89.4%) 0.825 Presence of bone erosions (%) 319 (64.2%) 65 (71.4%) 0.190 Disease duration, years 8.6±7.3 10.4±7.3* 0.035 DMARDs at baseline, number 2.9±0.9 2.7±0.9 0.095 MTX use (%) 393 (78.1%) 70 (76.1%) 0.766 MTX dose, mg/wk 11.2±6.2 10.1±6.2 0.128 Corticosteroid use (%) 486 (96.6%) 90 (97.8%) 0.752 Prednisolone dose, mg/day 8.3±3.5 8.6±3.1 0.411 Medical history (%) Extra-articular manifestations 54 (10.7%) 11 (12.0%) 0.870 Chronic pulmonary disease b 54 (10.7%) 26 (28.3%)** 0.000 Leucopenia 12 (2.4%) 4 (4.3%) 0.290 Diabetes mellitus 42 (8.3%) 15 (16.3%)* 0.028 Type of anti-tnf inhibitor Etanercept (%) 281 (55.9%) 38 (41.3%)* 0.014 Adalimumab (%) 222 (44.1%) 54 (58.7%) Abbreviation: TNF = tumor necrosis factor; DAS 28 = 28-joint disease activity score; RF = rheumatoid factor; CCP = cyclic citrullinated peptide; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate a Data presented as mean ± standard deviation or number (percentage) b Including interstitial pneumonia, chronic obstructive pulmonary disease, bronchial asthma, and bronchiectasis *p < 0.05, **p < 0.001, as detected by independent sample t test or chi-square test
Cheng et al Table 4. Univariate and multivariate logistic regression for risk factors of serious infection in patient with rheumatoid arthritis receiving therapy with etanercept or adalimumab Univariate Multivariate crude OR 95% CI p value aor 95% CI p value Chronic pulmonary disease a 3.28 1.92-5.59 <0.001*** 2.55 1.32-4.91 0.005** Diabetes mellitus 2.14 1.13-4.04 0.019* 1.34 0.63-2.86 0.445 Type of anti-tnf-α inhibitor Etanercept Reference Reference Adalimumab 1.80 1.15-2.82 0.011* 2.01 1.15-3.49 0.014* Age at the start of TNF inhibitor, years 1.06 1.04-1.08 <0.001*** 1.04 1.02-1.07 <0.001*** DAS28 1.33 0.98-1.80 0.070 1.29 0.93-1.77 0.126 Disease duration, years 1.03 1.002-1.06 0.036* 1.01 0.98-1.05 0.450 DMARDs at baseline, number 0.81 0.63-1.04 0.095 0.99 0.72-1.36 0.936 Abbreviation: TNF = tumor necrosis factor; DAS 28 = 28-joint disease activity score; DMARDs = disease-modifying antirheumatic drugs; OR = odds ratio; CI = confidence interval; aor=adjusted odds ratio a Including interstitial pneumonia, chronic obstructive pulmonary disease, bronchial asthma, and bronchiectasis *p < 0.05, ** p < 0.01, *** p < 0.001 Discussion Consistent with the findings of previous reports [16-17], our results showed a significantly higher risk of serious infections in RA patients treated with adalimumab than in those treated with etanercept, and the adjusted odds ratio was 2.01 (95% CI: 1.15-3.49). The most common site of infection and causative pathogen were the lower respiratory tract (34.0%) and bacteria (64.2%), respectively. Increasing age and chronic pulmonary diseases were also identified as independent risk factors for serious infections. The overall incidence rate of serious infections (6.45/100 patient-years) is comparable to that of previous reports such as 6.2-6.4/100 patient-years from a German RA registry [9], 6.1/100 patient-years from a British RA registry [24], and 6.4/100 patient-years from a Japanese RA registry [13]. The most common site of serious infections was the lower respiratory tract, followed by skin and soft tissue, which is consistent with other epidemiological studies of patients with RA [4,8-9]. The majority (64.2%) of serious infections in this study were bacterial, which was also the case in some previous studies [4,25]. We also found that the risk of serious infections was higher in the first year of treatment (when 48.1% of the serious infections occurred) than in the second year, which is compatible with several studies that showed time dependence of the risk for serious infections [14,26-27]. The decrease in risk might be explained partially by the effect of dropout patients who developed serious infections and stopped TNF-α inhibitors, and partially by the improvement in the clinical status and reduction of concomitant glucocorticoid therapy [27]. Most previous studies have reported that increasing age and pulmonary comorbidity were risk factors for serious infections [13,28-30], and our results confirmed that advanced age at the start of treatment and chronic pulmonary diseases were both associated with a significantly higher risk of serious infections. Previous long-term observational studies presented a conflicting picture of the risk of serious infections among different TNF-α inhibitors. Some of the studies revealed a trend towards a higher risk in infliximab-treated patients and a lower risk in those treated with etanercept; however, very few of them showed a significant difference between adalimumab and etanercept [8, 19-23]. The adjusted hazard ratio (HR) for serious infections in the study by Grijalva et al. [30] was higher in infliximab than in adalimumab (adjusted HR=1.23) and etanercept (adjusted HR=1.26), but no significant difference between