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  • Revised 10-30-2000 mwa
  • The therapeutic pyramid for Crohn’s disease is based upon clinical trials. Controlled release budesonide has been advocated for mild-moderate disease in countries where it is available. Infliximab has been efficacious independent of concomitant medications.
  • Steroid Dependence Patients who initially respond to treatment with corticosteroids frequently become dependent within months of that response. The prospective evaluation of Munkholm et al involving 196 patients with CD demonstrated that more than one third of patients who achieved complete or partial clinical remission of active CD with prednisolone therapy (1 mg/kg per day, reduced within weeks to a maintenance dose of 10–15 mg/d) developed a dependency on corticosteroids within the first year of treatment. In the Munkholm study, dependence was defined as 1. relapse within 30 days of steroid discontinuation, or 2. relapse upon dose reduction, impeding steroid discontinuation for more than 1 year. Because this definition of steroid dependency is considered excessively lenient, the dependence rate may be underestimated. A consensus has not formally been reached regarding the definition of steroid dependency, but many clinicians agree that recurrence of symptoms with dosage reduction prohibiting the cessation of steroid therapy after a period of at least 3 months constitutes dependency.
  • The ACCENT II trial was a Phase III study evaluating the safety and efficacy of long-term REMICADE ® (infliximab) treatment in patients with fistulizing Crohn’s disease. A total of 296 patients with at least one draining enterocutaneous fistula were included. At baseline approximately 80% of patients were receiving stable doses of ≥1 concomitant Crohn’s-related therapy. All patients received an initial 3-dose induction of REMICADE 5 mg/kg at Weeks 0, 2, and 6. Patients were then randomized based on clinical response at Week 14 to receive REMICADE 5 mg/kg q 8 weeks or placebo through Week 46. The primary endpoint of the study was time to loss of fistula response through Week 54 among patients responding at Week 14. Among patients responding at Weeks 10 and 14, 27% of patients in the placebo-maintenance group still had a response at Week 54 as compared with 49% of patients in the REMICADE 5 mg/kg maintenance group ( P =0.002). 23% of placebo maintenance patients had a complete response versus 40% of patients in the REMICADE maintenance group ( P =0.014). Analysis excluded patients who had no fistula evaluation at Week 54.
  • The ACCENT II trial was a Phase III study evaluating the safety and efficacy of long-term REMICADE ® (infliximab) treatment in patients with fistulizing Crohn’s disease. A total of 296 patients with at least one draining enterocutaneous fistula were included. At baseline approximately 80% of patients were receiving stable doses of ≥1 concomitant Crohn’s-related therapy. All patients received an initial 3-dose induction of REMICADE 5 mg/kg at Weeks 0, 2, and 6. Patients were then randomized based on clinical response at Week 14 to receive REMICADE 5 mg/kg q 8 weeks or placebo through Week 46. The primary endpoint of the study was time to loss of fistula response through Week 54 among patients responding at Week 14. Among patients responding at Weeks 10 and 14, 27% of patients in the placebo-maintenance group still had a response at Week 54 as compared with 49% of patients in the REMICADE 5 mg/kg maintenance group ( P =0.002). 23% of placebo maintenance patients had a complete response versus 40% of patients in the REMICADE maintenance group ( P =0.014). Analysis excluded patients who had no fistula evaluation at Week 54.
  • The most frequent AEs (by preferred term) in infliximab-treated patients in all studies were upper respiratory tract infections (27.9%), headache (25.7%), nausea (20.6%), abdominal pain (20.5%), pain (13.9%), pharyngitis (13.5%), arthralgia (13.0%), rash (12.9%), fatigue (11.9%), sinusitis (11.7%), vomiting (11.6%) fever (11.5%), diarrhea and dizziness (each 10.8%), and coughing (10.0%). p. 94 and 95 of ASPIRE ISS
  • Patients with a new mild to moderately severe flare of Crohn’s disease should be evaluated for an intercurrent enteric infection. Patients with ileal and/or right colonic disease respond more rapidly and completely to controlled ileal release budesonide, whereas patients with other anatomic localizations of disease may better respond to oral prednisone by a tapering regimen. Patients with colonic Crohn’s in particular may be considered for treatment with 5-aminosalicylate, particularly sulfasalazine, or antibiotics, such as metronidazole and/or ciprofloxacin. Patients unable to taper off budesonide or prednisone are considered steroid dependent and should be considered for treatment with an immune modulator. Alternatively, for patients with ileal/right colonic disease, a dose of budesonide 9 mg/d or less may be given to minimize symptoms.
