OVERVIEW – ACUTE COLITIS

| IBD, infective, and pseudomembranous colitis

| Background, aetiology, features of each condition

| Importance of Multidisciplinary approach

y Stomal therapist, nursing staff
y Dietician, social worker,
y Medical and Surgical collaboration

| Classes of drugs used:

y Aminosalycilates
y Corticosteroids
y Immunomodulatory agents

| Algorithms of management
COLITIS: DEFINITION
| Inflammation of the lining of the colon.
COLITIS
| Classified into: Non-infective and Infective
y Non Infective:
| Inflammatory
| Ischaemic

| Iatrogenic (Chemical, Radiation induced)

| Microscopic (Collagenous, Lymphocyctic, Eosinophilic)

| Atypical

y Infective:
| See over
INFECTIVE COLITIS
INFECTIVE COLITIS
| Viral colitis
y CMV, HSV, Adenoviral colitis
| Bacterial Colitis
y Salmonella, Shigella, Campylobacter, E. coli
y C. diff (Pseudomembranous)
y Chalmydia, Gonococcus

| Parasitic colitis
y Amoebiasis
y Cryptosporidium
y Giardia
INFECTIVE COLITIS:
INVESTIGATION
| Important to exclude in IBD patient
| Microscopic appearance like UC

| Stool specimen.
y Campylobacter and Shigella most likely
| If amoebiasis suspected:
y Specimen examined within hours
y Biopsy required to identify cysts

| Pseudomembranous colitis – specific culture

requirements
INFECTIVE COLITIS TREATMENT
| Dependent on cause
| Most are viral and self limiting

| Treatment usually recommended after persisting

symptoms
| Rarely surgery required for toxic megacolon
PSEUDO MEMBRANOUS COLITIS
PSEUDO MEMBRANOUS COLITIS

| Subsection of infective colitis

| Commonly associated with C.difficile infection

| Suspect following antibiotics or bowel surgery

| Antibiotics alter intestinal flora

| Toxin induces necrosis of mucosa

| Classically caused by Clindamycin

| Any antibiotic can cause it

| Endoscopy off-white slough mucosa

MANAGEMENT
| Cease offending antibiotic
| Metronidazole

| Vancomycin – quicker onset of action

| Caution in pregnant or breast feeding women

| Surgery required in <1%

ULCERATIVE COLITIS
ULCERATIVE COLITIS
| Aetiology unknown
y Genetic:
| p-ANCA more frequent in UC than CD
| HLA-DR2 subtype

| HLA-B27 associated with extra-intestinal manifestations

| More common in whites

| Less common in Blacks and Arabs

y Environmental
| NSAIDs direct mucosa cell toxicity Ï permeability
| Smoking protective against UC

| Low incidence in developing countries

| Increases with increasing wealth

ULCERATIVE COLITIS
| Incidence 10-12 per 100,000
| Twice as common as Crohn’s

| Malignant transformation
y Associated with length of disease
y 10% after 10 years

| Confined to colon – (backwash ilelitis)

| Mucosal inflammation only
y Severe UC can extend into muscularismucosae
| Continuous no skip lesions.
| Majority managed with medical treatment

| 30% - surgery
ULCERATIVE COLITIS
| Multidisciplinary approach optimizes care
| Stomal therapist

| Dietician

| Nursing staff

| Social worker

| Medical team

| Specialized IBD unit

| Joint outpatients/shared care

| Early surgical involvement in acute disease

PRESENTATION
| Severe colitis
y Severe local symptoms
y Profuse diarrhoea with blood
y Anorexia
y Dehydration and hyponatraemia
y Can progress to toxic megacolon and perforation
| Extra-intestinal manifestations
y Eyes – uveitis, episcleritis
y Skin – erythemanodosum most common
| Pyodermagangrenosum lower limb
y Liver – 5%
| Fatty infiltration progress to cirrhosis and PH
| Primary sclerosingcholangitis (rare)
y Arthopathy – polyarthritis, ankylosingspondylitis
ASSESSMENT OF SEVERITY
| Adapted from Truelove’s classification

