生物製劑在風濕病的臨床應用

生物製劑在風濕病的臨床應用 成大醫院 內科部過敏免疫風濕科 林理信 1

腫瘤壞死因子拮抗劑 1. 恩博 (Etanercept; Enbrel) 皮下注射 ; 一星期注射兩次類風濕性關節炎 (Rheumatoid arthritis; RA) 幼年性類風濕性關節炎 (Juvenile rheumatoid arthritis; JRA) 僵直性脊椎炎 (Ankylosing spondylitis; AS) 乾癬性關節炎 (psoriatic arthropathy; PsA) 乾癬 (psoriasis) 2

腫瘤壞死因子拮抗劑 2. 復邁 (Adalimumab; Humira ) 皮下注射 ; 兩星期注射一次 類風濕性關節炎 (Rheumatoid arthritis; RA) 僵直性脊椎炎 (Ankylosing spondylitis; AS) 乾癬性關節炎 (psoriatic arthropathy; PsA) 克隆氏症 (Crohn s disease) 3

B 細胞阻斷劑 1. 莫須瘤 (Rituximab; Mabthera) 靜脈注射 ; 半年注射兩次 第一及第十五天 淋巴癌 (non-hodgkin s Lymphoma) 類風濕性關節炎 (Rheumatoid arthritis; RA) 4

類風濕性關節炎 5

Rheumatoid Arthritis (RA) 一種病因不明的自體免疫疾病 西方國家盛行率約 1%, 台灣盛行率約 0.4% 以侵犯關節滑膜為主的全身性疾病 性別 : 以女性為主的慢性疾病, 女男比約 4 比 1 6

Rheumatoid Arthritis (RA) 年齡 : 各階層的年齡均可能發生, 但以 30-50 歲發病最多 前趨症狀包括疲倦 虛弱 晨間關節僵硬 關節疼痛 進而多關節腫 脹 熱 壓痛 伸展彎曲活動受限 7

Rheumatoid Arthritis (RA) 任何關節均可能發生, 但是以近側指趾間 掌指 腕 肘 足趾 踝和膝關節較常發生 頸椎是所有脊椎骨中最容易發生處 常見關節外的症狀 : 皮下類風濕性結節 次發性修格連氏乾燥症 肺部的病變等 8

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診斷標準 1. 晨間關節僵硬超過 1 小時 2. 三個以上的關節區域發炎 3. 侵犯手部關節的關節炎 4. 對稱性關節炎 5. 血清中類風濕因子陽性 16

診斷標準 6. 出現皮下類風濕性結節 7. 典型的放射線檢查關節變化 1-4 項診斷標準時間須持續六星期以上 七項診斷標準中符合四項以上即可診斷為類風濕性關節炎 17

Medical Treatment in RA Early start DMARDs (Diseses modifying anti-rheumatic drug) therapy Early DMARDs combination therapy Methotrexate Sulfasalazine Hydroxychloroquine Methotrexate is the most important DMARDs Slow acting (2-6 months) Add leflunomide or cyclosporine if refractory 18

治療 消炎止痛藥 消炎止痛藥 : 疼痛症狀緩解 1. 非類固醇類消炎止痛藥 NSAIDs 2. 類固醇 包括關節內注射 19

類固醇使用時機 1. 嚴重活動性多關節炎 2. 免疫調節劑尚未完全發揮藥效之前 約需二至六個月 3. 非類固醇類消炎止痛藥無法有效控制疼痛症狀 4. 固定少數慢性關節炎可以類固醇關節內注射治療 20

治療 免疫調節劑 免疫調節劑 : 緩解關節破壞 變形 1. Methtrexate (MTX) 2. Sulfasalazine (Salazopyrine) 3. Hydroxychloroquine (Plaquenil) 4. Azathioprine (Imuran) 21

治療 免疫調節劑 5. Cyclosporine A (Sandimmun Neoral; Gengraf) 6. Leflunomide (Arava; Arheuma) 7. Etanercept (Enbrel) 8. Adalimumab (Humira) 9. Rituximab (Mabthera) 22

