Dr/ Mohammed HussienAssistant Lecturer of Gastroentrology &

Hepatology Kafrelsheikh University

Inflammatory Bowel Disease

BY

What is Inflammatory Bowel Disease?

• IBD is a condition that is a recurrent and chronic immune response and inflammation of the gastrointestinal tract

• Autoimmune disorder of the gastrointestinal tract with possible multi-organ involvement

• Recent study >8000 IBD pts – 63% had another chronic inflammatory condition

*Ulcerative colitis is characterised by diffuse mucosal inflammation limited to the colon. It is classified according to the maximal extent of inflammation observed at colonoscopybecause this is most clearly related to the risk of complications, including dilatation and cancer. The implications of limited macroscopic disease with extensive microscopic inflammationremain unclear.

*Crohn’s disease is characterised by patchy, transmural inflammation, which may affect any part of the gastrointestinal tract. It may be defined by: age of onset, location, or behaviour.

*About 5% of patients with IBD affecting the colon are unclassifiable after considering clinical, radiological, endoscopic and pathological criteria, because they have some features of both conditions. This is now termed as ‘IBD, type unclassified (IBDU)’.*The term ‘indeterminate colitis (IC)’ should be reserved for cases where colectomy has been performed and the pathologis tremains unable to classify the disease after a full examination.

Gut Immunology and IBD

Genomics demonstrate common genetic signatures between IBD and other diseases.

RAMS

SLE ASPsoriasis

Alopecia

Behcet’s

Asthma

Leprosy

Celiac Dz

Type II DM

IBD

Why does IBD matter to the us?

• Causes significant morbidity• Causes large burden to society and health care system• There are approximately 1-1.3 million with IBD in the U.S. (CDC)• The cost of care for IBD patients is up to $8 billion a year• 10-25% of IBD patients will require surgery (CDC, AGA)• Recent Canadian studies noted the need for nurses to play a bigger role in the care of IBD patients

Clinical features and course of disease

*The cardinal symptom of ulcerative colitis is bloody diarrhoea.Associated symptoms of colicky abdominal pain, urgency, ortenesmus may be present.

*severe colitis is still a potentially life-threatening illness*An appreciable minority has frequently relapsing or chronic, continuous disease and overall, 20e30% of patients with pancolitis come to colectomy

Ulcerative colitis

Truelove Classification of U.C

Clinical features and course of disease

• Symptoms of Crohn’s disease are more heterogeneous, but typically include abdominal pain, diarrhoea and weight loss.• Systemic symptoms of malaise, anorexia, or fever are more common.

Crohn’s disease may cause intestinal obstruction due to strictures, fistulae (often perianal) or abscesses. • Surgery is not Curative and management is directed to minimising the

impact of disease. At least 50% of patients may require surgical treatment in the first 10 years of disease

Crohn’s disease

Both ulcerative colitis and Crohn’s colitis are associated with an equivalent increased risk of colonic carcinoma. Smoking increases the risk of Crohn’s disease, but decreases the risk of ulcerative colitis through unknown mechanisms

Extraintestinal Manifestation of IBD

Erythema nodosumPyoderma gangrenosum

Differential Diagnosis

Laboratory investigations• Full blood count, urea and electrolytes, liver function tests and erythrocyte

sedimentation rate or C reactive protein, ferritin, transferrin saturation, vitamin B12 and folate. • Serological markers such as pANCA, ASCA are present in a significant

proportion of patients with IBD but there is no evidence base to recommend their use in the diagnosis of IBD.• Faecal calprotectin is accurate in detecting colonic inflammation and can

help identify functional diarrhoea.• Microbiological testing for Clostridium difficile toxin, in addition to standard

organisms, is increasingly important. C difficile infection has a higher prevalence in patients with IBD through unknown mechanisms, may not be confined to the colon, and is associated with increased mortality.• Cytomegalovirus (CMV) should be considered in severe or refractory colitis

Endoscopy• Colonoscopy with multiple biopsies (at least two biopsies fromfive sites including the distal ileum and rectum) is the first line procedure for diagnosing colitis.

• It allows classification of disease Based on endoscopic extent, severity of mucosal disease and histological features

• In acute severe colitis, full colonoscopy is rarely needed and may be contraindicated• A rectal biopsy is best taken for histology even if there are no

macroscopic changes

Endoscopic Features:

Histopathology of IBD

Diagnosing IBD and discerning between CD vs UC.

