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End points in IBD treatment Mucosal healing Vs Symptom relief

End points in IBD treatment Mucosal healing Vs Symptom relief. Jose Francis Lakeshore Hospital Kochi. Introduction. No cure for IBD No end points available!!. Treatment goals. * Maintenance of remission * Maintenance of QOL. * SYMPTOM RELIEF. Additional goals!!.

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End points in IBD treatment Mucosal healing Vs Symptom relief

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  1. End points in IBD treatmentMucosal healing Vs Symptom relief Jose Francis Lakeshore Hospital Kochi

  2. Introduction • No cure for IBD No end points available!!

  3. Treatment goals * Maintenance of remission * Maintenance of QOL * SYMPTOM RELIEF

  4. Additional goals!! * Disease modification * Mucosal healing * Pharmacoeconomics * Disease prevention! * MUCOSAL HEALING

  5. New therapeutic goals in IBD Clinical Induction & maintenance of remission off steroids Closure of fistulas Bowel Mucosal & maintenance of healing Healing of fistula tracks Long term Avoidance of complications, hospitalizations, surgeries & mortality

  6. Definition - mucosal healing • Clinician will say - “I know it when I see it” * Intact bowel mucosa • Clinical trials - secondary endpoint • Remember!! - Normal mucosa whenbiopsied * Granulomas (ileum/colon) * Focal enhancing gastritis (antrum) * Lymphocytic infiltration (rectum)

  7. Key question • Does healing of mucosa * Improves the outcome? • Unfortunately treatments that heal * Do not cure • When one stops Rx, the disease will recur

  8. Not uncommon situation • Patient feels fine • Physicians say “you’re better now, let’s just keep doing what we’re doing” • Colonoscopy – activity • Physicians do not say “The fact that you are better now and we’ve achieved this level of mucosal healing through therapy escalation likely means that you’ll be in better shape in 10 years’’

  9. Clinical endpoints- Assessment • CDAI (Remission <150) • CAI • Difficulty in evaluation - Assess symptom relief only - Non specific & non sensitive - Inconsistencies in the way symptoms are reported, collected and understood, and symptom-based indices are limited when it comes to predicting how patients will fare • (CDAI) - Disease-focused, but not disease specific - Symptom-based index has little to no prognostic value

  10. Surrogates for Mucosal Healing • ESR • CRP • Calprotectin • Lactoferrin • Imaging (MRE, CT,USG) • Endoscopy – MAYO, CDEI • Histopathology Difficulty in evaluation - Invasive tests - the incidence of procedures & cost - Compliance (when pt. is feeling fine) - No standardization

  11. What’s Wrong with Using Clinical Endpoints Rather Than Mucosal Healing? • Crohn’s disease * No correlation with endoscopic findings * Patients treated to clinical endpoints - Have progression of disease • Ulcerative colitis * Complete clinical remission & mucosal healing (score of 0) - good prognosis * No escalation for mild residual symptoms

  12. Mucosal healing as a surrogate for longer term outcomes • Associated with * Better quality of life * Fewer hospitalizations * Fewer surgeries * Longer time to clinical relapse * Reduction in dysplasia/cancer

  13. Why is mucosal healing animportant treatment endpoint? • Mucosal healing - Measure of the underlying inflammation • Clinical symptoms - Secondary surrogate • Clinical symptoms are important, but treating the underlying inflammatory condition is likely the more critical factor

  14. To attain mucosal healing • Escalating dose • Adequate & Maintenance dose • Switching over • Combination • Efficacy of anti-TNF drug are trough levels • Adherence to treatment

  15. Escalatingdose • 3 weeks, mucosal healing • 65% with moderately active UC (4.8 g/d) • 58% of patients 2.4 g/d (P=.219) • After 6 weeks, mucosal healing • 80% compared with 68%(P=.012) Am J Gastroenterol. 2005;100:2478-2485 Aliment PharmacolTher. 2005;21:133-140. Can J Gastroenterol. 2007;21:827-834. ClinGastroenterolHepatol. 2007;5:95-102 Aliment PharmacolTher. 2011;33:672-678

  16. Infliximab Dose • Dose escalation - Decrease of the interval between infusions - Dose increase to 10 mg/kg • ACCENT I study - 90% who lose response can be rescued • ACCENT II study - Fistulizing disease - Successful in 60%

