Disease and Treatment Contents Introduction of Inflammation Bowel Disease Treatment Goals in IBD The Biologics Application in IBD Introduction of Inflammation Bowel Disease Historical timelines of Crohns disease and Ulcerative Colitis throughout the world ID: 779220
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Slide1
1
Current Situation of Inflammatory Bowel Disease in Taiwan
Disease and Treatment
Slide2Contents
Introduction of Inflammation Bowel Disease
Treatment Goals in IBD
The Biologics Application in IBD
Slide3Introduction of
Inflammation Bowel Disease
Slide4Historical timelines of Crohn’s disease and Ulcerative Colitis throughout the world.
Nature Reviews Gastroenterology &
Hepatology
12, 720–727
(2015)
Slide5The global prevalence of IBD on 2015
Nature Reviews Gastroenterology &
Hepatology
12, 720–727
(2015)
Slide6National health insurance database in Taiwan
-- 1998 ~ 2010 --TotalMaleFemaleUC23571434923CD558
384174Age at diagnosis:
UC vs. CD = 44.7 vs. 37.9 (p<0.001) Male vs. Female = 46.4 vs. 43.7 in UC (p<0.01) = 41.1 vs. 36.5 in CD (p=0.01)
Inflamm Bowel Dis 2013;19:2815
Slide7Young age on set + low mortality rate = increasing prevalence
Prevalence (per 105 inhabitants) Inflamm Bowel Dis 2013;19:28152.0
Crohn’s
diseaseUlcerative colitis
Annual prevalence (/10
5)
98 99 00
01
02
03
04
05
06
07
08
09
10
8.49
2.05
0.79
0.19
10.7x
10.8x
0.0
4.0
6
.0
8
.0
Slide8CD
UCAnnual incidence of IBD in Taiwan1.07 per 105 inhabitants 0.59
0.27 per 105 inhabitants 0.17
81%
59%
Inflamm Bowel Dis 2013;19:2815
Slide9Inflammatory bowel disease (IBD)
Ulcerative colitis Crohn’s disease Dignass A, et al. J Crohns
Colitis 2012;6:965–990J Chin Med Assoc 2012;75:
151
Slide10Ulcerative ColitisTarget organ: colonHistopathology: goblet cell depletion, crypt abscessEndoscopy: diffuse, continuous from rectumClinical feature: chronic mucosal inflammation, Complication: dysplasia-colitic cancer, PSC, skin lesion, etc
Inflammatory bowel disease (IBD)
Dignass
A, et al. J
Crohns
Colitis 2012;6:965–990J Chin Med
Assoc
2012;75:
151
Slide11Tenesmus
, urgencyFaecal incontinencePassage of mucus and fresh blood
Diarrhoea
Weight loss
Fever
Clinically significant blood loss
Abdominal pain
Pancolitis
Proctitis
Left-sided colitis
Bloody
diarrhoea
Sometimes proximal constipation
Dignass
A, et al. J
Crohns
Colitis
2012;6:965–990
J Chin Med
Assoc
2012;75:
151
Poor prognosis: Pancolitis, Steroids, Young age, high CRP/ESR
Rectal Rx
Rectal +
Systemic
Systemic
UC: Clinical Features
41%
37.9%
21.1%
Slide12Disease
extent: as a predictor of long-term d
isease outcome in UC
12
Langholz
E, et al. Gastroenterology
1994;103:1444–51 Ekbom
A,
et al. New Eng J Med
1990;323:1228–33
Ekbom
A,
et al.
