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 Ulcerative Colitis Steroid-Sparing

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

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

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

Long-Term Therapy for IBD is Sequential InductionMaintenance

Maintenance Therapy is Dictated by Induction Therapy Induction Maintenance Aminosalicylate Aminosalicylate

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

Maintenance Therapy is Dictated by Induction Therapy Induction Maintenance Cylcosporine Thiopurine

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

Maintenance Therapy is Dictated by Induction Therapy Induction Maintenance Natalizumab Natalizumab

“Natural History” of Disease Behavior in CD 100 90 Progression Toward Surgery 80 70 60 Penetrating Cumulative Probability (%) 50 40 Inflammatory 30 Stricturing 20 10 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

Cumulative Probability (%) Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression High Potential Low Potential 100 90 80 70 60 Penetrating Cumulative Probability (%) 50 40 Inflammatory 30 Stricturing 20 10 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk: N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

Difference between Early & Late Intervention with Immunosuppressants

60% exposed to IS therapy No Change in Surgery Rates

% Patients Not Failing Trial Duration of Trial (months) Efficacy of AZA as Crohn’s Disease Maintenance Therapy After Steroids in Adults* 100 AZA 2.5 mg/kg per d Placebo 80 60 40 20 % Patients Not Failing Trial 42% p=0.001 7% 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.

Efficacy of 6-MP as Crohn’s Disease Maintenance Therapy After Steroids in Steroid-naïve Children 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.

Dosing Considerations with Thiopurines

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-thiouric acid

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

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

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

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

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

Optimizing Dose of Thiopurines Consider 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

Methotrexate Maintenance after Steroids in Crohn’s Disease 100 90 80 70 60 50 40 30 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 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.

Yin & Yang of Concomitant Immunomodulators 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

Do Concomitant Immune-modulators Improve Efficacy of Infliximab in CD and UC? Ulcerative colitis % patients Pts were not randomised to IMMs, biased by indication Methods: Comparison of efficacy data with and without IMMs in IFX pivotal trials (ACCENT I, ACCENT II, ACT I and II) Results: Response and remission rates did not differ significantly when IFX was used with and without concomitant IMMs While there was a trend in favor of concomitant immunomodulators in some trials, there was a trend against them in other trials Three of the four trials showed a trend toward fewer hospitalizations when concomitant immunomodulators were used, and this trend was most pronounced in ACCENT I Conclusion: The use of concomitant immunomodulators does not improve clinical outcomes over 54 weeks 982 Infliximab Administered as 3-Dose Induction Followed by Scheduled Maintenance Therapy in IBD: Comparable Clinical Outcomes With or Without Concomitant Immunomodulators G. R. Lichtenstein1; R. H. Diamond2; C. Wagner3; A. Olson4; R. Hegedus2; M. Bala5; W. J. Sandborn6  Background and Methods: To assess whether concomitant immunomodulator therapy with infliximab (IFX) is associated with better clinical outcomes when 3-dose induction followed by scheduled maintenance therapy is used in inflammatory bowel disease (IBD), efficacy data from pivotal trials in Crohn’s disease and ulcerative colitis (ACCENT I & II, ACT I & II) were compared. Results: As shown in the table below, response and remission rates did not differ significantly when IFX was used with and without concomitant immunomodulators. While there was a trend in favor of concomitant immunomodulators in some trials, there was a trend against them in other trials. Three of the four trials showed a trend toward fewer hospitalizations when concomitant immunomodulators were used, and this trend was most pronounced in ACCENT I (luminal Crohn’s disease (CD)). Conclusions: The use of concomitant immunomodulators in patients receiving scheduled maintenance IFX therapy for IBD does not improve clinical outcomes over 54 weeks. Whether concomitant immunomodulators would improve clinical outcomes in patients treated beyond 1 year is unknown. Hospitalization rates may be lower with the use of concomitant immunomodulators, especially in CD. The benefits and risks of these agents in combination with IFX must be carefully weighed. The use of concomitant immunomodulators in patients receiving scheduled maintenance IFX therapy for IBD should be considered optional, not mandatory. Trial Endpoint With Concomitant Immunos Without Concomitant Immunos Odds Ratio of Outcome with Concom Immunos (95% CI) Statistical Significance       ACT I Response wk 30 52% 51% 1.05 (0.63-1.73) NS n=243 Response wk 54 45% 45% 1.00 (0.60-1.65) NS  Remission wk 30 34% 36% 0.91 (0.54-1.55) NS  Remission wk 54 34% 36% 0.92 (0.54-1.55) NS  Hospitalization wk 54 7.2% 5.1%  NS       ACT II Response wk 30 55% 53% 1.10 (0.66-1.84) NS n=241 Remission wk 30 36% 27% 1.57 (0.90-2.72) NS  Hospitalizations wk 30 3.9% 5.8%  NS       ACCENT I Response wk 30 63% 53% 1.53 (0.81-2.87) NS n=223 Response wk 54 50% 41% 1.46 (0.79-2.71) NS  Remission wk 30 52% 39% 1.71 (0.93-3.17) NS  Remission wk 54 37% 32% 1.24 (0.66-2.35) NS  Hospitalizations wk 54 1.9% 5.3%  NS       ACCENT II Maint of fistula closure wk 30 60% 65% 0.80 (0.33-1.95) NS n=96 Maint of fistula closure wk 54 43% 48% 0.83 (0.34-2.02) NS  Hospitalizations wk 54 3.3% 4.6%  NS 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 DDW 2007 - Crohn’s 28

