Game of Crohn’s: The good, the bad and the ugly sides of Inflammatory Bowel Disease (IBD) Disclosures

None to report Introduction Learning Objective(s)

• Describe and differentiate the epidemiology, pathophysiology, intestinal and extra-intestinal clinical presentation, laboratory, endoscopic, and radiological diagnostic assessment and findings, pharmaceutical and surgical treatment options, and potential complications of Crohn’s Disease vs. Ulcerative Colitis Inflammatory Bowel Disease (IBD) By Definition

Inflammatory Bowel Disease n. Abbr. IBD

A chronic disorder of the gastrointestinal tract, especially Crohn's disease or an ulcerative form of colitis (inflammation of the inner lining of the colon) Two Main Types Setting the Scene… IBD Overview

 There is NO cure  IBD is a result of an immune response against the bodies own intestinal system

 Most commonly begins in early 20’s to 30’s, but also seen in 50- 80 year old’s (but this peak is mainly for CD)

 Not contagious  Cause UNKNOWN  Both are characterized by diarrhea and abdominal pain Risk Factors

Age and gender:  15-40 years of age  2nd peak 50-80 years of age (CD)  Slight female predominance in CD  Slight male predominance in UC

Race and ethnicity:  Jews  Lower in black and Hispanic populations

Genetic susceptibility Etiology

Unknown but several contributing factors include:  Infectious  Environmental  Diet  Obesity  NSAID or aspirin use (Cyclooxygenase-mediated disruption of the intestinal epithelial barrier)

 Psychosocial factors – NO consistent psychopathology

 Smoking – negative correlation between smoking and UC (smoking may even decrease the risk of flares) but a positive correlation between smoking and CD recurrence Genetics

 Activation of the immune system is the cause of the inflammation in IBD

 It is believed that genetics plays a major role but no specific trigger has been identified.  First degree relatives 3-20 times more likely to develop IBD  Genetic factors more important in CD than in UC  First confirmed IBD gene (IBD1) confers increased risk of CD  Clinical features of CD demonstrate a heritable pattern with concordance in disease location  Over 100 distinct susceptibility loci for IBD  Several genetic syndromes have been associated with IBD including Turners syndrome, Hermansky-Pudlak syndrome, and glycogen storage disease type 1b Symptoms

 Abdominal cramps and pain - common  Diarrhea (can be bloody) - common  Urgency  Fever  Loss of appetite  Weight loss  Fatigue  Vomiting  Anemia Ulcerative Colitis Ulcerative Colitis

 Limited to mucosal layer of the colon  Toxic megacolon (clinical term, aka toxic colitis)  Bleeding from ulcers  The appearance of the mucosa in UC varies depending on the extent of the disease.  The inflammation always begins in the distal rectum and spreads proximally in continuous fashion.  The characteristic histologic lesion - is the crypt abscess (typical but not diagnostic) Extent of Involvement of Colon in UC

 Ulcerative proctitis - limited to the rectum

 Ulcerative proctosigmoiditis - limited to the rectum and sigmoid colon and not involving the descending colon

 Left-sided or distal ulcerative colitis - is disease that extends beyond the rectum and as far proximally as the splenic flexure

 Extensive colitis - disease extending proximal to the splenic flexure but sparing the cecum

 Pancolitis is used when the inflammatory process extends beyond the splenic flexure to the cecum Toxic Megacolon

 Rare, life-threatening form of ulcerative colitis

 Signs include  Fever >101oF/38.6oC  Tachycardia  Abdominal distention  Signs of localized or generalized peritonitis  Leukocytosis  A dilated colon

 It may occur anytime during the course of UC but usually occurs early on Toxic Megacolon: Presentation

Jalan et al described the diagnostic criteria, which are as follows:

 Radiographic evidence of colonic dilatation - The classic finding is more than 6 cm in the transverse colon

 Any 3 of the following - Fever (>101.5°F; 38.6°C), tachycardia (>120 beats/min), leukocytosis (>10.5 x 10 3/µL), or anemia

