Inflammatory Bowel Disease Kevin Luey, FRACP Gastroenterologist Inflammatory Bowel Diseases Infective colitis Ulcerative colitis Crohn’s colitis Ischaemic colitis NSAID-colitis Radiation colitis ULCERATIVE COLITIS CROHN’S DISEASE IBD Chronic inflammatory disorders of the gastrointestinal tract of unknown aetiology but with an autoimmune basis, characterised by ulceration and inflammation of the gut wall, causing abdominal pain, diarrhoea and rectal bleeding. Prevalence Prevalence varies world wide being more common in developed countries. 100-200 per 100,000 in western countries. ? Underestimate. Higher prevalence in white races and Jews. More common in close relatives. The prevalence of Crohn’s in the NZ population is approximately 100 per 100,000 Incidence Was doubling every 10 years since 1940 Improved recognition Appears to be increasing slowly now. Real increase Currently 10-20/100,000 Pathogenesis Still unknown nearly 100 years after first description A combination of environmental factors triggering chronic inflammation in a genetically predisposed hosts. Pathogenesis of IBD genes microflora food smoking drugs mucosal immunity mucosal inflammation IBD Differences between Crohn’s and UC Differences in disease phenotype Differences in genetic associations (e.g. IBD1 on chromosome 16 coding for NOD2 important in CD but not UC) Both diseases long thought of as centering on upregulated immune reactivity, but increasing evidence of disordered innate immunity in CD Phenotype Differences between Crohn’s disease and UC Crohn’s Disease Transmural Small and large bowel Skip lesions Rectal Sparing Granulomata common Ulcerative Colitis Mucosal Large bowel only Continuous disease Rectal involvement 95% Granulomata uncommon Clinical presentations and patterns of disease IBD: key clinical factors. Presentation Natural History diarrhoea, often bloody Onset any age, peaks early adulthood and 40-60 abdominal pain Relapse and remissions weight loss life-long malaise Ulcerative colitis Clinical features Unformed stools Blood and mucus Abdominal cramps Urgency Tenesmus Disease distribution Begins in rectum and extends continuously proximally UC Clinical course Natural history Fulminant (often first episode) Chronic relapsing and remitting Chronic continuous Self limiting (<10%) Relapse rate 50% in first year Colectomy Pancolitis 30-40% in 5 yrs Distal colitis; 10% in 5 yrs 1%/year thereafter for all These rates appear to be falling since Infliximab has become available ASSESSING SEVERITY OF UC (Truelove & Witts BMJ 1954) mild stools <5/d, trace blood temperature No fever pulse severe >5/d, bloody >37.8 <90 >90 Hb Normal <10.5 ESR <30 >30 Crohn’s disease Clinical features Systemic symptoms Due to chronic inflammation Lethargy Loss of appetite Weight loss Fever Intestinal symptoms Depend on disease distribution Abdominal pain Diarrhoea Weight loss Rectal bleeding Nausea Crohn’s disease Sites of involvement Small bowel 30% Terminal ileum 80% Small and large bowel 50% Large bowel 20% Diagnostic investigations Diagnosis Stool culture Blood tests Endoscopy and histology Radiology Nuclear med scans Inflammatory markers Nutritional markers White cell scans DEXA ASCA/ANCA Faecal calprotectin Blood tests Raised CRP/ESR Raised platelets: correlate well with IBD rather than infectious colitis Hypoalbuminaemia: correlates with high CRP Full blood count – anaemia, neutrophilia Iron, Vitamin B12, folate Renal function Liver function Endoscopy Oesophogastroduodenoscopy (gastroscopy) Ileo-colonoscopy (colonoscopy) Enteroscopy (small bowel) Capsule endoscopy Endoscopy (ILEO-colonoscopy) Histology Crypt distortion (implies inflammation for more than 6 weeks) Chronic inflammatory cells Granuloma formation Can help with diagnosing microscopic colitis Radiology Plain films Contrast studies ? outdated CT Collections (e.g. abcesses) Complications US Ba follow through, enema Bowel wall thickening Collections MRI Perianal disease Small bowel AXR IN ACUTE UC Transverse colon dilation, mucosal islands and thumbprinting Crohn’s disease Ileal stricture: CT enteroclysis Ileal stricture: MRI Treatment strategies MANAGEMENT OF IBD General Education - CCSG Psychological support Nutritional support Avoid risk factors smoking, drugs ‘MDT’ GP, physician, surgeon, counsellor, nurse, pharmacist, dietitian Specific therapy medical, surgical Ulcerative colitis Ulcerative colitis goals of therapy Induce remission Maintain remission Quality of life (IBDQ) Prevent complications Disease Therapy related Appropriate timing for surgery Ulcerative colitis Therapeutic considerations Extent Severity Disease complications Response to previous therapies Lifestyle considerations UC Treatment Options 5 ASA – topical / oral Steroids – topical / oral / systemic Azathioprine/6-MP/Methotrexate Cyclosporine – oral / systemic Immunological therapies - biologics Surgery Alternative therapies – e.g. Probiotics No treatment entirely effective or safe Management of fulminant colitis mortality reduced from 50% - 1.5% Meticulous clinical care Multidisciplinary approach IV hydrocortisone 100mg qds (60%) Prophylaxis against DVT/PE Cyclosporin 2mg/kg (levels 150-250) 60% initial response, 30% long term ? Biologics Azathioprine on discharge 5 ASA for active UC 60% remission