evidence-based medicine: treatment of ulcerative colitis · pdf fileevidence-based medicine:...
Post on 18-Mar-2018
221 Views
Preview:
TRANSCRIPT
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
top related