Pro: All medications may be stopped for Crohn’s disease patients in remission Miguel Regueiro, M.D. Professor of Medicine Associate Chief for Education Clinical Head and Co-Director, IBD Center University of Pittsburgh School of Medicine

This is Tom’s side: “Keep taking it Until Something Better Comes Along”

UPMC vs Mt Sinai Pittsburgh vs New York City Based on the name, the storied success of Mt Sinai IBD Center should win this debate, but….look beyond the name

UPMC and Pittsburgh on a typical summer morning

Mt Sinai on that same, bright summer morning

Why even have this debate? Safety Cost Maybe there ARE patients who can stop all treatment and do well. …..and this is probably the #1 question asked by patients starting meds……

Prior to considering discontinuation of treatment, is it possible that we are OVERtreating a subset of patients? What happens to patients NOT maintained on Biologics? In essence, pts brought into remission but then maintained on placebo? - Focus on placebo rates

Pediatric CD: Prednisone induction and 6-MP maintenance 50% on placebo maintain remission 100 200 300 400 500 600 0.00 0.25 0.50 0.75 1.00 6MP Control Remission Duration (days) Fractional Survival Markowitz, et al. Gastroenterol. 2000;119(4):895-902. David T. Rubin, MD 2007 Candy S et al. Gut. 1995;37:674-678.

Prednisone induction, MTX maintenance 39% on placebo maintain remission 100 90 80 70 60 50 40 30 76 patients in remission following MTX 25 mg IM x 16 wk Patients steroid-dependent Randomized to maintenance MTX 15 mg IM (N=36) or placebo (N=40) x 40 wk 65% Percent Remaining in Remission P=.044 39% Placebo MTX 0 4 8 12 16 20 24 28 32 36 40 Weeks Since Randomization Feagan BG, et al. N Engl J Med. 2000;342:1627-32.

Proportion of Patients ACCENT I: IFX induction and maintenance ~20% on placebo maintain remission Single Dose (n=102) 5 mg/kg q 8 wk (n=104) 10 mg/kg q 8 wk (n=105) P < .001 P < .001 60 50% 50 P = .01 P = .021 38% 40 36% Proportion of Patients 28% 30 20% 20 16% 10 Clinical Response Clinical Remission *Among patients responding at Week 2 Hanauer SB et al. Lancet. 2002;359:1541.

CLASSIC II: ADA induction and maintenance 44% on placebo maintain remission Placebo (n=18) 40 mg EOW (n=19) 40 mg wkly (n=18) LOCF; ITT population, n=55 *P<0.05 versus placebo Sandborn WJ, Gut 2007.

PRECiSE 2: Certolizumab induction and maintenance 29% on placebo maintained remission 100 3 Injections + Placebo Certolizumab Pegol 400 mg 80 p < 0.01 p < 0.01 % of Patients 60 47.9 42.0 40 28.6 25.7 20 All (N = 210/215) CRP ≥ 10 (N = 101/112) Schreiber S, et al, last and Senior Author Sandborn WJ NEJM 2007

20%-50% patients from the IMM and antiTNF studies maintain remission WITHOUT medication This means that maybe there are a cohort of pts we OVERtreat – once they are in remission on IMM/antiTNF, they can stop Rx The problem: correctly identifying the patients who can stop rx once they are in remission

…but the debate is about stopping treatment in patients in remission…. We could end the debate here and agree that up to 50% of pts may not need long term treatment – …but the debate is about stopping treatment in patients in remission….

Three Possible Scenarios Stop AZA/6MP and continue antiTNF Stop antiTNF and continue AZA/6MP Stop BOTH meds (no data at present) All antiTNF “stop” studies with IFX/ADA Most data in Crohn’s (less data in UC)

What are the data on stopping AZA/6MP in COMBO antiTNF? Van Assche et al Gastroenterol 2008 Oussalah et al Am J Gastro 2010 Kennedy et al Aliment Pharmacol Ther 2014 This last study evaluated stopping thiopurines alone

>6 months of IFX and IMM Disease controlled (median CDAI 138) Withdrawal of Immunosuppression in CD treated with Scheduled Infliximab Maintenance: A RCT Van Assche G, et al. Gastroenterol 2008;134:1861-1868 >6 months of IFX and IMM Disease controlled (median CDAI 138) Randomized 1:1 IFX 5mg/kg q 8wk with CONtinued IMM IFX 5mg/kg q 8wk with DIScontinued IMM Duration of study: 104 weeks (~ 2 yrs) Primary endpoint: decrease in interval or increase in dose or stopped IFX

Clinical Outcomes at 2 yrs were no different between CON and DIS IMM

Retrospective, observational study Predictors of Infliximab Failure after Azathioprine Withdrawal in CD Treated with Combination Rx Oussalah A et al. Am J Gastroenterol 2010;105:1142-1149 Retrospective, observational study 48 pts >6 mos AZA/IFX in remission AZA withdrawn in all (no control arm, part of investigator’s standard of care) IFX 5mg/kg continued every 8 weeks Primary endpoint: infliximab failure Change interval or dose in response to flare Intolerance of infliximab Abdominal surgery due to progression of CD

The majority of pts (73%) did NOT fail IFX after AZA withdraw median duration without failure = 23m

>3 yrs of 6MP/AZA (no antiTNF) for UC or CD Thiopurine withdrawal during sustained clinical remission in IBD: relapse rates and predictive factor Kennedy NA et al. AP&T 2014;40:1313-1323 >3 yrs of 6MP/AZA (no antiTNF) for UC or CD Sustained remission at time of withdrawal Retrospective 11 center clinical audit Minimum follow-up after withdrawal 12 mos. Primary endpoint: relapse at 12 months

