1. Ustekinumab Induction and Maintenance Therapy in Refractory Crohn’s Disease
William J. Sandborn, M.D., Christopher Gasink, M.D., Long-Long Gao, Ph.D., Marion A. Blank, Ph.D., Jewel Johanns, Ph.D., Cynthia Guzzo, M.D., Bruce E. Sands, M.D., Stephen B. Hanauer, M.D., Stephan Targan, M.D., Paul Rutgeerts, M.D., Ph.D., Subrata Ghosh, M.D., Willem J.S. de Villiers, M.D., Ph.D., Remo Panaccione, M.D.,
Gordon Greenberg, M.D., Stefan Schreiber, M.D., Simon Lichtiger, M.D.,and Brian G. Feagan, M.D.,
N Engl J Med 2012;367:
R2 Kyunghan Yoon / Prof. Changkyun Lee 

2. Background

3. BACKGROUND Refractory Crohn’s disease -> TNF antagonist
1/3 -> Do not have response to initial treatment (primary nonresponse)
1/3 -> Transient response or a switch to another therapy (secondary nonresponse).
Interleukin- 12 and interleukin-23
Overexpression, polymorphism-> Pathogenesis of Crohn’s disease
Ustekinumab : human IgG1κ monoclonal antibody, blocks the biologic activity of IL-12 & 23
Patients with moderate- to-severe Crohn’s disease that was resistant to TNF antagonists
-> Effect of Ustekinumab ??
Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care (ADDITION-Europe)

4. Method

5. Methods
Randomized, double-blind, placebo-controlled phase 2b trial of ustekinumab (Oct 2008 ~ Dec 2010)
Primary end point
Clinical response (≥100-p↓ from the baseline CDAI score) at week 6
Secondary end points
Clinical remission (CDAI score, <150 points) at week 6
Clinical response at week 4, and clinical remission at week 22 among patients with a response to ustekinumab at week 6.
Crohn’s Disease Activity Index (CDAI, 0~600)
- Higher scores indicating worse disease
- 50-point change indicating the minimal clinically important difference

6. 1st randomization
2nd randomization

7. Methods Inclusion criteria 18 years old ↑
3-month↑ history of Crohn’s disease with a score of 220 to 450 points on the CDAI
Primary nonresponse, a secondary nonresponse, or unacceptable side effects after receiving a TNF antagonist
No previous therapies specifically targeting interleukin-12 or interleukin-23
Exclusion criteria
Bowel resection within 6 months before enrollment and those with the short-bowel syndrome
Abscess, active tuberculosis, current infection, or other previous or current opportunistic infection or cancer.

8. Result

9. No significant difference
Results
Table 1. Baseline Characteristics of the Patients in the Induction Phase
No significant difference

10. Ustekinumab > Placebo No significant difference
Results
Figure 1. Efficacy of Ustekinumab in the Induction Phase
Response
Ustekinumab > Placebo
Remission
No significant difference

11. Response & Remission (maintenance phase) Ustekinumab > Placebo
Results
Figure 2. Efficacy of Ustekinumab in the Maintenance Phase
Response & Remission (maintenance phase)
Ustekinumab > Placebo
69.4
41.7
42.5
27.4
P<0.001
P= 0.03

12. Results Serious infections
Table 2. Adverse Events during the Induction Phase (Week 0 to Week 8)
Serious infections
Five patients receiving 6 mg/kg Ustekinumab(C. difficile infection, viral gastroenteritis, UTI, anal abscess, and vaginal abscess)
One patient receiving 1 mg/kg of ustekinumab (staphylococcal infection in a central catheter)
One patient receiving placebo (anal abscess)
Serious adverse events & Infusion reactions were uncommon

13. Results
Table 3. Adverse Events during the Maintenance Phase (Week 8 to Week 36)
There were no deaths, major adverse cardiovascular events, tuberculosis, or other serious opportunistic infections
One basal-cell carcinoma was reported in a patient who received 1 mg/kg of ustekinumab

14. Conclusion

15. Conclusions Induction therapy Maintenance therapy
Remission??
Response & Remission↑
Response↑
Ustekunumab
CD patients
When compared with routine care, an intervention to
promote target-driven, intensive management of
patients with type 2 diabetes detected by screening was
associated with small increases in the prescription of
drugs and improvements in cardiovascular risk factors,
but was not associated with signifi cant reductions in
the incidence of cardiovascular events or death over
5 years.
Placebo