Inflammatory Bowel Disease

“CROHN’S disease”
JEO THOMAS
SARVODAYA COLLEGE OF
NURSING
 DEFINITION:IBD
inflammatory bowel disease refers
to two chronic inflammatory GI
disorders:
regional enteritis (ie, Crohn’s diseas
or granulomatous colitis)
and ulcerative colitis.
 INCIDENCE
The incidence of IBD in the United States has
increased in the past century; 10,000 to 15,000 new
cases occur annually
In the past, a higher rate was observed among
Caucasians in general and the Jewish population in
particular.
Data now indicate a higher risk for African Americans
And lower risk for Jewish people
women appear to be at higher risk than before.
People between the ages of 10 and 30 are at greatest
risk.
 ETIOLOGY
cause of IBD is still unknown
environmental agents
such as pesticides, food additives,
tobacco, and radiation
Nonsteroidal anti-inflammatory drugs
have
been found to exacerbate IBD. Allergies
and immune disorders
have also been suggested as causes.
 CROHN’S DISEASE
DEFINITION:Regional
DEFINITION: enteritis or
crohn’s disease is a subacute and
chronic inflammation that extends
through all layers (ie, transmural
lesion) of the bowel wall from the
intestinal mucosa.
 INCIDENCE AND RISK
Regional enteritis commonly occurs in adolescents or
young adults but can appear at any time of life.
It is more common in women, and it occurs frequently
in the older population (between the ages of 50 and
80).
It can occur anywhere along the GI tract, but the
most common areas are the distal ileum and colon.
The incidence of Crohn’s disease has risen over the
past 30 years.
Crohn’s disease is seen two times more often in
patients who smoke than in nonsmokers
 PATHOPHYSIOLOGY
The disease process begins with edema and thickening of
the mucosa.
Ulcers begin to appear on the inflamed mucosa.
These lesions are not in continuous contact with one
another and are separated by normal tissue.
Fistulas, fissures, and abscesses form as the inflammation
extends into the peritoneum.
Granulomas occur in one half of patients.
In advanced cases, the intestinal mucosa has a
cobblestone appearance.
As the disease advances, the bowel wall thickens and
becomes fibrotic, and the intestinal lumen narrows.
Diseased bowel loops sometimes adhere to other loops
surrounding them.
 CLINICAL MANIFESTATION
lower right quadrant abdominal pain and
diarrhea.unrelieved by defecation.
crampy abdominal pains.
Abdominal tenderness and spasm.
weight loss, malnutrition and secondary anemia.
Chronic diarrhea and nutritional deficits
Chronic symptoms include diarrhea, abdominal
pain,steatorrhea, anorexia, weight loss, and
nutritional deficiencies.
 Assessment and Diagnostic
Findings
A proctosigmoidoscopic examination
is usually performed initially to
determine whether the rectosigmoid
area is inflamed.
A stool examination is also performed;
the result may be positive for occult
blood and steatorrhea (ie, excessive
fat in the feces)
 DIAGNOSTIC FINDING (cont)
Barium study of the upper GI tract that
shows the classic “string sign” on an
x-rayfilm of the terminal ileum, indicating the
constriction of a segment of intestine.
 Barium enema,CT scan,endoscopy,CBC,
 INTESTINAL BIOPSY
 Albumin and protein level assessment
 complication
Intestinal obstruction or stricture formation
Perianal disease
Fluid and electrolyte imbalance
Malnutrition
Fistula & abcess formation
Risk for colon cancer
 Systemic complication
Small bowel obstruction
Right-sided hydronephrosis
Nephrolithiasis
Cholelithiasis
Arthritis
Retinitis,
iritis
Erythema nodosum
 MEDICAL MANAGEMENT
Nutritional therapy:

Oral fluids and a low-residue, high-protein,

high-calorie diet with supplemental vitamin
therapy and iron replacement are
prescribed to meet nutritional needs, reduce
inflammation, and control pain and diarrhea.
Fluid and electrolyte imbalances from
dehydration caused by diarrhea are
corrected by intravenous therapy as
necessary
 Nutritional therapy
Any foods that exacerbate diarrhea
are avoided. Milk may contribute to
diarrhea in those with lactose
intolerance.
Cold foods and smoking are avoided
because it causes intestinal motility
 Drug Therapies

Glucocorticoids (steroids)

5-aminosalicylates (5-ASA)

Immunosuppressants

Antibiotics

Biological Therapy
 Goals of Treatment

Remission

Maintenance
How do we know a treatment
works?

