Presentation on theme: "Miguel Regueiro, M.D. Professor of Medicine"— Presentation transcript:
1 Pro: All medications may be stopped for Crohn’s disease patients in remission Miguel Regueiro, M.D.Professor of MedicineAssociate Chief for EducationClinical Head and Co-Director, IBD CenterUniversity of Pittsburgh School of Medicine
7 Why even have this debate? SafetyCostMaybe there ARE patients who can stop all treatment and do well.…..and this is probably the #1 question asked by patients starting meds……
8 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
9 Pediatric CD: Prednisone induction and 6-MP maintenance 50% on placebo maintain remission 1002003004005006000.000.250.500.751.006MPControlRemission Duration (days)Fractional SurvivalMarkowitz, et al. Gastroenterol. 2000;119(4):David T. Rubin, MD 2007Candy S et al. Gut. 1995;37:
10 Prednisone induction, MTX maintenance 39% on placebo maintain remission 1009080706050403076 patients in remission following MTX 25 mg IM x 16 wkPatients steroid-dependentRandomized to maintenance MTX 15 mg IM (N=36) or placebo (N=40) x 40 wk65%Percent Remaining in RemissionP=.04439%PlaceboMTXWeeks Since RandomizationFeagan BG, et al. N Engl J Med. 2000;342:
11 Proportion of Patients ACCENT I: IFX induction and maintenance ~20% on placebo maintain remissionSingle Dose (n=102)5 mg/kg q 8 wk (n=104)10 mg/kg q 8 wk (n=105)P < .001P < .0016050%50P = .01P = .02138%4036%Proportion of Patients28%3020%2016%10Clinical ResponseClinical Remission*Among patients responding at Week 2Hanauer SB et al. Lancet. 2002;359:1541.
12 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 placeboSandborn WJ, Gut 2007.
13 PRECiSE 2: Certolizumab induction and maintenance 29% on placebo maintained remission 1003 Injections + PlaceboCertolizumab Pegol 400 mg80p < 0.01p < 0.01% of Patients6047.942.04028.625.720All (N = 210/215)CRP ≥ 10 (N = 101/112)Schreiber S, et al, last and Senior Author Sandborn WJ NEJM 2007
14 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 RxThe problem:correctly identifying the patients who can stop rx once they are in remission
15 …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….
16 Three Possible Scenarios Stop AZA/6MP and continue antiTNFStop antiTNF and continue AZA/6MPStop BOTH meds (no data at present)All antiTNF “stop” studies with IFX/ADAMost data in Crohn’s (less data in UC)
17 What are the data on stopping AZA/6MP in COMBO antiTNF? Van Assche et al Gastroenterol 2008Oussalah et al Am J Gastro 2010Kennedy et al Aliment Pharmacol Ther 2014This last study evaluated stopping thiopurines alone
18 >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:>6 months of IFX and IMMDisease controlled (median CDAI 138)Randomized 1:1IFX 5mg/kg q 8wk with CONtinued IMMIFX 5mg/kg q 8wk with DIScontinued IMMDuration of study: 104 weeks (~ 2 yrs)Primary endpoint: decrease in interval or increase in dose or stopped IFX
19 Clinical Outcomes at 2 yrs were no different between CON and DIS IMM
20 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:Retrospective, observational study48 pts >6 mos AZA/IFX in remissionAZA withdrawn in all (no control arm, part of investigator’s standard of care)IFX 5mg/kg continued every 8 weeksPrimary endpoint: infliximab failureChange interval or dose in response to flareIntolerance of infliximabAbdominal surgery due to progression of CD
21 The majority of pts (73%) did NOT fail IFX after AZA withdraw median duration without failure = 23m
22 >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:>3 yrs of 6MP/AZA (no antiTNF) for UC or CDSustained remission at time of withdrawalRetrospective 11 center clinical auditMinimum follow-up after withdrawal 12 mos.Primary endpoint: relapse at 12 months
23 77% CD and 88% UC still in remission at 1 yr CD 23% 1 yr relapse CRP predicted relapseUC 12% 1 yr relapseWBC predicted relapse
24 All Studies Suggest: Patients in Remission on combination antiTNF and IMM or IMM alone MAY stop the IMM