Gastroenterology
1992;103:954
–
60
Colectomy in UC after 5 years
1
Colorectal cancer in UC after 25 years
2
35
30
20
10
5
0
Proctitis
Left-sided
colitis
Extensive
colitis
Percent
25
15
N=1161
9%
35%
19%
Standardised mortality ratio in UC after 10 years
3
2.5
2.0
1.0
0.5
0
1.5
Proctitis
Left-sided
colitis
Extensive
colitis
Ratio
N=2509
N=3117
80
60
20
0
Proctitis
Left-sided
colitis
Extensive
colitis
Observed cases
40
9
65
17
Slide13Utilize Mayo Score to Clinical
Activity
Severity of disease
Mayo
Subscore
0
1
2
3
Mayo index
0
1
2
3
Stool frequency
Normal
1–2/day
>normal
3–4/day
>normal
5/day
>normal
Rectal bleeding
None
Streaks
Obvious
Mostly blood
Mucosa
Normal
Mild
friability
Moderate
friability
Spontaneous
bleeding
Physician’s global assessment
Normal
Mild
Moderate
Severe
De
Chambrun
GP, et al. Nat Rev
Gastroenterol
Hepatol
. 2010;7 15-29.
Slide14Crohn’s diseaseTarget organ: mouth ~ anus (entire digestive organ)Histopathology: granuloma, fissuring ulcerEndoscopy: longitudinal ulcer, cobble stone appearance, skip lesionClinical feature: transmural inflammation, Complication: fistula,
stenosis, anal lesion, skin lesion, etc
Inflammatory bowel disease (IBD)
Pariente
B,
et al. Inflamm Bowel Dis 2011;17:1415–22
Slide15Crohn’s Disease is a Progressive Disease
Progression of digestive damage and inflammatory
activity in a theoretical patient with Crohn’s disease
(消化道損害與發炎在CD
病患身上會持續惡化
)
Pariente
B,
et al.
Inflamm
Bowel Dis
2011;17:1415–22
Surgery
Stricture
Stricture
Fistula
/
abscess
Disease
onset
Diagnosis
Early
disease
Inflammatory
activity
(CDAI, CDEIS, CRP)
Digestive damage
Slide16Crohn’s Disease:
腸道內常見的併發症
https://gi.jhsps.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=024CC2E1-2AEB-4D50-9E02-C79825C9F9BF&GDL_Disease_ID=291F2209-F8A9-4011-8094-11EC9BF3100E
30%
發炎
50%
狹窄
20%
廔管
Slide17評估
Crohn’s Disease 疾病嚴重度 - CDAI臨 床 或 檢 驗 項 目加權
得分
每星期中每天稀便與軟便次數之總和
X 2
每星期中每天腹痛分數之總和(0=無，1=
輕微，
2=
中度，
3=
嚴重；每星期總和：
0-21)
X 5
每星期中每天身體狀況分數之總和
(0=
好，
1=
稍差，
2=
差，
3=
很差，
4=
極差；每星期總和：
0-28)
X 7
併發症之發生
X 20
服用強的止瀉藥或鴉片類藥物來止瀉
X 30
腹部有腫塊
(0=
無，
2=
可能有摸到，
5=
確定有
)
X 10
血紅素
hematocrit
與正常值
(
男
47%,
女
42%)
之差距
(
差
1%=1
分
)
X 6
與標準體重之百分比差距
(
差
1%=1
分
)
X 1
有下列項目各加
1
分
關節痛或關節炎
眼睛炎
iris
or
uveitis
發生
erythema
nodosum
,
pyoderma
gangrenosum
,
或
aphthous
ulcers
肛裂或肛門廔管或膿瘍
身體其他地方廔管
最近一週內曾有發燒體溫超過
38.5
℃
總
分
Adapted from
衛生福利部中央健康保險署
Slide18https://gi.jhsps.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=024CC2E1-2AEB-4D50-9E02-C79825C9F9BF&GDL_Disease_ID=291F2209-F8A9-4011-8094-11EC9BF3100E
CD
與
UC:
臨床病灶、內視鏡與病理定義
Slide19IBD:
腸道外的併發症Dermatologic– Erythema nodosum, pyoderma gangrenosum• Hematologic– Anemia, venous thromboembolism• Hepatobiliary– Cholelithiasis
, PSC– Musculoskeletal– Peripheral arthralgias
and arthritis, spondyloarthritis
• Ocular
– Episcleritis, uveitis, scleroconjunctivitis• Renal
– Nephrolithiasis
19
PSC = primary
sclerosing
cholangitis.
Kornbluth
A, et al.
Am J
Gastroenterol
. 2010;105:501-523;
Lichtenstein
GR, et al.
