IBD : New Insights

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IBD New Insights

• Prof Osama Ebada Salem
• MD PhD MAGA
• Alexandria Faculty of Medicine

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Challenges in the Diagnosis of IBD

• Diagnosis is not straightforward
• Symptoms insidious
• 3. Multiple investigations may be required
• 4. Many other causes need to be excluded.

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Challenges in the Diagnosis of IBD

• 5. Useful diagnostic tests such as endoscopy may
  not be widely available
• 6. The diagnostic awareness of IBD by physicians
  in a geographic region ultimately may influence
  the incidence in that region.

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Epidemiology of IBD

• Incidence of IBD
• Developed countries Inc. or stabilized high
  rate
• U.C 1 every 600 (5500 new case/y in UK)
• C.D 1 every 1000 (3000 new case/y in UK)
• Regions w less common IBD Rising

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Epidemiology of IBD

• The Prevalence of IBD has continued to increase
  as a result of
• Rising incidence
• Improved survival

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Risk of cancer in IBD
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• In the general population the risk of colorectal
  cancer is 1 in 30

(after Kamm, 1999)
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Diagnosis of IBD

• Clinical
• Intestinal
• Extra-intestinal
• Lab.
• Basic
• Advanced
• Pathology

• Radiology
• Barium Studies
• C.T
• Endoscopy
• Ileo-Colonoscopy
• EGD
• Enteroscopy
• Capsule Endoscopy

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History

• Pain (pattern)
• Bowel Habits
• Bleeding
• Fever
• Extra-intestinal manifestations
• Smoking
• Better U.C
• Worse C.D

• Surgical History
• Appendectomy
• Anal Fissure
• Hemorrhoids
• Anal Fistula
• Adhesive Intestinal Obstruction
• Family History for IBD

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Clinical Presentations of IBD
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• U.C
• Bloody diarrhoea
• Fever
• Cramping abdominal pain
• Weight loss
• Frequency and urgency of defecation
• Tenesmus
• General malaise

• C.D
• Diarrhoea
• Abdominal pain
• Bleeding
• Pyrexia
• Weight loss
• Fistulae
• Perianal disease
• General malaise

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Distribution of Crohns Disease
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The Proportion of Patients in Medical Remission
Decreases Over Time

• Markov analysis of the projected lifetime
  clinical course of CD in a population-based
  retrospective study of 174 patients (19701993)

Silverstein MD et al. Gastroenterology.
199911749-57.
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Remission Within the First Year of Diagnosis May
Predict Future Disease Behavior

• The clinical course of CD was studied in a cohort
  of 480 consecutive patients followed from
  diagnosis up to 20 years (19801999)

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Remission
60
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Low Activity
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High Activity
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0
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Years After Diagnosis
Veloso FT et al. Inflamm Bowel Dis.
20017306-313.
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Investigations of IBD

• Lab.
• CBC
• ESR
• CRP
• Stool
• Occult Blood
• Albumin
• Serum Antibodies
• ASCA Ig A Ig G (quantitative)
• P-ANCA
• Anti-Omp C (E.Coli)
• Anti-12 (Pseudomonos Fluroscens)
• Anti-Flagellin C-Bir

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U. C
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Aphthoid ulcers in Crohns disease
C.D Upper GIT C.D Sigmoid
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Typical granuloma of Crohns disease
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Pathological features U.C Vs C.D
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Bruce E Sands Gastroenterology May 2004
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Pathological and Anatomical features U.C Vs C.D
(Cont)
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Bruce E Sands Gastroenterology May 2004
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Endoscopy in UC
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Resistance Example AMS 25 male

• Severe Rec abdominal pain altered bowel habits
  (diarrhea)
• Appendectomy 87 Alex
• Torsion of testis 90 Alex
• Gastro-jejunostomy 92 Mans
• Intestinal resections 93, 94 Alex
• Cholecystectomy 95 Alex

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AMS 25 male

• Intestinal Resections for ?Obst 98, 2003 Cairo
• The last 2 operations he had extensive adhesions
  (as his surgeon told him) bad wound healing
  for months
• A total of 8 operations 14 Endoscopies

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? Med. Fever

• Marked loss of weight Distension
• Surgical wound fistula was noted (for which his
  last surgeon was telling him that it is an
  infected site of a stitch that needs to be
  aggressively cleaned with another minor
  surgery)
• Hb 9.7,CRP 18 , ASCA (G 11.2/A 9.7), ANCA -.

