Inflammatory Bowel Disease

Dr. Abhimanyu ParasharAssistant Professor

Dept. Of Pharmacy PracticeMMCP, Mullana, Ambala

IBD

It is an idiopathic bowel disease which includes ulcerative colitis (UC) & crohn’s disease (CD)

UC & CD are chronic, relapsing inflammatory diseases of the gut may be associated with a range of extra intestinal manifestations

CD or Regional enteritis

It is an idiopathic chronic ulcerative IBD, characterised by transmural, non-caseating granulomatous inflammation affecting most commonly the segment of terminal ileum and/or colon though any part of the GIT may be involved

Ulcerative Colitis

Idiopathic form of acute & chronic ulcero-inflammatory colitis affecting chiefly the mucosa & submucosa of the rectum & descending colon, though it may involve the entire length of large bowel

Etiopathogenesis

1. Infectious mechanisms

2. Immunologic mechanismsi) humoral factorsii) cell mediated immunologic factorsiii) immunodeficiency

3. Others i) psychological factorsii) genetic factorsiii) racial factorsiv) dietv) social habitsvi) drugs

Infectious mechanisms

Bacterial infections:mycobacteriadysentery bacillichlamydia

Viral infections:roatvirusEB virusintestinal cytopathic virus

Certain protozoal & fungal infections

Immunologic mechanisms

i) Humoral factors a) the specific anti-colon antibodies to E.coli

causes the lesion, but no correlation b/n the levels of these antibodies & activity of the IBD

b) Increased synthesis of Ig Gby the lymphoid cells of diseased bowel, produce antibody mediated damagebut IBD was observed in agammaglobulinaemia also

c) Circulating immune complexesproduces extra intestinal lesions of IBD but their role in intestinal lesions of IBD is not established

d) IgE mediated hypersensitivity reactionleads to excessive histamine release by mast cells in the bowel wall may cause oedema of bowel wall in IBDBut administration of antihistamines does not alter the course of the disease

Cell mediated immunologic factors

a) Decreased number of peripheral T cells.b) presence of T cells sensitized to various

bowel antigens may be cytoyoxic to mucosac) Antibody dependent cellular cytotoxicity

(ADCC) may occur by interaction of K cells with humoral antibodies

immunodeficiency

Immunodeficiency of IgA in crohn’s disease has been suggested more recently as possible immune mechanism for the lesion

Others

Psychological factors:individuals who are sensitive, dependent on others & unable to express themselves suffer from irritable colon

Genetic factors:certain HLA have also been found to be associated with IBD

Racial factors:high incidence of IBD have been identified in Jews & in whites

Diet:milk, fibres & diet rich in CH provokes IBD

Social habits:smokers are more prone to develop IBD

Drugs:women who are on Ocs have increased risk of IBD

Pathologic changes - CD

CD may involve any portion of GIT but affects most commonly 15-25 cms of terminal ileum which may extend into the caecum & sometimes into the ascending colon

Transmural inflammatory cell infiltrate:It consists of chronic inflammatory cells

(lymphocytes, plasma cells & macrophages) – the classical microscopic feature

Non-caseating, sarcoid- like granulomasPresent in all layers of affected bowel & in

regional lymph nodes

Patchy ulceration of mucosaWhich may form deep fissures, accompanied by

inflammatory infiltrates of lymphocytes & plasma cells

Widening of submucosa due to oedema & foci of lymphoid aggregates

In chronic condition, fibrosis is prominent in all the layers disrupting muscular layer

Regardless of the site, bowel wall injury is excessive & intestinal lumen is often narrowed

The mesentery first becomes thickened & oedematous & then fibrotic

Ulcers tend to be deep & elongated & extend along the longitudinal axis of the bowel, atleast into the submucosa

The cobblestone appearance of the bowel wall results from deep mucosal ulceration intermingled with nodular submucosal thickening

Pathologic changes - UC

The characteristic feature is the continuous involvement of rectum & colon without any uninvolved skip areas as seen in CD

The appearance of colon may vary depending upon the stage & intensity of the disease because of remissions & exacerbations

Mucosa shows linear & superficial ulcers, usually not penetrating the muscular layer

The intervening intact mucosa may form inflammatory pseudo polyps

The muscle layer is thickened due to contraction producing shortening & narrowing of the affected colon with loss of normal haustral folds giving garden-hose appearance

Because of remission & exacerbations it is characterised by alternating active disease process & resolving colitis

Crypt distortion, cryptitis & focal accumulations of neutrophils forming crypt abscesses

Marked congestion, dilation & hemorrhages from mucosal capillaries

Superficial mucosal ulcerations, usually not penetrating into the muscle coat, except in severe cases & is accompanied by nonspecific inflammatory cell infiltrate of lymphocytes, plasma cells, neutrophils, some eosinophils & mast cells in the lamina propria

Goblet cells are markedly diminished in cases of active disease

Areas of mucosal regeneration & mucodeplition of lining cells

In long-standing cases, epithilial cytologic atypia ranging from mild to marked dysplasia & some times developing into carcinoma in situ & frank carcinoma

Types of UC

• Proctitis - ulcerative colitis affecting only the rectal mucosa.

