RA care about something how to do in your live

1. 類風濕性關節炎面面觀
臺北榮總 過敏免疫風濕科
廖顯宗
106.12.24

2. 類風濕性關節炎 (關節炎發炎之王)
Fusiform Swelling

3. 類風濕性關節炎-malalignment

4. 免疫系統發生問題，產生許多不必要的抗
體來破壞身體正常的結構，是一種高度發炎
的慢性疾病，病況輕微時僅感到局部關節僵
硬疼痛，嚴重時則會引起全身的關節腫脹、
疼痛及損壞，甚至造成畸形、殘障、失能。
其詳細致病機轉至今仍未完全被了解,和遺
傳基因及環境因素有關。台灣發生率大約
0.5-1%，好發於中年女性(女比男=3:1)。

5. 正常
免疫
系統

6. 正常
免疫
系統
免疫
失調

7. 類風濕關節炎的常見症狀
1.疲倦

8. 2.食慾不振
類風濕關節炎的常見症狀

9. 3.虛弱
類風濕關節炎的常見症狀

10. 4.晨僵現象
類風濕關節炎的常見症狀

11. 5.手腳關節會腫脹而僵硬
類風濕關節炎的常見症狀

12. 類風濕性關節炎(juxta-articular osteoporosis)

13. 類風濕性關節炎

14. 全身關節
慢性多發性對稱性

15. 類風濕性關節炎
 類風濕性關節炎是一
種免疫系統異常，而
造成關節破壞的疾病。
 滑膜發炎造成關節腫
痛，且可影響多個關
節。
 如果沒有好好控制，
長期發炎將導致關節
變形，無法行使日常
生活所需活動

16. 類風濕性關節炎骨頭破壞的病程
軟骨和關節腔是骨頭之
間的緩衝設計。
關節腔內側襯有一層滑
膜細胞。
自體免疫攻擊滑膜細胞
造成發炎。
發炎的滑膜開始增生，
且侵犯軟骨及骨頭。
最後軟骨完全消失，關
節彎曲困難、永久失去
活動功能。
健康關節 罹病關節
發炎的滑膜
骨
滑膜
關節包
關節軟骨

17.  得病第一年，關節侵蝕特別明顯
Harris, 1990; Pincus & Callahan, 1986; Scott et al, 1987

18. 類風濕性關節炎與細胞激素
 類風濕性關節炎患者體內，調節發炎的激素失去了平衡。
 發炎反應由兩大類發炎激素來調控，一類是具有促進發炎
功能，另一類則是扮演抑制發炎。
細胞激素是由細胞所製
造出來的蛋白質，用以
傳遞訊息給其他細胞，
可以說是細胞溝通的一
種方式
發炎反應由兩大類作用相反的激素來調節

19. 19

20. Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.
骨頭
發炎現象
與
關節破壞
軟骨
關節滑膜
嗜中性球
關節滑膜增生
T 細胞
B 細胞
造成類風濕性關節炎的病理機轉
導致發炎性細胞
激素(IL-6, IL-1,
TNFα)的生成
活化破骨細胞，
滑膜纖維母細胞
早期類風濕性關節炎
正常關節
風濕性關節炎

21. 1987年美國風濕病醫學會診斷標準
 在以下七項症狀或檢查項目中，若病人出現四個
項目或以上，且持續大於六星期，便可診斷為類
風濕性關節炎
• 早上關節僵硬持續一小時或以上
• 三個或以上關節發炎
• 手指、手掌或手腕關節發炎
• 對稱性關節發炎
• 皮下發現風濕性結節
• 類風濕性因子(RF)呈陽性反應
• X 光檢查發現關節變化

22. 2010 新版類風濕性關節炎診斷依據
A. 關節侵犯
• 1個大關節
• 2-10個大關節
• 1-3個小關節
• 4-10個小關節
• >10個關節 (需至少一個小關節)
得分
0
1
2
3
5
B. 血清學指標
• RF陰性 且 CCP抗體陰性
• RF弱陽性 或 CCP抗體弱陽性 (正常上限之1-3倍)
• RF強陽性 或 CCP抗體強陽性 (正常上限之3倍以上)
得分
0
2
3
C. 發炎指數
• CRP正常 且 ESR正常
• CRP 或 ESR異常升高
得分
0
1
D. 症狀持續時間
• <6週
• ≥6週
得分
0
1
四項總分 ≥6 可診斷為類風濕性關節炎
RF: 類風濕因子 / CCP抗體: 抗環瓜胺酸抗體 / CRP: C反應蛋白 / ESR: 紅血球沉降速率

23. 類風濕關節炎之臨床病程
 持續型，一發不可收拾 (預後差)
 間斷型，反反覆覆 (預後尚可)
 穩定型，幾年不發作 (預後最好)