We do a clinical trial
Statistical Analysis
Toss a coin 7 times
About 1 in 20 (5%)
chance of getting 6 or
7 heads
In medicine, this is
considered significant
Treatment being
tested is better
 Levels of Clinical Trials

New Therapeutic Group New Agent - Infliximab

Increasing Risk

New Therapeutic Group Known Agent - Salazopyrin

Known Therapeutic Group Known Agent - Asacol

 Side Effects of Therapy
Clinical trials
– Participants record all “events” during trial
– Headaches, nausea etc.
Theoretical
– Based on mechanism of drug
– E.g. prednisone has effects of glucocorticoids
Post marketing
– Increased use after general release
– Less common or rare events likely to show up
 What are steroids?
A natural hormone
Secreted by the adrenal
glands
Derived from cholesterol
Control metabolism,
especially glucose and
protein
Synthetic steroids (e.g.
prednisone) many times
more potent than natural
steroids
 Steroid Effectiveness

Highly effective for the induction of

remission in patients with active disease
Short-term response rates (12–16 weeks)
range from 70–90%
Not effective in maintenance of remission
 Steroid Side Effects
-Depression
-Acne -Anxiety
-“Moon” face
-Hair growth
-“Buffalo” hump

-Obesity
-Bruising
-Purple / red streaks
(striae)

-Muscle wekaness -Bone thinning

 Prolonged Steroid Therapy
Side Effect Frequency
“Moon” face 45%
Acne 30%
Bruising 15%
Raised Blood Pressure 15%
Increased Body Hair 7%
Striae 6%
 5-ASA Drugs
Sulphasalazine first agent discovered
Group now includes:
– Pentasa (mesalazine)
– Asacol (mesalazine)
– Dipentum (olsalazine)
– Salazopyrin-EN (sulphasalazine)
Work locally on the lining of the gut to
reduce inflammation
 Salazopyrin
5-ASA joined to a sulphur
group
To be active it requires
sulphur group to be
X-S
removed
This happens in the large
bowel
Sulphur group also has
an anti-inflammatory X X-S

effect on the joints

 Dipentum
Two 5-ASA molecules
joined together
Need to be broken
apart to be effective X-X

Bacteria in colon
break the molecules
X
apart
X X-X
Diarrhoea a common
side effect
 Pentasa
Pure 5-ASA
molecules
In micro pellets
Breaks up in the
stomach
Slowly dissolve as it
travels through the
intestine
 Asacol
Pure 5-ASA
molecules
In a solid capsule
Capsule responds to
changes in acidity
Slowly dissolves to
release 5-ASA
Some patients report
undissolved tablets
passed into toilet
 Efficacy of 5-ASA
Remission
– Up to 40% of patients brought into remission
– But , 30% will go into remission with placebo
Maintenance
– Possibly 1-2 less acute relapses per year
– Average relapses per year is 3-4
Real benefit
– Reduced risk of bowel cancer longer term
 The Role of Pro-inflammatory
Cytokines in Crohn’s Disease
Inflammation and
IL- tissue damage of
6 B cell intestinal mucosa

Plasma
Activation IL- cell
of T cells 8 Humoral
Antigen- immune
presenting respons
cell TNF e
α
IL- GM-CSF
Antigen 1

Leukotrienes,
Inflammatory superoxides, nitric
cell adhesion oxide and
prostaglandins

Sands BE. Inflammatory Bowel Dis 1997; 3: 95–113.

 Immunosupressants
Drugs include:
– Azathioprine
– 6-mercaptopurine
– Methotrexate
Interfere with inflammatory pathway
Effective
– Up to 75% of patients brought into remission
Slow
– Optimal effect often not seen until after 12 weeks of treatment
Need close monitoring for toxicity
Safety
– Methotrexate not to be used in pregnancy
 Azathioprine Metabolism

Azathioprine

6-Mercaptopurine

TPMT

6-TGN 6-MMPN

TPMT = thiopurine methyltransferase

6-TGN = 6-thioguanine nucleotide
6-MMPN = 6-methylmercaptopurine ribonucleotide
 Use of TPMT and 6-TGN
TPMT
– Tested before initiating therapy
– Low TPMT activity related to high 6-TGN levels,
increasing risk of toxicity
6-TGN
– Used to monitor therapy
– Levels above 230 associated with better effect
– Levels above 480 associated with more side effects
 Antibiotics
Metronidazole, ciprofloxacin
Precise role in management is unclear
Treatment of complications such as abscesses and
skin infections
No data from controlled trials have shown a benefit on
remission rates in patients with active disease
No benefit for the maintenance of remission has been
demonstrated for antibiotic therapy
No controlled data exist that show antibiotics are
successful for closing perianal fistulae
 Immune Therapy for Crohns
Disease
TNF-α is a key mediator of inflammation
TNF-α expressed in bowel wall in Crohns
disease and faecal concentrations reflect
disease severity
Products neutralising TNF-α are beneficial
in treatment of Crohns disease
Infliximab (Remicade) infusion
 TM
REMICADE (infliximab)
Mechanisms of Action
Infliximab

Neutralisation
of
transmembran
Neutralisatio e TNFα
n of soluble
TNFα

TNFα
producing
macrophages
of activated T
cells
van Deventer SJH. Gut 1997: 40; 443–8.
Scallon BJ et al. Cytokine 1995: 7; 251–9.
Feldmann M et al. Adv Immunol 1997; 64: 283–350.
 Remission-level Control
TM
With REMICADE (infliximab)

p < 0.001 Control

75
clinical response* (%)

