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Immunosuppressive Medications and IBD: Now and What’s Next

Immunosuppressive Medications and IBD: Now and What’s Next. Stephen B. Hanauer, MD University of Chicago. Indications for Immunosuppressives in IBD. Crohn’s Disease Steroid-Sparing (Maintenance) Maintenance after Biologics Reduction of Immunogenicity Post-Surgical Maintenance

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Immunosuppressive Medications and IBD: Now and What’s Next

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  1. Immunosuppressive Medications and IBD: Now and What’s Next Stephen B. Hanauer, MD University of Chicago

  2. Indications for Immunosuppressives in IBD • Crohn’s Disease • Steroid-Sparing (Maintenance) • Maintenance after Biologics • Reduction of Immunogenicity • Post-Surgical Maintenance • Ulcerative Colitis • Steroid-Sparing

  3. Conventional approach to Induction Therapy: step-up • Clinical approach to use “mildest” form of drug therapy to treat patients first • Move to next step in non-responders Anti TNF-α therapiesSurgery Disease severity Systemic corticosteroids AminosalicylatesNon-systemic corticosteroids Time

  4. Step-up management approach • Advantages • Patients attain remission with less toxic therapies • Potentially more toxic therapies reserved for more severe or refractory disease • Minimizes risk of adverse events • Cost sparing (short-term?) • Disadvantages • Patients have to “earn” most effective treatments • Decrease in quality-of-life before patients obtain optimal therapy • Likelihood of surgery is high • Disease is not modified

  5. IBDs are chronic, life-long We cannot just look at the short-term induction therapy

  6. Long-Term Therapy for IBD is Sequential InductionMaintenance

  7. Maintenance Therapy is Dictated by Induction Therapy InductionMaintenance Aminosalicylate Aminosalicylate

  8. Maintenance Therapy is Dictated by Induction Therapy InductionMaintenance Aminosalicylate (UC) Thiopurine Methotrexate (CD) Corticosteroid

  9. Maintenance Therapy is Dictated by Induction Therapy InductionMaintenance Cylcosporine Thiopurine

  10. Maintenance Therapy is Dictated by Induction Therapy InductionMaintenance Thiopurine (Steroid-Naïve) Anti-TNF Anti-TNF (Steroid-Refractory)

  11. Maintenance Therapy is Dictated by Induction Therapy InductionMaintenance Natalizumab Natalizumab

  12. “Natural History” of Disease Behavior in CD 100 90 Progression Toward Surgery 80 70 60 Penetrating 50 Cumulative Probability (%) 40 Inflammatory 30 Stricturing 20 10 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: 95 2002 552 229 37 N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

  13. Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression High Potential Low Potential 100 90 80 70 60 Penetrating 50 Cumulative Probability (%) 40 Inflammatory 30 Stricturing 20 10 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: 95 2002 552 229 37 N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

  14. Difference between Early & Late Intervention with Immunosuppressants

  15. 60% exposed to IS therapy No Change in Surgery Rates

  16. 80 60 40 20 0 Efficacy of AZA as Crohn’s Disease Maintenance TherapyAfter Steroids in Adults* 100 AZA 2.5 mg/kg per d Placebo % Patients Not Failing Trial 42% p=0.001 7% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Duration of Trial (months) *Remission induced by prednisolone tapered over 12 wk Inclusion: Patients were not steroid dependent Candy S, et al. Gut. 1995;37(4):674-678.

  17. Efficacy of 6-MP as Crohn’s Disease Maintenance TherapyAfter Steroids in Steroid-naïve Children 6-MP 91% P<.007 Control 53% N=55 At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission. Markowitz J et al. Gastroenterology. 2000;119:895.