24. 類風濕性關節炎好發的部位
 常受影響的關節
關節軟骨
滑膜
骨（關節頭）
關節包
關節腔
（關節液）
骨（關節窩）
關節的構造
顳顎關節 23%
環軸關節 34%
（第1.2頸椎間）
肩關節
胸鎖關節
肘關節 68%
腕關節
85%
股關節 27%
膝關節
79%
踝關節 71%
腳趾
手指
趾間關節
蹠趾關節 80%
踝關節
DIP
遠端指間關節
22%
PIP
近端指間關節
63%
MP
掌指關節 80%
腕關節 85%
腳趾掌關節
指掌關節

25. 類風濕性關節炎常見的併發症-1
血管炎
血管收縮
表皮血管炎、內臟動脈炎
雷諾氏現象
乾燥症候群 淚腺和唾液腺等外分泌腺因自體免疫侵犯而發生病變
神經肌肉病變 病變部位會出現感覺麻木及知覺障礙，甚至肌肉萎縮
肺部病變
肋膜疾病
間質性纖維化
結節性肺病
小支氣管炎
動脈炎併肺高壓
小氣道疾病
類風濕性結節
直徑約0.2~1.0公分，常見於手指、手肘的伸面或其他
受到壓迫的部位

26. 類風濕性關節炎常見的併發症-2
心臟病變
病變進行較緩慢，臨床表現較少，但做心臟超音波檢查
可發現
費爾替氏症候群 (felty’s
syndrome)
患者會有貧血、血小板減少、反覆發熱、感染、出血等
現象
成年型Still氏症
患者有不明原因的間斷性發燒、關節炎、肌肉痛、偶爾
有鮭魚色紅皮疹、淋巴腺腫大、喉嚨痛、肝脾腫大
腎臟病變
膜性腎臟炎、腎絲球性腎炎、類澱粉沉積、小血管炎…
貧血
一般少見，即使有，程度通常輕微
淋巴結腫大 與關節炎嚴重程度及血清高濃度類風濕因子呈正比
其他病變
1. 肝脾腫大
2. 骨質疏鬆
3. 大B細胞淋巴瘤

27. RA 合併血管炎

28. RA 合併血管炎
• 約2-5% RA會有血管炎
• 慢性RA病患較易得到:從診斷RA到發作血
管炎約13.6年
• RA男生比較容易得血管炎(男:女=2-4:1)
• 侵犯中、小型血管
• 高濃度的類風濕性因子(RF) 、低濃度的補體
(complement) 、RA疾病活動度高

30. RA 合併雷諾氏現象

32. Three phase (PCR)
• Pale
• Cyanosis
• Redness

33. RA 合併乾燥症
• Glandular manifestations
– Dry eyes(Keratoconjunctivitis sicca)
• 眼淚製造↓、燒灼、癢
– Xerostomia
• 吞嚥困難、蛀牙、氣管乾燥
– Parotid gland enlargement

34. 黴菌、疱疹病毒感染
舌頭乾裂

35. Schirmer’s test Rose bengal staining
1. 正常眼淚分泌: >10 mm/ 5分鐘
2. 乾眼症: <5 mm/ 5分鐘

36. 唾液腺攝影
唾液腺體管腔發炎、腫脹
唾液腺閃爍攝影

37. 小唾液腺病理切片
• 淋巴球浸潤、聚集(CD4+ T cell predominant
80%)
1.Focal, periductal
infiltrate
2.Loss of acinar
cells

38. Revised international classification
III. Ocular signs- that is, objective evidence of ocular involvemen defined as positive result for at
least one of the followng two tests:
1. Schirmer’s test, performed without anaesthesis(≤5mm in 5mins)
2. Rose bengal score of other ocular dry eye score(≥4 according to Biisterveld’s scoring system)

39. IV. Histopathology: In minor salivary glans focal lymphocytic sialoadenitis, with a focus score
≥1, defined as a number of lymphocytic foci(1 focus=mucus acini旁邊有超過50 顆
lymphocytes/ 4mm2)
V. Salivary gland involvement: 至少符合以下之一的diagnostic criteria
1.Unstimulated whole salivary flow(≤1.5ml in 15mins)
2.Parotid sialography showing the presence of diffuse sialectasias, without evidence of
obstruction in the major ducts
3.Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed
excretion of tracer

40. RA 合併眼睛侵犯
• Episcleritis (表鞏膜炎)
• Scleritis (鞏膜炎)

41. RA 合併肺纖維化 (RF/anti-ccp 很高)
DIP
NSIP
OP
UIP
LIP
DAD
Fibrosis

42. RA 合併肺纖維化 (RF/anti-ccp 很高)
UIP
(40-62%)
NSIP
(11-38%)
OP
DAD

43. RA 合併肺纖維化 (RF/anti-ccp 很高)

44. RA 合併類風濕節結

45. • 自體免疫性肝炎 (autoimmune hepatitis)
• 原發性膽道硬化症 (primary biliary cirrhosis)
RA 合併肝臟侵犯

