Upload
phunghuong
View
227
Download
0
Embed Size (px)
Citation preview
2013.05.09.
1
Inflammatory Bowel diseases
LAKATOS Péter László
Semmelweis University, 1st Department of Medicine
Inflammatory bowel diseases (IBD)
Colitis of known origin
– Infectious colitis (Salmonellas, Shigella, Campylobacter jejuni,
Yershinia, amoeba)
– Pseudomembranous – antibiotic associated colitis (Clostridium
difficile)
– Ischaemic colitis
– Collagen colitis
– Irradiation colitis
– Microscopic colitis, lymphocytic colitis
– Diverticulitis
Colitis of unkown origin
– Ulcerative colitis
– Crohn’s disease
IBD epidemiology
UC incidencie: 0,5-20/100 000
CD incidencie: 0,1-11/100 000
UC prevalence: 50-200/100 000
CD prevalence: 20-100/100 000
UC/CD ratio is decreasing (from 4-5:1 to
2:1)
Incidence in North America vs Europe
No Difference!
Logan RFA Gut 1998;42:309
2013.05.09.
2
Current trends
Current incidence in North America
Stabilizing?
Loftus EV Jr Inflamm Bowel Dis 2007;13:254-61.
Current studies in Western and Northern Europe:
Differences evolution of UC and CD incidence?
Molinie F Gut 2004;53:843-48
Current studies in Western and Northern Europe:
Still increasing numbers?
Vind I Am J GE 2006;101:1272-82.
Jacobsen BA EJGH 2006;18:601-6.
2013.05.09.
3
IBD epidemiolology
More prevalent in „Western” developed
countries
West to East greadient?
Urbanization and „western type diet”
Higher education
IBD epidemiology in Hungary
IBD epidemiolology
Gender: both sexes are affected almost equally
(CD slight female predominance, UC slight male
predominance)
Age at onset: late adolescence, early adulthood
Ethnic differences: determined by genetics
and/or environmental factors
Perinatal events, „hygene”, „Oversheltered
child”
IBD etiopatogenezise
I. Genetics
II. Environmental factors
Luminar antigens? Microbes? Diet?
Pszichosomatic disturbance?
III. Epithelial factors
IV. Immunological factors
2013.05.09.
4
IBD pathogenesis
Genetic predisposition, various environmental
and host factors (e.g. genetic-, epithelial-,
immune and non-immune) play a major role in
the pathogenesis of IBD
Genetics in the pathogenesis of IBD
Poligenic disease
Several loci and susceptibility genes have been
identifed
Some genes are associated with CD or UC, while
other are predicting disease phenotype or
progression
IBD locus Chromosome Identified genes Disease
IBD1 16q13 NOD2/CARD15 CD
IBD2 12q14 Not known
(VDR, NRAMp2, MMP18,
b2-integrin)
UC
IBD3 6p Not known
(HLA, TNF)
IBD
IBD4 14q11-12 Not known
(TCR, LTB4 receptor)
CD
IBD5 5q31-33 SLC22A4/A5
(IRGM, IL-4,6, CD14)
CD
IBD6 19p13 Not known
(ICAM1, C3, TBXA2)
IBD
IBD7 1p36 Not known
(TNF-R family, IL-23R)
IBD
IBD8 16p12 Not known CD
IBD9 3p26 Not known
(CCR5, CCR9, hMLH1)
IBD
10q23 DLG5 IBD
2q37 ATG16L1 CD
7q32 IRF5? IBD
Modifed from Lakatos PL Curr Genom 2006
Pattern recognition receptors (PRRs)
Important role in innate immunity
Recognition and response against Gram-negative bacteria
Extracellular – membrane bound, Toll Like Receptors (TLR)
Intracellular – in the cytosol, NOD2/CARD15
Some mutations predispose to bacterial infections, others to immune mediated diseases
2013.05.09.
5
NOD2/CARD15 as a
Pattern recognition receptor (PRR) NOD2/CARD15 mutations
„Major” NOD2/CARD15 mutation
– Missense: R702W (SNP8)
– Missense: 908R (SNP12)
– Frameshift-insertion ( C): 3020insC (SNP13)
Risk for CD
Heterozygous: 2-4x
Homozygous or compound: 20-40x
Ahmad T Gastroenterology 2002;122:854-66.
Satsangi J. Best Pract Reas Clin Gastroenterol 2003;17:3-18
Chamaillard M PNAS 2003;100:3455-60.
