The document discusses biologics and traditional disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatic diseases. It begins by comparing biologics to traditional DMARDs and discussing the indications for biologics in rheumatic conditions. It then covers post-marketing risk management of biologics, including risks of infection and cancer concerns. The document provides information on the mechanisms and uses of various biologics approved for treating diseases like rheumatoid arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, and systemic lupus erythematosus.

1. The day after Biologics
where will you be?
Taipei Medical University Shunang Ho hospital
Rheumatology Dr. KaiLuen Tsai

2. outline
• Biologics vs traditional DMARD
• Indication for Biologics in Rheumatic dz
• Post marketing risk management
• Risk of infection
• Cancer concern

3. Nature Reviews Gastroenterology & Hepatology 12, 363–368 (2015)

5. 風濕免疫科 常用 病程修飾藥劑 (DMARD)
• Hydroxychloroquin 羥基氯奎寧 (Plaquenil®, 必賴克僂; Geniquin® 殲瘧膜
衣錠)
• Sulfasalazine (Salazopyrin® 斯樂、撒樂腸溶錠)
• Leflunomide (Arava®,艾炎寧; Arheuma® 雅努麻)
• D-penicillamine 青黴素胺 (Metalcaptase® 滿克特)
• Methotrexate (MTX 滅殺除癌)
• Azathioprine (Imuran® 移護寧)
• Cyclophosphamide (Cytoxan®, Endoxan® 癌德星)
• Cyclosporine 環孢靈素 (Sandimmun Neoral® 新體睦, Equoral ®賽卜林)
• Mycophenolate mofetil (Cellcept® 山喜多)
• Mycophenolic acid (Myfortic® 睦體康)

6. 遠古時代:
Ancient time:
legends: Aspirin,
Colchicine
中世紀: Middle age: Gold salt,
penicillamine, salfazopyrine,
hydroxychloroquine, NSAID
文藝復興: Renaissance :
MTX 1951 Steroid 1948
現代Modern : Biologics:
Anti-TNF alpha 1980

7. Medication for JIA
Nature Reviews Rheumatology 11, 290–300 (2015)

8. 類固醇 steroid side effect
 月亮臉
 水牛肩
 中心性肥胖
 四肢肌肉萎縮
 骨質疏鬆
 壓迫性骨折
 食量增加
 糖尿病
 皮膚薄弱/瘀青
 多毛症
 皮膚及指甲黴菌感染
 低鈉
 低鉀
 血液鹼化
 嗜酸性白血球降低
 嗜中性白血球增加
 總白血球增加
 憂鬱症
 妊娠紋
 失眠
 心悸
 四肢顫動 (手抖)
 食量增加
 皮膚薄弱/瘀青
 青光眼
 水分滯留
 情緒，記憶，行為
等神經精神性問題

9. Steroid dose is commonly characterised into:
• Low dose (e.g. <7.5mg/day of prednis(ol)one)
• Medium dose (e.g. 10-20 mg/day of prednis(ol)one)
• High dose (e.g. >20mg/day of prednis(ol)one, sometimes more than
100mg/day).

10. 56 歲 男性
類風濕性關節炎
發病超過10年
心包膜積水倒下住院
DAS28 7.24
ESR 98 CRP 4.2
75 歲 婦女
類風濕性關節炎
發病超過20年
DAS28 5.32
ESR 65 CRP 5.2

11. 56歲男性 類風濕性
關節炎 發病三年
ESR 78 CRP 4.2

12. NEJM 2001
NEJM, 2006.
NEJM 2012
基礎醫學的進步是臨床治療進展發展的基石

14. Nature Reviews Gastroenterology & Hepatology 12, 363–368 (2015)

15. 融合瘤細胞技術是單株抗體成功的關鍵
http://speakingofresearch.com/tag/monoclonal-antibodies/

16. Nature Clinical Practice Neurology (2005) 1, 34-44
MURINE CIMETRIC RECOMSTRUCTIVE HUMAN
100% 33% 10% 0%
1975 1983 1988 1985/1990
Humira , an anti-TNF (Tumour Necrosis
Factor) treatment for rheumatoid
arthritis (RA), leads the way as the first
commercial, fully-human monoclonal
antibody drug. Marketed by Abbott, it
first appeared in 2003.

