Inflammatory bowel disease. Deb Datta Consultant Gastroenterologist

Transcription

1 Inflammatory bowel disease Deb Datta Consultant Gastroenterologist

2 All That in 45 Minutes??? THAT S UN-POSSIBLE!

3 Inflammatory bowel disease refers to two chronic diseases that cause inflammation of the intestines: ulcerative colitis and Crohn's disease. Although the diseases have some features in common, there are some important differences.

4 Inflammatory bowel disease??cause But researchers believe that a number of factors may be involved, such as environment diet genetics

5 Inflammatory bowel disease Likely genetic defect that affects how our immune system works and how the inflammation is turned on and off in those people with inflammatory bowel disease, in response to an offending agent, like: bacteria a virus or a protein in food

6 Epidemiology of IBD Ulcerative colitis Crohn s disease Incidence (US) 11/ / Age of onset & & Male:female ratio 1: :1 Smoking Oral contraceptive Appendectomy Monozygotic twins May prevent disease May cause disease No increased risk Relative risk 1.91 Not protective Protective 8% concordance 67% concordance

7 Ulcerative colitis is an inflammatory disease of colon. MucosaM - of the intestine becomes inflamed and develops ulcers is often the most severe in the rectal area, which can cause frequent diarrhea.

8 Ulcerative colitis microscopic features Process is limited to the mucosa and submucosa with deeper layer unaffected Two major histologic features: - the crypt architecture of the colon is distorted - some patients have basal plasma cells and multiple basal lymphoid aggregates

9 Ulcerative colitis macroscopic features 40-50% of patients have disease limited to the rectum and rectosigmoid 30-40% of patients have disease extending beyond the sigmoid 20% of patients have a total colitis Proximal spread occurs in continuity without areas of uninvolved mucosa

10 Ulcerative colitis macroscopic features Mucosa is : - erythematous, has a granular surface that looks like a sand paper In more severe diseases: - hemorrhagic, edematous and ulcerated In fulminant disease a toxic colitis or a toxic megacolon may develop ( wall become very thin and mucosa is severly ulcerated)

11 Ulcerative colitis clinical presentation The major symptoms of UC are: - diarrhea - rectal bleeding - tenesmus - passage of mucus - crampy abdominal pain

12 Ulcerative colitis clinical presentation Proctitis - fresh blood or blood-stained mucus either mixed with stool or streaked onto the surface of normal or hard stool Disease beyond the rectum, blood is usually mixed with stool or grossly bloody diarrhea may be noted Severe Disease- liquid stool containing blood, pus, fecal matter anorexia, nausea, vomiting, fever, weight loss

13 UC: Natural History Disease Severity at Presentation Severe Activity (9%) Mild Activity: < 4 stools daily No systemic disturbance ESR: Nl Patients with UC (%) Moderate Activity (71%) Mild Activity (20%) Disease Activity Moderate Activity: > 4 stools daily Minimal systemic effects Severe Activity: > 6 stools daily Bloody stools Fever Tachycardia Anemia ESR > 30 mm/hr Hendriksen C, Kreiner S, Binder V. Gut 1985;26:

14 Colitis Activity Assessment MILD SEVERE FULMINANT Stools (#/day) <4 >6 >10 Blood in stool Intermittent Frequent Continuous Temperature (C) Normal > 37.5 > 37.5 Pulse Normal > 90 > 90 Hemoglobin Normal <75% of normal Transfusion required ESR < 30 > 30 > 30 Hanauer SB. N Engl J Med 1996;334(13):

15 Radiologic change of UC Fine mucosal granularity Mucosa become thickenned and superficial ulcers are seen (collar-button ulcers) Loss of haustration

16 Ulcerative colitis - complication Hemorrhage Perforation Stricture Toxic megacolon (transverse colon with a diameter of more than 5,0 cm to 6,0 cm with loss of haustration) Cancer

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18 Colonic pseudopolyps

19 ulcerative colitis:the left side of the colon is affected The image shows confluent superficial ulceration and loss of mucosal architecture.

