Treating Ulcerative Colitis: Conventional Medications

1
Treating Ulcerative ColitisConventional
Medications

• Jose GP Ferraz, MD, PhD
• Inflammation Research Network
• Division of Gastroenterology
• University of Calgary

2
Overview

• Goals of Treatment
• Rationale
• Therapeutic Options

3
Treating UC - Objectives

• Induce/maintain remission
• Design treatment according to disease location
  and/or severity
• Assessment of options medical vs. surgical
• Steroid dependency vs. resistance
• Potential reduction in development of CRC

4
Inflammation in IBDWhat is the target?

• Phases of inflammation
• Acute, Peak, Resolution
• Available options
• 5-aminosalicylic acid compounds
• Steroids
• Immunomodulators
• Biologicals/Growth factors
• Probiotics/prebiotics
• Leukocytoapheresis

5
Inflammation - Basics
Serhan et al., FASEB J., 2007
6
How to Tailor Treatment in UC?

• UC as a model of intestinal inflammation
• Correlation between symptoms and endoscopic
  findings
• Symptomatic vs. endoscopic response
• Disease severity and extra-intestinal
  manifestations
• Recurrent nature of disease is critical
• Medical options and targets in inflammation
• Acute vs. peak vs. resolution vs. chronic
• Steroids may act on acute and resolution phase
• Impact on inflammatory process/phase
  unclear/unresolved for almost all other drugs
  anti-inflammatory vs. pro-resolution

7
Treatment Objectives

• Prevent induction of inflammation
• Genetics, risk factors, environment,
  host/bacterial interaction
• Target acute/chronic inflammation
• induce/maintain remission
• Promote resolution
• Recognize/prevent development of malignancy

8
Treating UC

• Significant advance in therapy over the last 50
  years
• 1950s25 mortality in first severe attack
• However,
• 29 of patients with a severe attack of UC will
  require a colectomy during the same hospital
  admission and a further 14 within 1 year of that
  admission.1

Travis et al., Gut, 1996
9
Natural History of Ulcerative Colitis

• Factors influencing disease course
• Disease course in preceding period
• Number of years with relapses from diagnosis
• Occurrence of systemic symptoms

Activity courses in years 3 years after
diagnosis in 600 patients with UC
Langholz et al., Gastroenterology, 1994
10
What to Expect FollowingDiagnosis of Ulcerative
Colitis
Langholz et al., Gastroenterology, 1994
11
Mortality in Ulcerative Colitis
N 278 180 84 33
N 1160 803 173 36
Overall survival of UC inception cohort in
Olmsted County, 1940 to 1993, expected survival
of age and sex matched Minnesota whites in
1990(Pgt.2, log rank test).
Cumulative survival of a population-based cohort
of 1160 patients with UC in Copenhagen County,
diagnosed between 1962 and 1987 and followed up
until 1997
Loftus et al., Gut, 2000Winther et al.,
Gastroenterology, 2003
Overall survival in UC is similar to expected
survival in general population.
12
Mortality From a Severe Attack of UC
Corticosteroids Introduced in 1952
13
Ulcerative Colitis Treatment Options
Baumgart and Sandborn, Lancet, 2007
14
Sulfasalazine Therapy for UC
SASP indicates sulfasalazine.
1Baron, Lancet, 1962 2Dick, Gut, 1964
3Misiewicz, Lancet, 1965 4Dissanayake, Gut,
1973.
15
Oral Mesalamine for UC
1Schroeder et al., NEJM, 1987 2Sninsky et al.,
Ann Internal Med, 19913Hanauer et al., Ann
Internal Med, 1996.
16
Rectal Mesalamine Therapy for UC
Hydrocortisone, Placebo
1Campieri et al., Lancet, 1981 2Sutherland et
al., Gastroenterology, 19873Miner et al.,
Gastroenterology, 1994 (Abstract).
17
Aminosalicylates and UCEvidence-Based Indications
I induction, M maintenance
Baumgart and Sandborn, Lancet, 2007
18
Corticosteroid Therapy
1Truelove et al., Br Med J, 1955 2Lennard-Jones
et al., Lancet, 1965 3Truelove et al., Lancet,
1974.
19
Immediate and Prolonged Outcomes of
Corticosteroid Therapy in UC
None 16 (n10)
Partial 30 (n19)
Complete 54 (n34)
30-Day Responses (n63)
Steroid Dependent 22 (n14)
Surgery 29 (n18)
Prolonged Response 49 (n31)
1-Year Responses (n63)

Faubion et al., Gastroenterology, 2001
20
Corticosteroids and UCEvidence-Based Indications
for Induction of Remission
Baumgart and Sandborn, Lancet, 2007
21
Immunomodulators and UCIndications

