1 / 31

“It’s Not J ust F or C. difficile Anymore ”

“It’s Not J ust F or 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)

milton
Download Presentation

“It’s Not J ust F or C. difficile Anymore ”

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. “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

  2. 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

  3. 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”

  4. FMT Outside Relapsing CDI-1 • FDA Guidance : FMT to treat C. difficile not responding to standard therapies • CEBER July 2013 • 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

  5. 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

  6. 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

  7. FMT Outside Relapsing CDI-2 • 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%

  8. 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

  9. 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

  10. 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

  11. 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

  12. Changes by Age Group

  13. 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

  14. 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

  15. 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, twice-weekly, weekly, FMT infusions. After 80 FMT he was re-colonoscoped 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

  16. Rectum Sigmoid colon Sigmoid colon Above: Rectum (L), Rectum (R) Above: Sigmoid colon (L), Terminal ileum (R)

  17. 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.

  18. Sigmoid colon Sigmoid colon, showing mucus, blood Sigmoid colon, showing pseudopolyps Transverse colon Transverse colon Hepatic flexure Hepatic flexure Caecum, infusing FMT Ascending colon

  19. 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

  20. 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 - Post FMT Rectum - Prior FMT

  21. Top: Rectum showing adenomatous polyp. Below: sigmoid colon Top: Rectum. Below: sigmoid colon

  22. 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

  23. Terminal ileum Terminal ileum Terminal ileum: erosions Terminal ileum Terminal ileum: no visible inflammation at all Terminal ileum

  24. CDI • No. of infusions: • SINGLE+ • Symptom Reversal • Rapid Cure • Remission • >90% • Possibility of Cure: • CURE > 95% • Measure of Success : • Negative Stool for CDI • No symptoms • Published Evidence • Large volume of small case reports > 1000 patients • IBD • No. of infusions: • MULTIPLE INFUSIONS • Symptom Reversal • Slow then rapid REVERSAL • Remission • > 80% • Possibility of Cure: • Real Possibility: 10-15% • Measure of Success : • Normal histology • No Symptoms • Published Evidence • Case reports [n=?12] VS

  25. 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

  26. 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 thesepatients remained asymptomatic after receiving FMT – F/U up to 17 y

  27. 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

  28. 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

More Related