Inflammatory Bowel Disease September 2013 Dr Tony Smith - - PowerPoint PPT Presentation

Inflammatory Bowel Disease September 2013

Dr Tony Smith Gastroenterologist

Your Questions

 What are I nflammatory 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.

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

Ulcerative colitis

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

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?

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)

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?

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

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?

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

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?

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 Thiopurines Dx 5-ASA Steroids MTX Surgery 5-ASA… 2004 Thiopurines Dx Steroids MTX Surgery 5-ASA?… IFX 2007 Thiopurines Dx Surgery … Anti-TNF / biologicals Steroids or anti-TNF MTX

← Immunosuppression →

Traditional “Step-Up” Medical Management

• f Inflammatory Bowel Disease (IBD)

Aminosalicylates (sulfasalazine and mesalazine)and antibiotics (metronidazole and ciprofloxacin) Corticosteroids – prednisolone and budesonide

Immunomodulators – azathioprine/6- mercaptopurine and methotrexate Biological therapies

• infliximab

MILD DISEASE SEVERE DISEASE

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

Sandborn W, Loftus E. Gut 2004;53:780–782

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 0.2% 0.5% 0.6% Non-Hodgkin’s lymphoma 0.2% 1.4% 0.2% Death 0.4% 1.2% 1.3%

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/mm3 and/or CD4 < 300/mm3



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

• r 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

5 10 15 20 25 30 35 40 45 wk30 wk54 plac 5mg 10mg

ACCENT 1 PERCENT IN REMISSION CDAI<150

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

5 10 15 20 25 30 35 40 45 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

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?

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

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?

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

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?

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 immuno-

modulators may be continued in pregnancy

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

I BD?

 When should I refer?

Familial risks

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

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 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

• f 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

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?