New 06 Terdiman NewParadigm - UCSF CME · 2016. 11. 15. · • Prolonged flare • Active...

10/20/16

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New Paradigms, New Management: Our Changing Understanding of Ulcerative Colitis and Diverticulitis

Jonathan P. Terdiman, MDProfessor of Clinical Medicine and SurgeryDirector, Gastroenterology Service

Disclosures

• None

2Hospitalized UC Patient|

UC: History• 20 year old woman, college student• Developed bloody diarrhea during midterm

examinations. 10+ BMs per day and night• Roommate brings her to ED

– Pale– Tachycardic (> 120), BP 85/45, afebrile– Abdominal pain, Tender in LLQ, focal rebound– Bloody bowel movements in ED– WBC 16K, Hct 22%, crp 70 mg/L

• Admitted to Hospital


In Hospital

• Dehydrated – IV fluids, VS normalize• Diet: Clear liquids

• CT scan

– LB wall thickening and fat stranding, no dilation of the colon• Stools collected for infectious agents

- for culture, E.coli 0157, O&P, C diff


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>10 stools/day, continuous bleeding, toxicity, abdominal tenderness/distension, transfusion requirement, colonic dilation on x-ray

<4 stools/day ± blood, normal ESR, no signs of toxicity

>6 bloody stools/day + fever, tachycardia, anemia, or ESR

≥4 stools/day, minimal signs of toxicity

Classification of UC Severity

Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.

Mild

Moderate

Severe

Fulminant

Predicators of Poor Response or Surgery


• Stoolfrequency

• >8or>5after3daysIVrx.

• Percentagebloodystools

• Bodytemperature>37.5

• Heartrate>90bpm

• CRP(>25,>45mg/L)

• Transversecolon>5cm

• Lowhemoglobin<10.5g/dL

• Serumalbumin

• ESR >30mm/h

• Bandemia

• Prolongedflare

• Activeinfection

• Hospitalizationsetting

• Diseaseduration

Lindgren SC et al. Eur J Gastroenterol Hepatol 1998;10(10):831-5. Gonzalez-Lama Y et al. Hepatogastroenterol2008;55(86-87):1609-14. Suzuki Y et al Dig Dis Sci 2006;51(11):2031-8. Cacheux W. et al. A,m J Gastroenterol2008;103(3):637-42. Ananthakrishnan AN et al. A, J Gastroenterol 2008;103(11):2789-98.

Flexible Sigmoidoscopy


• Limitedtorectosigmoid• Noprep• Mucosa:

• Edema,Erythema• DiffuseUlceration

• Pattern– Circumferential,continuous,noskipareas

Endoscopic Severity: UC


Mild

• Granularmucosa

• Edematous

• Lossofnormalvascularpattern

Sutherland LR, et al. Gastroenterology. 1987;92:1894-1898.

• Coarselygranular

• Smallulcerations

• Friable

Moderate

• Frankulcerations

• Spontaneoushemorrhage

Severe

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Endoscopic Severity Predicts Colectomy


Severeendoscopic colitis

Moderateendoscopic colitis

Carbonnel F et al. Dig Dis Sci. 1994;39:1550.

100

0

Colectom

y(%

)

Deep/extensive

ulcers

93%

Mucosaldetachment

30%

Largemucosal

abrasions

26%

Well-likeulcers

17%

>50%→colectomy

100

0Superficial

ulcers

77%

Deep butnonextensive

ulcers

8%

>20%→colectomy

Colectom

y(%

)

Infections in UC


• Nobroadspectrumantibiotics• C.difficile

– Oralvanco firstline(40v10%colectomyrate)

– 40%rule:40%ofUCflares,40%nopriorabx,40%colectomyrate

• CMV– IHC+upto20-30%ofsevereUC– Bystanderversuspathogen– Treatboth,avoidCsA

Meanwhile, back in the hospital …

• No progression of exam, VS stable, no need for further transfusion

• PPD placed, Hep serologies sent

• IV steroids started, solumedrol 1 mg/kg (40 mg) daily


IV Corticosteroids: Effective in Severe UC


Outcomes: Severe UC by Day 15

78% 69% 65% 70%

93%

53%

0%

20%

40%

60%

80%

100%

Dexa100mg x3

HC 400mg M-pred40mg

M-pred0 .75 -1 ..0

mg/kg

HC 400 mg M-pred 64mg

Daily Dose

% R

emis

sion

or

Sub

stan

tial

R

espo

nse

Sood,Aetal.JClinGastroenterol2002;35(4):328-31. Panes,Jetal.Gastroenterology2000;119:903-8.Mantzaris,GJetal.ScandJGastroenterol2001;36:971-4. Mantzaris,GJetal.AmJGastroenterol1994;89:43-6.D’HaensGetal.Gastroenterology2001;120:1323-9. Chapmanetal.Gut1986;27:1210-2

