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Evidence-based Medicine:
Treatment of Ulcerative Colitis
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
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• Sulfasalazine
• Aminosalycilates: 6 oral and 2 topical preparation [enema and
suppository].
• Budesonide: 1 oral and one topical preparation [foam]).
• Steroids: oral and 2 topical prepartions [enema and foam].
• Immunomodulator/ Immunosuppressants: thiopurines (azathioprine, 6-
mercaptopurine), cyclosporine, tacrolimus.
• Anti-TNF agents : infliximab, adalimumab, golimumab.
• Anti-adhesion agents: vedolizumab.
• Surgery
Therapeutic Armentarium for Treatment of Ulcerative Colitis
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Ulcerative Colitis – Clinical Care Pathway
Stratify according to colectomy risk
Low Risk Patient • Mild-moderate disease activity - <6 bloody bowel movements - No systemic signs of toxicity
• Limited anatomic extent • Mild endoscopic activity
High Risk Patient • Severe disease activity - ≥6 bloody bowel movement/day - and - Fever >99.5 F or - Tachycardia >90 BPM - Hemoglobin <10.5 mg/dl or - ESR > 30 mm or CRP > 30 mg/l
• Deep ulcer on endoscopy • Extensive colitis • C. diff or CMV infection • Steroid requiring disease
adapted from Dassopoulos 2014
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Low Risk Flare with mild to moderate activity
5-ASA +/- local therapy or Budesonide MMX Oral steroids
or Budesonide MMX
+/- oral 5-ASA
Maintenance therapy 5-ASA
Rem
issi
on
Algorithm for Induction and Maintenance of Remission in Mild-Moderate, Low-Risk Ulcerative Colitis
adapted from Dassopoulos 2014 and Bressler et al. 2015
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Approved 5-Aminosalycilates
Rectal Preparations
Azo-bonded Pro-drug
Moisture Dependent
Delayed Release pH ≥7
Delayed + Extended Release
pH ≥6
Azulfidine®
(sulfasalazine)
Rowasa®
(mesalamine)
Dipentum®
(olsalazine)
Pentasa®
(mesalamine)
Asacol®
(mesalamine)
Canasa®
(mesalamine)
Colazal®
(balsalazide
disodium)
Lialda®
(mesalamine)
APRISO™
(mesalamine)
Rectum /
left-colon Colon
Small bowel/
right colon
Terminal
ileum/
colon
Terminal
ileum/
colon
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• All 5-aminosalycilates are similar in clinical efficacy
• Efficacy for induction of response is 50%-70%
• Efficacy for induction of remission is 15%-40%
• Higher efficacy by combining oral and topical (enema) 5-ASA formulations in left-
sided and pan-colitis
• Overall excellent safety profile
• Similar adverse events except
- Sulfasalazine (sulfa allergy)
- Looser stools often seen with olsalazine
Differences • Pill burden and dosing frequency - may or may not influence adherence
• Insurance coverage
5-Aminosalycilates for Induction of Remission in Mild-Moderate UC
Feagan et al. 2013; Wang et al. 2016
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Colonic distribution of sulfasalazine enemas 100 ml
Left sided colitis, Moderate active 10 min after application and positioning in left lateral position
Kruis et al. 1981
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Local therapy of left sided ulcerative colitis -Metaanalysis-
Marshall et al. 2000
Pooled Odds ration (95% CI)
Active disease Clinical remission
Clinical improvement
Trials n
Rectal 5-ASA vs. placebo 7.7 (4.8-12.3) 6.9 (4.8-9.8) 6
Rectal 5-ASA vs. rectal steroids
2.4 (1.7-3.4) 1.4 (0.9-2.1) 5
Rectal vs. oral 5-ASA 4.1 (1.5-10.9) 6.3 (2.7-14.5) 3
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Oral versus Rectal Mesalamine versus Combination Therapy in the Treatment of Distal Ulcerative Colitis
2.9
3.8 3.9 3.9
4.4
5.2
0
1
2
3
4
5
6
3 weeks 6 weeks
5-ASA oral 3x800mg/d
5-ASA 4g/d enema
Combination
Impro
vem
ent
dis
ease
act
ivity index
(DAI)
M Safdi et al. 1997
*p<0.05 vs. oral 5-ASA
n=60
*
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40%
33%
59%
72%
66% 70%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2.4 g /day 4.8 g /day
Mild UC (A II) Moderate UC (A II) Moderate UC (A III)
4.8 g Mesalamine/day is Not Superior to 2.4 g/d Mesalamine in Mild-Moderate UC
A; Ascend II and Ascend III
Hanauer et al. 2005 ; Sandborn et al. 2009
p<NS (AII, mild UC)
p<0.05 (AII, moderate UC)
p<NS (AIII, moderate UC)
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7%
18% 13% 12%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Remission
Placebo MMX 9 mg MMX 6 mg 5-ASA 2.4 g
Budesonide MMX for Mild-Moderate Ulcerative Colitis Remission at Week 8
Sandborn et al. 2012
p<0.01
p<NS
p<NS
Patients
in r
em
issi
on:
co
mbin
ed c
linic
al and e
ndosc
opic
rem
issi
on
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High risk Flare with moderate-
severe activity Oral steroids
+/- oral 5-ASA
Maintenance therapy 5-ASA
Remission
Discuss Colectomy and
IPAA
Steroid refractory, no response to initial therapy and worsening
clinical symptoms
Steroid responsive:
• Thiopurine monotherapy
Steroid responsive or refractory:
• Anti-TNF therapy (infliximab, adalimumab,
golimumab) +/- thiopurine [or methotrexate]
• Vedolizumab +/- thiopurine or methotrexate
Algorithm for Induction of Remission in Moderate- Severe, High-Risk Ulcerative Colitis (Outpatient)
adapted from Dassopoulos 2014 and Bressler et al. 2015
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Maintenance of Remission in Ulcerative Colitis by Azathioprine or 6-MP
Gisbert et al. 2009
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Comparative Efficacy of Biologics for Moderately to Severely Active Ulcerative Colitis.
