2. Inflammatory Bowel Disease
E Rahimi, MD
Assiatant Professor
Department Of Internal Medicine
MUK

3. Inflammatory Bowel Disease (IBD) Ulcerative colitis and Crohn's disease
Chronic inflammatory diseases of the gastrointestinal tract
No single finding is diagnostic for these diseases
Epidemiological, clinical, laboratory, imaging and pathological characteristics
Some patients have a clinical picture that falls between the two diseases
מחלות כרוניות של מע' העיכול
האבחנה היא חשובה, אך לא החשובה ביותר. מחר נדבר על הטיפול.
נדבר על ההבדלים בין כרון ל-ulcerative colitis.
אין בדיקה סרולוגית או בדיקה בודדת להגיע לאבחנה של המחלות האלה – בונים תמונה המבוססת על שיטות שונות (אפידמיולוגיה, קליניקה, בדיקות מעבדה, הדמיה ופתולוגיה – הכי חשובות).
בכרון ובקוליטיס קשה להגדיר לאן חלק מהחולים שייכים: ל-20% מחולי כרון יש רק מחלה במעי הגס (הוא יכול להופיע לכל אורך ה-GI) לעומת קוליטיס שהוא מחלה של המעי הגס בלבד. 10% מהחולים ב-IBD הם בעלי indeterminate colitis. יש דרכים להבחין ביניהם, אבל לא תמיד אפשר.

4. Introduction
IBD characterized by a tendency for chronic or relapsing immune activation and inflammation within the GIT.
Crohn’s disease (CD) and ulcerative colitis (UC) are the 2 major forms of idiopathic IBD.

5. Less common entities are:
Microscopic colitis (collagenous and lynphocytic)
Others
Diversion colitis
Radiation colitis
Drug induced colitis
Infectious colitis
Ischemic colitis

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

7. IBD: Systemic Complications
Growth failure in children
Eye inflammation*
Lower bone density*
Kidney stones
Liver and bile duct inflammation
Subfertility*
Ovaries
Uterus
Gallstones
Patients with IBD frequently suffer from other chronic inflammatory diseases that affect other organ systems. The course of these diseases often runs independently of the course of IBD; however, they occur so frequently in patients with IBD that, rather than being regarded as comorbidities, they are seen as extraintestinal manifestations of the underlying disease.
Eye inflammations – iritis and uveitis – were the most common extraintestinal diseases found in a Canadian population-based survey, affecting about twice as many women as men. Primary sclerosing cholangitis was more common among men than among women with UC, as was ankylosing spondylitis. Among skin lesions, pyoderma gangrenosum was equally prevalent in men and women, but erythema nodosum was more common in women than in men. Overall, 6.2% of patients had 1 of those 6 major extraintestinal diseases.14 In some referral centers, however, the reported incidence has been as high as 21% in patients with UC, 42% in those with either UC or Crohn’s colitis, and 23% in those with CD confined to the small bowel.15,16
Additional systemic complications include reduced bone mineral density, or BMD, related to increased bone resorption without an increase in bone formation. This is more prevalent in women than in men and is independent of corticosteroid intake.17
Other extraintestinal manifestations include gallstones, kidney stones, liver inflammation, and arthritis.15
Fourteen percent to 88% of children with IBD are reported to have subnormal growth even before the time of initial diagnosis. Growth retardation may continue because of both malabsorption and reduced nutritional intake and because of growth-suppressing drugs such as corticosteroids.18
Arthritis and joint pains
Skin lesions
*Higher incidence in women.

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

9. Epidemiology

10. 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 16q contains the CD susceptibility gene, NOD2/CARD15.
Having one copy of the risk alleles confers a 2–4-fold risk for developing CD, whereas double-dose carriage increases the risk 20–40-fold.

