5-ASA Therapy, Steroids and Antibiotics in Inflammatory Bowel Disease

Transcription

1 5-ASA Therapy, Steroids and Antibiotics in Inflammatory Bowel Disease David T. Rubin, MD Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center University it of Chicago Medical Center

2 Relevant Disclosures P t d G bl Ph ti l Procter and Gamble Pharmaceuticals: consulting and grant support Salix Pharmaceuticals: grant support Shire Pharmaceuticals: consulting

3 Treatment Goals 2008 and beyond CURRENT Early accurate diagnosis Rapid effective induction of remission Stable steroid-free maintenance of remission Prevention of complications Disease related Therapy related Improved quality of life NEAR FUTURE. Incorporation of mucosal healing into plans for better outcomes Understanding of the right therapy at the right time (use of prognostic markers and individualized therapies early in disease course)

4 Outdated Therapeutic Pyramids Crohn s Disease Ulcerative Colitis Surgery Infliximab Fulminant Severe Surgery MTX AZA/6-MP Systemic Steroids Moderate Cyclosporine Infliximab Systemic Corticosteroids Budesonide Antibiotics 5-ASA Mild Aminosalicylates

5 Conventional Therapeutic Approach Severity and safety dictate t first line therapies NOT prognosis or likelihood of response Patients have to prove they need something stronger or riskier The chronicity of the disease is sometimes an afterthought Induction therapy dictates choice of maintenance therapy Better long term outcomes are an added bonus Usually less expensive (in the short run)

6 5-ASA Therapy in IBD Effective in induction and maintenance of mild-moderate UC May have benefit in mild CD- insufficient evidence Evolution from multiple l doses per day to single dose Simplified dosing regimen = increased patient adherence Topical therapy plus oral therapy is better than oral alone Unclear whether switching is effective Chemopreventive benefits

7 Details of Mesalamine Delivery Systems Sulfasalazine NHSO 2 COOH Olsalazine N N N=N 5-ASA CH 5-ASA N=N 5-ASA Sulfapyridine Mesalamine Controlled-release capsules Mesalamine Delayed-release capsules (Asacol) Mesalamine Gastro-resistant/pH (Lialda) Mesalamine Rectal suspension enema/ suppository Balsalazide disodium capsules NaOOC 5-ASA 5-ASA 5-ASA 5-ASA (ABA) inert carrier OH Ethylcellulose Microspheres Eudragit S MMX technology 5-ASA

8 Oral Mesalamine for mild-tomoderate UC Response (%)* Study Disease Status Placebo Mesalamine (g) Schroeder 1 (6 weeks) Sninsky 2 (6 weeks) Hanauer 3 (6 months) Active 18 (n=38) Active 23 (n=52) Maintenance 48 (n=87) 63 (n=90) 27 (n=11) 43** (n=53) 70 (n=87) 49*** (n=53) 74 (n=38) *Response defined as Schroeder: Combined complete and partial response Sninsky: Patients who improved and were in remission Hanauer: Maintenance of remission 1 Schroeder, et al. N Engl J Med **P=0.03, ***P=0.003, P=0.05, P=0.005 Sninsky, et al. Ann Internal Med Hanauer, et al. Ann Internal Med

9 Granulated Mesalamine: ITT Population Kaplan-Meier Plot of Relapse-Free Duration 1.00 Granulated Mesalamine 1.5 g/d 0.75 Placebo ty Probabilit p< Lichtenstein, et al. ACG Days

10 Delayed-Release Mesalamine: Dose Response at Week 6 Treatment Week 6 (%) Patients With T Success at W ASCEND II 1 ASCEND III 2 Mild UC (n=110) Moderate UC (n= 254) P<0.05 P=NS g/day 4.8 g/day Delayed-Release l Mesalamine* Treatment Week 6 (%) Patients With T Success at W Moderate UC (n= 772) 66 P=NS 70 * Asacol 2.4 g/day 4.8 g/day Delayed-Release l Mesalamine* 1. Hanauer SB et al. Am J Gastroenterol. 2005;100: Sandborn WJ et al. DDW 2008.