46. RA 合併腎臟侵犯
• Renal amyloidosis (腎臟類澱粉沉積): 嚴重蛋白尿

47. RA 合併腎臟侵犯
• 腎臟類澱粉沉積
• 腎絲球性腎炎 (vasculopathy、mesangial
infiltration) pathogenic deposition of immune
complexes
• 膜性腎臟發炎: treatment with penicillamine
and gold salts (membranous nephropathy)

48. RA 合併腎臟病變

49. RA 合併心臟血管侵犯
• 血管粥狀硬化
• 心肌梗塞
• 缺血性中風
• 心包膜炎
• 心內膜炎
• 心臟電氣傳導病變

50. RA 合併神經系統侵犯
• Peripheral neuropathy & mononeuritis
multiplex
• Carpal tunnel syndrome (by compression of the
median nerve by swelling around the wrist)
• Atlanto-axial (C1-C2) subluxation (due to erosion
of the odontoid process and/or transverse
ligaments in C-spine's connection to the skull.
• An erosion (>3mm) can give rise to vertebrae
slipping over one another and compressing the
spinal cord
• Quadriplegia

51. Peripheral neuropathy & mononeuritis multiplex

52. Carpal tunnel syndrome

53. Atlanto-axial (C1-C2) subluxation

54. RA 合併其他身體症狀
• 倦怠、無力
• 低度發燒
• 食慾降低
• 體重減輕
• 纖維肌痛症 (fibromyalgia)

55. • The cardinal manifestation is diffuse musculoskeletal
pain
• Patients typically complain of axial pain in the neck,
middle, and lower back, and pain in the chest wall,
arms, and legs
• The pain is chronic and persistent, although it usually
varies in intensity
• Pain is often aggravated by exertion, stress, lack of
sleep and weather changes
纖維肌痛症

56. Clinical Manifestations
• Fatigue is present in more than 90 percent of cases
and is occasionally the chief complaint
• sleep dysfunction, stiffness, depression, anxiety,
cognitive disturbance, exercise intolerance, ocular
dryness, multiple chemical sensitivity and allergic
symptoms, palpitations, dyspnea, vulvodynia,
dysmenorrhea, sexual dysfunction, weight
fluctuations, night sweats, dysphagia, dysgeusia, and
orthostatic intolerance

57. Classification Criteria
1. Widespread musculoskeletal
pain for at least 3 months
2. Excess tenderness in at least
11 of 18 predefined anatomic
sites
• The American College of Rheumatology 1990 Criteria for the Classification
of Fibromyalgia. Report of the Multicenter Criteria Committee.
– Arthritis Rheum 1990; 33:160–172.

58. Clinical Manifestations
1. Fibromyalgia is 10 times more common in females
2. The prevalence of this disorder in the community
increases with age from two percent at age 20 to
eight percent at age 70
3. Most patients present between the ages of 30 and
55
• The prevalence and characteristics of fibromyalgia in the general population.
» Arthritis Rheum 1995 Jan;38(1):19-28

59. 類風濕關節炎預後不良的因素
 類風濕性因子(Rheumatoid factor)
 出現類風濕皮下結節
 多發性關節炎
 發炎指數(ESR、CRP)一直居高不下
 對多種消炎鎮痛劑服用無效
 X光早期出現關節磨損
 Anti-CCP抗體陽性且濃度較高

60. 類風濕性關節炎的影響與預後
存活和死因
• 侵犯關節多,則預後差
• 一般比正常人少3-10年
• 心臟血管疾病為其主要死因
• 藥物引起的副作用亦很嚴重
• 社會家庭的沉重負擔

61. 類風濕性關節炎的治療
 藥物治療
 非藥物治療
• 護具，關節矯正裝置
• 熱療，冷療
• 復健
• 運動

62. 認識藥物

63. 類風濕性關節炎的治療藥物
類風濕性關節炎用藥
非類固醇抗發炎藥（NSAIDs）
類固醇類藥物（steroids）
疾病修飾抗風濕藥物（DMARDs）
生物製劑
消腫止痛。
抑制發炎、抑制免疫反應。
應避免長期使用。
抑制免疫反應、控制疾病活動度。
抑制各種發炎激素作用。
延緩骨骼關節破壞。
類風濕性關節炎的藥物治療

64.  一、非類固醇抗炎藥物（NSAIDs），其具有較快速
止痛消炎作用
 二、疾病修飾抗風濕病藥物（DMARDs），包括許多
疾病修飾抗風濕藥物如奎寧、MTX等，被視為可根本
改善病情
 三、類固醇製劑(corticosteroids )
 四、生物製劑（Biologics）。
 五、口服小分子藥物
目前這些藥物經常合併治療。

65.  在關節炎及各種疼痛疾病的消炎止痛及病程控制
上，還是佔有相當重要的地位，也是最被廣泛使用
的。
 副作用：可能會有消化不良、腸胃道出血及肝、
腎功能損傷、心血管作用的潛在風險等等。