  18. Dosing Considerations with Thiopurines

  19. AZATHIOPRINE/6-MERCAPTOPURINE 6-methyl-mercaptopurine (6-MMP) TPMT IMDPH GMPS HPRT Azathioprine 6-mercaptopurine Thioinosinic 6-thioguanine (AZA) (6-MP) acid (6-TG) XO 6-thiouricacid

  20. Distribution of Thiopurine Methyltransferase Enzyme Activity in the Population 12 % of Subjects/0.5 units of Activity TPMTH TPMTH 10 8 TPMTL TPMTH 6 4 TPMTL TPMTL 2 0 0 5 10 15 20 Erythrocyte TPMT Activity (UmL-1) Weinshilboum. Am J Hum Genet. 1980

  21. Early Evidence with Allopurinol HEPATOXICITY 6-MMP HPRT,IMDPH,GMPS ↑↑ACTIVITY 6-MP 6-TG X0 6-thiouric INACTIVE Sparrow & Hanauer DDW 2005

  22. CONTROVERSIES REGARDING THERAPEUTIC DRUG MONITORING • No Prospective Data • Time Course to AZA/6-MP Activity > 8-12 weeks • Sandborn I.V. Loading trial • Mechanisms of Action of 6-MP? • Relationship of 6-MMP to Bone Marrow  • Also of 6-Thioguanine to Bone Marrow  • Cost Effectiveness vs. Clinical Monitoring with WBC

  23. Indications for Therapeutic Monitoring • Primary Dosing Regimens • Aim for target levels • Expensive • Assessment of Non-Responders or Elevated Transaminases • Consistent with current practices • May be more cost-effective • Assessment of Adherence • Pediatrics

  24. SUMMARY • Pharmacogenitic Considerations are Important for IBD Therapeutics • Therapeutic Drug Monitoring May Offer Improvements If: • Prospectively Demonstrated • Superior Safety and Efficacy to Clinical and Routine Laboratory Monitoring

  25. Optimizing Dose of ThiopurinesConsider Pharmacology & TPMT Status • TPMT Homozygotes • Start very low (e.g. 25 mg, 2-3 times/week) • TPMT Heterozygotes • Start low dose (~1 mg/kg) • TPMT Normal • Start 2.5 mg/kg • TPMT High (abnormal LFTs, ↑6MMP) • Consider reducing dose & adding allopurinol

  26. Multicenter, randomized, controlled trial 76 steroid-dependent patients In remission following methotrexate 25 mg IM x 16 weeks Randomized to 15 mg IM or placebo x 40 weeks 65% of 45% responders= 30% overall Methotrexate Maintenance after Steroids in Crohn’s Disease 100 90 80 70 60 50 40 30 n=40 % Remission 65% n=36 Methotrexate Placebo 39% 0 4 8 12 16 20 24 28 32 36 40 Weeks since randomization Feagan B, et al. N Engl J Med 2000.

  27. All biologics are immunogenic Antibodies (at least to infliximab) Associated with acute/delayed infusion reactions Shorter duration of response (with episodic therapy) Immunomodulators reduce immunogenicity across all trials Yet… No difference in short- or long-term responses to induction + maintenance therapy Increase toxicity Serious infections Risk of neoplasia Yin & Yang of Concomitant Immunomodulators

  28. Do Concomitant Immune-modulators Improve Efficacy of Infliximab in CD and UC? IMM - IMM + Ulcerative colitis % patients ACT I 54 wk Response ACT I 54 wk Remission ACT I 54 wk Hosp ACT II 30 wk Response ACT II 30 wk Remission ACT II 30 wk Hosp All p-values = NS Crohn’s disease % patients ACCENT I 54 wk Response ACCENT I 54 wk Remission ACCENT I 54 wk Hosp ACCENT II 54 wk Response ACCENT II 54 wk Response Lichtenstein GR, et al. DDW 2007. #982

  29. CHARM: Concomitant adalimumab and immunosuppressive therapy DO NOT impact on remission at week 56 Patients in remission (%) Placebo 100 Adalimumab 40 mg EOW, sc Adalimumab 40 mg q-weekly, sc 50 39 37 33 13 12 0 131 136 121 39 36 36 With IMM Without IMM Week 56 Remission defined as CDAI <150 Colombel et al, Gastroenterology 2007; 132: 52

