Approach to New Patient with UC v3 Rubin...Stomach Jejunum Ileum Colon Sulfasalazine prodrug; azo...
Transcript of Approach to New Patient with UC v3 Rubin...Stomach Jejunum Ileum Colon Sulfasalazine prodrug; azo...
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