• Crohn’s - Endoscopic = 3 Major findings, Apthi (early) are transmural, Cobblestoning (ulcers are the ‘cracks’), and Discontinuous lesions (skip areas). Proximal to Distal.

• Ulcerative Colitis – Endoscopic = Edema, Erythema, Erosions, Friability, Granularity, Pseudopolyps, and Ulcers. Distal to Proximal.• UC Mayo Clinic Scores – 0-12

CD – Endoscopic views

UC – Endoscopic views

Pill Cam for visualizing the small bowel

Enteroscopes-Role in diagnosis

• Double Balloon (Fujinon)• Single Balloon (Olympus)• Single Balloon Smart system (Smart System w/ Pentax)• Spiral (EndoEase Discovery SBE)• SpyGlass ? (Boston Scientific)

Imaging modalities• Imaging can be helpful in diagnosis, assessment of disease extent and severity and for

investigation of suspected complications.• Ultrasound• Ultrasound cannot comprehensively assess the gut when used in isolation.Magnetic resonance imaging• Modern MRI hardware and software facilitate rapid and accurate assessment of the small

bowel.• Computed tomography scanning• CT imaging of the bowel (either CT enteroclysis or CT enterography) provides similar

information to MRI, although tissue characterisation capability is less. It is traditionally the ‘gold standard’ for the detection of extraluminal complications, notably abscess formation. Intravenous contrast administration is usually

• performed during CT. Advantages over MRI include widespread availability, rapid image acquisition (few seconds) and superior spatial resolution.

Radiologic evaluation: CT, CT-E, and CT-C

• Because of the transmural nature of the Crohn’s disease, mesenteric and perianal manifestations are fairly common. Because of the inflammation, strictures resulting from edema, inflammation, and, ultimately fibrosis and scaring, are frequent. Crohn disease is pervasive. The basic pathologic process of disease can occur at any segment of the alimentary tract.

• In ulcerative colitis, hemorrhagic and ulcerative inflammation is mostly limited to the mucosa, with recurrence leading to atrophic mucosa. Ulcers often have irregular borders, giving rise to a collar-stud effect.

Newer methods upcoming

Lower radiation dose PET/CTE for fistulas

Pelvic MRI of IBD perianal disease. Representative axial T2 fat suppressed (a, b) and post-contrast T1 fat-suppressed (c, d) images demonstrating an intersphincteric perianal fistula (a, c) and presacral abscess (b, d) in two patients with known Crohn’s disease. Arrows indicate sites of disease.

Barium fluoroscopy

• High-quality barium studies have superior sensitivity over crosssectional techniques for subtle early mucosal disease, although in those with established and/or more advanced disease, both• CT and MR may be equivalent and also provide information on

submucosal disease• Isotope-labelled

scansA variety of nuclear medical techniques can be used in the assessment of IBD, although they have no role in the primary diagnosis of IBD.47 Technetium-99m labelling of white blood cells remain a widely acceptable scintigraphic method for the evaluation of disease extension and severity

THERAPEUTIC OPTIONS IN THE MANAGEMENT OF IBD

Nutrition

Specific attention should be paid to nutrient deficits such as calcium, vitamin D, other fat soluble vitamins, zinc, iron and (after ileal resection especially) vitamin B12 status. Serum vitamin B12 is best measured annually in patients with ileal Crohn’s disease

MacronutrientsIn specific circumstances, protein and caloric support is indicated, such as when the gut is reduced in short bowel syndrome or in the perioperative care .This may mean total parenteral nutrition (TPN) including home TPN in a minority of Crohn’s disease patients with intestinal failure.

TPN in IBD

• Six trials noted TPN has no greater advantage over enteral nutrition in low risk IBD• However in moderate/severe cases w/ gut rest (77% remission) vs

continuing enteral route.• Multiple small bowel resections (+/- short gut syndrome)• Corrects nutritional micronutrient deficiency

Elimination Diet

• Remove food from the diet for a period of time and see if symptoms improve/resolve.• If on enteral nutrition/elemental diet then introduce 1 new food at a

time over a week each.• Comparison of steroids vs elimination diet alone noted that

relapse rate in 2 years was slightly lower in elimination diet (69%) vs steroids (72%).• Food intolerance was common with cereals, lactose, and yeast

products.• Elimination diet vs unrefined carbs diet. Relapse at 6 months after

remission was 30% for elimination dieters vs 100% unrefined carbs diet

Prebiotics & Probiotics

PrebioticsPrebiotics are non-digestible dietary carbohydrates,such as fructo-oligosaccharides which are fermented by the gut microflora to produce short-chain fatty acids. Their role is unproven to date.

