Inflammatory Bowel Disease

莊喬雄
國立成功大學醫學院附設醫院 消化內科
2017/9/22
IBD is a group of inflammatory conditions of the
colon and small intestine.
Crohn's Disease and Ulcerative Colitis are the
principal types.
What is ulcerative colitis (UC) ?

Chronic inflammatory condition

causing continuous mucosal
inflammation of the colon
without granulomas on biopsy,
affecting the rectum and a
variable extent of the colon in
continuity, which is
characterised by a relapsing and
remitting course.
2005 Montreal World Congress of Gastroenterology.
Can J Gastroenterol 2005;19(Suppl A):5–36.

台灣潰瘍性大腸炎 (ulcerative colitis) 的歷史起源於 1969

年台大醫院王正一教授診斷出的國內第一例個案
 What is Crohn’s disease?

• It was named after American gastroenterologist Burrill

Bernard Crohn, who, in 1932, together with two colleagues,
described a series of patients with inflammation of the
terminal ileum, the area most commonly affected by the
illness
• CD may affect any part of the GI tract from mouth to anus,
causing a wide variety of symptoms
• Regional enteritis, terminal ileitis, or granulomatous
ileocolitis

2018/12/4
2011/11/03
2012/9/6
Table 34-1. comparison of the clinical and pathological feature
http://jamanetwork.com/journals/jama/article-abstract/1690713
http://jamanetwork.com/journals/jama/article-abstract/1690713
Extra-intestinal manifestations of IBD
in 6-47% of IBD (CD > UC)
• Joint:
Axial arthritis: sacroieitis,
ankylosing spondylitis
Peripheral arthritis
• Skin:
Erythema nodosum
Pyoderma gangrenosum
Aphthous oral ulcer
• Eye: Uveitis, episcleritis, iritis
• Biliary: Primary sclerosing cholangitis
• Vessel: Venous thromboembolism
Inflamm Bowel Dis 2015;21:1982
Chronology of EIM

Inflamm Bowel Dis. 2015;21:1794

Relationship between EIM & IBD activity

Inflamm Bowel Dis. 2015;21:1982

Pathophysiology of EIM

• Enteric flora activate the immune system

-- against bacterial antigens
• For antigen mimicry between colonic mucosal and bacteria
-- Immune system act crossly against colonic mucosa
• Sharing of these colonic antigens by extraintestinal organs
-- Immune attack these extraintestinal organs

World J Gastroenterol 2005;11:7227

 Clinical nature course of IBD
CD UC
43% 55%

3%

19%

32% 37%

Solberg IC et al. CGH 2007;5:1430-1438 Solberg IC, et al. Scand J Gastroenterol 2009;44:431-40.
 Ulcerative Colitis
- disease distribution at time of diagnosis -

Proctitis (E1) Left side (E2) Extensive (E3)

41% 37.9% 21.1%

J Chin Med Assoc 2012;75: 151

 Nature course of UC

100
90 Colectomy
80
70
Percentage of patients

Disease activity
60
50
40
30
Remission
20
10
0
0 25
Years after diagnosis
n=1161

Adapted from Langholz E, et al. Gastroenterol 1994;107:3–11.

 Montreal
classification
for CD
30% 26.4% 38.2%
L1 ileum L2 colon L3 ileocolon

41.8% 33.6% 24.6%

B1 B2 B3 J Formos Med Assoc
Inflammatory stricturing penetrating 2011;110:600
 Nature course of CD
Cumulative probability (%)

100
90
80 70%
70 Penetrating
60
50
40
30 Stricturing 18%
20 Inflammatory Surgery
10
12%
0
Patients at 0 24 48 72 96 120 144 168 192 216 240
risk: Months
N= 2002 552 229 95 37

Cosnes J et al. Inflamm Bowel Dis 2002;8:244-250; Cosnes J et al. Gut 2005;54:237–241
 Dx of IBD Diagnostic tools:
Sometimes challenging:  Clinical history
 Gradual onset.  Endoscopy & radiology
 No single diagnostic gold standard.  Histology
 Broad differential diagnosis.  Blood test

CD

UC
Ileocecal ulcer:
 Tuberculosis
 Amebiasis

 lymphoma

 Crohn’s disease

 Bechet’s disease

 Vasculitis (H.-S. pupura)

 Amyloidosis

Proctitis:
 Bacterial or viral infection
 Clostridium difficile

 Ulcerative colitis

 Drug

 Radiation
CD UC

Korea
Japan H.K.Korea Japan H.K.
H.K Korea H.K.
H.K.

