Inflammatory Bowel Disease ( IBD ) Inflammatory Bowel Disease (IBD) is a designation commonly used to describe two idiopathic diseases of the gastrointestinal tract with closely related clinical presentations. These diseases are ulcerative colitis (UC) and Crohn’s disease (CD).

a. UC is a chronic inflammatory condition of the gastrointestinal tract mucosa and is primarily found in the rectum and colon.

b. CD is chronic transmural inflammation of the gastrointestinal mucosa and can be found throughout the gastrointestinal tract from the mouth to the anus. CD most commonly affects the small bowel and colon

ETIOLOG Y

a. Smoking has been associated with a decrease in UC rates (roughly 60% of rates seen in nonsmokers), but the risk factors to general health do not warrant forgoing counseling patients on the benefits of smoking cessation.

b. Former smokers are at increased risk of developing UC.

c. Smoking has been shown to be risk factor for developing CD (more than 1.75 times the rates seen in nonsmokers). CD patients who actively smoke also have increased morbidity compared to CD patients who stop smoking.

d. Appendectomy has been shown to be protective with regard to development of UC.

e. Use of oral contraceptives has been associated with increased risk of developing IBD.

Genetic predisposition to IBD is another area of recent research advances. Genetic predisposition to IBD is suggested by, among other factors, epidemiologic studies, studies of twins, family aggregation studies, and ethnic differences in disease patterns. The CARD15 (NOD2) genetic mutation, for example, is seen more oft en in CD than in the general population. The mutation has been associated with altered immune response to bacteria. There are limitations to CARD15 usefulness in clinical practice, but the identification of this mutation and others has opened the door for more work around genetic predisposition and possible disease mechanism. These may lead to new modes of therapy.

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PATHOPHYSIOLOGY: The major theories of the cause of IBD involve a combination of infectious,

genetic, and immunologic causes. The inflammatory response with IBD may indicate abnormal regulation of the normal immune response or an autoimmune reaction to self-antigens. Microflora of the GI tract may provide a trigger to activate inflammation. Crohn’s disease may involve a T lymphocyte disorder that arises in genetically susceptible individuals as a result of a breakdown in the regulatory constraints on mucosal immune responses to enteric bacteria.

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) 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 associating 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.

Manifestations

1. IBD

a. UC onset is frequently insidious with increasing stool urgency and frequency. In addition to urgency, bloody stool, and mucus in the stool can also gradually

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increase. The typical course of UC can be generalized as bouts of varied disease intensity interspersed with asymptomatic periods.

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.

b. CD onset is typically insidious but can present as severe or fulminate disease. Further, there may be patterns of symptoms, which relate to disease location as well as type (inflammatory, fibrostenotic, or fistulizing for example), which can be useful in determining therapy decisions.

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.

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EXAMINATION:

PHYSICAL :

Hydration & volume status determined by B.P

Pulse rate

Nutritional status

CD UC

Blood 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 UC

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Radiology

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 UC

Instant 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 hyperemia

High 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: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

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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 inflamatory mediators interleukin-1 and tumor necrosis factor-alpha as well as modulation of peroxisome proliferator activated receptor colonic inflammation 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 themainstay 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. Prednisolone

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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.

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

3. AZATHIOPRINE & 6-MERCAPTOPURINE: They are effective 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 effective for maintaining remission in CD.

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

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

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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 antibodie Anti-TNF-alpha therapy

mechanism of action:Tumor necrosis factor-alpha is a cytokinins 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 activat

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 infectioned T lymphocytes and monocytes.

8. Antispasmodics and antidiarrheals: Cramping and abdominal IBS-like symptoms are often noted in IBD patients

9.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.

7.Antibiotics:

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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 surgery that involves formation of a pouch.

ALGORITHM FOR UC:

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Ulcerative colitisInducing remission

Active/left sided or extensive disease :Oral aminosalicylate plus oral corticosteroids. If prompt response is required plus rectal aminosalicylate or corticosteroid if rectal symptoms

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

Severe: Intravenous and rectal steroids, fluids and electrolytes, heparin, nutrition, antibiotics then ciclosporin (or infliximab) Nutrition: calcium and vitamin D

ALGORITHM FOR CD

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Crohn’s disease Inducing remission

Active ileal/ileocolonic disease:Corticosteroids; elemental or polymeric diet; parenteral nutrition if complex fistulae; azathioprine or mercaptopurine as adjunctive therapy Infliximab or adalimumab if response or intolerance or contraindication to eithercorticosteroid and/or Immunosuppressants Surgery if medical treatment fails

Fistulating and perianal disease Antibiotics,Azathioprine or mercaptopurine or methotrexate then infliximab and/or surgery; Elemental or parenteral nutrition

Maintenance:Stop smoking; calcium and vitaminD supplementsAzathioprine OR mercaptopurine OR methotrexate and/orinfliximab/adalimumab

Post surgery High dose mesalazine (ileal resection only), azathioprine, mercaptopurine, methotrexate

REFERENCES:

1.Comprehensive pharmacy review by 8th edition,Leon shargel 907-929

2.Pharmacotherapy handbook by Dipiro, seventh edition,page no:282-293

3.Clinical pharmacy and therapeutics by Roger walker page no: 285-208

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