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DR. MOHAMED ISMAIL YASAWY
Associate Professor, M.D, D.T.M, A.F.I.M
Consultant Internist GastroenterologistCollege of Medicine
Dammam University Hospital, Al-Khobar
Your
Views
Crohn’s Disease Activity Index (C.D.A.I) is the most commonly used clinical assessment criteria
Harvey Bradshaw scoring system is more easily applicable than C.D.A.I
For well control C.D long term steroid therapy is the usual requirement
5ASA is essential for maintaining remission in C.D
Antibiotics i.e. Metronidazole and Cipro are essential in the treatment of C.D
Immunosuppressive e.g. Azothioprin are relatively effective for both induction of remission and maintaining the remission in C.D
ATNF (Biological agent) are used mainly as a curative treatment
F
F
F
F
F
T
T
CROHN’S DISEASE
What is Crohn’s Disease?
A serious Gastrointestinal chronic G.I Problem with
Exacerbation & Remission associated with life
threatening complications.
Crohn’s disease encompasses a spectrum of clinical and pathological patterns manifested by focal, asymmetric, transmural, and, occasionally, granulomatous inflammation affecting the gastrointestinal tract with the potential for systemic and extraintestinal complications.Data on file, Centocor.
Hanauer S et al. Am J Gastroenterol. 2001; 96: 635-643.
Large Intestine (Colon)
StomachSmall Intestine
Esophagus
Rectum
CROHN’S DISEASEWhat is Crohn’s Disease?
The incidence is evenly divided between UC & CD.
Approximately 10 to 20 %of pts will present with initial diagnosis of indeterminate colitis because a primary diagnosis is not possible.
CROHN’S DISEASE
Introduction
IBD
UC CD
Susceptibility Genes Environmental Factors
Environmental factors Environmental factors
Disease Specificity Genes
Genes DeterminingPhenotype
CROHN’S DISEASE
IBD – Aetiologic Concepts
In 1932, Crohn Ginzberg and Oppenheimer described this disease and noted it’s localization to segment of the ileum. It was later noted that Crohn’s Disease may involve any part of the (G.I) tract.
Crohn’s Disease is an idiopathic, chronic, transmural inflammatory process. It can affect any part of the gastrointestinal (G.I) tract from the mouth to the Anus.
CROHN’S DISEASEIntroduction
The condition is believed to be the result of an imbalance between pro-inflammatory and anti-inflammatory medias. Most C.D cases involves the small bowel particularly the terminal ileum.
CROHN’S DISEASE
Introduction
The exact cause of C.D remains unknown. Current theories implicate the role of genetic, microbial, immunological, environmental, dietary, vascular and even psychosocial factors as a causative agent. It has been suggested that, patients have an inherited susceptibility for an aberrant immunologic response to one or more of these provoking factors.
CROHN’S DISEASE
IBD - Aetiologic Concepts
IBD: PATHOGENESIS
Infection
Diet
Smoking
NSAIDs
Genetic susceptibility
Immune dysregulation
Environmental trigger
TH 1
TH 2
IBD
Chromosome 16 (IBD1)
Chromosome 12 (IBD2)
Chromosome 6 (IBD3-HLA)
Chromosome 14
NOD2
Ahmad et al, Aliment Pharmacol Ther 2001; Hugot et al, Science 2001
CROHN’S DISEASE
Incidence 5-15 / 100 000 population1
Prevalence 9 – 199 / 100 000 population1
1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18 2 Economou M and Pappas G. Inflammatory Bowel Diseases. 2008; 14: 709-720.
Global map of CD2
Annual incidence:- red >7/105
- orange 4-7/105
- green1-4/105
- blue <1/105
- white: absence of data
CROHN’S DISEASE
Crohn’s Disease - Presentation
Inflammatory• Pain, tenderness, diarrhea, RLQ mass
Obstruction• Cramps, distension, vomiting,
obstruction
Fistulizing• Enterocoutaneous, enteroenteric,
rectovaginal, enterovesical, etc.
CROHN’S DISEASE
Diarrhea Abdominal pain and tenderness Weight loss Fever Fatigue Rectal bleeding Nausea Anorexia
Knutson D et al. Am Fam Physicians. 2003; 68: 707-718.
