IBD Masterclass 14.06 - Mucosal Immunology · IBD Masterclass 14.06.2017. 2 ... Masterclass Lab...

MASTERCLASS

Prof. Xavier Roblin

gastro-entérologue au CHU de Saint-Étienne

xavier.roblin@chu-st-etienne.fr

Organiser : Pascal Juillerat, MD, MSc

IBD Masterclass 14.06.2017

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CASE 1

Brindusa Diaconu

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Mr CS, 7.07.1983

Crohn’s disease, diagnosed 2001 , Montréal A2L4B3

No extraintestinal manifestations

Previous therapies

• Long term Steroids -low dose

• Imurek 50mg daily

• Humira 40mg eow since 2011 –for small intestinal fistulas

• Endoscopic dilation of duodenal stenosis

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First consultation Inselspital 04/2016

• Acute, self limited diarrhea

• Clinical exam

• H=168cm, Weight=46.5 kg (BMI 16.5)

• No perianal fistulas

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Lab exams at first consultation

• Low vit D, Hb, Vit B12 and folic acid normal

• TPMT activity 71 (Normal values 35-115)

• 6 TGN : 129 (>235) / 6MMP : 170 (<5000)

[Imurek 50mg daily]

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Ulcera in the bulbus

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Relative Stenosis bulbus?pars II and fistula orifices

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MR Enteroclysis

• In the duodenum and jejunum –segmental thickening of

nondistended bowell walls, partially with enhancement of

the wall-compatible with subacute inflammation

• Increased number and volume of mesenterial lymph nodes

in the left upper abdomen

• No fistulas, no abscesses

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Therapeutic options ?

• Continuing the therapy

• Increase of the dosis of Imurek

• Increase of the dosis of Imurek and PPI 2x40mg daily

• Switch from Humira to Infliximab

• Infliximab plus Imurek plus PPI 2x40mg

• Infliximab plus Imurek

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Answer Prof.Roblin

• Switch from ADA to IFX plus Imurek Plus PPI

(there are some data from GETAID group that suggest that

IFX could be better than ADA for small bowel involvement)

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Therapy

• Switch from Humira to Infliximab

• PPI 2x40mg daily

• Increase of the dosis of Imurek to 2x50mg daily

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Evolution

• Abdominal pain

• Vomiting, Diarrhea

• Loss of weight

• No fever, no extraintestinal manifestations

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Cause of the worsened evolution

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Cause of the worsened evolution

• Compliance

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Cause of the worsened evolution

• Compliance

• Acute infection: bacterial, viral

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Cause of the worsened evolution

• Compliance

• Acute infection: bacterial, viral

• Non response to therapy-trough levels, antibodies against

TNF inhib

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Cause of the worsened evolution

• Compliance

• Acute infection: bacterial, viral

• Non response to therapy-trough levels, antibodies against

TNF inhib

• Occurence of complications

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Lab

• CRP=26, L=11.800, Hb 136 →to 125, Alb=18g/L

• Stool cultures negative, Clostridium difficile neg

• Infliximab trough level 2.23 microgr/ml

• Antibodies IFX negativ

Shortening of administration period to 4 weeks

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ulcers in the esophagus

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GERD

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Ulcera in the duodenum

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Fistula

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Histology and virology

• Virology and immunhistochemistry- neg for CMV, HSV

• Esophagus- Reflux esophagitis

• Stomach, duodenum- inflammatory changes/no possible

distinction between upper Crohn or peptic disease

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• Colonoscopy:

• 2-3 aphtoid lesions in the terminal ileum, colon-normal

• MR Enteroclysis -no abscesses or fistulas

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Therapy

• Enteral nutrition via naso-jejunal tube, later protein drinks

and Modulen

• 3x40mg Pantoprazol for 3 days, for longer time 2x40mg

p.o

• IFX 600mg (10 mg/Kg) every 4 weeks

• Azathioprin 2x50mg

• Substitution iron, Vit D

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Evolution

• Under IFX 10 mg/kg every 4 weeks – aggravation of

vomiting

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Questions/discussion

• Inflammatory or fibrotic stenosis in the duodenum?

• Fistula?

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Interdisciplinary discussion

• Ballon dilatation ?

• Temporary stent ?

• Gastro-Enterostomy ?