77% CD and 88% UC still in remission at 1 yr CD 23% 1 yr relapse CRP predicted relapse UC 12% 1 yr relapse WBC predicted relapse

All Studies Suggest: Patients in Remission on combination antiTNF and IMM or IMM alone MAY stop the IMM

What are the data on stopping antiTNFs from COMBO Rx? Crohn’s disease studies Waugh AP&T 2010 Louis Gastroenterol 2011 only study that prospectively withdrew infliximab in pts on combo therapy in remission Molnar AP&T 2012 Steenholdt Scand J Gastro 2012

Maintenance of Clinical Benefit in CD pts after Discontinuation of IFX Waugh et al. Aliment Pharmacol Ther 2010;32:1129-1134 48 CD pts in remission on IFX stopped IFX after 1 yr. 67% on concomitant IMM 44% on concomitant AZA 19% on concomitant MTX 4 % on concomitant 6MP 33% on no concomitant IMM Remission and relapse rates assessed over 7 years

1 yr after stopping IFX: 50% relapsed, BUT 50% remained in remission

Maintenance of CD Remission on AZA after Infliximab is Stopped (STORI) Louis et al. Gastroenterology 2011 115 pts in remission on IFX and AZA At least 1 year on IFX/AZA and > 6mos remission off of steroids Followed for at least 30 months

After Infliximab Withdraw: 50% do NOT relapse

STORI Study Conclusions – Infliximab Withdraw, AZA continue 50% did NOT relapse (maintained remission) after stopping IFX 50% relapsed within 1 yr of stopping IFX 88% of relapsers responded to retreatment with IFX

Predictors of relapse in pts with Crohn’s ds in remission after 1 year of biological therapy Molnar T et al. Aliment Pharmacol Ther 2013;37:225-233 121 CD pts in clinical remission on antiTNF stopped antiTNF after 1 year (Relapse After Stopping biologics in Hungary = RASH study) 87 IFX pts and 34 ADA (79% naïve to biologics) 103 pts (85.1%) on concom thiopurines Primary endpoints: time to clinical relapse that necessitated restarting biologics and >100 point increase in CDAI (the CDAI had to be over 150) Identification of factors associated with relapse

45% relapsed/resumed antiTNF (median time 6m)

RASH Study Conclusions – IFX withdrawal in CD remission after 1 yr 55% did NOT relapse (did not require resumption of antiTNF, CDAI<150) 45% DID relapse Previous antiTNF and dose intensification were predictors of relapse (p < .05) Smoking, Elevated CRP, Corticosteroids were likely predictors of relapse (p = .053 - .08) 54.7% of relapses responded to retreatment with IFX/ADA 9.1% did undergo surgery

Outcome after discontinuation of infliximab in IBD pts in clinical remission Steenholdt C et al. Scand J Gastroenterol 2012;47:518-27 81 IBD (53 CD and 28 UC) Observational, single center, retrospective All pts had primary response to IFX and were in a clinical remission Primary endpoints: Clinical relapse rate at 1 year Predictors of relapse

1 year after IFX Withdraw 61% CD and 75% UC do NOT relapse

All Studies Suggest: ONE – HALF OF PATIENTS ON COMBO MAY STOP ANTI-TNF The trick is picking the right patient to stop the antiTNF

Who is the WRONG patient to consider stopping meds. (i. e Who is the WRONG patient to consider stopping meds? (i.e. high likelihood of relapse) Signs of Active CD prior to stopping IFX: Hgb <145 g/L CRP >5 mg/mL Calprotectin >300 ug/g CDEIS >0 Smokers Prior Biologics Dose Intensification Need for steroids Louis et al. Gastroenterol 2011 and Molnar et al. AP&T

Who is the RIGHT patient to consider stopping antiTNF? …..the patient in a deep remission without recent steroid use…..

Deep Remission is Key at predicting maintenance of “anti-TNF free” remission Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn’s Disease (from “Step Up vs Top Down Study”) Baert et al. Gastroenterology 2010;138:463-468

62.5% of pts with complete MH at yr 2 (SES = 0) had IFX-free remission yrs 3-4

Putting the data all together….

Study 50:50 Chance of Relapse whether you stop or continue 55% ~2yr 1st author Stop IMM Cont aTNF Stop aTNF Cont IMM Cont ALL Stop Nothing (index) Overall Chance: Sustained Remission Van Assche 55% ~2yr 45% Oussalah 27% ~2yr 73% Waugh 50% 1 yr 50% Louis Molnar 45% 1 yr 50%-55% Steenholdt 39% CD 1 yr 25% UC 1 yr 61%-75% Six Studies CONTINUE 50%-58% 5 yr 42%-50%

What about stopping antiTNF and IMM? No data at this time on stopping both There are data on stopping 6MP/AZA monotherapy, > 75% still in remission Maybe this would be the group who could stop everything? Deep Remission for > 3 years Endoscopic scores 0 (sustained mucosal healing) Normal CBC, ESR/CRP, Fecal Calprotectin Normal histology Nonsmokers

…and as presented at the beginning of my talk, I’d like to leave you with something to think about….. Are we overtreating a subset of patients? Once deep remission is achieved, could we stop treatment? I think it depends if you/your pt has the “glass is half full or half empty” approach to life

When considering who wins this debate……. …….I showed you a lot of evidenced based data, I tried to take a scientific approach…..

…don’t get fooled by Tom’s Smoke and Mirrors approach

Synthesis and Consensus: Algorithm from Review article: why, when and how to de‐escalate therapy in inflammatory bowel diseases Alimentary Pharmacology & Therapeutics Pariente B and Laharie D, 10:338-353, JUN 2014

Monotx Mucosal ds Perianal ds Complicated ds Clinical remission Mucosa better, not perfect Short duration combo tx Deep remission Long duration combo tx