1. What do we do when the patient loses their response to an anti-TNF: Minor tweaks or major treatment changes? Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania, Perelman School of Medicine Director, Center for Pediatric IBD The Children's Hospital of Philadelphia

2. What is secondary loss of response ? Symptoms only “(1) an increase in the PCDAI of >15 points from the reference PCDAI at week 10 at 2 consecutive visits at least 7 days apart, or (2) the PCDAI was higher than 30 points at any scheduled or unscheduled visit” (Hyams J, Gastro 2007) “Patients who initially respond to anti-TNF therapy and subsequently lost clinical response…with a rise of >70 points of CDAI” (Allez M, ECCO Workshop, J Crohn Colitis 2010) “Symptoms plus evidence of inflammation” (Regueiro M, Inflam Bowel Dis 2007) Symptoms + inflammation “ Withdrawal of infliximab and switch of medical therapy or need for surgery” (de Ridder, Inflam Bowel Dis 2008) “Recurrent symptoms necessitating adalimumab dose escalation” Karmiris K, Gastro 2009 Symptoms + Treatment change

3. Intensification & Discontinuation of anti-TNF at 12 months Ben-Horin S, Aliment Pharmacol Ther 2011 At 12 months: Dose escalation - 23-46% Drug discontinuation - 5-13%

4. Cumulative rate of loss of response over time to anti-TNF treatment (adalimumab) Alimentary Pharmacology & Therapeutics Volume 33, Issue 9, pages 987-995, 2011 Volume 33, Issue 9, 2/3 of patients who lose response to anti-TNF do so within the first 12 months of therapy

5. Managing loss of response: Verify the cause of LOR Is it really inflammatory IBD activity ?

6. Uncontrolled IBD inflammation : (Low drug level) Loss of anti-TNF activity due to anti-drug antibodies Relentless TNF-mediated flare ‘consuming’ all anti-TNF Ab Loss of anti-TNF activity due to non-immune drug clearance Non-adherence to therapy Uncontrolled IBD inflammation: (Adequate drug level) Shift of disease pathway away from TNF to other mediators Non-IBD related inflammation: (Adequate drug level, High CRP) Infection ! Other (vasculitis, ischemia) Non-inflammatory mechanisms (Adequate drug level, Normal CRP) Fibrostenotic strictures Cancer IBS Miscellaneous (Amyloidosis, BOG, Bile salt diarrhea, etc) Possible mechanisms of worsening on anti-TNFs Adapted from Allez M, J Crohn Colitis 2010

7. Possible mechanisms of worsening on anti-TNFs Adapted from Allez M, J Crohn Colitis 2010 Scope, Scope and Scope…

8. Managing loss of response: Start with prevention…

9. Scheduled vs. Episodic IFX Matters Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:1248  54.

10. Clinical Remission CRP < 5 mg/dl Endoscopic Improvement >75% P<0.001 % of patients IFX Trough Levels are Important Outcomes at 1 year on scheduled infliximab therapy * * * Trough

11. Higher trough levels associated with better response Colombel JF, et al. N Engl J Med. 2010;362:1383-1395 HYPOTHESIS: Optimizing levels with anti-TNF monotherapy could be an alternate to dual therapy SONIC Trial

12. Effect of Infliximab Antibody Concentration on Duration of Response 0 20 40 60 80 100 120 140 Negative1.8–8.0 µg/mL8.0–20.0 µg/mL>20.0 µg/mL Concentration of Antibodies to Infliximab Days Until Subsequent Infusion P < 0.001 Baert F et al. N Engl J Med. 2003;348:601. 28 days 61 days

13. Relationship Between ATI Concentration and Infusion Reactions No Infusion ReactionInfusion Reaction ATI Level (µg/mL) 2 0 4 6 8 10 12 14 16 18 20 22 24 26 28 30 ATI levels  8.0 µg/mL More likely to experience infusion reactions (relative risk, 3.9; 95% CI 1.3 to 11.7; P = 0.04) Miele E et al. J Pediatr Gastroenterol Nutr. 2004;38:502.