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Hospital Day 3• Patient with minimal response

• Still multiple poorly –formed, bloody bowel movements, cramps (> 10)

• Hgb < 7, 2 units of blood given, CRP > 50, xray with T colon at 4 cm

• Options?1) Wait longer on IV steroids2) Start cyclosporin or tacrolimus3) Start infliximab4) Operation


SteroidFailure:Day3assessment

IV Cyclosporin: Highly Effective


Outcomes: Severe UC by Day 15

82%69%

79%

56%

91% 86%

64%

0%

20%

40%

60%

80%

100%

4mg/kg 4mg/kg 5mg/kg 4mg/kg 4mg/kg 4mg/kg 4mg/kg

Daily Dose

% R

espo

nse

Lichtiger et al. N Engl J Med 1994;330:1841-5. Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8.Van Gossum A et al. Acta Gastroenterol Belg 1997;60:197-200. Cohen RD et al. Am J Gastroenterol 1999;94:1587-92.Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3.

CSA: Colectomy Avoidance with AZA


Actis GC et al. BMC Gastro 2007;7:13-19

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Jarnerot G, et al. Gastroenterol. 2005;128(7):1805-1811.

80%

70%

60%

40%

10%

0%

29%

67%

Infliximab

Placebo

20%

30%

50%

1.0

0.8

0.6

0.4

0.2

0.0

0 30 60 90

P=0.0038(logrank– test)

TimeinDays

Prob

abilityNotOpe

rated

Infliximab

Placebo

No.ofPatientsatRiskInfliximab 24 17 17 17Placebo 21 7 7 7

Colectomy

Infliximab: IV steroid-refractory UC


• 23 GETAID and 6 ECCO centres• 111 pts failing 5 days IV steroids: : Lichtiger score>10• Patients randomized to either i.v.:

• Cys 2mg/kg/d x 1 week, then oral CSA x 91 days• IFX 5mg/kg at weeks 0-2-6

• All patients started on azathioprine 2.5 mg/kg/d• Steroids tapered• Failure:

• No response day 7• Absence Remission Day 98• Relapse Day 7 – 98• Severe AE or Death• Colectomy

CSA vs. IFX: Severe IV Steroid-Refractory UC

CSA vs. IFX: Severe IV Steroid-Refractory UC


p=0.97

Response:Lichtiger score< 10anddecrease≥3pointsascomparedtobaseline

85.4% 85.7%

0%

20%

40%

60%

80%

100%

Cys (n=55) IFX(n=56)

Response:Day7

p=0.4960%54%

0%

20%

40%

60%

80%

100%

Cys (n=55) IFX(n=56)

TreatmentFailure*

Laharie etal. 2011

*Failure:• Noresponseday7• AbsenceRemissionDay98• RelapseDay7– 98• SevereAEorDeath• Colectomy

IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)

Colectomy rates at 12 months


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IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)

• Drug adverse events

21Hospitalized UC Patient| 22Hospitalized UC Patient|

• Nevertogether.Toomuchrisk(20-30%SAE)• SomeExceptions:

1. Cyclosporin:effective,butthenhasallergicreactiontoazathioprine/6-MP.(washoutfor48-72hours)

2. Cyclosporin:intolerableside-effect(washoutfor48-72hours)

3. Infliximab:OncegivenNOCsA

BOTH Cyclosporin and Infliximab?

Infliximab: Not always successful


39%30%

26% 30%

0%

10%

20%

30%

40%

50%

UCCS <3 Baron = 0

Week 6 Results

Inflix imabPlacebo

P=0.76

P=0.96

ProbertCSJetal.Gut2003;52:998-1002.• NodifferenceinIBDQ orEuroQol Scores

• RandomizedPlacebo-ControlledTrial• Infliximab5mg/kg@weeks0,2• Placebo

Infliximab failure….Why?