11 Dose Response at Week 8: Delayed Release Mesalamine in Mild to Moderate UC Patient s in Clinical and Endoscopic Remission at Week 8 (%) 100 Kamm et al 1 90 Lichtenstein et al * P-values represent active treatment vs. placebo Lialda Placebo P=0.01* P=0.007* P<0.001* 2.4 g/day 29 P=0.009* 4.8 g/day Delayed Release Mesalamine 1. Kamm MA et al. Gastroenterology. 2007;132: Lichtenstein GR et al. Clin Gastroenterol Hepatol.2007;5:95.

12 Treatment of Distal UC: Oral and Topical Mesalamine Therapy Patients Rep porting No Rectal Blee eding (%) Oral (2.4 g/d) Rectal (4 g/d) Combined * 0 6 Weeks *P<0.002 vs oral alone, P=0.04 vs topical alone. Adapted from Safdi M et al. Am J Gastroenterol. 1997;92:1867.

13 Extensive Mild/Moderate UC: Oral and Rectal Mesalamine Therapy No. of Patien nts (%) P=NS Remission P= Improvement Mesalamine 4 g total PO (in divided doses; 2 g BID) + mesalamine enema 1 g HS (N=71) Mesalamine 4 g total PO (in divided doses; 2 g BID) + placebo enema HS (N=56) Week 4 Marteau P et al. Gut. 2005;54:960.

14 Meta-Analysis of Mesalamine* (4 g/day) in Active Crohn s Disease 0 0 Change From Baseline in CDAI Score P= P= P=0.005 P= P=0.005 P=0.7 P=0.05 P=0.04 Crohn s I n=155 Crohn s II n=150 Crohn s III n=310 Overall n=615 Crohn s I n=155 Crohn s II n=150 Crohn s III n=310 Overall n=615 Mesalamine* 4 g Placebo Mesalamine* 4 g minus placebo *Controlled-release capsules Hanauer S et al. Clin Gastroenterol Hepatol. 2004;2:379.

15 Mesalamine Maintenance of Remission in Crohn s Disease Study Year Pts (n) Caprilli McLeod Brignola Sutherland Overall 411 Thomson Prantera Brignola Gendre Bresci Thomson Arber Modigliani Sutherland De Franchis Overall 1, Favors Treatment Favors Control Risk Difference 95% CI Adapted from Cammà C et al. Gastroenterology. 1997;113: with permission from American Gastroenterological Association.

16 Does It Matter Which Aminosalicylate Is Used? Deliver to area of disease Insurance and adherence issues Don t settle for less than remission! Rationale that delivery system may make a difference, but untested/unproven e Oral aminosalicylates share more than they differ Pharmacokinetics Clinical efficacy Adverse events Different for prodrugs Sulfapyridine Looser stools Monitor renal function for all

17 Corticosteroid Therapy in IBD Effective in UC and CD The need (or choice) of steroids is a prognostic marker May represent a tipping point needing other therapies for maintenance Have an exit strategy! Systemic corticosteroids demonstrate substantial toxicity at higher doses and for longer periods of time The development of non-systemic steroid formulations provide benefit with less toxicity

18 Corticosteroid Therapy Study Truelove 1 (6 weeks) Disease State Active Steroid/ Dose Response (%)* Cortisone 100 mg Steroid 69 (n=109) Placebo 41 (n=101) Lennard- Jones 2 (6 months) Truelove 3 (5 days) Maintenance Prednisone 15 mg Severely Prednisolone (5 days) active 60 mg (Total n=49) 38 (n=34) 40 (n=35) 73 N/A *Response defined as Truelove: Patients who improved and were in remission Lennard-Jones: Maintenance of remission Truelove: Patients in remission 1 Truelove, et al. Br Med J. 1955;2: Lennard-Jones, et al. Lancet. 1965;1: Truelove, et al. Lancet. 1974;1:1067.

19 NCCDS: Response to Therapy for Crohn s Disease Remission Maintenance Prednisone 1/4 mg/kg (20 mg) Sulfasalazine 1/2 g/kg (2.5 g) Azathioprine 1 mg/kg (75 mg) Placebo Months After Randomization 24 Summers RW et al. Gastroenterology. 1979;77:847.

