Approach to Approach to a Newa New Patient with Patient with Ulcerative ColitisUlcerative Colitis

David T. Rubin, MDDavid T. Rubin, MDAssociate Professor of MedicineAssociate Professor of Medicine

CoCo--Director, Inflammatory Bowel Disease CenterDirector, Inflammatory Bowel Disease CenterUniversity of Chicago Medical CenterUniversity of Chicago Medical Center

What is Ulcerative Colitis?What is Ulcerative Colitis?

• Inflammatory bowel disease involving the large intestine (colon and rectum)• Variable extent of large bowel involvement– Almost always starts in the rectum and may involve

more bowel or progress proximally– Major symptoms usually come from the

inflamed rectum• Disease is characterized in most patients by active

inflammation alternating with periods of quiescence (remission)• Cause remains unknown, triggers of onset are usually

not identifiable

CaseCase

• A 23 year old woman presents to your office with 3 months of new onset rectal urgency and frequency.• Sensation of incomplete evacuation and small

amounts of bright red blood mixed with semi-formed stool.• Saw her primary care physician who diagnosed it as

irritable bowel and hemorrhoids.• Because of ongoing problems, she sees you for help.

Approach to the New PatientApproach to the New Patient

• Suspect the diagnosis• Rule out infections• Routine labs and stool cultures• Early endoscopic assessment of colorectum and

terminal ileum: clarify extent of disease macroscopically and microscopically• Biopsy confirmation of the diagnosis• Assess clinical severity of disease• Identify effective therapies to induce and

maintain remission• Prevention of long-term complications

Ulcerative ColitisUlcerative Colitis CrohnCrohn’’ss DiseaseDisease

Inci

denc

e / 1

00,0

00In

cide

nce

/ 100

,000

AgeAge--Specific Incidence of IBD*Specific Incidence of IBD*

*Per 100,000 population*Per 100,000 populationReprinted with permission from Reprinted with permission from LashnerLashner BA. In: Stein SH and Rood RP, eds. BA. In: Stein SH and Rood RP, eds. Inflammatory Bowel Disease Inflammatory Bowel Disease A Guide for Patients and Their Families.A Guide for Patients and Their Families. Philadelphia, Pa: LippincottPhiladelphia, Pa: Lippincott--Raven Publishers; 1999:23Raven Publishers; 1999:23--29.29.

1010

00

22

44

66

88

00 2020 4040 6060 8080

1010

00

22

44

66

88

00 2020 4040 6060 8080

Age (yrs)Age (yrs) Age (yrs)Age (yrs)

Presentation of UCPresentation of UC

• Symptoms depend on extent and severity of inflammation • Bloody diarrhea• Abdominal cramping• Tenesmus- fecal urgency• Systemic symptoms, fever, decreased stamina,

weight loss• Proctitis and Proctosigmoiditis

– 50% of patients– Constipation in 25%

• Extraintestinal manifestations (1/3 patients)

Clinical Presentation Clinical Presentation of Ulcerative Colitisof Ulcerative Colitis

85% 83%

63%47%

0%

20%

40%

60%

80%

100%

Urgency Increased Defecation

Tenesmus Hard or Formed Stools

RaoRao SS, et al. Gut 1988;29:342SS, et al. Gut 1988;29:342--345.345.

Natural History of UCNatural History of UC

• Within 2 years of diagnosis–17% experience colonic hemorrhage–13% experience toxic colitis

• Disease progresses in 54% of patients within5 years of diagnosis• Complications highest among pancolitis

patients• 20 - 38% ultimately require proctocolectomy• Increased risk of colon cancer

Farmer RG, et al. Dig Farmer RG, et al. Dig DisDis SciSci 1993;38(6):11371993;38(6):1137--1146.1146.

UC: Natural History*UC: Natural History*

*Percent of patients with disease activity, in remission, or hav*Percent of patients with disease activity, in remission, or having ing colectomycolectomy performed each year after diagnosisperformed each year after diagnosis

Langholz E et al. Gastroenterology. 1994;107:3.

