Case Management Conference

Report
“It’s Not Just For
C. difficile Anymore”
Prof Thomas J. Borody
MD, PhD, FRACP, FACP, FACG, AGAF
Centre for Digestive Diseases
Sydney, Australia
August , 2014
Disclosure statement
TJ Borody makes the following disclosures:
 RedHill Biopharma: scientific advisory board
(honorary)
 Salix Pharmaceuticals: research grant
 CIPAC Consultant (honorary)
 GSK, Salix Pharmaceuticals, Giaconda Pty Ltd:
stock
 Patents: in various fields, including FMT
 Pecuniary interest in Centre for Digestive
Diseases, where FMT is a treatment option
Centre for Digestive Diseases
 Established October 1984
 Free standing GI endoscopic Clinic
 6 Gastroenterologists and a staff of 47
 FMT since 1998; > 4500 procedures
 No restrictions on use in CDI nor non – CDI
indications
 Restriction on “supply”
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FMT Outside Relapsing CDI-1
 FDA Guidance : FMT to treat C. difficile not
responding to standard therapies
• CEBER July 2013
A. FMT in CDI and IBD
- Common (Issa et al I B Dis 2008)
- Eradicates 90% (Borody UEGJ 2013)
- Prolongs remission in minority
- Rarely dramatic reversal of IBD
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FMT IBD :CD
CASE 2
 47 y male, 1 yr Hx severe CD (previous 3 yr Hx UC)
 Diarrhea 20-25/day, bleeding, cramping, fatigue – possible
surgery candidate, toxin-positive CDI
 CRP=68.5*, Hb=114*
 35mg prednisone, 20mg/wk MTX
 Symptoms improved somewhat
on pre-FMT vancomycin regime
 Posterior fissures, very severe
distal inflammation with
pseudopolyps, ulcers and
scarring throughout bowel
Sigmoid colon, fully-prepped bowel
FMT IBD :CD
 Two-day infusion: transcolonoscopic + next day enema
 CDI eradicated.
At 13 mo F/U:
 1-2 formed stools/day. No bleeding, no mucus, no
urgency
 CRP=6, Hb=160
 Able to return to work, 20kg
weight gain
 No medication 1 year
 Best result
Sigmoid colon, unprepped bowel
FMT Outside Relapsing CDI-2
B. FMT in Non R-CDI
- With significant co-morbidities
- Immunosuppressed / transplants (Kelly et al 2014
AmJG)
- Pregnancy - ?
- With non-significant co-morbidities
- First time CDI – 2 infusions ~ 100%
- D-IBS + CDI –  Diarrhoea – occasional
cure
- C-IBS + CDI – Rare cure with 1-2 FMT
Eradication still >90%
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Disorders associated with altered
intestinal microbiome and/or
responded to FMT-1
GI
• Clostridium difficile infection (CDI)
• IBD – UC and Crohn’s*
• Sclerosing cholangitis*
• IBS
• Recurrent diverticulitis*
• Halitosis
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Disorders associated with altered
intestinal microbiome and/or
responded to FMT-2
Non GI
• Arthritis
• Autoimmune – ITP*
• Autism
• Chronic Fatigue Syndrome
• Diabetes mellitus and
insulin resistance
• Acne vulgaris
• Mood disorders
• Metabolic syndrome
• Multiple sclerosis*
• Parkinson’s disease
Modified : Brandt et al 2013 Am J
Gastro
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FMT: Inflammatory Bowel Disease
 1988: Our first case (indeterminate colitis): 2 infusions. Remains






cured > 25 years (Borody et al 1989)
1989, Bennet et al: self-treated with FMT, clinical and histological
normality. (Bennet et al Lancet 1989)
2003: 6 cases, remain ‘cured’ 1-15 years (Borody et al 2003)
2011: repeated enema infusions – key to IBD
2012: Systematic review. Majority of patients experience symptom
improvement (19/25), disease remission (15/24) and cessation of
medication (13/17) (Anderson et al, 2012)
2012: 62 cases UC – Prolonged histological ‘remission’ (Borody et al
2012)
Reports of isolated cases of dramatic clinical and histological
improvement:
- Kao et al, 2014 ; Gordon et al, 2014 ; Zhang et al, 2013
Retrospective Review – FMT in UC
 62 UC patients – No CDI
 Simple Clinical Colitis Activity Index (Walmsley)
 Reduction >4 points – Marked improvement
2-4 points – moderate
0 points – no improvement
• 17/62 (27%) – Marked improvement
• 26/62 (42%) – Moderate
• 16/62 (26%) – No improvement
• 3/62 (5%)
– Worsened
• 17 with marked improvement
• Clinically well, formed stool
• Endoscopically normal
• Histologically normal
• “Remission” = 1-24 years
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Changes by Age Group
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14
13
13
14
Worsening of
Symptoms
12
10
10
No Improvement
8
7
Moderate Improvement
6
4
2
3
1
2
Significant
Improvement
0
Group A (18 - 35 years) Group B (36 - 80 years)
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Retrospective Review – FMT in UC
 62 UC patients – No CDI
 Simple Clinical Colitis Activity Index (Walmsley)
 Reduction >4 points – Marked improvement
2-4 points – moderate
0 points – no improvement
• 17/62 (27%) – Marked improvement
• 26/62 (42%) – Moderate
• 16/62 (26%) – No improvement
• 3/62 (5%) – Worsened
• 17 with marked improvement
• Clinically well formed stool
• Endoscopically normal
• Histologically normal
• “Remission” = 1-24 years
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FMT for IBD: UC
Case 1:
 21 y; 10 yr Hx of severe UC failing Rx (steroids, anti-TNFs)
 Commenced FMT April 2010: immediate symptom
improvement, lowered CRP approx 1 month after starting
enemas
 Completed 26 FMT enemas
Pre-FMT
Post-FMT
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FMT for IBD: UC
Case 2
 33 y M. 8 wk abdominal pain, diarrhoea, mucus + blood.
First diagnosis of UC
 Rx: Standard anti-inflammatory : frequent relapses.
Before FMT pre-treated with ciprofloxacin,
metronidazole, mesalazine and prednisone.
 FMT via trans-colonoscopic infusion then daily, twiceweekly, weekly, FMT infusions. After 80 FMT he was recolonoscoped on 14/9/12.
 He was passing normal stool once per day and was off all
drugs then for 7 months and has continued well
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Before
After
Rectum
Above: Rectum (L), Rectum (R)
Sigmoid colon
Sigmoid colon
Above: Sigmoid colon (L), Terminal
ileum (R)
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FMT for IBD: UC
Case 3
 38y M. Distal colitis proximal pseudopolyps - sclerosing
cholangitis with elevated LFT’s. C. difficile negative
 1st infusion transcolonoscopic, followed by daily infusions,
then three per week and reducing. 2nd colonoscopy
3/10/2012 after ~ 100 FMT infusions. Once per week for
now. Stools formed for a couple of days after infusion and
then they became unformed.
 Next colonoscopy 6/2/2013. FMT now weekly or second
weekly. Regained weight. No blood, no mucus and formed
stools. Note: Serum ALP fell from 338 to 94 - other liver
functions normal.
 Unprepared colonoscopy showed no inflammation.
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Before
After
Sigmoid colon
Sigmoid colon, showing
mucus, blood
Sigmoid colon, showing
pseudopolyps
Transverse colon
Transverse colon
Hepatic flexure
Hepatic flexure
Ascending colon
Caecum, infusing FMT
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FMT for IBD: UC
Case 4
 53y M, severe distal colitis on immune-suppressants,
5ASA antibiotics facing surgery. Chose recurrent FMT, C.
difficile toxin positive found
 9/12/2011 - first FMT. Severe distal inflammation. For CDI
- had single trans-colonoscopic FMT followed by enema. 7
weeks later he felt “fantastic”. No urgency, no blood, one
motion per day.