Am
J
Gastroenterol
.
2009;104:465-483;
Peyrin-Biroulet
L, et al.
Inflamm
Bowel
Dis
.
2011;17:471-478
;
Rothfuss
KS, et al.
World J Gastroenterol.
2006;12:4819-4831.
Slide20如何區分
IBD種類: UC vs CD
Clinical Feature
CD
克隆氏症
UC
潰瘍性結腸炎
Presenting signs and
Symptoms
臨床症狀
腹痛 慢性腹瀉 噁心 嘔吐 體重下降 腸阻塞或穿孔
兒童
:
生長遲緩
,
骨鬆
腹痛 慢性
/
夜間腹瀉 血便
Location
位置
所有腸道均可能
大腸
,
直腸
,
結腸
Distribution pattern
分布
不連續
,
跳躍性發炎
連續性 直腸為原發處 惡化至全大腸結腸
Rectal involvement
是否侵犯結腸
常見
非常常見
Perianal disease
併發於肛門周圍
常見
不常見
Depth of inflammation
發炎深度
穿透黏膜層
黏膜
Fistulas/strictures
廔管與狹窄
非常常見
常見
Smoking
抽菸
加重疾病嚴重度
無相關
Cheifetz
AS. JAMA.
2013;309:2150-2158
Kornbluth
A, et al. Am J
Gastroenterol
. 2010;105:501-523
Lichtenstein
GR, et al. Am J
Gastroenterol
. 2009;104:465-483.
Slide21Treatment Goals in IBD
Slide22預測
IBD疾病可能的病程
0
10yrs
0
10yrs
預測較嚴重的
IBD
病程
Predictors
40
歲前確診
肛門周圍潰瘍
需提前使用類固醇
嚴重的內視鏡潰瘍
不過
,
目前缺乏
bio-marker
來預測可能的疾病病程！
Munkholm P,
et al
.
Scan J Gastroenterol
1995;30:699–706
Allez M,
et al. Am J Gastroenterol
2002;97:947–953
43%
3%
幾種可能的
IBD
疾病惡化方式
腸道症狀的嚴重度
Beaugerie L,
et al
.
Gastroenterology
2006;130:650–656
Lee JC,
et al.
J Clin Invest
2011;121:4170–4179
Henckaerts L,
et al. Clin Gastroenterol Hepatol
2009;7:972–980
Solberg IC,
et al. Clin Gastroenterol Hepatol
2007;5:1430–8
0
10yrs
0
10yrs
19%
32%
Solberg IC,
et al. Clinical Gastroenterol Hepatol
2007;5:1430–1438
Weersma RK
, et al. Gut
2009;58:388–395
Rutgeerts P,
et al
.
Gastroenterology
1990;99:956–963
Slide23IBD
的治療目標治療策略需要訂定明確的治療目標
深部緩解
1,3
黏膜癒合
1
,2
無類固醇緩解
臨床緩解
改善臨床症狀
改善疾病惡化
Colombel JF, et al. N Engl J Med. 2010;362(15):1383-95.
Baert FJ, et al. Gastroenterology 2010;138(2):463-8.
Colombel JF, et al.
Clin Gastroenterol Hepatol. 2013 Jul 12.
Slide24What is the Optimal Target?
Mucosal healing
Colonscope:
CDEIS,SES-CD
Image: MRE, CTE
Deep remission
Disease modification
Symptoms
QoL
PCDAI
Laboratory
CRP
ESR
Calprotectin
Stricture, Fistula
Surgery
Colombel
JF, et al. N
Engl
J Med. 2010;362(15):1383-95.
Baert
FJ, et al. Gastroenterology 2010;138(2):463-8.
Colombel
JF, et al.
Clin Gastroenterol Hepatol. 2013 Jul 12.
Slide25我們可以選擇的治療策略
IMS
+ TNF
antagonist
Corticosteroids
+ IMS
Corticosteroids
IMS
+ TNF
antagonist
Corticosteroids
+ IMS
IMS + TNF
antagonist
保守型
step
-care
加速型
step-care
積極型
top-down
Severe
Moderate
Ordás
I, et al. Gut. 2011;60(12):1754-63.