ACCENT I & II: Comparable clinical outcomes +/- immunomodulators (IMM) Patients (%) OR 1.53 Response Remission Patients (%) ACCENT II Maintenance of fistula closure Concomitant IMM in patients receiving scheduled maintenance IFX therapy does not improve clinical outcomes over 54 weeks should be considered optional for IBD Lichtenstein et al, Gastroenterology 2007; 132: A-146 (No. 982)

Concomitant Immunomodulators Do Not Improve the Clinical Outcomes of IFX Maintenance Therapy Clinical Remission (all P=NS) Percentage of Patients ACT II ACT I ACCENT I 30 Wk 54 Wk *Clinical response: ACT I/II=decrease in Mayo score (≥30% and ≥3 points) and a decrease in rectal bleeding score (≥1 or a score of 0 or 1 at Week 8); ACCENT I=improvement of ≥70 points in CDAI score and ≥25% improvement in CDAI score. Lichtenstein GR, Diamond RH, Wagner C, et al. Gastroenterology. 2007;132:A-146. [Abstract #982]

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 12 131 136 121 39 36 36 With IMM Without IMM Week 56 Remission defined as CDAI <150 Colombel et al, Gastroenterology 2007; 132: 52

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 (n=86) (n=87) (n=124) (n=128) With IMM Without IMM ***p<0.001 CR100 Schreiber et al, N Engl J Med 2007; 357: 239

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

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

COMMITT: MTX plus IFX in CD (2) 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

What about stopping Immunomodulators?

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) CHARM: Maintenance of Clinical Response in Crohn’s Disease With Adalimumab Randomized Responder Population Maintenance therapy with adalimumab for the treatment of CD was evaluated in the CHARM study.1 This was a double-blind, placebo-controlled, multicenter, 56-week study that evaluated the efficacy and safety of adalimumab for maintaining clinical remission in patients with active CD (CDAI scores of 220 – 450 points). In contrast to the ACCENT I study, where prior exposure to anti-TNF therapy was an exclusion criteria, approximately 50% of the 854 patients enrolled in the CHARM study had received prior treatment with anti-TNF antagonists. All patients received open-label induction with adalimumab 80 mg at week 0, and 40 mg at week 2. In the study design presented here, the 499 primary responders (the Randomized Responder Population) are considered—these patients had achieved a clinical response (decrease in CDAI score of ≥ 70 points from baseline) at Week 4 and were randomized to placebo, adalimumab 40 mg every other week (EOW), or adalimumab 40 mg weekly through week 56. However, both this responder group as well as the Week 4 nonresponders (Randomized Nonresponder Population) were randomized and evaluated in the CHARM study. Steroid tapering was permitted after week 8 for patients who achieved a clinical response. The coprimary endpoints of the study were remission (CDAI score < 150 points) at weeks 26 and 56. Reference 1. Colombel JF, et al. DDW 2006. Abstract 686d. 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] 37

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 20 40 60 80 100 Continued Discontinued Time (weeks) Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)

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.

