退化性關節炎治療的新進展 陳得源 藍忠亮 * 臺中榮總院本部 * 內科部 * 免疫風濕科
Musculoskeletal Conditions: Large Impact on Quality of Life Urogenital conditions Hearing impairment Psychiatric disorders Dermatologic conditions Cardiovascular conditions Cancer Endocrinologic conditions Visual impairment Chronic respiratory diseases Gastrointestinal conditions Cerebrovascular/neurologic Renal disorders Musculoskeletal conditions 0 10 20 30 40 50 60 70 80 90 Summed Rank Score of Impact on QoL Dimensions *Includes OA, RA, back impairments, and other joint complaints. Includes physical functioning, bodily pain, general health, vitality, social functioning, and mental health. Sprangers MAG et al. J Clin Epidemiol. 2000;53:895 907.
退化性關節炎 骨關節炎 (Osteoarthritis) 是成人最常見的慢性關節病變 根據最近世界衛生組織報導, 退化性膝關節炎佔女性失能原因的第四位, 在男性則佔第八位 根據放射學影象顯示大於 30% % 的 65 歲以上的老年人已有退化性膝關節炎的現象, 而其中有三分之一的病人有臨床症狀
退化性關節炎骨關節炎 (Osteoarthritis) A debilitating, progressive disease of diarthodial joints A disease of the whole joint (not just articular cartilage) 主要影響關節軟骨, 造成軟骨受損與關節腔狹窄, 並伴隨骨刺形成 不等程度的滑膜炎及關節囊膜增厚
退化性關節炎 (OA) 一種漸進性且發炎性之關節疾病 Of 270 subjects who had 470 OA knees with follow-up for 30 months, 22% knees showed progression (Rheumatology 2005;44:100-4) 4) In approximately 40% of patients, the classical picture of OA of the IP joints was complicated by erosive change (Osteoarthritis and Cartilage 2000;8:s45-54) 54)
Plain radiographs of OA Erosive OA Nodular OA
Hypervascularity in erosive OA shown by MRI and Sonography MRI Sonography
退化性關節炎之病因與疼痛之致病機轉 (Lancet 2005;365:965-73)
退化性關節炎之免疫致病機轉 軟骨細胞 Chondrocyte 細胞凋亡
spontaneous apoptosis & anti-fas Fas-induced apoptosis of PB lymphocytes from patients with erosive OA 自發性細胞凋亡 (TC-VGH) 活動引發性細胞凋亡
退化性關節炎疼痛之致病機轉 軟骨細胞受到不正常受力或創傷 關節囊膜細胞 細胞激素 (Cytokine):IL-1β,IL-6,TNF-α 活化 Cox- 2 發炎性 PG 細胞趨化素 (Chemokice):IL-8,MCP-1 發炎細胞浸潤 更多細胞激素 MMP-3 MMP-3 發炎反應 中性球聚集
退化性關節炎之致病機轉 (Lancet 2005;365:965-73) 近年來分子生物學的進展, 使得骨關節炎的致病機轉更加明確化 目前認為骨關節炎是起因於軟骨細胞外基質軟骨細胞外基質合成與分解 ( 耗損 ) 之間的不平衡 其中牽涉破壞性細胞激素 ( 如介白質 -1 腫瘤壞死因子 介白質 -17 與介白質 -32) 軟骨細胞之凋亡 調節性細胞激素 ( 如介白質 -4 介白質 -6 介白質 - 10 與介白質 -13) 13),, 以及促進軟骨細胞外基質合成之生長因子 ( 類胰島素生長因子 -1 貝他 - 轉化生長因子與骨形成基因蛋白 -2)
Destructive ET-1, Thromboxane cytokines A2 退化性關節炎之致病機轉 軟骨細胞外基質 (Extracellular matrix, ECM) 分解 (catabolism) 與合成 (anabolism) 之不平衡 IL-1 1 TNF-α IL-17 IL-18 IL-32 Oncostatin Cartilage ECM anabolism Cartilage ECM catabolism Growth factor NO IGF-1 1 TGF-β BMP2 (Bone morphogenetic protein)
退化性關節炎 1. Marginal osteophytes 2. Subchondral sclerosis 3. Subchondral cysts 4. Joint space narrowing 骨刺
手指退化性關節炎 Osteoarthritis, OA ACR
退化性關節炎治療的新進展 第二型環氧化酵素 COX2 抑制藥的使用 改變病程的抗骨關節藥物 ( 免疫調節藥 ) (DMOADs) 軟骨組織工程再造 幹細胞移植
2002 美國疼痛協會 (APS) 對關節炎疼痛 的臨床治療準則 American Pain Society. Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. 2002.