Lakatos PL World J GE 2005;11:1495
Peptidoglycan (G+) Lipoprotein Lipoarabinomannan (Mycobacterial) LPS (Leotosopia) LPS (Porphyromonas) GPI (Trypanosoma cruzi) Zymosan Yeast)
LPS (G-) Lipoteichoic acids (G+) RSV F Protein 9q32
dsRNA
Flagellin
Unmethylated CpG DNA
TLR9 TLR5 TLR3 TLR4 CD14 TLR1 TLR2 TLR6
MD-2
Toll-Like Receptor Ligands:
Recognition of Pathogen
associated molecular patterns
(PAMP)
NOD2/CARD15 mutations
+
a-defensin
lysosim
Pattern
recognition
receptorok
(PRRs)
2013.05.09.
6
Environmental factors Bacteria, viral factors?
bacteria (Diplostreptococcus, E. coli,
Proteus, Yershinia, Clostridium, Shigella)
Mycobacterium paratuberculosis
viruses (rotavirus, Norwalk)
Measles
fungi (Saccharomyces cerevisiae)
Smoking
Lakatos PL World J GE 2007
Diet Dietary factors:
– Brest feeding - protective
– Increased glucose intake in CD
– Lower fruit, vegetable intake
– The deleterious effect of certain proteins (e.g lactose) could not be proven)
No dietary factors were proven to play an important role in the pathogenesis
2013.05.09.
7
IBD pathogenesis
Conclusion Clinical symptoms in IBD
• Ulcerative colitis
Frequently typical
– Bloody/mucous diarrhea
– Tenesmus
– Symptoms of general
disease only in severe
cases: anaemia, weight
loss
• Crohn’s disease
Frequently atypical
– Non bloody diarrhea
– Abdominal pain
– Weight loss
– Palpable abdominal mass
– Fistula
– Malabsorption, anaemia
– Extraintestinalis
symptoms
IBD diagnostics
• Diagnosis
– Clinical picture
– Imaging: endoscopy, radiology, histology
• Differential diagnosis
– Other inflammaotry colitis cases, malignancy
– Irritable bowel syndrome
– Deifferentiation between UC and CD
IBD diagnosis
Complaints, symptoms
Stoll culture studies
Laboratory tests
Endoscopy
Imaging
X-ray- follow though
Enterography
UH
CT, MRI
Leukocyta scintigraphy
2013.05.09.
8
Serologic markers in IBD
Antibody Directed against CD UC
ASCA Mannose of Saccharomyces
cerevisiae
+ (40-60%) -
pANCA Neutrophils +
(UC-like CD)
+
(40-60%)
PAB Pancreas + (15-30%) +
Omp (C) Outer Membrane porin + (20-40%) +
I2 Pseudomonas fluorescens + (20-40%) -
cBir1 flagellin + (20-50%) -
ACCA glycan (Chitobioside) + (20-40%) -
ALCA glycan (Laminaribioside) + (20-40%) -
Papp M World J GE 2007
UC and CD clinical symptoms UC CD
Weight loss (+) ++
Abdominal pain (+) ++
diarrhoea +++ ++
Bloody stool +++ (+)
Tenesmus ++ (+)
Palpable mass - ++
fever (+) ++
mucus +++ (+)
Perianal lesions - ++
+++ typical ++ frequent + sometimes (+) rarely - none
Satsangi J Gut 2006;55:749-53.
Classification of Crohn’s disease
Vienna vs. Montreal Crohn’s disease stenosis
2013.05.09.
9
Crohn’s disease - fistula
Satsangi J Gut 2006;55:749-53.
Classification of ulcerative colitis
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve
Pro
bab
ilit
y (
%)
Patients at risk: Months
2002 552 229 95 37 N =
Penetrating
Stricturing Inflammatory
Long-term evolution of disease
behaviour in Crohn’s Disease
Lakatos PL Hepatogastroenterology 2005;52:817-22..
Long-term evolution of disease
behaviour in Crohn’s Disease
0
10
20
30
40
50
60
ileal colonic ileocolonic upper GI
%
<10 years
>10 years
0
10
20
30
40
50
60
inflammatory stricturing penetrating
%
<10 years
>10 years
P =0.03 P =0.0001
2013.05.09.
10
Natural History of Ulcerative Colitis*
Langholz E et al. Gastroenterology. 1994;107:3.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 2 4 6 8 10 12 14 16 18 20 22 24
Years After Diagnosis
Percen
t o
f P
ati
en
ts
Colectomy
Disease activity
Remission
Status at any given timepoint
Most patients with UC have an
intermittent course of disease activity
Langholz E et al. Gastroenterology. 1994;107:3-11
Cumulative probability of completely relapse free course was
18% at 5 years and 11% at 25 years
1161 patients followed up to 25 years
The nature of intermittant disease
600 patients in years 3 – 7 after diagnosis
Langholz E et al. Gastroenterology. 1994;107:3-11.
