Therapy ofInflammatory Bowel

Diseases2013

Gastroenterology Department

Division of Medicine

Eran Israeli MD

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

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Patients at riskMonths

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Penetrating

StricturingInflammatory

Long Term Evolution of Disease Behavior in CD

Goals of Treatment

Remission

Maintenance

Goals of therapy

Induce and maintain remissionAmeliorate symptomsImprove pts. quality of lifeAdequate nutritionPrevent complication of both the disease

and medicationsMucosal healing

Therapeutic PyramidTherapeutic Pyramidfor Active IBDfor Active IBD

SevereSevere

ModerateModerate

Aminosalicylates/AntibioticsAminosalicylates/Antibiotics

CorticosteroidsCorticosteroids

ImmunomodulatorsImmunomodulators

SurgerySurgery

InfliximabInfliximab

??((PrednisonePrednisone))

MildMild

((BudesonideBudesonide))

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

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

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

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

Corticosteroids

-Acne“-Moon” face-Hair growth

“-Buffalo” hump

-Obesity-Purple / red streaks(striae)

-Bone thinning

-Bruising

-Muscle weakness

Cataract

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

Azathioprine

6-Mercaptopurine

6-TGN 6-MMPN

TPMT

Azathioprine Metabolism

TPMT = thiopurine methyltransferase6-TGN = 6-thioguanine nucleotide6-MMPN = 6-methylmercaptopurine ribonucleotide

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

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.

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

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

Integrins

MAdCAM-1

VCAM-1

Gut-homingT-cell

Integrin

Integrin