Methotrexate (MTX) Anti-folate Start from 7.5 mg/week (3# qw) Slowly titrate to 15 ~ 20 mg/week (6 ~ 8#/qw) Adverse effects Mucositis GI toxicity Liver toxicity Pulmonary toxicity Renal toxicity Add folic acid 5 ~ 10 mg/week (1 ~ 2# qw) to diminish adverse effects (take the day after methotrexate) 23

Sulfasalazine Anti-inflammatory + antibiotics 1 ~ 3 g/day (1 ~ 3#/BID) Adverse effects Drug eruption GI toxicity Liver toxicity 24

Hydroxychloroquine (plaquenil) Anti-malaria 200 ~ 400 mg/day (1#/Qd ~ Bid) Contraindication G6PD deficiency Adverse effects Headache, dizziness Hair loss Retinopathy Liver toxicity 25

免疫調節劑使用原則 儘早使用免疫調節劑 多種免疫調節劑合併使用 免疫調節劑須長期規則服用, 否則無效 26

預後及注意事項 若無有效治療, 疾病末期可能會關節萎縮 變形 肌肉萎縮, 進而殘廢 可能會造成病人嚴重的失能, 嚴重的影響患者本身的身心狀況, 造成家庭 社會 與國家的沉重負擔 平均存活比正常人少 3-10 年, 心臟血管疾病為其主要死因 27

預後及注意事項 早期開始復健治療有助於症狀緩解及關節功能的保存 一般而言類風濕性關節炎與飲食無關 長期服用類固醇的患者宜儘早預防骨質疏鬆症, 以及飲食熱量控制以避免體重過度快速增加 28

預後及注意事項 患者可正常結婚 懷孕 生育 甚至女性患者懷孕期間病情常常自動緩解 遺傳給下一代的機率極低 29

生物製劑 腫瘤壞死因子拮抗劑 (tumor necrosis factor-alpha antagonist; TNF-α antagonist) 30

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Comparison for Biologics Etanercept Infliximab Adalimumab Class Soluble TNF receptor TNF-α monoclonal antibody TNF-α monoclonal antibody Construct Recombinant fusion protein Chimeric monoclonal antibody Human monoclonal antibody Origin Entirely human Human and murine Entirely human Half-life (days) 2.9 9.5 14 34

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Clinical Experience of TNF Blockade Therapy (Etanercept) in Patients with Rheumatoid Arthritis in NCKUH 林理信 王崇任 劉明煇 國立成功大學醫學院內科部過敏免疫風濕科 68

疾病活動度評估 :DAS 28 符合連續活動性關節炎之條件 間隔至少一個月的二次 DAS 28 積分皆大於 5.1 28 處關節疾病活動度評估 Disease Activity Score, DAS 28 附當時關節腫脹之相關照片或關節 X 光檢查報告 69

DAS 28 觸痛關節之總數 左邊 + 右邊 腫脹關節之總數 左邊 + 右邊 紅血球沉降速率 ESR, 毫米 / 小時 整體健康狀態評估 general health assessment :100 mm 圖像模擬量表中所呈現的整體健康狀態 70

Shoulder Elbow Wrist MCP I MCP II MCP III MCP IV MCP V IP I PIP II PIP III PIP IV PIP V Knee Right Left tenderness swelling tenderness swelling

DAS 28 DAS 28 score = 0.56 TJC + 0.28 SJC + 0.7 lnesr + 0.014 GH 整體健康狀態評估 GHA 0 100 無不舒適 極度不舒適 72

Patients and Methods 1. Fulfill criteria for the classification of rheumatoid arthritis 2. Active aggressive rheumatoid arthritis Disease activity (DAS 28) score > 5.1 twice continuously, separated one month at least DAS 28 score = 0.56 TJC + 0.28 SJC + 0.7 lnesr + 0.014 GH no discomfort general health status 0 100 extremely discomfort 73

DMARDs 符合標準 DMARDs 療法失敗 1. 至少同時使用二種以上 DMARDs 藥物 2. Methotrexate (MTX) 必須包含在治療的 DMARDs 藥物當中 3. DMARDs 藥物使用達治療劑量時間六個月以上 4. DMARDs 藥物使用達標準目標劑量時間二個月以上 74

