Inflammatory bowel disease (IBD): update

Ali Farag, MD
Kasr El-Aini School of Medicine ASGEM, AGAM, ESGE

What are we going to discuss?

1. 2. 3. 4. 5. 6. 7. 8. What is IBD? Types of IBD, how can you differentiate? Clinical Presentation Diagnosis of IBD Differential diagnosis of IBD Management IBD Case study What is new in IBD genetics, diagnosis, treatment?

What is IBD?
Idiopathic chronic inflammatory diseases involving an immune reaction of the body to its own intestinal tract.

Types of IBD?
Ulcerative Colitis Limited to the colon Mucosal inflammation Continuous Crohns disease Mouth Anus. Trans-mural inflammat. Skip areas

What do they share?

Waxing & Waning Extra- intestinal Manifestations

Pathogenesis
Genetics

Immune

IBD

Commensal Microbes

Environment

The intestinal innate immune barrier

Proposed Model for NOD2/CARD15 Function

Bacterial Peptidoglycans Monocytes/ Paneth Cells

CARD15

MDP

NF-B

Transcription
Inflammation

Frequency
Where?
Developed countries > developing countries Colder > Warmer. Urban > Rural
Incidence UC 7.3 cases per 100,000 Prevalence 116 cases per 100,000

CD

5.8 cases per 100,000

133 cases per 100,000

Before 1960 UC >>> CD now UC = CD

Age
UC & CD in young adults (ie, late adolescence to the third decade of life). vast majority of new diagnoses 15-40 years.
However, children younger than 5 years and elderly persons are occasionally diagnosed. Of patients with IBD, 10% are younger than 18 years.

Sex
The male-to-female ratio is approximately equal for both ulcerative colitis and Crohn disease.

Race
Highest in Jewish populations, followed by nonJewish white populations.

Clinical Presentation
You may like to know about pathology beforehand

Histopathology
UC CD

Crohns Disease

Ulcerative Colitis

Ulcerative colitis

Crohns disease

Histologic Findings
UC:
limited to the mucosa.

neutrophilic infiltrate along with crypt abscesses and

crypt distortion. Granulomas do not occur in ulcerative colitis.

CD
The entire intestinal wall

granulomas. The presence of granulomas is often

helpful for making the diagnosis but is not necessary.

Crohns Disease

Ulcerative Colitis

Symptoms
Manifestations depend on the area of the intestinal tract involved.
UC or CD colitis have bloody diarrhea, occasionally with tenesmus. CD small intestine have abdominal pain and diarrhea

A variety of intestinal and extraintestinal manifestations

Crohns disease
The most typical manifestations of Crohn disease are abdominal pain and diarrhea. Pain is particularly common, especially when some degree of obstruction is present. Fatigue: pain, inflammation, and anemia

Ulcerative colitis
The most typical manifestation of ulcerative colitis is bloody diarrhea. Pain is uncommon but may occur. Fatigue: Inflammation and anemia

Intestinal complications
Colon Cancer

Ulcerative Colitis
Colon cancer risk increases 8-10 years after diagnosis.

Crohns disease
Equal to ulcerative colitis if the entire colon is involved

Intestinal complications
Infectious colitis
Infectious colitis must be excluded before the diagnosis of UC can be made Superimposed infection, Clostridium difficile is by far most common.

Intestinal complications
Fistulae and perianal disease in CD. Toxic megacolon

Intestinal complications
Strictures and obstructions in CD
Frequently resolve with medical treatment.

UC strictures presumed to be malignant unless proven otherwise

Signs
Crohn disease Low-grade fever, weight loss and anemia are common. Growth retardation is seen in children and may be the only presenting sign in young patients. Fistulae and perianal disease. Right lower quadrant mass

Signs
Ulcerative Colitis Weight loss and anemia are common.

Differential Diagnosis
Crohns disease Causes of abdominal pain and chronic diarrhea Ulcerative colitis Causes of bloody diarrhea

Differential Diagnosis
Appendicitis Celiac Sprue Chronic Pelvic Pain Clostridium Difficile Colitis Cytomegalovirus Colitis Intestinal tuberculosis Diverticulitis Eosinophilic Gastroenteritis Food Poisoning Gastroenteritis, Bacterial Gastroenteritis, Viral Giardiasis

Differential Diagnosis
Intestinal Radiation Injury Irritable Bowel Syndrome Lactose Intolerance Salmonellosis Sarcoidosis Collagenous and Lymphocytic Colitis Perianal Abscess

Extraintestinal complications Skin

Ulcerated pyoderma gangrenosum

Pyoderma gangrenosum

Extraintestinal complications Skin

Erythema Nodosum

Extraintestinal complications Arthritis

Axial:

ankylosing spondylitis and sacroiliitis. ~ 5% of patients with IBD (often Crohn disease) independent of disease activity. HLA-B27.
vary with the activity of the underlying IBD. ~ 10% of patients with IBD nondestructive arthritis seronegative RF asymmetric, and it can be monoarticular large weight-bearing joints

The peripheral arthritides

Extraintestinal complications Eye

UC
Episcleritis and iritis (uveitis).