adalimumab and etanercept was noted. However, two recent prospective observational cohort studies of patients with RA treated with TNF-α inhibitors from the Italian [16] and Dutch [17] registries reported a significantly lower risk of serious infections for etanercept compared to infliximab and adalimumab. One reason for the difference in risk of serious infections between adalimumab or infliximab and etanercept might be the different modes of TNF-α-inhibiting action in the monoclonal antibodies and the TNF-α receptor fusion protein [1]. TNF-α-carrying cells are attacked by adalimumab and infliximab, causing impairment of their function, resulting in reduction of host immune responses [17]. Potential limitations of our study include a number of biases. The drugs were marketed at different times, and they were used in patients with different disease 71
serious infections in RA on anti-tnf characteristics. The choice of drug may also have been influenced by various confounding factors, e.g., physician preference. Patients who had serious infections may have been treated at other hospitals, but may not have reported this treatment during the followup. This omission may have led to underestimation of the incidence rate of serious infections. Besides, a small proportion of etanercept-treated patients had not received the tuberculin skin test before starting the TNF-α inhibitor, nevertheless there were fewer patients with TB infection among the patients treated with etanercept (0.9%) compared with those treated with adalimumab (2.5%). In conclusion, our results revealed the risk of serious infections in RA patients treated with adalimumab was significantly higher than in those treated with etanercept. 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Cheng et al 2009;8:266 73. 20. Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 2011;50:124 31. 21. Curtis JR, Xie F, Chen L, Baddley JW, Beukelman T, Saag KG, et al. The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis 2011;70:1401 6. 22. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-tnf-alpha agents. JAMA 2009;301:737 44. 23. Lane MA, McDonald JR, Zeringue AL, Caplan L, Curtis JR, Ranganathan P, et al. TNF-alpha antagonist use and risk of hospitalization for infection in a national cohort of veterans with rheumatoid arthritis. Medicine 2011;90:139 45. 24. Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, Silman AJ. Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 2007;56:2896-904. 25. Atzeni F, Bendtzen K, Bobbio-Pallavicini F, Conti F, Cutolo M, Montecucco C, et al. Infections and treatment of patients with rheumatic diseases. Clin Exp Rheumatol 2008;26:S67 73. 26. Curtis JR, Xi J, Patkar N, Xie A, Saag KG, Martin C. Drugspecific and time-dependent risks of bacterial infection among patients with rheumatoid arthritis who were exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum. 2007;56:4226-7. 27. Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A, et al. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis. 2011;70:1914-20. 28. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti tumor necrosis factor therapy. Arthritis Rheum 2006;54:628 34. 29. Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE, et al. Anti tumor necrosis factor α therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007;56:1754 64. 30. Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL, et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 2011;306:2331 9. 73
serious infections in RA on anti-tnf 類風濕性關節炎患者經不同抗腫瘤壞死因子藥物治療後比較其產生嚴重性感染的風險 1 鄭硯寧 1,2 陳一銘 1,2 謝祖怡 1,2 陳怡行 1,2 陳得源 1 臺中榮民總醫院過敏風濕免疫科 2 國立陽明大學醫學系 目的 : 評估台中榮總於 2007 至 2012 年間使用恩博或復邁治療類風濕性關節炎的患者其產生嚴重性感染的風險是否有所差異 方法 : 回溯性收集使用恩博或復邁的類風濕性關節炎患者其基本資料 臨床表徵 檢查結果, 以及紀錄恩博或復邁治療過程中產生的嚴重性感染 計算發生嚴重性感染的機率, 以及分析是否有獨立的危險因子 結果 : 共 595 位病人被納入, 其中 319 位 ( 佔 54%) 使用恩博, 另外 276 位 ( 佔 46%) 使用復邁 整體發生嚴重性感染的機會是每百人年 6.45, 恩博為每百人年 5.05, 而復邁為每百人年 8.28 經統計分析相對於恩博而言使用復邁確實有顯著較高的嚴重性感染率 此外, 若使用抗腫瘤壞死因子藥物當時的年紀較大, 或是原本有慢性肺部疾病的患者, 也有較高的機會會發生嚴重性感染 結論 : 本研究族群中使用復邁比恩博有更高的嚴重性感染的風險 關鍵詞 : 類風濕性關節炎 抗腫瘤壞死因子 感染 74
Formosan Journal of Rheumatology 2013;27:75 Clinical Image Left shoulder cystic mass with rice bodies formation Jia-Feng Chen 陳嘉夆 Division of Allergy, Immunology and Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 高雄長庚醫院過敏風濕免疫科 A B An 88-year-old male presented to ward with enlarged left shoulder mass in slow progression since more than 10 years ago. The mass texture was soft, no local heat and erythema, and there were no trauma or local injection history before. Musculoskeletal sonography revealed subcutaneous cystic mass with synovial membrane hyperplasia, and multiple digit or oval-like rice bodies, which were characterized by hypoechoic cores and hyperechoic rims (Fig. A). Arthrocentesis was done, and 38cc, turbid and xanthochromic synovial fluid was aspirated (Group II). The synovial culture showed negative result for bacterial and mycobacteria, but yielded yeast-like pathogen repeatedly at 2 weeks interval. This patient received synovectomy (Fig. B), and tissue culture developed candida spp. Under the impression of Candida septic arthritis, he took oral fluconazole (300mg per day) for 3 weeks, and there was no recurrence during follow up. 75
