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Management strategies in inflammatory bowel disease. https://youtu.be/ZVtMSTHb-JM
- 1. Management Strategies in IBD By Dr. Yasser M Abdel Halim, FRCP London Head of Gastroenterology Department, International Medical Centre Gastromilitary Meeting 15- 07-2021 ميحرلا نمحرلا هللا مسب
- 2. Objective Make the decisions about the IBD patient management easier.
- 3. Roadmap IBD Natural History. IBD Treatment: • Goals: What we’d like to accomplish as an idea. • Objectives: What we are trying to achieve clinically. • Strategies. How we are going to achieve the objectives. Conclusion.
- 6. GOAL, OBJECTIVES & STRATEGIES Blocking the structural bowel damage progression with the Least possible therapy side effects.& I. Deep remission as long as possible. BOWEL DAMAGE Irreversible
- 7. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 8. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 9. Why do we need a new Plan? 1. Limited available advanced options: Category/Class Members Cytokine blocker TNF Alpha blockers Remicade (Infliximab) & its Biosimilars Humira (Adalimumab) Simponi (Golimumab) Cimzia (Certolizumab Pegol) Interleukin blockers Stelara (Ustekinumab) Integrin blockers Entyvio (Vedolizumab) JAK inhibitors Xeljanz (Tofacitinib)
- 10. Why do we need a Plan? 2) Unsatisfactory efficacy of the current advanced Therapy-UC: 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% INFLEXIMAB ADALIMUMAB GLOMIMUAB USTEKINUMAB VEDOLIZUMAB TOFACINIB PLACEBO Induction of Remission rate in Moderate-severe UC Biologic naïve-UC (Endoscopic improvement) Biologic Experienced-UC (Clinical Remission) Updated Network Meta, Clin Gastroenterol Hepatol . 2020 Sep;18(10):2179-2191.e6.
- 11. Why do we need a Plan? 2) Unsatisfactory efficacy of the current advanced Therapy-UC: 58.7% 40.4% 42.7% 44.4% 51.9% 46.5% 30.0% 3.2% 26.3% 5.6% 26.9% 3.0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% INFLEXIMAB ADALIMUMAB GLOMIMUAB USTEKINUMAB VEDOLIZUMAB TOFACINIB PLACEBO Induction of Remission rate in Moderate-severe UC Biologic naïve-UC (Endoscopic improvement) Biologic Experienced-UC (Clinical Remission) Updated Network Meta-Analysis, Clinical Gastroenterology and Hepatology 2020;18:2179–2191
- 12. Why do we need a Plan? 2) Unsatisfactory efficacy of the current advanced Therapy-CD: 59.6% 48.7% 25.4% 40.7% 40.2% 20.0% 24.9% 19.3% 12.4% 8.5% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% INFLEXIMAB ADALIMUMAB CERTILIZUMAB USTEKINUMAB VEDOLIZUMAB PLACEBO Induction of Remission rate in Moderate-severe UC Biologic naïve-CD-(Clinical Remission) Biologic Experienced-CD-(Clinical Remission) Systematic review and network meta-analysis, Aliment Pharmacol Ther . 2018 Aug;48(4):394- 409.
- 13. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 14. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 15. 1. Early effective therapy for high risk 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% < 2 years 2-5 years > 5 years Disease Duration Subgroup-analysis of CHARM trial Remission induction in relation to disease duration J Crohns Colitis . 2013 Apr;7(3):213-21.
- 16. 1. Early effective therapy for high risk 51% 44% 35% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% < 2 years 2-5 years > 5 years Disease Duration Subgroup-analysis of CHARM trial Remission induction in relation to disease duration J Crohns Colitis . 2013 Apr;7(3):213-21.
- 17. 1. Early effective therapy for high risk 56.8% 44.4% 30.0% INFLEXIMAB-AZATHIOPRINE INFLEXIMAB AZATHIOPRINES SONIC Trial: Remission Induction-CD The New England Journal of Medicine. 2010. 362(15):1383-1395.
- 18. 1. Early effective therapy for high risk 56.8% 44.4% 30.0% INFLEXIMAB-AZATHIOPRINE INFLEXIMAB AZATHIOPRINES SONIC Trial: Remission Induction-CD The New England Journal of Medicine. 2010. 362(15):1383-1395.