12. Etiology inappropriate responses to bacterial
Mutations within the NOD2/ CARD15 gene contribute to CD susceptibility.
inappropriate responses to bacterial
the development and persistence of intestinal inflammation.
Initiating pathogen?
Infectious?
? Possibly non-pathogenic commensal enteric flora

13. Pathogenesis 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.
Activation of Th1 cells produce the down-regulatory cytokines IL-10 and TGF-.

14. Pathogenesis
A sequential casιade of inflammatory mediators extends the response; each step is a potential target for therapy.
Inflammatory cytokines such as IL- l ， IL-6， and TNF have divers, effects on tissues.
They promote fibrogenesis, collagen production activation of tissue metalloproteinases， and the production of other inflammatory mediators; they also activate the coagulation cascade.

15. Pathogenesis
These cytokines are normally produced in response to infection but are usually turned off or inhibited at the appropriate time to limit tissue damage.
In IBD their activity is not regulated, resulting in an imbalance between the proinflammatory and antiinflammatory medíators.
Therapíes such as the 5 – aminosalicylic acid (5 -ASA) compounds and glucocorticoids are potent inhibitors

16. Environmental Precipitants
Factors:
NSAIDs use (?altered intestinal barrier), and
Early appendectomy (increase UC incidence)
Smoking (protects against UC but increases the risk of CD).

17. CD: PATHOLOGY Early Findings: Late findings: Aphthous ulcer.
The presence of granulomas
Late findings:
Linear ulcers.
The classic cobble stoned appearance may arise.
Transmural inflammation
Sinus tracts, and strictures.
Fibrosis.

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. UC

21. Diagnosis
Exclude other possibilities (need good history, physical exam, labs, imaging and endoscopy with biopsy)
There are many distinguishing features of CD and UC.
In about 5% it is classified as indeterminate because of overlapping features.

22. Distinguishing characteristics of CD and UC
Feature
Only colon (rarely “backwash ileitis”
SB or colon
Location
Continuous, begins distally
Skip lesions
Anatomic distribution
Involved in >90%
Rectal spare
Rectal involvement
Universal
Only 25%
Gross bleeding
Rare
75%
Peri-anal disease No
Yes
Fistulization
50-75%
Granulomas

23. Endoscopic features of CD and UC
Continuous
Discontinuous
Mucosal involvement
Rare
Common
Aphthous ulcers
Abnormal
Relatively normal
Surrounding mucosa
Longitudinal ulcer No
In severe cases
Cobble stoning
Uncommon
Mucosal friability
distorted
Normal
Vascular pattern

24. Pathologic features of CD and UC
Uncommon
Yes
Transmural inflammation No
50-75%
Granulomas
Rare
Common
Fissures
Fibrosis
Submucosal inflammation

25. Radiologic features of CD and UC
Collar button ulcers
Nodularity
granularity
cobble stoning
string sign of SB

26. UC

27. CD

29. UC: Presentation Must exclude infectious cause before making Dx.
Rectal Bleeding
Diarrhea:
frequent passage of loose or liquid stool, often associated with passing large quantities of mucus.
Abdominal Pain:
it is not a prominent symptom.
Anorexia, nausea, fever…

30. DDX of UC
Infectious
Drug induced
Microscopic colitis

31. UC: Presentation

32. UC: Presentation
About 40-50% of patients have disease limited to the rectum and rectosigmoid
30-40% have disease extending beyond the sigmoid but not involving the whole colon
20% have a total colitis.

33. CD Anatomic distribution CD activity index
DDx (lymphoma, Yersinea Enterocolitis, TB)

34. CD: clinical presentations
Disease of the ileum:
May present initially with a small bowel obstruction.
Patients with an active disease often present with anorexia, loose stools, and weight loss.
Perianal disease
In 24% of patients with CD.
Skin lesions include superficial ulcers, and abscesses.
Anal canal lesions include fissures, ulcers, and stenosis.