Formosan Journal of Rheumatology 2013;27:76 Clinical Image Fulminant sarcoidosis with hemophagocytic lymphohistiocytosis Fu-Chiang Yeh 葉富強 Tri-Service General Hospital, Taipei, Taiwan 三軍總醫院 A 31-year-old man had been well until a month ago when he experienced intermittent lower back pain with radiation to the right leg and hypesthesia. One month later, he visited our hospital because of bladder and bowel incontinence. Computed tomography showed a soft tissue mass occupying the spinal cord from L3 to L5, with severe compression of the dural sac and cauda equina (Fig. A). Splenomegaly was noted, with several infiltrative lesions and multiple variously sized nodules in the paraaortic region (Fig. B, arrow). After posterior decompression with resection of the dural sac lesion and splenic/paraaortic lymph node biopsy, sarcoidosis was diagnosed on the basis of the histopathological features of noncaseating epithelioid-cell granulomas in different organs. Despite steroid administration, progressive ophthalmic infiltration resulted in retinal vasculitis (Fig. C), and hemophagocytic syndrome was confirmed because of pancytopenia, hypertriglycemia, hyperferritinemia, and hemophagocytosis in bone marrow (Fig. D, arrow). Currently, the patient s condition is stable with HLH-2004 chemotherapy. 76
SUBMISSION INSTRUCTIONS Formosan Journal of Rheumatology, formerly Journal of Rheumatology R.O.C.( 中華民國風濕病雜誌 )is the official publication of The Society of Rheumatology Association, Republic of China. The Journal publishes original work on all aspects of rheumatic and clinical immunological diseases. Papers relating to these fields are welcomed. General information he Journal accepts original articles, review articles and case reports. Submissions are accepted only on the understanding that they have not been submitted elsewhere and have not been and will not be published elsewhere and are subject to editorial revision. A covering letter to the manuscript signed by the corresponding author should indicate what type of manuscript is enclosed (Review article, Original article, or Case Report) and that the final manuscript has been approved by all the authors. Authors are encouraged to suggest the suitable reviewers (with full mailing address, phone numbers and e-mail addresses) for the manuscript. Articles should be written in English. Type all pages of the manuscripts, including tables, references, and figure legends, double-space in 12-point type, on one side only of A4 paper, with margins of 2 cm. Pages should be numbered, beginning with the title page, abstract, text, acknowledgements, references, tables, figures and figure legends in sequence. Three hardcopies of the manuscripts, figures and illustrations must be submitted with a matching Microsoft Word disk version. Manuscripts should be submitted to: Editorial Office Formosan Journal of Rheumatology Room 615, 6F, No 18, Ln 42, Fukang Road, Hxitun District, Taichung City, 40764, Taiwan or 中華民國風濕病雜誌編輯部 40764 台中市西屯區福康路 42 巷 18 號 6 樓 615 室 Manuscript formatting guidelines The manuscripts must be conformed to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (Ann Intern Med 1997;126:36-47). Use SI systems for measurements throughout the manuscript. All abbreviations must be fully defined when first mentioned in the abstract and the text, except mm, m, sec, min, h, μg, mg, g, kg, μl, ml, and L. Use Arabic numbering system throughout the manuscript except at the beginning of sentences. Title page. The title page should include: 1). the title of the article; 2). first, middle and last names of the authors; 3). affiliations of the authors; 4). full name, postal address, telephone, fax number and E-mail address for the corresponding author; 5). a running title not to exceed 45 characters. Abstract. No more than 250 words, summarizing the study question or purpose, the study design, the salient results and the principal conclusions under subheadings Objective, Methods, Results and Conclusions. Abstracts for case reports are unstructured, and limited to 150 words. Key words. The key words should be given beneath the Abstract, with the maximum of 5. Key words should be taken from the Medical Subject Headings (MeSH) list of Index Medicus. Title and Abstract in Chinese version. The Journal requests this page with title, names of the authors and their affiliations, abstract and key words in Chinese for Chinese readers. For authors who are not familiar with Chinese, the Journal will arrange for the translation. Text. For original articles, the text is divided into sections with