Results• IFX:Detectedinallptsstool.• Highestinthefirstdayspost

infusion.• Nonresponders,hadmuch

highamountsofdruglostinstool.

Brandse JF, et al. Presented at DDW; May ,2013. Abstract 157.

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Higher Trough Levels: Better Outcomes


Murthy S, et al. 2012

Steroid-free Remission by IFX/ATI Status100

0

60

20

Pat

ient

sin

Rem

issi

on(%

)

80

40

IFX+ATI-

70.0

16.6

28.5

13.0

IFX+ATI+

IFX-ATI-

IFX-ATI+

P=0.84

P=0.073P<0.001

Serum IFX≤ 2µg/ml

Serum IFX> 2µg/ml

Steroid-free Remission by IFX Trough Status100

0

60

20P

atie

nts

inR

emis

sion

(%)

80

4017.5

69.4

P<0.001

Colectomy by IFX Trough Status100

0

60

20Col

ecto

my

(%)

80

40

Serum IFX≤ 2µg/ml

55.5

17.7

Serum IFX> 2µg/ml

P<0.001

• 125Steroid-RefractoryUCpts• IFX“Infliximab”;ATI“Antibodyto

Infliximab”• TroughInfliximab>2µg/ml

• Remission:OR10(3,35)• Colectomy:0.18(0.07,0.44)

Accelerated Infliximab Dosing: Success ?


6.7%

40%

0% 20% 40% 60% 80%

100%

ColectomyDuringInduction

Accelerated Normal

• Retrospective• 50hospitalizedUCpts• Corticosteroidrefractory• Standarddoseinfliximab:5mg/kgWeeks0,2,6,

thenq8w• Accelerateddose:3doseswithinmedian24days

Gibson DJ et al. Clin Gastroenterol Hepatol 2014

Colectomy for severe UC• Colectomy

– Surgical consult by day 3 for refractory patients– Toxic megacolon, perforation, refractory

bleeding– Failure of medical therapy at 7-10 days

• Total abdominal colectomy with Hartmann– Mortality < 1%– Laparoscopic or robotic– J pouch in 3 stages if eligible, but NOT during

acute illness


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ColonicDiverticulitis:History

• 57yearoldmanwithsuddenonsetofLLQpain,constipationandfever

• Tis38.2,LLQtendertopalpationwithpalpablemass,butnorebound

• WBCis16K• CT

Diverticulitis• IVabx• IRplacesdrainagecatheter,Cx +E.coli• Within48hourspainandfeverandelevatedWBCresolve

• Management?1. Sigmoidcolectomypriortodischarge2. Sigmoidcolectomyafter2-4weeksofabx and

drainage3. Abx for2weeks,drainremovalafterabscess

resolves,observation

Departmentof Medicine

Burden of Disease• Prevalence of diverticulosis increased with age, affected 70%

of individuals 80+ years old• It is the most common finding reported on

colonoscopy

3

Everhart et al, Gastroenterology 2009

Taxonomy

Symptomaticuncomplicateddiverticular disease(SUDD)

Segmentalcolitisassociatedwithdiverticulosis (SCAD)

Strate et al, Am J Gastroenterol 2012

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Riskof diverticulitis

• The cumulative diverticulitis probability over 130 months was4.3 % . For every additional decade of life, there was a 24 % lower risk of diverticulitis.



vAge• Decreased risk with increased age of dx

vMedications• NSAIDs, steroids, opiates increase risk for

diverticulitis• Calcium channel blockers, statins may be protective

vGenetics• Twin studies Sweden and Denmark

• OR 3x higher in monozygotic vs. dizygotic twins• 40-50% of liability attributable to genetic factors

Templeton and Strate Curr Gastroenterol 2012

Riskfactors fordiverticulitis


Fiber Helps!• British study of cohort of 700,000

women with no known diverticulardisease, 6- year follow-up.

• 17,000 admitted to hospital withdiverticular disease.

• Higher intake of dietary fiber isassociated with reduced risk ofdiverticular disease.

29Crowe et al, Gut 2014

• The Health Professionals Follow-up Study,cohort ofmen prospectively followed 1986-2004.