66.  目的是控制住病情，讓器官不再破壞且能保有它們
原有的功能。
 開始作用的時間較長，故稱緩慢作用藥，但作用較
慢，但維持藥效較長。
 常見的滅殺除癌錠(MTX)、奎寧(Plaquenil)、斯樂
腸溶錠(Salazopyrin)

67. 滅殺除癌錠(MTX)
 藥品成分名： Methotrexate
 常用的風濕病用藥，效果佳，常用於類風濕性關
節炎及乾癬性關節炎。
 副作用：口腔潰瘍(可以併用葉酸改善)，腸胃不
適，肝功能異常，長期使用時醫師會定期抽血追
蹤。
 藥品外觀：

68.  請勿飲酒，因酒精會增加藥物對肝臟的負擔。
 預防感染的措施，服藥期間若有任何感染症狀，
請立即尋求醫師協助。
 請依醫師指示定期回診及檢驗。

69.  藥品成分名： Hydroxychloroquine sulphate
 減輕關節的疼痛和腫脹，還可減少關節被破壞，造成永久
性殘障的機率。
 副作用包括腸胃不適，皮疹或皮膚黑、癢，視網膜病變
(停藥可慢慢恢復) 。
 藥品外觀：

70.  藥品成分名：Sulfasalazine
 常用的風濕病用藥
 副作用：偶見的腸胃不適、頭暈、精蟲減少(停藥
可恢復)等。
 藥品外觀：

71.  能有效地減輕關節炎症狀。
 劑量愈高，使用愈久的病人，副作用愈明顯。醫師
常會在副作用可忍受的範圍內使用最低的有效劑量。

72. 類固醇副作用：
 外觀：因食慾變好、體重增加，臉變較圓（俗稱
月亮臉）。
 皮膚：皮膚變得較薄，傷口癒合較差。
 骨骼：骨質流失，應增加鈣質的攝取。
 血糖增加：應定期查驗血糖。
 免疫抑制：類固醇會壓抑免疫系統，使身體對病
菌的抵抗力降低，較易引起感染。感染後的復元
也會拖得較久。
個人體質不同，服用各種藥物或有任何不適， 副作用產生時，
應儘快回診，千萬不可擅自行停藥，以免加重病情。

73. (四) 生物製劑（Biologics）:
類風溼關節炎患者的福音
因為好的治療讓
舞者能重返舞台
因為好的治療讓
老師能重拾粉筆

74.  恩博(enbrel)、復邁(humira)、欣普尼(simponi)、
莫須瘤(mabthera)、安挺樂(actemra)、恩瑞舒
(orencia)、欣膝亞(cimzia)。
 適應症：對疾病修飾抗風濕病藥物（即DMARDs，包
括滅殺除癌錠）療效不彰之成人活動性類風濕性關節
炎，以及其他免疫疾病，如乾癬性關節炎等。

75. 正常
免疫
系統
免疫
失調

76. 生物製劑如何
幫助我們？

77.  副作用：大同小異，常見的有感染(呼吸道感
染、泌尿道感染、腸胃道感染)、皮膚疹、肺
結核、病毒性肝炎。
 積極預防：勤洗手、戴口罩、定期抽血監測
肝功能

78.  Tofacitinib (Xeljanz): 5mg bid

79. 要勤洗手，但如何洗？

81. 注意以下情形要暫緩治療：

82.  Enbrel
 Humira
 Simponi
 Cimzia
 Remicade

83. Three Different Approaches to TNF Inhibition
• Adapted from: Weir N et al. Therapy. 2006;3:535–545
Infliximab (IFX)
Adalimumab (ADA)
Golimumab (GOL)
Etanercept (ETN)
Certolizumab
pegol* (CZP)
IgG1
Fc
Fab
IgG1
Fc
Receptor
Monoclonal antibody
Recombinant
receptor/Fc fusion
protein
Fab′
PEG
PEGylated humanized
monoclonal Fab’
fragment
_
*The clinical relevance of the above structural differences are not known
Fab: Fragment antigen binding; Fc: Fragment crystallisable;
Ig: Immunoglobulin; PEG: Polyethylene glycol

84. Bioavailabity Data for Anti-TNF Agents
Agent
Administration
Route
Bioavailability
Infliximab (IFX)1 i.v. 100%1*
Certolizumab pegol (CZP)2 s.c. 80%2
Adalimumab (ADA)3 s.c. 64%3
Etanercept (ETN)4 s.c. 58%4
Golimumab (GOL)5 s.c. 51%5
1Infliximab Prescribing Information (US). Available online at: www.accessdata.
fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf.
2Cimzia® Summary of Product Characteristics. Available online at: www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001037/human
_med_001294.jsp&mid=WC0b01ac058001d124.
*IFX is administered via intravenous infusion, and as such has a 100% bioavailability
s.c.: subcutaneous; i.v.: intravenous
3Adalimumab Prescribing Information (US). Available online at: www.accessdata.fda.gov/
drugsatfda_docs/label/2014/125057s368lbl.pdf.
4Zhou H. Clin. Pharmacol. 2005;45:490–497
5Golimumab Summary of Product Characteristics. Available online at: www.ema.europa.eu/ema/index.jsp?curl=pages/
medicines/human/medicines/000992/human_med_001053.jsp&mid=WC0b01ac058001d124.

