Evidence-based Medicine:

Treatment of Ulcerative Colitis

Hans Herfarth, MD, PhD

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina

• 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

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

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

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

• 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

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

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

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

*

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)

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

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

Maintenance of Remission in Ulcerative Colitis by Azathioprine or 6-MP

Gisbert et al. 2009

Comparative Efficacy of Biologics for Moderately to Severely Active Ulcerative Colitis.

Vickers et al. 2016

Systematic Review with Network Meta-Analysis

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

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

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

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

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

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)

Things should be made as simple as possible but not any simpler

Albert Einstein

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