35. CD ilitis: DDx
Lymphoma
Yersinea Enterocolitis and TB

36. CD: clinical presentations
colonic disease
The typical presenting symptom is diarrhea, occasionally with passage of obvious blood.
proctitis
May be the initial presentation in some cases of CD

42. Extra-intestinal manifestations of IBD
Arthritis:
Peripheral arthritis, usu paralels the disease activity
Ankylosing Spondylitis, 1-6%, sacroiliitis
Ocular lesions:
Iritis (uvietis) (0.5-3%), episcleritis, keratitis,
Skin and oral cavity:
Erythema nodosum 1-3%
Pyoderma Gangrenosum 0.6%
Aphthus stomatitis, metastatic CD.

43. Dermatologic
Erythema nodosum (EN) occurs in up to 15% of CD patients and 10% of UC patients.
Attacks usually correlate with bowel activity; skin lesions develop after the onset of bowel symptoms， and patients frequently have concomitant active peripheral arthritis.
The lesions of EN are hot， red， tender nodules measuring 1-5 cm in diameter and are found on the anterior surface of the lower legs， ankles， calves， thighs，and arms.
Therapy is directed toward theunderlying bowel disease.

44. Dermatologic
Pyoderma gangrenosum (PG) is seen in % of UC patients and less ιommonly in Crohn's ιolitis.
Although it usually presents after the diagnosis of IBD.
PG may occur years before the onset of bowel symptoms
A course independent of the bowel disease， respond poorly to colectomy， and even develop years after proctocolectomy.

45. Dermatologic It is usually associated with severe disease.
Lesions are commonly found on the dorsal surface of the feet and legs but may occur on the arms，chest， stoma， and even the face. PG usually begins as a pustule andthen spreads concentrically to rapidly undermine healthy skin. Lesions then ulcerate， with violaceous edges surrounded by a margin of erythema.
Centrally， they contain necrotic tissue with blood and exudates.

46. Dermatologic
Lesions may be single or multiple and grow as large as 30 cm.
They are sometimes very difficult to treat and often require IV antibiotics, IV glucocorticoid， dapsone， azathioprine， thalidomide， IV cyclosporine，or infliximab

47. Dermatologic
Other dermatologic manifestations include pyoderma vegetans，which occurs in intertriginous areas.
Pyostomatitis vegetans， which involves the mucous membranes.
Sweet syndrome， a neutrophilic dermatosis.
metastatic CD， a rare disorder defined by cutaneous granuloma formation.

48. Dermatologic
Psoriasis affects % of patients with IBD and is unrelated to bowel activity consistent with the potential shared immunogenetic basis of these diseases.
Perianal skin tags are found in 75-80% of patients with CD， especially those with colon involvement.
Oral mucosal lesions， seen often in CD and rarely in UC， include aphthous stomatitis and cobblestone" lesions of the buccal mucosa.

49. Rheumatologic
Peripheral arthritis develops in % of IBD patients， is more common in CD， and worsens with exacerbations of bowel activity.
It is asymmetric， polyarticular， and migratory and most often affects large joints of the upper and lower extremities.
Treatment is directed at reducing bowel inflammation.
In severe UC， colectomy frequently cures the arthritis.

50. Rheumatologic
Ankylosing spondylitis (AS) occurs in about 10% of IBD patients and is more common in CD than Uc.
About two-thirds of IBD patients with AS express the HLA-B27 antigen. The AS activity is not related to bowel activity and does not remit with glucocorticoids or colectomy.
It most often affects the spine and pelvis， producing symptoms of diffuse low-back pain， buttock pain， and morning stiffness.

51. Rheumatologic
The course is continuous and progressive， leading to permanent skeletal damage and deformity.
Anti-TNF therapy reduces spinal inflammation and improves functional status and quality of life.
Sacroiliitis is symmetric， occurs equally in UC and CD， is often asymptomatic， does not correlate with bowel activity， and does not always progress to AS.

52. Rheumatologic
Other rheumatic manifestations include hyper trophic osteoarthropathy， pelvic!femoral osteomyelitis， and relapsing polychondritis.