- 19. 1. Early effective therapy for high risk 56.8% 44.4% 30.0% INFLEXIMAB-AZATHIOPRINE INFLEXIMAB AZATHIOPRINES SONIC Trial: Remission Induction-CD
- 20. 1. Early effective therapy for high risk 0.95 0.32 0.41 0.49 0.76 0.56 0.26 0.83 0.34 0.91 0 0.2 0.4 0.6 0.8 1 INFLEXIMAB ADALIMUMAB GOLIMUMAB USTEKINUMAB VEDOLIZUMAB TOFACINIB Relative efficacy of Biologics (+Tofacitinib) in moderate to severe UC Biologic Naive-UC-Endoscopic improvement Biologic Experienced-UC-Endoscopic improvement Updated Network Meta-Analysis, Clinical Gastroenterology and Hepatology 2020;18:2179–2191
- 21. 1. Early effective therapy for high risk 0.93 0.75 0.2 0.56 0.55 0.91 0.71 0.35 0 0.2 0.4 0.6 0.8 1 INFLEXIMAB ADALIMUMAB CERTILIZUMAB USTEKINUMAB VEDOLIZUMAB Relative efficacy of Biologics in moderate to severe CD Biologic Naive-CD-Clinical Remission Biologic experienced-CD-Clinical Remission
- 22. 1. Early effective therapy for high risk Choice order/efficacy of Biologics: Ulcerative colitis Crohn's disease Naive Experienced Naive Experienced Infliximab 1 (58.7%) 1 (59.6%) Adalimumab 6 (40.4%) 4 (3.2%) 2 (48.7%) 1 (24.9%) Golimumab 5 (42.7%) Certilizumab 5 (25.4%) Ustekinumab 4 (44.4%) 2 (26.3) 3 (40.7%) 2 (19.3%) Vedolizumab 2 (51.9%) 3 (5.6%) 4 (40.2%) 3 (12.4%) Tofacitinib 3 (46.5%)? 1 (26.9%) Aliment Pharmacol Ther . 2018 Aug;48(4):394-409. Clinical Gastroenterology and Hepatology 2020;18:2179–2191
- 23. 1. Early effective therapy for high risk Severity vs activity: • Disease Severity: describes the actual or predicted (Prognosis) whole course line of the disease (UC, CD). Mild course of disease. Moderate to Severe course of disease (High risk patients). • Disease Activity: describes a time point on the course line of the disease. Mid activity. Moderate to severe activity.
- 24. 1. Early effective therapy for high risk Colectomy risk Stratification (UC) Bowel damage risk Stratification (CD)
- 25. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 26. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 27. 2. Treat 2 Target Strategy Definition: • To use a predefined target to be reached with therapy. How to chose your target? • Good correlation with the clinical objective (Inflammation Remission): Sensitive, Specific, Objective • Convenient for frequent monitoring: Noninvasive, Simple & of low cost.
- 28. 2. Treat 2 Target Strategy Histology Cross- sectional BioMarkers Symptoms Endoscopy Potential targets in IBD treatment: STRIDE-II: Gastroenterology 2021;160:1570–1583
- 29. 2. Treat 2 Target Strategy Correlation with inflame. Remission: Histo- logy Endo- scopy Radio- logy Bio- markers Symp- toms Sensitive √√√ √√√ √√ √ √ Specific √√√ √√ √√ √ √ Objective ? √ √ √ X Non invasive X X √ √ √ Simple X X X √ √√ Low cost X X X √ √√ 5 4 2 1 3 STRIDE-II: Gastroenterology 2021;160:1570–1583
- 30. 2. Treat 2 Target Strategy Correlation with inflame. Remission: 4.5 1.0 0 1 2 3 4 5 6 7 8 9 10 Endoscopic Remission Histologic Remission Hazard Risk of relapse at one year Gastroenterology Jan 2001;120(1):13–20