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AMS 25 male

• BFT Gastro-jejunostomy Multiple strictures
  entero-enteral fistulae
• CT showed a minute collection (drained by US
  guided aspiration) with mildly distended bowel
  loops

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AMS 25 maleEndoscopy Terminal Ileum
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IBD - What is New

• Diagnosis
• Genetic
• Seromarkers
• Fecal Markers
• Capsule Endoscopy
• Chromoscopy

• Treatment
• New Trends
• Biologics
• Probiotics
• Parasites
• Endoscopic

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Seromarkers in IBD

• Serologic levels stay stable over time
• Higher titres of Abs Higher CD disease activity
  i.e more severe disease higher complications
  - Microbial Hits
• Landers etal Gastroenterology 2002
• Vermier et al IBD 2001
• Seromarkers are markers for CD course
  behaviour
• Mow WS et al Gastroenterology Feb 2004
• Vermiere S et al
  Gastroenterology Feb 2004 Desir et al Clin
  Gastroenterol Hepatol Feb 2004

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Clinical Use of Biomarkers in IBD

• I- Diagnostic Role
• IBD Vs IBS
• U.C Vs CD
• Indeterminate Colitis
• Aggressive Small Intestinal disease
• Overlap Patterns
• II- Therapeutic Response
• Anti-TNF Therapy
• Improving Selection for therapies w modest
  benefit
• III - Surgical Considerations

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Acute Phase Reactants Markers

• Fecal Lactoferrin
• Distinguishes between IBS IBD
• Does not distinguish between IBD infectious
  diarrhea, NSAID use Neoplasm
• Kane et al Am J Gastroenterol 2003
• Greneberg Et al J Infect D 2002
• Tibble et al Gut 1999

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Fecal Calprotectin

• The most promising emerging marker of mucosal
  inflammation
• Calprotectin is a marker of neutrophil turnover
  and is elevated in a number of inflammatory
  conditions.

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Fecal Calprotectin

• In UC
• Elevated in quiescent disease compared w healthy
  controls
• Correlates w endoscopic histological gradings
  of disease severity.
• (Roseth AG,et al Digestion 1997)
• In IBD
• Predict relapse rate over following 12 months.
• Sensitivity of 90 specificity of 83 in
  predicting subsequent relapse.
• (Tibble JA, Gastroenterology 2000).

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Fecal Calprotectin

• In chronic diarrhoea, faecal calprotectin is
  significantly associated with IBD subsequently
  using colonoscopic examination.
• Limburg PJ, et al Am J Gastroenterol 2000.

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CLINICAL
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CD Phenotypes

• Fibrostenosis
• Internal Perforation
• Abscess
• Entero-entero
• Entero-cutaneous
• Entero-vesical
• Peri-anal Fistulae
• Perianal abscess or fistula
• Recto-vaginal fistula
• U.C like

Mow WS et al Gastroenterology Feb 2004

• Vasiliausukias et al Gastroenterology 96
• Vasiliausukias et al Gut 2000
• Abrue et al Gastroenterology 2002

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Diagnosis of CD (At least Two of the followings)

• Clinical
• Perforation
• Stenosis
• Fistula
• Obstruction
• Endoscopic
• Deep linear ulcers
• Serpiguinous ulcers
• Cobble stoning
• Discontinous or asymmetric

• Radiology
• Small or large bowel Stritures
• Fistulae
• Skip lesions
• Pathology
• Submucosal or transmural
• Multiple granulomata
• Marked focal cryptitis
• Ch inflammatory infiltrate within or between
  biopsies
• Rectal sparing without local therapy

Mow WS et al Gastroenterology Feb 2004
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Capsule Endoscopy
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PillCam (PillCam SB)
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Treatment of IBD
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Treatment of IBD