Mild Severe Fulminant

Daily bowel <4 >6 >10

movements
Blood in stools Infrequent Frequent Profuse

Temperature Normal Normal/elevate Elevated

d
Pulse <90/min >90/min tachycardic

ESR <30mm/hr >30mm/hr >30mm/hr

Hb Normal <75% Normal Requires

transfusion

Truelove SC. Systemic and local corticosteroid therapy in ulcerative colitis. Br Med J, 1960, 1:464-7
ASSESSMENT OF SEVERITY
| Severity essentially correlates with anatomical
extent of disease
| Divided simply into:
y Distal disease
y Proximal extension
y Acute severe colitis – requiring admission

| Severity based on clinical symptoms and usually

anatomical extent, not histological severity of
inflammation
PREDICTING COLECTOMY IN UC
| Travis et al. analyzed the admission of 51 patients
with severe UC Radcliffe hospital Oxford
| Surgical intervention as an endpoint

| By day 5, stool frequency and CRP distinguished

between outcomes (p<0.00625)
| They predict that by day 3, stool frequency >8/day

| OR CRP >45g/dL and stool frequency between 3 and

8/day had 85% chance of a colectomy

S P Travis, et al. Predicting outcome in severe ulcerative colitis. Gut. 1996 June; 38(6): 905–910.
MANAGEMENT DISTAL DISEASE
| Local treatment usually sufficient
| Steroids to induce remission

| 5-ASA compounds to maintain it

| Steroids:
y Suppositories (rectal disease)
y Enemas (extend well into left side)

| Commence both on admission

MANAGEMENT OF DISTAL DISEASE
| Local steroids
y Suppositories (prednisone 5mg) – Rectal disease
y Enema –Sigmoidal disease

| Oral ASA
y Salazopyrinecheapest 3-4g/day
y ~20% unable to tolerate side effects-sulfapyradine
| Headache
| Skin erruptions

| Marrow toxicity, oligospermia (rare)

| Rectal ASAs also available

MANAGEMENT OF PROXIMAL
DISEASE
| Anti-inflammatory
y Steroids to induce remissions
y 5-ASA to maintain remission

| Nutritional assistance
| Symptomatic control

| Psychological support
y Social worker
y Vocational assistance
y Family education
MANAGEMENT OF PROXIMAL
DISEASE
| Prednisolone 30mg
| Azothiprine for steroid dependent or non-
responders
| Ciclosporin good for acute colitis
y No evidence for chronic
| Nutrition
| Anti-diarrhoeal agent
y Codeine
y Loperimide
ADMISSION FOR ACUTE COLITIS
| Multidisciplinary care
| Monitoring and Treatment

| Monitor:
y General observations including stool chart
y Regular weighs
y Hb, alb, and EUC
y Abdo distention – toxic megacolon

| Treatment:
y Bed rest
y Electrolyte correction – normal saline
y Nutrition (high protein/calorie diet)
ACUTE SEVERE COLITIS
MANAGEMENT
| Prednisone 60mg daily
| 5-ASA compounds ? value in acute disease

| H2 blocker

| Ciclosporin causes remission acutely in 50% who

do not respond to steroids
y Prone to relapse
| Infliximab if all else fails
INDICATIONS FOR SURGERY
ACUTE COLITIS
| Failure of medical management- recognize early
| Clinical deterioration
y Peritonism
y Megacolon
y Perforation (mortality 40%)

| Clinical stagnation
| Signs on admission that surgery likely
y Multiple bloody loose bowel actions
y Low alb
y Low Hb
y Sig. weight loss
y Recurrent attacks
SUMMARY UC MANAGEMENT
| Exclude infectious cause
| Assess severity

| Likelihood of colectomy

| Medical management
y ASAs
y Steroids
y Immunomodulatory agents

| Multi-disciplinary care essential

CROHN’S DISEASE
CROHN’S DISEASE
| Chronic transmural inflammation of bowel
| Associated with extraintestinal manifestations

| Discontinuous segments of disease

| Histology:
y Chronic inflammatory infiltrate (giant cell formation)
y Transmural
y Inflammation causes fistulas and stricturing
y Granulomas with giant cell formation
EPIDEMIOLOGY
| Prevalence 0.1% (half as common as UC)
| 5-6 per 100,000

| Peak age 15-25 years

| Higher in females

| Higher association with:

y urban dwelling
y cooler climate
y smoking
CROHN’S DISEASE
| Infection:
y Mycobacterium paratuberculosis
| Found in 66% those with Crohn’s
| 10% of controls