  30. 0 PRECiSE 2: Concomitant certolizmab pegol and immunosuppressive therapy DO NOT impact on Clinical response at week 26 Patients (%) 100 Certolizumab pegol (3 injections) + placebo *** *** 64 61 Certolizumab pegol q-4w 400 mg, sc 39 33 0 (n=124) (n=128) (n=86) (n=87) With IMM Without IMM ***p<0.001 CR100 Schreiber et al, N Engl J Med 2007; 357: 239

  31. 70 60 58 60 54 53 50 40 Percent 31 30 30 23 21 20 10 0 ENACT-2 Concomitant immunosuppressive DO NOT impact onRemission at 6 or 12 Months P≤0.009 for all comparisons with placebo Placebo Natalizumab (62) (111) (62) (60) (60) (106) (111) (106) - IMM + IMM - IMM + IMM Month 12 Month 6 Sandborn W, Colombel J-F, Enns R, et al. Presented at: DDW 2006; May 20-25, 2006; Los Angeles, CA.

  32. COMMITT: MTX plus IFX in CD (1) Methods: Randomized, double blind, PBO-controlled trial Patients with active CD on corticosteroids within last 6 weeks 1:1 randomization to IFX + PBO (n=63) IFX + MTX (dose escalation: 10 mg,10 mg, 20 mg, 25 mg) (n=63) Steroids withdrawn by Week 14 per protocol IFX at 0, 2, and 6 weeks then maintenance q8W Primary analysis: time to treatment failure CDAI <150, no prednisone by Week 14 and maintained to Week 50 Relapse: CDAI increase of 70 points Feagan B, et al. DDW 2008: #682C

  33. COMMITT: MTX plus IFX in CD (2) p=0.83 p=0.63 • No difference in ITT analysis, duration of disease <2 years, by CDAI score • No difference in infectious AEs (58.7% MTX vs 61.9% PBO) Feagan B, et al. DDW 2008: #682C

  34. What about stopping Immunomodulators?

  35. IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab Therapy Week 104 Randomization (N=80) Continued IMM (n=40) Discontinued IMM (n=40) Patients treated with AZA, 6-MP, or MTX plus IFX 5 mg/kg and in clinical remission for ≥6 months Percentage of patients requiring a change in IFX dosing or who discontinued IFX 6-MP=6-mercaptopurine; AZA=azathioprine; IFX=infliximab; IMM=immunomodulator therapy with AZA, 6-MP, or MTX; MTX=methotrexate Van Assche G, Paintaud G, Magdelaine C, et al. Gastroenterology. 2007;132:A-103. [Abstract #734]

  36. IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab Therapy No need for early ‘rescue’ IFX: primary endpoint Median IFX levels, Week 8 to Week 104 combined Cumulative survival IFX trough levels (μg) 1.0 100 p<0.005 Log Rank (Cox): 0735; Breslow: 0.906 0.8 0.6 10 0.4 Continued Discontinued 0.2 1 0.0 0 0 20 40 60 80 100 Continued Discontinued Time (weeks) Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)

  37. Risks Associated With Long-term Use of Immunosuppressants (AZA/6-MP)1,2 • Overall toxicity 15% • Pancreatitis 3.3% • Bone marrow depression (leukopenia) 2-5% • Allergic reactions 2% • Drug hepatitis 0.3% • Infectious complications 7.4% • Malignant neoplasm 3.1% • Opportunistic infections • Lymphoma • Associated with ≥fourfold increase in risk of EBV (+) lymphoma and prior treatment with AZA/6-MP • 1 additional lymphoma will occur every 300 to 4,500 years after therapy with AZA or 6-MP, depending on patient age • Consistent with RA reports Lymphoma Occurrence in IBD Patients Increased in the 8-year Period After Introduction of AZA and 6-MP Patients (%) EBV=Epstein-Barr virus Lag time observed between AZA/6-MP treatment and lymphoma development (median, 3.5 years) 1. Present DH, Meltzer SJ, Krumholz MP, et al. Ann Intern Med. 1989;111:641-649. 2. Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Gastroenterology. 2002;122:72-77.