14. Rapid IFX Clearance: Mechanism of Non-response in UC Kevans D, et al. DDW 2012

15. Undetectable Serum IFX Trough Predictive of Colectomy in UC 55% 17% P<0.001 Colectomy (% patients) Seow CH et al, Gut 2010;59:49-54

16. Managing loss of response: Dose intensification

17. Dose escalation results in ~60% (short-term??) response Managing loss of response – Dose intensification % regained response Ben-Horin S, Aliment Pharmacol Ther 2011 At 12 months: Regained response - 50-70%

18. Diverse Protocols Abound Infliximab Adalimumab 5mg/kg/6weeks 40mg/EW 7.5mg/kg/8weeks 80mg/EOW 10mg/kg/8weeks 40mg/10 days 5mg/kg/4weeks Re-induction followed by de-escalation How to intensify ?

19. 10mg/kg/8w 5mg/kg/4w P=0.2 Katz L, Inflamm Bowel Dis, 2012 Double dose (10mg/kg/8w) is at least as effective as interval halving (5mg/kg/4w) in loss of response to Infliximab

20. 0261422 wks. 0 3 10 µg/mL increased toxicity? The therapeutic window concept Nesterov I. J Rheumatol 2005 loss of efficacy

21. Antibody to IFX Can Be Transient 90 adult IBD patients – 1,232 serum samples 59% developed ATI – By study design ATI was transient in 28% Vande Casteele N et al. Am J Gastroenterol 2013

22. Vande Casteele N, Am J Gastroenterol 2013 Patients with sustained ATI developed significantly higher ATI levels over time compared with patients with transient ATI.

23. Vande Casteele N, Am J Gastroenterol 2013 Trough level of Infliximab (μg/ml) Dose-intensification must increase IFX trough level to regain response

24. Managing loss of response: Add an immunomodulator (6MP, AZA, MTX)

25. 0 10 20 30 40 Concentration (mcg/ml) Start MTX 10 20 30 40 50 Patient 1 Weeks 0 10 20 30 40 50 60 Start AZA Patient 3 Start 6-MP Patient 2 Start AZA 0 10 20 30 40 50 Patient 4 Concentration (mcg/ml) Weeks Ben Horin S, Clin Gastroenterol Hepatol 2013 Adding immunomodulator to revert immunogenicity Weeks Concentration (mcg/ml)

26. Predictive Value

27. Infliximab Trough May Predict Sustained Response in Crohn Disease Retrospective adult cohort 84 patients – IFX trough level measured at 14 or 22 wks Sustained clinical response IFX Trough level > 3 μg/ml Increase in ATI IFX Trough level < 3 μg/ml Bortlik M et al. J Crohns Colitis 2012

28. IFX Trough Levels Greatest predictor of IFX failure – Any IFX trough < 0.91 μg/ml IFX trough <2.2 μ g/ml at week 14 predicts – Develop ATI (p<0.0001) – Discontinue IFX for LOR/hypersensitivity (p=0.003) When escalating therapy – ATI > 9.1 U/mL   risk of failure (LR 3.6) – Patients with success had increase in IFX levels Vande Casteele N et al. Am J Gastroenterol 2013; epub ahead of print Authors suggest: dose escalation if IFX trough <2.2 at week 14 dose escalation can be attempted with low level ATI

29. Proposed Treatment Algorithm Positive ATI (detectable antibody) > 9 ≤ 9 Change to another anti-TNF Increase infliximab or add IM no success If persistent disease, change to Rx with different mechanism of action (non- anti-TNF agent) Therapeutic IFX conc (>3 mcg/ml trough level) Active disease on Endoscopy/radiology Inactive disease on Endoscopy/radiology Change to Rx with different mechanism of action (non- anti-TNF agent) Investigate for alternate etiology of symptoms Sub-therapeutic IFX (<3 mcg/ml trough level) Increase infliximab and/or add IM If persistent disease, change to another anti-TNF Adapted from Afif W et al. Am J Gastroenterol 2010; 105:1133-1139