Op#mizing)Management)in)IBD:) Mucosal)Healing)

Op#mizing)Management)in)IBD:) Mucosal)Healing) Vipul&Jairath&MD&PhD& Associate&Professor&of&Medicine,&Epidemiology&and& Biosta=s=cs& Western&University&&& Division&of&Gastroenterology,&& London&Health&Sciences&Network&

Biological)importance)of)mucosal)healing)

Mucosal)healing)in)UC:) Known)Knowns ) Associated&with&improved&clinical&outcomes& No&causal&proof&beJer&than&trea=ng&to&symptoms& Objec=ve&and&reliable&measure&of&disease&ac=vity& Discordance&between&symptoms&and&endoscopy& Will&soon&inform&regulatory&approval,&claims& labelling&and&reimbursement&

Early)Mucosal)Healing)with)IFX)and)Steroid) Free)Remission) 100 80 Patients (%) 60 40 20 0 46 0 (n=120) 34 1 (n=175) 11 2 (n=114) p<0.0001 6.5 3 (n=57) Endoscopic score at Week 8 (ACT 1 & 2) Colombel JF et al. Gastroenterology 2011;141:1194 201.

Early)Mucosal)Healing)with)IFX)is)Associated) with)reduced)risk)of)colectomy) 1.00) Propor#on)with)colectomy) 0.75) 0.50) 0) p=0.0004) Endoscopy)subscore)=)0) Endoscopy)subscore)=)1) Endoscopy)subscore)=)2) Endoscopy)subscore)=)3) 10) 20) 30) 40) 50) Time)to)colectomy)(weeks)) Colombel)JF)et#al.)Gastroenterology#2011;141:1194 201.)

Early)Response)to)Steroids)and)5\year)Outcome) #& *& *& #& #& *& *& *p<0.05&vs.&clinical&and&endoacopic&remission& #&p<0.05&vs.&clinical&remission&(+ /X&endoscopic&remission)& Ardizzone S, et al. Clin Gastroenterol Hepatol. 2011;9:483-9

Severity)of)Inflamma#on)is)a)Risk)Factor)for) Variable) Colorectal)Neoplasia)in)UC) Controls) (n=136)) Cases) (n=68)) 2.22& (0.78)& 2.38& (0.56)& Odds)ra#o)(95%) confidence)interval)) P)value) Colonoscopy) inflamma#on)score) 1.89&(0.52)& 2.54&(1.45 4.44)& 0.001& Histological) inflamma#on)score) 2.05&(0.41)& 5.13&(2.36 11.14)& <0.001& Family)history)of)CRC) (%)) 18&(14)& 7&(12)& 1.09&(0.40 2.94)& 0.17& PSC)(%)) 2&(2)& 4&(6)& 4.00&(0.73 21.84)& 0.11& Mesalamine)use)(%)) 122&(90)& 65&(96)& 2.38&(0.67 8.54)& 0.32& Azathioprine)use)(%)) 37&(28)& 12&(18)& 0.73&(0.30 1.78)& 0.22& Folate)supplement)(%)) 5&(4)& 1&(1)& 0.40&(0.05 3.42)& 0.40& Current)smoker)(%)) 9&(7)& 2&(4)& 0.43&(0.08 2.23)& 0.37& Segmental colonoscopic and histological inflammation was recorded by using a simple score (0, normal; 1, quiescent/chronic inflammation; and 2, 3, and 4, mild, moderate, and severe active inflammation, respectively). Rutter M et al. Gastroenterology. 2004;126:451-9

Mucosal)Healing)in)UC:) Known)Knowns ) Associated&with&improved&clinical&outcomes& No&causal&proof&beJer&than&trea=ng&to&symptoms& Objec=ve&and&reliable&measure&of&disease&ac=vity& Discordance&between&symptoms&and&endoscopy& Will&soon&inform&regulatory&approval,&claims& labelling&and&reimbursement&