- 31. 2. Treat 2 Target Strategy Correlation with inflame. Remission: 57% 30% 43% 70% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Symptomatic Remission Symptomatic Activity SONIC Trial Endoscopic Remission Endoscopic Activity J Gastrointest Liver Dis 2018;27:299–306. Inflammatory Bowel Dis 2012; 18: 2218–2224. √ X Faecal calprotectin Symptoms Correlation with endoscopic activity: • Sensitivity: 82% • Specificity: 72 % Correlation with endoscopic activity: • Sensitivity: 65.5% • Specificity: 62 %
- 32. 2. Treat 2 Target Strategy Convenience for frequent monitoring: Histo- logy Endo- scopy Radio- logy Bio- markers Symp- toms Sensitive √√√ √√ √ √ ? Specific √√ √√ √√ √ ? Objective ? √ √ √ X Non invasive X X √ √ √ Simple X X X √ √√ Low cost X X X √ √√ 1 2 5 3 4 STRIDE-II: Gastroenterology 2021;160:1570–1583
- 33. 2. Treat 2 Target Strategy Which target should we use? Histo- logy Endo- scopy Radio- logy Bio- markers Symp- toms Sensitive √√√ √√ √ √ √ Specific √√ √√ √√ √ ? Objective ? √ √ √ X Non invasive X X √ √ √ Simple X X X √ √√ Low cost X X X √ √√ STRIDE-II: Gastroenterology 2021;160:1570–1583
- 34. 2. Treat 2 Target Strategy Which target should we use? ALL. STRIDE-II: Gastroenterology 2021;160:1570–1583
- 35. 2. Treat 2 Target Strategy Which target should we use? ALL. • Short-term targets: Clinical response and normalization of serum (CRP, ESR) and fecal markers (FC). • Long-term targets: Clinical remission, endoscopic healing, absence of disability, restoration of quality of life, and normal growth in children. • Measures of the remission depth: Transmural healing in Crohn’s disease and histological healing in ulcerative colitis. STRIDE-II: Gastroenterology 2021;160:1570–1583
- 36. 2. Treat 2 Target Strategy Which target should we use? ALL. • REACT trial Symptoms. • CALM trial symptoms + Biomarkers. • REACT II Endoscopy. REACT: Lancet 2015; 386: 1825-1834 CALM: Lancet 2018; 390: 2779-2789
- 37. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 38. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 39. 3. Tight Control Strategy Definition: • Quick reaction to the disease activity with effective treatment escalation in order to quickly achieve the treatment target.
- 40. 3. Tight Control Strategy 3a. Frequent Monitoring (of Target) 1. Start early effective therapy for high risk patient 2. Select a target for monitoring 3b. Early detection of Response Remission Not Achieved Remission Achieved De-escalate to Maintenance 3c. Reactive TDM & Optimization 3d. Early detection of Relapse
- 41. 3. Tight Control Strategy 3a. Frequent Monitoring (of Target) 1. Start early effective therapy for high risk patient 2. Select a target for monitoring 3b. Early detection of Response 3d. Early detection of Relapse Remission Not Achieved Remission Achieved De-escalate to Maintenance 3c. Reactive TDM & Optimization
- 42. 3a. Frequent Monitoring of “Target” How Frequent Measurement? • REACT Trial 12 weeks • CALM Trial • More frequent is better.