Vickers et al. 2016
Systematic Review with Network Meta-Analysis
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24%
50%
37%
22%
69%
55%
40%
77%
63%
0%
20%
40%
60%
80%
100%
Steroid-free Remission Response Mucosal Healing
AZA (n=76) IFX (n=77) AZA+IFX (n=78)
Infliximab, Azathioprine or Combination – UC SUCCESS Trial: Week 16 Results
Panaccione et al 2014
Patients
(%
)
Remission: Steroid-free + Mayo <2, Mucosal Healing: endoscopy 0 or 1
Patients naïve to anti-TNF and AZA or >3 months stop of AZA before trial
p<0.02
p<0.001 p<0.001
p<0.03
p<0.02 p<0.03
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Total number of subjects required for comparative efficacy RCTs between anti-TNF agents for Induction / Maintenance of remission
Infliximab Golimumab Adalimumab
Infliximab - 214 / 1870 174 / 204
Golimumab 214 / 1870 - 13562/ 420
Adalimumab 174 / 204 13562 / 420 -
Stidham et al. 2014
Comparative Effectiveness Trails of Anti-TNF Agents in Ulcerative Colitis
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Infliximab Concentration and Clinical Outcome – ACT1 and ACT2 Study
*Data presented for the 5 mg/kg groups in ACT 1 & ACT 2
26.3
14.6 21.1
37.9
5.5
55.0
43.9
59.6
79.0
43.1
52.1
60.0
0
20
40
60
80
100
Clinical Remission week 8 Clinical Remission Week 30 Clinical Remission Week 54
Pro
po
rtio
n o
f P
ati
en
ts i
n
Re
mis
sio
n (
%)
1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
<21.3 <0.11 ≥21.3- <33.0
≥33.0- <47.9
≥1.4- <3.6
>47.9 >8.1
Week 8 p=0.05
Reinisch W, et al. Presented at DDW; May 20, 2012. Abstract 566. Reinisch et al DDW 2012
Infliximab 5 mg/kg bodyweight week 0,2,6, IFX level week 8
≥0.11- <2.4
≥2.4- <6.8
>6.8 ≥3.6- <8.1
<1.4
Week 30 p=0.0001
Week 54 p=0.007
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20.6%
3.2%
26.3%
6.6%
39.0%
9.8%
53.1%
23.1%
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Clinical Responseprior anti-TNF
Clinical Remissionprior anti-TNF
Clinical Responseanti-TNF naïve
Clinical Remissionanti-TNF naive
Placebo VDZ
Delta: 18.4% Delta: 6.6% Delta: 26.8% Delta: 16.5%
Vedolizumab (VDZ)in UC – Clinical Response and Remission Week 6 Depending on Prior anti-TNF Exposure
n=206 n=145
Patients
(%
)
Feagan et al 2016
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Algorithm for Maintenance of Remission in Moderate- Severe, High-Risk Ulcerative Colitis (Outpatient)
Failure to maintain remission on thiopurines
or vedolizumab
Thiopurines
Check 6-TGN levels
6-TGN < 230 Increase thiopurine dose
6-TGN > 230 Switch drug class
Vedolizumab
Increase dose to 300 mg / q 4 weeks [+ consider adding immunomodulator]
No response
Switch drug class
6-TGN < 230, 6-MMP high Consider adding
allopurinol + reduce thiopurine dose to 20-25% of previous dose
Discuss Colectomy and
IPAA
Course of disease, risk
factors for CRC
adapted from Dassopoulos 2014 and Bressler et al. 2015
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Check anti-TNF levels + drug antibodies
Low level, no antibody
Low level, high antibodies
If no response switch to
another anti-TNF or out of
class
Increase dose
Therapeutic level
Switch class or
increase dose + add immunomodulators
Switch class
adapted from Dassopoulos 2014 and Bressler et al. 2015
Failure to maintain remission on anti-
TNF
Algorithm for Maintenance of Remission in Moderate- Severe, High-Risk Ulcerative Colitis (Outpatient)
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Things should be made as simple as possible but not any simpler
Albert Einstein
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Aminosalicylate or Thiopurine or Vedolizumab Corticosteroid
Anti-TNF Vedolizumab Cyclosporine
Surgery
Anti-TNF Vedolizumab Thiopurine
Aminosalicylate Aminosalicylate Budesonide MMX
Induction Maintenance
Step-Up according to severity or failure at prior step
Mild
Moderate
Severe
Conventional Treatment Strategy for Ulcerative Colitis
adapted from S. Hanauer