Inflammatory bowel disease essentials Dr. Jeremy Sanderson Guy s & St. Thomas Hospitals
Inflammatory bowel disease(s) IBD Crohn s disease (CD) Ulcerative colitis (UC) + several other rarer types of IBD
Inflammatory bowel disease(s) IBD Chronic Relapsing / remitting Uncertain aetiology Significant negative QOL impact Relatively uncommon increasing? 2-3 cases per 1000 population GP practice of 20,000 : 40-60 cases
Crohn s disease (CD) = mouth to anus Ulcerative colitis (UC) = colon only + extra-intestinal complications : joints, eyes, skin.
Aetiology of UC Early life exposure Early life exposure Microbiota diversity function pathogenicity Gut immunity Tolerance Innate immunity Environment Epithelial & mucus layer Integrity function Genetics
E.coli persistence in CD macrophages Benefit of intracellular antibiotics?
Negative QOL in IBD Nature of symptoms! Educational loss Occupational loss Reduced aspiration Social avoidance Relationship avoidance Care (Primary to tertiary) = Chronic disease management
What is best practice in IBD?
IBD standards Specialist IBD team 2 WTE IBD Gastroenterologists 2 WTE IBD Colorectal surgeons 1.5 WTE IBD Clinical Nurse Specialists 0.5 WTE CNS in stoma/pouch therapy 0.5 WTE Dietitian 0.5 WTE Admin support for IBD service 1 Named Gastro Histopathologist 1 Named Gastro Radiologist 1 Named Gastro Pharmacist IBD Multi-disciplinary meeting Medical Surgical interaction Arrangements for biologic and immunosuppressive treatment Arrangements for care of children and young adults with IBD Access to Nutritional support and therapy Arrangements for care of in-patients with IBD Arrangements for care of out-patients with IBD
Implementing IBD standards How do we do at GSTT??
IBD standards Specialist IBD team 2 WTE IBD Gastroenterologists 2 WTE IBD Colorectal surgeons 1.5 WTE IBD Clinical Nurse Specialists 0.5 WTE CNS in stoma/pouch therapy 0.5 WTE Dietitian 0.5 WTE Admin support for IBD service 1 Named Gastro Histopathologist 1 Named Gastro Radiologist 1 Named Gastro Pharmacist IBD Multi-disciplinary meeting Medical Surgical interaction Arrangements for biologic and immunosuppressive treatment Arrangements for care of children and young adults with IBD Access to Nutritional support and therapy Arrangements for care of in-patients with IBD Arrangements for care of out-patients with IBD
IBD standards Specialist IBD team 2 WTE IBD Gastroenterologists 2 WTE IBD Colorectal surgeons 1.5 WTE IBD Clinical Nurse Specialists 0.5 WTE CNS in stoma/pouch therapy 0.5 WTE Dietitian 0.5 WTE Admin support for IBD service 1 Named Gastro Histopathologist 1 Named Gastro Radiologist 1 Named Gastro Pharmacist IBD Multi-disciplinary meeting Arrangements for biologic and immunosuppressive treatment Access to Nutritional support and therapy Arrangements for care of out-patients with IBD
IBD standards Medical Surgical interaction Arrangements for care of children and young adults with IBD Arrangements for care of in-patients with IBD
IBD standards Primary : secondary / tertiary care interface in IBD? Key issues : Complex disease, low prevalence Patients want rapid access to advice re flares, questions GP s want / need rapid advice re the same Increasingly complicated treatment All secondary care? Shared care agreements for immunosuppression Key roles for IBD Nurse specialists and IBD pharmacists
IBDHELPLINE IBD PHONE
What is best practice in IBD?
Changing goals of therapy in IBD..mucosal healing feasible with more aggressive therapy = not using ineffective Rx = early use of azathioprine / mercaptopurine = greater use of biologics (eg anti-tnf agents)
Anti-TNFa antibody strategies for CD.... most important advance in IBD since corticosteroids
Efficacy of anti-tnf agents in Crohn s disease % SONIC Week 26: Corticosteroid-free clinical remission p=0.022 Out of trial experience.80% clinical benefit
Efficacy of anti-tnf agents in Crohn s disease Mucosal healing Therefore.. Reduced complications Reduced hospitalisation Reduced surgery Improved QOL
GSTT Specialist IBD service : CCG agreed treatment pathway Moderate severe UC Failing oral immunosuppression Golimumab Inflimxab / Adalimumab Clinical trial Vedolizumab
GSTT Specialist IBD service : CCG agreed treatment pathway Moderate severe CD Failing oral immunosuppression Inflimxab / Adalimumab Clinical trial Vedolizumab
All roads lead to a thiopurine? Mild CD Post-op CD Moderate CD Severe CD Mild Non-healing Rx 5-ASA Diet Antibiotics AZA / 6-MP Steroids Biologics
Personalised approach to IBD treatment.. Pharmacogenetics individual variation in the handling of drugs in the body according to genetically determined factors.
Adverse drug reactions (ADR) and hospital admissions 6.5% admissions due to ADR in 6 months In 80% of cases, median bed stay 8 days 4% of hospital bed capacity Overall fatality 0.15% Projected cost to NHS - 466 million pa Most ADR avoidable Pirmohamed et al, BMJ 3 July 2004
Zaza Gianluigi et al. "Thiopurine pathway" Pharmacogenetics and genomics (2009)
Old dogs..new tricks..