 Any 1 of the following - Dehydration, altered mental status, electrolyte abnormality, or hypotension Toxic Megacolon: Pathophysiology & Epidemiology

 Although the precise pathophysiology is unproven, several factors may contribute to its development and precipitation

 The microscopic hallmark of TM is inflammation extending beyond the mucosa into the smooth-muscle layers and serosa

 The lifetime risk of TM in ulcerative colitis has been estimated to be 1-2.5%

 No data exist regarding race or gender and the incidence of TM Toxic Megacolon: Treatment

• Treatment of TM includes 3 main goals: 1. Reduce colonic distention to prevent perforation, 2. Aggresive correction of fluid and electrolyte disturbances, and 3. Treatment of toxemia and precipitating factors with broad-spectrum antibiotics

• Careful and frequent monitoring of the patient is required, especially in the first 12 hours

• Patients should be put on bowel rest, and a nasogastric tube (NGT) or long intestinal tube should be placed to assist with gastrointestinal decompression Toxic Megacolon: Prognosis

 The survival prognosis of TM should be excellent in the absence of perforation

 In the case of ulcerative colitis, a proctocolectomy cures patients of the disease

 With the use of tumor necrosis factor (TNF)-alpha inhibitors, it is hoped that more cases can be managed medically in future Crypt Abscess

“The tubular crypt of Leiberkuhn rounds the corner, in and out of the plane of section twice, giving it a double look. Contrast the healthy crypts at the left edge with the abscessed crypt, and the neutrophils in the crypt abscess with the lymphocytes and plasma cells between the crypts.” Crohn’s Disease Crohn’s Disease

 Transmural inflammation and skip lesions  Mouth to anus  Obstruction and strictures  Perforation of bowel  Abscesses (up to 20 percent; intra-abdominal or extra-abdominal)  Fissures (40 percent; a small tear) and fistulas (an abnormal connection between organs)  Clinical manifestations of CD more variable than UC  Fatigue  Prolonged diarrhea with abdominal pain with or without gross bleeding  Weight loss  Fever  malabsorption

Malignancy

 Risk and incidence increases 8-10 years after diagnosis

 The extent of colonic involvement and the duration of the disease are strongly correlated with cancer risk Extraintestinal Complications

• Depression • Arthritis • Liver and kidney disorders including renal stones • Inflammation of the eye (Anterior Uveitis) • Skin conditions (Erythema Nodosum / Pyoderma Gangrenosum) • Bone loss and osteoporosis • Primary Sclerosing Cholangitis • Venous and arterial thromboembolism • Vitamin B12 deficiency • Spondyloarthropathy and ankylosing spondylitis

Physical Examination

 For UC & CD physical examination is often normal at presentation

 Some of the findings that may be seen include:  pallor  evidence of weight loss  abdominal tenderness  red blood on rectal examination

 Crohn’s disease - More specific findings include perianal skin tags and sinus tracts Routine Laboratory Studies

Tests that may be done but do not confirm IBD include:  Fecal occult blood test  Complete blood count (CBC)  Blood chemistry including electrolytes, renal function tests, liver enzymes, and blood glucose  Erythrocyte sedimentation rate (ESR)  C-reactive protein (CRP)  Serum iron and vitamin B12 level  Stool Cultures – Ova and Parasites, C. Difficile, Giardia stool antigen test  STI – for UC

Antibody Tests – used to distinguish between CD and UC and to determine the probability of IBD vs. other types of colitis Antibody Tests

 Antineutrophil cytoplasmic antibodies (pANCA) and anti- Saccharomyces cerevisiae antibodies (ASCA)

 The sensitivity of the antibody tests alone or in combination was in the range of 40 to 60 percent, and the specificity was greater than 90 percent for distinguishing patients with IBD from controls.