DMARDs treatment failure Standard target does Therapeutic does Methotrexate 15-20 mg/week 7.5 mg/week Hydroxychloroquine 6.5 mg/kg/day 200-400 mg/day Sulfasalazine 40 mg/kg/day 2 g/day Azathioprine 2 mg/kg/day 100 mg/day D-penicillamine 500-750 mg/day 500-750 mg/day Intramuscular Gold 50 mg/week 50 mg/week Cyclosporine 2.5-5.0 mg/kg/day 2.5 mg/kg/day Leflunomide 10-20 mg/day 10-20 mg/day Methtrexate plus one another above DMARDs at least Duration 6 months with standard target does 2 months Treatment failure: DAS 28 score decreases 1.2 or DAS 28 score remains > 3.2 75

Contraindications Pregnant or breast feeding women Active infectious disease Malignancy Multiple sclerosis High risk for infection Chronic foot ulcers Tuberculosis history Septic arthritis in past 12 months Prosthetic septic arthritis Intractable or recurrent pulmonary infectious disease Urinary catheterization 76

Patients and Methods 20 patients enrolled (18 RA and 2 JRA) 2 patients withdrawn UTI by 2 weeks Palpitation, dizziness by 3 weeks 18 patients continued (16 RA + 2 JRA patients) June, 2003 ~ September, 2004 12 ~ 48 weeks 77

Patients and Methods Etanercept 1 vial (25mg) twice a week subcutaneously (JRA: 0.8 mg/kg/week) Continuing all original medications before etanercept Taper some oral medications gradually after etanercept except methotrexate Assessment every 12 weeks (week 8, 20, 32, 44): DAS 28, tender joints, swollen joints, ESR, CRP, rheumatoid factor, autoantibodies, CXR 78

Baseline Characteristics Age, years Mean: RA: 56 JRA: 11 (8 and 14) Range: RA: 38 ~ 74 JRA: 8 ~14 Sex Female: male = 16: 2 (RA = 15: 1; JRA = 1: 1) Duration of RA, years Mean: 9.56 Range: 2 ~18 79

Baseline Characteristics Rheumatoid factors positive 88.89% (16/ 18) Bony erosions positive (bilateral hands X-ray) 83.33% (15 /18) Concomitant therapy Methotrexate: 83.33% (15/ 18) prednisolone (5-10 mg/day): 88.89% (16/ 18) 80

Baseline Characteristics DAS 28 score Mean: 6.54 No. of tender joints Mean: 17.35 No. of swollen joints Mean: 7.23 ESR Mean: 45.31 81

Results Before etanercept (n=13) 8 weeks later (n=13) P-value DAS 28 score 6.58 (±0.63) 3.89 (±1.02) <0.0001 * No. of tender joints No. of Swollen joints 17.35 (±6.15) 4.46 (±2.96) <0.0001 * 7.23 (±3.14) 1.54 (±1.61) <0.0001 * ESR 45.31 (±24.20) 24.31(±19.80) 0.007* 82

Results Before etanercept (n=6) 20 weeks later (n=6) P-value DAS 28 score 6.51 (±0.52) 3.42 (±0.98) 0.002* No. of tender joints No. of Swollen joints 16.17 (±5.49) 4.17 (±4.31) 0.004* 8.17 (±4.43) 0.33 (±0.52) 0.002* ESR 45.92 (±30.21) 23.50 (±21.88) 0.240 83

Results 8 weeks later (n=6) 20 weeks later (n=6) P-value DAS 28 score 4.29 (±1.14) 3.42 (±0.98) 0.310 No. of tender joints No. of Swollen joints 5.67 (±2.66) 4.17 (±4.31) 0.240 2.17 (±1.60) 0.33 (±0.52) 0.041* ESR 28.33 (±25.97) 23.50 (±21.88) 0.818 84

DAS 28 Score 7 6 5 4 3 2 1 0 6.51 4.29 3.42 0 4 8 12 16 20 24 P<0.0001* P= 0.310 P=0.002* Time (weeks)