 10/1/2013 – colonoscopy; tubular adenoma removed but
mucosa normal. Histology - small numbers of neutrophils
within laminar propria - focal mild cryptitis The patient
was passing normal formed stools daily. Remains clinically
well currently
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FMT for PROCTITIS: UC
Case 5
 57y F. Nine y history of refractory proctitis (failed 5-ASA , steroids,
antibiotics, probiotics, immunosuppressants and acetarsol).
 FMT commenced Dec 2007 (69 sessions of infusions)
 10 days into FMT immediate clinical response diarrhoea ceased
Colonoscopy at 3y and 5y showed no visible or histological
inflammation. Now asymptomatic >5y years + off all meds without
relapse
Rectum - Prior FMT
Rectum - Post FMT
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Before
Top: Rectum. Below: sigmoid colon
After
Top: Rectum showing adenomatous polyp.
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Below: sigmoid colon
FMT for IBD: CD
Case 1:
 14 y M: Severe Crohn’s ileitis, C. difficile positivity on
Prednisone and Imuran. Marked symptoms – poorly
controlled.
 Terminal ileitis - 17/1/2012, FMT 17/4/2012. Instead of doing
2 infusions mother continued home infusions with marked
improvement. Total of 60 infusions. No antibiotics. Able to
stop Imuran. Acne healed by 7 days. Stools: 1-2 formed per
day with all inflammatory parameters normal.
 15/11/2012 – Colonoscopy; terminal ileum was totally normal
,no aphthoid erosions, no cobblestoning, no inflammation.
Donor was 15 year old cousin. Normal colonocopy March 2014
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Before
After
Terminal ileum
Terminal ileum
Terminal ileum:
erosions
Terminal ileum
Terminal ileum
Terminal ileum:
no visible
inflammation at
all
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CDI
IBD
• No. of infusions:
•SINGLE+
• No. of infusions:
•MULTIPLE INFUSIONS
•Symptom Reversal
•Rapid
Cure
•Remission
• >90%
•Symptom Reversal
•Slow then rapid REVERSAL
•Remission
• > 80%
•Possibility of Cure:
•CURE > 95%
VS
•Possibility of Cure:
•Real Possibility: 10-15%
•Measure of Success :
•Negative Stool for CDI
•No symptoms
•Measure of Success :
•Normal histology
•No Symptoms
•Published Evidence
•Large volume of small case
reports > 1000 patients
•Published Evidence
•Case reports [n=?12]
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Experience in IBS
 First reported by us in 1989 in 55 patients – most IBS
 @ CDD - most common indication is D-IBS
 Constipation-IBS more difficult to reverse – requires
repeated bowel cleaning and enema infusions
 Several ‘chronic nausea’ patients treated
 Several ‘abdominal pain’ only also treated
Borody et al 1989; MJA 150: 604
 Refractory D-IBS in 13 patients – 70% Improved
Pinn et al 2013; Am J Gast 108:S563
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Use of FMT in Neurological
conditions
 FMT in three atypical MS patients at CDD.
 FMT found to reverse MS symptoms in 3/6
cases resulting in regaining lower motor skills
and urinary function and these patients
remained asymptomatic after receiving FMT –
F/U up to 17 y
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Future of FMT
 Initial use of ‘frozen’ microbiota preparation
 Development and use of freeze-dried ‘enteric-coated’
microbiota capsules
 Expansion of use to growing number of applications
including – IBD, IBS, Diverticulitis; Acne; Halitosis;
Anorexia Nervosa; Metabolic Syndrome; Autism; Other
Neurologic indications; Autoimmune diseases;
?Prevention of Ca colon; Others
 Post-Antibiotic microbiota restoration
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CONCLUSIONS
 FMT in Relapsing CDI is becoming mainstream
 In IBD FMT shows promise but need for repeated infusions is




a barrier
Many unanswered questions in IBD – e.g. treat actively using
FMT inflamed mucosa or heal first with conventional therapies
Future oral enteric coated FMT may be the ultimate therapy –
to maintain remission
Given the unprecedented sporadic IBD resolution with FMT
the mechanisms underlying IBD may need re-examination
Other areas are of interest and expose new mechanisms
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