Reliability)of)UC)Endoscopic)Assessment) Indices) UCDAI) Sigmoidoscopy) Score) Intraobserver)Agreement) All)7) Central) Readers) Instrument) Modified)Baron) Score) Ulcera#ve)Coli#s) Endoscopic)Index) of)severity) Visual)Analogue) Scale) 0.89)(0.85\0.92)) 0.88)(0.84\0.92)) 0.89)(0.85\0.93)) 0.91)(0.88) )0.94)) Es#mates)of)Intra\rater)and)Inter\rater)Agreement)Based)on)Data)from)50)Random) Videos)Evaluated)3)Times)by)7)Blinded,)off\site)readers) Feagan)BG.)et)al.)Gastroenterology)2013;145:149\157))

Discrepancy)Between)Symptoms,)Endoscopy) and)histology) Colombel)J,)Gut)Sept)2016)

Regulatory)Considera#ons) Mucosal&healing&has&been&included&as&a&secondary&endpoint&in& many&clinical&trials.&&in&many&clinical&trials,&mucosal&healing&has&been& defined&as&mayo&endoscopic&subscore&of&less&than&or&equal&to&1& point.&&however,(a(claim(of(mucosal((healing(would(not(be(supported( through(endoscopy(that(provides(only(an(assessment(of(the(visual( appearance(of(the(mucosa.&any&claim&related&to&findings&on& endoscopy,&in&the&absence&of&validated&histological&assessment&of& the&mucosa,&would&be&limited&to&the&endoscopic&appearance&of&the& mucosa & FDA&Drai&Guidance&2016&

Mucosal)Healing)in)CD:) Known)Knowns ) Associated&with&improved&clinical&outcomes& Surgery,&hospitaliza=on,&longterm&remission& Severity&of&lesions&correlates&with&prognosis& A&predictor&or&relapse&aier&withdrawal&of&an=XTNF& therapy&

Early)Mucosal)Healing:)Long\Term)Remission) EXTEND: Endoscopic response at week 12 and 1 year remission Patients (%) 80 70 60 50 40 30 20 10 68 p<0.0001 10 0 5 (n=31) >5 (n=31) SES-CD score at Week 12 Clinical remission defined as a CDAI score <150 EXTEND subanalysis; primary endpoint was complete mucosal healing at Week 12 (p=0.056); all patients received adalimumab induction therapy from Week 0, before being randomised to placebo or adalimumab maintenance therapy at Week 4 Rutgeerts P et al. Gastroenterology. 2012 May;142(5):1102-1111

Predic#ve)Factors)at)Year)2)for)Remission) During)Year)3)and)Year)4)(SUTD) P<0.05 P<0.05 Baert F, et al. Gastroenterology 2010; 138:463-8

Mucosal)Healing)and)Resec#on)in)CD) IBSEN Study: risk of future surgery in patients with mucosal healing at 1 year (n=146) 1.0 Proportion of patients not resected 0.9 0.8 0.7 0.6 0.5 No mucosal healing Mucosal healing HR = 0.42, 95% CI 0.20 0.89; p=0.027 Adjusted for age and disease extent at diagnosis 83% 69% 0 1 2 3 4 5 6 7 8 Time in years after 1-year visit 9 Solberg IC et al. Clin Gastroenterol Hepatol. 2007;5:1430-8.

Severity)of)Endoscopic)Lesions)and)Long) Term)Outcome)in)CD) Development of fistulizing disease Colectomy P=0.02 6/53 Allez M et al. Am J Gastroenterol 2002;97:947 53.

