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 OF CROHN’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 COURSE OF 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 SUPPORT STEP 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 (Study of 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 & WHEN TO 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 must be 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.