IMS, immunosuppressive; TNF, tumour necrosis factor.
Slide26Therapy is stepped up according to severity at presentation or failure at prior step
Aminosalicylate
Oral/Topical/Combo
Corticosteroid
Anti-TNF +/-IS
Anti-Integrin +/- IS
Disease Severity
at Presentation
Cyclosporine
Colectomy
Aminosalicylate/
Thiopurine
Anti-TNF/Anti-Integrin
+/- IS
Induction
Maintenance
Aminosalicylate
Oral/Topical/Combo
Sequential Therapies for
IBD
Severe
Moderate
Mild
Ordás
I, et al. Gut. 2011;60(12):1754-63.
Slide27Treatment goals in IBD: can our current therapies deliver?
5-ASA, mesalazine; AZA, azathioprine; MTX, methotrexate.
Rutgeerts
P,
et al. Gastroenterology
2012;142:1102–11
Lakatos PL, et al. Am J Gastroenterol
2012;107:579–88
Colombel
JF,
et al. N
Engl
J Med
2010;362:1383–95
Sandborn
WJ,
et al. Gastroenterology
2012;142:257–65
Feagan
B,
et al. N
Engl
J Med
1995;332:292–7
Ardizzone
S,
et al. Gut
2006;55:47–53
Candy S,
et al. Gut
1995;37:674–8
Peyrin-Biroulet
L,
et al.
J
Crohns
Colitis
2011;5:477–83
Leading change: Local and Global Perspective
Focus on Crohn’s Disease Management: treatment goals
Slide28The Role of Biologics in
IBD Treatment
Slide29The Map of Inflammation in IBD
Nature Reviews Gastroenterology &
Hepatology
12, 271–283
Slide30Structure of Different TNF Antagonists
D. Tracey et al. Pharmacology & Therapeutics 117 (2008) 244-279
Slide31Nature Reviews Gastroenterology &
Hepatology 12, 537–545 (2015)Availability and drug labelling of biologic agents for IBD
Anti TNF-
α
Anti-
α
4
β
7
Slide32重大傷病診斷為下列病名者，請另檢附相關
文件克隆氏症、慢性潰瘍性結腸炎需另檢附: 病歷摘要或病歷影本病理組織報告內視鏡或X光報告
重大傷病證明卡申請
與換發注意事項
需終身治療之全身性自體免疫症候群
: ICD-10-CM/PCS
碼(2014年版)
重大傷病項目
英文疾病名稱
證明有效期
限
K50.00-K50.919
克隆氏症
Crohn’s disease
永久
K51.00-K51.919
慢性潰瘍性結腸炎
Ulcerative colitis
永久
Ref.
衛生福利部中央健康保險署
BNHI Requirement
Slide33重大傷病卡
Ref. 衛生福利部中央健康保險署
Slide34Available biologics in Taiwan for
IBD克隆氏症治療部分 8.2.4.7.1.Adalimumab（如Humira）、infliximab（如Remicade）vedolizumab(如
Entyvio) ：成人治療部分1.
限具有消化系專科證書者處方。2.
須經事前審查核准後使用。
3.須經診斷為成人克隆氏症，領有克隆氏症重大傷病卡，並符合下列條件之一；且申請時應附上影像診斷評估報告。(1)克隆氏症病情發作，經
5-aminosalicylic acid藥物 (sulfasalazine, mesalamine, balsalazide)、類固醇、及/
或免疫抑制劑
(azathioprine, 6-mercaptopurine, methotrexate)
充分治療超過六個月
，仍然無法控制病情
(CDAI≧300)
或產生嚴重藥物副作用時，且病況不適合手術者。
(2)
克隆氏症經
5-aminosalicylic acid
藥物如
(sulfasalazine, mesalamine, balsalazide)
、類固醇、及免疫抑制劑
(azathioprine, 6-mercaptopurine, methotrexate)
充分治療超過六個月，或
外科手術
治療，
肛門周圍廔管或腹壁廔管仍無法癒合
且
CDAI≧100
者
。
(3)
克隆氏症經
5-aminosalicylic acid
藥物如
(sulfasalazine, mesalamine, balsalazide)
、類固醇、及免疫抑制劑
(azathioprine, 6-mercaptopurine, methotrexate)
充分治療，仍於一年內因克隆氏症之併發症接受
二次
(
含
)
以上之手術治療且
CDAI≧100
者。
Ref.