- 43. 3a. Frequent Monitoring of “Target” How Frequent Measurement? • Short-term targets: (days to weeks) Clinical response and normalization of serum (CRP, ESR) and fecal markers (FC). • Long-term targets: (Months) Clinical remission, endoscopic healing, absence of disability, restoration of quality of life, and normal growth in children. • Measures of remission depth: (Months) Transmural healing in Crohn’s disease and histological healing in ulcerative colitis. STRIDE-II: Gastroenterology 2021;160:1570–1583
- 44. 3. Tight Control Strategy De-escalate to Maintenance 3a. Frequent Monitoring (of Target) 3b. Early detection of Response 3d. Early detection of Relapse 3c. Reactive TDM & Optimization Remission Not Achieved Remission Achieved 1. Start early effective therapy for high risk patient 2. Select a target for monitoring
- 45. 3b. Early detection of “Treatment response” Calprotectin as predictor of response: • Absolute value interpretation: • Dynamic changes interpretation: 80% reduction at wk 2 predicts endoscopic remission at wk 10. Baseline value at endoscopic activity time allow better correlation in same individual. Inflammatory Bowel Disease 2017 Jun; 23(6): 894–902. J Crohns Colitis. 2012 Jun;6(5):557-62. Level Sensitivity Specificity Endoscopic healing < 250 µg/g 42-96% 72-83% Histologic healing < 100 µg/g 71% 92%
- 46. 3. Tight Control Strategy 3a. Frequent Monitoring (of Target) 3b. Early detection of Response 3d. Early detection of Relapse Remission Not Achieved Remission Achieved 1. Start early effective therapy for high risk patient 2. Select a target for monitoring De-escalate to Maintenance 3c. Reactive TDM & Optimization
- 47. 3c. Reactive TDM & Optimization Expected time in weeks for target achievement: STRIDE-II: Gastroenterology 2021;160:1570–1583
- 48. 3c. Reactive TDM & Optimization Adequate Switch class Class mechanism has failed Low Dose Escalation Low Remission Not Achieved Drug Ani- bodies Level Switch within same class High Drug Concentration Level
- 49. 3c. Reactive TDM & Optimization Level before considering class failure: Biologic Level Infliximab > 10 µg/mL Adalimumab > 12 µg/mL Certolizumab > 36 µg/mL Golimumab > 9 µg/mL Vedolizumab > 35 µg/mL Ustekinumab > 4.5 µg/mL Clinical Gastroenterology and Hepatology 2019;17:1655–1668
- 50. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 51. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 52. 3. Tight Control Strategy De-escalate to Maintenance 3a. Frequent Monitoring (of Target) 3b. Early detection of Response 3d. Early detection of Relapse 3c. Reactive TDM & Optimization Remission Not Achieved Remission Achieved 1. Start early effective therapy for high risk patient 2. Select a target for monitoring
- 53. 3d. Early detection/Prevention of Relapse Fecal Calprotectin as a predictor of relapse: • Absolute value interpretation: > 100 Histological Activity. > 250 Endoscopic Activity. • Dynamic changes interpretation: Starts to increase 2-3 months before symptomatic relapse. Baseline value at endoscopic remission time allow better correlation in same individual. Inflammatory Bowel Disease 2017 Jun; 23(6): 894–902. Level Sensitivity Specificity Endoscopic Activity > 250 µg/g 76% 86% Histologic Activity > 100 µg/g 71% 92%
- 54. 3d. Early detection/Prevention of Relapse Adequate Switch class Class mechanism has failed Low Dose Escalation Low Relapse predicted Drug Ani- bodies Level Switch within same class High Drug Concentration Level
- 55. 3. Tight Control Strategy Tight control Results? 66% 46% 62% 30% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Symptoms-REACT Symptomatic Remission Symptoms & Biomarkers- CALM-Mucosal Healing Endoscopy-React II Tight control Conventional Management REACT: Lancet 2015; 386: 1825-1834 CALM: Lancet 2018; 390: 2779-2789
- 56. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 57. GOAL, OBJECTIVES & STRATEGIES GOAL OBJECTIVES STRATEGIES Blocking the structural bowel damage progression with the Least possible side effects I. Early inflammation Remission, 1. Early effective therapy for high risk patient, 2. Treat to Target, 3. Tight Control, a. Frequent Monitoring, b. Early Detection of Treatment Response, c. Reactive TDM/Optimization, II. Maintaining inflammation Remission, d. Early Detection & Prevention of Relapse, III.De-escalation when Longstanding Remission 4. Exit Strategy.
- 58. 4. Exit Strategy Relapse rates: 30% 50% 30% 50% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Relapse at 1 year Relapse at 2 year Relapse at 5 years Relapse rate Axis Title Relapse Rate by duration after drug withdrawal Immunomodulators Anti-TNF Journal of Crohn's and Colitis, 2017,1-15
- 59. 4. Exit Strategy Risk factors for Relapse after biologic withdrawal: • Residual inflammation detected by Histology, Endoscopy, radiology, Biomarkers or symptoms. • Previous need for anti-TNF dose escalation. Journal of Crohn's and Colitis, 2017,1-15
- 60. 4. Exit Strategy General considerations • Confirm longstanding deep Remission, • Confirm Drug & Drug Ab level, • Discussion with the patient: Risks of relapse estimation, Same drugs might not work again, New complications may develop. • Close & continuous monitoring, • Early detection & prevention of relapse, • Predefined Rescue Strategy. Journal of Crohn's and Colitis, Volume 12, Issue 1, January 2018, Pages 17–31,
- 61. Conclusion No satisfactory therapy for IBD till now. Conventional step care has failed to modify the natural course of IBD. New strategies have shown better results. Four pillars of the modern therapeutic Approach: 1. Early effective therapy for high risk pts, 2. Treat to target, 3. Tight control & 4. Exit strategies.