OR 2.0 cf placebo in metaanalysis Topical in left sided disease (70% response) Dose dependant Renal toxicity Dose dependant nephritis Class effect Which 5ASA? What dose stomach jejunum ileum colon Pentasa (slow-release mesal) Asacol, Salofalk (pH-dependent mesalazine) sulphasalazine, olsalazine, balsalazide (azo-bonded) CORTICOSTEROIDS IN IBD Restrict to active IBD No prophylactic role Co-prescribe bone protection Minimise long-term use RESPONSE TO STEROIDS IN IBD 65% remission/improvement in 4/12 50% Crohn’s patients relapse or are steroiddependent at 1 year ` PROBLEMS WITH STEROIDS Given inappropriately Recurrence after stopping Side-effects Failure to heal mucosa SIDE-EFFECTS OF STEROIDS osteoporosis - give calcium/vit D diabetes infections osteonecrosis of hip hypertension glaucoma/cataracts skin changes………. Maintenance therapy for UC 5 ASA Azathioprine Biologics Azathioprine Long term maintenance strategy Slow onset 2-3 months Mainly uncontrolled data 36% 1 year relapse compared to 59% ??duration of therapy Side effects of Azathioprine Allergic responses Leucopenia Nausea and vomiting Pancreatitis Dermatological ? Malignancy ? Effects in pregnancy Monitoring: regular FBC and LFT Surgery for UC Fulminant colitis Failed medical treatment Complications Cancer risk Surgery for UC Panproctocolectomy Ileostomy Pouch formation Close stoma Crohn’s disease Crohn’s disease Goals of therapy Similar to UC Nutrition/growth Surgery – Not curative - High relapse rate Fistula management 5ASA INDICATIONS Crohn’s mild-moderately active disease – esp. colon ? Effectiveness as maintenance prophylaxis only after small bowel resection Steroids in Crohn’s disease Gut, 1994; 35: 360 Antibiotics in Crohn’s disease Metronidazole Perianal / colonic disease ?active disease Some benefit post surgery 1yr Neuropathy Azathioprine as maintenance in Crohn’s disease Benefit at 2.5mg/kg but not much beyond Methotrexate in Crohn’s disease Start 25mg s/c weekly MTX for 16 weeks Then maintain with 15mg s/c or oral weekly Side effects of methotrexate Allergic reaction Folate deficiency Oral ulceration Bone marrow suppression Pneumonitis/pulmonary fibrosis Hepatic fibrosis Teratogenic Healing of Colonic Ulceration with Anti-TNF Antibodies Van Dullemen Gastroenterology 1995 Biologics Anti- TNF alpha antibodies. TNF alpha important near the beginning of the inflammatory cascade Blocking this prevents inflammation and resultant ulceration etc. Anti-TNF Antibodies Binding Site for TNF IgG •Infliximab •Chimeric monoclonal antibody •Given as iv infusions (approx every 2 months) •Adalimumab •Fully humanised •Given as subcut injection every 2 weeks k k Infliximab Results Chronic active 30% remission 30% improvement Fistulation Early recurrence on stopping Concurrent immunosuppressives or maintenance therapy essential 60% closure General Contraindications Intestinal sepsis pregnancy, lactation (experience reassuring) Infection – check esp. for TB heart failure malignancy Side Effects infusion reactions acute 20% delayed hypersensitivity 2% ANA - 50% dsDNA Abs lymphoma? aplastic anaemia heart failure demyelination, aseptic meningitis infections !!Cost - $5000 per infusion!! Adalimumab Humanised alpha TNF antibody Therefore less immunogenic Given subcutaneously rather than iv Similar results to Infliximab Same precautions and side effects Given 2 weekly COMPLICATIONS OF IBD LOCAL ulceration bleeding stricture perforation fistula abscess cancer SYSTEMIC eyes joints skin liver thrombosis Extra-intestinal manifestations of IBD Erythema nodosum Pyoderma gangrenosum Colorectal Cancer in UC High risk in Ulcerative Colitis Very high risk if have sclerosing cholangitis Risk increases with duration and extent of disease 2% after 10 years 9% after 20 years 19% after 30 years Colonoscopic Surveillance in UC Recommended colonoscopic surveillance with multiple biopsies Every 2 years from 8-10 years after diagnosis Annually after 20 years High grade dysplasia – colectomy Low grade dysplasia ? Colectomy ? 6 monthly colonoscopies Colorectal Cancer in Crohn’s Colitis Evidence less clear cut than in UC Increasing evidence that the risk is similar to UC in Crohn’s colitis. Most experts recommend same surveillance programme as for UC PROGNOSIS OF IBD lifelong relapses and remissions bowel resections » » UC 20% Crohn’s 70% mortality increasing slightly in Crohn’s mortality decreasing rapidly in UC Time trends of death from ulcerative colitis (full line) and Crohn's disease (dashed lines). Sonnenberg A Int. J. Epidemiol. 2007;36:890-899 Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2007; all rights reserved. Summary IBD common and affects wide range of age groups, often the young Multidisciplinary and holistic care is essential in such a chronic condition Treatment relies on induction of remission then maintenance with anti-inflammatory and immunosuppressive treatments Steroids are not useful for maintenance Immunosuppressive regimens are applied in a step-wise approach UNDERWRITERS’ VIEW INCREASING PREVALENCE DECREASING MORTALITY – Life ratings MORE EFFECTIVE MEDICATIONS but not without morbidity – probably balancing out for TRB and Trauma (critical illness) ? For IP BOWEL CANCER RISK LOWER THAN PREVIOUSLY THOUGHT – Trauma and IP Future genetic tests ?