Inflammatory Bowel Disease September Dr Tony Smith Gastroenterologist

Inflammatory Bowel Disease September 2013 Dr Tony Smith Gastroenterologist

Your Questions What are Inflammatory Bowel Diseases? What are the causes? What are the symptoms? How is it diagnosed? What treatments are available? What are the complications of the disease and treatment? What about diet? What about pregnancy? What are the risks to family members getting IBD? When should I refer?

Definition A group of chronic inflammatory intestinal conditions cause not known Crohn s disease (CD) may affect mouth to anus and Ulcerative colitis (UC) is confined to the colon Infections of the intestine must be excluded Exclude microscopic colitis, coeliac disease, NSAIDs, pancreatic insufficiency, colon cancer and small intestine pathology.

Ulcerative colitis Rectosigmoid 40% Left-sided 30% Total colitis 30%

Ulcerative colitis

Crohn s disease

Crohn s disease Transmural

Inflammatory Bowel Disease Crohn s Extensive Full thickness Fistulae & stenosis Skip lesions Cancer risk Smoking worsens Granuloma Ulcerative colitis Limited to colon Mucosal No fistula Continuous Cancer risk Smoking protects Appendicectomy <20yrs protects No granuloma

What clinical Features suggest IBD? Age no barrier Acute diarrhoea which persists sugests UC Rectal bleeding and pus common in UC Abdominal pain more common in CD Extra-intestinal manifestations affect joints skin eyes and the liver Weight loss and fever are serious symptoms

Causes Genetics Environment Triggers eg bacterial infection Geographical variation Abnormal inflammatory response to an environmental trigger

Genes NOD2/CARD15 Implicated in 15% of CD Chromosome 16 single point mutation Gene product alters intra-cellular proteins Gene expressed by leukocytes, monocytes, antigen presenting cells and epithelial cells Activates inflammation in response to bacterial proteins Involved in cell death (apoptosis)

Bacterial Enviroment Crohn s disease Ulcerative colitis Lesions in areas of highest bacterial count Divert faecal stream Immune reactivity ASCA antibodies Germ free animals Starts in rectum and migrates proximally Pouchitis panca (70% UC) cross reacts with bacterial proteins Metronidazole for pouchitis Probiotics

Rising incidence of Crohn s Christchurch 2004: 16.5/100,000pa (Gearry et al 2006)

Stable incidence of UC Christchurch 2004: 7.6/100,000pa (Geary, 2006)

Symptoms (intestinal) Diarrhoea Rectal bleeding Rectal mucus +/- pus Abdominal pain Nausea +/- vomiting Fever

Symptoms Joint pain +/- swelling Back pain Skin ulcers Liver Function abnormalities Malabsorption of calcium, folic acid and vitamin B12 Anaemia

Diagnosis History Examination proctoscopy or sigmoidoscopy FBC, CRP, U&E, creatinine, albumin, LFTs Faeces tests Micro for red and white cells AXR and erect CXR CT and MRI scans Colonoscopy and biopsies Bone density

Treatment Nutrition supplements Replace iron calcium folic acid and B12 Probiotics Medication Surgery

Long-term objectives in the management of IBD Achieve and maintain remission Heal fistulae and avoid stenosis Reduce or eliminate steroid use Avoid hospitalisation and surgery Prevent complications (including adverse effects of treatments) Improve quality of life

Shifting the paradigm 1990 Dx 5-ASA Steroids Thiopurines MTX Surgery 5-ASA 2004 Dx Steroids Thiopurines MTX IFX Surgery 5-ASA? 2007 Thiopurines MTX Dx Anti-TNF / biologicals Surgery Steroids or anti-tnf Immunosuppression

Traditional Step-Up Medical Management of Inflammatory Bowel Disease (IBD) SEVERE DISEASE Biological therapies - infliximab Immunomodulators azathioprine/6- mercaptopurine and methotrexate MILD DISEASE Corticosteroids prednisolone and budesonide Aminosalicylates (sulfasalazine and mesalazine)and antibiotics (metronidazole and ciprofloxacin)

Drug treatment 5 Amino salicylates (5 ASA) Cortico-steroids Immuno modulatory drugs (azathioprine 6 Mercaptopurine and Methotrexate) Biologics (Infliximab, Adalimumab) Cyclosporin

Toxicity associated with anti- TNF (Opportunistic) infections Immunogenicity Auto-immunity Malignancies Rare AEs: heart failure, demyelination

Safety profile Antibody formation 13% (anti HACA) Infusion reactions in 17%, but only 0.5% are serious Anti dsdna antibodies develop in 9% PMFLE JC virus (Natalizumab) Schiabe T. Can J Gastroent 2000; 14: 29