(n = 24)
Patients achieving

48% Infliximab 5 mg/kg

50 (n = 27)
39%

25

4% 4%
0
Week 2 Week 4

Targan SR et al. N Engl J Med 1997; 337:

*Clinical remission defined 1029–35.
as a CDAI score < 150. Data on file, Centocor, Inc.
Endoscopic Improvement With
TM
REMICADE (infliximab)

Pre-treatment 4 weeks post-treatment

Reprinted with permission of van Dullemen HM et al. Gastroenterology 1995; 109: 129–35.
Abdominal Fistula: Case Study

Pre-treatment 2 weeks

10 weeks 18 weeks
Data on file, Schering-Plough.
 Remission-Level Control with Repeated
Infusions of REMICADE™ (infliximab)
p = 0.013
60
Control (n = 36)
Patients in clinical remission (%)
53%
50 Infliximab (n = 37)

40

30

20%
20

10

0
Week 44
(8 weeks after final infusion)

Clinical remission defined as a CDAI score < Rutgeerts P et al. Gastroenterology 1999; 117:
150. 761–9.
Remicade (Infliximab) Safety
Hypersensitivity
– Allergic reaction at time of infusion – 5%
Autoimmune syndromes
– Lupus like illness – rare and recovers on stopping on therapy
Infection
– Profound immunosuppression occurs
– Opportunistic infections can occur
– Tuberculosis high risk
– Hepatitis B can be reactivated
Cancer
– Recent data suggests that overall cancer rates may be reduced
– Hepatosplenic T-cell lymphomas – 1 in 20000 patients
 Summary of Standard Therapy
Induction of Maintenance of Adverse Effects
Remission Remission
Steroids Established 70-90% Ineffective Yes

5-ASA Minor effect Conflicting evidenceYes

Antibiotics No No

Immune Established 55% Established Yes

Suppresants
Methotrexate Established Not demonstrated Yes - teratogenic

Biologicals Established Established Yes

Non-Drug Approaches – Cigarette
Smoking

Smokers with Ulcerative

Colitis
– Have less relapses
Smokers with Crohn’s
disease
– Have more relapses
– Disease more difficult to
treat
– Stopping smoking reported
to have same effect on
Crohn’s disease as giving
steroids.
 Fish Oil
What is it? Patients in Remission
at 1 Year
– Derived from fish
– Contains omega-3 fatty 60
acids 50
What do they do? 40
– Anti-inflammatory effect % 30
– Reduces leukotriene B4 20
10
How do you take it?
0
– Enteric coated capsules to Fish Oil Placebo
avoid “fishy smell”
Authors Subjects Duration Intervention/Design Dosage Outcome

Tsujikawa et 20 Crohn's 1 month Open trial using diet Not given Decreased CRP, improved
al Disease containing n-3:n-6 remission rates
patients ratio of 0.5
Lorenz et al 39 IBD patients 7 months Double-blind, placebo- 1.8 g EPA and 1.3 g Decreased inflammatory
(29 controlled crossover of DHA daily mediators TXB2 &
Crohn's fish oil LTB4, improved
Disease morphology, no
patients) change in disease
activity

Hillier et al 10 IBD patients 12 weeks Open label - fish oil versus 18 g per day, Decreased inflammatory
olive oil containing 3.2 g mediators PGE2,
EPA, 2.2 g DHA TXB2, & LTB4

Lorenz-Meyer 204 Crohn's 1 year Fish oil supplementation 6 g daily (containing No Difference in relapse
et al Disease compared with placebo 3.3 g EPA, 1.8 g rate in fish oil vs.
patients in or low-carbohydrate DHA) placebo
remission diet

Belluzzi et al 78 Crohn's 1 year Double-blind, placebo 4.5 g daily 41% fewer relapses in
Disease controlled study of fish (containing 1.8 fish oil group; 33%
patients in oil g EPA, 0.9 g more patients in
remission DHA) remission at 1 year

Arslan at al 10 IBD patients 10 days Open label pilot study of 30 mL daily Decreased disease
(5 Crohn's seal oil (containing 1.8 activity, decreased
Disease, 5 g EPA, 2.6 g joint pain
Ulcerative DHA, 1.0 g DPA)
Colitis
 Another Option
42 yr old male with Crohns disease 20 yrs
several bowel resections for strictures
– ileostomy eventually formed
maximal medical therapy
– azathioprine, budesonide, mesalazine
ongoing ulceration of stoma site and
“flares” of disease
over last 6 months, no further ulcers...
 What did he do?
Probiotics
– about 6 months ago started using a
combination of probiotic products available
over the counter
– no further problems with ulcers and no flares
of disease symptoms
 Probiotics

“...living micro-organisms which upon ingestion

in certain numbers exert health benefits beyond
inherent general nutrition…”
 Trichuris suis ova (TSO)
Pig whipworm ova taken
as a drink
– Does not survive long in
humans
– Need repeated drinks
High rate of remission
reported
– 50% in UC, 70% in Crohns
Intestinal helminthes
induce cytokine release
and downregulate cell
mediated responsiveness