CROHN’S DISEASE
Common Symptoms Of Crohn’s Disease
It is not IBS
Arthritis Axial – Ankylosing
Spondylitis Peripheral
Skin Erythema
nodosum Pyoderma
gangrenosum Eyes
Anterior uveitis Episcleritis/Iritis
Liver PSC Autoimmune
hepatitis
CROHN’S DISEASEExtra G.I Manifestaions
Uncommon <1% of IBD pts
Sterile ulcerating skin lesions
Overhung violaceous borders
Exhibits pathergy May be independent of
IBD May be difficult to treat
Characteristic skin rash - raised nodules on shins
Septal panniculitis in subcutis May occur in up to 10% of
patients, depending on study population
CD>>UC F>>M (5:1) Often occurs with relapse of
IBD
? More common in colonic disease
Associated with other EIMs
Arthritis, uveitis
Sweet’s Syndrome
Acute red eye associated with relapse of IBD
Usually iritis or anterior uveitis
Rarely posterior uveitis
May occur with arthritis
Occurs in 3-5% of IBD patients
F>M 3:1
Needs ophthalmological assessmentEye: does not correlate well with
disease activity. Episcleritis, uveitis
More common in persons with Crohn’s disease.
Calcium oxalate stones are the most common type of renal calculi
Treatment is to increase hydration and to use oral calcium citrate supplements, which bind the oxalate within the intestinal tract and prevent its excretion in the urinary tract.
Because of its proximity to the ureters, inflammation of the small bowel may involve the ureters, causing obstruction and hydronephrosis.
Fistulae occasionally occur between the bowel and bladder or ureters.
-Sclerosing cholangitisis most commonly associated with ulcerative colitis. 5% of all IBD patients.
Gallstones are common in persons with Crohn disease
Malabsorption may result from extensive ileal resection and produce deficiencies, of fat-soluble vitamins, vitamin B12, or minerals, resulting in anemia, hypocalcemia, hypomagnesemia, clotting disorders, and bone demineralization. In children, malabsorption retards growth and development.
CROHN’S DISEASEDiagnosis
History Physical Findings Contrast Study Endoscopies Surgical specimen and Histology
CROHN’S DISEASE
ILIOSCOPIC FINDINGS
CROHN’S DISEASE INVOLVING ILEUM
CROHN’S DISEASE
Colonoscopic appearance of Crohn’s Disease
CA
PS
ULE E
ND
OS
CO
PIC
FIN
GIN
GS
CA
PS
ULE E
ND
OS
CO
PIC
FIN
GIN
GS
Symptoms Stage
People with mild to moderate Crohn’s disease are able to eat food normally without dehydration, fevers, stomach pain, blockages in their intestines or losing more than 10% of their body weight.
Mild to
Moderate
Crohn’s
DiseasePeople are considered to have moderate to severe Crohn’s disease if they do not respond to treatment for mild to moderate Crohn’s disease or if they have high fevers, significant weight loss, stomach pain or tenderness, occasional nausea or vomiting or significant anemia.
Moderate to
Severe
Crohn’s
DiseasePeople with Severe Crohn’s disease have symptoms despite taking steroids, or have high fevers, persistent vomiting, blockages in their intestines, or an abscess
Severe
Crohn’s
Disease
Goals of Treatment
Remission
Maintenance
Summary of Standard Therapy
Induction of Remission
Maintenance of Remission
Adverse Effects
Steroids Established 70-90%
Ineffective Yes
5-ASA Minor effect Conflicting evidence
Yes
Antibiotics No No
Immune Suppresants
Established 55% Established Yes
Methotrexate Established Not demonstrated
Yes - teratogenic
Biologicals Established Established Yes
CROHN’S DISEASE
The “conventional” Therapeutic Pyramid for Active Crohn’s Disease
Aminosalicylates/Antibiotics
Corticosteroids
Immunomodulators
Surgery
Anti-TNF
Budesonide
Severe
Moderate
Mild
CROHN’S DISEASE
COMPLICATIONS OF CROHN’S DISEASE
Ulcers Fistulas Abscesses Intestinal blockage Extra-intestinal disorders
Inflammation of the eyes, skin, or joints
Malnutrition Growth failure in children
Hanauer SB et al. Am J Gastroenterol. 2001; 96: 635-643.
