Transcript
Page 1: Therapy of Inflammatory Bowel Diseases 2013

Therapy ofInflammatory Bowel

Diseases2013

Gastroenterology Department

Division of Medicine

Eran Israeli MD

Page 2: Therapy of Inflammatory Bowel Diseases 2013

Cosnes J et al. Inflamm Bowel Dis 2002;8:244-50.

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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


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