Endoscopic)Scoring)System)for) Postopera#ve)Recurrence)(Rutgeerts)Score) Post-operative recurrence after ileo-colonic resection Percent 100 80 60 40 20 0 Survival without: Endoscopic lesions Laboratory recurrence 0 1 2 3 4 5 6 7 8 Years Symptoms Surgery Symptom free survival (%) 1 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 6 7 8 Years i4 i2 i3 i0 + i1 Rutgeerts P, et al. Gastroenterology 1990;99:956 963

Relapse)Upon)Infliximab)Discon#nua#on)(STORI) Treated with combined scheduled infliximab+immunosuppressive therapy for at least 1 year. In stable remission without steroid for more than 6 months CDESI=0, low CRP, Normal HB = sustained clinical remission in 80% patients 1 Index # relapse Proportion 0.8 0.6 0.4 0.2 4 2/19 =5 10/36 Global 40/107 =6 13/24 =7 25/28 0 0 3 6 9 12 15 18 21 Months since inclusion 24 27 30 33 # at risk:115 102 79 63 51 47 39 27 20 12 9 Louis E et al Gastroenterology 2012;142:63 70

Known)Unknowns :)Defini#ons!) UC& Absence&of&friability,& blood,&erosions,&ulcers& Severity&of&bleeding& without&considering& ulcers& Mayo&0&or&1& UCDAI& 1& CD& Absence&of&ulcera=on& No&ulcera=on&in&any& segment& SESXCD& 5& CDEIS& 2,& 3& Rutgeerts& i1&

Peyrin-Birolet et al. Am J Gastro

Ulcera#ve)Coli#s:)What)is)the) Consensus)Target?) Peyrin-Birolet et al. Am J Gastro

Crohn s:)what)is)the)consensus)target?) Peyrin-Birolet et al. Am J Gastro

Measuring)the)Score)

The)Mayo)Endoscopic)Subscore) Findings of flexible proctosigmoidoscopy 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) Schroeder&KW,&et(al.(N(Engl(J(Med(1987;317:1625 9.&

UCEIS:)Reliability)and)Ini#al)Valida#on) Descriptor) (score&most&severe& lesions)) Likert)scale)anchor) points) Defini#on) Vascular)paoern) Normal)(0)& Normal)vascular)paoern)with)arboriza#on)of)capillaries)clearly) defined)or)with)blurring)or)patchy)loss)of)capillary)margins) Patchy)oblitera#on)(1)& Patchy)oblitera#on)of)vascular)paoern) Obliterated)(2)& Complete)oblitera#on)of)vascular)paoern) Bleeding) None)(0)& No)visible)blood) Mucosal)(1)& Some)spots)or)streaks)of)coagulated)blood)on)the)surface)of) the)mucosa)ahead)of)the)scope)that)can)be)washed)away) Luminal)mild)(2)& Some)free)liquid)blood)in)the)lumen) Luminal)moderate)or) severe)(3)& Frank)blood)in)the)lumen)ahead)of)the)endoscope)or)visible) oozing)from)a)haemorrhagic)mucosa) Erosions)and)ulcers) None)(0)& Normal)mucosa,)no)visible)erosions)or)ulcers) Erosions)(1)& Tiny)( 5&mm)&defects)in)the)mucosa)of)a)white)or)yellow)colour) with)a)flat)edge) Superficial)ulcer)(2)& Larger)(>5&mm)&defects)in)the)mucosa.)Which)are)discrete) fibrin\covered)ulcers)when)compared)with)erosions)but) remain)superficial) Deep)ulcer)(3)& Deeper)excavated)defects)in)the)mucosa)with)a)slightly)raised) Vascular&paJern&provide&discrimina=on&for&lower&levels&of&severity& edge) Bleeding&discriminate&between&higher&levels&of&severity& NOTE. The worst affected area of the colon visible at sigmoidoscopy was scored. Although the original version of UCEIS gave a score of 1 to the normal appearance of a descriptor, a collective decision was made to change the numbering of the levels with normality awarded a score of 0, so that the simple sum of the UCEIS ranges from 0 to 8 Travis S, et al. Gut 2012;61:535 42;

UCEIS:)Examples) UCEIS 0 (V0, B0, E0) UCEIS 5 (V2, B1, E0) UCEIS 8 (V2, B3, E3) Vascular pattern V0: Normal; V1: Patchy obliteration; V2: Obliterated Bleeding B0: None; B1: Mucosal; B2: Luminal mild; B3: Luminal moderate or severe Erosions and ulcers E0: None; E1: Erosions; E2: Superficial ulcer; E3: Deep ulcer Walsh A, et al. Gastrointest Endosc Clin N Am 2014;:367 78.