  17. Adequate dose • ASA • Steroids • Azathiopurine • Biologic agents

  18. Maintenance dose

  19. 5-ASA switching • Few studies • Granulated mesalamine 1.5 g once daily or placebo • Maintained remission after 6 months of treatment 78% vs 59%; P<.001 • Relapse-free at 6 months (77% vs 50%; P<.001). Am J Gastroenterol. 2008;103(Suppl 1):A429-A430

  20. Infliximab - switching • Switching to another biologic agent • Adalimumab • Certolizumab

  21. ASA - Oral/rectal combination therapy • Decrease in CAI scores • Decrease in no. of relapses Am J Gastroenterol. 1997;92:1867-1871 Am J Gastroenterol. 1997;92:1143-1147

  22. Infliximab/Azathioprinecombination

  23. Mesalaminefor postsurgicalmaintenance in Crohn’s disease? • Preventing relapse (OR, 0.68; 95% CI 0.52 to 0.90) Gastroenterology. 2000;118:264-273. Cochrane Database Syst Rev. 2011:CD008414

  24. Infliximab for postsurgicalmaintenance in Crohn’s disease? • 5 mg/kg within 4 weeks of surgery • Maintenance for 1 year • Endoscopic recurrence from 85% to 9% Gastroenterology 2009; 136: 441–50e1

  25. Trough levels Trough levels

  26. THIOPURINES - levels • Active metabolites 6-thioguanine (6-TGN) 6-methylmercaptopurine nucleotide (6-MMPN) • Meta-analysis of 12 studies 6-TGN levels higher among patients in remission - 62% with 6-TGN levels above 230–260 pmol/8 x108 RBC - 36% below this value(P<.001) • Gastroenterology. 2006;130:1047-1053.

  27. Managing adherence • 89% remain in remission over the long term • 39% of those who are nonadherent • Pill burden • Educational intervention Am J Med. 2003;114:39-43. Am J Gastroenterol. 2002;97:1853

  28. Infliximab - Antibodies • Human antichimeric antibodies (HACAs) - Episodic dosing 37% to 61% - Scheduled infliximab 6% and 16% • Similar in adalimumab & certolizumab • Detectable trough concentrations had - Higher rates of clinical remission - Lower CRP - Higher rate of endoscopic improvement Lancet. 2002;359:1541-1549 N Engl J Med. 2003;348:601-608 ClinGastroenterolHepatol. 2006;4:1248-1254

  29. Early Aggressive Biologic Therapy Vs Conventional management of Crohn’s Disease

  30. Step Up Vs Top Down Results D'Haens G, et al. Lancet 2008;371:660-667

  31. Step Up Vs Top DownComplete Remission at 2 Years

  32. Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions Rutgeerts P, et al. Gastroenterology. 1990;99:956-963

  33. Safety issues • Infections • Reactivation of latent TB • Possible lymphoma risk • Hepatosplenic T-cell lymphoma in young patients on infliximab plus concomittantazathioprine (n = 8)

  34. Weighing the Value of Top-Down Therapy Benefits Disadvantages • Side effects • Cost • Majority of patients may not require more potent treatments initially • Under-treatment of most severe patients with episodic strategy? • Maintenance of remission • Improved function and QOL • Early promotion of mucosal healing to prevent complications Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10:S2–S10.Caprilli R, et al. Digestive Liver Dis. 2005;37:973–979.

  35. Crohn’s disease Young age of onset (<40 years) Ilealor ileocolonic extent Fistulizingdisease at diagnosis Early need for steroids ASCA / other serologies? Genetics? Ulcerative Colitis Extensive colitis Male gender Early need for steroids Early hospitalization Predictors of More Severe Disease

  36. Mucosal healing • Existing evidence • Achieve mucosal healing in about 44% Colombel JF et al N Engl J Med 2010: 362: 1383 - 1395

  37. SUMMARY • There is no “one size fits all” to IBD therapy • Tailored to the individual • Current Rx guidelines for CD / UC - Step-up treatment • There is insufficient data to universally adopt top-down therapy into clinical practice at the present time

  38. Symptom relief Vs Mucosal healing Long way to go!!

  39. Thank You

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