53. Ocular
The incidence of ocular complications in IBD patients is %.
The most common are conjunctivitis， anterior uveitis/iritis， and episcleritis.
Uveitis is associated with both UC and Crohn's colitis
may be found during periods of remission
may develop in patients following bowel resection.
Symptoms include ocular pain， photophobia， blurred vision， and headache.

54. Ocular
Prompt intervention， sometimes with systemic glucocorticoids， is required to prevent scarring and visual impairment.

55. Ocular
Episderitis is a benign disorder that presents with synptoms of mild ocular burning.
It occurs in 3-4% of IBD patients
more commonly in Crohn's colitis
is treated with topical glucocorticoids

56. Hepatobiliary
Hepatic steatosis is detectable in about one-half of the abnormal liver biopsies from patients with CD and UC; patients usually present with hepatomegaly.
Fatty liver usually results from a combination of chronic debilitating illness, malnutrition, and glucocorticoid therapy.
Cholelithiasis occurs in 10-35% of CD patients with ileitis or ileal resection.

57. Hepatobiliary
Gallstone formation is caused by malabsorption of bile acids, resulting in depletion of the bile salt pool and the secretion of lithogenic bile.
Primary sclerosing cholangitis (PSC) is a disorder characterized by both intrahepatic and extrahepatic bile duct inflammation and fibrosis.
Frequently leading to biliary cirrhosis and hepatic failure.
5% of patients with UC have PSC, but 50-75% of patients with PSC have IBD.

58. Hepatobiliary PSC occurs less often in patients with CD.
Although it can be recognized after the diagnosis of IBD
PSC can be detected earlier or even years after proctocolectomy.
Consistent with this, the immunogenetic basis for PSC appears to be overlapping
IBD and PSC are commonly pANCA positive.

59. Hepatobiliary
Most patients have no symptoms at the time of diagnosis; when symptoms are present， they consist of fatigue, jaundice, abdominal pain， fever, anorexia, and malaise.
The traditional gold standard diagnostic test is endoscopic retrograde cholangiopancrea tography (ERCP)
magnetic resonance cholangiopancreatography (MRCP) is also sensitive and specific.
MRCP is reasonable as an initial diagnostic test in children and.

60. Hepatobiliary
In patients with PSC. both ERCP and MRCP demonstrate multiple bile duct strictures alternating with relatively normal segments.
The bile acid ursodeoxycholic acid (ursodiol) may reduce alkaline phosphatase and serum aminotransferase levels， but histologic improvement has been marginal.
High doses (25-30 mg/kg per day) may decrease the risk of colorectal dysplasia and cancer in patientswith UC and PSc.

61. Hepatobiliary
Endoscopic stenting may be palliative for cholestasis secondary to bile duct obstruction.
Patients with symptomatic disease develop cirrhosis and liver failure over years and eventually require liver transplantation.
PSC patients have a % lifetime risk of developing cholangiocarcinoma and then cannot be transplanted Patients with IBD and PSC are at increased risk of colon cancer and should be surveyed yearly by colonoscopy and biopsy.

62. Hepatobiliary
Cholangiography is normal in a small percentage of patients who have a variant of PSC known as small duct primary sclerosing cholangitis.
This variant (sometimes referred to as "pericholangitis") is probably a form of PSC involving small-caliber bile ducts.
It has similar biochemical and histologic features to classic PSc.
It appears to have a significantly better prognosis than classic PSC， although it may evolve into classic PSc.

63. Hepatobiliary
Granulomatous hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD.

64. Urologic
The most frequent genitourinary complications are calculi， ureteral obstruction， and ileal bladder fistulas.
The highest frequency of nephrolithiasis ( %) occurs in patients with CD following small bowelresection.
Calcium oxalate stones develop secondary to hyperoxaluria，which results from increased absorption of dietary oxalate.

65. Urologic
Normally，dietary calcium combines with luminal oxalate to form insoluble calcium oxalate， which is eliminated in the stool.
In patients with ileal dysfunction， however， nonabsorbed fatty acids bind calcium and leaveoxalate unbound.
The unbound oxalate is then delivered to the colon, where it is readily absorbed， especially in the presence of inflammation hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD.

