Presented by,THUSHARA. C

1ST YEAR MPHARMPHARMACY PRACTICE

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a group of long-term conditions that cause inflammation of the gastrointestinal tract (gut)

There are two forms of idiopathic inflammatory bowel disease (IBD): CROHN’S DISEASE: A transmural inflammation of GI mucosa that may occur in any part of the GI tract ULCERATIVE COLITIS: A mucosal inflammatory condition confined to the rectum and colon.

TYPES

Crohn’s disease

Extends into the deeper layers of the intestinal wall, and may affect the mouth, esophagus, stomach, and small intestine.

Transmural inflammation and skip lesions.

In 50% cases -ileocolic,30% ileal and 20% -colic region.

Regional enteritis

Ulcerative colitis

causes ulceration and inflammation of the inner lining of the colon and rectum.

It is usually in the form of characteristic ulcers or open sores.

ETIOLOGY

Immunology

Initiating pathogen

Environmental Factors

Genetic factors

Bacterial antigens are taken up by specialized M cells, pass between leaky epithelial cells or enter the lamina propria through ulcerated mucosa

After processing they are presented on type 1 T-helper cells by antigen presenting cells (APC) in the lamina propria.

T-cell activation and differentiation results in Th1 T cell mediated cytokine response

With the secretion of cytokines including gamma interferon (IFNƴ)

PATHOPHYSIOLOGY

Further amplification of T cells perpetuates the inflammatory process with activation of non immune cells and release of the important cytokines. Eg: IL-12, IL-23, IL-1, IL-6 and tumor necrosis factor (TNF)

These pathways occur in all normal individual exposed to inflammatory insults and this is self limiting in healthy subjects

In genetically predisposed persons, dysregulation of innate immunity may trigger inflammatory bowel disease.

Smoking appears to be protective for ulcerative colitis but associated with

increased frequency of Crohn’s disease. Ulcerative colitis and Crohn’s disease differ in two general respects: anatomic sites and depth of involvement within the bowel wall. There is, however, overlap between the two conditions, with a small fraction of patients showing features of both diseases

ULCERATIVE COLITIS

Ulcerative colitis is confined to the colon and rectum and affects primarily the mucosa and the submucosa.

The primary lesion occurs in the crypts of the mucosa in the form of a crypt abscess.

Local complications (involving the colon) occur in the majority of ulcerative colitis patients. Relatively minor complications include hemorrhoids, anal fissures, or perirectal abscesses.

The patient with toxic megacolon usually has a high fever, tachycardia, distended abdomen, elevated white blood cell count, and a dilated colon.

ulcerative colitis have hepatobiliary complications including fatty liver, pericholangitis, chronic active hepatitis, cirrhosis, sclerosing cholangitis, cholangiocarcinoma, and gallstones.

Arthritis commonly occurs in IBD patients and is typically asymptomatic and migratory. Arthritis typically involves one or a few large joints such as the knees, hips, ankles, wrists, and elbows

CROHN’S DISEASE Crohn’s disease is a transmural

inflammatory process. The terminal ileum is the most common site of the disorder but it may occur in any part of the GI tract.

Patients often have normal bowel separating segments of diseased bowel; that is, the disease is often discontinuous.

Complications of Crohn’s disease may involve the intestinal tract or organs unrelated to it. Small-bowel stricture and subsequent obstruction is a complication that may require surgery. Fistula formation is common and occurs much more frequently than with ulcerative colitis.

Systemic complications of Crohn’s disease are common and similar to those found with ulcerative colitis. Arthritis, iritis, skin lesions, and liver disease often accompany Crohn’s disease.

Nutritional deficiencies are common with Crohn’s disease.