0%10%20%30%40%50%60%70%80%90%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24

Perc

ent o

f Pat

ient

s

Years After Diagnosis

Colectomy

Disease activity

Remission

Severity of Ulcerative ColitisSeverity of Ulcerative ColitisModified Truelove and Modified Truelove and WittsWitts CriteriaCriteria

Sign/Symptom Mild Moderate Severe

Bowel movementsBowel movements

Temperature (Temperature (��F) F) Weight loss (%)Weight loss (%)

Pulse (beats/minute)Pulse (beats/minute)HematocritHematocrit (%)(%)

ESR (mm/h)ESR (mm/h)Albumin (Albumin (g/dLg/dL))

<4/d<4/d

NormalNormalNoneNone<90<90

NormalNormal<20<20

NormalNormal

44--6/d6/d

9999--10010011--1010

9090--1001003030--40402020--30303.03.0--3.53.5

>6/d >6/d (mostly bloody)(mostly bloody)

>100>100>10>10>100>100<30<30>30>30<3.0<3.0

Truelove SC, Witts LJ. Br Med J. 1955;2:1041-1048.

Kornbluth A, Sachar D. Am J Gastroenterol. 2004;99:1371-1385.

MILD

>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

SEVERE FULMINANTMODERATE

Determining Clinical Determining Clinical Severity of DiseaseSeverity of Disease

0

20

40

60

80

100

Disease Activity

Patie

nts

with

UC

(%)

Mild Activity (20%)

Moderate Activity (71%)

Severe Activity(9%)

Adapted from Langholz E et al. Scand J Gastroenterol. 1991;26:1247-1256.

Increasing activity from diagnosis, leading to colectomy or death within 1

year

>4 stools daily and/or daily presence of blood/pus and/or systemic symptoms

≤4 stools daily and/or presence of blood and/or pus in the stools less than daily; no systemic symptoms

Disease Severity in UCDisease Severity in UC

UC: Location and ExtentUC: Location and Extent

40% Distal/Left-sided

colitis

30%30%Extensive/Extensive/PancolitisPancolitis

30%30%ProctitisProctitis

• Infectious colitis (including Clostridium difficile)• Ischemic colitis• Drug-induced (NSAID)

enterocolitis• Solitary rectal ulcer

syndrome• Radiation enterocolitis

• Diversion colitis• Endometriosis• Malignancy• Functional (IBS)• Diverticular disease

Adapted from Forcione DG, Sands BE. In: Sartor RB, Sandborn WJ. Kirsner’s Inflammatory Bowel Diseases. 6th ed. New York: Saunders; 2004:359-379.

Most Common Most Common ““ImpostersImposters”” in the in the Differential Diagnosis of IBDDifferential Diagnosis of IBD

Historical Features that Help to Confirm a Historical Features that Help to Confirm a Diagnosis of Ulcerative ColitisDiagnosis of Ulcerative Colitis

• Appendectomy protects against UC• Ex-smokers may develop

UC• Smokers have CD• Family history usually

concordant

Andersson RE, et al. N Engl J Med. 2001;344:808–814.

Early Appendectomy Early Appendectomy Protects Against UCProtects Against UC

Cases of C. difficile in IBD Patients*

*At IBD Center of the Medical College of Wisconsin, years 2003 to 2005.

Issa, et al. Clin Gastroenterol and Hep. 2007. Binion, et al. Inflamm Bowel Dis. 2008.

Is it Clostridium Is it Clostridium difficiledifficile??

– 8-fold increase in the number of C. difficile cases in last 5 years

– 14-fold increase in the number of hospitalizations for C. difficile in IBD in last 5 years

– 5-fold increase in the number of colectomies in IBD patients who are C. difficile positive

0

10

20

30

40

50

60

714

56

2003 2004 2005

Sands BE. Gastroenterology. 2004;126:1518-1532. Podolsy DK. N Engl J Med. 2002;347:417-429.