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24 Crohn s disease Most commonly affects the last part of the small intestine and parts of the large intestine. Crohn's disease can affect any part of the digestive tract Crohn's disease generally tends to involve the entire bowel wall

25 Crohn s disease macroscopic features Can affect any part of GI tract from the mouth to the anus 30-40% of patients have small bowel disease alone 40-55% of patients have both small and large intestines disease 15-25% of patients have colitis alone In 75% of patients with small intestinal disease the terminal ileum in involved in 90%

26 Crohn s Disease: Anatomic Distribution Small bowel alone (33%) Ileocolic (45%) Freq of involvement Colon alone (20%) Most Least

27 Crohn s disease macroscopic features CD is a transmural process CD is segmental with skip areas in the midst of diseased intestine In one third of patients with CD perirectal fistulas, fissures, abscesses, anal stenosis are present

28 Crohn s disease macroscopic features mild disease is characterized by: aphtous or small superficial ulcerations In active disease: stellate ulcerations fuse longitudinally and transversely to demarcate island of mucosa that are histologically normal Cobblestone appearance is characteristic of CD (both endoscopically and by barium radiography)

29 Crohn s disease macroscopic features Active CD is characterized by focal inflammation and formation of fistula tracts The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstruction

30 Crohn s disease macroscopic features Aphtoid ulceration and focal crypt abscesses with loose aggregation of macrophages which form granulomas Transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall

31 serpiginous ulcer, a classic finding in Crohn's disease

32 Crohn s disease sign and symptoms Ileocolitis - right lower quadrant pain and diarrhoea - palpable mass, fever and leucocytosis - pain is colickly and relieved by defecation Jejunoileitis - inflammatory disease is associated with loss of digestive and absorptive surface

33 Crohn s disease sign and symptoms Colitis and perianal disease - low grade fever, malaise, diarrhea, crampy abdominal pain, sometimes hematochezia - pain (narrowed and inflamed segments of large bowel) Gastroduodenal disease - nusea, vomiting, epigastric pain - second portion of duodenum is more commonly involved than the bulb

34 Endoscopic image of Crohn's colitis showing deep ulceration.

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40 IBD is associated with variety of extraintestinal menifestation. Almost one-third of the patients have at least one.

41 Extraintestinal manifestation Dermatologic 1. Erythema nodosum occurs in up to 15% of CD patients and 10% of UC patients The lesions of EN are hot, red, tender nodules measuring to 5cm in diameter 2. Pyoderma gangrenosum (PG) is seen in 1 to 12% of UC patients and is less common in CD colitis. PG may occur years before the onset of bowel symptoms.

42 Extraintestinal manifestation Rheumatologic Peripherial arthritis developes in 15 to 20% of IBD patients, is more common in CD. It is asymmetric, polyarticular and migratory. Most often affects large joints of the upper and lower extremities emities Ankylosing spondylosis (AS) occurs in 10% of IBD. Sacroilitis is symetrical, occurs equally in UC and CD, often asymptomatic

43 Extraintestinal manifestation Ocular Incidence 1 to 10% The most common is conjunctivitis, anterior uveitis, episcleritis Symptoms include: : ocular pain, photophobia, blurred vision, headache

44 Extraintestinal manifestation Urologic calculi, ureteral obstruction, fistulas The highest frequency of nephrolithiasis (10-20%) occurs in patients with CD.

45 Increased prevelance of osteoporosis secondary to vitamin D deficiency, calcium malabsorbtion, malnutrition, corticosteroid use Cardiopulmonary manifestations - endocarditis, myocarditis, pleuropericarditis and interstitial lung disease.