25 What are the data on stopping antiTNFs from COMBO Rx? Crohn’s disease studiesWaugh AP&T 2010Louis Gastroenterol 2011only study that prospectively withdrew infliximab in pts on combo therapy in remissionMolnar AP&T 2012Steenholdt Scand J Gastro 2012
26 Maintenance of Clinical Benefit in CD pts after Discontinuation of IFX Waugh et al. Aliment Pharmacol Ther 2010;32:48 CD pts in remission on IFX stopped IFX after 1 yr.67% on concomitant IMM44% on concomitant AZA19% on concomitant MTX4 % on concomitant 6MP33% on no concomitant IMMRemission and relapse rates assessed over 7 years
27 1 yr after stopping IFX: 50% relapsed, BUT 50% remained in remission
28 Maintenance of CD Remission on AZA after Infliximab is Stopped (STORI) Louis et al. Gastroenterology 2011115 pts in remission on IFX and AZAAt least 1 year on IFX/AZA and > 6mos remission off of steroidsFollowed for at least 30 months
30 STORI Study Conclusions – Infliximab Withdraw, AZA continue 50% did NOT relapse (maintained remission) after stopping IFX50% relapsed within 1 yr of stopping IFX88% of relapsers responded to retreatment with IFX
31 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;37:121 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 thiopurinesPrimary 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
33 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 relapsePrevious antiTNF and dose intensification were predictors of relapse (p < .05)Smoking, Elevated CRP, Corticosteroids were likely predictors of relapse (p = )54.7% of relapses responded to retreatment with IFX/ADA9.1% did undergo surgery
34 Outcome after discontinuation of infliximab in IBD pts in clinical remission Steenholdt C et al. Scand J Gastroenterol 2012;47:518-2781 IBD (53 CD and 28 UC)Observational, single center, retrospectiveAll pts had primary response to IFX and were in a clinical remissionPrimary endpoints:Clinical relapse rate at 1 yearPredictors of relapse
35 1 year after IFX Withdraw 61% CD and 75% UC do NOT relapse
36 All Studies Suggest: ONE – HALF OF PATIENTS ON COMBO MAY STOP ANTI-TNF The trick is picking the right patient to stop the antiTNF
37 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/LCRP >5 mg/mLCalprotectin >300 ug/gCDEIS >0SmokersPrior BiologicsDose IntensificationNeed for steroidsLouis et al. Gastroenterol 2011 and Molnar et al. AP&T
38 Who is the RIGHT patient to consider stopping antiTNF? …..the patient in a deep remission without recent steroid use…..
39 Deep Remission is Key at predicting maintenance of “anti-TNF free” remission Mucosal Healing Predicts Sustained Clinical Remission in Patients WithEarly-Stage Crohn’s Disease (from “Step Up vs Top Down Study”)Baert et al. Gastroenterology 2010;138:
40 62.5% of pts with complete MH at yr 2 (SES = 0) had IFX-free remission yrs 3-4
42 Study 50:50 Chance of Relapse whether you stop or continue 55% ~2yr 1st authorStop IMMCont aTNFStop aTNFCont IMMCont ALLStop Nothing(index)Overall Chance:Sustained RemissionVan Assche55% ~2yr45%Oussalah27% ~2yr73%Waugh50% 1 yr50%LouisMolnar45% 1 yr50%-55%Steenholdt39% CD 1 yr25% UC 1 yr61%-75%Six StudiesCONTINUE50%-58%5 yr42%-50%
43 What about stopping antiTNF and IMM? No data at this time on stopping bothThere are data on stopping 6MP/AZA monotherapy, > 75% still in remissionMaybe this would be the group who could stop everything?Deep Remission for > 3 yearsEndoscopic scores 0 (sustained mucosal healing)Normal CBC, ESR/CRP, Fecal CalprotectinNormal histologyNonsmokers
44 …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
45 When considering who wins this debate……. …….I showed you a lot of evidenced based data, I tried to take a scientific approach…..
46 …don’t get fooled by Tom’s Smoke and Mirrors approach
47 Synthesis and Consensus: Algorithm from Review article: why, when and how to de‐escalate therapy in inflammatory bowel diseasesAlimentary Pharmacology & Therapeutics Pariente B and Laharie D, 10: , JUN 2014