1. Inflammatory Bowel Disease

2. Introduction
There are two forms of inflammatory bowel disease (IBD): ulcerative colitis (UC), a mucosal inflammatory condition confined to the rectum and colon, and Crohn’s disease, a transmural inflammation of gastrointestinal (GI) mucosa that may occur in any part of the GI tract.
Crohn’s disease (CD) and ulcerative colitis (UC) are the 2 major forms of idiopathic IBD.

4. CD is a condition of chronic inflammation potentially involving any location of the GIT from mouth to anus.
UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon.

5. Epidemiology CD: UC: 1st peak 15-30 years of age, 2nd peak around 60 y
High incidence areas: US, UK, northern Europe
Young adults, common in females

6. Pathogenesis: Genetics
Studies suggested that 1st degree relatives of an affected patient have a risk of IBD that is 4-20 times higher than that of general population.
The best replicated linkage region, IBD1, on chromosome 16 contains the CD susceptibility gene, NOD2/CARD15.

7. Mutations within the (nucleotide oligomerization )
NOD2/ CARD15 gene contribute to CD susceptibility.
Functional studies suggest that inappropriate responses to bacterial components may alter signaling pathways of the innate immune system, leading to the development and persistence of intestinal inflammation.

8. Infectious agents
The mucosa of CD patients is dominated by Th1 (T helper), which produce interferon-γ and IL-2.
In contrast, UC dominated by Th2 phenotype, which produce transforming growth factor (TGF-) and IL-5.

9. Environmental Precipitants
Factors:
NSAIDs use ? (altered intestinal barrier), and
Early appendectomy
Smoking.

10. CROHNS DISEASE
Crohn 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.
Complications of Crohn disease may involve the intestinal tract or organs unrelated to it.
Small bowel stricture with subsequent obstruction is a complication that may require surgery. Fistula formation is common (20%–40% lifetime risk) and occurs much more frequently than with UC.

11. • Systemic complications of Crohns disease are common and similar to those found with UC.
Nutritional deficiencies are common with Crohn disease (weight loss, iron deficiency anaemia, vitamin B12 deficiency, folate deficiency, hypoalbuminemia, hypokalemia,).

13. CD: PATHOLOGY Early Findings: Late findings:
Aphthous ulcer.(superficial lesion)
The presence of granulomas
Late findings:
Linear ulcers.
The classic cobble stoned appearance may arise.
Transmural inflammation (penetration to muscularies mucosa)
Strictures.
Fibrosis.

15. Ulcerative colitis
UC 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 (crypts of Lieberkühn) in the form of a crypt abscess.
Local complications (involving the colon) occur in the majority of patients with UC.
A major complication is toxic megacolon, a severe condition that occurs in up to 7.9% of UC patients admitted to hospitals. The patient with toxic megacolon usually has a high fever, tachycardia, distended abdomen, elevated white blood cell count, and a dilated colon.

16. Approximately 11% of patients with UC have hepatobiliary complications, including fatty liver, pericholangitis, chronic active hepatitis, cirrhosis
and gallstones.
Arthritis commonly occurs in patients with IBD and is typically asymptomatic and migratory. Arthritis typically involves one or a few large joints, such as the knees, hips, ankles, wrists, and elbows.
Ocular complications (iritis, episcleritis, and conjunctivitis) occur in 2% to 29% of patients.
Skin and mucosal lesions associated with IBD include erythema nodosum,pyoderma gangrenosum, aphthous ulceration.

18. Main types of UC
Proctitis. Disease confined to the rectum (the lower part of the colon that connects with the anus). In about a third of patients, ulcerative colitis begins with ulcerative proctitis.
Proctosigmoiditis. Disease that affects the rectum and the sigmoid colon (the lower part of the colon located above the rectum).
Left-Sided Colitis. Disease that causes continuous inflammation throughout the left side of the colon from the rectum to the area near the spleen.
Pancolitis. Disease and inflammation throughout the entire colon.

19. UC: PATHOLOGY
The inflammation is predominantly confined to the mucosa.
Non-specific (can be seen with any acute inflammation)
The lamina propria becomes edematous.
Inflammatory infiltrate of neutrophils
Neutrophils invade crypts, causing cryptitis & ultimately crypt abscesses.
Specific (suggest chronicity):
Distorted crypt architecture, crypt atrophy and a chronic inflammatory infiltrate.

20. Diagnosis
Endoscopic approaches are typically used and may include colonoscopy, proctosigmoidoscopy, or possibly upper GI endoscopy in patients with suspected CD.
Endoscopy is useful for determining the disease distribution, pattern and depth of inflammation, and to obtain mucosal biopsy specimens.

21. Diagnosis cont.
Supplemental information from imaging procedures, such as (CT), abdominal x-ray, abdominal ultrasound, or intestinal barium studies may provide evidence of complications such as obstruction, abscess, perforation, or colonic dilation

23. Blood and stool tests may be used:
Blood tests are used for various purposes, including to determine the presence of anemia (low red blood cell count). An increased number of white blood cells or elevated levels of inflammatory markers such as C-reactive protein may indicate the presence of inflammation.
A stool sample may be taken and examined for blood, infectious organisms, or both.

