IBD lecture. Undergrad medicine

2. IBD for Final Meds
Anthony O’Connor
Sept 2021

3. 1. Clinic management
2. Post-op management
3. Small bowel Imaging
4. Care of In-patients
Contents

4. a) Assessing and monitoring disease
b) Initiating and monitoring therapies
c) Practicalities of monitoring patients
Who, how, where and when?
The IBD clinic consult

5. Physician’s global assessment?
Disease activity scores eg. HBI or Mayo?
Haematological and biochemical
parameters
Biomarkers eg calprotectin?
A. Monitoring the disease

8. IBS or IBD?
Active or inactive IBD?
Mucosal healing?
Response to treatment?
Predict relapse?
What can FC tell us?

9. Adults in primary care
Age 16-40 Symptoms compatible with
IBS-D without alarm symptoms*,
negative coeliac serology
Faecal calprotectin
> 50µg/g
YES
Refer for urgent GI
Investigation to exclude IBD
NO
Manage as IBS-D along
NICE IBS primary care guidelines.
Routine referral to secondary care
in refractory cases
Adults with an established diagnosis of IBD in clinic
Ulcerative colitis Clinical remission, stable therapy
Possible relapse
Acute severe disease
Don’t test
Optimise therapy if Fc elevated
Scope if fail to settle or
clinical concern
Crohn’s disease Clinical remission, stable therapy
Possible relapse Check Fc elevated to aid further investigation or treatment
Biologics monitoring Pre-biological therapy to establish baseline → Fc
Possible relapse → Fc
As part of annual assessment → Fc
3-6 monthly after withdrawal to predict relapse → Fc
Don’t test
If elevated consider dose optimisation or switch agent
If elevated continue therapy if normal consider scope/MRE
Before discussing withdrawal
Consider reintroduction if climbing Fc as
predicts clinical relapse

10. B. Initiating and Monitoring
therapies

11. WHAT TYPES OF MEDICATIONS ARE
AVAILABLE TO TREAT IBD?
DRUG UC CD COMMENTS
STEROIDS ✔ ✔ Not long term
MESALAZINES ✔✔ rarely Better for UC
IMMUNOMODULATOR
azathioprine ✔ ✔ monitor
methotrexate ? ✔ monitor
ciclosporin ✔ x Severe UC
BIOLOGICS
Anti-TNF ✔ ✔ IFX best for perianal
Vedolizumab ✔ ✔ Poor for CD
Ustekinumab ✔ ✔ UC limited benefit
Tofacitinib ✔ x UC only

12. ULCERATIVE COLITIS
- does extent matter?

13. Algorithm for managing
ulcerative colitis
MILD MODERATE SEVERE
5 ASA / steroid
(topical:supp/enema)
PROCTITIS
LEFT SIDED
PANCOLITIS
5 ASA / steroid
(topical:enema
+/-systemic)
5 ASA
(systemic+/-topical)
5 ASA / steroid
(topical:supp/enema)
+/-
Systemic steroids
+/-
Immunomodulator
(azathioprine/6MP/
Mycophenolate)
+/-
Biologics
+/-
surgery
Parenteral
steroids
+/-
Ciclosporin
or IFX
+/-
surgery

14. High or Standard Dose (>2g/day) vs.
Low Dose (<2g/day) of 5-ASA
Favours high or standard dose 5-ASA Favours low dose 5-ASA
Relapse of disease activity: 7 trials, 1534 patients, I2 = 55.9%
Number needed to treat = 10; 95% CI 5 to 33
0.1 0.2 0.5 1 2
Kruis 2011 0.91 (0.72, 1.14)
Paoluzi 2005 0.95 (0.78, 1.16)
Kruis 2001 0.39 (0.21, 0.70)
Fockens 1995 0.80 (0.58, 1.08)
Travis 1994 0.87 (0.60, 1.22)
Green 1992 0.95 (0.57, 1.57)
Azad Khan 1980 0.35 (0.17, 0.69)
Pooled relative risk 0.79 (0.64, 0.97)
Ford et al., Am J Gastroenterol. 2011 Apr;106(4):601-16.

