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You Can Never Stop a Biologic

You Can Never Stop a Biologic. Scott D Lee MD Associate Professor of Medicine Director, Clinical Inflammatory Bowel Diseases Program University of Washington Seattle, WA March 23 rd , 2013. General Considerations in IBD Patients Started and Maintained on Biologics.

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You Can Never Stop a Biologic

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  1. You Can Never Stop a Biologic Scott D Lee MD Associate Professor of Medicine Director, Clinical Inflammatory Bowel Diseases Program University of Washington Seattle, WA March 23rd, 2013

  2. General Considerations in IBD Patients Started and Maintained on Biologics • Diagnosed with moderate to severe disease • At risk for complications of IBD • Have had significant improvement • Discontinued or on significantly less steroids • Do not have related limiting side effects • Have not develop contraindication • Cancer • Active infection • Demyelinating disease

  3. ACCENT I Week 54 Remission after Response to InfliximabDiscontinued vs Continued Therapy P<0.001 P=0.021 Proportion of Patients (%) 5 mg/kgq 8 wks(n=104) 10 mg/kgq 8 wks(n=105) Single Dose(n=102) Remission defined as: CDAI <150 points

  4. ACCENT I P=0.005 P=0.059 P=NS Proportion of Patients (%) 6/54 18/53 14/56 Single Dose 5 mg/kgq 8 wks 10 mg/kgq 8 wks Week 54 Steroid Free Remission After Response to InfliximabDiscontinued vs Continued Therapy

  5. P=0.003 P=0.42 P=0.42 Proportion of Patients(%) Episodic Strategy Maintenance q 8 weeks 10 mg/kg Maintenance q 8 weeks 5 mg/kg Proportion of Patients with ATI* Through Week 54 ACCENT I Infliximab Antibody FormationDiscontinued vs Continued Therapy Hanauer S, et al., ClinGastroenterolHepatol. 2004;2:542–553.

  6. 140 63% of Patients (n=79) 120 37% of Patients (n=46) 100 80 Days of Response 60 40 20 71 days of clinical response to Infliximab therapy 35 days of clinical response to Infliximab therapy 0 Negative 1.7 - 7.9 g/mL 8.0 - 20.0 g/mL >20.0 g/mL Antibody Formation and Effect on Response with Episodic Treatment with Infliximab Duration of Response by Antibody Level Baert F, et al. N Engl J Med. 2003;348:601-608.

  7. Episodic Strategy 10 mg/kg Scheduled Strategy 5 mg/kg Scheduled Strategy Combined Schedule Strategy 50 40 30 P=0.023 P=0.047 P=0.014 20 10 0 Week 54 ACCENT I Continued Therapy Is Associated with Fewer Hospitalizations Number of Hospitalizations per 100 Patients Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

  8. Episodic Strategy 10 mg/kg Scheduled Strategy 5 mg/kg Scheduled Strategy Combined Schedule Strategy 50 40 30 20 10 P = 0.07 P = 0.04 P = 0.01 0 Week 54 ACCENT 1 Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries Proportion of Patients With Surgeries Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

  9. ACT 1 UC Response and RemissionIFX Discontinued vs Continued Therapy Remission Response 100 50 †P<0.001 † 90 45 † † 39 † ‡P<0.01 80 37 40 ‡ † 69 34 70 32 35 62 † ‡ 60 30 52 51 50 Percent of Patients Percent of Patients 25 37 40 20 16 30 15 30 15 20 10 10 5 0 0 8 Weeks 30 Weeks 8 Weeks 30 Weeks Placebo infusions 5 mg/kg infliximab 10 mg/kg infliximab Rutgeerts P. N Engl J Med. 2005;353:2462-2476.

  10. Sustained remission up to month 18 67,7 100 NRI 57,1 LOCF 100 p= 0.5 p= 0.2 44,1 75 75 38,1 % patients % patients 50 50 25 25 0 0 AZA Placebo EFFICACY OF AZA THERAPY Early Use of AZA After First Steroid Induction 150 125 100 Mean CDAI 75 P= 0.07 50 P< 0.01 25 0 2 3 4 7 8 9 10 11 12 13 5 6 Visit number Sans M. Gastroenterology 2011 (Abstract)

  11. Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy p<0.001 p=0.028 p=0.035 41/170 59/169 78/169 SONIC All Randomized Patients (N=508)* Colombel JF et al. NEJM 2010.

  12. SONIC Mucosal Healing at Week 26AZA vs IFX vs Dual Therapy 100 p<0.001 80 p=0.023 p=0.055 60 Proportion of Patients (%) 44 40 30 16 20 18/109 28/93 47/107 0 AZA + placebo IFX + placebo IFX+ AZA

  13. Mucosal Healing Predicts Sustained Clinical Remission in Early CD Mucosal Healing is Predictive of Sustained Remission Simple endoscopic score 1-9 Simple endoscopic score 0 100 * ** ** 80 60 % of patients 40 20 0 Remission at year 3+4 Remission offsteroids at year 3+4 Remission offsteroids at year 3+4 and no flare during year 3+4 * P < 0.05; ** P < 0.01 (Fischer’s exact) Baert FJ, et al. Gastroenterology 2010 .

  14. Risk of Lymphoma Associated with Immunomodulators RISK OF THERAPY - MALIGNANCY • 19,486 IBD patients • 30.1% currently receiving thiopurines • 14.4% discontinued thiopurines • 55.5% never exposed to thiopurines Receiving thiopurines vs. never exposed HR 5.28 (2.01-13.9) Beaugerie et al, Lancet 2009;7:374.

  15. Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents RISK OF THERAPY - MALIGNANCY • 8905 patients representing 20,602 pt-years of exposure • 13 Non-Hodgkin lymphomas  6.1/10,000 pt years • This HR is very similar to SIR with thiopurines • Mean age 52, 62% male • 10/13 exposed to IM* (This is really a risk of combo Rx) • Lymphoma SIR does not appear increase with addition of anti-TNF • Lymphoma SIR appears to be dependent on thiopurine use *not reported in 2 Siegel et al, CGH 2009;7:874.

  16. Anti-TNF Meta-Analysis And Malignancies -0.14% (-0.4-0.2, P=0.39) Risk difference Controls Anti-TNF Difference in effect: treatment minus placebo (CI 95%) RISK OF THERAPY - MALIGNANCY Peyrin-Biroulet et al CGH 2008;6:664.

  17. Conclusions • Discontinued biologic vs continued use leads to: • Higher recurrence rates of disease activity • Lower likelihood of steroid free remission • Increased risk of antibody formation • Antibody formation leads to loss of response • Continued biologic therapy vs Thiopurines is: • More effective maintenance therapy • Thiopurines appear to be the primary risk of lymphoma • Results in higher rates of mucosal healing • Once biologic therapy it should not be stopped as the risks outweigh the benefits • A transition to thiopurinesas maintenance is less effective and potentially higher risk

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