46 Different clinical features Blood in stool Mucus Systemic symptoms Pain Abdominal mass Perineal disease UC Yes Yes Occasionally Occasionally Rarely No Crohn s disease Occasionally Occasionally Frequently Frequently Yes Frequently

47 Different clinical features Fistulas Small intestine obstruction Colonic obstruction Response to antibiotic Recurrence after surgery UC No No Rarely No No Crohn s disease Yes Frequently Frequently Yes Yes

48 Different endoscopic features Rectal sparing Continuous disease cobblestoning Granuloma on biopsy UC Rarely Yes No No Crohn s disease Frequently Occasionally Yes Occasionally

49 The Short List Laboratory testing Serologic markers Genetic testing Metabolite monitoring Markers of disease activity (serum, stool) Radiography Enterography (CT, MRI) Pelvic imaging (MRI) Ultrasound Endoscopy Chromoendoscopy Advanced endoscopic imaging Rectal EUS for fistulae

50 Serology: The Two Jakes ASCA: The Crohn s Disease Ab + in 60% of CD 1-3 IgA + IgG vs. cell wall of S. cerevisiae panca: The Ulcerative Colitis Ab + in 40-80% UC, 2-28% 2 28% CD ( UC-like CD) 4 Newer assay more specific for UC Loss of perinuclear stain after DNAse

51 CT Enterography Allows visualization of lumen, mucosa, bowel wall and extraluminal pathology Traditional oral contrast has similar attenuation to enhancing mucosa Multidetector CT scanner Traditional IV contrast

52 CT Enterography Abscess seen better after positive oral contrast

53 Normal Terminal Ileum CT Enterography

54 CT Enterography Active Disease

55 CT Enterography

56 RADIOLOGY Enteroclysis 100% agreement with surgical findings of fistula and stricture SBFT Reported 85-95% sensitivity/specificity for identification of stricture, fistula and mucosal abnormalities 101 Incorrectly identified stricture number in 31% vs. operative findings 102

57 MRI Better visualisation of small bowel Detection of collection/abscess Contraindications Ongoing studies

58 Chromoendoscopy (CE) Chromo= dyes applied to mucosa during endoscopy highlight and better characterize specific mucosal changes Allows visualization of otherwise invisible mucosal changes enhancing detection and accuracy Absorptive, reactive, and contrast staining dyes Indigo carmine: : nonabsorbed; collects in mucosal depressions Methylene blue: : absorbed in normal cytoplasm; irregularities pale Cresyl violet: : taken up in crypts of Leibeukuhn; appears as dots/pits. Pit patterns have histologic correlates. Can be used with the above 2 stains

59 Chromoendoscopy in IBD Dye spraying adds about 10 minutes to colonoscopy 67 Abandoning random bx will shorten procedure Should be pretty even in terms of time after learning curve

60 Goals of Therapy for IBD Inducing remission Maintaining remission Restoring and maintaining nutrition Maintaining patient s quality of life Surgical intervention (selection of optimal time for surgery)

61 Therapeutic Pyramid for Active UC Severe Surgery Cyclosporine Moderate Infliximab Systemic Corticosteroids Oral Steroids AZA/6-MP Mild Aminosalicylates

62 Sequential Indications Induction of remission Treatment of acute disease Maintenance of remission Medical maintenance Steroid-sparing

63 Ulcerative Colitis: Induction of Remission Mild disease Aminosalicylate Topical therapy (distal disease) Oral therapy (extensive disease)

64 Comparative Doses: Mild to Moderate UC Recommended Treatment Dose Equivalent 5-ASA dose Sulfasalazine 3-44 grams grams Mesalamine 2.4 grams 2.4 grams Balsalazide 6.75 grams 2.4 grams

65 5-ASA Delivery Systems PENTASA ASACOL SASP/OLS/BALS ENEMA SUPP JEJUNUM / ILEUM / ASC / DES / SIG / RECT

66 Maintenance Therapies for Ulcerative Colitis Aminosalicylates Azathioprine/6-MP

67 Controlled Trial of AZA in Management of Chronic UC - Results Mean Total Score Total General Health Score* P=NS First 3 Weeks Last 3 Weeks Reduction of Prednisone Dose (mg/day) Reduction of Prednisone Dose (mg/day) First 3 Months ** Last 3 Months Placebo (N=14) Azathioprine (N=16) Placebo (N=14) Azathioprine (N=16) *Combined scores for the number of bowel movements, state of health, findings on proctoscopy and rectal biopsy. **P<0.05 compared to placebo and baseline Rosenberg J, et al. Gastroenterology ;65:

