Crohn\'s: Step Up or Step Down Therapy?
- 1. GI Workshop February22, 2008 Ada Kong
- 2. STEP UP STEP DOWN Biologics SEVERE Surgery AZA/6MP MTX MODERATE Biologics Surgery AZA/6MP MTX MILD Steroids/budesonide 5-ASA Antibiotics
- 3. EFFICACY OF MEDICATIONS INDUCTION MAINTENANCE 5-ASA/sulfasalazine / Antibiotics (perianal) (post-surg) STEROIDS 6MP/AZA/MTX INFLIXIMAB/anti-TNFs From: Management of Crohn’s Disease in Adults. ACG 2009 practice guidelines
- 4. NATURAL HISTORY OFCROHN’S • Progressive, chronic disease. Luminal inflammation • Majority of patients present with inflammatory disease at diagnosis. • Approx. 80% will require surgery in lifetime.1 Stricturing/ • More than 50% treated with steroids fistulizing will become steroid-dependent.2 complications • Step-down therapy may alter course of disease, ↓use of steroids, ↓hospitalizations & surgery. Surgery 1. Inflamm Bowel Dis 2002;8(4):244-250. 2. Gastroenterology 1993;105:1716-1723.
- 5. ALTERING THE COURSEOF CROHN’S ⇓ NEED MUCOSAL LESS FOR HEALING SURGERIE STEROID S STEROIDS S N/A NO NO 6MP/AZA YES YES NO MTX YES YES NO INFLIXIMA YES YES YES B Adapted from Aliment. Pharmacol.Ther. 2007;25(1):3-12
- 6. DATA TO SUPPORTSTEP DOWN THERAPY PEDIATRIC TRIALS • Early use of immunosuppressants/biologics may alter course of CD, response to treatment may be related to disease duration D’HAENS et al. Lancet 2008;371:660-67 • Infliximab + AZA (step-down) vs. conventional steroid induction (step-up). • Results: Step-down tx resulted in ↑ remission than step-up. Significantly ↑ mucosal healing in step-down tx.
- 7. SONIC TRIAL (Studyof Biologic & Immunomodulator Naïve Patients in Crohn’s) Sandborn, W et al. SONIC trial. ACG 2008. Latebreaking abstract Infliximab + AZA: 56.8% response rate, 43.9% mucosal healing • Infliximab + placebo: 44.4% response rate, 30.1% mucosal healing • AZA + placebo: 30.6% response rate, 16.5% mucosal healing Safety data similar for all groups COMMIT TRIAL (trial completed, results not published) INF+MTX vs. INF alone to induce & maintain remission
- 8. SAFETY OF BIOLOGICS •Hypersensitivity reactions, CHF, malignancy. ∀ ↑risk for infections (FDA warning): TB, invasive fungal infections, pneumonia. • Lymphoma/non-Hodgins. Hepatosplenic T-cell lymphoma in adolescents & young CD patients associated with infliximab & immunomodulator use (FDA warning). • Progressive multifocal leukoencephalopathy (PML): associated with natalizumab. • TREAT registry: infliximab not associated with ↑ mortality, risk of lymphoma slightly elevated.
- 9. WHO & WHENTO START BIOLOGICS? • Need to identify patient at highest risk for complications. • Biologics effective for mod-severe disease (refractory to conventional treatment). “Increasing evidence that top- down therapy…may offer steroid sparing benefits for steroid naï ve patients.” (ACG guidelines 2009) • Infliximab effective for perianal/fistulizing disease (ACG 2009). Factors associated with poor outcomes: • Young age at dx (<40yr), perianal disease, early use of steroids, small bowel involvement, smoking. Beaugerie et al. Gastroenterology 2006;130:650-656. Coming in the future: • Serologic markers: S.cerevisiae, OmpC, CBir1 antibodies. • Genetic markers: Mutations in NOD2/CARD15 gene.
- 10. CONCLUSIONS • Therapy mustbe individualized. • Consider severity of disease, fistulizing/non- fistulizing, high risk for complications, risk vs. benefit, patient factors (e.g. age, contraindications) • Step down therapy may be warranted for moderate-severe or fistulizing disease. • Unknown factors: what to do after loss of response to biologics, cost benefit of tx, monotherapy vs. combination tx, duration of tx with biologics, long-term efficacy of step- down therapy.