Can We Predict the Natural History of Ulcerative Colitis? · Can We Predict the Natural History of...

Can We Predict the Natural Can We Predict the Natural History of Ulcerative Colitis?History of Ulcerative Colitis?

Edward V Loftus, Jr, MDEdward V Loftus, Jr, MDProfessor of MedicineProfessor of Medicine

Mayo ClinicMayo ClinicRochester, Minnesota, USARochester, Minnesota, USA

OverviewOverview•• EndpointsEndpoints

–– HospitalizationHospitalization–– SurgerySurgery–– Colorectal cancerColorectal cancer–– DeathDeath

•• Risk FactorsRisk Factors–– ExtentExtent–– Age at DiagnosisAge at Diagnosis–– PSCPSC

Rochester Epidemiology ProjectRochester Epidemiology Project•• Mayo Clinic and Olmsted Medical Group Mayo Clinic and Olmsted Medical Group

provide essentially all medical careprovide essentially all medical care•• Computer linkage for medical diagnoses, Computer linkage for medical diagnoses,

surgical proceduressurgical procedures•• Access to records of all providers, Access to records of all providers,

including ambulatory careincluding ambulatory care•• Identifies full spectrum of diseaseIdentifies full spectrum of disease•• Over 1600 epidemiological reports on Over 1600 epidemiological reports on

acute and chronic diseaseacute and chronic disease

Melton LJ, Mayo Clin Proc 1996;71:266Melton LJ, Mayo Clin Proc 1996;71:266

UC Cohort, Olmsted County, 1970UC Cohort, Olmsted County, 1970--20042004

Ingle SB et al. DDW 2007, UEGW 2007, and ACG 2007 abstracts.Ingle SB et al. DDW 2007, UEGW 2007, and ACG 2007 abstracts.

UC Cohort, Olmsted County, 1970UC Cohort, Olmsted County, 1970--20042004

Ingle SB et al. DDW 2007, UEGW 2007 and ACG 2007 abstracts.Ingle SB et al. DDW 2007, UEGW 2007 and ACG 2007 abstracts.

Cumulative Risk Of Hospitalization From UC Cumulative Risk Of Hospitalization From UC DiagnosisDiagnosis

28.8%38.7%

49.8%

Ingle SB et al. DDW Ingle SB et al. DDW 2007, UEGW 2007,2007, UEGW 2007, and ACG 2007 abstracts.and ACG 2007 abstracts.

Cumulative Risk Of Hospitalization, Stratified Cumulative Risk Of Hospitalization, Stratified By Decade Of UC DiagnosisBy Decade Of UC Diagnosis

20%

30%

45%


Cumulative Risk Of Hospitalization, Stratified Cumulative Risk Of Hospitalization, Stratified By Initial UC ExtentBy Initial UC Extent


Cumulative Risk Of Hospitalization, Stratified Cumulative Risk Of Hospitalization, Stratified By Initial Need For CorticosteroidsBy Initial Need For Corticosteroids


Cumulative Risk Of Hospitalization, Stratified Cumulative Risk Of Hospitalization, Stratified By Initial Need For HospitalizationBy Initial Need For Hospitalization


Risk Of Initial Hospitalization After First 90 Risk Of Initial Hospitalization After First 90 Days: Cox proportional hazards regressionDays: Cox proportional hazards regression

HR (95% CI) HR (95% CI) PP--valuevalueExtensive diseaseExtensive disease 1.58 (1.101.58 (1.10--2.26) 2.26) 0.01260.0126Early steroid use 1.85 (1.23Early steroid use 1.85 (1.23--2.80) 2.80) 0.00350.0035Early hospitalizationEarly hospitalization 1.61 (1.081.61 (1.08--2.40)2.40) 0.01820.0182


UC Hospitalization UC Hospitalization -- ConclusionsConclusions

•• 47% of UC patients were hospitalized at least 47% of UC patients were hospitalized at least once between 1970 and 2004once between 1970 and 2004

–– Mean length of stay of 9.6 daysMean length of stay of 9.6 days•• 55--year cumulative risk of hospitalization year cumulative risk of hospitalization

increased from 20.2% in the 1970's to 44.7% in increased from 20.2% in the 1970's to 44.7% in 20002000--2004.2004.

•• Extensive disease, early corticosteroid use and Extensive disease, early corticosteroid use and early hospitalization were associated with early hospitalization were associated with increased risk of hospitalization.increased risk of hospitalization.