Ulcerative Colitis Crohn’s Disease

Distribution Continuous, symmetric, and diffuse distribution

Distribution is often discontinuous and asymmetric with skipped segments and normal intervening mucosa

Depth of Inflammation

Mucosal/submucosalinflammation

Mucosal, submucosal, and/or transmural inflammation

Site Colon affected exclusively May affect any part of GI tract

Rectal Involvement

Almost always involves the rectum

Relative rectal sparing may be present

Distinguishing Ulcerative Distinguishing Ulcerative Colitis from Colitis from CrohnCrohn’’ss DiseaseDisease

IBD Specific Serologic IBD Specific Serologic Immune MarkersImmune Markers

AntibodyAntibody AntigenAntigen NonNon--IBD IBD (%)(%) CD (%)CD (%) UC (%)UC (%)

pANCApANCAHistoneHistone HH11, , bacterial bacterial antigen?antigen?

<5%<5% 1010––25%25% 5050––65%65%

ASCAASCAAntiAnti--SaccharomycesSaccharomycescerevisiaecerevisiaeantibodyantibody

5%5% 5555––65%65% 5%5%

OmpCOmpC E. ColiE. Coli <5%<5% 3838––50%50% 2%2%

AntiAnti--ΙΙ22 Pseudomonas Pseudomonas fluorescensfluorescens <5%<5% 54%54% 2%2%

AntiAnti--FlagellinFlagellin CBirCBir 1 Antigen1 Antigen 88--14%14% 50%50% 6%6%

AntiAnti--CBir1 Helps Distinguish CBir1 Helps Distinguish Between Between pANCApANCA+ Patients+ Patients

0

1

2

3

pANCA+ UC

pANCA+ CD

Ant

i-CB

ir1 (O

.D.)

1/25

11/25

4%

44%P<0.001 (level)

0.255

0.623

Targan SR, et al. Gastroenterology. 2005;128:2020-2028.

Ulcerative Colitis: EndoscopyUlcerative Colitis: Endoscopy

Ulcerative Colitis: EndoscopyUlcerative Colitis: Endoscopy

PeriPeri--AppendicealAppendiceal Red PatchRed Patch

IBD: ExtraIBD: Extra--intestinal Manifestationsintestinal Manifestations

SkinEye

Bones and JointsKidney

Hepatobiliary

IBD: DermatologicIBD: Dermatologic

• Pyodermagangrenosum

• Erythema nodosum

IBD: ArthritisIBD: Arthritis

• 20-25% of patients• Axial skeleton (disease independent)

– Ankylosing spondylitis– Sacroileitis

• Peripheral arthritis (related to disease activity)– Type 1: asymmetric, limited– Type 2: chronic, symmetric

IBD: IBD: HepatobiliaryHepatobiliary

• Primary sclerosing cholangitis– Inflammation and fibrosis of biliary

tree– 75%-80% of PSC patients have

IBD (UC)– 5% of UC patients have PSC– Bowel disease independent,

transplantation may be required• Autoimmune hepatitis

– More often with UC• Gallstones

– Cholesterol crystals and stones– Worse with colectomy

IBD: OcularIBD: Ocular

• 1-13% of patients• Anterior uveitis and

scleritis (disease-related)• Keratitis• Steroid-associated

– Cataracts (85% after 4 years of use)

– glaucoma

Goals of Goals of ManagementManagement of Ulcerative Colitisof Ulcerative Colitis

• Confirm accurate diagnosis• Induce remission

– Defined as absence of inflammatory symptoms, feeling “well”

• Maintain remission– 95% of patients require maintenance therapies– Transition to maintenance occurs after successful induction– Need effective and safe long-term therapies

• Avoid surgery when possible, embrace it when necessary• Enhance quality of life• Avoid complications of

– The disease– Therapy

Clinical RemissionClinical Remission

•No urgency•No bleeding•No nocturnal symptoms• Formed stools• Able to distinguish flatus from stool

UC Treatment Pyramid:UC Treatment Pyramid:A A ““StepStep--upup”” ApproachApproach

Adapted from Isaacs KL et al. Inflamm Bowel Dis. 2005;11(suppl 1):S3-S12.Sutherland L et al. Cochrane Database Syst Rev. 2003:CD000543.Kornbluth A et al. Am J Gastroenterol. 2004;99:1371-1385.

5-ASAs = 5-aminosalicylate agents.