the headings: Introduction, Materials and Methods, Results and Discussion. Subheadings within some sections may be included for clarification and ease of reading. The section of Introduction should give brief description of the background that led to the study. The Materials and Methods section should describe the details relevant to the conduct of the study so that experiments can be repeated. Statistical methods should be clearly explained at the end of this section. The Results should include pertinent findings and necessary tables and figures. Undue repetition in text and tables should be avoided. The Discussion should contain the interpretation of the findings of the study in relation to other relevant published data, and a conclusion for clinical applications or implications for future research. Acknowledgments. Individuals or grants that have substantive contribution to this study may be acknowledged. References. In the text references are given as numbers in square brackets, i.e. [ ], on the line in order of appearance. At the end of the paper references are given in accordance with the Vancouver system, cited by the numerical system, and listed in the order cited in the text. List all authors when six or less; when seven or more, list only the first six and add et al. Journal titles are abbreviated in accordance with the style in Index Medicus. For references to manuscripts accepted but
not published yet, designate the journal and add (in press). Information from manuscripts submitted but not accepted yet should be cited in the text as (unpublished observations). In general, the number of references should not exceed 50. Examples of references are shown below. Journals: 1. Hsieh CW, Lin SC, Chen KH, Tsai JJ. Impaired monocyte oxidative burst activity in HLA-B27-positive ankulosing spondylitis patients. J Rheumatol R.O.C. 2002;17:31-9. Books: 2. Tsao BP. The genetics of human lupus. In: Wallace DJ, Hahn BH, eds. Dubois Lupus Erythematosus. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2002:97-120. Tables and Figures. Three sets of Tables and Figures should be enclosed. Tables and Figures should be 8.0cm or 12-17cm in width. Table should be the same format as the article. Abbreviations used in the table and not defined in the text should be defined in footnotes. Defined symbols should use a,b, c etc. consecutively. Figures should be drawn with black ink on white paper. Photographs should be black and white glossy prints. Arrows and other symbols must be of professional quality. Legends should be listed on a separate page with Arabic numerals corresponding to the figures. Provide each table and figure with an explanatory title. All symbols and abbreviations not defined in the text should be defined in the legend. All the illustrations (photographs, line drawings, graphs etc.) should be saved as a single image TIFF, GIF, or high quality JPEG files to a minimum of 300dpi on the disk. Single page powerpoint files as one slide per file are also acceptable. Other categories of papers Review Articles. Review articles should be critical assessments of recent developments of research or clinical practice in rheumatic or clinical immunolo- gical diseases. They should consist of a Title page, Abstract, Key words, Text, References, Tables and/ or Figures sections. The page of Title/Authors/ Abstract /Key words in Chinese is also requested. Case Reports. Case reports should contain sections of Title page, Abstract, Key words, Introduction, Case report, Discussion, References, Tables and/or Figures. The page of Title/Authors/Abstract/Key words in Chinese is also requested. Clinical Images. Clinical images are photographic depictions (clinical, radiologic, or pathologic) of interesting rheumatologic phenomena. Clinical images should consist of no more than 4 figures and text of no more than 300 words. Figure legends are not required; the entire Clinical Image text is the figure legend. Reference citations are not requested, if references are included, there should no more than 3. Copyright transfer. With the acceptance of a manuscript for publication, the Journal acquires the full copyright. The authors are requested to sign a copyright transfer statement. Author corrections on proofs. The corresponding author will be provided with page proofs and asked to check for errors and editorial queries. Proofs must be returned to the Journal with the original manuscript within 72 hours of receipt. Reprints. 25 copies will be supplied to the corresponding author free of charge. Reprints other than 25 copies will be charged and may be purchased from the Editorial Office. 中華民國風濕病雜誌 中華民國一 二年十二月三十日發行 發 行 人 : 蔡嘉哲 總 編 輯 : 李修身呂聆音 執行編輯 : 李修身呂聆音 編輯委員 : 陳忠仁蔡嘉哲許秉寧劉明煇賴振宏 蔡文展蔡長佑蔡肇基吳詹永嬌 ISSN: 2075-0374 發 行 所 : 中華民國風濕病醫學會 地 址 : 台中市南區建國北路一段 110 號 ( 內科部 ) 電 話 : 886-04-24719140 印 刷 者 : 哲興印刷事業股份有限公司 地 址 : 台中市工業區 21 路 7 號 電 話 : 886-4-23598883