CROHN’S DISEASE
CROHN’S DISEASE COMPLICATIONS: FISTULAS
A “tunnel” between two sections of the intestines or between the intestines and other organs, including the skin
Data on file, Centocor.West R and Scott NA. Chapter 37. In: Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003.
CROHN’S DISEASE
ANAL AND PERIANAL FISTULA PRE AND POST TREATMENT
Steroids have serious side effects
• Osteoporosis/osteonecrosis
• Higher risk of infections• Oedema/cushing syndrome
• Cataracts/glaucoma• Growth retardation • Behavioral changes• Striae• Diabetes• Cardiovascular complications
Satsangi et al. Inflammatory Bowel Diseases. Churchill Livingstone, 2003 Yang & Lichtenstein Am J Gastro 2002; 97:803-823 Lukert BP et al. Ann Intern Med. 1990;112:352Sandborn WJ Canadian Journal of Gastroenterology. 14 Suppl C:17C-22C, 2000 Sep
CROHN’S DISEASE
Crohn’s disease usually has a chronic indolent course. Mortality appears to be the highest in the 4-5 years after the diagnosis.
The chance of death and complication with proximal small bowel disease have a higher risk of mortality.
CROHN’S DISEASE
Mortality / Morbidity
As the disease progresses, medical therapy becomes less effective. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course.
Most patients develop complications that require surgery ( approximately 80%)
Crohn’s disease frequently recurs after surgery.
CROHN’S DISEASE
Mortality / Morbidity
Treatment goals in biological treatment era
Sustained Clinical remission off steroids
Intestinal healing
Prevention of complications
Prevention of hospitalization &
surgery
CROHN’S DISEASE
0
2400 12 24 36 48 60 72 84 96108120132144156168180192204216228
100
90
80
70
60
50
40
30
20
10
Progression of Crohn's Disease
Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.
Patients at risk:N= 2002 552 229 95 37
Penetrating
Stricturing
Cu
mu
lati
ve P
rob
ab
ilit
y (
%)
Inflammatory
Months
CROHN’S DISEASE
Timing is important in treating
Crohn’s disease
Biologics
(eg. Infliximab)
Prednisone
Corticosteroids
Budesonide
Surgery
Early
Late
5 -ASA?Antibiotics
AZA/6- MP/
MTX
Aminosalicylates/Antibiotics
Corticosteroids
ImmunomodulatorsSurgery
Anti-TNF
Budesonide
Severe
Moderate
Mild
CROHN’S DISEASETherapy for CD:
A -Conventional Treatment
B -Inverted Pyramid
Therapy for CD: Inverting the Pyramid?
Biologics
(eg. Infliximab)
Prednisone
Corticosteroids
Budesonide
Surgery
Early
Late
5 -ASA?Antibiotics
AZA/6- MP/
MTX
CROHN’S DISEASE
BIOLOGICAL TREATMENT
o Module 1 Selecting patients
o Module 2 Starting patients
o Module 3 Optimizing treatment
o Module 4 Monitoring the patient
o Module 5 Watching for and managing issues
Anti-TNF agents in Crohn's disease are indicated for:Europe: Treatment of severe, active Crohn's disease are
in patients who have not responded despite a full and adequate course of therapy with corticosteroid and/or an immunosuppressant; or patients who are intolerant to or have medical contraindications for such therapies*
US:Reducing signs and symptoms and inducing and
maintaining clinical remission in patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy*
EUROPEAN AND US REGISTRATION
Infliximab is also indicated for fistulating Crohn’s diseaseAdapted from EMEA therapeutic indications, and FDA indications and usage, for Humira and Remicade. Please see EMEA summary of product characteristics and FDA drug product label for Humira and Remicade
RECOGNIZING THE RIGHT INDICATIONS
Do not treat too late1
Tailor treatment to the individual.
Start with widely accepted indications.