5-ASAs

5-ASAsCorticosteroids

SurgeryCyclosporine

Azathioprine/6-Mercaptopurine

Infliximab

Dis

ease

Sev

erity

Mild

Moderate

Severe

Ulcerative Colitis:Ulcerative Colitis:Induction of RemissionInduction of Remission

• Mild disease– Aminosalicylate (5-ASA)

• Topical therapy alone (distal disease)• Oral (extensive disease)• Or combination

• Moderate disease– Steroid taper– Infliximab

• Severe disease– IV steroids– Infliximab– Cyclosporine

Ulcerative Colitis:Ulcerative Colitis:Maintenance of RemissionMaintenance of Remission

• Steroids ineffective– Steroid-dependent vs. maintenance

• Aminosalicylate dose-response– Topical therapy for distal disease

• Azathioprine/6-MP for steroid-dependence and after cyclosporine• Infliximab

UC Treatment CycleUC Treatment Cycle

Kornbluth A et al. Am J Gastroenterol. 2004:1371-1385.Xu C-T et al. World J Gastroenterol. 2004;10:2311-2317.Becker JM. Gastroenterol Clinics North Am.1999;28:371-390.Farmer RG et al. Dig Dis Sci. 1993;38:1137-1146.

ComplicationsComplicationsComplications

DiseaseActivityDiseaseDiseaseActivityActivity

DiagnosisDiagnosisDiagnosis

Treated with 5-ASA (mild to moderate)

Treated with 5Treated with 5--ASA ASA (mild to moderate)(mild to moderate)

Adequate maintenance of remission

Adequate maintenance Adequate maintenance of remissionof remission

FLARETreated

with steroidsTreated Treated

with steroidswith steroids

CONTINUED FLARES

Treated with steroids, with/without

immunomodulator(moderate to severe)

Treated with steroids, Treated with steroids, with/without with/without

immunomodulatorimmunomodulator(moderate to severe)(moderate to severe)

More aggressive steroid therapy,

with/without immunomodulator

(severe to fulminant)

More aggressive More aggressive steroid therapy, steroid therapy,

with/without with/without immunomodulatorimmunomodulator

(severe to (severe to fulminantfulminant))

Treated with immunomodulator

Treated with Treated with immunomodulatorimmunomodulator

DiseaseActivityDiseaseDiseaseActivityActivity

TAPER

Surgery Cumulative risk of surgery ~34% within 10

years of diagnosis

Surgery Surgery Cumulative risk Cumulative risk of surgery ~34% within 10 of surgery ~34% within 10

years of diagnosisyears of diagnosis

55--ASA Delivery SystemsASA Delivery Systems

MMX = multimatrix technology.

Bacterial Cleavage

Time Release SystemEthylcellulose-encapsulated mesalamine microspheres

Acrylic polymer coated mesalamine

Lialda™

Inert Carrier

BalsalazideOlsalazine

NHSO

O

Sulfasalazine

pH Dependent Systems

Asacol®

Pentasa®

MMX™mesalamine

Dipentum™ Colazal™

Location of 5Location of 5--ASA ReleaseASA Release

Stomach Jejunum Ileum Colon

Sulfasalazine prodrug; azo bond of 5-ASA +

sulfapyridine

Dipentum®(olsalazine sodium)

prodrug; azo bond of 2 5-ASA molecules

Lialda™ (mesalamine) Delayed Release Tablets

Colazal®(balsalazide disodium)prodrug; azo bond of 5-

ASA + 4-ABA carrier

Pentasa® (mesalamine) Controlled-Release Capsulescoated to release over time

Asacol® (mesalamine) Delayed-Release Tablets

Azulfidine [prescribing information]. August 2002. Dipentum [prescribing information]. November 2001. Colazal [prescribing information]. December 2006. Asacol [prescribing information]. September 2006. Lialda [prescribing information]. January 2007. Pentasa [prescribing information]. January 2007.