15. Once Daily Dosing Schedule vs.
Conventional Dosing of 5-ASA
Favours once daily dosing of 5-ASA Favours conventional dosing of 5-ASA
Relapse of disease activity: 7 trials, 2745 patients, I2 = 33.2%
0.2 0.5 1 2
Hawthorne 2011 (CODA) 0.68 (0.48, 0.97)
Kruis 2011 1.03 (0.79, 1.33)
Sandborn 2010 0.99 (0.81, 1.22)
Prantera 2009 1.06 (0.81, 1.38)
Dignass 2009 (PODIUM) 0.75 (0.56, 0.99)
Kane 2008 0.80 (0.36, 1.87)
Kamm 2008 1.16 (0.85, 1.59)
Pooled relative risk 0.94 (0.82, 1.08)
Ford et al., Am J Gastroenterol. 2011 106(12):2070-7

16. Inducing remission:
Doses of 5-ASA > 2.5g are more effective than < 2g
Combined oral and topical 5-ASAs are more
effective than oral 5-ASAs alone
Preventing relapse:
Doses of 5-ASA > 2g are more effective than < 2g
Improving adherence:
Once daily dosing is not associated with an
increased risk of relapse of disease activity
Summary

17. MONITORING
5-ASA : FBC, RENAL PROFILE, LFT AT BASELINE, 3/12 AND ANNUALLY

18. Thiopurines

20. Commencing azathioprine therapy
Check TPMT
Homozygous deficient
No thiopurine
Normal Homozygous deficient
2-2.5mg/kg 1-1.5mg/kg
Side effects (except pancreatitis) Myelotoxicity Hepatotoxicity Response with
Normal LFT/FBC
Continue therapy
Relapse
Metabolite testing and interpret as per table
6TGN (pmol/8×108
RBC) 6-MMP iNTERPRETATION
Very low / undetectable Very low / undetectable Suggests non-adherence
Low (<235) Not elevated (<5 700) Underdosed – consider
increase
In range (235-450) Not elevated (< 5 700) Adequate dose if
ineffective suggests
refractory to thiopurines
High (>450) Any High 6-TGN predisposes to
myelosuppression. Consider
dose reduction, especially if
cytopenic
Low/low normal High (> 5 700) Unfavourable metabolite
profile. Consider reduced dose
and co-therapy with allopurinol
OUR ACCESS TO TGN IS
LIMITED. REMEMBER! A
7 POINT RISE IN
BASELINE MCV
APPROXIMATES TGN>230

21. Efficacy of immunosuppressive therapy for inflammatory bowel
disease: a systematic review and meta-analysis.
Khan et al., Am J Gastroenterol. 2011 Apr;106(4):630-42.
Three CD AZA withdrawal trials of 163 patients that indicated
continuing medication did prevent relapse (RR=0.39; 95% CI=0.21-
0.74).
In quiescent UC: three trials involving 127 patients with
statistically significant benefit of AZA preventing relapse
(RR=0.60; 95% CI=0.37-0.95).
Fraser Gut 2002 No difference in relapse rate according to
duration of therapy
Re-treatment with azathioprine after relapse is effective (Nachwyer
et al., 2003 DDW)
How long to use it for?

22. Relapse after withdrawal
of azathioprine
Lémann M et al Gastroenterology 2005; 128: 1812-1818
84 CD in remission >42
months with AZA
AZA n=40
Placebo n=43
% of clinical relapse at 18
months?
21.3%
7.9%

23. Independent risk factors
Old age
Male
Longer duration of IBD
Multivariate HR analysis confirms
Continuing exposure related to increased
Risk. Multivariate analysis of received vs
All others = 5.26 (2.2-12.6, p=0.0002)
Beaugerie et al., Lancet 2009
Lymphoma Risk

24. MONITORING
THIOPURINES : FBC, RENAL PROFILE, LFT, AT BASELINE, WEEKLY FOR
1 MONTH, MONTHLY FOR 3 MONTHS, THEN EVERY THREE MONTHS

25. Anti-TNF drugs
2. Monitoring therapies

26. Clinical positioning of current biologics
CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis
Danese S, Panés J. Gastroenterology 2014; Epub 14 September (DOI: 10.1053/j.gastro.2014.08.044).
26
Anti-TNF Anti-integrin
UC
• Induction / maintenance UC / /
• Steroid-refractory fulminant UC
• Steroid-refractory UC (post-hoc)
• Early UC / Late UC (post-hoc)
• Safety in UC
CD
• Induction / maintenance luminal CD / /
• Perianal fistulising CD
• Early luminal / Late luminal CD (post-hoc) / /
Infliximab
Favourable efficacy and/or safety profile Less favourable profile

