Transcript WHAT`S BUGGING YOUR GUT?

INFLAMMATORY BOWEL
DISEASES 101
Anita Afzali MD, MPH
UW Medicine– Harborview Medical Center
February 9, 2016
LEARNING POINTS
1.
2.
3.
4.
Basics of IBD
Understanding your immune system
Current treatments in IBD
Newer therapies in IBD
INFLAMMATORY BOWEL DISEASE (IBD)
 A group of chronic diseases that
causes inflammation in the large
intestines (colon) and/or small intestines
 Periods of relapse and remission
 Symptoms vary widely based on
disease location and severity of
inflammation
3
INFLAMMATORY BOWEL DISEASES
Are Not:
Are:
 Irritable bowel
syndrome (IBS)
 An allergy
 An immune deficiency
 Inflammatory =
activated immune
system in the
intestinal tract
 Chronic =
lasts a long time
(maybe a lifetime)
 Treatable
IBD 101: TWO MAIN TYPES
•
•
•
•
•
Ulcerative Colitis
Contiguous &
circumferential,
superficial
inflammation
Erythema, Edema
Loss of vascular
pattern
Friability
Granularity
•
•
•
•
Crohn’s Disease
Discontinuous,
patchy, full-thickness
inflammation
Mouth-to-anus
involvement
Strictures
Fistulas and
abscesses
5
ILEOCOLONOSCOPY
Normal findings of terminal ileum and
colon
UC
Spectrum of Disease
Normal
Moderate
Mild
Severe
7
CD
Spectrum of Disease
8
CD SPECTRUM OF DISEASE
Taken from Steven Mills, MD
9
CLINICAL FEATURES OF IBD
Typical Symptoms
• Abdominal pain
• Diarrhea
• Fever
• Fatigue
• Rectal bleeding
• Weight loss
• Anorexia
• Nausea
Common Physical
Examination Findings
• Abdominal
tenderness
• Palpable mass
• Perianal disease
• Extra-intestinal
manifestations:
–
–
–
–
–
Mouth
Skin
Eyes
Joints
Liver
Common Laboratory &
Radiographic Findings
• Anemia
• Leukocytosis
• Elevated
ESR/CRP**
• Guaiac-positive
stool
• Small bowel
disease
• Fistulas
• Strictures
CRP = C-reactive protein
ESR = erythrocyte sedimentation rate
Podolsky DK. N Engl J Med. 2002
IMPACT OF IBD
Medical Impact
85% of patients suffer from
diarrhea1
51% of patients were
hospitalized in the last 3
years2
•
•
64% required
surgery2
~90% of CD will have
surgery in their lifetime
Work Disability Impact
55% missed work due to disease
in the past year3
5.3% become permanently work
disabled2
Emotional Impact
70% of patients report anxiety or
depression, compared with
30% of population norms4
1. Knutson D, et al. Am Fam Physician. 2003.
2. Ananthakrishnan AN, et al. Am J Gastroenterol. 2008.
3. Kiebles JL, et al. Inflamm Bowel Dis. 2010.
4. Feagan BG, et al. Am J Gastroenterol. 2009.
IBD CHARACTERIZED BY CHRONIC
INFLAMMATION IN THE GUT
Dysregulation of the immune system
WHAT IS THE IMMUNE SYSTEM?
• Cells (T cells, B cells,
macrophages) that defend
the body against attack from
infections
• To eradicate infection, the
immune system turns on,
causes inflammation
• Once an infection is
eliminated, the immune
system knows how to turn
itself off
Photo courtesy of Scott Plevy, MD
DYSREGULATED IMMUNE SYSTEM
• In IBD, the “off” switch
is broken
• Inflammation is a Key
Aspect of IBD
CHRONIC INFLAMMATION:
PROTEINS CALLED CYTOKINES ARE THE LIGHT SWITCH
IL-10
TGF
IFN
IL-12
IL-1Ra
IL-4/IL-13
IL-8
IL-1
TNF
“On”
“Off”
Multiple Sclerosis
Asthma
Crohn’s Disease
Ulcerative Colitis
Psoriasis
Rheumatoid Arthritis
EXACT ETIOLOGY UNKNOWN:
INAPPROPRIATE IMMUNE RESPONSE
Genetics
Immune System/
Inflammation
Environmental
Influence
Luminal microbial
antigens/adjuvants
CD=Crohn’s disease;
IBD=inflammatory bowel
disease.