 Anti-OmpC antibody – The anti-OmpC antibody has been identified as a potential serologic marker of IBD Diagnosis

 Characteristic history

 Typical endoscopic appearance of the mucosa

 Confirmatory histology seen on colonic biopsy Diagnostic Studies for IBD

• Upper GI series with small bowel follow through (SBFT) – initial study • Barium enema • Contrasted CT scan – used more to determine complications of the disease such as abscesses or fistulas rather than for specific diagnosis • May show marked thickening of bowel wall in UC, but finding is nonspecific • Endoscopy – preferred study • Small bowel enteroscopy • Capsule endoscopy • EGD (ulcerations occur in the stomach and duodenum in 5-10% of patients with crohn’s disease)

Endoscopy Findings in UC

 In mild disease:  A fine granular appearing mucosa

 In more severe disease:  Discrete ulcers are seen

 In long-standing disease:  Loss of haustral markings  Shortening of the colon  Tubular appearance of the colon along with pseudopolyps

Endoscopy Findings in CD

Characteristic findings of small bowel disease include:  Skip lesions  Cobblestoning  Luminal narrowing

Characteristic findings on colonoscopy include:  Aphthae ulcers (small shallow ulcers with a red halo)  Skip lesions  Rectal sparing

Differential Diagnosis

Broad - because of the segmental nature of CD, a variety of disorders can mimic its clinical presentation

 IBS  Lactose intolerance  Infectious colitis  Appendicitis  Diverticulitis  Diverticular colitis  Ischemic colitis  Perforating or obstructing carcinoma  Lymphoma  Chronic ischemia  Endometriosis and carcinoid - NB: Can both give a radiologic and clinical picture that is easily confused with CD of the small bowel Disease Severity

An overall assessment of severity is determined by evaluating the patient’s symptoms, including:

 Number of bowel movements  Presence and amount of blood per rectum  Severity of abdominal pain  Impact of the disease on daily function  Physical findings such as fever and dehydration (+/-) Presence of abnormal lab tests Disease Severity

 Clinical trials of CD often use formal grading systems to describe disease severity

 Two commonly used systems are the Crohn's Disease Activity Index (CDAI) and the Harvey-Bradshaw Index (HBI) which is a simplified derivative of the CDAI Disease Severity Guidelines

The following working definitions may be more practical for clinical practice:

 Asymptomatic remission (CDAI <150) – Patients who are asymptomatic either spontaneously or after medical or surgical intervention. Patients requiring steroids to remain asymptomatic are not considered to be in remission but are referred to as being "steroid-dependent”

 Mild to moderate Crohn's disease (CDAI 150-220) – Ambulatory patients able to tolerate an oral diet without dehydration, toxicity, abdominal tenderness, mass, obstruction, or >10 percent weight loss

 Moderate to severe Crohn's disease (CDAI 220-450) – Patients who have failed treatment for mild to moderate disease or patients with prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or anemia

 Severe-fulminant disease (CDAI >450) – Patients with persisting symptoms despite conventional glucocorticoids or biologic agents (infliximab, adalimumab, certolizumab pegol, or natalizumab) as outpatients, or individuals presenting with high fevers, persistent vomiting, intestinal obstruction, significant peritoneal signs, cachexia, or evidence of an abscess  For UC

 Scores range form 0-12

 Post- Endoscopy Medical Treatment

Choice of therapy depends on: Supportive Treatment is Always Key!  Anatomic location of disease  Severity of disease  (2) Goals of therapy  Decrease the frequency of flare-ups  Achieve / maintain remission

Stepwise vs. step-down approach Pharmacological Treatment

 Step I drugs: Aminosalicylates (Sulfasalazine (Azulfadine); Mesalamine (Asacol))

 Step IA drugs: Antibiotics (Ciprofloxacin, Metronidazole)

 Step II drugs: Oral Corticosteroids (Prednisolone (Conventional), Budesonide (Non-systemic))

 Step III drugs: Immunomodulators (Azathioprine)  Step IV: Clinical Trial Agents Immunomodulators

A class of drugs that weaken the immune system by reducing lymphocytes.