  • Patients with more active symptoms may require a course of oral or intravenous steroids. Patients who are unable to successfully taper steroids, or who do not respond fully should be considered for 6-mercaptopurine, azathioprine, or methotrexate. Patients who do not fully respond to optimized dosing with these agents may be considered for infliximab, surgery, or investigational therapy.
  • Once a decision to treat with infliximab has been made, infectious complications need to be first guarded against by diagnosing and treating enteric pathogens, abscess, tuberculosis, or other infectious issues. Concurrent treatment with an immune modulator is desirable to minimize risk of antibodies to infliximab and subsequent loss of response. Similarly, once a course of treatment has been begun, maintenance dosing at regular intervals of 8 weeks or less should ensue, again to minimize the formation of antibodies to infliximab. Patients who do not respond to 5 mg/kg may respond to dose escalation, while patients who require treatment intervals of less than 8 weeks may be maintained at shorter intervals.
  • Evaluation of fistulas begins with definition of anatomic course and exclusion of complicating factors such as abscess. Superficial fistulas may respond to a course of antibiotics, or to fistulotomy. Patients with more complicated fistula anatomy will likely require a combined medical and surgical approach with placement of seton. Patients who do not respond to antibiotics or 6MP/azathioprine may be tried on infliximab, with maintenance using the agent that led to fistula response. Tacrolimus may be effective in closing fistulas, but also has a high rate of adverse effects in association with its use. Ultimately, some patients will fail to respond to all best efforts and may require surgery, including possible proctectomy and permanent stoma.
  • Premise and Preview

    1. 1. Treatment Algorithms in Crohn’s Disease Gary R. Lichtenstein, M.D. Professor of Medicine University of Pennsylvania School of Medicine Hospital of the University of PA Philadelphia Pennsylvania
    2. 2. Premise and Preview <ul><li>In Most Clinical Scenarios of Crohn’s Disease </li></ul>Therapy is Sequential
    3. 3. Goals of Therapy for IBD <ul><li>Inducing remission </li></ul><ul><li>Maintaining remission </li></ul><ul><li>Restoring and maintaining nutrition </li></ul><ul><li>Maintaining patient’s quality of life </li></ul><ul><li>Surgical intervention (selection of optimal time for surgery) </li></ul>
    4. 4. Crohn’s Disease: Anatomic Distribution Small bowel alone (33%) Colon alone (20%) Ileocolic (45%) Least Most Freq of involvement
    5. 5. Long-term Evolution of Disease Behavior in CD Cosnes J et al. Inflamm Bowel Dis . 2002;8:244. 240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0 0 10 20 30 40 50 60 70 80 90 100 Cumulative Probability (%) Patients at risk: Months 2002 552 229 95 37 N = Penetrating Stricturing Inflammatory
    6. 6. Proportion of CD Patients in Each Treatment State by Year Since CD Diagnosis Silverstein MD et al. Gastroenterology 1999;117:49 Years after Diagnosis Probability Post-surgery remission Surgery Drug refractory Drug dependent Drug responsive Mild Remission
    7. 7. Cumulative Probability of Surgical Intervention in CD Munkholm P et al. Gastroenterology . 1993;105:1716. Years Probability (%) Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1 0 20 40 60 80 100 0 2 5 8 11 14 17 20 Dx ± 2 SD
    8. 8. Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids Days Cumulative Probability (%) 0 20 40 60 80 100 0 30 60 90 182 365 Faubion WA Jr et al. Gastroenterology. 2001;121:255. N = 77.