Khor B, et al. Nature.2011.
Cosnes J, et al.
Gastroenterology. 2011.
GENETICS
IS IBD A GENETIC DISORDER?
Approximately 10% of patients have
positive family history for IBD
2%–10% risk for IBD if first-degree
relative affected
Identical twins: 40-60% that both
affected
“Complex” genetic disorders
Yang H, et al. Inflammatory Bowel Disease. 1993.
ENVIRONMENT
YOU ARE ONLY 10% HUMAN
= 1012 to 1013 Cells
= 1013 to 1014
Intestinal Bacteria
WHAT IS THE ‘MICROBIOME’?
 Refers to entire microbial gut composition
 What is the role of intestinal microbiome
in good health?
 How does the intestinal microbiome
change in IBD?
 Unhealthy microbiome = ‘Dysbiosis’
Role of fecal microbial transplantation
(‘stool transplant’) in restoring healthy
microbiome?
Proposed Model Leading to IBD:
Interaction of Genes and Environment
Lee YK and Mazmanian SK. Science 2010
Environmental Triggers of IBD
Acute
infections
Antibiotics
IBD
Diet
NSAIDs
Onset and
Reactivation
Stress
Smoking
Ratio Rate
EFFECT ON CHANGE IN MICROBIOME?
Hviid A et al. Gut 2011
U.S. INCIDENCE AND PREVALENCE
Approximately 1.5 million Americans suffer
from IBD
Prevalence ~1/200 people have IBD in U.S.
Men and women are affected equally
Bimodal distribution: 20-30 and ≥60 yr
Increase among different race/ethnic
groups (HMC)
About Crohn’s disease. CCFA
Crohn’s disease. NIDDK
IBD and older adults. CCFA
Afzali A et al. Inflamm Bowel Dis 2016 (in press)
IBD ‘MEDICINE CABINET’
Over-the-Counter
Antibiotics
5-Aminosalicylates/Mesalamine
Corticosteroids, Budesonide
Immunomodulators – AZA/6MP, MTX
Biologics - Target Protein Specific
Anti-TNFs in IBD
Change in Natural disease progression
Infliximab
approved for
CD 1998
Adalimumab for
CD 2002
Infliximab
approved for UC
2005
Certolizumab pegol
for CD 2008
Adalimumab
for UC 2012
Golimumab
for UC 2013
Adapted from Curr Opin Rheumat 2014
Fausel R & Afzali A. Ther Clin Risk Manag 2015
WHY DO WE NEED PERSONALIZED
MEDICINE?
STAGES OF RHEUMATOID ARTHRITIS
Early
Intermediate
Late
Courtesy of J. Cush, 2002
Change in Joint Damage
Mean through 102 Weeks – anti-TNF
Mean change from baseline
through 102 weeks
Placebo
3 mg/kg qw8
10 mg/kg qw8
3 mg/kg qw4
10 mg/kg qw4
14
12
10
8
6
p < 0.001 for each infliximab arm vs.