• Proctosigmoiditis – It involves rectum and the colon

• Colitis- It involves other parts of the colon.

Complications - CD

MalabsorptionFistula formationStricture formationCarcinomaBleeding Hypochromic anemiaSystemic complications like, arthritis, iritis, skin

lesions, liver disease, renal stones, gall stones, weight loss, growth failure

Complications of - UC

Toxic megacolonPerianal fistulaCarcinomaStricture formation

CLINICAL PRESENTATION

Clinical presentation

Crohn’s disease Ulcerative colitis

Malaise, fever Common Un common

Abdominal tenderness

Common May be present

Rectal bleeding Less 100%

Illeal Very common Rare

Granulomas Common Rare

Fistulas Common Rare

Management

Goals:

to induce remission in active diseaseto maintain remission / prevent relapse

CD

Mild to moderate diseaseActive CD: oral/parenteral steroids- most

effective & safer than oral aminosalicylates

CD of colon: aminosalicylatesCrohn’s ileitis- mesalazine should be used

as 5 aminosalicylic acid is not released in the small bowel from sulfasalazine or olsalazine

Dose of aminosalicylates required for CD is more than of UC especially in small bowel disease

Prednisolone/prednisone 20-60 mg PO/D for 8-12 weeks

Or budesonide CR 9 mg PO/D for 8-12 weeks

Aminosalicylates:Sulfasalazine 2-4 g PO/d in DDMesalazine 3-4.8 g PO/d in DDOlsalazine 2-3 g PO/d in DD

Metronidazole is as effective as sulfasalazine for colonic disease

Metronidazole 20 mg/kg PO/d in DDSevere disease:Hydrocortisone 100 mg IV Q6H orHydrocortisone 300-400 mg by CIVIF/d orMethylprednisolone 60-80 mg IV/d in DD or by CIVIF

for 5-10 daysOral steroids should be substituted when disease

activity has subsidedPrednisolone or prednisone 40-60 mg/d POGradually reducing to zero over 8-12 weeks

Chronically active disease:Patients who do not respond to steroids or

require continuous steroids to control disease activity

AZT6-MPSurgery should be considered if more than 5-10

mg of prednisolone/d is requiredAZT 2-2.5 mg/kg PO/d or6-MP 1-1.5 mg/kg PO/d

Newer agents:Infliximab- monoclonal antibody directed against the

proinflammatory cytokine TNF-alphaEffective in patients with refractory & acutely or chronically

active diseaseDose: 5 mg/kg IVIFMaintenance therapy:AZT & 6-MP effective as prophylactic agents in patients

with frequent relapses & in those who are steroid dependent

AZT 2-2.5 mg/kg/PO/d6-MP 1-1.5 mg/kg/PO/d

Management - UCMild disease- topical therapy for proctitisModerate/severe/more extensive- oral/IV

Aminosalicylates:Effective in inducing remission in active colitis/proctitisResponse is dose realtedSulfasalazine 6g/dMesalazine 4g/dOlsalazine 3g/dADRs of s & o are dose related hence should be started

at low doses & titrated to recommended dose

Immunosupressive agents:AZT & 6-MP, effective for both remission induction &

maintenance therapyTakes 3-6 months to achieve benefitSignificant ADRs

Active proctitis/distal colitis:I-line:Topical steroids alone or with oral aminosalicylatesPrednisolone sod.phosphate 20 mg/100ml/d enema

rectally at night or twice daily

Hydrocortisone acetate 10% foam rectally/d at night or twice daily or

Prednisolone 5 mg rectally twice dailyAlong with,Sulfasalazine 2-4 g/PO/d in 3-4 DDMesalazine 1-1.5 g/PO/d in 3 DDOlsalazine 1-1.5 g/PO/d in 2-3 DD

CTE:5-aminosalicylic acid enemas are superior to topical

steroidsCombination oral & topical 5 AS therapy is more effective

than either therapy alone

II-line:Addition of an oral CS to I-line Prednisolone or prednisone 20-60 mg/PO/d for

8-12 weeks

Extensive UC:Mild to moderate disease:Prednisolone or prednisone 20-60 mg/PO/d for

