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Therapy of Inflammatory Bowel Diseases 2013

Gastroenterology Department Division of Medicine. Therapy of Inflammatory Bowel Diseases 2013. Eran Israeli MD. 100. 80. Penetrating. 60. % Cumulative Probability. 40. Inflammatory. Stricturing. 20. 0. 0. 12. 24. 36. 48. 60. 72. 84. 96. 108. 120. 132. 144. 156. 168. 180.

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Therapy of Inflammatory Bowel Diseases 2013

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  1. Gastroenterology DepartmentDivision of Medicine Therapy ofInflammatory Bowel Diseases2013 Eran Israeli MD

  2. 100 80 Penetrating 60 % Cumulative Probability 40 Inflammatory Stricturing 20 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk 95 2002 552 229 37 N = Long Term Evolution of Disease Behavior in CD Cosnes J et al. Inflamm Bowel Dis 2002;8:244-50.

  3. Goals of Treatment Remission Maintenance

  4. 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

  5. Therapeutic Pyramidfor Active IBD Surgery Severe Immunomodulators Infliximab (Prednisone) ? Moderate Corticosteroids (Budesonide) Mild Aminosalicylates/Antibiotics

  6. 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

  7. 5-aminosalycylates • 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

  8. 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 • 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.

  9. Corticosteroids • 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

  10. Corticosteroids -Acne -“Moon” face -Hair growth Cataract -“Buffalo” hump -Obesity -Purple / red streaks (striae) -Bruising -Bone thinning -Muscle weakness

  11. Immunomodulators • Inhibit ribonucleotide synthesis; • Induce T cell apoptosis • by modulating cell (Rac1) signalling • Metabolised to mercaptopurine • 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

  12. Azathioprine Metabolism TPMT = thiopurine methyltransferase 6-TGN = 6-thioguanine nucleotide 6-MMPN = 6-methylmercaptopurine ribonucleotide

  13. 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

  14. Biological therapyanti-TNFa Infliximab Neutralisation of transmembrane TNF Neutralisation of soluble TNF TNF producing macrophages of activated T cells 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.

  15. Mouse Human PEG, polyethylene glycol. Construct of Anti-TNF-α Biologic Agents Certolizumab Pegol Infliximab Adalimumab VL VH CH1 No Fc PEG IgG1 IgG1 PEG Human recombinant antibody (100% humanIgG1 isotype) Chimeric monoclonal antibody (75% humanIgG1 isotype) Humanized Fab’fragment (95% humanIgG1 isotype)

  16. Anti-TNFa 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

  17. Integrins VCAM-1 MAdCAM-1 Integrin a4b7 Gut-homing T-cell Integrin a4b1

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