Ulcerative Colitis

Crohn’s Disease – Macroscopic Features

Crohn’s disease – sign and symptoms

Colitis and perianal disease - low grade fever, malaise, diarrhea, crampy abdominal

pain, sometimes hematochezia - pain is caused by passage of fecal material through

narrowed and inflamed segments of large bowel

Gastroduodenal disease - nusea, vomiting, epigastric pain - second portion of duodenum is more commonly

involved than the bulb

INTESTINAL OBSTRUCTION IN CD:Postprandial bloating,cramping pains & loud

borborygmi(narrowing can occur due to inflammation

spasm or fibrosis)FISTULATING DISEASE: Can result in intra abdominal or retroperitoneal

abscess menifested by fever chills, a tender abdominal mass & leucocytosis.

Enterocolic fistulas :presents with diarrhoea , weight loss & malnutrition.

Enterovesical fistulas/enterovaginal fistulas:presents with recurrent infections.

Enterocutaneous fistulas: usually develop at site of surgical scars.

Endoscopic image of Crohn's colitis showing deep ulceration.

EXTRA INTESTINAL MANIFESTATIONS

Ulcerative colitis – clinical presentation

The major symptoms of UC are:Bloody diarrohea(hallmark)TenesmusPassage of mucusCrampy abdominal pain

Patients with proctitis usually pass fresh blood or blood-stained mucus either mixed with stool or streaked onto the surface of normal or hard stool

When the disease extends beyond the rectum, blood is usually mixed with stool or grossly bloody diarrhea may be noted

When the disease is severe, patients pass a liquid stool containing blood, pus, fecal matter

Other symptoms in moderate to severe disease include: anorexia, nausea, vomitting, fever, weight loss

MILD DISEASE (UC)

Gradual onset Infrequent diarrhoea (<5movements/day)

Intermittent rectal bleeding. Stool may be formed or too loose in consistency

Fecal urgency ,tenesmus,left lower quadrant pain relieved by defecation

NO significant abdominal tenderness

MODERATE DISEASE (UC)

More severe diarrhoea with frequent bleeding

Abdominal pain & tenderness but not severe

Mild fever , anemia & hypoalbuminemia

SEVERE DISEASE (UC) Severe diarrhoea with >6-10 bloody bowel

movements /day Severe anemia , hypovolemia ,imparied nutrition

& hypoalbuminemia Abdominal pain & tenderness FULMINANT COLITIS:

Subset of severe disease with rapidly worsening symptoms & signs of toxicity

ulcerative colitis:the left side of the colon is affected The image shows confluent superficial ulceration and loss of mucosal architecture.

EXAMINATION PHYSICAL:

Hydration & volume status determined by B.P

Pulse rateNutritional status

ABDOMINAL:Tenderness & evidence of peritoneal

inflammation Presence of red blood on DRE

INVESTIGATIONS

CD UCBlood Test

•CP with morphology: Normocytic normocromic anemia of chronic disease•Serum B12 level may be low.•Raised ESR, CRP and raised WBC count.•Hypo albuminaemia.•Blood culture in septicaemia.

•Fe deficiency anemia•Raised white cell and platelet count•Raised ESR, CRP•Hypo albuminaemia

Serological Test

•Saccharamyces cerevisiae antibody is usually present•P-ANCA negative

•P-ANCA may be positive

Stool culture

•Should always be performed in both to rule out infective cause

CD UCRadiology

Plain ABD. X-ray:•Intestinal obstruction or displacement of bowel loops by a mass.

•Extent of the disease can be judge by air distribution in the colon and the presence of colonic dialatation

Ultrasound:•Thickened small bowel loops and mesentery or abscess

•Thickening of colonic wall and presence of free fluid in abdominal cavity

Barium follow through:•Asymmetrical alteration mucosal pattern with narrowing or stricturing.•Skip lesions

•Fine mucosal granularity•Mucosa become thickenned and superficial ulcers are seen (collar-button ulcers)•Loss of haustration

CD UCInstant Barium enema•Patchy sup. Ulceration to wide spread deep (rose thorn ulcer)•Cobble stone appearance and narrowing

•Superficial ulcers •Shortened and narrowed colon in long standing disease

Colonoscopy•Fissures and fistulae •Pseudopolyps

•Mucosal granularity and hyperemiaHigh resolution USG. And spiral CT•Radionuclide scan with gallium labeled polymorphs or indium or technetium labeled leucocytes •Capsule imaging of the gut.