Ingle SB et al. DDW Ingle SB et al. DDW 2007, UEGW 2007,2007, UEGW 2007, and ACG 2007 abstracts.and ACG 2007 abstracts.

Surgery in UC Surgery in UC -- Study Population, Study Population, 19701970--20042004

•• 365 UC pts were followed for 5,260 365 UC pts were followed for 5,260 personperson--years (median followyears (median follow--up was up was 13.8 years; range, 1 month 13.8 years; range, 1 month --36 years).36 years).

•• 23% (85/365) of pts had at least one 23% (85/365) of pts had at least one surgery.surgery.

•• 21% (75/365) of pts had a colectomy21% (75/365) of pts had a colectomy•• 71% (60/85) of pts had more than one 71% (60/85) of pts had more than one

surgery. surgery. Ingle SB et al. ACG 2007 and UEGW 2007 abstracts.Ingle SB et al. ACG 2007 and UEGW 2007 abstracts.

Colectomy TypeColectomy Type

Ingle SB et al. ACG 2007 and UEGW 2007 abstracts.Ingle SB et al. ACG 2007 and UEGW 2007 abstracts.

Cumulative Risk Of Colectomy By UC Cumulative Risk Of Colectomy By UC DurationDuration

13.1%19.4%19.4%

27.5%27.5%


Cumulative Risk Of ColectomyCumulative Risk Of ColectomyStratified by GenderStratified by Gender

HR= 2.26 (1.3 - 3.8)


Cumulative Risk Of Colectomy Cumulative Risk Of Colectomy Stratified By Decade Of DiagnosisStratified By Decade Of Diagnosis

HR=2.3 (1.2-2.6)HR=3.9

(1.7–8.7)HR=1.0

HR=1.3 (0.6–2.7)


UC Surgery UC Surgery -- ConclusionsConclusions•• Among 365 UC patients diagnosed Among 365 UC patients diagnosed

between 1970between 1970--2004, 20.5% required 2004, 20.5% required colectomy.colectomy.

•• The cumulative incidence of colectomy The cumulative incidence of colectomy increased to 19.4% at 10 years and almost increased to 19.4% at 10 years and almost 30% at 25 years from UC diagnosis.30% at 25 years from UC diagnosis.

•• Male gender and diagnosis after 1990 Male gender and diagnosis after 1990 were associated with greater risk of were associated with greater risk of colectomy. colectomy.


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25

0 5 10 15 20 25 30

Risk of Colorectal Cancer in UCMeta-Analysis

Risk of Colorectal Cancer in UCRisk of Colorectal Cancer in UCMetaMeta--AnalysisAnalysis

Cumulativeprobability

(%)

CumulativeCumulativeprobabilityprobability

(%)(%)

Time from diagnosis (years)Time from diagnosis (years)Time from diagnosis (years)

UCUCUC

ControlControlControl

Eaden: Gut 2001; 48:526EadenEaden: Gut 2001; 48:526: Gut 2001; 48:526CP1169260-22

Risk Factors for IBDRisk Factors for IBD--Related Related Colorectal CancerColorectal Cancer

•• Classic risk factorsClassic risk factors–– Increased extent (i.e., pancolitis vs. proctitis)Increased extent (i.e., pancolitis vs. proctitis)–– Increased durationIncreased duration

•• Newer risk factorsNewer risk factors–– Primary sclerosing cholangitis (PSC)Primary sclerosing cholangitis (PSC)–– Family history of CRCFamily history of CRC–– Backwash ileitis?Backwash ileitis?–– Severity of inflammation?Severity of inflammation?

0

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40

0 10 20 30 40

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%)

Cum

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%)

Years from diagnosisYears from diagnosisNo. at risk

376 220 109 46 10No. at risk

376 220 109 46 10

ObservedExpectedObservedExpected

CP1188395-2

Cumulative Risk of Colorectal Cancer Among 376 Ulcerative Colitis Patients From Olmsted County,

Minnesota

Cumulative Risk of Colorectal Cancer Among 376 Cumulative Risk of Colorectal Cancer Among 376 Ulcerative Colitis Patients From Olmsted County, Ulcerative Colitis Patients From Olmsted County,

MinnesotaMinnesota

Jess T, et al, Gastroenterology 2006Jess T, et al, Gastroenterology 2006

Colorectal Cancer Risk in UC Colorectal Cancer Risk in UC --Olmsted County, 1940Olmsted County, 1940--20012001