24. Presentation of Inflammatory Bowel Disease
Symptoms
Ulcerative colitis: Diarrhea (bloody, watery, or mucopurulent), rectal bleeding, abdominal pain/cramping, weight loss and malnutrition, constipation (with proctitis)
Crohn’s disease: Diarrhea (less bloody than UC), rectal bleeding (less than UC), abdominal pain/cramping, weight loss and malnutrition (more common than UC), fatigue/malaise

25. Signs
Ulcerative colitis: Fever, tachycardia (with severe disease), dehydration, arthritis, hemorrhoids, anal fissures, perirectal abscesses
Crohn’s disease: Fever, tachycardia (with severe disease), dehydration, arthritis, abdominal mass and tenderness, perianal fissure or fistula

27. Laboratory Tests
Ulcerative colitis: Leukocytosis, decreased hematocrit/hemoglobin, elevated erythrocyte sedimentation rate (ESR),, (+) perinuclear antineutrophil cytoplasmic antibodies (pANCA; up to 70% of patients)
Crohn’s disease: Leukocytosis, decreased hematocrit/hemoglobin, elevated ESR, positive, (+) anti–Saccharomyces cerevisiae antibodies (up to 50% of patients) hypoalbuminemia with severe disease.

28. Endoscopic features of CD and UC

33. Extra-intestinal manifestations of IBD
Arthritis:
Peripheral arthritis,
Ankylosing Spondylitis,
Ocular lesions:
Iritis (uvietis) (0.5-3%), episcleritis,
Skin and oral cavity:
Erythema nodosum 1-3%
Pyoderma Gangrenosum 0.6%
Aphthus stomatitis, metastatic CD.

36. Extra-intestinal manifestations of IBD
Liver and Biliary tract disease:
fatty infiltration, gallstones
Thromboembolic disease, vasculitis, Renal disease (urolithiasis ).

38. Complications of IBD
Bleeding
Stricture
Fistula
Toxic megacolon
Cancer

39. DESIRED OUTCOME
Goals may relate to resolution of acute inflammatory processes, resolution of attendant complications (e.g., fistulas and abscesses), alleviation of systemic manifestations (e.g., arthritis), maintenance of remission from acute inflammation, or surgical palliation or cure.

40. Treatments
The major types of drug therapy used in IBD include aminosalicylates, corticosteroids, immunosuppressive agents (azathioprine, mercaptopurine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit TNF-α (anti–TNF-α antibodies) and leukocyte adhesion and migration (natalizumab).

41. Sulfasalazine, an agent that combines a
Sulfonamide (sulfapyridine) antibiotic and mesalamine (5-aminosalicylic acid) in the same molecule, has been used for many years to treat IBD but was originally intended to treat arthritis.
Sulfasalazine is cleaved by gut bacteria in the colon to sulfapyridine (which is mostly absorbed and excreted in the urine) and mesalamine (which mostly remains in the colon and is excreted in stool).

42. Corticosteroids and adrenocorticotropic
hormone have been widely used for the treatment of ulcerative colitis and Crohn’s disease, given parenterally, orally, or rectally. Corticosteroids are believed to modulate the immune system and inhibit production of cytokines and mediators. It is not clear whether the most important steroid effects are systemic or local (mucosal).
Budesonide is a corticosteroid that is administered orally in a controlled-release formulation designed to release in the terminal ileum. The drug undergoes extensive first-pass metabolism, so systemic exposure is thought to be minimized.

43. Immunosuppressive agents such as azathioprine, mercaptopurine (a metabolite of azathioprine), methotrexate, or cyclosporine are sometimes used for the treatment of IBD. Azathioprine and mercaptopurine are effective for long-term treatment of Crohn’s disease and ulcerative colitis.
Cyclosporine has also been of short-term benefit in treatment of acute, severe ulcerative colitis when used in a continuous intravenous infusion. Lower-dose continuous infusions (2 mg/kg vs. 4 mg/kg daily), or oral daily doses of 5 to 6 mg/ kg.

44. Methotrexate given 15 to 25 mg intramuscularly once weekly is useful for treatment and maintenance of Crohn’s disease but not ulcerative colitis.
Antimicrobial agents, particularly metronidazole and ciprofloxacin are frequently used in attempts to control Crohn’s disease but are not useful in ulcerative colitis
Infliximab is an anti-TNF antibody that is useful in moderate to severe active disease and steroid-dependent or fistulizing disease, but the cost far exceeds that of other regimens. Adalimumab is another anti-TNF antibody that is an option for patients with moderate to severe active Crohn disease or UC previously treated with infliximab who have lost response. Natalizumab is a leukocyte adhesion and migration inhibitor that is used for patients with Crohn disease who are unresponsive to other therapies.