19. outline
• Biologics vs traditional DMARD
• Indication for Biologics in Rheumatic dz
• Post marketing risk management
• Risk of infection
• Cancer concern

20. Nature Reviews Gastroenterology & Hepatology 12, 363–368 (2015)

21. 可用生物製劑治療的免疫風濕疾病
類風濕性關節炎 (RA)
僵直性脊椎炎 (AS)
無法明確分類的脊椎關節炎 (USpA)
乾癬及乾癬性關節炎 (Psor, PsA)
發炎性腸炎(CD, UC)
修格蘭氏症候群 (SS)
紅斑性狼瘡 (SLE)
硬皮病 (PSS or SSc)
骨質疏鬆症 (Osteoporosis)
氣喘病/異位性皮膚炎 (BA/AD)
天疱瘡/類天疱瘡 (Pemphigus, bullous pemphigoid)
血管炎 (Vasculitis)

22. 2016/1/14
英文藥名 台灣商品名 作用機轉 注射方式 適應症 健保給付
Etanercept
(Enbrel)
恩博 抗腫瘤壞死因子TNF 皮下注射
類風濕性關節炎、僵直性脊椎
炎、乾癬、乾癬性關節炎
有
Adalimumsb
(Humira)
復邁 抗腫瘤壞死因子TNF 皮下注射
類風濕性關節炎、僵直性脊椎
炎、乾癬、乾癬性關節炎
有
Golimumab
(Simponi)
欣普尼 抗腫瘤壞死因子TNF 皮下注射
類風濕性關節炎、僵直性脊椎
炎、乾癬性關節炎
有
Rituxtimab
(MabTheRa)
莫須瘤 B細胞CD20抗原 靜脈注射
類風濕性關節炎 有
Abatacept
(Orencia )
恩瑞舒 T細胞因子 靜脈注射
類風濕性關節炎 有
Tocilizumab
(Actemra )
安挺樂 細胞激素
IL-6
靜脈注射
類風濕性關節炎 有
Ustekinumab
(Stelara)
喜達諾 細胞激素
IL-12/IL-23
皮下注射
乾癬、乾癬性關節炎 有
Belimumab
(Benlysta)
奔麗生 B細胞表面細胞激素
接受器
靜脈注射
全身性紅斑狼瘡 無
Omalizumab
( Xolair )
樂無喘 IgE 免疫球蛋白 皮下注射
伴隨高IgE血清濃度的氣喘病 有
Denosumab
(Prolia)
保骼麗 RANKL 皮下注射
骨質疏鬆症 有
Tofacitinib
(XELJANZ)
捷抑炎 The JAK inhibitor
tofacitinib
口服
類風溼性關節炎 有
台
灣
目
前
核
准
上
市
之
免
疫
標
靶
藥
物

23. 類風濕性關節炎
RHEUMATOID ARTHRITIS

24. Chronic
Systemic
Autoimmune disease
Synovitis / ACCP / RF

27. Others:
小分子標靶藥物
Tofacitinib(Xeljanz
CTLA4-Ig

28. 1. Adapted from Waldburger JM et al. Arthritis Res Ther 2009;11:206.
2. Adapted from Shuai K et al. Nat Rev Immunol 2003;3:900–911.
3. Adapted from Jiang JK et al. J Med Chem 2008;51:8012–8018.
XEL-FM-1409007

29. 類風濕性關節炎病患
DAS 28 (28處關節疾病活動度評估
DAS28 = 0.56 √ (TJC28) + 0.28 √ (SJC28) +
0.70 Ln (ESR) + 0.014 (GH)
• 健保給付申請基本條件:
• 28處關節疾病活動度積分 (Disease Activity
Score, DAS 28) 必須大於5.1
• 六個月的標準疾病修飾抗風濕病藥物
(DMARD) 療法治療不具成效。MTX base +
另外兩種DMARD 達標準劑量以上失效。
• ESR>