Biotransformation of 6-MP to thioguanine nucleotides imidazole 6-TU Immunosuppression Aza TPMT 6-MP Xanthine Oxidase TGNs Methyl metabolites Cytotoxicity
Polymorphic Trimodal distribution of TPMT activity 700 600 Normal activity 90% 500 Frequency (no. patients) 400 300 200 1 in 300 Zero activity 1 in 10 Intermediate activity Very high activity 100 0-100 0 10 20 30 40 50 60 70 80 TPMT TPMT activity distribution in 5000 PRL samples, 1990-2001 Sanderson et al ACB 2004
Biotransformation of 6-MP to thioguanine nucleotides Allopurinol imidazole 6-TU _ Immunosuppression Aza 6-MP Xanthine Oxidase TGNs _ TPMT? TPMT inhibitor Methyl metabolites Cytotoxicity
TGN monitoring in routine clinical practice: review of 190 patients on AZA for IBD High 29% Very low 6% Low 21% 10% preferential methylation [~60% non-response] Smith M UEGW 2009 Therapeutic 41%
AZA treatment?..before starting... IBD Check panel TPMT : TPMT + Enzyme ITPA, AOX,HLA-G, / genotype ABCB5 Homozygous deficient Heterozygous deficient Consider 5-10mg AZA or avoid AZA Alternative Rx Very high Normal Allopur 100mg + AZA 0.5mg/kg Initiate at 100mg Build to 2mg/kg 4 WEEK TGN level 4 MONTH 4mo TGN level Persuade to take! Increase, continue, decrease dose Switch to allo/aza Switch drug Duration of Rx?? Initiate at 25mg Build to 1mg/kg Nausea Flu-like illness Pancreatitis Hepatitis Myelosuppression Reduce dose Switch to 6-MP V slow escalation 6-MP, check ITPA Alternative Rx 6-TG, MTX, MMF Allopurinol + AZA Dose by TGNs Check dose Parvovirus, drugs etc
Can pharmacogenetics / TGN s achieve this? 10-20% more?? % success
Can pharmacogenetics / TGN s achieve this? % success YES TPMT AOX TGN Allo/AZA Calculation of opportunity from 6-MP switch individualised approach: Using 17% hypermethylation and 6-20% published side effect rates Opportunity for allopurinol / thiopurine = 12-24%
What has that got to do with me?? Earlier diagnosis is important Treatment before complications develop Issues for prescribing and monitoring More difficult to give advice (super-specialised) *** Treatment of flares of IBD ***
Case for discussion 29 year old female lawyer Known to have ulcerative colitis 4 years c/o rectal bleeding with mucus, urgency, 6-7x day 3 weeks Sometimes normal stool Feels tired but working Stressed Stopped smoking one month ago No FH of IBD
Question : Which missing information do you need to guide your decision on initial treatment? 1.Details of the type of IBD and distribution? 2.Current therapy for IBD? 3.Currently pregnant? 4.Travel History? 5.All of the above?
Managing a flare of IBD What type of IBD Crohn s or UC? Which site or pattern of IBD? Distal UC vs pnacolitis Ileal vs colonic CD How severe? Mild/mod/severe. What is the current treatment? None? Mesalazine? Steroids? Could it be intercurrent infection? Travel? Others ill.. Is there a plan for flare up agreed with IBD clinic?
Managing a flare of UC Consider infection history, stool mcs + / - Blood tests FBC, biochem, CRP (not essential to Rx) Faecal calptotectin Sigmoidoscopy / colonoscopy - consider if uncertainty regarding diagnosis - concern re nature of symtpoms
Managing a flare of UC Mesalazine at active disease dose Eg Pentasa 4g daily, Asacol 2.4g daily Mezavant 2.4g Proctiits use suppository 1g mesalazine Left sided consider addition of 1g foam or liquid enema If already on mesalazine, consider high dose (8g / 4.8g) THEN..consider steroid Prednisolone 20mg daily 2 weeks in moderate Prednisolone 40mg reducing course in mod-severe
5-ASA for proctitis and proctosigmoiditis Rectal 5-ASA >> rectal steroid Rectal 5-ASA > oral 5-ASA Rectal and oral even better
Case history.. Stool culture pending (subsequently negative) Consultant letters indicate proctitis (distal UC) Currently on Asacol 1.2g daily Decision to increase to 2.4g daily and add 1g suppository 5-ASA Hold off steroids Says 7 weeks pregnant does it matter?
Managing a flare of Crohn s Consider infection history, stool mcs Assess severity mild / mod / severe Is it an obstructive episode? Mesalazine is NOT an effective drug in Crohn s Antibiotics are a GOOD option for temporary treatment ileal or colonic Ciprofloxacin 500mg bd or Metronidazole 400mg tds THEN..consider steroid Prednisolone 20mg daily 2 weeks in moderate Prednilonone 40mg reducing course in mod-severe Obstructive episodes may settle with liquid diet but consider admission
IBDHELPLINE IBD PHONE
IBD essentials Key points Complex chronic conditions Uncommon but not rare Significant QOL impairment Treatments increasingly specialized but successful IBD standards have helped to drive quality of care Primary / secondary / tertiary care interface very important Access to prompt specialist advice critical Knowledge of managing certain aspects in primary care important