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Therapy

• Gastro-enterostomy

• 2 weeks after surgery – restart IFX

• Imurek, Pantoprazol

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Evolution

• Weight reduction of 2 kg in 3 months

• Vomiting 2 times a week

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Questions

• New flare ?

• Technical problem with anastomosis?

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Upper endoscopy

• Duodenal stenosis- acute ulcerations

• Efferent loop –stenotic: passage with nasal endoscope and

blind biopsies

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Gastro-entero -anastomosis

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Radiology –evacuation mainly through bulbus, stenosis of efferent

loop

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Histology

• High inflammatory activity in the duodenum and in the

jejunum, compatible with Crohn s disease

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Questions-therapy

• Parenteral nutrition plus IFX optimisation according to

trough levels plus Azathioprin ?

• Parenteral nutrition plus IFX plus Azathioprin plus

corticosteroids for short term cortcosteroid treatment ?

• Switch to another class-Ustekinumab?

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Answer Prof.Roblin

• Parenteral nutrition mandatory !!!plus switch to

Ustekinumab

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CASE 2

Ioannis Kapoglou

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Patient: Mr. W.L. 21 yo

Indeterminate Colitis Diagnosed 3/14

• Colonoscopy at diagnosis:

- proctosigmoiditis and erosions at ileoceacal valve and term. Ileum, Calprotectin: >1`800 mg/kg

- mesalazin oral (3g) and local with inadequate response

• Sigmoidoscopy 6 months later:

- moderate left sided colitis

- Hb 8,3 g/l

- addition of foam budesonide (not well tolerated)

Induction with systemic steroids

• Despite therapy escalation persistent symptoms

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02.02.2015 follow up visit

• 3-4 bowel movements per day occasionaly with blood

• MR-enteroclysis 14.01.2015: wall thickened Sigma (20

cm), otherwise normal

• Osteodensitometry 02.02.2015: normal

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Question 1

• How to proceed?

• AZA?

• Anti-TNF?

• Vedolizumab?

• Combination?

• Watch and wait?

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Answer

• Both options available:

• Anti-TNF alone

• Anti-TNF with Immunomodulator

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02.06.15 follow up

• After induction with IFX and under prednison 10mg 1-0-0,

Mesalazine 500 mg 2-2-2 fewer symptoms

• Decision to taper prednisone

• Calprotectin 10.07.2015: 97 mg/kg

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14.07.2015 till 18.07.2015

• Hospitalization due to increasing symptoms

• 15.07.2015 rectosigmoidoscopy:

– rektosigmoiditis Mayo Score 3.

• Other causes such as C. diff, viral superinfection were

excluded

• Stool culture :Campylobacter concisus

• Adenovirus-Ag positive

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Question 2: How to treat?

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Question 2: How to treat?

• All measures below were justified:

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Question 2: How to treat?

• All measures below were justified:

• Systemic prednison was paused

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Question 2: How to treat?

• All measures below were justified:

• Systemic prednison was paused

• Budesonide foam

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Question 2: How to treat?

• All measures below were justified:

• Systemic prednison was paused

• Budesonide foam

• Ciprofloxacin and metronidazol

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Question 2: How to treat?

• All measures below were justified:

• Systemic prednison was paused

• Budesonide foam

• Ciprofloxacin and metronidazol

• Mesalazine was suspended

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11.8.15 follow up

• Under IFX 400 mg every 8w and prednisone 10 mg 1-0-0

• 4-5 bowel movements daily, no blood

• Decision to further taper prednison

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13.10.15 follow up

• 1 month after prednisone cessation

• New flare (10 bloody bowel movements daily)

• Increase steroids to 30 mg for 7 days then tapered again

• November 15: new flare prednisone to 50 mg/d

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07.12.2015 follow up

• Pat. still takes 30mg prednisone

• Generally better

• More symptoms just before the next IFX-Application

• Calprotectin 824 mg/kg

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Question 3: How to proceed?

• Change IFX to other anti-TNF?

• Change Class?

• Measure trough levels and Ab?

• Optimise therapy?

