Dilemmas In Ulcerative Colitis

1
Dilemmas In Ulcerative Colitis
Stephen J. Bickston, MD University of Virginia
Digestive Health Center of Excellence
2
Traditional Approach To Therapy For Ulcerative
Colitis
Severe
Surgery CSA
Moderate
Mild
3
Case 1 Musician With L-UC

• Started by referring MD on mesalamine enemas with
  initial success
• Switched to oral mesalamine 2.4g for flare
• Steroids 40, then 60 begun for subsequent flares
  
• Empiric course of metronidzole
• Still has 8 BM/day, malaise without fever. Works
  but wants to feel good and get it on the good
  foot.
• NL vital signs in clinic. Mild anemia
• Good God! Now what??

4
The Walking (working) WoundedHow Do We Optimize
Care?
5
ASA More is Better
ASCEND I, II

N223
N223
N198
N200
p0.0034
p0.058
6
(No Transcript)
7
Corticosteroids Dependency Short and Long Term
Efficacy
30 days after initiating corticosteroid therapy
Faubion W, et al. Gastroenterology. 2001121255.
8
Risk of Resection in UC After 1st Course of
Steroids An Indication for CRS Consultation
185 patients in Olmsted County, MN diagnosed
with UC from 1970 to 1993
Faubion WA Jr, et al. Gastroenterology.
2001121255.
9
Controlled Trial of AZA in Management of Chronic
UC - Results
Mean Activity Score at Baseline and 6 Months
Reduction of Prednisone Dose (mg/day) at Baseline
and 6 Months
30
10
Plt0.001
pNS
plt0.001
9
8.1
23.2
25
7.7
22.2
8
7
20
6
5.3
Reduction of Prednisone Dose (mg/day)
13.6
15
5
Mean Activity Score
4.2
4
10
3
2
5
2.3
1
0
0
Placebo n20
Azathioprine n24
Placebo n20
Azathioprine n24
Comparison between azathioprine and placebo at 6
Months
Kirk A, et al. British Medical Journal.
19822841291-2.
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6-MP Maintenance therapy for UC

• 83 patients in remission induced by 6-MP
• Mean of 60 month follow-up

George J, et al. Am J Gastroenterol. 1996911711.
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Methotrexate for Active UC and Induction of
Remission
n37
PNS
n30
49
47
Patients
Time to first remission for MTX was 4.1 months
vs. placebo (3.4 months)
Oren R, et al. Gastroenterology. 19961101416.
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Infliximab for UC ACT I and II Remission
Without Steroids Wk 30
p 0.039
plt0.001

• Both 62-site global RCT for moderate to severe UC
  (by Mayo score)
• Pts failed to successfully taper, tolerate, or
  respond to steroids in past 18 months AND
• Failed to tolerate or respond to 6-MP, AZA in
  past lt 5 years
• ACT II Failure of antimetabolites OR ASA within
  previous 18 months

Rutgeerts P. N EJM. 2005353(23)2462-76.
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Case 2 Actor With Refractory Pan-colitis

• Formerly in remission on AZA

• 10-20 BM/day
• Progressive weight loss
• Transferred by air ambulance
• IV steroids, PRBC, TPN

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Sick Unto Colectomy
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Refractory UC and CMV Culprit or Companion?

• Detection of CMV genome is higher in IBD in
  general 1
• Current systemic steroids related to CMV
  infection (p  0.03) pNS for severity, past Rx
• Colectomy specimens (n85) 20 stained positive2
• 27 (15/55) of steroid-refractory
• 9 (6/68) positive PRE-op biopsies
• 1 pt received pre-op anti-viral therapy
• Still required surgery
• NO post-op CMV in any of 85 (pouch bx)
• High false neg in pre-op bx, small n

1)Dimitroulia E. IBD 2006. 12(9)879-84 2)
Maconi G. Dig Liver Dis 2005. 37(6)418-23
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Does Anti-Viral Therapy Help?

