1. Current and Evolving Therapy of Crohn’s Disease (CD) Orooj khan MBBS Ali Minhas MBBS Maya Srivastava MD PhD

2. Introduction Crohn's disease (CD) is a chronic inflammatory disorder of the digestive tract with a wide spectrum of clinical presentations and an unpredictable disease course. The estimated annual prevalence is 50 per 100,000 The estimated annual incidence of CD is five per 100,000 CD is more prevalent in Western countries Affects all age groups, but is more commonly diagnosed in adults during the second and third decades of life.

3. Introduction Patients are faced with a lifetime of recurrent disease flare-ups and remission CD remains medically and surgically incurable (despite advancements in understanding its etiology and pathogenesis) Management strategies must be targeted towards lifelong management (both short- and long-term aspects of the disease).

4. Changing Standards… The ultimate goal is Inducing and Maintaining clinical remission The current standard medical practice-‘Step-up'–sequential approach by using first-line agents (aminosalicylates [5-ASA], corticosteroids, and antibiotics), then immunomodulators and then biological therapy. This approach does successfully treat the acute disease, and maintains remission, but does not alter the long-term course of CD. The question- “Is it possible to alter the natural history of CD?” by an early introduction of therapies currently reserved for the 'top' (i.e.'top-down' approach). We aim to present the rationale for the use of 'top-down' versus 'step-up' therapy for the treatment of CD.

6. Natural history of CD Intermittent exacerbation of symptoms alternating with periods of quiescence A cohort study from Scandinavia by Munkholm et al. demonstrated: -13% of patients will achieve complete remission -20% of patients will experience annual relapse -67% will have a combination of relapse and remission within the first 8 years after initial diagnosis.

7. In a population-based cohort study, Silverstein et al found that a CD patient spends: -24% of the time in medical remission without medications -41% of the time in postsurgical remission without medications -7% of the time in medical treatment with 5-ASA derivatives -7% of the time having disease activity mandating treatment with corticosteroids or immunomodulators.

8. Disabling course…. A population-based study from Olmsted County, MN, USA by Schwartz et al. demonstrated: Risk for the development of fistulas was 33% at 10 years and 50% after 20 years The majority (83%) of fistulae required a surgical approach Recurrence rate of perianal fistulae has been reported to be as high as 59-71% presence of perianal disease, younger age of disease onset, need for corticosteroids predict a disabling course (85% of patients developed a disabling course within 5 years of diagnosis). (Beaugerie et al.)

11. Current Available Therapies The First-Line therapies: 1) 5-ASA (not FDA approved)- -exert their therapeutic effect topically within the intestinal lumen. -include the slow-release formulations -A Cochrane systematic review ( 6 randomized placebo controlled trials with 12-month follow-up) demonstrated no superiority of 5-ASA over placebo in maintaining remission of CD

12. First Line Therapies 2) Antibiotics (not FDA approved): -Metronidazole and ciprofloxacin are the most widely used -Can be used alone or in combination. -In a Scandinavian Trial Metronidazole was found to be equally efficacious to sulfasalazine -Data are limited on the efficacy of antibiotics as maintenance therapy. -Potentially serious side effects (peripheral neuropathy and tendinitis or tendon rupture)

13. 3) Budesonide (oral)- controlled-release high topical activity and low-systemic bioavailability used in patients with mild-to-moderately active CD involving the ileum and/or right colon. No evidence for the use of budesonide in fistulizing disease. Not recommended as a maintenance treatment for CD.

14. Second-line therapy (Systemic corticosteroids) Highly effective in achieving clinical remission. A population-based cohort study observed that 84% of patients had either complete or partial response. But, within 1-year, 28% of patients with CD became corticosteroid-dependent 38% of CD patients underwent surgery Increased risk of significant side effects, so long-term use is not recommended

15. Third-line therapy ( immunomodulators & methotrexate) AZA and 6-MP Effective in maintaining clinical remission with steroid sparing effect Slow onset of action of 3-6 months precludes their use as inductive agents Serious side effects associated with the prolonged use of these medications- non-Hodgkin lymphoma and hepatosplenic T-cell lymphoma.