3 years 28%
< 3 years 29%
IBD complications
Intestinal
Severe bleeding
Toxic megacolon
Perforation
Stenosis- ileus
abscess
Fistula
Malignancy (tumor surveillance !)
2013.05.09.
11
IBD complications contd.
Extraintestinal
Hepatobiliar (PSC, steatosis,
CAH)
Joint (sacroileitis, polyarthritis,
spondylarthritis)
Occular (episcleritis, uveitis,
iridocyclitis)
Skin (erythema nodosum,
pyoderma gangraenosum)
Haematological (anaemia,
thrombosis, haemolysis)
Treating systemic disease: extra-intestinal
manifestations common in CD patients
Ocular inflammation 2-13%
Oral ulceration 20-30%
Satsangi et al. (ed.) Inflammatory Bowel Diseases, Churchill Livingstone, 669-684 (2003)
Lakatos L World J GE 2003;10:2300-7.
Ankylosing spondylitis 1-6%
Peripheral arthritis 10-20%
Erythema nodosum 6-15%
Pyoderma gangrenosum 0.5-2%
Erythema nodosum in IBD Pyoderma gangraenosum in IBD
2013.05.09.
12
Endoscopy in ulcerative colitis Endoscopic picrute of Crohn’s disease
Inflemmatory mass in CD on CT scan
Jobb flexura
Crohn’s disease - fistula
2013.05.09.
13
Crohn’s disease- progressive fistulas
Crohn’s disease – stenosis – X-ray
irrigoscopy
•Atrophy
Crohn histology
2013.05.09.
14
• A: ulcer and almost normal mucosa
• B: non-regenerative hyperplasia. pseudopolyp
Crohn histology
A B
• C: Transmural inflammation, epitheloid granuloma
• D: Hyperplasia of the myenteric plexus, typical for CD
C D
Crohn histology
UC and CRC
First case was described by
Crohn and Rosenberg (UC
and rectal tumor) in 1925
2013.05.09.
15
Background: Pathogenesis
Rhodes JM Trend in Mol Med 2002; 10-16
Rutter M, Gastroenterology 2004;126:451-459
Lakatos PL LAM 2006;16: 121-9.
long standing inflammation?
environmental factors?
predisposed host?
Background: Pathogenesis-genetics
Lakatos PL Orv Hetil 2006;147:363-9.
Fleisher AS Cancer Res 2000;60:4464-8.
Background: UC and CRC
IBD has been widely recognised to be associated
with an increased risk for CRC
accounts for approximately 10-15% of all deaths
in IBD
accounts for 1–2% of all CRC cases
Munkholm P. Aliment Pharmacol Ther 2003;18(suppl2):1-5.
Langholz E, et al. Gastroenterology 1992; 103: 1444–51.
Lennard-Jones JE, et al. Lancet 1983 ii:149-152. Loftus EV Jr Gastroenterol Clin N Am 2006
„Patients with UC are at increased risk of CRC, but a series of population-
based studies published within the past 5 years suggest that this risk has
decreased over time. The crude annual incidence rate of CRC in UC ranges
from approximately 1 in 500 to 1 in 1600.”
2013.05.09.
16
IBD: therapy
Medical treatment
Surgical treatment
Supportive care
IBD treatment
The ultimate cause of the disease is not
known
There is no cure just care
Goal is achive and maintain of „remission”
A good doctor-patient relationship is needed
to achieve high compliance
Treatment starts at anamnesis
Detailed clinical history
Exclusion of other diseases
Assessement of IBD
Type
Location
Severity
The outcome of previous treatment options
Others (e.g. age, pregnancy, concomittant diseases)
ASSESSMENT of UC activity
(Truelove, Witts B M J 1955;2:1041)
mild moderate severe
Stool no <4 >6 >10
Haematochesia intermittant Frequent continuous
temperature Normal >37,5 >37,5
Pulse Normal >90 >90
Haemoglobin Normal <75 % Needs transfusion
We <30 >30 >30
Plain abd x-ray - Oedema, air in the
bowels
dilatation
2013.05.09.
17
Clinical Activity Index in UC (CAI) Rachmilewitz D. Br M J 1989;298:82
Stool no/week
Bloody stool no/week
General assessement
Abdominal pain
Fever
Extraintestinal symptoms
We, Hb alteration
mild: < 6
moderate: 6-12
severe: >12
Harvey-Bradshow „simple” CD activity
index Harvey RF. Brawshaw JM. Lancet 1980;1:514
General well being 0- 4
Abdominal pain 0- 3
Lose stools/day
Plapable abd mass 0- 3
Extraintestinal manifestations (No)
4-5 HB ~ Best index 150
Endoscopic Activity Index in UC (EAI) Rachmilewitz D. Br M J 1989;298:82
Granulation
Vessel signs
Contact mucosal injury
Mucosal lesions (mucus, erosion, ulcus)
– mild: <5
– moderate: 5-8
– severe: >8
Apoptosis of lymph.