| Doesn’t explain immune response

| Anti TB treatment ineffective

y Measles virus
| DNA found in paitents with Crohn’s
| Suggests granulomatousvasculitis occurs secondary to
measles
| Reverse PCR unable to find evidence of virus
GENETIC FACTORS
| Genetics:
y 2.5 times more likely in siblings with CD
y 50% concordance in monozygotic twins
y IBD-1 gene on ch 16
y NOD2/CARD15 gene variations associated with CD
y Ileal disease not colonic
y Clearly polygenetic with complex interplays
PRESENTATION
| Depends on site
| Ileal disease – appendicitis

| Colonic disease – fulminant colitis

| Diarrhoea

| Abdominal pain

| Rectal bleeding

| Perianal disease

| Systemic symptoms
y Wt loss, bleeding tendancies (Vit K), anaemia (B12)
| Extraintestinal manifestations
EXTRA-INTESTINAL
MANIFESTATIONS
| Related to disease activity
y Aphthous ulceration
y Erythemanodosum
y Arthopathy
y Eye complications

| Unrelated to disease activity

y Sacroilitis
y Gallstones (30%)
y Renal calculi (5-10%)

| Amyloidosis found in 25% at autopsy, only 1%

have clinical manifestations
y Resection of bowel results in regression.
Aphthous ulceration

Erythemanodosum
PATHOGENESIS OF CD
| Inappropriate inflammatory response to mucosal
antigens
| 2 abnormalities
y Increased permeability (?1o or 2o)
y Abnormal T (CD4+) cell response

| Subsequent release cytokines (IL-1, IL-2, IL-6,

and TGFs) explains clinical features of CD
| Fever
| Acute phase response

| Hypoablbunaemia

| Weight loss

| Mucosal permeability

| Endothelial damage
DISTRIBUTION OF DISEASE
| Small bowel alone 30-35%
| Colon alone 25-35%

| Small and colon 30-50%

| Anal lesions 50%

| Stomach and duodenum 5%

INVESTIGATIONS
| Bloods
y CRP generally relates to disease activity
| Alb, selenium, Mg and Zn levels
| Radiology
y Small bowel follow through
y Barium enema
y CT- thicken bowel wall
y MRI for perianal disease

| Endoscopy
y Colonoscopy – terminal ileum biopsies
WORKING DEFINITIONS OF
CROHN'S DISEASE ACTIVITY
| Mild to moderate disease:
y The patient is ambulatory and able to take oral intake.
| Moderate to severe disease
y Either the patient has failed treatment for mild to moderate
disease
y OR has more pronounced symptoms including fever,
significant weight loss, abdominal pain or tenderness,
intermittent nausea and vomiting, or significant anemia.
| Severe fulminant disease
y Either the patient has persistent symptoms despite outpatient
steroid therapy
y OR has high fever, persistent vomiting, evidence of intestinal
obstruction, rebound tenderness, cachexia, or evidence of an
abscess.
| Remission
y The patient is asymptomatic OR without inflammatory
sequelae, including patients responding to acute medical
intervention.
Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am
J Gastroenterol 2001;96:635-43.
TREATMENT ALGORITHM FOR CD
NUTRITION AND ANTIBIOTICS
AS A TREATMENT
| TPN induces remission in 60-80%
| Same effect as steroids

| Not as effective in isolated colonic disease

| Prone to relapse unless long course TPN

undertaken
| Metronidazole most commonly used

| Decreases disease activity in colonic and not

small bowel disease
| Little data on efficiency
OTHER IMMUNOMODULATORY
AGENTS
| Other immunomodulatory agents have been
studied in active, refractory Crohn's disease:
y Cyclosporine,
y Methotrexate
y Tacrolimus.
y Parenteralmethotrexate in a dosage of 25 mg per
week has shown effectiveness in steroid-dependent
patients, allowing for steroid tapering.
y Guidelines for using tacrolimus and cyclosporine
have yet to be determined
FIRST LINE TREATMENT
| Mild/Moderate:
y ASA
y Flagyl
y Prednisone

| Severe:
y IV hydrocortisone
y Fluid and electrolyte replacement
y Nutritional support

| Remission maintenance
y Azothiaprine
INFLIXIMAB
INFLIXIMAB
| Chimeric monoclonal antibody
| Human portion constant Fc

| Mice portion VH and VK portions specifically

targeted against TNFα
| Inactivates TNFα by preventing binding to
inflammatory cells and releasing cytokines
| IV infusion

| Expensive

| Huge list of adverse reactions

y Anaphylaxis
y Tolerance
INFLIXIMAB
| In persons unresponsive to salicylates,
antibiotics, corticosteroids, or
immunosuppressants, infliximab has proved
successful in closure of fistulas, steroid-refractory
disease,
| Improves moderate to severe disease.