Approach to 5Approach to 5--ASA Use in IBDASA Use in IBD

• Choose drug and route of delivery to maximize dose at location of disease

• Consider disease and patient variables in customizing therapy– Be aware of interpatient variability

– Encourage adherence to therapy• Achieve remission before transitioning to maintenance therapy

– No evidence to support dose reduction

– Dose to achieve remission may be dose necessary for “durable” remission

• Encourage adherence to therapy

Effective Dosages of Effective Dosages of Oral 5Oral 5--ASAs for UCASAs for UC

AGENT INDUCTION (g/d)(note different MW)

MAINTENANCE (g/d)

Sulfasalazine 4 2

Olsalazine 1.5, 3 1

Delayed-release mesalamine 1.6, 2.4, 4.8 0.8, 1.6

Mesalaminemicrospheres 2, 4 2

Balsalazide 6.75 3, 6

Cochrane Database Cochrane Database SystSyst RevRev. 2003;2:CD000543.. 2003;2:CD000543.

MesalamineMesalamine for Mild to Moderate UCfor Mild to Moderate UC

0

10

20

30

40

50

60

% o

f Pat

ient

s

Placebo M 1.6g/d M 2.4g/d

Remission Improved Maintained Worsened

Mesalamine 2.4g/d vs. placebo, P = 0.003 Mesalamine 1.6g/d vs. placebo, P = 0.03

Sninsky CA, et al. Ann Intern Med 1991; 115(5):350-355.

Schroeder KW, et al. N Engl J Med. 1987;317:1625–1629.

Efficacy of Oral Efficacy of Oral MesalamineMesalamine in in Treatment of Active UCTreatment of Active UC

5% 9%

24%13%

18%

50%

Patie

nts (

%)

Complete RemissionPartial Response

Placebo(n = 38)

1.6 g/day(n = 11)

4.8 g/day(n = 38)

100

80

60

40

20

0

N = 87 (6 weeks)

Oral Oral vsvs Rectal Rectal MesalamineMesalamine vsvs Combination Combination Therapy in Active Distal UCTherapy in Active Distal UC

Safdi M, et al. Am J Gastroenterol. 1997;92(10):1867-1871.

% o

f Pat

ients

With

Ces

satio

n of

Blee

ding

*

**p< .05 vs oral mesalamine N=60, 6 weeks

58%53%

41%

72%

58%

34%

0%10%20%30%40%50%60%70%80%

Moderate Population p=0.0034

Mild+Moderate Population p=NS

Mild Population p=NS

% o

f Pat

ient

s Im

prov

ed

2.4 g/day4.8 g/day

*

Treatment Success at Week 6Pooled Population

Assessing the Safety and Clinical Efficacy Assessing the Safety and Clinical Efficacy of a New Dose of of a New Dose of AsacolAsacol (800 (800 mg)ASCENDmg)ASCEND

I+III+II

Hanauer SB, et al. Am J Gastroenterol 2005; 100:2478-2485.

Sandborn W, et al. DDW 2005

Multi Matrix System Multi Matrix System MesalamineMesalamine

% in clinical and endoscopic remission at 8 weeks

Kamm et al.1 Lichtenstein et al.2

MMX 2.4 QDMMX 2.4 QD 40.5*40.5* --

MMX 4.8 BIDMMX 4.8 BID -- 34.1*34.1*

MMX 4.8 QDMMX 4.8 QD 41.2*41.2* 29.2*29.2*

AsacolAsacol 2.4 TID2.4 TID 32.632.6 --

PlaceboPlacebo 22.122.1 12.912.9

*p<.01 vs. placebo

1Kamm MA et al Gastroenterol. 2007;132:66-752Lichtenstein GR et al Clin Gastroenterol Hepatol. 2007;5(1):95-102

GastroGastro--resistant, pH dependent coatingresistant, pH dependent coatingLipophilicLipophilic and hydrophilic matricesand hydrophilic matrices

Prevalence and Impact of Prevalence and Impact of NonadherenceNonadherence on Outcomes in IBDon Outcomes in IBD

• 41.2% patients nonadherent– 81% of these “unintentional”

• Predicted by – Disease activity

(OR, 0.55; P = 0.002)– New patient status

(OR, 2.14; P = 0.04)– Disease duration

(OR, 0.5; P = 0.0001)

Sewitch MJ, et al. Am J Gastroenterol. 2004;99(10 suppl). Abstract.Kane SV, et al. Am J Gastroenterol. 2003;98:1309–1314.