1 Schreibers S et. Al. Gastroenterology 2007, 132 (4 Supp): A-147
Early indications of anti-TNF Inhibitors reasonable in: - Steroid – dependency
- Smokers
- Rectal disease
- Parianal lesions
- Extensive small bowel disease
- ileocolonic disease
- Severe upper GI disease
- Younger patients
- Patients with early stricturing / penetrating disease
- Patients with deep colonic ulcers
CROHN’S DISEASE
HOW TO IDENTIFY EARLY THOSE PATIENTS WITH A POOR PROGNOSIS
Young age on onset (<40 years)1
Perianal disease at diagnosis1,2
Severe disease at onset (Weight loss>5kg at presentation, steroids for first attack)1,2
Stricturing disease at diagnosis 2
Deep colonic ulcers3
Extensive disease at diagnosis1,2
Positive predictive value 70-90% if 2 or more factors
present1.2
1. Beaugerie L, et al. Gastroenterology 2006; 130:650-62. 2.Loly C et al. Scand J Gastroenterology 2008; 43:948-543. 3. Allez M, et al. Am J Gastroenterol 2002; 97:947-53
WHAT WE CAN EXPECT FROM ANTI-TNF THERAPY?
In Controlled clinical trials, we see Significant rates of clinical remission and response
1-
3
In anti-TNF naïve and experienced patients Significant rates of steroid-free remission,
4 and
steroid discontianuation5
Decreased risk of hospitalisation5,6
and surgery5,7
Maintenance of efficacyIn addition Anti-TNF therapy may be effective in reducing
extaraintestinal manifestations including arthralgia, arthritis, pyoderma gangrenosum and erythema nodosum
8,9
1. Hanauer S, et al. Gastroenterology 2006; 130:323-33; 2. Hanauer S, et al. Lancet 2002;359:1542-9.3 Colombel J-F, et al. Gastroenterology 2007 ;132:52—65; 4. Kamm M, et al. J Crohns colitis 2009;3:S43: 5. Rutgeerts et al. Gastroenterology 2004;126:402—13; 6. Fegan B, et al. Gastroenterology 2007;132:A –513(T1312); 7. Schreiber S, et al. am J Gastroenterol 2008;103(Suppl 1):S379(#965); 8. Louis E, et al. J Crohns Collitis 2009;3”:S57; 9. Siemanowski B, Regueiro M. Curr Treat Options Gastroenterol 2007;10:178--84
TNF- Binding Proteins
Adalimumab
(Humira®)
Infliximab
(Remicade®)
5 mg/kg BW i.v.
Week 0, 2, 6
than every 8 weeks
160 or 80 mg s.c. 1x
than 80 or 40 mg 1x
than 40 mg s.c. eow
ANTI- TNF THERAPY: DOSE
Subcutaneous (adalimumab)
In patients with a severe flare or for a more rapid response:
- 160mg at week 0 followed by 80 mg at week 2- Then a 40mg every other week
1
In patients with less severe breakthrough symptoms: - 80mg at week 0 followed by 40mg at week 2- Then 40mg every other week
Intravenous (infliximab)2,3
5mg/kg at 0 weeks, 2 weeks and 6 weeks Then 5mg/kg every 8 weeks
1. Hanauer S,et al. Gastroenterology 2006; 130:323-332. Rutgeerts P, et al. Gastroenterology 2004; 126: 402-133. Hanauer SB, et al. Lancet 2002; 359:1541-9; EMEA SPC, Humira & Remicade
CHARM: CD – RELATED HOSPITALIZATION AND SURGERY
ANTI- TNF THERAPY: EXCLUSION CRITERIA
Heart failure Current malignancy Active infectious disease Latent or active tuberculosis Abscess Pregnancy * Previous malignancy:* Previous breast cancer, or other malignancies 1 within past 5 years Multiple sclerosis Active Hepatitis B infection
Sources include: EMEA SPC, Humira & Remicade* Relative contraindications* Excluding non-melanoma skin cancer
ANNUAL RISK OF LYMPHOMA WITH ANTI-TNF THERAPY (WORST-CASE)
Ten thousand People
The paling Palette of 10,000 people. www.riskcomm.com
BASELINE EXAMINATION : PERIANAL FISTULAE
If perianal fistulae are present, exclude abscessDetermination may entail: Clinical examination under anesthesia and/or Imaging (MRI or endoscopic ultrasound)
If abscess is present: Ensure full drainage Consider leaving a loose seton in place, at