  38. Opportunistic infections and anti-TNF therapies : Ex: from Risk Factors for Opportunistic Infections in IBDA Case-Control Study of 100 Patients (1998-2003) Toruner M, et al. Gastroenterol. 2008.

  39. Infliximab + Azathioprine in Patients WithActive Steroid Dependent Crohn’s Disease • 115 pts active CD (CDAI >150) despite treatment with prednisone 10 mg/d for 6 mo • Stratified for pre-study use of AZA/ 6-MP for > 6 mo, or no prior AZA/6-MP • All treated with AZA 2 to 3 mg/kg or 6-MP 1 to 1.5 mg/kg • Randomized to infliximab 5 mg/kg or placebo at 0, 2, 6 weeks • Steroids systematically tapered • Primary endpoint: % clinical remission & off steroids at Week 24 • No difference in outcome for AZA/6-MP treated and naive patients P<0.001 P=0.003 P=0.04 Lemann. Gastroenterology. 2006

  40. Conventional Treatment of UC: Immunomodulators • Immunomodulators are effective for maintenance of remission, but not induction • Blinded, controlled clinical trial data are limited compared to CD

  41. AZA Withdrawal in Patients With UC Who Required AZA to Achieve Remission P=.04 N=79 Randomized controlled trial of patients who had been receiving AZA for 6 months Hawthorne AB et al. BMJ. 1992;305:20.

  42. AZA vs 5-ASA for Steroid-Dependent, Active UC P=.006 † N=72 *Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score  1) plus steroid discontinuationPatients treated with concurrent tapering dose of steroids † 0.8 g at breakfast and lunch and 1.6 g at dinner Ardizzone S et al. Gut. 2006;55:47.

  43. Conventional Treatment: CsA • CsA is effective for induction of remission in severe UC • CsA has demonstrated little efficacy for maintenance of remission • Use is limited due to significant safety concerns

  44. Intravenous CsA: Severe Active Steroid-Refractory UC P<.001 * N=20 *Lichtiger score <10 points for 2 consecutive days Lichtiger S et al. N Engl J Med. 1994;330:1841.

  45. 65% 42% 90% 56 responders to CsA Oxford 1996 to 2003 76 patients with severe UC CsA Use in Acute UC: Long-Term Experience Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79.

  46. Avoidance of Colectomy with Azathioprine After CYSA Induction Probability of Avoiding Colectomy Cohen, Stein, Hanauer. Am J Gastroenterol 1999;94(6):1587-1592

  47. Cyclosporine as a “Bridge” to Azathioprine Maintenance in UC Study No. CYA Initial Sustained Sustained Dose Response Response Response on AZA no AZA Fernandez 13 4 mg/kg IV 12/13 7/8 1/4 Ramkrishna 6 1-2 mg/kg IV 5/6 4/5 0/1 Cohen 42 4 mg/kg IV 36/42 20/25 6/11 Rowe 36 2.5 mg/kg IV 26/36 7/19 5/7 Stack 22 4 mg/kg IV 20/22 7/10 5/10 ____ ___ ___ 99/119(83%) 45/67(67%) 17/33(51%)

  48. Cyclosporine Use in Acute Ulcerative Colitis: Long-Term Experience 142 patients with severe acute UC treated with IV CyA 118 (83%) responded 44 patients (31%) were on AZA, 74 (52%) were started de novo At 1 year, 23/44 (52%) of patients on AZA required colectomy compared with 12/74 (16%) starting AZA Moskowitz. Gastroenterology 2005 Abstract

  49. Anti-TNF is more efficacious than conventional therapies Anti-TNFs are safer than conventional therapies (Corticosteroids) May be more cost-effective (over time) than conventional therapies Conventional Therapies Induce/Maintain Remissions in majority of patients Majority of patients do not need cost/toxicity risks of biologics Long-term safety experience in children & pregnancy Can we transition back to conventional immune modulators as in RA? Should Biologics be used Earlier in IBD?

  50. When to Introduce Biologics? The “Tipping Point” may be Corticosteroids?

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