PatientsPatients(n(n)) PersonPerson--yearsyears ObsObs ExpExp SMR (95% CI)SMR (95% CI)

TotalTotal 378378 55675567 66 5.385.38 1.1 (0.4 1.1 (0.4 -- 2.4)2.4)GenderGender

WomenWomen 166166 26182618 22 2.562.56 0.8 (0.1 0.8 (0.1 -- 2.8)2.8)MenMen 212212 29492949 44 2.822.82 1.4 (0.4 1.4 (0.4 -- 3.6)3.6)

Age at diagnosis Age at diagnosis (yrs)(yrs)00--2929 149149 22732273 11 0.430.43 2.3 (0.1 2.3 (0.1 -- 12.8)12.8)3030--4949 144144 22882288 44 1.861.86 2.2 (0.6 2.2 (0.6 -- 5.5)5.5)50+50+ 8585 10061006 11 3.093.09 0.3 (0.01 0.3 (0.01 -- 1.8)1.8)

Calendar year at diagnosisCalendar year at diagnosis19401940--19591959 3434 874874 11 1.201.20 0.8 (0.02 0.8 (0.02 -- 4.6)4.6)19601960--19791979 143143 29332933 55 1.921.92 1.9 (0.6 1.9 (0.6 -- 4.5)4.5)19801980--19891989 8585 10841084 00 0.000.00 0.0 (0.0 0.0 (0.0 -- 3.9)3.9)19901990--20022002 116116 676676 00 0.000.00 0.0 (0.0 0.0 (0.0 -- 7.7)7.7)

Jess T et al, Gastroenterology 2006Jess T et al, Gastroenterology 2006

Overall Survival From Diagnosis of 378 Overall Survival From Diagnosis of 378 Ulcerative Colitis Patients From Olmsted Ulcerative Colitis Patients From Olmsted

County, Minnesota, 1940County, Minnesota, 1940--20012001

Jess T et al, Gut 2006Jess T et al, Gut 2006

62 deaths total62 deaths total

12 deaths (19%)12 deaths (19%)due to GI causesdue to GI causesor GI cancersor GI cancers

CauseCause--Specific Mortality in Ulcerative Specific Mortality in Ulcerative ColitisColitis

WomenWomen MenMenCausesCauses ObsObs ExpExp SMR(95% CI)SMR(95% CI) ObsObs ExpExp SMR(95% CI)SMR(95% CI)Infection Infection 00 0.50.5 0.0 (0.00.0 (0.0--7.4)7.4) 00 0.90.9 0.0 (0.00.0 (0.0--4.0)4.0)Cancer Cancer 55 8.28.2 0.6 (0.20.6 (0.2--1.4)1.4) 1010 11.011.0 0.9 (0.40.9 (0.4--1.7)1.7)

IntestinalIntestinal 11 1.01.0 1.01.0 (<0.1(<0.1--5.3)5.3) 44 1.21.2 3.3 (0.93.3 (0.9--8.4)8.4)PulmonaryPulmonary 00 1.61.6 0.0 (0.00.0 (0.0--2.4)2.4) 22 3.93.9 0.5 (0.10.5 (0.1--1.9)1.9)

Heme Heme 00 0.10.1 0.0 (0.00.0 (0.0--26)26) 11 0.10.1 7.1 (0.27.1 (0.2--39)39)CNS CNS 22 0.70.7 3.1 (0.43.1 (0.4--11)11) 11 0.70.7 1.5 (<0.11.5 (<0.1--8.3)8.3)Cardiac Cardiac 88 18.118.1 0.4 (0.20.4 (0.2--0.9*)0.9*) 1515 18.918.9 0.8 (0.40.8 (0.4--1.3)1.3)Respiratory Respiratory 44 2.92.9 1.4 (0.41.4 (0.4--3.5)3.5) 22 3.63.6 0.6 (0.10.6 (0.1--2.0)2.0)GI GI 22 1.31.3 1.5 (0.21.5 (0.2--5.5)5.5) 44 1.71.7 2.4 (0.72.4 (0.7--6.2)6.2)GUGU 22 0.70.7 2.7 (0.32.7 (0.3--10)10) 00 0.60.6 0.0 (0.00.0 (0.0--6.1) 6.1) Suicide Suicide 00 0.20.2 0.0 (0.00.0 (0.0--16)16) 11 1.01.0 1.01.0 (<0.1(<0.1--5.6)5.6)AccidentsAccidents 11 0.90.9 1.2 (<0.11.2 (<0.1--6.5)6.5) 11 2.02.0 0.5 (<0.10.5 (<0.1--2.8)2.8)All otherAll other 22 2.22.2 0.9 (0.10.9 (0.1--3.4)3.4) 11 2.32.3 0.4 (0.10.4 (0.1--2.4)2.4)TotalTotal 2626 36.336.3 0.7 (0.50.7 (0.5--1.1)1.1) 3636 42.942.9 0.8 (0.60.8 (0.6--1.2)1.2)Jess T et al, Gut 2006Jess T et al, Gut 2006