衛生福利部中央健康保險署
Slide35a
p <
0.001; bp < 0.05; cp = 0.01; dp = 0.007; ep = 0.002
Clinical response
Δ70 or Δ100 = CDAI* decreases from baseline ≥ 70 or ≥ 100
a
c
e
d
Hanauer SB, et al. Gastroenterology. 2006;130:323-33.
b
Adalimumab
– for Moderate to Severe Crohn’s Disease Patients
CLASSIC
1
:
Induction
of remission and response at Week 4
Slide36LOCF; ITT population,
n=55; *p<0.05
versus placebo
CLASSIC II
Sandborn
WJ, et al. Gut. 2007;56(9):1232-9.
0
20
30
50
70
90
100
Weeks
Patients (%)
Placebo
HUMIRA 40 mg weekly
94*
HUMIRA
40 mg
eow
4
80
60
40
10
8
12
16
20
24
28
32
36
40
44
48
52
56
84*
50
83*
79*
50
Adalimumab
– for Moderate to Severe Crohn’s Disease Patients
CLASSIC 2:
Maintenance
of remission and response through Week 56
(CDAI < 150)
Slide37Presentation Title | Date xx.xx.xx | Company Confidential © 2012
37Sandborn WJ, et al. Gut. 2007;56(9):1232-9.
Adalimumab
– for Moderate to Severe Crohn’s Disease Patients
CLASSIC 2: Safety analyses to the end of Week 56
Slide38潰瘍性結腸炎治療部
分 8.2.4.9. Golimumab(如Simponi)、Adalimumab（如Humira）、
Vedolizumab（如Entyvio
）1.須經事前審查核准後使用。
2.
須經診斷為成人潰瘍性結腸炎，並符合下列條件之一：(1)同時符合下列條件：Ⅰ.領有潰瘍性結腸炎重大傷病卡
（直腸型排除）。Ⅱ.經5-aminosalicylic acid
藥物
(
如
sulfasalazine
、
mesalamine
或
balsalazide)
、類固醇、及免疫調節劑
(
如
azathioprine
或
6-mercaptopurine)
充分治療無效
(
須有病歷完整記載用藥史，連續治療達
6
個月以上
)
，或對
5-aminosalicylic acid
藥物、免疫調節劑產生嚴重藥物副作用。
Ⅲ.
Mayo score ≧9
分
且
Mayo Endoscopic subscore ≧2
分
(
需檢附兩個月內之大腸鏡報告，內含可供辨識之彩色照片
)
。
(2)
急性嚴重的潰瘍性結腸炎，同時符合下列四要件
:Ⅰ.內視鏡下符合潰瘍性結腸炎。
Ⅱ.病理切片排除巨細胞病毒腸炎、阿米巴結腸炎、淋巴癌。Ⅲ.糞便檢測排除困難梭狀桿菌感染。
Ⅳ.Mayo Score為12分，經類固醇全劑量靜脈注射(如methylprednisolone 40-60mg/day
等
)
連續治療
5
天無效。
Available biologics in Taiwan for
IBD
Ref.
衛生福利部中央健康保險署
Slide39Adalimumab
– for Moderate to Severe UC Patients ULTRA 2: Induction of remission, response and mucosal healing at Week 839
Sandborn WJ, et al. Gastroenterology 2012;142:257–65
Proportion of patients
(%)
p
=0.019
p<
0.001
p
=0.032
Placebo
(n=246)
HUMIRA 160/80*
(n=248)
Co-primary endpoint
# Clinical remission: Mayo score ≤2 with no individual
subscore
>1.
# Clinical response per partial Mayo score: decrease in Mayo Score ≥3 points and ≥30% from baseline, with a decrease in
the
rectal bleeding
subscore
≥1 or an absolute rectal bleeding
subscore
of 0 or 1.