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Answer

• Optimize Anti-TNF Therapy

• change application intervall from 8 to 4 w

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Decision

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Decision

• No Ab against IFX

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Decision

• No Ab against IFX

• Optimise IFX every 4 w instead of every 8 w

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Decision

• No Ab against IFX

• Optimise IFX every 4 w instead of every 8 w

• Try to further taper prednisone

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02.02.16 follow up

• Pat. is doing better, currently under 12.5 mg prednisone

and IFX every 4 w

• Calprotectin 77,2 mg/kg

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04.04.16

• Steroid dependency (<10mg/d not possible)

• IFX trough levels 0.66 ng/ml November 2015, no Ab

• Decision to increase the IFX-dosage to 600mg every 4 w

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25.5.16

• Trough levels IFX:

–30.03.2016 6,53 µg/ml

–27.04.2016 14,3 µg/ml

• Still under prednisone 12,5 mg/d

– (was afraid to reduce it further)

• Pat. stable, no blood in stool

• Decision to decrease the IFX-dosis: 400mg every 4 w

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13.6.16 follow up

• Stable under prednisone 12,5 mg/d and IFX 400mg every 4 w

• 09.06.16: Calprotectin 132 mg/kg

• 24.07.16: Calprotectin 99.6 mg/kg

Goal to further reduce prednisone

20.11.16 acute EBV-Infektion

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30.12.16 follow up

26.12.16: Calprotectin >2400 mg/kg

Infliximab trough levels 2.08 mcg/l, no Ab

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Question 4: How to proceed?

• Change anti-TNF?

• Change Class?

• Top up prednisone?

• Do a colonoscopy?

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Answer

• Re-evaluation with colonoscopy justified

• Inflamatory activity control with top up of prednisone

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16.01.17 colonoscopy:

• Left sided colitis with moderate activity from rectum to left

flexur

Rectum C.ascendens

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21.2.17:

• Pat. is doing better

• Currently under prednisone 12,5 mg/d and IFX 400mg every 4 w

• 13.03.17: Calprotectin 113 mg/kg

• Decision to re-taper prednisone

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9.5.17

• Pat. is doing fine under 5mg prednisone and IFX

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Question 5?

• What to do if a new flare arises?

• Combination therapy after mononucleosis?

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Answer

• Best option would be to switch class i.e. Vedolizuimab

• Cortiment could be used as bridging

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CASE 6

Ioannis Linas

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25 yo Male

• Ulcerative pancolitis with backwash Ileitis (02/2013)

• Montréal Classification E3

• initial manifestation 2011: elevated stool frequency, later bloody

stools

• No extraintestinal, no perianal manifestation

• Non smoker

• Negative IBD Family history

Initial Therapy (02/2013): Mesalazine, Budesonide

• No response

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25 yo Male

• Ulcerative pancolitis with backwash Ileitis (02/2013)

• Montréal Classification E3

• initial manifestation 2011: elevated stool frequency, later bloody

stools

• No extraintestinal, no perianal manifestation

• Non smoker

• Negative IBD Family history

Initial Therapy (02/2013): Mesalazine, Budesonide

• No response

Steroid tapper (03/2013)

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25 yo Male

• Ulcerative pancolitis with backwash Ileitis (02/2013)

• Montréal Classification E3

• initial manifestation 2011: elevated stool frequency, later bloody

stools

• No extraintestinal, no perianal manifestation

• Non smoker

• Negative IBD Family history

Initial Therapy (02/2013): Mesalazine, Budesonide

• No response

Steroid tapper (03/2013)

• No response

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• 4 cycles of Infliximab

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• 4 cycles of Infliximab

• No response

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• 4 cycles of Infliximab

• No response

Adalimumab 09-10/2013

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• 4 cycles of Infliximab

• No response

Adalimumab 09-10/2013

• No response

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• 4 cycles of Infliximab

• No response

Adalimumab 09-10/2013

• No response

Patient frustrated

Alternative medicine 10/2013 – mid 2014

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• 4 cycles of Infliximab

• No response

Adalimumab 09-10/2013

• No response

Patient frustrated

Alternative medicine 10/2013 – mid 2014

• No response

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• 4 cycles of Infliximab

• No response

Adalimumab 09-10/2013

• No response

Patient frustrated

Alternative medicine 10/2013 – mid 2014

• No response

Colonoscopy 05/2014: Ulcerative pancolitis with backwash Ileitis

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• Steroid induction + Azathioprine maintenance therapy

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• Steroid induction + Azathioprine maintenance therapy

• No response

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• Steroid induction + Azathioprine maintenance therapy

