Inflammatory Bowel Disease Dr. WM Simmonds Internal Medicine Gastroenterology 29/08/2011

Inflammatory Bowel Disease Objectives Understand the pathogenesis of inflammatory bowel disease Know the differences between Crohn`s disease and ulcerative colitis Have an approach to the new patient with bloody diarrhoea Know the differential diagnosis of IBD Know the exta-intestinal manifestations of IBD Know the principles of therapy of inflammatory bowel disease

Inflammatory Bowel Disease Introduction Inflammatory bowel disease (IBD) is an immune mediated, heterogeneous syndrome which is divided into 2 major phenotypes: Crohn`s disease (CD) Ulcerative Colitis(UC). There is no pathognomomic test for either CD or UC. Diagnosis is made on a combination of clinical, radiological, endoscopic and histological grounds.

Inflammatory Bowel Disease Epidemiology IBD is a condition of developed countries and outside of Europe, the United Kingdom and North America, is seen in Australia, South-Africa, and Israel at an appreciable frequency. IBD is more common in urban areas and in high socioeconomic settings. It is more common in caucasians, and especially those of Jewish extraction. It occurs less frequently in other race groups. Smokers have double the risk of developing CD as opposed to non-smokers. In contrast to this, smoking protects against UC. First degree relatives of those with IBD have an increased risk of developing IBD.

Inflammatory Bowel Disease Etiology and pathogenesis IBD is currently thought to be due to a dysregulated immune response to an as yet unidentified environmental antigen (possibly enteric microbes). As such the abnormal immune response develops in those with a genetic predisposition, and is modified by certain factors (smoking). The current hypothesis holds that the immune response in patients with IBD is against normal bowel flora which is erroneously perceived as being pathogenic.

Inflammatory Bowel Disease Etiology and pathogenesis Numerous genetic polymorphisms have been identified to date which confer a certain risk, and in certain cases predict disease behaviour (e.g. NOD2/CARD15 on chromosome 16, which is associated with CD of the terminal ileum). Some genetic polymorphisms are specific for CD or UC and some are shared. Genes implicated are involved in regulation of the innate immune system, the adaptive immune system and autophagy. An alternative hypothesis that patients with IBD have an abnormalities in mucosal defence (defensin production).

Ulcerative Colitis Disease is confined to the large bowel (that is apart from extra-intestinal manifestations). The disease is characterised by mucosal inflammation of the large bowel. Perianal disease, fistulas and small bowel strictures are NOT part of the clinical picture and are suggestive of CD.

Ulcerative Colitis Clinical picture Blood per rectum Bloody diarrhoea (including nocturnally). Blood macroscopically visible in 95% of active disease. Cramps (especially before bowel movements) Urgency and at times incontinence Tenesmus Tenderness over inflamed colon Extra intestinal manifestations

Ulcerative Colitis Endoscopic characteristics Rectum almost always involved Extends continuously for varying distances proximally 20% have pan-colitis Pan-colitics may have “backwash ileitis” Longstanding colitis may manifest as a featureless colon, which is narrow and shortened Pseudopolyps are a manifestation of prior severe inflammation

Ulcerative Colitis

Ulcerative Colitis Severity: Truelove en Witts Classification Mild Severe <4 stools per day >6 liquid stools per day Minimal or no bleeding Bloody No fever T⁰>37.5⁰C No tachycardia Pulse > 90bpm Mild anaemia at most Hb <10.5(<75%) ESR <30mm/H ESR >30mm/H

Ulcerative Colitis Endoscopic grading of UC Mayo grade: Loss of vascular pattern Friability Spontaneous haemorrhage

Ulcerative Colitis Microscopic characteristics Inflammation is limited to mucosa and superficial sub mucosa, except with fulminant colitis when it may become transmural Features of chronicity Crypt architectural distortion (branching and fallout) Basal plasma cells and lymphoid aggregates Active disease Neutrophyl infiltration of epithelium and crypt abscesses

Ulcerative Colitis

Ulcerative Colitis Radiological Characteristics Plain abdominal x-ray Collapse of involved segment Haustral thickening (“thumb printing”) Dilated colon (>6 cm dilatation of caecum or transverse implies megacolon) Ba enema (not used much now) Ulceration Featureless, shortened colon (chronicity features) “lead pipe” CT scan Dilated loops of colon Enhancement of colonic wall

Ulcerative Colitis

Ulcerative Colitis Complications Colonic haemorrhage Toxic megacolon Perforation Longstanding disease (> 10 years) increases the risk of colon Ca.

Crohn’s Disease Transmural inflammation of bowel, which may affect any part of the GI tract from the mouth to the anus, but tends to affect individual patients in a particular location, which remains stable over time. It follows that resected Crohn`s disease tends to recur at the site of resection.

Crohn’s Disease Disease behaviour may follow one of 3 patterns or combinations there of, i.e. Luminal inflammatory disease Stricturing disease Fistulating /penetrating disease.

Crohn’s Disease Disease pattern/behaviour /ultimate phenotype may not be apparent initially and develops over a period of years. 30% of patients have isolated ileal disease 30% have ileo-colitis 30% have isolated colitis. Peri-anal disease with fisures and fistulas is common. Upper gastrointestinal involvement occurs less frequently.