30. Nature Reviews Rheumatology 11, 276–289
(2015)

31. Nature Reviews Rheumatology 11, 276–289 (2015)

32. 關節不痛之後呢?
各內科次專科所面對的相對問題?
心血管 CV risk significant decreased
胸腔 1. Tuberculosis
2. COPD patient : treated with ORENCIA developed adverse events
more frequently than those treated with placebo
腎臟 RA+CKD pt, associated with less renal function decline
(Rheumatol Int. 2015 Apr;35(4):727-34.
肝膽腸胃 1. HBV, HCV
2. Anti-Il-6: bowel perforation risk
感染 Increase infection risk
新陳代謝 Base on which kind of biologics: IL6, JAK inhibitor -> dyslipidemia
Decrease steroid dose -> had benefit for blood sugar control
血液腫瘤 Hema: Base on which kinds of biologics
Onco: Cancer risk +/-
風免 Biologics induce lupus

34. 僵直性脊椎炎
ANKLYOSING SPONDYLITIS

36. Nature Reviews Rheumatology 6, 75-81

38. Biologics for AS
現在能用的
Further:
Anti-IL 17
Anti-JAK
Anti-WNT

39. 乾癬
PSORIASIS (PSO)
乾癬性關節炎
PSORIATIC ARTHRITIS(PSA)
2016/1/14

40. 43 y/o F

41. 60 y/o f

42. 38 y/o m

44. 乾癬的免疫細胞問題
in psoriatic lesions
induces proliferation of
keratinocytes
角質形成細胞
N Engl J Med 2009; 361:496-509

45. 環境因素
壓力
感染
藥物
受傷
抽菸
基因因素
淋巴結
啟動樹突細胞
受傷害細胞釋放發炎物質
輔助T細胞被啟動
角質形成細胞
發炎物質訊號吸引
更多發炎細胞過來
一部分的發炎物質訊號隨
著血液流竄全身，進而引
起關節炎
N Engl J Med 2009; 361:496-509

46. Nature Biotech
Ustekinumab (Stelara) 喜達諾

47. Adalimumab Etanercept Infiximab Golimumab Ustekinumab 45/90

48. For PsO and PsA
Anti-TNF
– Etanercept
– Adalimumab
– Golimumab
Anti-IL12/23
– Ustekinumab
Future
IL 17 inhibitor
Abatacept (CTLA4-Ig,
Costimulation blockade
Tofacitinib (JAK inhibitor)
PDE4 inhibitor
IL 6 ?
Anti-CD 20 ?

49. INFLAMMATION BOWEL DISEASE
CROHN'S DISEASE AND
ULCERATIVE COLITIS

50. Nature Reviews Gastroenterology & Hepatology 7, 110-
117 (February 2010)

51. Biologics for IBD
Nature Reviews Gastroenterology & Hepatology
12, 537–545 (2015)

52. SYSTEMIC LUPUS ERYTHEMATOUS
全身性紅斑狼瘡

53. 2016/1/14
Lupus pathway
Rituximab
Abatacept
Belimumab
CD20

54. Regimen ?
Rituximab for SLE
1. refractory LN ( 30%~50% )
2. Hemolytic anemia (50%~)
Two major clinical trials have not met their endpoints, but ACR and EULAR guidelines
suggest consideration of rituximab for patients with active lupus nephritis
refractory to conventional therapies. By Lancet Vol 384 November 22, 2014

55. Belimumab is approved in the United States, Canada and Europe for treatment of SLE.
However, the major phase III trials excluded the more severe cases of SLE with kidney and brain
damage, so its effectiveness has not been demonstrated in those cases.
Muco-cutanous

56. Anti-dsDNA, median % change
anti-CD 20+ B cell, median % change
Belimumab

57. Abatacept(CTLA4-Ig

58. To be continuous……….
Nature Reviews Rheumatology 10, 97–107 (2014)
An easy-to-fail endpoint and aggressive back ground meds

59. 乾燥症(修格蘭症候群)

60. B Cell-targeted Therapies seems effect in Sjogren syndrome
Rheumatology (2015) 54 (2): 219-230.

61. 全身性血管炎
Nature Reviews Rheumatology 10, 463–473 (2014)

