Mucosal Healing in Crohn s Disease Geert D Haens MD, PhD University Hospital Gasthuisberg University of Leuven Leuven, Belgium
Mucosal Lesions in CD: General Features CD can affect the entire GI tract CD is a segmental disease CD is a transmural disease Mucosal lesions > endoscopic samples Deeply situated lesions > surgical samples
Microscopic Features in CD: Early Lesions Early lesions occur in a background of normal mucosa (focal lesions) Types Summit lesions : damage of small capillaries and loss of epithelial cells Epithelial patchy necrosis Mucosal microulcerations (loss of up to 6 cells) Aphthoid ulcer Mountain peak ulcer : ulcers at the base of crypts
Crohn s disease : Microscopic features & Diagnosis Epithelial alterations Cytological changes > damage & repair Architectural changes Metaplastic changes Inflammatory response Intensity Composition Distribution
Treatment of CD: Is Mucosal Healing Important? Prolongs remission duration? Prevents complications, eg, stenosis, fistulas, growth failure, and cancer? Reduces rate and limits scope of surgical intervention? Improves quality of life long term? Changes the natural history of the disease?
Healing of the Bowel as Primary Endpoint of Treatment in CD Altering the course of IBD is only possible when healing of the bowel is induced and maintained long term Sustained healing could result in avoidance of complications and maintained quality of life Candidate drugs for induction of healing: rapid healers : corticosteroids, infliximab, newer biologicals slow healers : azathioprine/6-mp, MTX
Endoscopic Healing With Steroids at 7 Weeks in CD 100 80 71% Patients* (%) 60 40 29% 93/131 20 38/131 0 9% 12/131 Remission No Remission Endoscopic Status Worsened *Among patients with clinical remission, n=131 Modigliani R et al. Gastroenterology. 1990;98:811.
Steroids: endoscopic healing and risk of clinical relapse 100% 92% 80% 80% 65% 65% 60% In endoscopic remission (n=52)* 40% Not in endoscopic remission (n=80)* 20% 0% Weaned from pred Relapse at 18 mo *After 3-12 weeks of prednisone (1mg/kg/d) Landi B et al. Gastroenterology. 1992;102: 1647-53.
Effect of budesonide and azathioprine on endoscopic lesions after 12 months (randomised trial) CDEIS 7 6 5 4 3 2 1 0 At inclusion Bud Aza Endoscopic remission 100% 80% 60% 40% 20% 0% 24% Bud 73% N=39 N=38 N=39 N=38 From Mantzaris et al, DDW 2002 Aza
Endoscopic Healing With Azathioprine in CD Demonstrated after a minimum of 6 months therapy in: Postoperative recurrent inflammation Primary colitis and ileocolitis
Randomised,, double-blind, blind, placebo-controlled, controlled, multicenter azathioprine withdrawal trial in Crohn's disease Lemann et al, DDW 2002 Azathioprine Start of azathioprine therapy 42 months Randomisation N=83 18 months Clinical remission prednisone < 10 mg/d ENDOSCOPY N=45 Placebo
Proportion of patients in remission on azathioprine/placebo 1,0 0,8 0,6 0,4 Remission (months) mean ± SE Azathioprine 17.3 ± 0.5 Placebo 15.9 ± 0.7 0,2 0,0 Months after randomization Patients at risk (relapses) 0 6 12 18 40 38 (1) 34 (2) 23 (3) Aza 43 40 (3) 35 (7) 27 (9) Placebo (Lémann et al, DDW 2002)
Endoscopic lesions after 42 months of remission on azathioprine 14 100% 12 80% CDEIS 10 8 6 No ulceration 60% 40% 46% 62% 4 2 20% 0 Azathioprine Placebo 0% Azathioprine Placebo N=24 N=21 Lémann et al, N=39 Gastroenterology, N=38 in press
Mucosal healing with infliximab
Crohn s disease : Healing with Infliximab before Week 4
Colon TNF stain before Week 4
ColonIcam-1and LFA-1stains (courtesy K. Geboes)
Endoscopic Healing With Infliximab 100 95% 96% % Resolution of Ulceration 80 60 40 20 74% 79% 77% 0 Ileum Ascending Colon Transverse Colon Descending Colon Rectum D Haens G et al. Gastroenterology. 1999;116:1029.
Endoscopic Healing With Infliximab in CD Change From Baseline in CDAI 100 50 0-50 -100-150 -200 Placebo Infliximab -250 r=0.561-300 P=0.002-350 -20-18 -16-14 -12-10 -8-6 -4-2 0 2 Change From Baseline in CDEIS D Haens G et al. Gastroenterology. 1999;116:1029.