85. CZP is the only PEGylated anti-TNF1
• This leads to increased half life, reduced immunogenicity and reduced mast cell degranulation (in vitro)*, compared to the
non-PEGylated protein1
̶ This effect of PEG on mast cells may explain the low level of injection site pain observed with CZP in clinical trials2
• PEGylation may also explain the observed enhanced penetration of CZP into inflamed tissues,3–5 which is particularly
relevant in the treatment of inflammatory diseases3
CZP is the only anti-TNFwith no Fc region4
• Therefore it may avoid Fc-mediated effects such as:
− Complement- or antibody-dependent cytotoxicity*4,6
− Recycling by FcRn, which could lead to longer residency
in inflamed tissue*3
• This may also explain the low level of placental transfer observed,
compared to other anti-TNFs7
CZP is the only univalent anti-TNF8
• This means it does not cross-link antigens to form large immune complexes,4 which can cause neutrophil degranulation,
superoxide production (in vitro)*9, and increased clearance10
1Pasut G. Biodrugs. 2014;28 (Suppl. 1):S15–S23
2Lamour S et al. Ann Rheum Dis. 2009;68(Suppl 3):188. Abstract THU0050
3Palframan R et al. J Immunol Methods. 2009;348:36–41
4Shim H. Exp Mol Med. 2011;43:539–549
5Carron P et al. Arthritis Rheum. 2013;65(10)(Suppl.):S472 Abstract 1113
6Nesbitt A et al. Inflamm Bowel Dis. 2007;13(11):1323–1332
7Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11:286–292
8Cassinotti A et al. Core Evid. 2007;2(3):209–224
9Henry A et al. Ann Rheum Dis. 2007;66(Suppl II):82. Abstract OP0100
10Vincent FB et al. Ann Rheum Dis. 2013;72:165-178
Structure of Certolizumab Pegol (CZP)
*The clinical relevance of the structure of CZP
in humans is not fully understood
Figure modified from: Weir N et al. Therapy.
2006;3:535–545
Fab′
PEG

86. • The results of in vitro experiments using isothermal calorimetry and dynamic light scattering studies,
showed that CZP does not form large immune complexes, whereas bivalent antibodies readily crosslink
TNF trimers to form large complexes.2,3 However, to date, it has not yet been determined as to what
degree these complexes are formed in patients2,4
Immune Complex Formation with TNF by Anti-TNF Molecules
1FDA Guidance for Industry: Immunogenicity Assessment for Therapeutic
Protein Products. Available online at: www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf
Certolizumab Pegol + TNF
Univalent Binding2
Antibodies (eg. IFX and ADA) + TNF
Bivalent Binding
Immune Complex Formation2
TNF TNF TNFTNF
2Henry A et al. Gastroenterol. 2007;132:A-231. Abstract S1609
3Nesbitt A et al. EULAR 2007. Poster FRI0054
4van Schouwenburg P et al. Nat Rev Rheumatol. 2013;9:164–172
• Immune responses secondary to immune complex formation may elicit clinical signs including fever, rash,
arthralgia, myalgia, hematuria, proteinuria, serositis, central nervous system complications and
haemolytic anemia1
*The clinical relevance of these data in humans is unknown

87. Thisslidesetisforunsolicitedrequestsonly
• Adapted from: Smolen, JS. et al. Lancet . 2016. Epub Ahead of Print
Safety Set (n=914)
NMSC: non-melanoma skin cancer
Treatment-emergent adverse events were defined according to MedDRA version 18.1
Patients who received CZP+MTX and ADA+MTX are counted after respective switching in both columns
CZP + MTX (n=516) ADA + MTX (n=523)
n % Incidence (95% CI) n % Incidence (95% CI)
Any TEAEs 389 75 139.9 (126.4, 154.5) 386 74 134.8 (121.7, 149.0)
Serious TEAEs 67 13 9.4 (7.3, 11.9) 58 11 7.7 (5.9, 10.0)
Serious infections and infestations 17 3 2.2 (1.3, 3.6) 16 3 2.0 (1.2, 3.3)
Serious cardiac disorders 8 2 1.1 (0.5, 2.1) 9 2 1.1 (0.5, 2.2)
Serious vascular disorders 4 1 0.5 (0.1, 1.3) 0 0 0.0
Discontinuation due to TEAEs 65 13 8.7 (6.7, 11.0) 63 12 8.1 (6.2, 10.3)
All malignancies 8 2 1.1 (0.5, 2.1) 7 1 0.9 (0.4, 1.8)
All malignancies (excluding NMSC) 5 2 0.7 (0.2, 1.5) 5 1 0.6 (0.2, 1.5)
Opportunistic infections (excluding
tuberculosis)
3 1 0.4 (0.1, 1.1) 3 1 0.4 (0.1, 1.1)
Tuberculosis (confirmed) 0 0 0.0 1 <1 0.1 (0.0, 0.7)
Deaths (TEAEs leading to death) 3 1 - 3 1 -
Mean time of drug exposure was 542.0 days for CZP+MTX and 554.5 days for ADA+MTX
CZP deaths (n=3): coronary artery disease (n=1); myocardial infarction (n=1); respiratory non-small cell malignancy (n=1)
ADA deaths (n=3): sudden death (n=1); bronchopulmonary aspergillosis (n=1); pneumonia (n=1)
Incidence of TEAEs by Treatment at AE Onset:
Overview References
& AbbreviationsHome
Study
Design
Certolizumab pegol is not yet registered in Taiwan