•Radionuclide scan used to assess colonic inflammation

TREATMENT OBJECTIVES

IBD: Induce remission with control of acute

inflammatory flare. Maintain remission as long as possible. Normalize bowel function when possible. Maintain nutritional status. Improve quality of life (QOL).

NON PHARMACOLOGICAL TREATMENT

Nutritional Support• Patients with moderate to severe IBD are often malnourished.• The nutritional needs of the majority of patients can be adequately addressed with enteral supplementation. Patients who have severe disease may require a course of parenteral nutrition.• Probiotic formulas have been effective in maintaining remission in ulcerative colitis.

Surgery For ulcerative colitis, colectomy may be performed

when the patient has disease uncontrolled by maximum medical therapy or when there are complications of the disease such as colonic perforation toxic dilatation (megacolon), uncontrolled colonic hemorrhage, or colonic strictures.

The indications for surgery with Crohn’s disease are not as well established as they are for ulcerative colitis, and surgery is usually reserved for the complications of the disease. There is a high recurrence rate of Crohn’s disease after surgery.

PHARMACOLOGICAL TREATMENT

1.AMINOSALICYLATES: Sulfasalazine, mesalazine, olsalazine, balsalazide

Effective therapy of UC, but little to no benefit for CD. MOA: varied mechanisms including blockade of the infl ammatory mediators interleukin-1 and tumor necrosis factor-alpha as well as modulation of peroxisome proliferator activated receptor colonic infl ammation is reduced.

Precautions and adverse effects: Fever, dizziness, headache, itching,

rash,granulocytopenia, luecopenia, thrombocytopenia, aplastic anemia,

hepatotoxicity, chronic renal injury2. STEROIDS Glucocorticoid properties of hydrocortisone and

prednisolone are the mainstay of treatment in active ulcerative colitis and Crohn's disease

Prednisolone administered orally or rectally is the steroid of choice although in emergency situations hydrocortisone or methylprednisolone is used when the parenteral route is required.

Corticosteroids have direct anti-inflammatory and immunosuppressive actions whichrapidly control symptoms.

They can be used either alone or in combination, with a suitable mesalazine (5-aminosalicylic acid, 5-ASA) formulation or immunosuppressant, to induce remission.

Oral corticosteroids should not be used for maintenance treatment because of serious long-term side effects, and abrupt withdrawal should be avoided.

Formulations. Oral prednisolone will control mild and moderate

IBD and 70% of patients improve after 2–4 weeks of 40 mg/day. This is gradually reduced over the next 4–6 weeks

Mechanism of action. The glucocorticoid and mineralocorticoid eff ects of the steroids used in IBD are wide ranging. The anti-infl ammatory eff ects are likely due to glucocorticoid suppression of proinfl ammatory cytokines.

3. AZATHIOPRINE & 6-MERCAPTOPURINE They are ef fective at inducing and maintaining

remission in IBD. Response is slow and may take months to be fully effective.

Mechanism of action. Azathioprine and 6-MP are purine antimetabolite drugs, which interferewith DNA synthesis, with disruption of the infl ammatory response seen in IBD

Precautions and adverse eff ects. Bone marrow suppression. Both azathioprine and 6-MPhave been implicated in increased risk for Epstein Barr related non-Hodgkin lymphoma. This risk appears to be small but is serious..

4. METHOTREXATE: An effective treatment for inducing remission, maintaining remission, and steroid sparing in CD. Parenteral methotrexate is also effectivefor maintaining remission in CD.

Mechanism of action: Methotrexate is a folate analog and inhibits dihydrofolate reductase with multiple modes of anti-infl ammatory eff ects.