66. Metabolic Bone Disease
Low bone mass occurs in 3-30% of IBD patients.
The risk is increased by glucocorticoids， cyclosporine， methotrexate， and total parenteral nutrition (TPN) .
Malabsorption and inflammation mediated by IL- 1 ，IL 6， TNF， and other inflammatory mediators also contribute t o low bone density.
An increased incidence of hip， spine， wrist， and rib fractures has been noted: 36% in CD and 45% in Uc.

67. Metabolic Bone Disease
The absolute risk of an osteoporotic fracture is about 1 % per person per year.
Fracture rates， particularly in the spine and hip， are highest among the elderly (age >60).
One study noted an OR of for vertebral fracture and an OR of for hip fracture.
The disease severity predicted the risk of a fracture.
Only 1 3 % of IBD patients who had a fracture were on any kind of antifracture treatment.

68. Metabolic Bone Disease
Up to 20% of bone mass can be lost per year with chronic glucocorticoid use.
The effect is dosage-dependent.
Budesonide may also suppress the pituitary-adrenal axis and thus carries a risk of causing osteoporosis.
Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse.

69. Metabolic Bone Disease
The pain is aggravated by motion and swelling of the joints.
It affects the hips more often than knees and shoulders， and in one series， 4.3% of patients developed osteonecrosis within 6 months of starting glucocorticoids.
Diagnosis is made by bone scan or MRI， and treatment consists of pain control， cord decompression，osteotomy， and joint replacement.

70. Thromboembolic Disorder
Patients with IBD risk of both venous and arterial thrombosis even if the disease is not active.
Factors responsible for the hypercoagulable state: d:
abnormalities of the plateletendothelial interaction
Hyperhomocysteinemia
alterations in the coagulation cascade
impaired fibrinolysis
involvement of tissue factor-bearing microvesicles
disruption of coagulation system by autoantibodies
genetic predisposition.
A spectrum of vasculitides involving small， medium， and large vessels has also been observed.

73. Extra-intestinal manifestations of IBD
Liver and Biliary tract disease:
Pericholangitis, fatty infiltration, PSC (1-4%, more with UC), cholangiocarcinoma, gallstones
Thromboembolic disease, vasculitis, Renal disease (urolithiasis, GN), clubbing, amyloidosis.

75. IBD: Systemic Complications
Growth failure in children
Eye inflammation*
Lower bone density*
Kidney stones
Liver and bile duct inflammation
Subfertility*
Ovaries
Uterus
Gallstones
Patients with IBD frequently suffer from other chronic inflammatory diseases that affect other organ systems. The course of these diseases often runs independently of the course of IBD; however, they occur so frequently in patients with IBD that, rather than being regarded as comorbidities, they are seen as extraintestinal manifestations of the underlying disease.
Eye inflammations – iritis and uveitis – were the most common extraintestinal diseases found in a Canadian population-based survey, affecting about twice as many women as men. Primary sclerosing cholangitis was more common among men than among women with UC, as was ankylosing spondylitis. Among skin lesions, pyoderma gangrenosum was equally prevalent in men and women, but erythema nodosum was more common in women than in men. Overall, 6.2% of patients had 1 of those 6 major extraintestinal diseases.14 In some referral centers, however, the reported incidence has been as high as 21% in patients with UC, 42% in those with either UC or Crohn’s colitis, and 23% in those with CD confined to the small bowel.15,16
Additional systemic complications include reduced bone mineral density, or BMD, related to increased bone resorption without an increase in bone formation. This is more prevalent in women than in men and is independent of corticosteroid intake.17
Other extraintestinal manifestations include gallstones, kidney stones, liver inflammation, and arthritis.15
Fourteen percent to 88% of children with IBD are reported to have subnormal growth even before the time of initial diagnosis. Growth retardation may continue because of both malabsorption and reduced nutritional intake and because of growth-suppressing drugs such as corticosteroids.18
Arthritis and joint pains
Skin lesions
*Higher incidence in women.