27. Hamlin et al., Frontline Gastroenterology 2011

28. TRIAL DESIGN OUTCOMES QOL change COMMENTS COST
ADALIMUMAB
ULTRA 1
Reinisch Gut
2011
160/80
40MG EOW
REMISSION WK8 18.5% V 9.2% (p=0.031)
RESPONSE 54.6% v 44.6% (ns)
IBDQ/SF36
(ns) WK 8
NNT=11 £352.14 for
40mg pen or
syringe or
0.8ml vial
(excl VAT)
Induction
= £2113
4/52maint =
£704
ADALIMUMAB
ULTRA 2
Sandborn Gastro
2012
DBRCT 494pts REMISSION WK8 16.5% v 9.3% (p=0.019)
WK 52 17.3% v 8.5% (p=0.004)
IBDQ 27 v 19
(p<0.05)
Included non-niave
anti-TNF pts
NNT=11 @ wk 52
ADALIMUMAB
Suzuki et al
J Gastroenterol
2014
160/80 40 or
Placebo or
80/40 then 40 or
placebo
WK8 REMISSION RATES similar
WK 8 RESPONSE > IN 160/80: (50% V 35% p=0.044)
Grps combined for week 52 analysis:
RESPONSE 31% v 18% (p=0.021)
REMISSION 23% v 7% (p=0.001)
N/A Japanese only
NNT=6
GOLIMUMAB
PURSUIT-SC
Sandborn et al
Gastro 2014
DBRCT dose finding
study
200 /100mg
(100/50 &
400/200)
RESPONSE WK 6 51% v 30.3% (p<0.0001)
REMISSION 17.8% v 6.4% (p<0.0001)
IBDQ 27 v 14.8
(p,0.0001)
NNT= 9
£762.97 for
50mg pen or
syringe
£1525.94 for
100mg (excl
VAT) *NHS
scheme =.
Induction
£2289
4/52 maint=
£763
GOLIMUMAB
PURSUIT – M
Sandborn et al
Gastro 2014
464 responders in
2 trials :
GO
50/100/placebo
MAINTAIN RESPONSE TO WK 54
47% V 49.7% v 31.2% (p=0.01 & p<0.001)
REMISSION WK 30 & 50
23.2% v 27.8% v 15.6% (p=0.122 & p=0.004)
NICE: Biased as
included
Responders
NNT=8 for 100mg
3 deaths / 4 TB
INFLIXIMAB
ACT 1
INFLIXMAB
ACT 2
Rutgeerts NEJM
2005
placebo v IFX 5 or
10mg/kg 1:!:!
364pts
WK 8 RESPONSE 69% v 37% (p<0.001)
Wk 30 RESPONSE p <0.002
WK 54 RESPONSE 46% v 20% (p<0.001)
Increased QOL
IBDQ/SF-36
NNT=6 for steroid
free remission wk 30
£419.62 for
100mg vial
@77kg
Induction
= £5035
4/52 maint
= £839
Procurement?
placebo v IFX 5 or
10mg/kg 1:!:!
364pts
WK 8 RESPONSE 65% v 29% (p<0.001)
WK 30 RESPONSE (p<0.002)
Increased QOL
IBDQ/SF-36
NNT=7 for steroid
free remission wk54
INFLIXIMAB
Probert et al
REMISSION WK 6 39% v 30% (p=0.76) IBDQ/EQ5D
improved
UC-SUCCESS Combo v IFX v WK16 STEROID FREE REMISSION IBDQ/SF36 90% aza niave

29. TRIAL DESIGN OUTCOMES COMMENTS
GEMINI I
Feagan et al., 2013 NEJM
Cohort 1 374 pts 300mg v
placebo IV wk 0,2
Cohort 2: open label wk 0,2
assess wk 6
RESPONSE WEEK 6
47.1% V 25.5%
P<0.001
Cohort 2 open label therefore
bias
GEMINI 1 maintenance
Feagan et al., 2013 NEJM
Responders from cohorts 1 or 2
randomised to placebo / 4
weekly or 8 weekly Vedo for 52
weeks
REMISSION WK 52
15.9% v 44.8% v 41.8%
P<0.001
Only randomise responders
therefore biased (but real life!)
NNT=4 for both schedules
Parikh et al., IBD 2013 After placebo controlled study
38 UC – 2,6 or 10mg/kg at
1,15,43 days then q8. 34 rx
niave (15 UC, 19CD) same
regimen
UC
21/53 (39%) response
38/53 (58%) remission
Safe
Improved IBDQ
Parikh et al., IBD 2012 Dose ranging RCT
2,6 or 10 mg/kg or placebo days
1,15,29 and 85
[drug], safety etc
Response (Mayo), FC
Well tolerated,safe
VEDOLIZUMAB TRIAL DATA IN UC