88. 懷孕時期生物製劑之胎盤穿越

89. Thisslidesetisforunsolicitedrequestsonly
Placental Transfer

90. 90
Investigator-Initiated Study of Anti-TNF Placental Transfer
• Examined transfer of anti-TNFs to the fetus in Inflammatory bowel disease (IBD) patients
• Plasma was collected from the mother, the cord blood and the infant on the day of birth
• CZP levels were measured by using a validated ELISA
Mahadevan U et al. Clin Gastroenterol Hepatol;2013;11;3;286–292
10 patients on ADA treatment
10 patients on CZP treatment
11 patients on IFX treatment
31 pregnant IBD
(CD and UC)
patients†
• There were 2 sets of twins in the CZP group, giving a total of 33 infants
CD: Crohn’s disease; UC: ulceratrive colitis
†In the Australia, CZP is not registered for use in Crohn’s disease or
ulcerative colitis. CZP is Pregnancy Category C
HQ/0316/CI/00028
ELISA: Enzyme-linked immunosorbent assay;
Certolizumab pegol is not yet registered in Taiwan

91. 91
Thisslidesetisforunsolicitedrequestsonly
Maternal Characteristics
Adapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292
CD: Crohn’s Disease, UC: Ulcerative Colitis, 6MP: 6-MercaptoPurine
IFX ADA CZP
Patients, N 11 10 10
Median maternal age, yrs (range) 36 (29 – 40) 32.5 (25 – 40) 28 (22 – 42)
Disease type, CD:UC* 7:4 8:2 10:0
Median disease duration, yrs (range) 10 (2 – 24) 11 (2 – 24) 6.5 (1 – 10)
Concomitant medications
None
5-aminosalicylates
Azathioprine/6MP
Prednisone
2
7
3
2
7
3
0
1
5
2
2
3
 Placental Transfer
Background
CZP Nonclinical
Placental Transfer
Home Abbreviations
CZP Human
Placental Transfer
CZP Breast Milk
Transfer
CZP Semen
Quality
CZP Pregnancy
Outcomes
CZP Labeling References
CZP-EDU-000462-062014
Updation/expiry date: Dec 15th 2014/Dec 14th 2015
Certolizumab pegol is not yet registered in Taiwan

92. Pt
IFX dose
(mg/kg)
IFX interval
(wks)
Time from last
dose to birth
(days)
IFX (µg/ml) at birth
Mother: Cord: Infant
Ratio Cord/
Mother (%)
Month IFX
undetectable
Newborn complications
1a 10 6 14
40
(6 wks)
-
39.5b
(6 wks)
- 7 None
2 5 6 30 15.1 - 25.3 - 5 Meconium
3a,c 5 6 2 1.4 2.0
2.9b
(2 wks)
143 2
Hand-foot-mouth (9mos);
respiratory distress (11mos)
4a,c 5 6 14 19.2 26.5 23.6 138 7
Oral candida (10 wks);
GERD (4 mos)
5 5 8 91 3.8 3.3 4.2 87 2 Jaundice
6 5 8 15 4.8 8.8 8.7 183 3 None
7 5 8 55 14.5 20.5 28.2 141 4 URI 2 wks
8 5 6 46 16.5 26.5 27.5 160 5 None
9 5 8 35 2.2 8.4 10.6 381 4 None
10 5 6 77 4.1 13.6
4.7b
(4 wks)
332 - None
11 10 8 74 5.1 20.4
8.4b
(4 wks)
400 4 None
aFlare of disease in post-partum; bIn some cases infant levels were not obtained on day of birth but a few weeks later; cFlare of disease in trimester
3
92
Thisslidesetisforunsolicitedrequestsonly
IFX Concentrations on Day of Birth
Adapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292
In every case, the cord or
infant level of IFX was
higher than the mother’s
at the time of delivery
 Placental Transfer
Background
CZP Nonclinical
Placental Transfer
Home Abbreviations
CZP Human
Placental Transfer
CZP Breast Milk
Transfer
CZP Semen
Quality
CZP Pregnancy
Outcomes
CZP Labeling References
CZP-EDU-000462-062014
Updation/expiry date: Dec 15th 2014/Dec 14th 2015
Certolizumab pegol is not yet registered in Taiwan