    9. 9. Inductive Therapies for Crohn’s Disease <ul><li>Aminosalicylates </li></ul><ul><li>Antibiotics </li></ul><ul><li>Corticosteroids </li></ul><ul><li>Infliximab </li></ul>
    10. 10. Therapeutic Pyramid for Active Crohn’s Disease Severe Moderate Aminosalicylates/Antibiotics Corticosteroids Immunomodulators Surgery Infliximab ? (Prednisone) Mild (Budesonide)
    11. 11. Treatment of Mild-Moderate Crohn’s Disease
    12. 12. NCCDS: Response to Therapy for Active Crohn’s Disease NCCDS, National Cooperative Crohn’s Disease Study. Summers RW et al. Gastroenterology 1979;77:847-869 Patients (%) Weeks after Randomization Sulfasalazine 1 g/15 kg (5 g) Placebo 13% 0 5 10 15 60 50 40 30 20 10 0 70
    13. 13. Meta-Analysis of Pentasa ® (4g/day) in Active Crohn’s Disease P=0.005 P=0.7 P=0.5 P=0.04 Hanauer, Stromber. Clinical Gastroenterology & Hepatology 2004 P=0.005 P=0.7 P=0.05 P=0.04 -80 -70 -60 -50 -40 -30 -20 -10 0 Crohn's I n=155 Crohn’s II n=150 Crohn's III n=310 Overall n=615 Change from baseline in CDAI score Pentasa ® 4 g Placebo -60 -50 -40 -30 -20 -10 0 Crohn's I n=155 Crohn's II n=150 Crohn's III n=310 Overall n=615 Pentasa ® 4 g minus Placebo
    14. 14. Antibiotics in Active CD Metro + Cipro Metro Cipro vs. Me-Pred vs. SASP vs. Mesalamine % Remission Prantera 1996; Ursing 1982; Colombel 1999
    15. 15. Corticosteroids in Crohn’s Disease <ul><li>Faubion et al (Olmsted County, 1970-93) </li></ul><ul><li>“Only 43% of inception cohort ever required steroids” </li></ul>
    16. 16. Corticosteroids in CD: Induction of Remission *Randomized controlled trial † Multicenter prospective trial Malchow H et al. Gastroenterology. 1984;86:249. Modigliani R et al. Gastroenterology . 1990;98:811. Summers RW et al. Gastroenterology . 1979;77:847. Clinical Remission % Patients 30% 82%* 38% p not calculated 92% † 60%* 17 weeks 18 weeks 7 weeks 0 20 40 60 80 100 Corticosteroids Placebo NCCDS ECCDS GETAID
    17. 17. Corticosteroid Therapy for Crohn’s Disease *30 days after initiating corticosteroid therapy Complete Remission 58% (n = 43) Partial Remission 26% (n = 19) Immediate Outcome* (n = 74) 1-Year Outcome (n = 74) Steroid Dependent 28% (n = 21) Prolonged Response 32% (n = 24) Surgery 38% (n = 28) No Response 16% (n = 12) Faubion W et al. Gastroenterology 2001;121:225
    18. 18. Outcome of Corticosteroid Therapy for CD Munkholm. Gut 1994;35:360-362 * Remission at 12 Months = 25% Remission 48% Improved 32% No change 20% 12-month outcomes 1-month outcomes Remission 54% Relapse 46% Improved 57% Relapse 43%
    19. 19. Corticosteroids: Maintenance of Remission 23% 75% 30% 76% 0 10 20 30 40 50 60 70 80 Smith Summers Malchow Steroid Placebo n=59; p =NS % Patients in Remission n=274; p =NS n=237; p =NS 36 months 12 months 24 months Smith RC et al. Gut . 1978;19:606. Summers RW et al. Gastroenterology . 1979;77:847. Bergman L et al. Scand J Gastroenterol . 1976;11:651. Malchow H et al. Gastroenterology . 1984;86:249. 55% 58%
    20. 20. Overview of Corticosteroids in CD <ul><li>Induce remission (NCCDS, * ECCDS, † GETAID ‡ ) </li></ul><ul><li>Provide rapid symptomatic relief (NCCDS, * ECCDS, † GETAID ‡ ) </li></ul><ul><li>Frequent corticosteroid dependency with prolonged use </li></ul><ul><li>DO NOT maintain remission </li></ul><ul><li>Dose- and duration-related adverse events with acute and chronic therapy </li></ul>Faubion WA Jr et al. Gastroenterology . 2001;121:255. Keenan GF et al. Clin Chest Med. 1997;18:507. Munkholm P et al. Gut . 1994;35:360. Singleton JW et al. Gastroenterology. 1979;77:870. Steinhart AH et al. Cochrane Database Syst Rev. 2003;CD000301. *Summers RW et al. Gastroenterology . 1979;77:847. † Malchow H et al. Gastroenterology. 1984;86:249. ‡ Modigliani R et al. Gastroenterology . 1990;98:811.