ADR: The most common risks are rash, nausea, pneumonitis or Mycoplasma pneumonia, and elevated serum transaminases. CD patients treated with methotrexate appear to be at low risk for hepatic toxicity

5. Cyclosporine and tacrolimus Immunosuppressive agents that have been

shown to be effective in IBD. They are typically used for severe acute IBD

Mechanism of action: Both cyclosporine and tacrolimus are calcineurin inhibitors and are potent inhibitors of T-lymphocyte activation

Precautions and adverse events:paresthesias, hypertension, hypertrichosis, renal insuffi ciency, infection, gingival hyperplasia and seizure. Patients should be closely monitored for effects on blood pressure, electrolytes, renal function, and cholesterol. Hypocholesterolemia and hypomagnesemia increase the risk of seizure.

6. BIOLOGICS Infliximab , adalimumab , and certolizumab pegol

These agents are anti-tumor necrosis factor-alpha antibodies

Anti-TNF-alpha therapy mechanism of action: Tumor necrosis factor-alpha is a cytokine involved in multiple proinflammatory and

proliferative pathways in IBD. These agents bind TNF-alpha preventing its binding to cell

surface receptors and subsequently decreases inflammatory cytokines and increasing apoptosis of activated T lymphocytes and monocytes.

Adverse effects: All anti-TNF-alpha antibodies carry black box warnings

for increased risk of opportunistic infections (e.g., tuberculosis, invasive fungal infections such as histoplasmosis, blastomycosis, or pneumocystis, viral infections such as hepatitis B.

Use of concomitant immunosuppressive agents may increase risk of infection

7.Antibiotics: Use of select antibiotics such as metronidazole,

ciprofloxacin, clofazimine, or rifaximin with the specifi c goal of remission of acute IBD iscontroversial.

Metronidazole and ciprofl oxacin are used widely by convention as maintenance therapy in CD but controlled trial results do not conclusively support this use.

Metronidazole has been useful in patients suffering from pouchitis postbowel resection surgerythat involves formation of a pouch.

8. Antispasmodics and antidiarrheals: Cramping and abdominal IBS-like

symptoms are often noted in IBD patients9.Analgesics: There is rarely a need for pain control in UC as the

disease is limited to the mucosa of the colon with limited involvement of tissue containing pain receptors. Narcotics are to be avoided in UC therapy outside of perioperative situations as they increase the risk of toxic megacolon and can mask signs of perforation. NSAID medications should be avoided as they have been implicated in inducing IBD flares.

ALGORITHM FOR UCUlcerative colitis

Inducing remission

Active/left sidedor extensive disease

Oral aminosalicylate plus oral corticosteroids.If prompt

response is required plus rectal aminosalicylate or corticosteroid

if rectal symptoms

Active distal diseaseTopical aminosalicylate (suppositories and enemas)or topical steroid plus oral aminosalicylate or corticosteroid to give prompt relief

SevereIntravenous and rectal steroids,fluids and electrolytes, heparin,nutrition, antibiotics thenciclosporin (or infliximab)

MaintenanceIn order of preferred choice:aminosalicylates, azathioprine,mercaptopurine, infliximabNutrition: calcium and vitamin Dsupplements

ALGORITHM FOR CD

Crohn’s diseaseInducing remission

Active ileal/ileocolonic disease Corticosteroids; elemental or polymeric diet; parenteral

nutrition if complex fistulae; azathioprine or mercaptopurine asadjunctive therapy Infliximab or adalimumab if response orintolerance or contraindication to eithercorticosteroid and/or

Immunosuppressants Surgery if medical treatment fails

Fistulating and perianal diseaseAntibiotics,Azathioprine or mercaptopurineor methotrexate then infliximab and/or surgery; Elemental or parenteral nutrition

MaintenanceStop smoking; calcium and vitamin

D supplementsAzathioprine OR mercaptopurine OR

methotrexate and/orinfliximab/adalimumab

Post surgeryHigh dose mesalazine (ileal

resection only), azathioprine,mercaptopurine, methotrexate

Chronic active and steroiddependant

Azathioprine, mercaptopurine,methotrexate or infliximab/adalimumab Adjunctive treatments including

analgesia, antidiarrhoeals, nutritional supplements (e.g. iron, vitamin B12,calcium and vitamin D) may be necessary

THANK YOU…..