• 64 non-refractory IBD pts ( UC 23CD 43) 1
• 42 (66) had serology 3 recvd DHPG
• 1 had CMV Ag and biopsy-proven CMV colitis
• only this patient benefited
• 40 refractory UC40 non-refractory UC2
• 2/40 HE 10/40 Immunostain in refractory UC
• 0/40 HE, 1/40 Immunostain non-refractory
• 2 CMV refractory recognized early, treated
• 2/2 Able to taper steroids, avoid surgery
• 47 inpatients with UC checked for CMV Ag in
  blood3
• 12/16 UC pts with CMV treated
• 8 (66.7 ) responded

1) de Saussure P. APT 2004201323 2) Kambham N
Am J Surg Pathol. 200428(3)365-73 3) Wada YDis
Col Rect. 2003 46(10)S59-65.
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Does Anti-Viral Therapy Help?

• 62 pts with severe colitis (55 UC7 CD)
• 7 (5UC,2 CD) out of 19 (36) pts with refractory
  disease, CMV found in rectal bx as well as buffy
  coat
• 5/6 treated patients went into remission after
  antiviral treatment (3 DHPG, 2 foscarnet). 1 did
  not-gtsurgery
• Paralysis by analysis? No.
• Reasonable to perform rectal bx for IHC stain
  early, treat if positive

Cottone M. AJG. 2001. 96(3)773-5.
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When to Infuse Dirt?

• CyA 2 vs 4 mg/kg/d IV (n142) Same
  response/tox 1
• 41 (35) of the 118 responders eventually reqd
  colectomy (despite scripted AZA, steroids, repeat
  CyA) 2
• Mean days to colectomy 542 (421271 d)
• Same complication rate on CyA as off gt 3 months

1) Van Assche G. Gastro 2003.
125(4)1025-1031 2) Moskovitz DN. Gastro 2006
4(6)760-765
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Infliximab Rescue for Sick Unto Colectomy?

• N45 RCT IFX 24 vs placebo 21
• s/p 4d IV steroids if fulminant s/p 6-8 d for
  severe or mod severe (by scoring system)
• 1º endpoint Colectomy or death at 90d
• No deaths
• Colectomy 7 IFX vs 14 placebo (p .017)
• More post-op complications seen with placebo
• 6 plus months f/u (none 12)
• Additional 2/24 IFX and 2/21 placebo have had a
  colectomy.

Jarnerot G Gastro. 200512818051811
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Current Therapeutic Choices in SuC UC

• CyA
• Infliximab
• Clinical Trial
• Colectomy
• Choice will depend on center expertise with drug
  choices and availability of expert surgical
  support
• Greatly tempered by pt preference
• Averaged preferences support the use of medical
  interventions, 1/3 of individuals may benefit
  most from proceeding directly to colectomy

Arseneau K. Clin Gastro Hep 2006. 4(9)1135-1142
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Complications of UC Surgery

• Mortality (lt0.5)1
• 3-10 stools/24 hrs 1
• Impotence (1.5)2
• Pouchitis (10-60)1
• SBO (20)1
• ?? fertility (56-98)3-5
• Pouch-vag fistula (4)1

Delaney CP Ann Surg. 2003238221-228.
1Sagar PM, Pemberton JH. In Satsangi J,
Sutherland L, et al, eds. Inflammatory Bowel
Diseases. Spain Elsevier Limited 2003491 511.
2Pemberton JH, et al. Ann. Surg.
1987206(4)504-513.
3Olsen, KO, et al. Gastroenterology.
200212215-19.
4Johnson P, et al. Dis Colon Rectum.
20044711191126. 5Gorgun E, et
al. Surgery. 2004136(4)795803.
22
Ileal Pouch Cumulative Incidences Pregnancy
Plt0.001 vs. Controls
Olsen KO, et al. Gastroenterology.
200212215-19.
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Bringing Therapy to PatientsAccelerating

• Stages in Drug Development

Improving!
Pharmaceutical Industry Profile 2005. Wash, DC
PhRMA March 2005.
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New Targets, New Agents

• MAb to a4 integrin (natalizumab)
• MAb to IL-2Ra (daclizumab)
• MAb to IL-2R (basiliximab)
• anti-CD3 (visilizumab)
• EGF (enema)
• Apheresis (Adacolumn)
• IFN
• Opiate receptor

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• Summary
• Walking wounded
• More is better for ASA (dose, route)
• Expanding role for biologic agents
• Shrinking role for steroids
• Colorectal surgery consult at 1st course
• Sick unto colectomy
• Biologic therapy edging into CSA pool
• Bx for CMV
• Optimism for drug development