    21. 21. Remission Rates in Acute Crohn’s Studies with Budesonide CIR Bud CIR Bud CIR Placebo Pentasa ® Prednisolone 9 mg QD 4.5 mg BID 2 g BID 40 mg Remission rates at 8 weeks (%) Greenberg 1994; Rutgeerts 1994; Thomsen 1998 0 10 20 30 40 50 60 70
    22. 22. Maintenance Therapy for Crohn’s Disease: Issues <ul><li>Definition of remission </li></ul><ul><ul><li>Clinical, endoscopic, radiologic, laboratory </li></ul></ul><ul><li>Induction therapy </li></ul><ul><ul><li>5-ASA, steroids, antibiotics, immunomodulators </li></ul></ul><ul><ul><li>Surgery </li></ul></ul><ul><li>Disease location </li></ul><ul><li>Disease behavior </li></ul><ul><ul><li>Inflammatory, fibrostenotic, fistulizing </li></ul></ul><ul><li>Smoking </li></ul>
    23. 23. Months after Randomization Summers. Gastroenterology 1979 NCCDS - Response to Therapy for Crohn’s Disease Remission Maintenance
    24. 24. Mesalamine Maintenance of Remission in Crohn’s Disease Camma. Gastro 1997 Favors Treatment Study Year Pts (n) Caprilli 1994 95 McLeod 1995 163 Brignola 1995 87 Sutherland 1997 66 Overall 411 Thornson 1990 248 Prantera 1992 125 Brignola 1992 44 Gendre 1993 161 Bresci 1994 66 Thornson 1995 286 Arber 1995 59 Modigliani 1996 85 Sutherland 1997 180 De Franchis 1997 117 Overall 1,371 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 Favors Control Risk Difference 95% CI
    25. 25. Oral Budesonide as Maintenance Therapy for CD Adapted from Greenberg GR et al. Gastroenterology 1996;110:45-51 P = ns Budesonide 6 mg Budesonide 3 mg Placebo Days 0 100 200 300 Cumulative probability of remission 0 0.5 1
    26. 26. Outcomes for Mild-Moderate Disease Mild-Moderate Disease Aminosalicylate Response 40-50% Antibiotic (Colonic Disease) Response 40-50% Budesonide (Ileum-Right Colon) Response 50-65% Placebo Response 30-40%
    27. 27. “Evidence-Based” Approach of Sandborn and Feagan Mild-Moderate Crohn’s Disease Left-sided disease restricted to colon Disease involving the ileum and/or ascending colon Sulfasalazine 16 weeks Budesonide capsules 8-16 weeks Sulfa-allergic/failed treatment Failed treatment Conventional steroids >60% 45% acute 80% 1 year Sandborn, Feagan, 2003
    28. 28. Evidence/Experience Aminosalicylate Induction Mesalamine/Sulfasalazine Response No Response Maintain Ileum-R. Colon Colon Moderate Disease Budesonide Antibiotic Prednisone/ Elemental Diet Infliximab
    29. 29. Prescriptions are Written on Paper… Not in Stone Until we can predict course in individual patients… Advance to more potent, more toxic agents if no initial response or relapse
    30. 30. Topics <ul><li>Antimetabolite therapy </li></ul><ul><li>Anti-inflammatory cytokines </li></ul><ul><li>TNF blockade </li></ul>
    31. 31. AZA: Induction of Remission 0 20 40 60 80 % Response 0 10 Weeks Prednisone Placebo AZA P =0.17 NCCDS Data
    32. 32. AZA and 6-MP: Induction of Remission in CD Pearson DC et al. Ann Intern Med 1995;122:132-142 .