No. of Tender joints 20 15 10 16.17 5 5.67 4.17 0 0 4 8 12 16 20 24 P<0.0001* P= 0.240 Times (weeks) P=0.004*

No. of swollen joint 10 8 6 4 2 0 8.17 2.17 0.33 0 4 8 12 16 20 24 P<0.0001* P= 0.041* Time (weeks) P=0.002*

ESR 50 40 30 20 10 0 45.92 28.33 0 4 8 12 16 20 24 P=0.007* P= 0.818 P=0.240 23.5 Time (weeks)

Adverse Events URI increased: 33.33% (6/ 18) Injection site reaction: 27.78% (5/ 18) all transient Anti-nDNA: 16.67% (3/ 18) 1: 320, 160, and 80 Skin rash: 11.11% (2/ 18) Dizziness: 5.56% (1/ 18) Lower legs edema: 5.56% (1/ 18) Post-injection short-term arthritis flares: 5.56% (1/ 18) 89

Discussion 1. No morbidity for hospitalization 2. No serious infection occurred, including pulmonary and extrapulmonary TB 3. No CHF occurred 4. No lupus-like syndrome occurred Anti-nDNA disappeared after DC etanercept (2/3) 5. 2 patients are HBV carrier 6. JRA significant response 7. DC Etanercept: arthritis flares in 1 ~ 8 weeks 8. Combination therapy vs monotherapy 9. 1 vial (25 mg) every week 10. No complete remission 90

Conclusion Etanercept is rapid-onset, effective, safety, convenient, well-tolerable, but expensive TNF antagonist for rheumatoid arthritis and juvenile rheumatoid arthritis patients 91

亞培復邁 (Humira) in Taiwan 適應症 : 類風濕性關節炎, 僵直性脊椎炎, 乾癬性關節炎, 克隆氏症 健保價 1 syringe = 17,784 ( 一月兩次, 每月為 35,568) 給付標準 2 個傳統 DMARDs 使用無效超過 6 個月 DAS28> 5.1 給付標準同 Etanercept 92

HUMIRA 的臨床療效 Reduces Signs and Symptoms Inhibits Radiographic Progression Inflammation Destruction RA Functional Disability Improves Physical Function 93

TSS Mean Change from Baseline 復邁可有效抑制 RA 病患關節的骨骼受損 HUMIRA 40 mg eow + MTX Placebo + MTX 4 Blinded Open-label 3 2.8 3.0 2 1 0 0.0 0.3 1 0 12 24 36 Months Keystone EC, et al. Ann Rheum Dis 2005;64(suppl):S419. Abstract SAT0034 94

2001 年結核病的估計盛行率 per 100 000 pop < 10 10-24 25-49 50-99 100-299 300 or more No estimate The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. White lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2003 95

The Structure of Rituximab The variable region is from the anti-cd20 murine Rituximab comprises antibody fragment IDEC-2B8 human IgG and k-constant regions 96

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Rituximab: Clinical Experience in non-hodgkin s Lymphoma (NHL) Rituximab was the first monoclonal antibody approved for the treatment of relapsed or refractory CD20+ B cell NHL Recommended dosage is 375 mg/m² given as a slow iv infusion once weekly for 4 or 8 doses > 540,000 NHL patient treatments since 1997 B-cell levels remained depleted for 9 12 months 98 czman et al, 1999; Hainsworth et al, 2002; Leget & Czuczman, 1998, McLaughlin et al, 1999)

Rituximab: General Safety Rarely Reported Events in NHL Severe infusion reactions hypotension, angio-oedema, hypoxia or bronchospasm Tumour lysis syndrome occurrence 12 24 hours following first infusion Mucocutaneous reactions paraneoplastic pemphigus, Stevens Johnson syndrome, toxic epidermal necrolysis occurring 1 13 weeks post- treatment 99

% patients with ACR20 ACR Responses Over 2 Years 80 70 60 50 40 30 20 10 0 0 20 40 60 80 100 120 Weeks MTX R R+CTX R+MTX 100

Dr. 林理信 101