Multivariate Analysis of Multivariate Analysis of Survival: Ulcerative ColitisSurvival: Ulcerative Colitis

•• Independent predictors of mortalityIndependent predictors of mortality–– Male genderMale gender–– Older ageOlder age–– Diagnosis after 1980 was protectiveDiagnosis after 1980 was protective

•• No associationNo association–– Extent (trend with extensive UC)Extent (trend with extensive UC)

JessJess T et al, Gut 2006T et al, Gut 2006

Classification by ExtentClassification by Extent•• ProctitisProctitis

–– Limited to rectumLimited to rectum–– Within 15Within 15--20 cm of anal verge20 cm of anal verge

•• LeftLeft--sided colitissided colitis–– Distal to splenic flexureDistal to splenic flexure–– Within 60 cm of anal vergeWithin 60 cm of anal verge

•• Extensive colitisExtensive colitis–– Proximal to splenic flexureProximal to splenic flexure

UC Disease Extent Predicts SeverityUC Disease Extent Predicts SeveritySettingSetting Colectomy RatesColectomy Rates

ProctitisProctitis LL--sidedsided ExtensiveExtensiveSt MarkSt Mark’’ss 2%2% 6%6% 20%20%Cleveland Clinic 14%Cleveland Clinic 14% 52%52% 61%61%CopenhagenCopenhagen 9%9% 35%35%IBSENIBSEN 2%2% 2%2% 9%9%

LennardLennard--Jones, Scand J Jones, Scand J GastroenterolGastroenterol SupplSuppl 19831983Farmer, Dig Farmer, Dig DisDis SciSci 19931993LangholzLangholz, , GastroenterolGastroenterol 19921992MoumMoum, Scand J , Scand J GastroenterolGastroenterol 19971997

UC Disease Extent Influences UC Disease Extent Influences Colorectal Cancer RiskColorectal Cancer Risk

•• Uppsala, Sweden: relative risk of CRCUppsala, Sweden: relative risk of CRC–– Proctitis, 1.7Proctitis, 1.7–– LeftLeft--sided, 2.8sided, 2.8–– Extensive, 14.8Extensive, 14.8

•• Cleveland Clinic: cumulative risk of CRC Cleveland Clinic: cumulative risk of CRC after 30 years of diseaseafter 30 years of disease

–– LeftLeft--sided, 4%sided, 4%–– Extensive, 25%Extensive, 25%

Ekbom, N Ekbom, N EnglEngl J Med 1990J Med 1990MirMir--MadjlessiMadjlessi, Cancer 1986, Cancer 1986

UC Disease Extent May Influence UC Disease Extent May Influence MortalityMortality

•• Copenhagen CountyCopenhagen County–– Subgroup with extensive colitis had Subgroup with extensive colitis had

standardized mortality ratio standardized mortality ratio (observed/expected) of 1.68(observed/expected) of 1.68

–– Other Other SMRsSMRs not significantly elevatednot significantly elevated•• Extended followExtended follow--up in this cohortup in this cohort

–– Again showed elevated SMR in extensiveAgain showed elevated SMR in extensive–– Also showed a significantly lower SMR Also showed a significantly lower SMR

for proctitisfor proctitis

LangholzLangholz, Gastroenterology 1992, Gastroenterology 1992WintherWinther, Gastroenterology 2003, Gastroenterology 2003

Is Age of Diagnosis a Prognosis Is Age of Diagnosis a Prognosis Indicator?Indicator?