| A study using infliximab in patients with

moderate to severe Crohn's disease showed
improvement in 65 percent of patients, with
complete remission in 33 percent
Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term
study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's
Disease cA2 Study Group. N Engl J Med 1997;337:1029-35.
INFLIXIMAB
|Single-dose infusions of 5 mg per kg, 10 mg per
kg, and 20 mg per kg were used, with the best
response seen at 5 mg per kg.
| Another study showed improvement in four
weeks in more than 80 percent of patients
treated with 5 mg per kg, and more than 50
percent achieved remission.

Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety
of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's
disease. Gastroenterology 1999;117:761-9
INFLIXIMAB – DOWN SIDE
| Sepsis is an absolute contraindication -
overwhelming septicaemia.
| Increases risk of TB

| Worsens CCF

| Longterm safety unknown

y ?increased risk of malignancy
| Case reports of Hepatosplenic T cell lymphoma in
children (6 out of 8 died)
TOP DOWN APPROACH VS STEP UP
| Traditional approach was “step up” from least toxic
to more toxic dependent on severity
| Disadvantage of this approach is some patients will
fail treatment and have uncontrolled inflammation
| “Top down” approach is to start with biologic
therapy early and gain remission quickly
| Prevents prolonged uncontrolled inflammation

| The overall aim is to avoid using steroids and thus

their complications
| Theory is long-term steroid use may inadvertently
propagating abnormal loss of tolerance
SUMMARY OF MANAGEMENT FOR
CD
| ASAs
| Steroids
| Antibiotics
y Flagyl useful only in colonic disease
| Nutrition
y TPN induces remission in 60-80%
y Less effective in colonic disease
| Immunomodulatory
y Azothioprine
y Mercaptopurine
y Monoclonal Ab
y Ciclosporin
PHARMACOLOGY
Mesalamine 5-amino-2-hydroxybenzoic acid

2-(acetyloxy)benzoic acid
Aspirin
PHARMACOLOGY 5-ASA
COMPOUNDS
| Some jejunal absorption
| Majority passes to colon

| Reduced by the bacterial enzyme azoreductase

| Coliform bacteria are necessary to reduce the

relatively inactive parent drug to its active
moieties
| Modulates prostagladin pathways

| Also inhibits production of IL-1, IFγ and TNF

AMINOSALICYLATES
| In 1965, Misiewicz et al. performed first RCT
that sulfasalazine was useful for maintaining
remission in patients with UC
| 73% on placebo relapsed

| 21% on ASA relapsed within a year

Misiewicz JJ, Lennard-Jones JE, Connell AM, et al. Controlled trial of sulfasalazine in maintenance
therapy for ulcerative colitis. Lancet. 1965;285:185-188.
ASA ADVERSE REACTIONS
| Nausea, vomiting, headaches, folate-dependent
anemia, and abnormal sperm production.
| Significant hyper- sensitivity reactions to
sulfasalazine:
y such as anaphy- laxis, fever, severe skin reactions,
profound bone mar- row suppression, and
pancreatitis
| These avoided by using other ASAs
| 10-20% will have a reaction to these
STEROIDS
| Affects arachadonic acid metabolism
y Inhibits phospholipase A2
AZOTHIAPRINE AND
MERCAPTOPURINE
| Azothiaprine acts as a pro-drug
| Converted to mercaptopurineintracellularly

| Purine anti-metabolite agents

| Exact action unknown

| May disrupt DNA repair mechanisms

| May induce T cell apoptosis

| Both take weeks to achieve therapeutic levels

CICLOSPORIN
| Ciclosporin is thought to bind to the cytosolic
protein in T lymphocytes
| Forms a complex that inhibits transcription of
IL-2 and lymphokine production
| Leads to reduced function effector T cells

| Not as cytoxic

| Causes nephrotoxicity

| Small series caused remission in 80% after short

course
| Not good for maintaining remission
SUMMARY
| Important to rule out infectious colitis and
pseudomembranous colitis as cause of presentation
| Multidisciplinary care essential

| 3 main classes of drugs

y ASAs
y Steroids
y Immunomodulatory agents

| Nutritional care
| Quality of life issues