CDEIS) Numerical grading system: 0-44

Simple)Endoscopic)Score)for)CD:)SES\CD) Numerical grading system: 0-56 Variable) Size)of)ulcers) None) Aphthous)ulcers) (0.1)to)0.5)cm)) Presence)and)size)of)ulcers)(0\3)) Extent)of)ulcerated)surface)(0\3)) Extent)of)affected)surface)(0\3)) Ileum& SES\CD)Score) Right& colon& SES\CD)values) 0) 1) 2) 3) Transverse& colon& Large)ulcers) (0.5)to)2.0)cm)) Very)large)ulcers) (>)2)cm)) Ulcerated)surface) None) <)10%) 10\30%) >)30%) Affected)surface) Unaffected)segment) <)50%) 50\75%) >)75%) Presence)of)narrowing) None) Single,) Can)be)passed) Mul#ple,) Can)be)passed) Cannot)be)passed) Lei&colon& Rectum& Total& Every segment of the bowel is scored on a scale from 0 to 3 using the endoscopic variables. If a segment was not seen due to nonpassable stenosis or was removed due to the previous surgery it scores 0. The sum of the scores for each endoscopic variable ranges from 0 to 15, except for stenosis, where it varies between 0 and 11, because 3 represents a stenosis through which a colonoscope cannot be passed and that can be observed only once. Patients with ileo-rectal anastomosis should be excluded as there are only 2 segments to consider. Presence)and)type)of)narrowings) (0\3)) SES\CD= Adult 8 mm Size references Adult endoscope D=13.6 mm Pediatric endoscope D=11.6 mm Pediatric ~ 7mm With fully open jaws Daperno M,. Gastrointest Endosc. 2004 Oct;60(4):505-12.

SES\CD:)Example) Variable: Ulcer Variable: Ulcerated and Affected Surface Aphthous ulcer - a tiny (< 5mm) flat defect of the mucosa of whitish, yellowish or greyish color with erythematous halo 10-30% ulcerated surface < 50% affected surface Large ulcer a discrete, fibrin-covered defect of the mucosa (>5mm but less< 2cm ) of whitish, yellowish or greyish color with flat or excavated edges > 30% ulcerated surface 50-75% affected surface Very large ulcer - a discrete, fibrin-covered defect of the mucosa (> 2cm) of whitish, yellowish or greyish color with flat or excavated edges > 30% ulcerated surface > 75% affected surface These are the single frames of the endoscopic video. Assessment of the sequences of video frames is required to score the entire segment/s of the bowel.

SES\CD:)Example) Aphthous ulcers (0.1-0.5 cm) are present in the ileum Score = 1.0 for the ileum Extent of ulcerated surface is 10-30% in the ileum Score = 2.0 for the ileum Extent of affected surface is >75% in the ileum Score = 3.0 for the ileum There is no narrowing/s in the ileum Score = 0.0 for the ileum TOTAL SCORE FOR THE SEGMENT: 6.0 Aphthous ulcers in the ileum

Rutgeerts )Endoscopic)Score)for)Recurrence)of) CD)in)Neoterminal)Ileum) Score Criteria 0 1 2 No lesions < 5 Aphtoid ulcers > 5 aphtoid ulcers with normal mucosa in between or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis 3 4 Difuse ileates with large ulcers, normal mucosa in between Difuse ileitis with large ulcers, nodules/narrowing without normal mucosa in between