Editor's Notes
- بسم الله الرحمن الرحيم: أهلا بكل الموجودين وخاصة أساتذتنا د. أحمد الصاوي ود. بهاء. ودلوقتي خلونا نبدأ التوك واللي عنوانها Management Strategies in IBD.
- After this talk, the audience should be able to: Make decisions about the IBD patient management with more comfort & ease. أنا طبعا بأخاطب الأجيال الحديثة أساتذتنا أكيد المحاضرة بالنسبة لهم هتبقي تكرار للي يعرفوه ويعذروني لو فيها أي أخطاء.
- The talk is going to start by a Brief description of the IBD Natural History, Then the main part of the talk will be about the Management Goals & clinical Objectives, & then the strategies used to achieve them? & finally the Conclusion.
- The course of the Crohn’s disease (CD) and ulcerative colitis (UC) diseases was used to be described as chronic relapsing and remitting. However, this description was found later on to be inaccurate, because it describes only one process of the disease which is the uncontrolled inflammation. It is now well established that with every relapse, an accumulating & progressive structural bowel damage occurs, that at a certain point becomes irreversible. Mainly in in UC: colonic fibrosis, narrowing and colectomy. & CD: strictures, fistulas and resections strictures, fistulae, surgery, intestinal failure and cancer Causes of disease progression: Delayed diagnosis. Inappropriate care. Careless follow-up. Intractable disease. Although there has been much progress in the management of IBD with established and evolving therapies including the use of monoclonal antibodies, most current approaches that are directed only toward symptom control have failed to change the natural course of the disease. In a Danish cohort, even though mortality from ulcerative colitis (UC) decreased from 1982 to 2010, largely because of reduced mortalities from gastrointestinal disorders and colorectal cancer, people with CD had 50% greater mortality than the general population, and this value did not change over this time period.
- Therefore, the goal of therapy has now shifted from mere control of symptoms to altering natural course of the disease by preventing the bowel damage and disability. The modern goal of treatment now is to block that progressive structural bowel damage before it becomes irreversible, & complicated & of course with the least possible side effects. However, in some patients, this objective is not possible because they already had complicated disease because of delayed diagnosis, or failure of previous treatment. Therefore your objective will be to prevent further irreversible bowel damage.
- & to achieve this goal we need to translate it into clinical objectives. To prevent bowel damage we need to settle down the inflammation that is causing that damage: we have to bring the patient into a deep remission as early as possible after diagnosis & to maintain him in deep remission as long as possible. & to reduce the therapy side effect expenses we have to de-escalate therapy when it is appropriate. We three clinical objectives: early remission, maintaining remission & re-escalating therapy when longstanding remission.
- & to achieve our clinical objectives we have to adopt strategies: For early remission we need Early effective therapy for high risk patient strategy, Treat to Target strategy & Tight Control strategy, & to achieve maintaining remission continuation of tight control strategy. & for de-escalation of therapy when longstanding remission we have the Exit strategy. To summarize we have one goal is to block that structural bowel damage progressive before it becomes irreversible, with the least possible side effects. & we have three clinical objectives Early Remission, Maintaining Remission, De-escalation when Longstanding Remission. & to achieve objectives we have four strategies. Early effective therapy for high risk patient, Treat to Target, Tight Control, Exit Strategy.
- But why do we need new goals, objectives & strategies? Is not conventional plan of care enough? The answer is No, the conventional step care is not good enough? For two main reason:1. we do have only limited effective therapy options in the market. We have three categories The Cytokines blocker, the integrin blockers & the jak inhibitors. In the first category we have the anti- TNF alpha class that include Remicade (Infliximab) & its Biosimilars, Humira (Adalimumab), Simponi (Golimumab)& Cimzia (Certolizumab Pegol), & we have in the interleukin class Stelara (Ustekinomab). The in the second category include Entyvio or vedolizumab & in the third category we have Xeljanz (Tofacitinib). By the way Tofacitinib is not a biologic therapy it is a small molecule drug. You know that the biologic drugs are made biologically by fungi or bacterial cultures & they are antibodies with very large molecules that we have no direct control on its structure, every culture can produce only similar biologic, not identical biologic, therefore, the other generics are called biosimilar, while the tofacitinib is a chemical small molecule that are made in lab & every molecule of the drug should be identical to the other.