Extraintestinal complications Eye

Iritis

Urinary Tract Complications

More common in Crohn disease.
Calcium oxalate stones Involvement of the ureters, causes obstruction and hydronephrosis. Fistulae between the bowel and bladder or ureters.

Hepato-Biliary
Sclerosing cholangitis is most commonly associated with ulcerative colitis. Gallstones are common in persons with Crohn disease, but these persons are usually asymptomatic

Blood
Anemia
iron deficiency anemia (chronic blood loss) anemia of chronic disease.

A hypercoagulable state is associated with IBD.

Diagnosis
Clinical picture Endoscopic findings Histopathology Imaging

Endoscopy: normal vascular pattern

Endoscopic UC

Endoscopic CD

Wireless video capsule endoscopy

45

Enteroscopy

Radiological Findings

Crohns disease

Ulcerative Colitis

Barium Studies

Abdominal Ultrasonography

CT Enterography

MRI Enterography

 MRI is particularly useful in perianal fistula of Crohns disease

Positron Emission Tomography (PET)

Biomarkers in inammatory bowel disease

Serum
Markers of acute inflammation Serologic markers

Stool

Serum Markers of Acute Phase Response

C-reactive protein
Pro
easily and reliably short plasma half-life of 19 h

Con
not specic to IBD as levels, also increased in various disorders

Erythrocyte sedimentation rate

Pro
Easy to do, cheap

Con
Several factors influence the ESR Compared with CRP, the ESR peaks less rapidly and resolves more slowly

Other laboratory markers

Platelet count:
if elevated, may alert the clinician to ongoing inflammation

The white blood cell count:

nonspecific and may be influenced by therapies

Serum albumin:
may be low with acute inflammation

Serologic Markers/Antibodies

ANCA, ASCA
pANCA (Anti-neutrophil cytoplasmic antibodies)

ASCA (anti-Saccharomyces cerevisiae antibodies)

ANCAs
Present in a variety of immune conditions, such as Wegeners granulomatosis and rheumatoid arthritis, as well as in UC. Perinulear ANCA (pANCA):
20% - 85% of UC 2% - 28% of CD
ANCA positivity can be found in other forms of colitis, such as eosinophilic and collagenous colitis

ASCA
binds mannose sequences in phosphopeptido-mannan located in the cell wall of S. cervisiae (bakers yeast) ASCA is most prevalent in CD patients
39%to 76% of patients with CD up to 15% of patients with UC 5% of healthy controls.43
positive ASCA has also been seen in patients with Behcets disease, celiac disease, autoimmune hepatitis, and primary biliary cirrhosis.

Anti-OmpC
Anti-OmpC is an antibody to an outer membrane protein isolated first from Eschericia coli
Adherent-invasive E. coli has been found in ileal CD lesions, and OmpC has been shown to be required for these organisms to thrive in the GI tract

Anti-OmpC has a prevalence of

approximately 50% in CD patients 5% to 11% in UC patients 4% to 8% in healthy controls

Serologic markers IBD vs. non-inflammatory

The presence of either pANCA or ASCA is able to differentiate between IBD and non-IBD with a sensitivity of 63% and a specificity of 93%

Serologic markers UC vs. CD

ASCA+/ pANCA test has a sensitivity of 55% and a specificity of 93% for CD. Sensitivity and specificity of the pANCA tests for UC is 55.3% and 88.5% respectively

Fecal Biomarkers

Fecal Biomarkers
Specific to GIT Principle? The most frequently used fecal markers are calprotectin and lactoferrin S100A12 recently been studied and may be superior to the fecal markers currently used in IBD

Fecal calprotectin
Calprotectin is a protein that binds zinc and calcium and has antimicrobial effects Calprotectin makes up 50% to 60% of granulocyte cytosolic protein and is released with cell death or activation, making it a sensitive marker of inflammation
Other conditions with elevated fecal calprotectin include neoplasia, polyps, non-steroidal anti-inflammatory enteropathy, increasing age, celiac disease, microscopic colitis, allergic colitis, and infections

Fecal lactoferrin
Lactoferrin is an iron binding glycoprotein found in neutrophil granules, and possesses antimicrobial properties It is also measured by ELISA and is resistant to freeze-thaw cycles and degradation, facilitating its use as a laboratory test

Fecal S100A12
S100A12 is similar to calprotectin in its calcium-binding properties This protein activates NF-kB signal transduction and increases cytokine release

When to use fecal markers

1. In differentiating IBD from non-inflammatory diarrheal disorders 2. In evaluating disease activity in patients with IBD 3. In assessment of response to therapy, mucosal healing and post-op recurrence. 4. In predicting disease relapse.

