therapy of inflammatory bowel diseases 2013 gastroenterology department division of medicine eran...
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Therapy ofInflammatory Bowel
Diseases2013
Gastroenterology Department
Division of Medicine
Eran Israeli MD
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Cosnes J et al. Inflamm Bowel Dis 2002;8:244-50.
24022821620419218016815614413212010896847260483624120
0
20
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%C
um
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tive
Pro
bab
ilit
y
Patients at riskMonths
2002 552 229 95 37N=
Penetrating
StricturingInflammatory
Long Term Evolution of Disease Behavior in CD
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Goals of Treatment
Remission
Maintenance
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Goals of therapy
Induce and maintain remissionAmeliorate symptomsImprove pts. quality of lifeAdequate nutritionPrevent complication of both the disease
and medicationsMucosal healing
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Therapeutic PyramidTherapeutic Pyramidfor Active IBDfor Active IBD
SevereSevere
ModerateModerate
Aminosalicylates/AntibioticsAminosalicylates/Antibiotics
CorticosteroidsCorticosteroids
ImmunomodulatorsImmunomodulators
SurgerySurgery
InfliximabInfliximab
??((PrednisonePrednisone))
MildMild
((BudesonideBudesonide))
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5-aminosalicylates
The mainstay treatment of mild to moderately active UC and CD (colitis).
5-ASA may act by blocking the production of prostaglandins and
leukotrienes, inhibiting bacterial peptide–induced
neutrophil chemotaxis and adenosine-induced secretion,
scavenging reactive oxygen metabolites
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Sulphasalazine first agent discovered
Group now includes: Pentasa (mesalazine) Asacol (mesalazine) Rafassal (mesalazine) Salazopyrin-EN
(sulphasalazine) Work locally on the lining
of the gut to reduce inflammation
5-aminosalycylates
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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
Topical corticosteroids can be used as an alternative to 5-ASA in ulcerative proctitis or distal UC.
Corticosteroids
Enter cells and bind to and activate specific cytoplasmic receptors
Steroid-receptor dimers enter cell nucleusactivate steroid-responsive elements in DNA
Gene repression or induction anti-inflammatory effects
Anti-inflammatory effects take several hours
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IV -for patients who are sufficiently ill to require hospitalization; the majority will have a response within 7 to 10 days
Budesonide: less side effects, its use is limited to patients with distal ileal and right-
sided colonic disease
Corticosteroids
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Corticosteroids
-Acne“-Moon” face-Hair growth
“-Buffalo” hump
-Obesity-Purple / red streaks(striae)
-Bone thinning
-Bruising
-Muscle weakness
Cataract
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Immunomodulators
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
• Inhibit ribonucleotide synthesis; • Induce T cell apoptosis by modulating cell )Rac1( signalling• Metabolised to mercaptopurine
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Azathioprine
6-Mercaptopurine
6-TGN 6-MMPN
TPMT
Azathioprine Metabolism
TPMT = thiopurine methyltransferase6-TGN = 6-thioguanine nucleotide6-MMPN = 6-methylmercaptopurine ribonucleotide
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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
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Biological therapyanti-TNF
Infliximab
Neutralisation of soluble
TNF
TNF producing
macrophages of activated T
cells
Neutralisation of transmembrane TNF
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.
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Chimeric monoclonal antibody (75% human
IgG1 isotype)
InfliximabInfliximab
IgGIgG11
MouseMouse HumanHuman
PEG, polyethylene glycolPEG, polyethylene glycol..
Humanized Fab’fragment (95% human
IgG1 isotype)
Certolizumab PegolCertolizumab Pegol
PEGPEG
PEGPEG
VHVHVLVL
CCHH11
No FcNo Fc
Human recombinant antibody (100% human
IgG1 isotype)
AdalimumabAdalimumab
IgGIgG11
Construct of Anti-TNF-α Biologic Agents
Construct of Anti-TNF-α Biologic Agents
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Anti-TNF 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
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Integrins
MAdCAM-1
VCAM-1
Gut-homingT-cell
Integrin
Integrin