退化性關節炎的治療 第二型環氧化酵素 COX2 抑制藥 非類固醇消炎藥物 (NSAIDs) 具有消炎 鎮痛及消腫的功效 其效果出現快, 通常在數小時或數日內見效 傳統 NSAID 的副作用是胃腸不適 胃及十二指腸潰瘍 胃出血 水和鹽分排除減少 血壓增高和腎功能障礙等 目前已有 第二型環氧化酵素 COX2 抑制藥, 對於有消化性潰瘍或出血之虞的患者或年紀較大者, 可考慮使用
使用傳統 NSAIDs 大約有 15-30% 出現胃腸道副作用 大部份為輕微的腸胃不適 其中有部份發生嚴重消化性潰瘍, 出血甚至胃腸穿孔 Patients with Ulcers (%) 50 40 30 20 10 0 23.3 Indomethacin (n=180) 17.8 Naproxen (n=247) 22.5 Ibuprofen (n=173) 胃腸副作用高危險因子為 : 年齡超過 60 歲, 過去有消化性潰瘍病史, 使用類固醇, 幽門螺旋桿菌帶原者 17.8 Diclofenac (n=461) 43.9 Aspirin (n=57)
Cumulative probability of complicated upper GI events in OA patients treated with CELEBREX and ns-nsaids Celecoxib Versus Naproxen and Diclofenac in Osteoarthritis Patients: SUCCESS-I Study; The American Journal of Medicine (2006) 119, 255-266
Cumulative Incidence (%) However, behind GI safety Serious CV Thrombotic Events in VIGOR 2.5 2.0 1.5 1.0 0.5 0 0 2 4 6 8 10 12 Rofecoxib 50 mg/d Naproxen 1,000 mg/d No. at risk Rofecoxib Naproxen Months of Follow-up n = 4,047 n = 3,643 n n = 4,029 n = 3,647 = 3,405 n = 3,177 n = 2,806 n = 1,067 n = 531 n = 3,395 n = 3,172 n = 2,798 n = 1,073 n = 514 FDA Arthritis Advisory Committee Meeting. February 7, 2001. Gaithersburg, Maryland.
Meta-analysis analysis of RCTs CV Death, MI, and Stroke: Celecoxib vs Placebo and vs Traditional NSAIDs Celecoxib daily dose 200 mg RR (95%CI) vs Placebo vs All NSAIDs combined vs Naproxen vs Diclofenac vs Ibuprofen 1.26 (0.57-2.80) 0.86 (0.59-1.26) 1.11 (0.41-3.01) 0.81 (0.49-1.35) 0.88 (0.43-1.82) 0.1 0.3 1.0 3.0 10.0 Favours Celecoxib Favours Comparator
退化性關節炎治療的新進展 第二型環氧化酵素 COX2 抑制藥的使用 改變病程的抗骨關節藥物 ( 免疫調節藥 ) (DMOADs) 軟骨組織工程再造 幹細胞移植
改變病程的抗骨關節藥物 DMOADs 這類藥物要服用較長時間 (>( 八週 ), 才會出現療效 Glucosamine sulfate Chondroitin sulfate Topical cream (glucosamine & chondroitin) Intra-articular articular hyaluronic acid Diacerein (Diacerhein) Tetracyclines (Minocycline) Hydroxychloroquine Green Tea (Epigallocatechin-3-gallate, gallate, EGCG) Inducible NOS synthetic inhibitor (1400W) Pentosan polysulfates (CaPPS) SYSADOA Symptomatic slow-acting drugs for OA
(Rheum Dis Clin Glucosamine sulfate Clin North Am 1999;25:379; J Rheumatol 1999;26:2423) Stimulates cartilage to synthesize glycosaminoglycans & proteoglycans Inhibits cartilage ECM degradation Is widely available in pharmacies and health food stores A review of 20 clinical studies showed glucosamine had a favorable effect on OA pain, but no significant improvement in disability