Management of IBD

Management Goals Current Expectations

Induction of clinical remission. Maintenance of clinical remission. Improve patient quality of life.
Plus Healing the mucosa & maintaining healing Decrease hospitalization/surgery and overall cost Minimize disease related and therapy related complications

Current Therapeutic Options

Traditional therapies for CD
Aminosalicylates
Sulfasalazine 5-ASA preparations

Corticosteroids Immunosuppressive agents Antibiotics

Newer and Future treatment

Biologic therapy Non biologic therapy

Standard Treatment
Surgery Biological Therapy AZA/6-MP Prednisone 5-ASA Step up Therapy of CD MTX Budesonide Antibiotics

Sulfasalazine
Its sulfapyridine and 5-ASA joined by an azo bond. 75% of the ingested sulfasalazine enters the colon. The azo bond is cleaved by colonic bacteria to yield 5-ASA and sulfapyridine. 5-ASA is the therapeutic agent in sulfasalazine

How 5-ASA works?

Inhibits cyclooxygenase, blocking prostaglandin production Inhibits lipoxygenase, blocking LTB4 production. Free radical scavenger. Inhibits immunoglobulin secretion.

5-Aminosalicylates
Rectal
Mesalamine: Enemas, Suppositories

Oral
Sulfasalazine (Sulfa= 5-ASA) 500 mg tab Pentasa (mesalamine) 250 mg Capsules Asacol (mesalamine) 400 mg Capsules

Steroids
Important role in acute disease Long term use limited by side effects
Osteoporosis, cataract, poor tissue healing

No beneficial role noted for doses higher than 40-60 mg/d

Steroid therapy for CD: range of Toxicities

Metabolic-altered electrolytes, fluid retention, hyperglycemia Musculoskeletal-osteoporosis, osteonecrosis Gastrointestinal-dyspepsia Neuropsychiatric-depression, anxiety Ocular-cataract, glucoma Skin-stria Endocrine-growth failure (pediatric)

EntocortTM EC (Budesonide) Capsules Pharmacological Properties

High glucocorticosteroid receptor affinity High topical glucocorticosteroid activity Absorption and high first pass metabolism to metabolites with negligibel GCS activity Reduced adrenal gland suppression

Entocort EC (budesonide) Capsules Absorption and Metabolism

TM

Immunomodulators
They act by blocking lymphocyte proliferation, activation, or effector mechanisms. Extensive experience
Azathioprine and its metabolite 6mercaptopurine (6-MP)

Azathioprine and 6-Mercaptopurine

Effective in both in treating active disease and in maintaining remission Initial doses:
1 to 1.5 mg/kg for 6-MP and 2.0 to 2.5 mg/kg for azathioprine.

There is a delay between the initiation of therapy and the clinical response. This delay is typically 3-4 mo When to use?
Unresponsive to steroids (refractory patients) Steroids cannot be withdrawn (steroid-dependent patients).

Azathioprine and 6-MP also are useful as maintenance therapy in Crohn's disease.

Azathioprine and 6-Mercaptopurine

Side effects:
Pancreatitis (3.3%) Bone marrow depression (2%) Allergic reactions (2%) Infectious complications were seen in 7%

Antibiotics
Metronidazol Ciprofloxacin

Antibiotics
Ulcerative colitis:
Except in cases of overt sepsis, antibiotics appear to have little role in the management of ulcerative colitis.

Antibiotics
Crohns disease:
Metronidazole:
Perianal and colonic Crohns

Ciprofloxacin:
Perianal disease

Biologic Therapy for IBD

The use of a medication that is tailored to specifically target an immune mediator of disease

Tumor necrosis factor

A member of a group of cytokines that stimulate systemic inflammation & acute phase reaction. Produced chiefly by activated macrophages.

The TNF pathway: regulation, effects and potential therapeutic targets

How TNF- works?

Mechanism of Action of anti-TNF Agents

Lymphocyte
TNFRI

Infliximab or Adalimumab

TACE ProTNF Nat Clin Pract Rheumatol 2008 Jun;4(6):3009, c 2008.)8

Macrophage

(IBD) Current Biological Therapy

Infliximab Adalimumab Cetrolizomab pegol

Natalizumab

Infliximab, Remicade
Recombinant human murine chimeric IgG1 monoclonal antibody 5 mg/kg IV in normal saline (sodium chloride 0.9%) over 2 hours Antibodies against it increases clearance.

Tagran, et al. Trial

70% 60% 50% 40% 30% 20% 10% 0% 4 weeks clinical response 4 weeks clinical remission (CDAI decrease 70 points) (CDAI decrease < 150 points)
Adapted from Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor- for Crohns disease. N Engl J Med. 1997;337(15):1029-1035.