30. 30
GEMINI I: vedolizumab in UC
Induction phase: outcomes at Week 6
25.5
5.4
24.8
47.1
16.9
40.9
0
20
40
60
80
100
Clinical response Clinical remission Mucosal healing
21.7 (11.6, 31.7) 11.5 (4.7, 18.3) 16.1 (6.4, 25.9)
Patients
(%)
Mean D% (95% CI)
VDZ vs. PBO
ITT, intent to treat; PBO, placebo; VDZ, vedolizumab; Mean D % (95% CI) = mean percentage point
difference VDZ vs. PBO
(95% confidence interval)
Primary outcome Secondary outcomes
PBO (n=149)
VDZ (n=225)
Induction ITT population
p<0.001
p<0.001 p<0.001
Adapted from: Feagan BG, et al. N Engl J Med 2013;369:699–710.

31. 29.1
7.0
20.6
3.2
51.7
21.0
39.0
9.8
0
20
40
60
80
100
Clinical response Clinical remission Clinical response Clinical remission
22.7 (10.1, 35.3) 14.0 (5.4, 22.6)
Prior anti-TNFα failure
(n=145)
Anti-TNFα naïve
(n=229)
Patients
(%)
Mean D% (95% CI)
VDZ vs. PBO
*Pre-specified exploratory analysis
CI, confidence interval; PBO, placebo; TNF, tumour necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab
PBO
VDZ
Adapted from: Rutgeerts P, et al. Presentation at UEGW 2012 (Abstract OP280).
GEMINI I: vedolizumab in UC
Induction phase: outcomes at Week 6 in patients
with prior anti-TNFα failure*
31
18.4 (3.9, 32.9) 6.6 (–9.8, 22.8)

32. Vedolizumab UC:
Primary and Secondary Outcomes Through 52 Weeks
%
***
***
***
*** ***
***
***
**
**
*
Δ26.1 Δ29.1 Δ32.8 Δ28.5 Δ32.0 Δ36.3 Δ11.8 Δ15.3 Δ17.6 Δ31.4
72 70 73
n:
*P<0.05 **P<0.01 ***P<0.0001
Maintenance ITT Population
Feagan NeJM 2013

33. Biological therapy for Moderate-Severe UC - (usually failure of mesalazine and thiopurines)

34. ANTI-TNF : FBC, RENAL PROFILE, LFT, AT BASELINE,
AT INFUSIONS FOR IV THERAPIES, AND FOR
SCTHERAPIES, EVERY 3-6 MONTHS.
Monitoring Anti-TNFs, drug and
Ab testing

35. Distribution of drug levels in IBD patients with
durable response (n=275 - TAXIT study)
Vande Casteele N et al Gastroenterology 2015
Receive too much drug?
Can they be de-escalated? Receive not enough drug?
Should they be escalated?
Receive no drug?
Can they be stopped?

36. TAXIT study Leuven
prospective controlled Trough level Adapted infliXImab Treatment trial
TL
measurement
undetectable
TL
(TL < 0.3µg/ml)
ATI
measurement
high ATI level
(ATI > 8µg/ml)
physician
decides: dose
increase/SWITC
H
low ATI level
(ATI < 8 µg/ml)
dose increase
(by 5 mg/kg) to
max 10 mg/kg
(2x)
TL < 3µg/ml
1) interval
decrease (by
2weeks) to min of 4
weeks
2) dose increase
(by 5 mg/kg) to
max 10 mg/kg
3µg/ml < TL <
7µg/ml
no dose
adaptation
TL > 7µg/ml
1) dose decrease
(by 5 mg/kg) to min
5 mg/kg
2) interval increase
(by 2 weeks) to max
12 weeks
Vande Casteele N et al Gastroenterology 2015