47. Ulcerative Colitis 1)Mild to moderate
The first line of drug therapy for patients with extensive disease is oral sulfasalazine or an oral mesalamine derivative. Topical mesalamine is more effective than oral mesalamine or topical steroids for distal disease.
When given orally, usually 4 to 6 g/day, and possible up to 8 g/day, of sulfasalazine is required to attain control of active inflammation. There does not appear to be an increased rate of response with increased dosage over 6 g/day, although side effect increase. Even with the use of adequate doses, patient improvement usually takes 4 weeks, and sometimes longer

48. Steroids have a place in the treatment of moderate to severe active ulcerative colitis regardless of disease location, or in those patients who are unresponsive to maximal doses of oral and/or topical mesalamine derivatives.
Oral steroids (usually up to 1 mg/ kg per day of prednisone equivalent or 40 to 60 mg daily) may be used for patients who do not have an adequate response to sulfasalazine or mesalamine.

49. 2)Severe or Intractable Disease
Patients with uncontrolled severe colitis or who have incapacitating symptoms require hospitalization for effective management. Under these conditions, patients generally receive nothing by mouth to put the bowel at rest. Most medication is given by the parenteral route.
Sulfasalazine or mesalamine derivatives are not beneficial for treatment of severe colitis because of rapid elimination of these agents from the colon with diarrhea, thereby not allowing sufficient time for gut bacteria to cleave the molecules.

50. Steroids have been valuable in the treatment of severe disease because the use of these agents may allow some patients to avoid colectomy. Intravenous hydrocortisone 300 to 400 mg daily in three divided doses or methylprednisolone 48 to 60 mg once daily are considered first-line agents. Methylprednisolone is typically preferred because of its lesser mineralocorticoid effects.
Patients who are unresponsive to parenteral corticosteroids after 7 to 10 days should receive cyclosporine by intravenous infusion. Seventy to 80% of hospitalized patients who are unresponsive to corticosteroids will respond to cyclosporine.

51. Maintenance of Remission
After remission from active disease is achieved, the goal of therapy is to then maintain remission. The major agents used for maintenance of remission are sulfasalazine and the mesalamine derivatives.
Steroids do not have a role in the maintenance of remission with ulcerative colitis because they are ineffective. Steroids should be gradually withdrawn after remission is induced (over 3 to 4 weeks). If they are continued, the patient will be at risk for steroid induced adverse effects without likelihood of benefits

52. . For patients who require chronic steroid use (steroid dependency), there is a strong justification for alternative therapies or colectomy. Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required before beneficial effects are noted.
For patients who initially respond to infliximab, continued dosing of 5 mg/kg as maintenance therapy every 8 weeks is another alternative for corticosteroid dependent patients, or those failing immunosuppressive therapy

53. Active Crohn’s Disease
In the majority ,of patients, active Crohn’s disease is treated with sulfasalazine, mesalamine derivatives, or steroids, although azathioprine, mercaptopurine, methotrexate, infliximab, and metronidazole are frequently used.
Mesalamine formulations such as Pentasa or Asacol have the ability to release mesalamine in the small bowel, thus targeting ileal disease, yet have demonstrated variable results in patients with active Crohn’s disease

55. Steroids are frequently used for the treatment of active Crohn’s disease, particularly with more moderate to severe presentations, or in those patients unresponsive aminosalicylates. Budesonide (Entocort) is a viable first-line option for patients with mild to moderate ileal or right-sided (ascending colonic) disease.
Metronidazole (given orally up to 20 mg/kg per day in divided doses) has demonstrated variable efficacy, but may possibly be useful in some patients with Crohn’s disease, particularly in patients with colonic or ileocolonic involvement, or in those patients with perineal disease

56. The immunosuppressive agents (azathioprine and its metabolite mercaptopurine) are effective, but are generally limited to use in patients who are not achieving adequate response to standard medical therapy, or to reduce steroid doses when high steroid doses are required.
The usual dose of azathioprine is 2 to 3 mg/kg per day; the usual dose of mercaptopurine is 1 to 1.5 mg/kg per day. Starting doses are typically 50 mg/day and increased at 2-week intervals; complete blood counts with differential should be monitored every 2 weeks while doses are being titrated

57. Infliximab is used for treating moderate to severe active Crohn’s disease in patients failing immunosuppressive therapy, in those who are corticosteroid dependent, and for treatment of fistulizing disease.
In large trials, a 5-mg/kg single intravenous infusion of infliximab resulted in clinical improvement in 58% of patients at 2 weeks and in 65% of patients at 8 weeks

58. Maintenance of Remission
Prevention of recurrence of disease is clearly more difficult with Crohn’s disease than with ulcerative colitis. There is minimal evidence to support sulfasalazine and oral mesalamine derivatives’ effectiveness for maintenance of Crohn’s disease following medically induced remission
Azathioprine, mercaptopurine, and methotrexate are useful in some patients to maintain remission

59. Systemic steroids have no place in the prevention of recurrence of Crohn’s disease. These agents do not appear to alter the long-term course of the disease and predispose patients to serious adverse effects with long-term use.
Although budesonide at maintenance doses of 6 mg/day demonstrated efficacy in maintaining remission at 3 months, use longer than this is not recommended as a loss of efficacy is seen after this timeframe