Patie

nts

with

Q

uies

cent

UC

(%)

0 300

Adherent to 5Adherent to 5--ASA therapyASA therapy

NonadherentNonadherent to 5to 5--ASA therapy*ASA therapy*

Time (months)

100

75

50

25

10 20

**P P <0.001<0.001

Corticosteroids: DependencyCorticosteroids: Dependency——ShortShort-- and Longand Long--term Efficacyterm Efficacy

*30 days after initiating corticosteroid therapy.

Faubion W et al. Gastroenterology. 2001;121:255-260.

1-Month Outcomes*

(n=63)

1-YearOutcomes

(n=63)

Steroid Steroid DependentDependent

22%22%(n=14)(n=14)

Prolonged Prolonged ResponseResponse

49%49%(n=31)(n=31)

Surgery Surgery 29%29%

(n=18)(n=18)

Complete Complete Remission Remission

54%54%(n=34)(n=34)

Partial Partial Remission Remission

30%30%(n=19)(n=19)

No Response No Response 16%16%

(n=10)(n=10)

Serious Potential Adverse Effects From Serious Potential Adverse Effects From Prolonged Corticosteroid TherapyProlonged Corticosteroid Therapy

Hypertension 20Diabetes 2.23 relative risk for beginning insulinInfection 13–20Osteonecrosis 5Osteoporosis ?50Myopathy 7Cataracts 22 (dose-dependent)Glaucoma ? frequency (response genetically determined)Psychosis 3–5

Adverse effectPotential for developing adverse effect

(%)

Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.

Risk of Surgical Resection in PatientsRisk of Surgical Resection in Patientswith UC After Starting Corticosteroids*with UC After Starting Corticosteroids*

*185 patients in Olmsted County, MN diagnosed with UC from 1970 to 1993.Faubion WA Jr et al. Gastroenterology. 2001;121:255-260.

Days

% C

umul

ativ

e Pr

obab

ility

0

20

40

60

80

100

0 365182906030

AZA AZA vsvs 55--ASA for ASA for SteroidSteroid--Dependent, Active UCDependent, Active UC

N=72

*Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score ≤ 1) plus steroid discontinuation. Patients treated with concurrent tapering dose of steroids. †0.8 g at breakfast and lunch and 1.6 g at dinner.

Ardizzone S, et al. Gut. 2006;55:47-53.

05-ASA 3.2 g per day(in 3 divided doses†)

AZA 2 mg/kg per day

% o

f Pat

ient

s

20

30

40

50

60

10

Treatment Success* After 6 Months

P=.006

53%

19%

66--Mercaptopurine as Maintenance Mercaptopurine as Maintenance Therapy for Ulcerative ColitisTherapy for Ulcerative Colitis

UC – Maintenance Therapy n=83

George J et al. Amer J Gastroenterol 1996; 91:1711

Prob

abili

ty o

f Rem

issi

onM

aint

enan

ce

Months

1.0

.8

.6

.4

.2

00 20 40 60

InfliximabInfliximab for Ulcerative Colitis:for Ulcerative Colitis:ACT1 and ACT2ACT1 and ACT2

37

6962

29

65 69

0

20

40

60

80

Placebo 5 mg/kg 10 mg/kg

15

3932

6

3428

0

10

20

30

40

50

Placebo 5 mg/kg 10 mg/kg

Prop

ortio

n of

pat

ient

s

Rutgeerts P et al. NEJM, 2005.

Clinical response Clinical remission

Prop

ortio

n of

pat

ient

s

ACT1 ACT2

Communicating with your PatientCommunicating with your Patient

• Emphasize that this is a treatable condition• Remind the patient about the importance of adherence to therapy

and maintenance of remission• Anticipate their questions about the disease:

– Does stress cause colitis?– What role does diet play in causing or controlling the

disease?– Are there “natural remedies” or alternative therapies?

• Provide additional educational resources– www.ccfa.org

• Plan healthy follow-up visits

Summary: The New Patient with UCSummary: The New Patient with UC

• Early and accurate diagnosis• Assessment of extent and severity of disease• Choice of induction therapy determines your

maintenance therapy• Discuss the importance of maintenance

therapy• Ongoing monitoring and follow-up