The efficacy of Glucosamine sulfate 對於症狀緩解之 EBM (1A) The effect on OA pain and disability (JAMA 2000;283:1469) 6 studies of glucosamine involving 911 OA patients Improve pain and disability (Lequesne( index), but the magnitude of effect is unclear The effect on cartilage loss (joint-space narrowing) A 3-year 3 RCT involving 212 patients with OA knee: The glucosamine group showed less joint-space loss (Lancet 2001;357:251) Recent 4 published studies showed no beneficial effects on joint-space loss in the glucosamine groups (Arch Intern Med 2003;163:1514)
Chondroitin sulfate 軟骨膠硫酸鹽 A predominant glycosaminoglycan found in articular cartilage May have chondroprotective properties Clinical evidence is limited A year 2003 meta-analysis analysis of 8 trials including 755 OA patients: more effective on OA pain (Arch Intern Med 2003;163:1514) EBM 1A Combination of glucosamine and chondroitin was showed to improve OA pain (JAMA 2000;283:1469)
Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT): 24-Week Study Design (OA of Knee) Placebo Rheumatology 2005 Double-blind randomised Glucosamine 500 mg tid 1583 patients with knee OA* Chondroitin sulphate 400 mg tid Glucosamine 500 mg tid + chondroitin sulphate 400 mg tid Celecoxib 200 mg/d Arthritis assessments X X X X X Baseline Week 4 Week 8 Week 16 Week 24 In all patients, celecoxib 200 mg/d was statistically significantly superior to placebo Differences between other treatment groups and placebo did not reach statistical significance
Intra-articular articular hyaluronic acid ( 玻尿酸 ) for OA knee Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine linked by β1-3 3 and β1-4 glycosidic bonds. D-glucuronic acid N-acetyl-D-glucosamine : hydrophobic face OH : hydrophilic face
Hyaluronic acid
Morphological assessment of chondrocyte vitality significant increase of cell density and anabolic activities after intra-articular articular injection of HA vs MTP (40 mg) 0,8 Zone I Difference (Final-Basal) 0,7 0,6 0,5 0,4 0,3 0,2 0,1 * * p < 0.01 * * 0,0 Methylprednisolone Hyaluronic acid Difference (Final-Basal) 60 40 20 0-20 -40 RER * Golgi * Mitoch. * Lysosomes MTP HA Glycogen * Lipids zone I Filaments Rheumatology 2001;40:158-69 Osteoarthritis Cart 2001;9:371-81; J Orthopaed Traum 2002;3:89-96 *
In patients with OA knee, is hyaluronic acid effective for relieving pain? A RCT including 100 patients with OA knee, hyaluronic acid 20mg/2ml given in 5 weekly intra-articular articular injection In patients with OA knee, hyaluronic acid was effective for reducing pain on walking at 6 months and improving knee function (Lequesne( function index) for 4 months EBM 1B Rheumatol 1999; 38:602; EBM 2000;5: 73
四環黴素 Tetracyclines Potent inhibitors of two major MMPs: collagenase (MMP-1 1 and MMP8) and gelatinase (MMP-13) via chelation of zinc and /or calcium Potent inhibitors of chondrocyte apoptosis In dog model of OA, prophylactic adminstration of tetracycline markedly reduced the severity of OA (Arthritis Rheum 1992;35:1150) A current multicenter study is underway to determine the effect of doxycycline in humans with OA