ProbioticsBacteria or yeast generally ingested orally as therapy are termed probiotics. They may be administered as a single organism or a defined mixture, aiming to beneficially alter the microbial ecology of the gut.

Smoking cessation• Smoking is an important environmental factor in the pathogenesis of IBD,

though the mechanisms remain under investigation. Current smokers are more likely to develop Crohn’s disease and, following diagnosis, have a poorer prognosis with a significantly higher chance of surgical resection.• and (if smoking still continues) a greater chance of recurrence at the

surgical anastomosis.• Smoking cessation is associated with a 65% reduction in the risk of a

relapse as compared with continued smokers,• a similar magnitude to that obtained with immunosuppressive therapy

Non-steroidal anti-inflammatory drugs

• There are many publications claiming an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) in precipiating de novo IBD or exacerbating pre-existing disease, although the evidence remains contradictory and confusing

• Selective inhibition with COX-2 inhibitors or COX-1 inhibition with low dose aspirin seems to be safe, at least in the short term

Drugs For IBD & its side effects

Types of Aminosalicylic acid

Approach To Management Of Ulcerative Colitis

•Goals of treatment : are induction and maintenance of remission of symptoms to provide an improved quality of life, reduction in need for long-term corticosteroids, and minimization of cancer risk.

• Patients with mild to moderate distal colitis may be treated with oral aminosalicylates, topical mesalamine, or topical steroids

(Topical mesalamine agents are superior to topical steroids or oral aminosalicylates)• The combination of oral and topical aminosalicylates is more eff

ective than either alone In patients refractory to oral aminosalicylates or topical corticosteroids, mesalamine enemas or suppositories may still be effective• The unusual patient who is refractory to all of the above agents in

maximal doses, or whose systemically ill, may require treatment with oral prednisone in doses up to 40– 60 mg per day, or infl iximab with an induction regimen of 5 mg / kg at weeks 0, 2, and 6,.

ACG Recommendations For Ulcerative Colitis

RECOMMENDATIONS FOR MAINTENANCE OFREMISSION IN DISTAL DISEASE• Mesalamine suppositories are effective in the maintenance of

remission in patients with proctitis, whereas mesalamine enemas are effective in patients with distal colitis when dosed even as infrequently as every third night• Sulfasalazine, mesalamine compounds, and balsalazide are also

effective in maintaining remission; the combination of oral and topical mesalamine is more effective than either one alone• Topical corticosteroids including budesonide, however, have not proven

effective for maintaining remission in distal colitis• When all of these measures fail to maintain remission in distal disease,

thiopurines (6-mercaptopurine (6-MP) or azathioprine) and infliximab (, but not corticosteroids, may prove effective

RECOMMENDATIONS FOR MANAGEMENT OF MILD –MODERATE EXTENSIVE COLITIS: ACTIVE DISEASE• Patients with mild to moderate extensive colitis should begin therapy with oral sulfasalazine in daily doses titrated up to 4 – 6 g per day, or an alternate aminosalicylate in doses up to 4.8 g per day of the active 5-aminosalicylate acid (5-ASA) .• Oral steroids are generally reserved for patients who are refractory to

oral aminosalicylates in combination with topical therapy, or for patients whose symptoms are so troubling as to demand rapid improvement• 6-MP and azathioprine are effective for patients who do not respond to

oral steroids, and continue to have moderate disease, and are not so acutely ill as to require intravenous therapy• Infliximab is an effective treatment for patients who are steroid refractory

or steroid dependent despite adequate doses of a thiopurine, or who are intolerant of these medications

• The infliximab induction dose is 5 mg / kg intravenously at weeks 0, 2, and 6 weeks.

• Infliximab is contraindicated in patients with active infection, untreated latent TB, preexisting demyelinating disorder or optic neuritis, moderate to severe congestive heart failure, or current orrecent malignancies.