76. Complications of IBD
Bleeding
Stricture
Fistula
Toxic megacolon
Cancer

77. Complications of IBD

78. Treatment Goals of therapy Induce and maintain remission.
Ameliorate symptoms
Improve pts quality of life
Adequate nutrition
Prevent complication of both the disease and medications

79. 5-Aminosalicylic Acids
The mainstay treatment of mild to moderately active UC and CD (induction).
5-ASA may act by
blocking the production of prostaglandins and leukotrienes,
inhibiting bacterial peptide–induced neutrophil chemotaxis and adenosine-induced secretion,
scavenging reactive oxygen metabolites

80. 5-Aminosalicylic Acids
For patients with distal colonic disease, a suppository or enema form will be most appropriate.
Maintenance treatment with a 5-aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohn's disease.

82. Corticosteroids
Topical corticosteroids can be used as an alternative to 5-ASA in ulcerative proctitis or distal UC.
Oral prednisone or prednisolone is used for moderately severe UC or CD, in doses ranging up to 60 mg per day.
IV is warranted for patients who are sufficiently ill to require hospitalization; the majority will have a response within 7 to 10 days.

83. Corticosteroids
No proven maintenance benefit in the treatment of either UC or CD.
Many and serious side effects.
Budesonide:
less side effects,
its use is limited to patients with distal ileal and right-sided colonic disease

85. Immunosuppressive Agents
These agents are generally appropriate for patients in whom the dose of corticosteroids cannot be tapered or discontinued.
Azathioprine & 6-MP
The most extensively used immunosuppressive agents.
The mechanisms of action unknown but may include
suppressing the generation of a specific subgroup of T cells.
The onset of benefit takes several weeks up to six months.
Dose-related BM suppression is uniformly observed

86. Immunosuppressive Agents
Methotrexate
Effective in steroid-dependent active CD and in maintaining remission.
Cyclosporine
Severe UC not responding to IV steroid &need urgent proctocolectomy.
50% of the responders will need surgery within a year.

87. Anti-TNF Therapy: Infliximab
It is a chimeric monoclonal antibody, binds soluble TNF.
Prompt onset, effects takes 6weeks to max of 6m.
Indicated in fisulizing crohns, refractory CD and refractory UC
Complications (it is safe and usu tolerable)
Acute infusion reactions, which may include chest tightness, dyspnea, rash, and hypotension.
Delayed hypersensitivity reactions, consisting of severe polyarthralgia, myalgia, facial edema, urticaria, or rash, are an unusual complication occurring from 3 to 12 days after an infusion.

88. Infliximab: side effects
Increase risk of upper respiratory infections.
Any patient suspected of having a pyogenic complication of CD or any serious infection should undergo adequate drainage and treatment with antibiotics before starting infliximab.
Reactivation of tuberculosis has been observed and has resulted in disseminated disease and death.

89. INDICATIONS FOR SURGERY
In patients with UC:
Severe attacks that fail to respond to medical therapy.
Complications of a severe attack (e.g., perforation, acute dilatation).
Chronic continuous disease with an impaired quality of life.
Dysplasia or carcinoma.
In patients with CD
Obstruction, severe perianal disease unresponsive to medical therapy, difficult fistulas, major bleeding, severe disability
30 % relapse rate

90. IBD Sequelae
UC:
Risk of cancer begins after 8 years, risk of pancolitis 7% at 20 years and 17% at 30 years.
Increased risk: early age of onset, pancolitis.
Need for colonoscopic screening after 8 years
CD:
True incidence of cancer is uncertain, but could be as high as UC
Need the same screening policy.

91. IBD conclusion It is a chronic disorders
Need to exclude other possibilities
Need to differentiate between the two
Need long term management with primary goal to induce then maintain remission and prevent complications of both the disease and drugs.