Green Tea (Camellia sinensis) (Epigallocatechin-3-gallate, gallate, EGCG) EGCG inhibits IL-1β-induced NO production via inhibition of inos by suppressing IKB-α degradation EGCG inhibits IL-1β-induced activation of p-38 p MAPK expression apoptosis of synoviocytes Haqqi et al. PNAS 1999;96:4524 Singh. Osteoarthritis Cartilage 2001
改變骨關節炎病程的藥物 (DMOADs) 在實証醫學方面 目前僅發現 Glucosamine sulfate Chondroitin sulfate 與關節內注射之玻尿酸在關節疼痛與活動受限方面具有療效 但在骨關節炎病程改善方面並無明顯效果 因此,DMOADs, 在骨關節炎治療的角色仍有待未來進一步的評估
退化性關節炎治療的新進展 第二型環氧化酵素 COX2 抑制藥的使用 改變病程的抗骨關節藥物 ( 免疫調節藥 ) (DMOADs) 軟骨組織工程再造 幹細胞移植
明日骨關節炎治療之星 軟骨組織工程再造 ( 中榮 中興 ) 將受力較少的軟骨用關節鏡取出 0.1 公克, 以膠原蛋白酶將軟骨細胞分離出來, 再用適當的培養液促使軟骨細胞分裂增殖, 一般都能將細胞數目放大一萬倍 將軟骨細胞植入一個特製的支架內, 給軟骨細胞刺激, 希望軟骨細胞分化成軟骨間質, 終至形成正常的透明軟骨, 最後將軟骨細胞植入軟骨的缺損區域
退化性關節炎治療的新進展 第二型環氧化酵素 COX2 抑制藥的使用 改變病程的抗骨關節藥物 ( 免疫調節藥 ) (DMOADs) 軟骨組織工程再造 幹細胞移植
骨髓中之成體幹細胞 (HSC, MSC)
間葉系幹細胞之分化 (Blood 2006;107:367)
以 實證醫學 為導向的治療方式 退化性關節炎最妥善的治療方法為藥物治療加上非藥物治療的方式 非藥物治療方式非藥物治療方式包括運動課程 物理治療 減重配合運動以及使用足部楔形輔具 應該根據病人的個別狀況加以調整 包括 :(a): 膝關節炎的危險因子 ( 如肥胖 不良的機械因子與日常生活方式等 ) (b) 一般危險因子 ( 如年齡 罹患其它疾病等 ) (c) c) 疼痛的程度及功能減退的程度 (d) d) 局部關節發炎的程度 ( 如積液等 ) 以及 (e) 局部關節構造損壞的位置及程度 ( 歐洲抗風濕病聯盟於 2003 年 )
文獻研究之實證依據和專家及實證醫學之建議使用強度 治療方法 證據等級 建議強度 治療方法 證據等級 建議強度 普拿疼 1B A 針灸 1B B 鴉片性止痛藥 1B B 雷射 1B B 傳統性非類固醇止痛藥 1A A 脈衝式電輻射治療 1B B COX2 止痛藥 1B A 水療 (SPA) 1B C 精神科輔助用藥 1B B 經皮電刺激 (TENS) 1B B 局部非類固醇止痛藥 1A A 導入式超音波治療 1B C 局部使用辣椒膏 1A A 減重 1B B 葡萄醣胺 1A A 關節保護具 ( 護膝 / 彈繃 ) 1B B 軟骨膠硫酸鹽 1A A 關節內注射玻尿酸 1B B 雙醋瑞因 1B B 關節內注射類固醇 1B A 酪梨大豆異形油 (ASU) 1B B 關節內沖洗術 1B B 補充維他命 / 礦物素 1B C 關節置換術 1B B 衛教 1A A 電話諮詢 1B B 運動 1B A
針刺 (Acupuncture) 治療 退化性膝關節炎屬於傳統醫學的 骨痹 範疇 Vas 等人 (British Medical Journal, 2004; 20, 1216-1219 1219 ) 的研究中發現, 針刺治療膝退化性關節炎的病患, 能有效達到疼痛緩解 減緩關節僵硬和增加身體活動的功能 陳 ( 中醫骨傷科醫學雜誌 2005) ) 利用針刺治療膝退化性關節炎病患, 發現每週兩次, 共四週的針刺治療, 對於晚上疼痛的緩解有明顯的改善
針刺 (Acupuncture) 治療 退化性膝關節炎的針刺治療多取膝關節局部膝關節局部之腧穴位為主, 例如 : 鶴頂 內膝眼 外膝眼 血海 梁丘 足三里 陽陵泉 陰陵泉以及阿是穴, 有時亦依辨證取穴或循經取穴原則, 選取大杼 絕骨 曲池等 除了單獨使用針刺外, 亦常配合溫灸 電針以及中藥薫洗, 以期提高療效 採用遠端穴位遠端穴位則較局部副作用, 然而相關的臨床研究較少, 本院中醫科游文仁醫師專長醫師專長
復健職能治療 : 增強關節相關肌肉的力量 ~ 團體衛教 ~ (EBM IB)
Severe Principles of the management of OA Surgery partial or total joint replacement and Surgery (joint preserving) osteotomy, resurfacing (Lancet 2005;365:965-73) Few Some Advanced non-surgical interventions Intra-articular injections Simple non-surgical interventions NSAIDs, physiotherapy/occupational therapy, DMOADs Medications simple analgesics, topical agents All Mild Information and advice Education, weight loss, exercise, lifestyle alterations Numbers of people