Infliximab Maintenance Therapy for CD: ACCENT I Design: 1-y, multicenter, randomized, double-blind Patients: N=573 Adults with moderately to severely active CD (median CDAI=297) Treatment: Initial: Single 5 mg/kg infliximab infusion Maintenance regimen: Placebo; 5 mg/kg infliximab, or 10 mg/kg infliximab Episodic retreatment: Patients who lost response; +5 mg/kg over maintenance dose Endpoints: Clinical response and remission Steroid-sparing efficacy Endoscopic healing
ACCENT I: Endoscopic Substudy Patients: n=99 Endoscopic Assessment: 25 selected European sites 2-wk responders and recipients of episodic retreatment Crohn s Disease Endoscopic Index of Severity (CDEIS) Wk 0, 10, and 54 Definition of Healing: Mucosal ulceration at Wk 0 and no mucosal ulceration at follow-up
ACCENT I Infliximab: Endoscopic Healing* Single dose Patients Demonstrating Endoscopic Healing (%) 70 60 50 40 30 20 10 0 P=0.007 P=0.026 53% 46% P=0.010 31% 7% 0/17 10/32 1/14 5/11 8/15 Week 10 Week 54 Combined dose group (5 mg/kg & 10 mg/kg infliximab maintenance) 5 mg/kg infliximab maintenance 10 mg/kg infliximab maintenance *Among Week-2 responders (n=66) Rutgeerts P et al. Gastroenterology. 2002;122(suppl):A-618.W1367.
Recurrence of ulcers in the same locations as pre-infliximab over night
Stenosis as a complication of healing
Complete ileal healing
ACCENT I Infliximab: Endoscopic Healing and Risk of Clinical Relapse 25 Median Time to Clinical Relapse (Week) 20 15 10 5 12 20 19 4 0 All n=19 Complete Incomplete n=9 n=6 Endoscopic Healing None n=4 D Haens GR et al. Gastroenterology. 2002;122(suppl):A-100.776.
ACCENT I Infliximab: Endoscopic Healing and Reduced Hospitalization and Surgeries Rate of Hospitalizations and Surgeries (%) 50 40 30 20 10 46% 25% 8% Patients with no healing (n=74) Patients with healing at 1 visit (10 or 54 wk) (n=16) Patients with healing at both visits (10 and 54 wk) 0 (34*) (4*) (6*) 0% Hospitalization 0% Surgery 0% *Number per 100 patients Rutgeerts P et al. Gastroenterology. 2002;123(suppl):43.M2138.
ACCENT I Infliximab: Endoscopic Healing and Reduced Hospitalization Patients Hospitalized (%) 30 25 20 15 10 5 0 24.3% 18.8% 0% No healing Healing at 1 visit Healing at both visits n=17 n=16 n=9
ACCENT I Infliximab: Endoscopic Healing and Reduced Surgeries Patients Undergoing Surgery (%) 6 5 4 3 2 1 0 5.4% 0% 0% No healing Healing at 1 visit Healing at both visits n=74 n=76 n=9
Mucosal healing Effect of different drugs % of mucosal healing 100 90 80 70 60 50 40 30 20 10 0 6 10 52 250 weeks Prednisone (Modigliani et al) Budesonide (Mantzaris et al) Azathioprine (Mantzaris et al, Lémann et al) Infliximab (Rutgeerts et al)
Mucosal healing Effect of different drugs 5-ASA Antibiotics Steroids Azathioprine Methotrexate Infliximab Natalizumab CNI-1493 Unknown Unknown Limited Yes (slow) Yes? Yes (rapid?) (YES) Yes (rapid)
Mucosal Healing in CD: novel agents Natalizumab (anti-alpha4-antibody Antegren): currently under study Etanercept: little clinical benefit, no endoscopic nor histological changes observed Map-kinase inhibitors
NATALIZUMAB (Antegren ) in CD Multinational study with 905 pts / 59 in colonoscopy substudy 12 sites N= 42 Antegren 300 mg IV w 0,4 and 8 N=15 placebo Colonoscopy at week 0 and 10 50 % reduction in CDEIS with ANT vs 7 % with PLAC Ulcer-free pts at week 10: 22 % ANT vs 8 % with PLAC Strong correlation histological / endoscopic improvement Rutgeerts et al., Gastroenterology 2004 (abstr)
Immunomodulation and healing in Crohn s Disease Biologicals: -Anti-TNF - Anti-IL12 -Anti-IFN -etc. IL-12 IL-1 TNF IFN IL-18 Small Molecules: - MAPK inhibitors (CNI-1493) - p38 inhibitors - JNK inhibitors Transcription Factor: - Corticosteroids - Thalidomide
Disease Modification in CD: Unanswered Questions What are the clinical benefits of mucosal healing? Improved quality of life? Longer duration of clinical remission? Limited need for or scope of surgery? Decreased complications (eg, growth failure)? Should therapies that provide mucosal healing be introduced earlier in the disease course? Post diagnosis? Post surgery? How will the next generation of therapies perform?