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Gastroenterology Department Division of Medicine Therapy of Inflammatory Bowel Diseases 2013 Eran Israeli MD Long Term Evolution of Disease Behavior in CD % Cumulative Probability 100 80 Penetrating 60 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 N= 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis 2002;8:244-50. 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 Surgery Severe Immunomodulators Infliximab (Prednisone) Moderate Corticosteroids (Budesonide) Mild Aminosalicylates/Antibiotics ? 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 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 Corticosteroids 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. Enter cells and bind to and activate specific cytoplasmic receptors Steroid-receptor dimers enter cell nucleus activate steroidresponsive elements in DNA Gene repression or induction antiinflammatory effects Anti-inflammatory effects take several hours 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 rightsided colonic disease Corticosteroids -Acne -“Moon” face -Hair growth Cataract -“Buffalo” hump -Obesity -Purple / red streaks (striae) -Bruising -Bone thinning -Muscle weakness Immunomodulators Drugs include: Azathioprine 6-mercaptopurine Methotrexate • Inhibit ribonucleotide synthesis; • Induce T cell apoptosis by modulating cell (Rac1) signalling • Metabolised to mercaptopurine 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 Azathioprine Metabolism Azathioprine 6-Mercaptopurine TPMT 6-TGN 6-MMPN 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-TNFa Infliximab Neutralisation of soluble TNFa Neutralisation of transmembrane TNFa TNFa 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. Construct of Anti-TNF-α Biologic Agents Infliximab Adalimumab Certolizumab Pegol VL VH CH1 No Fc PEG IgG1 Chimeric monoclonal antibody (75% human IgG1 isotype) Mouse Human PEG, polyethylene glycol. IgG1 Human recombinant antibody (100% human IgG1 isotype) PEG Humanized Fab’ fragment (95% human IgG1 isotype) 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 Integrins VCAM-1 MAdCAM-1 Integrin a4b7 Integrin a4b1 Gut-homing T-cell