• Induction of Remission
• Maintenance of Remission
• Cancer Surveillance

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Treatment of IBD

• Food ( Probiotics)
• Standard Pharmacologic Therapy
• Biologic Therapy

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FOOD INTOLERANCE
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Probiotics

• Microorganisms w beneficial properties for host
• Most derived from food sources, e.g cultured milk
  products
• Lactic acid bacilli (eg Lactobacillus
  Bifidobacterium)
• Nonpathogenic strain of E. coli

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Probiotics - Final Word

• No probiotic strategy represents standard of care
  - yet
• Pouchitis benefit suggested from VSL3 in
  primary secondary prevention
• U.C unproven
• E. coli Nissle 1917 promise in maintenance
• C.D benefit unproven.

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Pharmacological treatment of IBD
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• 5-ASA-containing compounds
• Mesalazine
• Pentasa Asacol
• Claversal/Mesasal/Salofalk
• Sulphasalazine Salazopyrin
• Olsalazine Dipentum
• Corticosteroids
• Immunosuppressants
• AZA
• 6 MP
• Methotrexate

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U.C
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Treatment of IBD

• Severity of Disease
• Extent of Disease
• Special Situation

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Higher-Dose Mesalamine Formulation

• Sandborn et al 2004 conducted a RCT mesalamine
  4.8 g d in a new formulation of 800-mg tablets
  vs mesalamine 2.4 g d in the 400-mg tabs
• 268 pts w moderately active U.C .
• Remission 71.8 in 4.8 g d group vs 59.2 in
  lower-dose group (P lt .04)
• No differences in adverse effects

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Treatment of Patients with an Adenoma-like DALM
UC patient with adenoma-like DALM
Within colitis
Outside colitis

• Polypectomy
• Repeat colonoscopy with multiple biopsies

Flat dysplasia or adenocarcinoma

• No flat dysplasia
• No adenocarcinoma

• Age lt 50 years
• Colitis gt 10 years
• Histology positive
• P53 positive
• Beta oatenin negative

• Age gt 50 years
• Colitis lt 10 years
• Histology negative
• P53 negative
• Beta oatenin positive

Probable UC-related DALM
Indeterminate
Probable non UC-adenoma

• Polypectomy
• Regular or surveillance

• Polypectomy
• surveillance
• ? colectomy

Colectomy
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Treatment of C.D
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Crohns Disease---Terminal Ileum
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C.D Rectal Stricture
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Medical Management of Crohns disease

• 5 ASA
• Antibiotics
• Corticosteroids
• Immunosuppressive
• Azathioprine
• 6 M.P
• Methotrexate
• Infliximab (Remicade)

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• Prior Options

• Current Options

Active C.D

• Prednisone
• Mesalamine
• Sulphasalazine
• Metronidazole
• 6 MP or AZA
• Steroid dependency

• Prednisone
• Controlled ileal release budenoside
• Sulphasalazine
• Methotrexate
• AZA or 6 MP
• Infliximab
• AZA or 6 MP
• Methotrexate
• Infliximab
• Controlled ileal release budenoside
• Metronidazole

C.D in Remission
C.D In Remission
Egan LJ el al Gastroenterology May 2004
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• Current Options

• Prior Options

Fistulizing C.D

• 6 MP or AZA
• Antibiotic

• AZA or 6 MP
• Infliximab
• Tacrolimus

C.D in Remission
Egan LJ el al Gastroenterology May 2004
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Biologic Therapy
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Cytokine Imbalance in Chronic Inflammation
Anti-inflammatory
Pro-inflammatory
adapted from Papachristou G et al. Pract
Gastroenterol. 20042818-30.
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Monoclonal Antibodies Prevent Interactions of
Cytokines With Cellular Receptors
Monoclonalantibody
Cytokine (IL-12 or TNF)
Cytokine receptor
No signal
Choy EHS et al. N Engl J Med. 200134490716.
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Evolution of Monoclonal Antibodies
Fully Human
Humanized
Chimeric
Human(No Mouse Protein)
Murine
Adalimumab (D2E7)
510 Mouse Protein
25 Mouse Protein
100 Mouse Protein
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Infliximab VS PlaceboIn Induction of Remission
in CD
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Biologic Agents Evaluated in C.D (in R, Db, PC
trials)
Egan LJ el al Gastroenterology May 2004
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Indications of Infliximab In IBD
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ADVERSE EVENTS

• Infusion reactions
• Antichimeric Abs
• Autoantibodies
• Infections
• Malignancy
• Neurologic disease
• Hematologic events
• Hepatotoxicity

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Episodic Infliximab vs Systemic Maintenance
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Contraindications of Infliximab In IBD
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IBD Treatment Algorithm

• What Am I Going to do ?