• 47,000 men, age 40-75 years, baseline were free ofdiverticulosis and returned a food-frequency questionnaire.

• Outcome was incident diverticulitis and diverticularbleeding.

Nuts, corn, popcorn to blame?

Strate et al, JAMA 2008

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No increased risk!

Strate et al, JAMA 2008

Antibiotics for acute diverticulitis?• MulticenterrandomizedcontrolledtrialinSwedenandIcelandof623patientswithuncomplicatedleft-sideddiverticulitis(confirmedonCT),excludedifabscess,fistula,freeair,highfever,peritonitis,orsepsis

• Randomizedtobroad-spectrumantibioticsofIVfluidsalone

• Alsonodifferenceinmeanhospitalstay,complications,orrecurrentdiverticulitisnecessitatingre-admissionover1year

• Authorsconcludedthatantibioticsshouldbeusedonlyincasesofcomplicateddiverticulitis

Chabok et al, Br J Surg 2012

Antibiotics for acute diverticulitis?

• Retrospectivecohortof246patientsadmittedwithdiverticulitisin2011toVastmanlandHospital,Sweden

• AllcasesconfirmedbyCT,195withAUD• 178(91.3%)werenotgivenantibiotics• 6ptsreadmitted,2hadabscess• Only25patients(12.8%)presentedwithrecurrenceat1year

Wille-Jorgensen Coch Syst Rev 2012

When to operate?

• Emergency• Free Perforation• Diffuse Peritonitis• Complete Colonic Obstruction

• Relative emergency• Fail medical therapy, 72-96 hours• Recurrence in the same admission• Partial colonic obstruction• Immunocompromised patients• Unable to r/o carcinoma

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Whathappensafteranepisodeofdiverticulitis?

Recurrence free survival N=2366

3165patients12KaiserhospitalsinSouthernCaliforniaEmergentcolectomy 20%Nonopmanagement80%Ofthose

13%hadrecurrence7%hadcolectomy

Meanfollowup9years

0.00

0.25

0.50

0.75

1.00

Time to Recurrence (months)

0 20 40 60 80 100

0.00

0.25

0.50

0.75

1.00

Time to Recurrence (months)

0 20 40 60 80 100

Freefromrecurrence Freefromrecurrencewcomplication

Hazard Ratio 95% CI

Retroperitoneal Abscess

4.5 1.1-18.4

Family history of diverticulitis

2.2 1.4-3.2

Segment > 5 cm 1.7 1.3-2.3Right colonic disease

0.27 0.09-0.86

RiskofRecurrenceper#ofpriorepisodes

Number Patients Follow-Up Recurrence0 2052 9years 5%1 222 9years 11%2 65 10years 21%3 18 9years 33%4 5 7years 57%

Do Multiple Recurrences Predict a Less Favorable Outcome?

• Prior episodes 1-2 >2• # of patients 122 35• Perforation 17% 0%• Stoma 37% 3%

Chapman et al, Ann Surg 2006

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Surgeryafterpercutaneousdrainage

LambandKaiserDis ColonRect 2104 LiD,etal.AnnSurgery2014


• Retrospective chart review of 1100 cases diverticulitis atUCLA Veteran’s Administration Hospital + matched controls

• Cases were 4.7 fold (CI 1.6-14; p = 0.006) more likely to bediagnosed with IBS (CI 1.6-14)

• 2.4 fold (CI 1.6-3.6; p = < 0.001) more likely to be diagnosedwith a functional bowel disorder

Post-diverticulitis IBS

Incidence of new IBS diagnosis

Cohen et al, Clin Gastroenterol Hepatol 2013

Incidence of new functional bowel disorder


IBS and diverticulosis

23

Jung et al, Am J Gastroenterol 2010

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• Case series demonstrate chronic inflammation inbiopsy specimens taken from within and around diverticula of patients without overt diverticulitis orcolitis.

– Abnormal pathology in random biopsies taken from 16 of 17 patients with diverticulosis, with most demonstrating alymphocytic infiltrate without overt colitis

– There was evidence of chronic inflammation in and arounddiverticula in three quarters of resected specimens from 930patients undergoing surgery for symptomatic uncomplicateddiverticular disease but not overt diverticulitis

Floch et al, J C lin Gastroenterol 2006; Horgan et al, D is Colon Rectum 2001

InflammationDepartmentof Medicine

Visceral hypersensitivity

• Study of 10 patients with asymptomatic diverticulosis (ADD),11SUDD patients, 9 controls.