- The second reason, why, we do need new strategies, is that the current therapy is int that effective. This slide may be shocking for some. Most of the advanced therapy did not induce remission in the more than half of naïve & more than three quarters of experienced Ulcerative colitis patients. The same picture worse in the crhon’s patients. & it seems that we are not going to have more effective therapy in the near future, therefore, we need to use the same medications in another way trying to at least improve the their result. Did you notice the difference between the naïve & experienced patient responses, experienced patient response is about less than half of the naïve response. & the big message here is that. The first biologic is the first biologic & you should not switch to another biologic without good evidence of its failure as we are going to see later.
- Now let us see what the new strategies can add to the results of IBD therapy: He first strategy to enhance early remission results is early effective therapy for high risk patients.
- There is concept called disease burden or inflammation burden: Early disease means light inflammation burden & the chance of your weapons to beat it high. While Old disease means heavy inflammation burden, & chance of your weapon to beat it is reduced. & that theory was proved by the subgroup analysis of the charm trial, that showed better response to treatment with earlier treatment.
- The sonic trial showed that combined biologic and immunomodulators is more effective than biologic monotherapy and biologic monotherapy is more effective than IM. & that was reflected on the AGA guide lines for moderate to severe UC & CD. Both of them suggest against use of thiopurine monotherapy,
- & suggested using biologic monotherapy over thiopurines
- & in UC guidelines suggested combining all using all biologics with thiopurines & methotrexate, while in CD guidelines, infliximab only because as you know Infliximab is a chimeric antibodies, not full humanized therefore it’s the most immunogenic. & it seems that the role of thiopurines is to decrease the antibodies formation against the biologics.
- Which Biologic is more effective than the others? Unfortunately, we do not have high quality evidence regarding this point, because we have just one head to head trial only. Therefore the best evidence regarding this question is coming from a network meta-analysis of the RCTs that comparing each biologics to a placebo. These Network meta-analysis, showed these comparative efficacy between biologics the blue columns for naïve & the green for experienced, & its results were reflected on the AGA guidelines for moderate to severe UC, that suggested infliximab or vedo for naïve & & Ustekinumab or Tofa for experienced.
- On the other hand, the AGA, followed the Network meta-analysis evidence in moderate to severe, ulcerative colitis & recommended, infliximab, adalimumab or ustekinumab & then vedo & at last certolizumab for naïve patients & suggested Ustekinumab for experienced primary non-responders & adalimumab or ustekinumab for secondary non-responders.
- This is a table illustrates the relative & absolute efficacy of all advanced therapies in both naïve & experienced UC & crohn’s disease. The number on the left outside the brackets are the relative efficacy, while the numbers inside the brackets are the aboulte efficacy in induction of remission. For example infliximab in naïve UC is number one between biologics with induction of remission rate about 58%. & so on. Regarding tofacitinib, it was not recommended for naïve patients because of FDA black box warning about fatal pulmonary embolism. In experienced patients, the benefit may outweigh that risk.
- We have explained what is meant by early effective treatment, now, who are the high risk patients? Before we answer that question we should first know the difference between disease severity & disease activity: the word disease severity is now used to describe the actual or predicted (Prognosis) whole course line of the disease (UC, CD). While the disease activity describes a time point on that line. For example your patient may be symptom free now (therefore he has mild disease activity), but at the same time he is a steroid dependent, therefore he has got a severe disease. He has mid activity but severe disease. We mean by high risk patients, patients with moderate to severe disease.
- Now How do you know them? That Question was nicely answered by AGA. Patients with severe UC are those with extensive colitis, deep ulcers, steroid dependent, requiring hospitalization, with associated C difficile or CMV colon infection & with high CRP & ESR or patients under age of 40 at onset. While patients with severe crohn’s disease are patients with age < 30 years at onset, extensive disease, with deep ulcers, perianal & rectal disease or stricture or fistulas or prior surgical resection. when the patient is found to be of high risk you should start treatment by advanced therapy.