 Examples include:  Azathioprine (Imuran) – first to be used  6-mercaptopurine (6-MP) (active metabolite of azathiprine)  Methotrexate – both an immuno-modulater and an anti-inflammatory agent NB: Need to add folic acid 1 mg/day to decrease adverse effects  Infliximab (Remicade) – anti-TNF therapy  Adalimamab (Humira)- anti-TNF therapy

Side effects of these drugs can be very serious and include:  lowering the body’s immune system  Hepatitis  Pancreatitis  bone marrow toxicity  increasing risk of developing lymphoma Medical Treatment

Other options include:

 Antidiarrheal medications (i.e. symptomatic therapy)  Use with caution in UC (Toxic Megacolon)  e.g. Loperamide

 Probiotics

 Lactose avoidance Medical Treatment: UC Only

 5-ASA suppositories  5-ASA enemas

NB: If 5-ASA aren’t effective alone then steroid foam preparations and steroid suppositories Surgery in UC

 Usually surgery is curative but involves removing the whole colon and rectum

 Reserved for patients who:  Have fuliment colitis or toxic megacolon and aren’t responding to medications  Patient’s with pancolitis or left-sided colitis who are at risk for developing colon cancer  Patients who have had years of severe colitis who aren’t responding to medications. Surgery in CD

 No surgical cure for CD

 Surgery in CD is only used to  Remove a section that is causing an obstruction  Drain an abscess  Treatment of a fistula that isn’t responding to drugs  IN CASE OF EMERGENCY

 50% of patients can expect return of symptoms within 4 years of surgery

UC & CD: Quick Summary

Ulcerative Colitis (UC) Crohn’s disease (CD)

- Only affects the colon (hence the - May affect any area in the GI name Colitis) tract from mouth to anus - Only affects the inner lining of - Is transmural, meaning it can the mucosa affect all layers of the bowel wall - Diarrhea is likely to be bloody - Diarrhea usually not bloody - Surgery can be curative in many - Surgery can be helpful if cases complications, but not as likely - Area of inflammation are - Usually has areas of continuous inflammation interspaced with areas of normal tissue Prognosis

 Patients who are in remission for one year have an 80 percent chance of remaining in remission for the subsequent years.  Patients who have active disease within the past year have a 70 percent chance of remaining active in the forthcoming year and a 50 percent chance of being in remission within the ensuing three years.  Overall, 13 percent of patients will have a relapse-free course, while 20 percent have annual relapses and 67 percent have a combination of years in relapse and years in remission within the first eight years after initial diagnosis.  Fewer than 5 percent will have a continuous course of active disease.  Recurrence of perianal fistulas after medical or surgical therapy is common (59 to 82 percent). Effect of IBD on Patient’s Lives

IBD can have significant and severe effects on patients and their families:

 IBD can keep patients from being able to attend school or work (economical cost)  Increase cost of health insurance or inability to get health insurance  It can keep patients from getting disability or life insurance

 Keep patients from traveling, or if they do travel it can ruin vacations  Keep patients from committing to social activities or playing sport

Learning Objective(s) Recap

• Describe and differentiate the epidemiology, pathophysiology, intestinal and extra-intestinal clinical presentation, laboratory, endoscopic, and radiological diagnostic assessment and findings, pharmaceutical and surgical treatment options, and potential complications of Crohn’s Disease vs. Ulcerative Colitis. References & Further Reading

1. American College of Gastroenterology (2009). An evidence-based position statement on the management of irritable bowel syndrome. American Journal of Gastroenterology, 104(Suppl 1): S1-S7

2. Longstreth GF, et al. (2006).Irritable bowel syndrome section of Functional bowel disorders. In DA Drossman et al., eds., Rome III: The Functional Gastrointestinal Disorders, 3rd ed., pp. 490-509. McLean, VA: Degnon Associates

3. Rubio-Tapia A et al. (2013) ACG clinical guidelines: Diagnosis and management of celiac disease. Am J Gastroenterol; 108:656

4. World Gastroenterology Organisation Global Guideline (2009). Inflammatory bowel disease: a global perspective. Munich, Germany: World Gastroenterology Organisation (WGO) THANK YOU

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