Experts )and) Non\Experts )Can)Score)Just)as)Well) Dubenco, E. JCC, 2016

Alterna#vely)\)Describe)what)You)See) Perineal&exam& Loca=on&and&extent&of&inflamma=on&(e.g.&%&surface&area)& If&the&bowel&involvement&is&con=nuous&or&patchy& Comment&on:& Erythema& loss&of&vascularity& bleeding&(spontaneous&or&contact)& erosions&or&ulcera=ons&(superficial&or&deep)& Strictures&or&fistulas& Overall&impression:& Endoscopically&quiescent&remission &

Looking)Beyond)the)Mucosa)

How) Deep )is)remission?) Neurath and Travis, Gut 2012

)Predictors)of)Relapse)in)UC) Hazard)ra#o) (95%)CI)) P)value) Age) 0.4 a )(0.2 0.7)) 0.003) Basal) plasmacytosis) No.)of)prior) relapses) (women)) No.)of)prior) relapses)(men)) 4.5)(1.7 11.9)) 0.003) 1.6 b )(1.2 1.9)) <0.001) 0.93))(0.7 1.3)) 0.64) a Per&decade.& &b No&significant&differences&in&WBC,&Hb,&and&albumin.& Propor#on)of)pa#ents)in)remission) 1) 0.75) 0.5) 0.25) 0) 0) Basal)Plasmacytosis) Absence) Presence) 2) 4) 6) 8) 10) 12) Months)on)study) Bitton A, et al. Gastroenterology 2001;120:13 20

Histological)Remission)Predicts)Lower) Hospitaliza#on)Rates)and)steroid)use) Histological)remission)is)associated)with)a)4\fold)reduc#on)in) hospitalisa#on) Hospitaliza#on) 1) Clinical) 1) Endoscopic) 1) Histological) 0.5) 0.5) 0.5) 0) 0) 10) 20) 30) 40) Time)(months)) Clinical)remission) No)clinical)remission) 0) 0) 10) 20) 30) 40) Time)(months)) Endoscopic)remission) No)endoscopic)remission) 0) 0) 10) 20) 30) 40) Time)(months)) Histological)remission) No)histological)remission) Clinical)remission) Endoscopic)remission) Histological)remission) Hazard)Ra#o)(95%)CI)) 0.24)(0.05 )1.10) 0.53)(0.18 1.56) 0.27)(0.07 0.95) P)value) 0.07) 0.25) 0.048) Bryant RV, et al. Gut, 2015

Ultrastructural)Healing) Normal mucosa CDEIS<4 with endomicroscopic activity Active CD Mucosal healing at endomicroscopy Neurath and Travis, Gut 2012

Can)Our)Current)Armamentarium)Achieve) Mucosal)Healing?)

Crohn s UC 5-ASA - 44% 1 Steroids -? 30% 2 Azathioprine 53% 3 53% 4 Methotrexate 11% 5? Infliximab 48% 6 50% 7 Certolizumab 4% 8? Adalimumab 24% 9 41% 10 Vedolizumab? 51% 11 1. Römkens TEH, et al. Inflamm Bowel Dis. 2012;18:2190-8 2. Truelove SC, Witts LJ. Br Med J. 1954;4884:375-378 3. Lémann M, et al. Gastroenterology. 2005 ;128:1812-8. 4. Ardizzone S, et al. Gut 2006;55:47 53 5. Laharie D, et al. Aliment Pharmacol Ther. 2011;33:714-21 6. Ferrante M et al. Gastroenterology. 2013;145:978-986 7. Rutgeerts P, et al. N Engl J Med. 2005;353:2462-2476 8. Hébuterne X, et al. Gut. 2013;62:201-8 9. Rutgeerts P et al. Gastroenterology. 2012;142:1102-11 10. Sandborn WJ et al. Gastroenterology. 2012;142:257-65 11. Feagan BG et al. N Engl J Med. 2013;369:699-710

Surrogates)for)endoscopic)disease)ac#vity)

Surrogates)for)endoscopic)disease)ac#vity) CRP& 20%&do&not&mount&a&response& Differs&in&CD&vs&UC& Confounded&by&age,&sex,&BMI& Calprotec=n& Higher&levels&in&colon&vs.&Ileum& CutXoffs&unclear& IntraXindividual&varia=on,&assay&standardiza=ons& Lactoferrin& Unstable&at&room&temperature& Unclear&cutXoffs&