# Mucosal healing: endoscopy
subscore
of 0 or 1.
*160/80 mg HUMIRA at Week 0/2; 40mg HUMIRA every other week beginning at Week 4
Slide40Sandborn
W, et al. ECCO 2012;P207Sandborn W, et al. Aliment Pharmacol Ther 2013;37:204–13Sandborn W, et al. Gastroenterology 2012;142:257–65
Week 52clinical remissionWeek 52
clinical responsePatients (%)
0
20
60
100
Non-responder imputation
40
80
ADA (PMS)
ADA (FMS)
17.3
30.9
28.8
Patients (%)
0
20
60
100
Non-responder imputation
40
80
ADA (PMS)
ADA (FMS)
30.2
49.6
47.2
ADA, ITT
ADA
Wk
8 responders
ADA, ITT
ADA
Wk 8 responders
N=248
N=123
N=125
N=248
N=123
N=125
ITT, intent to treat; PMS, partial Mayo score; FMS, full Mayo score
Adalimumab
– for Moderate to Severe UC Patients
ULTRA 2:
Maintenance
of remission and response at Week 52
(Week 8 ADA responders)
Slide41ULTRA 2: treatment emergent adverse events in double blind period, safety analysis set
Sandborn WJ, et al. Gastroenterology Vol. 142, Issue 2, Pages 257-265.e3Placebo
(N = 260)
ADA 160/80 mg
(N =
257)
n (%)
E (E/100PY)
n (%)
E (E/100PY)
Any adverse event
218 (83.8%)
1007 (845.9)
213 (82.9%)
1083 (744.0)
Any AE at least possibly drug related
86 (33.1%)
202 (169.7)
101 (39.3%)
271 (186.2)
Any serious AE
32 (12.3%)
44 (37.0)
31 (12.1%)
45 (30.9)
Any AE leading to discontinuation of study drug
33 (12.7%)
47 (39.5)
22 (8.6%)
24 (16.5)
Any infectious AE
103 (39.6%)
175 (147.0)
116 (45.1%)
210 (144.3)
Any serious infectious AE
5 (1.9%)
7 (5.9)
4 (1.6%)
4 (2.7)
Any malignancy
0
0
2 (0.8%)
2 (1.4)
Any Non-melanoma skin cancer (NMSC)
0
0
1 (0.4%)
1 (0.7)
Any malignant AE (excluding NMSC and lymphomas)
0
0
1 (0.4%)
1 (0.7)
Any malignant AE (including lymphomas and exclude NMSC)
0
0
1 (0.4%)
1 (0.7)
Any injection site reaction
10 (3.8%)
17 (14.3)
31 (12.1%)
58 (39.8)
Any opportunistic infection (excluding TB)
3 (1.2%)
3 (2.5)
5 (1.9%)
6 (4.1)
Any congestive heart failure
0
0
1 (0.4%)
1 (0.7)
Any
demyelinating
disease
0
0
0
0
Any hepatic AE
7 (2.7%)
11 (9.2)
10 (3.9%)
16 (11.0)
Any allergic reaction
1 (0.4%)
1 (0.8)
4 (1.6%)
4 (2.7)
Any lupus-like syndrome
0
0
1 (0.4%)
1 (0.7)
Any hematologic AE
0
0
5 (1.9%)
5 (3.4)
Death
0
0
0
0
Slide42Baseline
D
R
Mayo endoscopic
subscore
2
Week 26
0
Week 8
2
9
7
2
Mayo score
Week 8
Adalimumab
treated UC case sharing
0
Adapeted
from Dr.
Tu’s
slides.
Slide4343
Overall conclusions
IBD is a chronic, progressive inflammatory disease.
Impact of IBD on patients is highly burdensome: it affects the physical, social, and psychosocial well-being of patients.
Goals of therapy include:
Inducing and maintaining remission of symptoms and mucosal healingReducing the risk of complicationsAvoiding the need for surgeryImproved survivalBiologics provide a promising treatment choice for IBD patients to achieve remission and mucosal healing.
Slide44Thanks for your attention