• Purine analogs
• Infliximab
• Adalimumab
• Visilizumab
Activity of effect.c.
• 5-ASA
• CS
• IL-10
Antigen stimulation
• Probiotics
• Antibiotics
Migration of Leu
• Natalizumab
• Leukoaferesis
Cytokines
• anti IL-12
• Certolizumab
Regulation of T cells
• Trichuris suis
IBD
Therapy of IBD
2013.05.09.
18
Outcome of steroid therapy*
for patients with CD
* Prednisone 1 mg/kg for 1 month
• Munkholm P et al. Gut 1994;35:360
1 Month
Outcomes
(n = 109)
Remission
48%
Improved
32%
No response
20%
Remission
54%
Relapse
46%
Improved
57%
Relapse
43%
12 Month
Outcomes
(n = 87)
Steroid dependent
36%
(n = 39)
Prolonged response
44%
(n = 48)
Steroid resistant
20%
(n = 22)
Summary
Outcomes
(n = 109) 16
38
26
58
32
28
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 month 1 year
% p
ati
en
ts
Steroids for the treatment of Crohn’s
Disease – benefit for the patient
remission
partial
remission
no
response
prolonged
response
steroid
dependent
surgery
N = 74 N = 73
“positive”
outcome
“negative”
outcome
Faubion WA et al. Gastroenterology. 2001;121:255.
• Candy S et al. Gut 1995;37:674
AZA vs placebo for steroid
withdrawal in CD
80
60
40
20
0
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33) 80
60
40
20
0
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33) 80
60
40
20
0
Placebo (n=30)
AZA 2.5 mg/kg per d (n=33)
% P
ati
en
ts N
ot
Fa
ilin
g T
ria
l
Duration of Trial (Months)
Remission induced by prednisolone; tapered over 12 wk
Safety of purine analogs
Adverse effects of
purine analogs
28% treated
Intolerance Idiosyncrasy
primary toxic effect
- genetic defect
(TPMT 3A)
-drug overdose
• nauzea
• emesis
• abdominal
pain
• hepatitis
•pancreatitis
•systemic
toxoallergic reaction
Myelotoxicity 2%
2013.05.09.
19
Biologic therapy in IBD
• Anti TNF a antibodies
• Infliximab (Centocor, Schering-Plough CEAG)
• Adalimumab (Abbott)
• Certolizumab (UCB-Pharma)
• Selective adhesion molecule inhibitors
• Natalizumab (Protein Design Labs)
• MLN-02 (Pfizer)
• Anti-CD3 antibodies
• Visilizumab (Protein Design Labs)
Anti-TNF-a biologicals
Chimeric
monoclonal
antibody
Humanized
monoclonal
antibody
Human
recombinant
antibody
Humanized
Fab
fragment
Human
recombinant
receptor / Fc
fusion protein
79% human 95% human 100% human 100% human PEG PEG
Side effects of infliximab
• Immunogenicity
• Reactivation of TBC
• Infections
• Lymphoma (hepatoplenic lymphoma risk)
• Malignancy?
How do current treatment options for
Crohn’s Disease address these objectives?
Aminosalicylates
Steroids
Infliximab/biologicals
Immunosuppressants
The classical Step-Up-treatment paradigm
Surgery
Which patients should be
treated with biologicals?
What is optimal treatment
with biologicals?
2013.05.09.
20
Remission
dependent
5-ASA
Oral Steroids
AZA
refractory
Colectomy
Severe Mild
Current treatment algorithm
Mild to Severe UC
ifx to induce remission
ifx to maintain remission Rescue
Colectomy
CsA
IV steroids
Acute Severe
Current treatment algorithm
Acute severe UC
ifx to induce remission
ifx to maintain remission
Indications for surgery in UC
Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004
Failure of
medical
therapy
74%
Perforation
6%
Toxic UC
10%
Colorectal
Carcinoma
7%
Dysplasia
3%
Analysis of 917 UC patients at
Heidelberg University between
1982 and 2001
Successful IPAA outcome
Satsangi et al. Inflammatory Bowel Diseases. Churchill Livingstone, 2003
Stool frequency
- by day
- by night
3-9 times (mean 6)
0-1 time (mean 1)
Stool weight 650 g semisolid/d
Fecal seepage
- by day
- by night
33% of women, 14% of men
56% of women, 44% of men
Use of antidiarrheal medication 20% of patients at 1 year
Unable to discriminate gas from stool 30% of patients at 1 year