93. Pt
ADA dose
(mg)
ADA interval
Time from last
dose to birth
(days)
ADA (µg/ml) at birth
Mother: Cord: Infant
Ratio Cord/
Mother (%)
Follow ADA
levels
Newborn complications
1a,b 40 EOW 7 6.05 9.29 6.17 153 - None
2b 40 EOW 56 1.84 5.39 6.01 293
1.94
( 6 wks)
Pulmonary edema, brief at
birth
3a,b 40 EOW 7 3.84 4.57 - 119 - None
4a 40 EOW 42 0 0.16 - - - None
5 40 EOW 35 2.2 4.18 4.28 190
0.934
(8 wks)
None
6 40 EOW 42 3.21 4.74 4.87 148
1.31
(7 wks)
None
7b 40 EOW 42 3.36 8.94 8.09 266
0.529
(11 wks)
None
8 40 Weekly 1 16.1 19.7 17.7 122 - None
9 40 EOW 49 2.24 4.95 4.64 220 - None
10 40 EOW 7 8.48 8.29 9.17 98 - None
EOW: Every Other Week; a Flare of disease in trimester 3; b Flare of disease in post-partum
ADA Concentrations on Day of Birth
93
Thisslidesetisforunsolicitedrequestsonly
Adapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292
In every case, the cord or
infant level of ADA was
higher than the mother’s on
the day of birth
 Placental Transfer
Background
CZP Nonclinical
Placental Transfer
Home Abbreviations
CZP Human
Placental Transfer
CZP Breast Milk
Transfer
CZP Semen
Quality
CZP Pregnancy
Outcomes
CZP Labeling References
CZP-EDU-000462-062014
Updation/expiry date: Dec 15th 2014/Dec 14th 2015
In every case, infant or cord blood levels were higher than the mother's plasma
level of ADA on the day of birth and the median ratio of cord to maternal ADA level
was 179% Certolizumab pegol is not yet registered in Taiwan

94. Pt
Last dose
(days)
Day of birth CZP concentrations (µg/ml)
Lower limit of quantification <0.41
Ratio Cord/
Mother (%)
Day of birth PEG concentrations
(µg/ml).b Lower limit of quantification <9
Mother Cord Infant Mother Cord Infant
1 14 18.83 1.65 - 8.8 33.4 a a
2 7 59.57 0.94 1.02 1.6 51.3 a a
3 28 4.87 1.19 1.22 24 a a a
4 17 20.13 0.57 0.44 2.8 34.7 a a
5 21 16.49 <0.41 <0.41 2.5 27.7 a
No sample
6 24 34.65 1.66 1.58 4.8 34.4 a a
7 28 1.87 <0.41 <0.41 22 a a a
8-A
42 6.32
<0.41 0.58 6.4
11.1
a a
8-B <0.41 <0.41 6.4 a a
9-A
6 42.7
1.28 1.34 3.0
62.1
a a
9-B 1.16 1.18 2.7 a a
10 5 37.83 0.55 0.6 1.5 74.9 a a
a Less than the lower limit of quantification, PEG = 9 µg/ml; b For babies 3, 7 and 9B lower limit of quantification (LLOQ) was 18 µg/ml. For babies 8A
and 9A, LLOQ was 36 µg/ml. Click for further information regarding pre-term births and low births weights.
94
Thisslidesetisforunsolicitedrequestsonly
CZP Concentrations on Day of Birth
In every case, the cord or
infant level of CZP was
lower than the mother’s at
the time of delivery.
All cord and infant CZP
levels were <2 µg/ml.
Adapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292
 Placental Transfer
Background
CZP Nonclinical
Placental Transfer
Home Abbreviations
CZP Human
Placental Transfer
CZP Breast Milk
Transfer
CZP Semen
Quality
CZP Pregnancy
Outcomes
CZP Labeling References
CZP-EDU-000462-062014
Updation/expiry date: Dec 15th 2014/Dec 14th 2015
Certolizumab pegol is not yet registered in Taiwan