8-12 weeks and/orOral aminosalicylate

Severe disease:

More than 6 bloody stools/dTemp more than 37.5Pulse more than 100 bpmHb less than 100g/lS.Alb less than 35 g/l

Fluid, electrolyte or blood replacement should be considered

Early surgical consulatation is essential

Hydrocortisone 100 mg IV Q6H or by CIVIF orMethylprednisolone 60-100 mg IV/d in DD or by

CIVIFFor 5-10 days and should be substituted with oral

steroidsIf deteriorating or failure to respond consider

colectomy or IV cyclosporinAvoid:Loperamide & other antidiarrhoeals &

anticholinergics in severe disease as it may leads to toxic megacolon

Chronically active disease:AZT, 6-MP, surgeryAZT 2-2.5 mg/kg PO/d or6-MP 1-1.5 mg/kg PO/dADRs of s&o are dose related hence should be

started at low doses & titrated to recommended dose

Proctocolectomy, ileal pouch anal anastomosis may be considered for the traetment of chronic refractory disease

Maintenance therapy:To reduce the relapse-aminosalicylates or

immunosupressive agentsSulfasalazine 2-3 g/Po/d in 3-4 DDIncidence of ADRs increases with increase in

doseMesalazine 1-1.5g/PO/d in 3 DD Olsalazine 1-1.5 g/PO/d in 2-3 DDADR: watery diarrhoea (10-15%)

Patients responded to topical AMS preparations may continue to use as maintenance therapy at reduced doses

Mesalazine 2-4 g in 60 ml enema rectally 2-3 times a week

A prolonged remission may be achieved with,AZT 2-2.5 mg/kg/Po/d or6-MP 1-1.5 mg/kg/PO/d

Pouchitis:

In patients who have undergone ileal-pouch anal anastomosis may develop inflammation of ileal pouch

Metronidazole 20mg/kg/po/d in DD, probiotic is also useful

Treatment approach for CD

Treatment approach for UC

Treatment optionsDRUGS DOSE MAINTENANCE DOSE

SITE OF ACTION

Sulfasalazine 3 – 4 gm/day 2 – 4 g/day colon

Olsalazine 2 – 3 gm/day 1g/day colon

Balsalazide 2 – 6.75 gm/day 2 – 6.75g/day colon

Mesalamine(DR)

2.4 – 4.8 gm/day 2.4-4.8g/day Distal ileum and colon

Mesalamine (enema) 1 – 4 g/day 0.8 – 4.8 g/day Rectum and terminal colon

Mesalamine (SR) 2 – 4 g/day 1.5 – 4 g/day Small bowel and colon

Mesalamine suppository 1 – 1.5g/day 0.5 – 1 gm/bedtime

Rectum and terminal colon

corticosteroidsDRUGS DOSE

Methylprednisolone (IV) 40 – 60mg/day

Prednisolone ( IV) 60 – 80 mg/day

Hydrocortisone IV 300mg/day

Prednisone( oral) 20 – 60mg/day

Budesonide( oral) 9 mg/day

Hydrocortisone enema 100 – 200 mg/day

DRUGS ROUTE REMISSION DOSE MAINTENANCE DOSE

Azathioprine Oral 2–3 mg/kg/day 2–3 mg/kg/day

6-Mercaptopurine Oral 1–1.5 mg/kg/day 1–1.5 mg/kg/day

Cyclosporine IV 2–4 mg/kg/day Not indicated

Oral 4–8 mg/kg/day Not indicated

Tacrolimus IV 0.01 mg/kg/day Not indicated

Oral 0.1–0.2 mg/kg/day Not indicated

Methotrexate IM 25 mg/wk 25 mg/wk

Oral 15–25 mg/wk 15–25 mg/wk

Infliximab IV 5 mg/kg 5–10 mg/kg

ANTIMICROBIALS

DRUGS REMISSION DOSE MAINTANANCE DOSE

MetronidazoleOral

10–20 mg/kg/day Not indicated

CiprofloxacinOral

1–1.5 g/day Not indicated

FOODS TO AVOID• Alcohol (Mixed Drinks, Beer, Wine)• Butter, Mayonnaise, Margarine, Oils• Carbonated Beverages• Coffee, Tea, Chocolate• Corn Husks• Dairy Products (If Lactose Intolerant)• Fatty Foods (Fried Foods)• Foods High In Fiber• Gas-producing Foods (Lentils, Beans, Legumes, Cabbage, Broccoli, Onions)• Nuts And Seeds (Peanut Butter, Other Nut Butters)• Raw Fruits• Raw Vegetables• Red Meat And Pork• Spicy Foods • Whole Grains And Bran