    33. 33. Azathioprine for Crohn’s Disease 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Duration of Trial (months) AZA Placebo Percent on Trial Candy S et al. Gut 1995
    34. 34. Combination Induction Therapy 6-MP + Prednisone <ul><li>Pediatric CD </li></ul><ul><li>Patients who required steroid therapy </li></ul><ul><li>6-MP 1.5 mg/kg added as primary therapy </li></ul><ul><li>Improved outcomes </li></ul>Markowitz J. Gastroenterology 2000;119:895-902 Days Since Steroids Discontinued 0 100 200 300 400 500 600 0 .25 .50 .75 1.00 Fraction Steroid Free
    35. 35. Azathioprine and 6-Mercaptopurine in IBD: Toxicity <ul><li>Common </li></ul><ul><ul><li>Gastrointestinal intolerance </li></ul></ul><ul><ul><li>Myalgia </li></ul></ul><ul><li>Uncommon </li></ul><ul><ul><li>Bone marrow suppression </li></ul></ul><ul><ul><li>Pancreatitis </li></ul></ul><ul><ul><li>Allergic reactions </li></ul></ul><ul><ul><li>Hepatic toxicity </li></ul></ul>Present DH. Gastroenterol Clin North Am 1989;18:57-71 <ul><ul><li>Opportunistic infection </li></ul></ul><ul><ul><li>Neoplasm </li></ul></ul>
    36. 36. Methotrexate
    37. 37. Historical Overview <ul><li>1948 – first “designer drug” specific antagonist of folic acid </li></ul><ul><li>1950’s – serendipitous discovery of activity in psoriasis </li></ul><ul><li>1960’s – widely used for psoriasis – hepatotoxic </li></ul><ul><li>1966 – Enderlin reported use in RA </li></ul><ul><li>1985 – Wienblatt defines pharmacokinetics in RA </li></ul><ul><li>1980-2000 – treatment of choice for RA </li></ul>
    38. 38. Feagan. N Eng J Med . 1995;332(5):292-7 % Response 0 25 19.1% 39.4% P =0.025 Placebo MTX 50 MTX Results: Remission
    39. 39. Methotrexate: Time to Relapse % Remission Weeks Since Randomization P =0.044 Methotrexate Placebo Feagan BG. N Engl J Med 2000;342(22):1627-32
    40. 40. Methotrexate in IBD: Toxicity <ul><li>Major </li></ul><ul><ul><li>Hepatic </li></ul></ul><ul><ul><li>Myelosuppressive </li></ul></ul><ul><ul><li>Pulmonary </li></ul></ul><ul><ul><li>Fertility-related </li></ul></ul><ul><ul><li>Teratogenic </li></ul></ul><ul><ul><li>Enteritic/colitic </li></ul></ul>Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80 <ul><li>Minor </li></ul><ul><ul><li>Gastrointestinal </li></ul></ul><ul><ul><li>Alopecia-inductive </li></ul></ul><ul><ul><li>Allergic </li></ul></ul><ul><ul><li>Neurologic </li></ul></ul>
    41. 41. Cyclosporine
    42. 42. Cyclosporine in CD Feagan BG. Inflammatory Bowel Dis 1995;1:335-339
    43. 43. Biologic Therapy
    44. 44. Infliximab: Mechanism of Action
    45. 45. Healing of Colonic Ulceration with Infliximab Van Dullemen HM et al. Gastroenterology 1995;109:129-135 Pretreatment 4 weeks post-treatment
    46. 46. Median Time to Loss of Response Through Week 54 Week 2 Responders ACCENT I Hanauer S, Feagan B. Lancet . 2002;359:1541-9
    47. 47. Clinical Remission at Week 54* *Week-2 responders 0 10 20 30 40 50 Single Dose (n=110) Proportion of Patients (%) 5 mg/kg q 8 wk (n=113) 10 mg/kg q 8 wk (n=112) P <0.001 P =0.007 P =NS 14% 28% 38% ACCENT I Hanauer SB, et al. Lancet 2002
    48. 48. REMICADE ® (infliximab) in Patients with Fistulizing Crohn’s Disease P =0.001 P =0.04 *Placebo=Conventional Therapy * Present, et al. Present D, et al. N Engl J Med . 1999;340:1398-1405. Complete Response: All Fistulas Closed
    49. 49. Fistula Response at Week 54 P =0.014 Patients in Response (%) P =0.002 Sands BE, et al NEJM 2004 ACCENT II Among Patients Responding at Weeks 10 and 14 41/83 24/89 41/83 24/89
    50. 50. Fistula Response at Week 54 P =0.014 Patients in Response (%) P =0.002 Sands, B et al. NEJM 2004 ACCENT II Among Patients Responding at Weeks 10 and 14 41/83 24/89 41/83 24/89