• No response

Golimumab 05/2015

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• Steroid induction + Azathioprine maintenance therapy

• No response

Golimumab 05/2015

• Subjectively partial response

• No blood, no abdominal pain, no arthralgia

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• Steroid induction + Azathioprine maintenance therapy

• No response

Golimumab 05/2015

• Subjectively partial response

• No blood, no abdominal pain, no arthralgia

But…

• Persistent diarrhea > 5-6x/d, stool urgency

• Under golimumab intermittent gingival bleeding

• Calprotectin > 1800mg/Kg

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• Steroid induction + Azathioprine maintenance therapy

• No response

Golimumab 05/2015

• Subjectively partial response

• No blood, no abdominal pain, no arthralgia

But…

• Persistent diarrhea > 5-6x/d, stool urgency

• Under golimumab intermittent gingival bleeding

• Calprotectin > 1800mg/Kg

07/2015 Golimumab every 3 weeks and referral to us

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Work up

• Partial clinical response, 5-6x/d diarrhea good condition

• Calprotectin > 1800 mg/Kg, CRP<3 mg/L, WBC: 4.6 G/L,

• Negative stool microbiology, parasites

• No extraintestinal manifestation

• Colonoscopy: ulcerative pancolitis with sparse ulcera but

spontaneous mucosal bleeding and backwash Ileitis.

• Mayo 3, maximal manifestation in rectum.

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Histopathology:

• Chronic ulcerative pancolitis

• Minimal signs of inflammatory activity

• No CMV (IHC / PCR)

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Question 1: What would you do next?

• Other anti-TNF?

• Combination therapy?

• Anti-integrin?

• Calcineurin inhibitors?

Answer Prof Roblin: In this case I would avoid trying yet another new

therapy since we do not know how well the options up to now where uset

and optimized. If you would like to change class anyway vedolizumab could

be an option

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Question 1: What would you do next?

• Other anti-TNF?

• Combination therapy?

• Anti-integrin?

• Calcineurin inhibitors?

Answer Prof Roblin: In this case I would avoid trying yet another new

therapy since we do not know how well the options up to now where uset

and optimized. If you would like to change class anyway vedolizumab could

be an option

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• Combination golimumab + azathioprine

• Local therapy with alternating budesonide and

mesalazine for stool urgency

But then……

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03/10/2015

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• 2x Punch biopsy, Microbiology, direct immunofluorescence

• Pemphigus vegetans type hallopeau associated with the anti-

TNF therapy

• Superinfection with S. aureus

• Azathioprine stopped by the patient,

• Local steroids, antiseptics and antibiotics

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with autoimmune bullous skin disease?Answer Prof Roblin: I have used anti-TNFs extensively since

the time they were introduced and never encountered this

side effect

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Question 3: What do we do next?

• Calcineurin inhibitors?

• Vedolizumab?

• Ustekinumab?

• Surgery?Answer Prof. Roblin. I would probably go for Vedolizumab in

this mildly active but refractory colitis. Another option but

still experimental would be the combination of vedolizumab

with an calcineurin inhibitor for induction of remission and

then maintenance with vedolizumab

Question 2: In your experience anti-TNF associated

with autoimmune bullous skin disease?Answer Prof Roblin: I have used anti-TNFs extensively since

the time they were introduced and never encountered this

side effect

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Question 3: What do we do next?

• Calcineurin inhibitors?

• Vedolizumab?

• Ustekinumab?

• Surgery?Answer Prof. Roblin. I would probably go for Vedolizumab in

this mildly active but refractory colitis. Another option but

still experimental would be the combination of vedolizumab

with an calcineurin inhibitor for induction of remission and

then maintenance with vedolizumab

Question 2: In your experience anti-TNF associated

with autoimmune bullous skin disease?Answer Prof Roblin: I have used anti-TNFs extensively since

the time they were introduced and never encountered this

side effect

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Our decision: vedolizumab

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Our decision: vedolizumab

Question 4: After those adverse effects would a

combination with azathioprine still be an option in the

future?

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Our decision: vedolizumab

Question 4: After those adverse effects would a

combination with azathioprine still be an option in the

future?

Answer Prof. Roblin: Concerning the combination of

vedolizumab with azathioprine there are only low quality data

from a post hoc analysis that are negative. So probably that is

not the best option irrespective of side effects. However there

are many centers that do it and claim to have good results.