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Treatment Paradigm for UC
UC
Moderate
Mild
Severe
Admit IV Corticosteroids35 days
Prednisone
Oral /- Topical Mesalamine/ Sulfasalazine
IFX 0, 2, 6Scheduled Maintenance /- Immunomod.
FAIL 24 wk
Surgery
IFX, infliximab Cyclosporine may be considered
in some cases.
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Moderate UC Algorithm Time Bound
Moderate
Prednisone
Corticosteroid Refractory
Corticosteroid Dependent
24 Weeks
1624 Weeks
Respond and Taper Maint. 5-ASA
IFX 0, 2, 6 Scheduled Maintenance/- Immunomod.
AZA ? 16 Weeks
FAIL
IFX, infliximab
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Fistulising CD Algorithm
Fistulising CD
Simple
Complex
IFX 0, 2, 6 Scheduled Maintenance Immunomod.
Trial of Antibiotics Fistulotomy
FAIL
Panaccione R. Oral presentation presented at
United European Gastroenterology Week 15-19
October 2005 Copenhagen, Denmark.
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Luminal CD
Luminal
Mild
Severe
Moderate
Symptoms Burden of Disease History
Prednisone
IFX 0, 2, 6 Scheduled Maintenance Immunomod.
Budesonide(R. colon/ileal)
FAIL 48 wk
Sulfasalazine(left colon)
Panaccione R. Oral presentation presented at
United European Gastroenterology Week 15-19
October 2005 Copenhagen, Denmark.
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Moderate CD Algorithm Time Bound
Moderate
Prednisone
Corticosteroid Refractory
Corticosteroid Dependent
24 Weeks
1624 Weeks
Respond and Taper
IFX 0, 2, 6 Scheduled Maintenance Immunomod.
MTX 12 Weeks Or AZA 16 Weeks
FAIL
Panaccione R. Oral presentation presented at
United European Gastroenterology Week 15-19
October 2005 Copenhagen, Denmark.
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Indications for Surgery in U.C
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• Perforation
• Toxic dilatation
• Massive hge
• Chronic ill-health
• Risk of cancer

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Classic Appendectomy
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OM 32 M

• Severe Abd pain in Right iliac region
• Rec. Diarrhea
• Diagnosed as Appendicitis
• Complicated post-operative

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OM A32 M

• Because of the stormy post operative course, He
  went abroad
• Diagnosed as CD
• ASA, Corticosteroids, A.B, AZA

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OM A32 M

• Improved for 4 y but infrequent diarrhea
  persisted
• Severe agonizing pain forced him to consult
  Here

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OM A 32 M

• Hb 10.9, WBC 13.5
• ESR 58/ CRP 98
• ASCA Neg A14.5 G 12.4
• ANCA Neg

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OM A 32 M

• Ileocolonoscopy

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• Balloon Dilatation of Narrowing

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Take Home Messages
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Take Home Message 1

• IBD is increasing all over the world should be
  increasing in Egypt as well Globalization !!
• We need Not to Resist diagnosing IBD esp. C.D
• We need to put IBD in our DD search for it
• IBS
• Mediterranean fever

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Take Home Message 2

• We need to try our best to enter terminal ileum
  in every colonoscopy
• Serum ASCA ANCA could be a valuable
  non-invasive good positive test in pts with
  chronic abdominal symptomatology suspicious for
  IBD

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Take Home Message 3

• Under-diagnosis of IBD
• Ignoring
• Over-looking
• Under-estimating
• Resisting
• Over-diagnosis of
• IBS
• Mediterranean fever

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• IBD
• Is NOT Really Rare in Egypt
• WE ONLY Need to Remember

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Thank you