•• Some studies suggest that childhoodSome studies suggest that childhood--onset onset UC has higher rate of complications, is more UC has higher rate of complications, is more severe, has higher risk of CRC, etcsevere, has higher risk of CRC, etc

–– Data are conflictingData are conflicting–– Colectomy rates similarColectomy rates similar

•• Likewise, older studies suggest that lateLikewise, older studies suggest that late--onset UC is milderonset UC is milder

–– Data again conflictingData again conflicting•• Insufficient evidence for age as a risk factorInsufficient evidence for age as a risk factorDevroedeDevroede GJ et al, N GJ et al, N EnglEngl J Med 1971; Jackman RJ et al, Am J J Med 1971; Jackman RJ et al, Am J DisDis Child 1940; Child 1940;

LangholzLangholz E et al, Scand J E et al, Scand J GastroenterolGastroenterol 1997; Brandt LJ et al, Am J 1997; Brandt LJ et al, Am J GastroenterolGastroenterol 1982.1982.

IBD Associated with Primary IBD Associated with Primary Sclerosing Cholangitis (Sclerosing Cholangitis (‘‘PSCPSC--IBDIBD’’))•• PSC and IBD are closely linkedPSC and IBD are closely linked

–– 5% of UC has PSC5% of UC has PSC–– 7070--80% of PSC has IBD (usually UC)80% of PSC has IBD (usually UC)

•• PSCPSC--IBD is typically extensiveIBD is typically extensive–– High rate of rectal sparingHigh rate of rectal sparing–– High rate of backwash ileitisHigh rate of backwash ileitis

•• PSCPSC--IBD associated with dysplasia and IBD associated with dysplasia and CRCCRC

•• PSCPSC--IBD more likely to develop pouchitisIBD more likely to develop pouchitis•• Is PSCIs PSC--IBD a special phenotype of IBD?IBD a special phenotype of IBD?PeridigotoPeridigoto, DDW abstract 1991; , DDW abstract 1991; PennaPenna, Gut 1996; , Gut 1996; FaubionFaubion, J , J PediatrPediatr

GastroenterolGastroenterol NutrNutr 2001; 2001; JayaramJayaram, Gut 2001; Loftus, Gut 2005, Gut 2001; Loftus, Gut 2005

Is Natural History of UC Different in Is Natural History of UC Different in Asia?Asia?

•• Similar rates of relapse and proximal Similar rates of relapse and proximal progressionprogression

•• Perhaps a lower risk of CRCPerhaps a lower risk of CRC•• Lower prevalence of PSCLower prevalence of PSC•• Perhaps lower colectomy ratesPerhaps lower colectomy rates

–– Less severe disease?Less severe disease?–– Greater reluctance to accept surgery?Greater reluctance to accept surgery?

•• Need more natural history cohorts Need more natural history cohorts with longer durations of followwith longer durations of follow--upup

Ling KL et al, J Ling KL et al, J ClinClin GastroenterolGastroenterol 2002; Park SH et al, 2002; Park SH et al, InflammInflamm Bowel Bowel DisDis2007; 2007; ZhengZheng JJ et al, J Dig JJ et al, J Dig DisDis 2007.2007.

ConclusionsConclusions•• In our populationIn our population--based inception based inception

cohort:cohort:–– Extensive disease, early steroids, early Extensive disease, early steroids, early

hospitalization were associated with hospitalization were associated with subsequent hospitalizationsubsequent hospitalization

–– Male gender and diagnosis after 1980 Male gender and diagnosis after 1980 were associated with increased risk of were associated with increased risk of colectomycolectomy

–– No risk factors for CRC were observed, No risk factors for CRC were observed, although no CRC were observed in although no CRC were observed in patients diagnosed after 1980patients diagnosed after 1980

Conclusions (2)Conclusions (2)•• In our populationIn our population--based cohort:based cohort:

–– Male gender and older age were risk Male gender and older age were risk factors for mortality but diagnosis after factors for mortality but diagnosis after 1980 was protective1980 was protective

–– A nonsignificant trend of increased A nonsignificant trend of increased mortality with increased extent was notedmortality with increased extent was noted

•• In other cohorts:In other cohorts:–– Increased extent has been associated Increased extent has been associated

with increased colectomy rates, cancer with increased colectomy rates, cancer risk and mortalityrisk and mortality

–– Data on age at diagnosis conflictingData on age at diagnosis conflicting–– PSC increases cancer risk and mortalityPSC increases cancer risk and mortality

Conclusions (3)Conclusions (3)

•• We need more natural history studies We need more natural history studies incorporating all of these endpoints incorporating all of these endpoints as well as other markersas well as other markers

–– Serologies?Serologies?–– Genetic polymorphisms?Genetic polymorphisms?–– Inflammatory biomarkers?Inflammatory biomarkers?

•• CRPCRP•• Fecal stool markersFecal stool markers

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