20 Corticosteroids: Short- and Long-Term Efficacy in UC 1-Month Outcomes* (n=63) Complete Remission 54% (n=34) Partial Remission 30% (n=19) ( ) ( ) No Response 16% (n=10) 1-Year Outcomes (n=63) Prolonged Response 49% (n=31) Steroid Dependent 22% (n=14) Surgery 29% (n=18) *30 days after initiating corticosteroid therapy Faubion W, et al. Gastroenterology. 2001;121:255.

21 Corticosteroids: Short- and Long- Term Efficacy in Crohn s Disease 30-Day Responses (n=74) Complete 58% (n=43) Partial 26% (n=19) None 16% (n=12) 1-Year Responses (n=74)* Prolonged response 28% (n=21) Steroid dependent 32% (n=24) Surgery 38% (n=28) *1 patient lost to follow-up Faubion WA Jr. et al. Gastroenterology. 2001;121:255.

22 Mortality Associated with Current and Recent Corticosteroid Use Adjusted HR (95% CI) 5 4 Hazard Ra atio % CI: ( ) 95% CI: ( ) Current Use of Corticosteroids Recent Use of Corticosteroids Lewis JD, et al. Am J Gastroenterol. 2008;103:

23 Oral Budesonide: Efficacy as Maintenance Therapy Cumulative Probability of Remis ssion Budesonide 6 mg Budesonide 3 mg Placebo Time (Days) Adapted from Greenberg GR et al. Gastroenterology. 1996;110:45-51 with permission from American Gastroenterological Association.

24 Antibiotic Therapy in IBD Less rigorously studied Crohn s disease: Infectious complications Peri-anal disease Crohn s colitis Prevention of post-op recurrence Small bowel bacterial overgrowth Ulcerative colitis: No convincing evidence of primary efficacy Prophylaxis when on cyclosporine therapy Pouchitis

25 Therapy of Active Crohn s Disease 150 p= p=ns Placebo Metronidazole Change in CDA AI p= Small intestine n=24 No difference in clinical remission rates. Sutherland L, et al. Gut. 1991;32(9): Small/Large intestine n=31 Large intestine n=8

26 Antibiotics in Active CD 70 Patients in Re emission (%) Metro + Cipro vs Me-Pred 1 Metro vs SASP 2 Cipro vs Mesalamine 3 * *Mesalamine controlled-release capsules Metro, metronidazole; Me-Pred, methylprednisolone; Cipro, ciprofloxacin; SASP, sulfasalazine 1. Prantera C et al. Am J Gastroenterol. 1996;91: Ursing B et al. Gastroenterology. 1982;83: Colombel JF et al. Am J Gastroenterol. 1999;94:674.

27 Ornidazole Post-op Prophylaxis in Crohn s Disease % of Recur rrence p=0.09 p= % 59% p= % 79% p=.1 p= p=.002 p=ns p=< % 37% 27% 45% Ornidazole Placebo p=.27 p=s 35% 48% N= Months 12 Months 12 Months 24 Months 36 Months Endoscopic Clinical Rutgeerts P, et al. Gastroenterology Apr;128(4):

28 Antibiotics in Pouchitis Uncontrolled trials: Oral metronidazole or ciprofloxacin: 96% response 1 Local metronidazole ( mg/d per rectum): 11/11 patients responded 2 Oral rifaximin (1 g BID) + ciprofloxacin (500 mg bid): 3 86% improvement in refractory disease 3 Controlled trial: metronidazole (400 mg PO TID): stool frequency, no change endoscopy 4 1. Hurst RD, et al. Arch Surg. 1996;131: Nygaard K, et al. Scand J Gastroenterol. 1994;29: Gionchetti P, et al. Gastroenterology. 1997;119:A Madden MV, et al. Dig Dis Sci. 1994;39:

29 Conclusions: 5-ASA, Steroids and Antibiotics in IBD 5-ASA therapy is effective for induction and maintenance of UC, limited in CD Topical therapy is effective for distal and additive in extensive UC. There does not appear to be a dose-response for oral 5-ASA in UC. Simplified dosing regimens and delivery systems have provided many options for patients and providers. Corticosteroids remain effective induction agents in UC and CD Should be considered markers of disease prognosis and paired with effective maintenance strategies. Limited by toxicity- non-systemic steroids provide new options. Broad-spectrum antibiotics have an important role in infectious complications of IBD and for pouchitis Despite interest in the infectious cause of IBD this remains elusive.