- We have just finished the first strategy to enhance early remission, Now to the second strategy which is treat to target strategy.
- It means to use a predefined target to be reached with therapy. How to chose your target? The target should have a Good correlation with the clinical objective which in our case is Inflammation Remission, it is better to be Sensitive, Specific, Objective for measuring your objective. Also, it should be Convenient for frequent monitoring: it is better to be Noninvasive, Simple & of low cost.
- Our first clinical objective as we said is early remission. To calm the beast of inflammation down & put it into a deep sleep underground. We have five potential targets that are correlated with this objective & could be used as a target for treatment. The first potential target is the histology target which assesses the bowel inflammation at the microscopic level. The next is the endoscopy target which assesses the bowel inflammation at the macroscopic level. Then, we have the cross sectional or radiology target which in some cases might be the best available when the inflammation is outreach of the endoscope. , then the Biomarkers target which includes the fecal calprotectin c r p or e s r. & finally we have the symptoms target.
- Which target have more correlation with the inflammation remission? Which one is more sensitive, specific & objective? The first regarding the correlation is the histology followed by the endoscopic, then the radiologic then the biomarkers & at last the symptoms.
- There evidence that risk of relapse at one year is much much lower lower when the patient has got histologic remission than endoscopic remission only, which proves that it has better correlation with inflammation remission than endoscopy target.
- There also an evidence that the sensitivity & specificity of the Biomarkers are higher than that of symptoms using the endoscopy as a gold standard. Which proves that Biomarkers specially fecal calprotectin has a better correlation with inflammation remission than symptoms target.
- Which target is more convenient for more frequent use? The first is the symptoms followed by the biomarkers followed by the radiologic & at last the endoscopic and histologic.
- Which target should we use? The answer is all. STRIDE II suggested algorithm for using targets in ibd, it suggested, using all of them, formally, Clinical response and normalization of serum (CRP, ESR) and fecal markers (FC), as a short-term targets, & Clinical remission, endoscopic healing, absence of disability, restoration of quality of life, and normal growth in children. As Long-term targets: & non-formal use of the transmural healing in Crohn’s disease and histological healing in ulcerative colitis as Measures of the remission depth.
- The REACT study used symptoms as a target, the calm trial used symptoms & Biomarkers & the REACT II uses the Endoscopy.
- Now we started early biologic to our high risk patient & selected a suitable targets. What is the next strategy to use? It is The tight control strategy. It involves four sub strategies, arranged in a closed loop algorithm. It involves Frequent Monitoring, Early Prediction of Treatment Response, Reactive TDM/Optimization, Early Prediction & prevention of Relapse,
- Which could be defined as a Quick reaction to the disease activity with effective treatment escalation in order to quickly achieve the treatment target.
- The tight control start after early starting biologic for high risk patient, & selected a suitable targets. It involves frequent monitoring for the target for early prediction of response & if remission is not achieved we do Reactive Therapeutic drug monitoring & optimization & continue frequent monitoring of the target & to predict the response to drug optimization & so on till the remission achieved. & when remission is achieved we de-escalate to maintenance & continue frequent monitoring for early prediction of relapse & so on.
- How frequent is the monitoring of the target?
- We have two trials that used tight control, React & calm trials, & both of them measured the target every 12 weeks.
- However, STRIDE II classified the targets as short term & long term targets & according to that classification it is logic to measure the short term targets more frequently than the long term targets, for example if we have an admitted patient with severe flare, we might do measuring his symptoms & his CR daily. Therefore, It Depends on the context & the decision needed to be taken at the time. But propably not more than 12 weeks. Alleviating patient symptoms is a priority target, However, treating symptoms in IBD patient with biologic is something different. Which Target definition is better? Recommended (STRIDE): Histologic. Target of the future! Endoscopic. Reliable Radiologic. Sensitivity problem Biomarkers. Reliability problem? Symptoms. necessary to treat symptoms!!!!!
- We do frequent monitoring to early detect treatment response.