37. Proposed algorithm

38. Predicting relapse on infliximab withdrawal
What is the STORI
N= 100 74 55 31 Louis E, et al. Gut 2008; 57 (s2): A66
93%
79%
64%
57%
3 6 9 12 15 18
Kaplan-Meier curve of relapse (n=115).
Median follow-up 12± 1 month (IQR: 8-18 months)
Proportion
(%)
Relapses over time after infliximab cessation in patients with stable remission for
>1 year under combined IS+IFX therapy
0
100

39. CD 44% (FU range 6-125 months)
UC 38% (FU range 6-24 months)
Systematic review: factors associated
with relapse of IBD after discontinuation
of anti-TNF therapies.
Gisbert et al., APT Aug 2015

41. 69 studies: 18 on IM dose reduction/cessation as monotherapy, 8
on IM de-escalation from combo therapy, 43 on anti-TNF de-
escalation
Stopping IM monotherapy high risk of relapse in CD and UC (75%
at 5 years)
No difference in CD relapse rate when stopping IM in combo
therapy (only 1 UC study suggesting continue IM)
50% stopping anti-TNF remain in remission at 24 months
Systematic review of effects of withdrawal of
immunomodulators or biologic agents from patients with IBD.
Torres et al., Gastro Sept 2015

42. Who: GI, CNS, GP?
How: OP, phone clinics, virtual biologics
clinic
Helpline
When: annually?
Practicalities of monitoring

43. Symptoms
Medications
Monitoring drug Rx
Opportunities to ‘de-escalate’ – how hard
was it to achieve remission? Consequences
of relapse?
Vaccinations
Surveillance: CRC, bone health
Role of FC, endoscopy, MRE and Capsule –
THINK BEFORE YOU BOOK!
The stable IBD consult - conclusions

44. 4.Post-op Crohn’s
management

45. Summary of Crohn’s disease management
Crohn’s disease
Active inflammatory disease Complications of Crohn’s disease
Abscess Perforation
Fistula Cancer
Stricture
Surgery
Medical management

46. Complete resection of
diseased segment?
No Yes
Continue, Start or optimise Biologic Therapy
Peri-anal disease or EIMs
Yes No
Low/Medium-
Risk
High risk
Consider Biologic Therapy
Colonoscopy 6-12 months
Stratification of Risk at
MDT
≤i2a
≥i2b
Start or optimise Biologic Therapy
Watchful wait :Annual review, FC, CRP
Smoker? No
Yes
Smoking cessation
Low / medium risk

47. 5. Small Bowel Imaging

48. Diagnosis
Phenotype
Assessment of severity / complications
Contemplating therapeutic options: escalation
or withdrawal of medical therapy, surgery
Assisting intervention
When might we ask for small
bowel imaging?

51. Is this Crohn’s disease?
Is it complicated? mass, stricture (obstructed?), fistula, abscess,
cancer
If stricture – fibrostenotic or inflammatory?
If abscess – amenable to drainage?
Length and site of involved disease?
What are the implications for medical or surgical management
(MDT)?
Length or normal SB remaining?
Have there been complications of my therapy
(TB, cancer, lymphoma, perforation etc)?
What I would like to know from the report
(and therefore should probably ask on the request!)

52. Role of Capsule/ Enteroscopy

53. 6. Care of In-patients

54. Crohn’s and UC
All patients medically-admitted with new IBD or
complications of known IBD should be under the care
of a Gastroenterologist
Early surgical input for all inpatients, even if it’s just a
courtesy phone call
Inform the IBD nurses
Engage your brain before prescribing
steroids

55. Crohn’s and UC
All patients should be on a stool chart. Please monitor HR, temperature, BP
very carefully.
All patients should see dietetics
All patients with diarrhoea should have stool cultures and stool for C. diff
All patients should be prescribed prophylactic LMWH, even if bleeding unless
there is a very strong contraindication
All patients prescribed steroids should be co-prescribed Calcium
Avoid steroids in perianal disease. Be very
cautious when imminent risk of surgery

56. Acute Severe Colitis
A medical emergency
TRUELOVE AND WITTS CRITERIA
BO >6/24 Hours
Plus….
One or more of CRP>30, Hb <10.5, HR>90, Temp >37.5

57. Acute Severe Colitis
Order very early flexible
sigmoidoscopy (unprepped,
unsedated is fine) and stool
cultures
Need to outrule C.diff and CMV
(biopsies/PCR)
Need to be ready to escalate to
rescue therapy, so check
Quantiferon, UBV. HCV, HIV,
VZV on admission if these not
done in last 1 year.

58. Acute Severe Colitis

59. Any
Questions