65%

33%

Placebo (n=26) all infliximab (n=83)

17%
4%

ACCENT I
INFUSION Week 0 All patients n=573 Remicade 5 mg/kg

Responders at Week 2 n=335 (58%)

Single Dose Group Placebo 188
Crossover To 5 mg

Non-responders Week 2 n=235 (42%)

3 Dose Induction Group 5 mg/kg N=192
Crossover To 10 mg

Week 2 Week 6 Week 14 Week 22 Week 30 Week 38 Week 46 Week 54

10 mg/kg N=193
Crossover To 15 mg

EVALUATION

Adapted from Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohns disease. Gastroenterology. 2004;126(2):402-413.

Week 2 responders-clinical remission at 30 weeks

P < 0.001
50%

P=0.386 P=0.003
39% 45%

45%

% Patients in Remisssion

40% 35% 30% 25% 20% 15% 21%

10%
5% 0% N=

Single Dose 110

5 mg/kg q 8 ws 113

10 mg/kg q 8 ws 112

Centocor Ortho Biotech Inc. Data on file. 200

ACCENT II Trial
(Infliximab Maintenance Study in Fistulizing Crohns Disease)

3 months later

ACCENT II: Complete Fistula Response at Week 54

40% P= 0.009 36%

35%
Proportion of Patients in Complete Fistula Response (%) 30% 25% 20% 15% 10% 5% 0% 19%

Placebo maintenance

5mg/kg infliximab maintenance

Adapted from Sands BE, Blank MA, Patel K, van Deventer SJ. Long-term treatment of rectovaginal fistulas in Crohns disease: response to infliximab in the ACCENT II Study. Clin Gastroenterol Hepatol. 2004;2(10):912-920.

SONIC: Corticosteroid-Free Clinical Remission at Week 26

100%

Proportion of patients (%)

90%
80% 70% 60% 50% 40% 30% 30.6% p = .006

p < 0.001 p = .022

56.8% 44.4%

20%
10% 0% 52/179 75/169 96/169

AZA + placebo

IFX + placebo

IFX + AZA

Adapted from Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohns disease. N Engl J Med. 2010;362(15):1383-1395.

What about ulcerative colitis?

Two large-scale, randomized, double-blind, placebo-controlled, multicenter clinical studies, the 54-week ACT1 and the 30-week ACT2 trials Investigated infliximab in patients with active UC who had failed to respond to steroids or other conventional treatments.

Active Ulcerative Colitis Trial 1: Clinical Response

80%

P < 0.001

70%
60% 50% 40% 30% 20% 10% 0% Week 8 Week 30 Week 54

Placebo

Remecade 5 mg/kg Remecade 10 mg/kg

Safety of antiTNF- agents

1. 2. 3. 4. Opportunistic infection Autoimmunity Infusion reactions Lymphoma

Case Study

Case #1

A Young Man With Abdominal Pain

History of The Present Illness

An 18-year-old, male Presented with recurrent diffuse abdominal pains and diarrhea of one year duration. He lost around 4 kg in the last 4 months. No joint pains or oral ulcers He reported having occasional fever No urinary troubles or skin rash
File No: 2866647

Physical Examination
Average built, good general condition. V/S : normal. Chest: normal. Heart: normal. Abdomen:
Tenderness in right iliac fossa with a palpable tender mass

Laboratory Investigations
HGB: 11.1 MCH: 71 WBC: 19.5
PMN: 84% EOS: 1.3

HT: 36%

RBC: 4.1

LYMP: 8.7 BASO: .8

MONO: 4.3

Surgical Consultation
? Appendicites Admitted for laparoscopy

Laparoscopy

Colonoscopy

Non-caseating granuloma

What is your diagnosis? How would you manage such patient? How would you follow him up? What is the prognosis. What are the possible complications?

Case #2

A woman with bleeding per rectum

History of the present illness

B.M, a 54-year-old, man Presented with recurrent dysentery, bloody diarrhea and weight loss of 2 two years duration He was treated several times with antibioitcs and metronidazole with recurrence of her symptoms.

Physical Examination
An average built man Pale BWt 43 kg BP: 120/80 P: 76/min Chest, Heart: normal Abdomen: Tender left colon

afebrile

Laboratory Investigations
Stool analysis:
RBC: 100/hpf No ova or parasites Pus cells: 20-30/hpf

HGB: 8 g/dl MCV: 69 WBC: 9000 normal differential PLT: 300000

MCH: 30

Colonoscopy

Crypt abscesses

What is your diagnosis? How would you manage such patient? How would you follow him up? What is the prognosis. What are the possible complications? When would you need surgery in such patient, what type of surgery, what the complications of surgery?