least until the end of induction therapy Consider transit Co-treatment with
antibiotics
USE OF CONCOMITANT IMMUNOSUPPRESSANT'S 1
If the patient is immunosuppressant-naïve
Start anti-TNF monotherapy or start anti-TNF/immunosuppressant combined therapy
The choice is based on a risk/benefit evaluation for each patient
-- Combined therapy is more efficacious-- However, it may be associated with a higher risk of lymphoma, including hepatosplenic T-cell lymphoma,
1 and(possibly) of
opportunistic infection2
-- Favour combined therapy in patients with severe extensive disease, in whom rapid healing is very important If using combined therapy, consider stopping one drug after
6-12 months-- Cessation of immunosuppressant does not appear to affect clinical outcome
3
-- Cessation of anti-TNF agent has not been adequately evaluated, but should be preceded by careful evaluation to confirm complete endoscopic and biological disease control
4
1. Mackry AC, et al. J Ped Gastroenterol Nutr 2007; 44:265-7 2. Toruner M, et al. Gastroenterolgy 2006; 130:A-71 [Abstract #489]
3. Van Assche G, et al. Gastroenterology 2008; 134:1861-8 4. Louis E, et al. DDW 2009; Abstract 961
USE OF CONCOMITANT IMMUNOSUPPRESSANT'S 2
ACCENT I & II: EFFECT OF CONCOMITANTIMMUNOSUPPRESSANTS WITH INFLIXIMAB
MAINTAINING REMISSIONWith regular maintance therapy: Remission with anti-TNF agents can be
maintained through at least 3 years of treatment (based on data available adalimumab)
1
There is no good medical reason to stop anti-TNF therapy in patients showing good efficacy and toleranceIf treatment cessation is considered for any reason:
First aim for stable, steroid-free remission for at least 1 year
2
Assess CRP levels and perform endoscopy, and avoid cessation if any sign of disease activity
2
CRP = C-reactive protein1. Panaccione R, et al. J Crohn’s Colitis 2009; 3:S69-S70; 2. Louis E, et al. DDW 2009; Abstract 961
“TOP-DOWN” VERSUS “STEP-UP”STRATEGY, INFLIXIMAB
BASELINE MONITORING: DISEASE ACTIVITY
(HARVEY BRADSHAW INDEX)
Remission <5Mild Disease 5 – 7
Moderate Disease 8 – 16Severe Disease >16
WHAT HAPPENS IF: INFUSION REACTION
Slow down or interrupt the infusion if: Mild acute reaction (monitor as appropriate)
Stop the infusion if: Moderate or severe acute reaction(Hydrocortisone or other treatment as appropriate)
Delayed reaction: Intravenous or oral steroids
Prophylaxis before next dose of Infliximab: Antihistamine and hydrocortisoneEMEA Summary of product characteristics (SPC), Remicade 100mg powder for concentrate for
solution for infusion
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
Patient Exposure since Launch: Therapeutic Area - Worldwide
Post-marketing surveillance
* EU includes Norway, ROW includes Japan and Canada
Cumulative Since Launch: 24 Aug 1998-23 Feb 2009
Total treated patients - Worldwide: 1,153,934
Data on file, Centocor (PSUR 19, April 2009).
Luminal CD
Mild
Moderate
Severe
Budesonide(R. colon/ileal)Sulfasalazine(left colon)
Symptoms
Burden of Disease
History
Anti-TNFScheduledMaintenance
Prednisone
FAIL 4–8 wk
1-2wk steroi
ds
Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008
MTX × 12 WeeksOr
AZA × 16 Weeks
Moderate CD Algorithm: Time Bound
Moderate
Prednisone
CorticosteroidRefractory
CorticosteroidDependent
Anti-TNFScheduledMaintenance
MTX × 12 WeeksOr
AZA × 16 Weeks
2–4
W
eeks
16–2
4
Weeks
Respondand Taper
FAIL
Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008
Predictors of very severe Crohn’s Disease
- >70cm resection, >2 resections, colectomy, stoma,
complex perianal disease.
- 18% of patients at 5 years.