• Relapse while on oral aminosalicylates
• Steroid-dependent patients
• Severe UC (cyclosporine,tacrolimus)
• Severe UC that required cyclosporine, tacrolimus,
  ?biologics (azathioprine, 6-MP)
• Methotrexate not an option

22
Azathioprine/6-Mercaptopurinefor Moderately
Active UC
Jewell et al., Br Med J, 1974
23
AZA in Acute Ulcerative Colitis Relapse Rate
at 1 Year
P.18
80 patients (40 each group) with acute clinical
attack of UCFailed to achieve remission
Jewell et al., Br Med J, 1974
24
Azathioprine/6-Mercaptopurinefor
Steroid-Dependent UC
1Rosenberg, et al. Gastroenterology. 1975 2Kirk,
et al. Br Med J. 1982, 3Ardizzone et al., Gut,
2006.
25
Methotrexate for Active UC and Maintenance of
Remission
Oren et al., Gastroenterology, 1996
26
UC Cyclosporine
Monotherapy vs Prednisolone

78
64
53
40
37
36
Response 8 Weeks
Response 1 Year
Colectomy 1 Year
Azathioprine
D'Haens, Gastroenterology, 2001
27
UC Cyclosporine
Cyclosporine 4 mg/kg vs 2 mg/kg
86
84
24
13
9
9
Response 8 Days
Colectomy
Hypertension

Van Assche, Gastroenterology, 2003.
28
UC Cyclosporine A
Adverse Effects
29
Immunomodulators and UCEvidence-Based Indications
I induction, M maintenance
Baumgart and Sandborn, Lancet, 2007
30
Treatment of Ulcerative Colitis with Conventional
Meds Summary

• Aminosalicylates
• Many patients can be managed effectively
• Indicated for induction and maintenance of
  remission
• Sulfasalazine may promote resolution
• Corticosteroids
• PO can induce but not maintain remission
• IV corticosteroids effective for refractory
  disease
• Participate in resolution

31
Treatment of Ulcerative Colitis with Conventional
Meds Summary

• Antimetabolites
• AZA and 6-MP not clearly effective to induce
  remission in placebo-controlled trials
• AZA and 6-MP possibly effective to maintain
  remission and for steroid sparing
• May promote resolution
• CsA/Tacrolimus/MTX
• IV CsA is effective in severely active disease
• PO maintenance therapy not viable option due to
  toxicity
• Tacrolimus and MTX may promote resolution. MTX
  not effective in UC

32
Surgery for Ulcerative Colitis
Reasons for not performing a restorative
proctocolectomy in patients with ulcerative
colitis
Indications for surgery in patients treated for
ulcerative colitis
Longo WE et al. Am J Surg. 2003186514.
33
UC Surgical Options
Ileo-anal anastomosis with reservoir
Conventional ileostomy (Brooke)
Continent ileostomy (Kock pouch)
34
Functional Outcomes After IPAA for UC Pouch
Failure
Median length of follow-up was 8 years. Pouch
failure in 92 of 1386 patients6.6
Farouk R et al. Ann Surg. 2000231919.
35
Functional Outcomes After IPAA for UC
Incontinence
Occasionalspotting of mucus lt2
times/wkFrequentspotting ?2 times/wk or actual
fecal incontinence
Farouk R et al. Ann Surg. 2000231919.
36
Functional Outcomes After IPAA for UC Pad Usage
and Con Meds
Pad usage after IPAA
Constipating medication requirement after IPAA
As reported by patient questionnaire
Farouk R et al. Ann Surg. 2000231919.
37
Functional Outcomes After IPAA for UC Sexual
Dysfunction
Farouk R et al. Ann Surg. 2000231919.
38
Pouch Surgery in Older IndividualsFunctional
Outcomes
Delaney, et al. Ann Surgery. 2003.
39
Complication Rate by Time Periods University of
Toronto Experience
MacRae, et al. Dis Colon Rectum. 1997.
40
Reoperative Rate by Time Period
MacRae, et al. Dis Colon Rectum. 1997.
41
Failure Rate by Time Periods
MacRae, et al. Dis Colon Rectum. 1997.
42
Pouchitis and PSC
Penna C et al. Gut. 199638234.
Svaninger G et al. Scand J Gastroenterol.
199328695.
43
Female Fecundity Before Diagnosis,During
Disease, and After Surgery
Olsen KO et al. Gastroenterology. 200212215.
44
Fertility After IPAA

• Observed/expected pregnancies based on population
  data is 0.49 (0.350.69)1
• Infertility rate 38.1 in women having surgery vs
  13.3 in women not having surgery for UC2
• Increased age was significantly associated with
  failure to become pregnant
• 56 of those wanting to become pregnant post-op
  were successful vs 96 of those not having
  surgery

1Olsen, et al. Br J Surg. 1999 2Johnson, et al.
Dis Colon Rectum. 2004.