• In the rectum, the SUDD group had increased perception scores compared with the control group (p = 0.010) and the ADD group (p = 0.030). In the sigmoid colon, in the pre- and postprandial periods, the SUDD group had increased perception scores compared with the control group (p = 0.018)

21Clemens et al, Gut 2004


Colonic Motility

• 12 patients with SUDD underwent 24-hour colonic manometric recordings and compared to 20 healthy controls

• Patients with SUDD displayed increased duration of rhythmic, low frequency, contractile activity, particularly inthe segments bearing diverticular – a pattern described as“spastic colon”.

• Patients with diverticulosis have significantly reduceddensity of interstitial cells of Cajal – the so- called“pacemaker cells” of the intestine.

25Bassotti et a l, D ig Dis 2012; Bassotti Eur J Gastroenterol Hepatol 2004

• Hypothesis - Shifts in intestinal microbiota lead tochronic inflammation. Fecal stasis may lead tochronic dysbiosis in turn promote formation ofabnormal metabolites.

• Study of 90 patients with history of diverticulitis, 60%had small bowel bacterial overgrowth

• Use of probiotics and rifaximin help symptoms?

Intestinal Microbiota?

27Tursi et al, W orld J Gastroenterol 2005

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New Paradigm ofchronicillness?



• Multicenter, double-blind, placebo-controlled trial of 120 patients in Germany• Randomized to mesalazine 1g PO TID vs. placebo

• 6 week trial, primary end point = change in abdominal pain after 4 weeks• A daily dose of 3.0 g mesalazine may relieve pain of uncomplicated

diverticular disease.

MesalamineDifference of daily pain intensity score

Median

time to

complete

painrelief

%patients

with com

pletepain

relief

K ru is et al, A ilment Pharmacol Ther 2013


Mesalamine

• Multicenter, double-blinded, placebo-controlled study. 210 SUDD patients randomized to mesalazine (1.6g/day) + probiotic placebo, probiotic + mesalazine placebo, probiotic + mesalazine, placebo only) for 10 days/ mo x 12 months

• Both cyclic mesalazine and Lactobacillus casei subsp., particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease

placebo

Tursi et al, A l Pharm Ther, 2013

Mesalazine + lactobacillus

lactobacillusmesalazine


Rifaximin for SUDD

• In symptomatic uncomplicated diverticular disease, treatment with rifaximin plus fibre supplementation is effective in obtaining symptom relief and preventing complications at 1 year

• NNT = 3 for symptom relief; NNT = 59 for complicationsBianchi et al, Aliment Pharmacol Ther 2011

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CombinationRxforSUDD

• 218 patients with recurrentdiverticulitis

• Randomized to rifaximin 400mg po bid + mesalazine 2.4g/day x 7 days each month vs. rifaximin alone

• Severity of symptoms improved significantly in dual therapy group and more likely to prevent recurrence

Tursi et al, D ig Liver D is 2002Gastroenterology 2014 147, 793-802DOI: (10.1053/j.gastro.2014.07.004)

Mesalamine Did Not Prevent Recurrent Acute Diverticulitis in Phase 3 Controlled Trials

(N = 590, 592)

Raskin JPGastroenterology2014


Rifaximin forAcute RecurrentDiverticulitis

• Multicenter, randomized, open controlled study in 165patients with recent episode of diverticulitis

• Rifaximin 400mg BID + fiber vs. fiber alone for 1 week/ month x 12 months

• OR 3.2 (95% CI 1.16-8.82, p=0.025)• Cyclic rifaximin treatment reduces the risk of recurrences

of diverticulitis.

Lanas et al, D ig Liver D is 2013

TakeHomePoints

• IVabx maynotbeneededforacuteuncomplicateddiverticulitis.

• Operativetherapyisrarelyneededforrecurrentuncomplicateddiverticulitisorcomplicateddiverticulitis.

• Diverticulardiseaseiscomplexdisorder(motility,heightenedvisceralsensation,bacterialovergrowth,immune)andnoveltherapiesmaybeeffective.

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