RECOMMENDATIONS FOR MILD – MODERATEEXTENSIVE COLITIS: MAINTENANCE OF REMISSION*Once the acute attack is controlled, a maintenance regimen is usually required, especially in patients with extensive or relapsing disease. Sulfasalazine, olsalazine, mesalamine, and balsalazide are all effective in reducing relapses

*Patients should not be treated chronically with steroids. Azathioprine or 6-MP may be useful as steroid-sparing agents for steroid-dependent patients and for maintenance of remission not adequately sustained by aminosalicylates, and occasionally for patients who are steroid depend ent but not acutely ill

*Infliximab is effective in maintaining improvement and remission in the patientsresponding to the infl iximab induction regimen

RECOMMENDATIONS FOR MANAGEMENT OF SEVERECOLITIS

• The patient with severe colitis refractory to maximal oral treatment with prednisone, oral aminosalicylate drugs, and topical medications may be treated with infliximab 5 mg / kg if urgent hospitalization is not necessary.

• The patient who presents with toxicity should be admitted to hospital for a course of intravenous steroids

• Failure to show significant improvement within 3 – 5 days is an indication for either colectomy or treatment with intravenous cyclosporine in the patient with severe colitis. Long-term remission in these patients is significantly enhanced with the addition of maintenance 6-MP

• Infliximab may also be effective in avoiding colectomy in patients failing intravenous steroids but its long-term efficacy is unknown in this setting

RECOMMENDATIONS FOR SURGERY*Absolute indications for surgery are exsanguinating hemorrhage, perforation, and documented or strongly suspected carcinoma*Other indications for surgery are severe colitis with or without toxic megacolon unresponsive to conventional maximal medical therapy, and less severe but medically intractable symptoms or intolerable medication side effects

*Patients who develop typical symptoms and signs of pouchitis after the IPAA should be treated with a short course of antibiotics*Controlled trial studies show efficacy for metronidazole in a dose of 400 mg three times daily, or 20 mg / kg daily, or ciprofl oxacin 500 mg twice dailyOther etiologies mimicking pouchitis include irritable pouch syndrome, cuffitis, CD of the pouch, and postoperative complications such as anastomotic leak or stricture. Inadequate evidence exists to recommend routine surveillance of the pouch for dysplasia or adenocarcinoma

RECOMMENDATIONS FOR THE MANAGEMENT OFPOUCHITIS

RECOMMENDATIONS FOR CANCER SURVEILLANCE*Aft er 8 – 10 years of colitis, annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals should be performed

*The finding of HGD in flat mucosa, confirmed by expert pathologists ’ review, is an indication for colectomy, whereas the fi nding of LGD in fl at mucosa may also be an indication for colectomy to prevent progression to a higher grade of neoplasia

Approach To Management Of Crhons Disease

•Goals of treatment : are induction and maintenance of remission of symptoms to provide an improved quality of life, reduction in need for long-term corticosteroids, and minimization of cancer risk.

Recommendations for Induction of Remission*ACG Against Using Thiopurine Monotherapy to Induce Remission in Patients With Moderately Severe CD.

*Using Methotrexate to Induce Remission in Patients With Moderately Severe CD Using Anti–TNF-a Drugs in Combination With Thiopurines Over Thiopurine Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD.

* Using Anti–TNF-a Monotherapy Over Thiopurine Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD.

*Using Anti–TNF-a Drugs in Combination With Thiopurines Over Thiopurine Monotherapy to Induce Remission in Patients Who Have Moderately Severe CD

Recommendations for Maintenanceof Remission

• Using Thiopurines Over No Immunomodulator Therapy to Maintain a Corticosteroid-Induced Remission in Patients With CD

• Using Anti–TNF-a Drugs Over No Anti–TNF-a Drugs to Maintain Corticosteroid- or Anti–TNF-a—Induced Remission in Patients With CD

• Make No Recommendation for or Against the Combination of an Anti–TNF-a Drug and a Thiopurine Versus an Anti–TNF-a Drug Alone to Maintain Remission Induced by a Combination of These Drugs in Patients With CD

Summary

Recent Options for treatment• Anti-Integrin antibodies

• Natlizumab (Tysabri) – anti-alpha-4 integrin • Vedolizumab (Entyvio) –anti-alpha-4-beta-7 integrin

• Anti-IL-12 and IL-23 – inhibit their receptors on Tc, NKc, and APC• Ustekinumab blocks IL-12 and IL-23 receptors

• Anti-IL-17 antibodies inhibit TH17 activation

• TPN and gut rest

• Antibiotics – Cipro and Metroniazole, ? Xifaxan, ?Alinia