- Independent predictors at diagnosis:
- Age <40
- Stricturing or intra-abdominal penetrating
- Fever
- Loss of >5kg
- Increased platelets counts
Infliximab in Patient with Fistulizing Crohn’s Disease Before & After
treatment
CROHN’S DISEASE
Conclusions- Poor disease control leads to development of
complications, severe disease and disability
- Selecting patients for an appropriate treatment strategy is critical to achieving optimal disease control
- Early treatment in appropriate patients appears to avoid some of the worst outcomes of the disease
- Anti-TNF therapy appears to help us achieve long-term, steroid-free remission and possible mucosal healing
- Scheduled maintenance therapy appears more effective than episodic treatment
- Concomitant immunosuppression may be beneficial in selected cases
- There are no data supporting stopping therapy, although early intensive treatment with anti-TNF in RA maintained remission without therapy
Thank You
Cumulative risk of intestinalresection
Cosnes et al. Gut 2005
1978-1982 n=2231993-1997 n=530
1983-1987 n=330 1998-2002 n=335
1988-1992 n=480
CD
-rela
ted
su
rgeri
es (
% p
at.
)
Month after diagnosis
0
10
20
30
40
50
0 12 24 36 48 60 72
CROHN’S DISEASE
A Significant Number of CD Patients Suffer Unemployment and Need Social
Welfare
Feagan BG, et al. J Clin Gastroenterol. 2005;39:390–395.
Prior bowel resection is associated with a higher likelihood of unemployment and of receiving disability
compensation
48% Full Time
13%Part
Time 39%Unemployed
75% Not Receiving
Disability
25% Receiving
Disability
Employment DisabilityCompensation
Hypersensitivity 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
CROHN’S DISEASE
Patient Exposure since Launch: Therapeutic Area - Worldwide
Post-marketing surveillance
* EU includes Norway, ROW includes Japan and Canada
Cumulative Since Launch: 24 Aug 1998-23 Feb 2009
Total treated patients - Worldwide: 1,153,934
Data on file, Centocor (PSUR 19, April 2009).
Luminal CD
Mild
Moderate
Severe
Budesonide(R. colon/ileal)Sulfasalazine(left colon)
Symptoms
Burden of Disease
History
Anti-TNFScheduledMaintenance
Prednisone
FAIL 4–8 wk
1-2wk steroi
ds
Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008
MTX × 12 WeeksOr
AZA × 16 Weeks
CROHN’S DISEASE
Predictors of very severe Crohn’s Disease
- >70cm resection, >2 resections, colectomy, stoma, complex perianal disease.
- 18% of patients at 5 years.
- Independent predictors at diagnosis:
- Age <40
- Stricturing or intra-abdominal penetrating
- Fever
- Loss of >5kg
- Increased platelets counts
0
2400 12 24 36 48 60 72 84 96108120132144156168180192204216228
100
90
80
70
60
50
40
30
20
10
Progression of Crohn's Disease
Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.
Patients at risk:N= 2002 552 229 95 37
Penetrating
Stricturing
Cu
mu
lati
ve P
rob
ab
ilit
y (
%)
Inflammatory
Months
CROHN’S DISEASE
WHAT COULD BE THE OTHER OPTIONS IN
MANAGEMENT OF CROHN’S
DISEASE?
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.
Probiotics
TRICHURIS SUIS OVA (TSO)
Fish Oil
WHAT COULD BE THE OTHER OPTIONS IN MANAGEMENT OF
CROHN’S DISEASE?
Diseases and conditions where stem cell treatment is promising or emerging.[38] Bone marrow transplantation is, as of 2009, the only established use of stem cells.
:// . - . / / - - - - .http www news medical net health What are Embryonic Stem Cells aspx
Thank You
Incidence5-15 / 100 000 population1
Prevalence9 – 199 / 100 000 population1
1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds .Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18
2 Economou M and Pappas G, Inflammatory Bowel Diseases. 2008; 14: 709-720.
Global map of CD2
Annual incidence:- red >7/105
- orange 4-7/105
- green 1-4/105
- blue <1/105
- white absence of data
CROHN’S DISEASE
Incidence & Prevalence
WHERE IS 11 E??
IBD is an idiopathic & inflammatory disorder of GIT, comprise primarily UC & CD
Approximately 1 million people in the USA have been diagnosed with IBD & an additional 30,000 people are newly diagnosed each year.
CROHN’S DISEASE
Introduction
Highest age adjusted incidence rate of IBD (15-30) overlap reproductive years.
Improved Medical & Surgical treatment of IBD has allowed pts with more significant illness to consider pregnancy & having children.
Optimal management of reproductive health in IBD pts is a challenge to gastroenterologist obstetrician & IBD surgeons.