Opportunistic infections and anti-TNF therapies : Ex: from Risk Factors for Opportunistic Infections in IBD A Case-Control Study of 100 Patients (1998-2003) Odds Ratio (95% CI) P value Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab) 3.50 (1.98-6.08) <0.0001 5-ASA 0.98 (0.61-1.56) 0.94 Corticosteroids 3.35 (1.82-6.16) AZA/6MP 3.07 (1.72-5.48) 0.0001 MTX 4.00 (0.36-4.11) 0.26 Infliximab 4.43 (1.15-17.09) 0.03 One medication 2.65 (1.45-4.82) 0.0014 Two medications 9.66 (3.31–28.19) Toruner M, et al. Gastroenterol. 2008.

Infliximab + Azathioprine in Patients With Active 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

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

AZA Withdrawal in Patients With UC Who Required AZA to Achieve Remission This graph shows that relapse rates were significantly higher among patients who discontinue AZA and receive placebo when compared with patients who continue to receive AZA, indicating that AZA is more effective than placebo for maintaining remission. This randomized, placebo-controlled trial enrolled 79 patients who had been receiving AZA for at least 6 months and who were in remission. N=79 Randomized controlled trial of patients who had been receiving AZA for 6 months Hawthorne AB et al. BMJ. 1992;305:20.

AZA vs 5-ASA for Steroid-Dependent, Active UC This graph shows that AZA was significantly more effective than 5-ASA (Asacol) for achieving and maintaining remission in steroid-dependent UC. 72 patients with: Active UC (Powell-Tuck Score  8 and Baron Score  2) Steroid-dependency (at least 10 mg prednisolone/day and at least 2 unsuccessful attempts in previous 6 months to discontinue) No concurrent meds allowed All patients given 40 mg/d prednisolone until week 2. The dose was then tapered to 30 mg until week 4, and then 20 mg until week 8. Dose was further tapered by 5 mg per week as long as the patient was stable or had improved. If the patient worsened, the dose was raised to 40 mg day and the tapering schedule was begun again. † N=72 *Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score  1) plus steroid discontinuation Patients 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.

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

Intravenous CsA: Severe Active Steroid-Refractory UC P<.001 The left graph shows that CsA was more effective than placebo for inducing remission in patients with severe, active, steroid-refractory UC. The right graph shows that at week 2, Lichtiger scores were significantly more improved in the CsA group than in the placebo group. This trial enrolled 20 patients with severe UC whose condition had not improved after at least 7 days of intravenous corticosteroid therapy. A clinical response was defined as a Lichtiger score less than 10 points for 2 consecutive days. * N=20 *Lichtiger score <10 points for 2 consecutive days Lichtiger S et al. N Engl J Med. 1994;330:1841.

CsA Use in Acute UC: Long-Term Experience Oxford 1996 to 2003 76 patients with severe UC 56 responders to CsA 65% 90% 42% The left graph shows that 90% of patients who had an acute attack of UC and were successfully treated with CsA relapsed by month 40. The left graph shows that 58% of patients underwent colectomy by 72 months post-treatment. These data indicate that CsA is ineffective for maintenance of remission in UC. This trial was a retrospective trial of 76 UC patients requiring CsA between 1996 and 2003 in Oxford, England. CsA was started on the basis of C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone. 54 patients received i.v. CsA (4 mg/kg) 22 received oral CsA (5 mg/kg). 74% of patients achieved initial remission. After 1 year, 65% had relapsed, and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy. Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79.

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

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%)

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 Year 1 2 3 4 5 6 7 Percent without colectomy 67 57 48 41 31 16 12 Percent in remission 35 25 18 8 Moskowitz. Gastroenterology 2005 Abstract

Should Biologics be used Earlier in IBD? 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?

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

Challenges of InductionMaintenance 2008: Consider the Population Steroid-Naïve Steroid-Induction Thiopurine/MTX Maintenance Anti-TNF Induction

Challenges of InductionMaintenance 2008: Consider the Population Steroid-Dependent Thiopurine/MTX Maintenance Failure Biologic

Challenges of InductionMaintenance 2008: Consider the Population Steroid-Refractory Immunosuppressive naïve Anti-TNF induction Thiopurine/MTX Maintenance? Steroid-Refractory Despite Immunosuppressive Anti-TNF induction & Maintenance Stop Immunosuppressive Fail Anti-TNF + Switch Fail Switch or Natalizumab

Summary Immunosuppressives in IBD Most Effective as Maintenance Therapies After Steroids After Biologics After Cyclosporine (UC) Early Aggressive Therapy is most effective Optimal Dosing for Thiopurines Remains to be Established Consider Pharmacogenomics Role for Methotrexate Continues to Evolve Cyclosporine for Severe/Fulminant UC Monotherapy with Biologics appears effective and safe