placebo
at week 30, 54, and 102
4
2
0
Baseline
Week 30
Week 54
Week 102
90
%
75
%
Respons
e
Remission
<1
Year
1-<2
years
57
%
PRECISE trial (certolizumab)
44
%
n=98
24
%
n=131
n=131
n=55
2-<5
years
Sandborn WJ et al. Am J Gastro 2006
Colombel et al, NEJM 2007
33
%
29
%
n=98
47
%
n=45
36
%
n=45
n=20
n=22
36
%
n=20
n=35
37
%
n=19
37
%
55
%
n=55
50
%
62
%
n=22
68
%
n=35
100
%
90
%
80
%
70
%
60
%
50
%
40
%
30
%
20
%
10
%
0
%
n=19
% in CDAI Response or
Remission
RESPONSE AND REMISSION TO
ANTI-TNF BY DISEASE DURATION
>=5
years
Placebo
Response
Placebo
Remission
WE DON’T SEE THE DEFORMITIES OF
THE INTESTINES UNTIL COMPLICATION…
Early
Intermediate
Late
Courtesy of J. Cush, 2002
ANTI-TNF: ENDOSCOPIC HEALING
INFLAMMATION -> FISTULA, STRICTURE
Taken from M. Shaikhani MD
35
THE EVOLUTION OF CROHN’S DISEASE:
INFLAMMATION LEADS TO DAMAGE
Cumulative Probability (%)
100
80
70%
60
Penetrating
40
Inflammatory
Stricturing
20
18%
0
0
12 24 36 48 60
72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Months
Over a 20-year period, 88% risk of developing
stricturing (18%) or penetrating (70%) disease
Cosnes J et al. Inflamm Bowel Dis. 2002
NATURAL HISTORY
MOST CROHN’S PATIENTS WILL REQUIRE
SURGERY
Mekhjian HS et al. Gastro 1979.
NATURAL HISTORY OF
ULCERATIVE COLITIS
100
90
Colectomy
Patients (%)
80
70
Disease activity
60
50
40
30
Remission
20
10
0
n=1161
0
Years after diagnosis
25
Risk of colectomy:
24% after 10 years
~ 30% after 20 years
Significant Increased risk of cancer
Adapted from Langholz E, et al. Gastroenterology 1994
TEMPORAL TRENDS OF COLECTOMY UC
Kaplan GG et al. AJG 2012
Since introduction of biologic agents/anti-TNFs,
decrease in total colectomy in UC patients
WHAT’S NEW?
IBD DRUG PIPELINE
Taken from E. Loftus AIBD 2015
GY Melmed & SR Targan 2010
LYMPHOCYTE TRAFFICKING IN IBD
Accumulation of excess infiltrating WBC
is one of hallmarks in IBD
“Gut specific” WBC causes damage in gut
Multi-step adhesion cascade:
Rolling -> Tethering -> Adhesion -> Migration
Laroux et al. 2001
IBD Immunology 101
Taken with permission from RW Stidham
IBD Immunology 101
Mucosa
Submucosa
Blood
Vessels
Taken with permission from RW Stidham
IBD Immunology 101
Mucosa
Submucosa
Blood
Vessels
Taken with permission from RW Stidham
IBD Immunology 101
Mucosa
Submucosa
Blood
Vessels
Taken with permission from RW Stidham
Blockade of Adhesion Molecules:
VEDOLIZUMAB (ENTYVIO®)
Block WBC
Binding to
Integrins
Anti-Integrin
Coating
BLOCKADE OF CELL-ACTIVATING SIGNALS:
USTEKINUMAB (STELARA®)
IL-12
Receptor
IL-12/23
Ligand
T-cell
Interferon
Dendritic cell
T-cells
ACTIVATED
IL-17
ORAL SMAD7 ANTISENSE
OLIGONUCLEOTIDE:
MONGERSEN
SMAD7
Mongersen
Presence of Smad7:
In absence of
•TGFβ1Smad7:
signalling
blocked
TGFβ1 is an effective
•T-cells
continue
to
inhibitor of promake pro-inflammatory
inflammatory T-cells
cytokines
Adapted from Monteleone G et al. NEJM 2015
QUESTIONS
ANITA AFZALI MD, MPH
http://www.uwgi.org/ibd/
For appointments: 206-744-2788