- It is useful to memorize two numbers about fecal calprotectin, 250, below it, means endoscopic remission & 100 below it, means histological remission & There is evidence that 80% reduction at weeks 2 predicts endoscopic remission at weeks 10. therefore, Baseline value at flare time allow better correlation in same individual. For example if you find the fecal calprotectin at flare time is 1000 & the level decreased to within 2-3 weeks that could mean incoming remission.
- Now we early detected that remission is not achieved: what to do? We do what is called Reactive therapeutic drug monitoring & drug optimization.
- But when we do that? When we can say that the target is not achieved? This table shows, the expected time in weeks, Required for Achieving the targets, After Starting Treatment, for Crohn’s disease & ulcerative colitis.
- When the target is not achieved, We do drug & drug antibodies concentration level & if the drug level is low we do look for the Drug antibodies concentration if it is also low, that means that the dose is low & should be escalated. But if the antibodies concentration is high that means that the drug antibodies preventing the drug from action but the class mechanism of action could be still working, therefore you can switch within the same class. On the other hand, if the drug level is adequate from the start, that means class mechanism failure & you should switch class.
- If there is no response to treatment after the expected time, what drug levels above we say there is a class mechanistic failure & we could switch the class. For Infliximab, > 10 µg/mL, for Adalimumab, > 12 µg/mL, for Certolizumab, > 36 µg/mL, for Golimumab, > 9 µg/mL, for Vedolizumab > 35 µg/mL, for Ustekinumab, for > 4.5 µg/mL.
- Now we achieved our first objective & the patient went into an early remission, How to achieve the second objective, How to maintain this remission, we achieve it by frequent monitoring to early detect & then prevent the relapse.
- Now our patient is in remission, what we should do is continue monitoring to early predict & prevent relapse.
- It is useful to memorize two numbers, 100 above it, means histological activity & 250, above it, means endoscopic activity endoscopic. There is evidence that Fecal calprotectin Starts to increase 2-3 months before symptomatic relapse. Therefore, Baseline value at endoscopic remission time to allow better correlation in same individual. For example if you find the fecal calprotectin 150 & the patient level at remission was 75, that means incoming relapse.
- When relapse is predicted, we do drug & drug antibodies level, & do changes accordingly trying to prevent the full relapse.
- Is there any evidence for the benefit of tight control strategy? Yes there is. The REACT trial used tight control but used symptoms only as a target, it did not show significant better outcome with tight control. Compared to conventional step care. While in the more recent CALM, trial showed better outcomes for tight control compared to conventional therapy when used biomarkers combined with symptoms as a target. There is another ongoing multicentral trial that uses endoscopy as a target & we are still waiting for its results.
- Now our patient is in long standing remission, could we de-escalate or withdraw therapy? That is the place of the last strategy which is the exit strategy.
- Despite high rate of relapse after therapy withdrawal, about 50% for biologic at tow years, there still the remaining 50% benefit from from withdrawal. We just need to predict which patient is going to benefit from drug withdrawal.
- It was found that the main risk factors for relapse after drug withdrawal are the presence of Residual inflammation detected by Histology, Endoscopy, radiology, Biomarkers or symptoms. Two, Previous need for biologic dose escalation.
- Therefore, before trying drug withdrawal, we have to confirm deep remission by combined all potential targets, histology, endoscopic, radiologic, biomarkers & symptoms. The patient should have Complete mucosal healing + Histological remission, normal radiology, Low Biomarkers, & free of symptoms. Next we have to Confirm Drug & Drug Ab level, The patient should know that there is a considerable risk of relapse, that the same drug might not work again, & that New complications may develop. We should continue monitoring for early prediction of relapse. & we should be ready with a predefined Rescue Strategy. Confirm longstanding Deep Remission. Confirm Drug & Drug Ab level, Discussion with the patient: Risks of relapse estimation: Same drugs might not work again. New complications CRP & Calprotectin monitoring. Monitoring to allow early detection of relapse when they are more likely to respond to therapeutic intervention. If you stopped aza before TNF drug & Ab monitoring Rescue strategy.
- In conclusion there is no satisfactory effective therapy for IBD till now. Conventional step care therapy has failed to modify the natural course of IBD. New strategies have shown better results. These strategies are the pillars of the modern therapeutic Approach: Early effective therapy for high risk pts, Treat to target, Tight control & Exit strategies.