62. JAMA, August 8, 2007—Vol 298, No. 6 (

63. Nature Reviews Rheumatology 10, 502–510 (2014)
potential therapeutic targets in AAV and LVV,

64. 骨質疏鬆OSTEOPOROSIS
2016/1/14

65. 2016/1/14
破骨與成骨
破骨細胞
成骨細胞巨噬細胞
幹細胞

66. 2016/1/14RANKL在破骨作用中 的角色
破骨細胞
成骨細胞
破骨細胞
破骨細胞

67. OSTEOARTHRITIS 退化性關節炎

68. Osteoarthritis 退化性關節炎
β-nerve growth factor (β-NGF), IL-1β or TNF?
Hyaluronic acid
Platelet-rich plasma
Stem cells
Ann. Rheum. Dis. 71, 891–898 (2012).

69. Even brain, may be the further target
Nature Reviews Immunology 16, 22–34 (2016)

70. outline
• Biologics vs traditional DMARD
• Indication for Biologics in Rheumatic dz
• Post marketing risk management
• Risk of infection
• Cancer concern

71. ANTI-TNF ALPHA
Volume 8, No. 10, p601–611, October 2008

72. Kalb R, et al. G2C 2014. P1643
Cumulative Incidence Rates of Serious Infections per 100
Patient-years, Overall Population

73. Abatacept

74. Figure 3
The Lancet 2015 386, 258-265DOI: (10.1016/S0140-6736(14)61704-9)

76. – Histoplasmosis, coccidioidomycosis, blastomycocis
– Pulmonary aspergillosis
– Listeriosis
– PcP
– Strongyloidiasis
– PML
– Hepatitis B reactivation
– MOTT (atypical mycobacterias)
– Tuberculosis
Infectious considerations of
biologic DMARDs

77. The cytokine TNF plays an important role in
defense against TB infection through several
mechanisms, including macrophage activation
and formation of granulomas.
Volume 3, No. 3, p148–155, March 2003

78. Volume 8, No. 10, p601–611, October 2008
Progression of M tuberculosis infection
It is important to remember that >50% of reported TB cases
associated with anti-TNF therapy are extrapulmonary.

79. Ann Rheum Dis 2010;69:522–528
UK
Higher numbers of patients are at risk of developing TB with anti-TNF-a therapy
in Asia compared with Western Europe and North America.
International Journal of Rheumatic Diseases 2014; 17: 291–298

80. 生物製劑後的健康管理對策

83. The question?
每半年照X光片，抽QuantiFERON
Base survey
有症狀才照X光，抽QuantiFERON
Half year
不知過多久

84. Question ?
1. LTBI 再以預防性INH後 能不能用anti-TNF ? 如
果使用，復發機率是多少?
2. TB reactivation後，完整治療後能不能用anti-
TNF?
3. 預防性INH的保護能有多少?9個月後如果再度
有TB的機率?
4. 遇上使用INH 副作用? Liver toxicity ?

85. Non cases of LTBI(latent TB infection) re-activeation
were observed inpatients receiving concomitant
INH prophylaxis for LTBI.

86. Hepatitis B and Hepatitis C

87. Risk of cancer
• Anti-TNF alpha:
• Clinical data on the risk of lymphomas, leukemias,
and solid malignancies, as well as the overall risk of
malignancy stemming from the use of TNF
inhibitors, are mixed.
• The risk of melanoma is uncertain but may also be
increased.
• Taiwan data:
• the risk of cancer was significantly reduced in
biologic users compared with DMARD-only patients
(HR 0.63, 95% CI 0.49-0.80, P<0.0001),

88. PSOLAR: Malignancy rates
• Excludes non-melanoma skin cancer
• Limitation: Numbers of malignancy events are small. Unadjusted rates of
malignancies (differences in baseline characteristics: older patients in non-
biologic group)
Langley R, et al. Presented at the 21st EADV Congress; Prague Czech Republic, September 27–30, 2012. P973.
0.60
0.65
0.60 0.61 0.61
0.0
0.2
0.4
0.6
0.8
1.0
UST INF/GOL Non-sponsored
biologics
No biologic All
Rateper100PY
Malignancy Incidence Rates