    51. 51. Incidence of Antibodies-to-Infliximab (ATI) Maintenance Studies* Maintenance Studies % of Pts without ATI % of Pts with ATI % of Patients Inconclusive † * pts with evaluable samples Antibody-to-Infliximab (ATI) Status † pts with long-lasting serum concentrations of infliximab and never ATI (+) ASPIRE: Integrated Safety Summary, Sep. 18, 2003 ACCENT I CD n = 514 Week 72 ACCENT II CD n = 258 Week 54 ATTRACT RA n = 295 Week 102 ASPIRE RA n = 629 Week 54
    52. 52. Infliximab and Antibody Formation <ul><li>Cohort study (n = 125): mean of 3.9 infusions / 10 months </li></ul><ul><li>61% of patients developed ATI </li></ul><ul><li>Antibody formation inversely associated with serum infliximab concentration </li></ul><ul><li>ATI formation > 8 ug predicted shorter duration of response (35 vs. 71 days) – present in 37% </li></ul><ul><li>Approximately 2.5 times as likely to form ATI if concomitant antimetabolite therapy was not used </li></ul>Baert et al. N Engl J Med 2003;348:7
    53. 53. Prevention of ATIs <ul><li>Avoid intermittent therapy </li></ul><ul><li>Use effective preventative strategies: </li></ul><ul><ul><li>200 mg solucortef IV ADC at time of dosing if not on a therapeutic dose of antimetabolite* </li></ul></ul><ul><ul><li>MTX/AZA for chronic use </li></ul></ul>* Farrell R. Gastroenterology 2003;124(4):917-24
    54. 54. CD: Mild to Moderate Active symptoms/ flare Budesonide Observe Taper Consider budesonide titrated to symptoms or 6-MP/AZA or MTX Not confined to Prednisone Taper 6-MP/AZA or MTX Consider 5-ASA Consider Abx Observe No flare No flare Flare Response No response Exclude enteric pathogen Flare Response Ileal/ R colon ileal/ R colon
    55. 55. CD: Moderate to Severe Moderate CD Observe Taper Success PO Steroids 6-MP/AZA Consider change to MTX Add infliximab Surgery or investigational therapy Severe CD IV Steroids Adequate response Inadequate response <ul><li>Consider infliximab + 6-MP/AZA or MTX </li></ul><ul><li>Consider surgery </li></ul>Adequate response Failure Maintain 6-MP/AZA or MTX Maintain infliximab + 6-MP/AZA or MTX Adequate response Adequate response Adequate response Inadequate response Inadequate response/intolerant Inadequate response/intolerant Inadequate response/intolerant
    56. 56. Infliximab Infliximab indicated <ul><li>Exclude enteric pathogen </li></ul><ul><li>Exclude abscess, stricture </li></ul><ul><li>Exclude latent/active TB </li></ul><ul><li>Infliximab 5 mg/kg wks 0, 2, 6 </li></ul><ul><li>Consider steroid pre-treatment </li></ul><ul><li>Consider acetaminophen, diphenhydramine pre-treatment </li></ul>Infliximab 10 mg/kg Surgery or investigational Rx Observe up to 8 wks Recurrent sx ≤ 4 wks Recurrent sx > 4 - < 8 wks Recurrent sx ≥ 8 wks Response Maintain infliximab 5 mg/kg q 4-8 wks Inadequate response Escalate dose or shorten interval Loss of response Inadequate response Inadequate response (Start 6-MP/AZA or MTX) Maintain infliximab 5 mg/kg q 8 wks
    57. 57. Fistula Fistula Diagnostic evaluation Fistula type Not superficial Superficial <ul><li>Antibiotics </li></ul><ul><li>Consider fistulotomy </li></ul>Observe Failure Failure Failure Definitive surgery Maintain 6-MP/AZA and/or infliximab Failure Tacrolimus <ul><li>Seton </li></ul><ul><li>Antibiotics </li></ul><ul><li>6-MP/AZA ± infliximab </li></ul>
    58. 58. Final Points <ul><li>There is no “one size fits all” to IBD therapy </li></ul><ul><ul><li>Therapy and decision making are tailored to the individual </li></ul></ul><ul><li>Algorithms are based upon available evidence </li></ul><ul><ul><li>Evidence is in constant flux </li></ul></ul><ul><li>Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome </li></ul><ul><ul><li>Skillful application of medical therapy makes all the difference in outcomes </li></ul></ul>

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