Gastroenterology 2012;142:46-54
 Prevalence
8.0
8.49
Annual prevalence (/105)

6.0

4.0
10.7x

2.0
2.05
10.8x
0.0
98 99 00 01 02 03 04 05 06 07 08 09 10

per 105 inhabitants Years

Inflamm Bowel Dis 2013;19:2815
Japan Nationwide prevalence
 Gender Ratio (M/F) in Asia
Male/Female ratio
Country Period Study type
UC CD
Taiwan 1998-2010 Nationwide 1.50 2.14

Korea: Songpa-Kangdong 1986-2005 Population 0.99 2.83

Japan 1991 Nationwide 1.32 2.22

China: Guangdong 2011-2012 Population 1.58 2.4

ACCESS: Asia 2011-2012 Population 1.38 1.59

ACCESS: Australia 2011-2012 Population 0.84 0.91

Caucasian 2015 16 countries 1.05 0.78

Yang et al, Inflamm Bolwe Dis 2008 Morita et al, J Gastroentrol 1995
Zeng et al, J gastroenterol Hepatol 2013 Zhao, et al Inflamm Bowel Dis 2013
Ng et al, Gastroenterology 2013 Lancet 2015-online first: Cleynen I, et al
 Pathogenesis

Gene

Environment
Microbiota
 Immunopathogenesis of Ulcerative Colitis

Very Early Early Late

Lumen
Structural changes
The intestinal to the intestinal
mucosal barrier
epithelial
mediates anbarrier allow between
equilibrium microbialgut
antigens
microbiota
Antigen from
Pro-inflammatory and
presentationthe gut
to Tlumen
cytokines
immune tolining
enter
upregulate
cells
cells stimulates
thethe
host 1
Microbial antigens
adhesion
an adaptivemolecule GI tissue
immune expression
tract 1
response; on
vascular endothelial cells 3
Dendritic
Macrophage IL-15/ Th cells are involved in the ;production
recruitmentof
cell IL-8 of leukocytes is mediated
pro-inflammatory cytokines. by
interactions between adhesion
IL-17A molecules known as response
integrins results
and thein
IL-1β A continuing
Immune cells (including immune
dendritic cells
intestinal endothelium 1
and macrophages)
Th0 theare
cytokine-mediated
activated in the chronic cycle of
inflammation 1
presence of microbial antigens and
produce proinflammatory cytokines1
IL-15 TNF-α

Lamina IL-6
propria Pro-inflammatory cytokines upregulate
IL-21
NK-T adhesion molecule
Th17 expression
NK-T cells on vascular
secrete abundant
3
endothelial cells ; recruitmentIL-22
of leukocytes
2 is
IL-5 and IL-13
mediated by interactions between adhesion
IL-5
Treg IL-13 molecules known as integrins and the
intestinal endothelium1

Endothelial cells
Integrin-mediated
Systemic Integrins recruitment of
circulation leukocytes
Leukocyte

31
IL=interleukin; NK=natural killer; Th=T helper; TNF=tumor necrosis factor; Treg=regulatory T cell.
Production of mucin
Tightening of tight junction
Defensin production
“Controlled Inflammation”
 Intestinal Inflammation
Intestinal Lumen
Microbes
~ ~ ~ ~ ~ ~~ Damage to

~ ~ Epithelial Cell Barrier

~ ~ Microbial Invasion

~ DC

~ T cells

Activated T cells
Cytokines/Chemokines
Intestinal LP
 Intestine: Steady State
Intestinal Lumen
Microbes

~ ~ ~ ~ ~~ ~
M Cells
~ Intact
~ Epithelial Cell Barrier

~ DC

Intestinal LP Blood
T cells Treg

MLN
Why Doesn’t Everybody Have IBD?
Vaccine Helminth
Hygiene Protozoa
Antibiotics Virus
Bacteria
Pharmacological therapy for IBD

Anti-TNF

Thiopurine/MTX
steroid Cyclosporine
Tacrolimus
5-ASA
Enzymatic pathways in AZA metabolism

6-TU
(thiouric acid) 6-TG
Efficacy (>235 pmol/8x108 RBC)
XO HPRT Risk of myelotoxicity

AZA 6-MP 6-TIMP

TPMT
6-MMP Potential hepatotoxicity
Circulation Intracellular if >5700 pmol/8x108 RBC
TPMT activity to guide the initial dosage

Wild type (89%)

Initiate AZA in
1/3-1/2 usual dose
Avoidanc Heterozygous
e
of AZA
Mutation (11%)
Homozygous
Mutation
(0.3%)

N Z Med J 2005;118:1324
TPMT mutations are less frequent in Asians (2 vs 11%)

Asians develop more leukopenia than Caucasians.

NUDT15 genetic determinant

• NUDT15 SNP is a pharmacogenetic determinant for thiourine-

indused leukopenia in Asians (encoding p.Arg139Cys).
• In Korean patients, sensitivity =89.4% & specificity=93.2%
• NUTD15 risk allele present in 89.4% (59/66) of the early
leukopenia cases
• Carrying one copy of the risk allele (heterozygous) has 88x risk
for developing leukopenia.

• In TPMT variants, sensitivity = 12.1%, and specificity=97.6%.

Yang SK, Nature Genetics 2014;46:1017

Frequency of risk allele
• TPMT: Taiwanese: 1.6% in ALL children
0.5% in adults control

• NUTD15: Taiwanese: 11.6% in ALL children

15.5% in adults control Liang DC, Pharmacogenomics J 2016;16:536

Korean: 10.4% East Asian:9.8%

Japanese: 7% Hispanics: 3.9%
Chinese: 13% European: 0.2%
American: 2% African: 0%

Yang SK, Nat Genet 2014;46: 1017, etc Yang JJ, J Clin Oncol 2015;33:1235
Adjust dosage according to 6-TG & 6-MMP level
-o-mab -xi-mab -zu-mab -u-mab
Treatment target
 FMT
(Fecal Microbiota Transplant )
NEJM 2013;368:407