CROHN’S DISEASE
Introduction
CD: INCIDENCE & PREVALENCE
Incidence5-15 / 100 000 population1
Prevalence9 – 199 / 100 000 population1
1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds .Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18
2 Economou M and Pappas G, Inflammatory Bowel Diseases. 2008; 14: 709-720.
Global map of CD2
Annual incidence:- red >7/105
- orange 4-7/105
- green 1-4/105
- blue <1/105
- white absence of data
CROHN’S DISEASE
THE ROLE OF PRO-INFLAMMATORY CYTOKINES IN CROHN’S DISEASE
Sands BE et al. Inflammatory Bowel Diseases. 1997; 3: 95-113. Feldmann M et al. Adv Immunol. 1997; 64: 283-350.
CROHN’S DISEASE
Add the second conclusion slide 74
TREATING CD B1,2,3
Fish Oil What is it?
Derived from fish Contains omega-3 fatty
acids What do they do?
Anti-inflammatory effect Reduces leukotriene B4
How do you take it? Enteric coated capsules
to avoid “fishy smell”
0
10
20
30
40
50
60
%
Fish Oil Placebo
Patients in Remission at 1 Year
CAPSULE ENDOSCOPY
FINDINGS
Probiotics
“...living micro-organisms which upon ingestion in certain numbers exert health benefits beyond
inherent general nutrition…”
Copyright © 2009 Elsevier B.V.
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
Crohn’s Intestinal helminths
induce cytokine release and down regulate cell mediated responsiveness
http://www.slideworld.org/viewslides.aspx/Treatment-of-Inflammatory-Bowel-Disease-ppt-28078
TRICHURIS SUIS OVA (TSO)
REGENERATIVE MEDICINE
Arthritis Axial – Ankylosing
Spondylitis Peripheral
Skin Erythema nodosum Pyoderma
gangrenosum Eyes
Anterior uveitis Episcleritis/Iritis
Liver PSC Autoimmune
hepatitis
Common Extra G.I. Complications
Extraintestinal manifestations of IBD are important to consider in the management of patients with Crohn's disease and ulcerative colitis. They are most commonly associated with active bowel disease, but can also occur prior to bowel disease or during periods of remission. Although management typically involves control of the active disease, there are treatment options for those patients who continue to be symptomatic despite treatment of their bowel disease
Drug Therapies
Glucocorticoids (steroids)
5-aminosalicylates (5-ASA)
Immunosuppressants
Antibiotics
Biological Therapy
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
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
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
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
TNF- binding proteins
Adalimumab
(Humira®)
Infliximab
(Remicade®)
5 mg/kg BW i.v.
Week 0, 2, 6
than every 8 weeks
160 or 80 mg s.c. 1x
than 80 or 40 mg 1x
than 40 mg s.c. eow
Treatment goals in biological treatment era
Sustained Clinical remission off steroids
Intestinal healing
Prevention of complications
Prevention of hospitalization &
surgery
Luminal CD
Mild
Moderate
Severe
Budesonide(R. colon/ileal)Sulfasalazine(left colon)
Symptoms
Burden of Disease
History
Anti-TNFScheduledMaintenance
Prednisone
FAIL 4–8 wk
1-2wk steroi
ds
Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008
MTX × 12 WeeksOr
AZA × 16 Weeks
Moderate CD Algorithm: Time Bound
Moderate
Prednisone
CorticosteroidRefractory
CorticosteroidDependent
Anti-TNFScheduledMaintenance
MTX × 12 WeeksOr
AZA × 16 Weeks
2–4
W
eeks
16–2
4
Weeks
Respondand Taper
FAIL
Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008
Conclusions- Poor disease control leads to development of
complications, severe disease and disability
- Selecting patients for an appropriate treatment strategy is critical to achieving optimal disease control
- Early treatment in appropriate patients appears to avoid some of the worst outcomes of the disease
- Anti-TNF therapy appears to help us achieve long-term, steroid-free remission and possible mucosal healing
- scheduled maintenance therapy appears more effective than episodic treatment
- Concomitant immunosuppression may be beneficial in selected cases
- There are no data supporting stopping therapy, although early intensive treatment with anti-TNF in RA maintained remission without therapy
PILES – LEADING TO MASSIVE G.I BLEEDING
CROHN’S DISEASE INVOLVING ILEUM