95. Pt
Last dose
(days)
Day of birth CZP concentrations (µg/ml)
Lower limit of quantification <0.41
Ratio Cord/
Mother (%)
Day of birth PEG concentrations
(µg/ml).b Lower limit of quantification <9
Mother Cord Infant Mother Cord Infant
1 14 18.83 1.65 - 8.8 33.4 a a
2 7 59.57 0.94 1.02 1.6 51.3 a a
3 28 4.87 1.19 1.22 24 a a a
4 17 20.13 0.57 0.44 2.8 34.7 a a
5 21 16.49 <0.41 <0.41 2.5 27.7 a
No sample
6 24 34.65 1.66 1.58 4.8 34.4 a a
7 28 1.87 <0.41 <0.41 22 a a a
8-A
42 6.32
<0.41 0.58 6.4
11.1
a a
8-B <0.41 <0.41 6.4 a a
9-A
6 42.7
1.28 1.34 3.0
62.1
a a
9-B 1.16 1.18 2.7 a a
10 5 37.83 0.55 0.6 1.5 74.9 a a
a Less than the lower limit of quantification, PEG = 9 µg/ml; b For babies 3, 7 and 9B lower limit of quantification (LLOQ) was 18 µg/ml. For babies 8A
and 9A, LLOQ was 36 µg/ml. Click for further information regarding pre-term births and low births weights.
95
Thisslidesetisforunsolicitedrequestsonly
CZP Concentrations on Day of Birth
• Below the lower limit of
quantification in all plasma
from mothers except 2.
• None detected in any of
the infant plasma or cord
plasma
Adapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292
 Placental Transfer
Background
CZP Nonclinical
Placental Transfer
Home Abbreviations
CZP Human
Placental Transfer
CZP Breast Milk
Transfer
CZP Semen
Quality
CZP Pregnancy
Outcomes
CZP Labeling References
CZP-EDU-000462-062014
Updation/expiry date: Dec 15th 2014/Dec 14th 2015
Certolizumab pegol is not yet registered in Taiwan

96. 96
1. Based on the minimal placental transfer described in this
study, CZP can be continued on schedule throughout
pregnancy until delivery without concern for significant
placental transfer.
2. The pregnant woman and the woman considering
pregnancy in the very near future, CZP may be considered
as the anti-TNFα agent of choice given its lack of placental
transfer; however the ultimate decision needs to be based
on the clinical scenario and patient preference.
Summary of CZP
Certolizumab pegol is not yet registered in TaiwanAdapted from: Mahadevan U et al. Clin Gastroenterol Hepatol. 2013;11;3;286-292

97. 1. 哪裡痛？
2. 甚麼時候覺得痛？
3. 痛多久了？
4. 有沒有發現任何腫脹？
5. 現在不容易做哪些日常工作？
6. 你的關節曾經有意外傷害，或因為你的工作或
嗜好而曾經過度使用關節嗎？
7. 你的家人（父母或兄弟姊妹）有類似的困擾嗎？
如何早期知道類風濕性關節炎 警覺!!

98. 類風濕性關節炎的臨床症狀
 關節和皮膚方面症狀：
• 關節疼痛、僵硬、腫脹 (尤其早上起床的時候，這種情況可
稱為「晨僵」)
• 用手接觸關節時會有暖暖的感覺
• 皮膚發紅
• 手腕、手指關節和膝蓋等，並常有「對稱」的情況出現
• 皮膚下出現風濕性結節
 全身性症狀：
• 疲勞
• 食慾不振
• 體重下降
• 貧血
• 肌肉痛
• 輕微發燒
• 整體有不舒服的感覺

99. 預警徵兆
• 疼痛
• 僵硬
• 行動困難
• 腫脹

100. 1. 詢問病史
2. 關節理學檢查
3. X光及其他檢驗

101. 如何早期知道類風濕性關節炎
 早期症狀
 有家族史
 Anti-CCP或RF出現陽性且濃度較高
 超音波檢查
 核磁共振檢查

102. 早期診斷類風濕關節炎之重要性
 類風濕關節炎通常在剛發病的三個月為治療之黃金期
 部份患者可因延誤治療，關節破壞甚至殘障
 目前世界各國也正在推動類風濕性關節炎Treat-to-
Target (T2T) 的概念，也就是達標治療。
 類風濕性關節炎的達標治療
• 治療的目標的訂定
• 發展治療的策略的訂定

103. 類風濕性關節炎的疾病活動性評估
- ACR 20、50、70
• 美國風濕學院(American College of Rheumatology,
ACR)制訂的反應標準
• 20、50、70代表疼痛或腫脹關節的數目、急性反
應蛋白、病人及醫師評估、疼痛量尺、失能問卷
等五項中的三項進步達20%、50%、70%的比率

104. 類風濕關節炎的疾病活動度
 28處關節疾病活動度(Disease
Activity Score, DAS 28)是用
來評估用藥是否有效改對類風
濕性關節炎的症狀。
 此評估表就是以數值評分來對
左右兩邊肩關節、手肘、手腕、
手掌骨關節、膝關節的觸痛、
腫脹程度，以及全身的健康狀
況和血液化驗等，去計算分數
作出評估。

105. 類風濕性關節炎的「達標」治療
(Treat-to-Target, T2T)
 根據歐洲抗風濕病聯盟(EULAR)的達標小組最新發
表類風濕性關節炎治療建議，歸納出簡單「1．2．
3 守則」希望能夠讓病友輕鬆了解，不但類風濕性
關節炎是可以被控制的，且有具體的目標可以依從，
內容包含：
• 1 個月回診一次
• 2 個治療目標：(1) 低度疾病活動度 ( DAS 28 ≤ 3.2 )
(2) 使疾病達到緩解( DAS 28 < 2.6 )，
使生活品質最佳化
• 3 個月後未達目標，請和醫生討論是否需調整用藥

106. 復健治療與居家照護…

107. 謝謝聆聽!!