Crohn’s Disease Clinical features Weight loss Diarrhoea (only bloody in 50% of patients with colonic disease) Abdominal pain Symptoms of obstruction (if stricturing disease) Peri-anal symptoms and disease Palpable abdominal mass High fever suggests abscess formation (intra-abdominal, ischio-rectal) General features of chronic inflammation with pallor, cachexia if severe uncontrolled disease.

Crohn’s Disease Endoscopic characteristics Depends on distribution Ileitis Colitis Rectum involved in 50% of patients with colitis Ulceration: Aphthous Stellate Serpigenous Skip lesions

Crohn’s Disease

Crohn’s Disease Microscopic characteristics Transmural inflammation Granulomas (non-caseating) Only seen in 20% of mucosal biopsies and 50% of full thickness biopsies

Crohn’s Disease Radiological characteristics Ba small bowel enemas Strictures (“string sign”) Separation of loops (inflammation with thickening of the bowel wall) Mucosal ulceration Fistulous tracts CT scan Abscesses/fluid collections Thickened bowel MRI Especially good for perianal disease Fistulas

Crohn’s Disease

Crohn’s Disease Complications Strictures Fistulas Entero-enteric Entero-vaginal (usually only after hysterectomy) Entero-cutaneous Recto-vaginal Peri-anal Abscess formation Gallstones Kidney stones (oxalate)

Extra-intestinal manifestations Associated with disease activity Independant of Arthropathy Pauciarticular (type 1) large peripheral joints Small joint peripheral arthropathy (type 2) Axial arthropathy (HLA B27) Sacro-ileitis Ankylosing spondylitis Ocular manifestations -Episcleritis -Uveitis Skin -Erythema nodosum -Pyoderma gangrenosum Hepato-biliary -PSC

Uveitis

Erythema nodosum

Pyoderma gangrenosum

Differential diagnosis of IBD Infectious Non-infectious -Bacteria Salmonella Shigella Campylobacter Yersinia (Ileitis) E.coli (enteroadherent, enteroinvasive, enterohemorrhagic) Clostridium difficile -Inflammatory Diverticular colitis Ischaemic colitis Radiation colitis Solitary rectal ulceration Appendicitis Behcet’s disease -Mycobacateria Tuberculosis (Ileo-caecal disease) -Parasites Entamoeba histolytica Trichuris trichura (whipwurm) Necator americanus (hakwurm) Strongyloides stercoralis -Neoplastic Lymphoma (terminale ileum) Carcinoma Viruses CMV HSV HIV -Medication NSAID’s Chemotherapy Bowel preparation -Fungi Histoplasmosis (ileitis)

Clinical approach to a patient with bloody diarrhoea History and clinical examination Stool sample Microscopy, Culture and sensitivity Clostridium difficile toxin assay Sigmoidoscopy and biopsy (if biopsy available) Full length colonoscopy in the absence of a diagnosis and persistent disease or alarm features weight loss anaemia, age >50 years)

Truelove en Witt’s Classification Mild Severe <4 stools per day >6 liquid stools per day Minimal or no bleeding Bloody No fever T⁰>37.5⁰C No tachycardia Pulse > 90bpm Mild anaemia at most Hb <10.5(<75%) ESR <30mm/H ESR >30mm/H

Therapy Induction of remission with corticosteroids Then: Stop. Hydrocortisone 100 mg q 6 hourly IVI for 3 days Then: Prednisolone 40 mg per day po 1 week Prednisolone 30 mg per day po 1 week Prednisolone 20 mg per day po 1 month (Initiation of maintenance therapy) Prednisolone 15 mg per day po 1 week Prednisolone 10 mg per day po 1 week Prednisolone 5 mg per day po 1 week Stop.

Therapy Maintenance of remission (UC) Mild to moderate UC 5-ASA preparations Sulphasalazine Mesalazine Balsalazide Severe or steroid dependant UC Thiopurines Azathioprine 2-2.5 mg per kg per day 6 mercaptopurine 1-1.5 mg per kg per day Steroid refractory UC Cyclosporine Anti-TNFα Colectomy

Therapy Maintenance of remission (CD) Crohn`s disease(5 ASA probably does NOT work) Very mild disease (nothing) Moderate to severe disease Azathioprine or 6 MP Methotrexate Primary prophylaxis Severe disease unresponsive to immunomodulators Biological agents/antibodies Infliximab (Anti-TNF) Adalimumab Vedolizumab ?“Top down” therapy – Biologic agents first.

General measures Stop smoking (especially CD patients) Avoid NSAID`s Drug compliance Remember complications of therapy Steroids: osteoporosis, diabetes, cataracts, osteonecrosis, Cushingoid habitus, hypertension, mood changes 5-ASA: bone marrow suppression (rare), and male infertility Thiopurines hepatitis, pancreatitis, bone marrow suppression Methotrexate: teratogenic, liver fibrosis All drugs may be used in pregnancy & before conception (according to indication) except Methotrexate which is absolutely contraindicated. If you are a GP, remember initial correct diagnosis and therapy should be followed by timely referral to a specialist.

Indications for surgery UC Treatment refractory disease Toxic megacolon Colonic haemorrhage Dysplasia/cancer CD Strictures/obstruction Treatment refractory fistulae Abscesses Massive haemorrhage(rare)

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