16. Methotrexate MTX was three-times more efficacious than placebo in maintaining remission of CD (Cochrane database meta-analysis of (3 randomized placebo-controlled trials) Potential adverse events- liver fibrosis, pneumonitis and bone marrow suppression Therefore the optimal duration of maintenance therapy remains unknown

17. The fourth-line therapy: anti-TNF (infliximab, adalimumab & certolizumab pegol) Designed to block or neutralize proinflammatory cytokines 1)Infliximab (FDA approved) For induction and maintenance therapy in patients with moderate-to- severe CD refractory to conventional therapies (ACCENT I trial) Effective in reducing the number of draining fistulae and maintaining fistula closure Maintenance therapy was associated with: higher clinical response and remission rates significant reduction in hospitalizations and surgical procedures prolonged mucosal healing, faster steroid weaning, better quality of life.

18. 2) Adalimumab- monoclonal anti-TNF antibody of fully human origin (Approved by the FDA in 2007) As an induction agent (CLASSIC I trial) A maintenance agent (CLASSIC II and CHARM trials) in adult patients unresponsive to conventional therapy Patients intolerant to or lost response to infliximab Patients with fistulizing CD treated with adalimumab had a significantly decreased number of draining fistulae per day (CHARM trial)

19. 3) Certolizumab pegol (FDA approved 2008) High binding affinity for TNF-alpha. Effective in inducing clinical response (PRECISE I trial) Maintaining Remission (PRECISE II trial) Not more efficacious on fistula closure (either of the mentioned trials).

20. Medical therapy for the nonresponders: selective adhesion molecule inhibitors (natalizumab) Natalizumab - new class of biologic agents (approved by the FDA in 2008 Targeted against the [alpha]4 subunit of integrin molecules Treatment to induce clinical response ENCORE trial Maintain Remission ENACT 2 trial Only in patients who had inadequate response or intolerance to conventional CD therapies, including the anti-TNF-[alpha] agents. Approved for use only as a monotherapy owing to an underlying risk of PML.

23. So which one is better? Step-up versus top-down Step-up therapy Refers to a sequential treatment strategy Begins with a less effective, potentially less toxic treatment strategy, ( aminosalicylates, antibiotics or budesonide) Escalation to the highly effective but potentially more toxic treatment (prednisone, immunomodulators and biological therapy) In this strategy-avoid overtreating and unnecessary exposure to the risk of developing adverse events. For the reason of toxicity, physicians are often reluctant to advance therapy (may result in inadequate treatment and prolonged inflammation).

24. Top-down therapy Many studies have shown that most patients treated with the conventional step-up therapy go on to develop stricturing or penetrating disease. UK Study- looked at the influence of (infliximab) on resources in CD and found: There were fewer bed days and number of abdominal operations was halved (Jewell et al)

25. ACCENT I trial- demonstrated significant mucosal healing in 73% of patients treated early imunosuppression. There was a greater proportion of patients who achieved early clinical remission at week 14 (p = 0.0001) and week 26 (60 vs 36%; p = 0.0062) A significant difference- number of patients in remission without corticosteroids and without surgery at weeks 26 and 52. Safety issues remain a major concern in the top-down approach. Increased risk of TB, opportunistic infections and malignancy. The risks of lymphoma and hepatosplenic T-cell lymphoma have been found to be associated with long-term immunomodulator use. The cost for initiating treatment may be higher in patients receiving early combination therapy But take account indirect costs- as cost of lost productivity, quality of life, hospitalization and surgery rate,

26. 1-year data from the recent SONIC trial have shown that monotherapy with infliximab or combination therapy consisting of infliximab and AZA are more likely to maintain long-term corticosteroid-free remission than monotherapy with AZA

27. Whom & when to treat? There are no simple answers Our ability to risk stratify patients remains rudimentary Identify clinical factors associated with a disabling course and certain genetic and serologic profiles that may require a more aggressive therapy The real challenge- development of an improved classification system (identify subgroups to maximize the treatment benefit-risk profile).

28. The Future….. Need to improve our ability to assess prognosis at the time of diagnosis, personalize treatment and target the patients will develop complicated disease we hope to invert the treatment pyramid in selected target populations Goals of disease modification, mucosal healing, reduced pharmacoeconomics, Improved quality-of-life