Adverse events with infliximab in CD Clinical trials Ljung et al. Colombel et al. Serious AEs 4.0 4.6% 8.3% 8.2% Opportunistic infections 0.3% 0.9% 0.2% Serum sickness 1.9% 2.3% 2.8% Drug-induced lupus Non-Hodgkin s lymphoma 0.2% 0.5% 0.6% 0.2% 1.4% 0.2% Death 0.4% 1.2% 1.3% Sandborn W, Loftus E. Gut 2004;53:780 782

Vaccination and systematic workup to consider before introducing Anti-TNF therapy Detailed interview Physical examination Laboratory tests Screening for tuberculosis Vaccination

Laboratory tests before starting anti-tnf Full blood cell count Caution if lymphocytes <600/mm 3 and/or CD4 <300/mm 3 Liver tests CRP Serology HIV HBV and HCV VZV (unless past medical history of chickenpox) CMV, EBV Anti-nuclear antibodies, anti-dna if ANA+

ACCENT 1 trial Aim to establish efficacy and safety of repeated infusions of IFX for active Crohn s disease (CDAI>220) Hypothesis maintenance more effective than single infusion Secondary objectives for IFX corticosteriod sparing effect RTC Lancet 2002;359:1541

ACCENT 1 trial 335 pt responded to a single infusion IFX Randomised to infusions of placebo, 5mg/kg or 10mg/kg weeks 2,6 and then every 8 weeks Safety data Serious infection 4% Intestinal stenosis 2% IFX pts more likely to be off steroids

ACCENT 1 PERCENT IN REMISSION CDAI<150 45 40 35 30 25 20 15 10 5 0 wk30 wk54 plac 5mg 10mg

ACCENT 1 trial Maintenance IFX more effective in treating moderate to severe Crohn s Disease Time to relapse was prolonged QoL improved Serious infection 3-4% Six malignancies and 3 deaths randomly distributed between the groups

Sonic Study RTC comparing IFX, Aza or combination in moderate to severe Crohn s Disease No previous treatment with the above CDAI 220-450 Primary endpoint CDAI<150 steroid free at 26 weeks Secondary endpoints mucosal healing at 26 weeks NEJM 2010:362;1383

Mucosal healing % Week 26 45 40 35 30 25 20 15 10 5 0 AZA IFX AZA+IFX

Adalimumab CHARM RTC 56 week with 854 pts CDAI 220-450 Pts in remission at 4 weeks 80/40mg Randomised to plac, ADA 40mg eow, ADA 40mg weekly Endpoints CDAI <150 at 26 and 56 weeks 499 pts Current meds 5ASA, IM, C-S & previous biologics Gastroenterology 2007:132;52

Adalimumab CHARM

Other Treatments Worms Heparin Apheresis Appendicectomy Alternative medicine

Summary of Treatments Biologic agents are a significant advance in the treatment of IBD Two edged sword Risk v benefits Patient groups with aggressive IBD Consider Top Down treatment Patients fully informed and investigated

Complications of disease Anaemia and rectal bleeding Osteoporosis Strictures ie narrowing of the bowel Fistula ie abnormal tracts to other organs eg bladder skin vagina Abdominal mass and pain Dilated colon Colon cancer Peri-anal disease Extra-intestinal complications

Extraintestinal IBD

Drug treatment side effects 5 Amino salicylates (5 ASA) Cortico-steroids Immuno modulatory drugs (azathioprine 6 Mercaptopurine and Methotrexate) Biologics (Infliximab, Adalimumab) Cyclosporin

Diet Healthy avoid excess sugar and fat Supplements with ensure or fortisip Low fibre for patients with CD strictures Oily fish eg salmon or tuna may be helpful ie diets rich in omega3 Elemental diets for acute Crohn s disease

Pregnancy Folic acid 5mg daily 6 weeks before conception Remission of symptoms at conception Untreated disease in pregnancy results in small for dates fetus Medication with 5ASA and immunomodulators may be continued in pregnancy

Familial risks Siblings 1-3% Parents 1-5% Identical twins 33% Jewish 8%

Definition of Acute Severe Colitis BO >6x/24hrs Hb<10.5 ESR>30 P>90 T>37.5 Exclude infection toxic megacolon and perforation Truelove and Witts BMJ 1955

Option for Treatment Nutrition enteral +/- antibiotics DVT prophylaxis (clexane) IV hydrocortisone 100mg q6h or equiv Re-assess patient daily At day 3 decide either infliximab or cyclosporin A At day 5-7 decide continue medical management or surgery

Outcomes of patients with UC Acute severe colitis affect 25% of pts Colectomy rates one or more episodes of severe flare 39% Colectomy rate in patients who did not need admission 3.4% (p<0,0001) 30-40% fail to respond to intensive therapy Dinesen LC et al J Crohns Colitis 2010;4:431