Calprotec#n)to)detect)ac#ve)inflamma#on:UC) Variable) Sensi#vity) Specificity) CRP) IBD) Calprotec#n) CD) UC) &0.49&(0.34,&0.64)&& &0.87&(0.82,&0.91)&& &0.88&(0.84,&0.92)&& &0.92&(0.72,&0.98)&& 0.67&(0.58,&0.75)&& &0.79&(0.68,&0.87)&& Stool)Lactoferrin) IBD) 0.82&(0.73,&0.88)&& &0.79&(0.62,&0.89)&& Mosli et al; Am J Gastroenterol. 2015 Jun:110(6):802-15

How)Important)is)Mucosal)Healing)in)the) Course)of)IBD?) Mucosal&healing,&which&can&be&achieved&by&several& drugs,&is&associated&with&bejer&outcomes& Lower&hospitaliza=on&rates,&relapse&rates& Mucosal&healing&may&be&associated&with&a&lower&risk& of&colorectal&cancer&in&uc& Mucosal&healing&is&associated&with&less&bowel& damage&in&cd& Mucosal&healing&is&a&predictor&of&relapse&aier&an=X TNF&withdrawal&

Unanswered)Ques#ons) How&much&mucosal&healing&is&needed&to&modify&disease& course?& Should&therapies&be&op=mized&to&achieve&MH&or&to&avoid& adverse&outcomes&in&the&absence&of&healing?& When&is&the&best&=ming&for&endoscopic&reXevalua=on&aier& interval&change&in&therapy&& Is&trea=ng&to&mucosal&healing&any&beJer&than&trea=ng&to& clinical&symptoms&(will&pa=ents&accept&this?)& Is&trea=ng&beyond&mucosal&healing&beJer&than&to&mucosal& healing&or&symptoms&(will&pa=ent&accept&this?)& Can&dose&deXescala=on&occur&aier&a&period&of&deep& remission?&

Randomized)Trials)in)the)Pipeline) REACT)2) Cluster&trial& Algorithmic&approach&of& trea=ng&to&symptoms& vs.&mucosal&healing& 24&months&follow&up&of& CD&related& hospitaliza=on/&& complica=ons/surgeries& CALM)Trial) Individual&randomized& Tight&disease&control& (CDAI,&CRP,&Calpro)&vs.& management&using&less& stringent&disease& criteria&(cdai)& Studies are needed in Ulcerative Colitis

Prac#cal)Recommenda#ons:)UC) Baseline)endoscopy:)first)presenta#on)of)significant)symptoms) Follow)up)colonoscopy))at)3\6)months:)Adjust)therapy)accordingly) Stra#fy)according)to)relapse)risk) High)Risk) o Flare<12)months) o Recent)therapy)change) o Persistent)lesions) o Persistent)neutrophils) o Smoking)cessa#on) o Poor)adherence) Low)Risk) o Remission>12)months) o Stable)maintenance) therapy) o Endoscopic)healing) o Histological)healing) o Smoker) o Good)adherence) Clinic)3\4)months) Calprotec#n)2\3)months) CRP)2\3)months) Re\scope)if)symptoms)or)abnormal) biomarkers) Clinic)6\12)months) Calprotec#n)3\6)months) CRP)3\6)months) Re\scope)if)symptoms)or)abnormal) biomarkers)

Stratify low / high risk: Age; disease location; disease behavior, smoking; deep ulceration TNF ; Immunosuppressants Other treatment options Complete Clinical remission Biomarker normalization at 12-16 weeks + endoscopy Complete Clinical remission Biomarker normalization at 12-16 weeks Yes No No Yes Monitor symptoms & biomarkers every 3-6 months When altered Endoscopy and / or cross-sectional imaging Adapt therapy and further monitoring according to drug class After 6months