Therapy of Inflammatory Bowel Diseases 2013 Gastroenterology Department Division of Medicine Eran Israeli MD

Cosnes J et al. Inflamm Bowel Dis 2002;8: % Cumulative Probability Patients at risk Months N = Penetrating Stricturing Inflammatory Long Term Evolution of Disease Behavior in CD

Goals of Treatment Remission Maintenance

Goals of therapy Induce and maintain remission Ameliorate symptoms Improve pts. quality of life Adequate nutrition Prevent complication of both the disease and medications Mucosal healing

Therapeutic Pyramid for Active IBD Severe Moderate Aminosalicylates/Antibiotics Corticosteroids Immunomodulators Surgery Infliximab ? (Prednisone) Mild (Budesonide)

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 nucleus activate 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

- 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-TGN6-MMPN TPMT Azathioprine Metabolism TPMT = thiopurine methyltransferase 6-TGN = 6-thioguanine nucleotide 6-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 therapy anti-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 IgG 1 isotype) Infliximab IgG 1 Mouse Mouse Human Human PEG, polyethylene glycol. Humanized Fab’ fragment (95% human IgG 1 isotype) Certolizumab Pegol PEG PEG VHVL CH1CH1CH1CH1 No Fc Human recombinant antibody (100% human IgG 1 isotype)Adalimumab IgG 1 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 patients

Integrins MAdCAM-1 VCAM-1 Gut-homing T-cell Integrin     Integrin    