68 Controlled Trial of AZA in Management of Chronic UC - Results Mean Activity Score Mean Activity Score at Baseline and 6 Months Placebo n=20 P<0.001 *p=ns Azathioprine n=24 *Comparison between azathioprine and placebo at 6 Months Reduction of Prednisone Dose (mg/day) Reduction of Prednisone Dose (mg/day) at Baseline and 6 Months 30 *p< Placebo n= Azathioprine n=24 Kirk A, et al. British Medical Journal ;284:

69 Cyclosporine in Patients with Severe Ulcerative Colitis 20 Patients 11 Cyclosporine 1 Elective colectomy 9 Response 8 Oral Cyclosporine 2 No Response: surgery Lichtiger S et al. NEJM 1994

70 IV Cyclosporine: Major Toxicity Renal insufficiency 23% Infection 20% Seizures 3% Deaths 2% Anaphylaxis 1% Sternthal J et al. Gastroenterol 1996

71 Complications of Surgery: Ileal Pouch-Anal Anastomosis (IPAA) Pelvic sepsis Leakage Incontinence Intestinal obstruction Anastomotic strictures Sexual dysfunction Pouchitis Female infertility Potential short-term complications Potential long-term complications Lichtenstein G. The Clinician s Guide to Inflammatory Bowel Disease. SLACK;2003:

72 Complications of UC Surgery Mortality (<0.5%) stools/24 hrs so bowel pattern not normal 1 Impotence (1.5%) 2 Pouchitis (10-60%) 1 Small bowel obstruction (20%) 1 Decrease in female fertility (56-98%) 3-5 Pouch-vaginal fistula (4%) 1 1 Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003: Pemberton JH, et al. Ann. Surg. 1987;206(4): Olsen, KO, et al. Gastroenterology. 2002;122: Johnson P, et al. Dis Colon Rectum. 2004;47; Gorgun E, et al. Surgery. 2004;136(4):

73 Ulcerative Colitis: Moderate to Severe Moderate Severe Oral steroid Inadequate response Adequate response IV Steroid Inadequate response Consider CyA Taper Successful Unsuccessful 6MP/AZA Success Response Failure Infliximab No response No response Response Maintain on 5-ASA and observe Maintain 6-MP/AZA Maintain infliximab Colectomy

74 Inductive Therapies for Crohn s Disease Aminosalicylates Antibiotics Corticosteroids Infliximab

75 Therapeutic Pyramid for Active Crohn s Disease Severe Surgery Moderate Immunomodulators (Prednisone) Corticosteroids Infliximab? Mild (Budesonide) Aminosalicylates/Antibiotics

76 Corticosteroids in CD: Induction of Remission % Patients 100 p not calculated 92% Corticosteroids 82%* Placebo 80 60% * % 30% 20 0 NCCDS ECCDS GETAID 17 weeks 18 weeks 7 weeks *Randomized controlled trial Multicenter prospective trial Clinical Remission Malchow H et al. Gastroenterology. 1984;86:249. Modigliani R et al. Gastroenterology. 1990;98:811. Summers RW et al. Gastroenterology. 1979;77:847.

77 Corticosteroids: Maintenance of Remission % Patients in Remission n=59; p=ns 55% 58% n=274; p=ns 75% 76% Steroid Placebo n=237; p=ns 23% 30% Smith Summers Malchow 36 months 12 months 24 months Bergman L et al. Scand J Gastroenterol. 1976;11:651. Malchow H et al. Gastroenterology. 1984;86:249. Smith RC et al. Gut. 1978;19:606. Summers RW et al. Gastroenterology. 1979;77:847.

78 Outcome of Corticosteroid Therapy for CD 1-month outcomes Remission 48% Improved 32% No change 20% 12-month outcomes Remission 54% Relapse 46% Improved 57% Relapse 43% Munkholm. Gut 1994;35: * Remission at 12 Months = 25%

79 Overview of Corticosteroids in CD Induce remission (NCCDS, * ECCDS, GETAID ) Provide rapid symptomatic relief (NCCDS, * ECCDS, GETAID ) Frequent corticosteroid dependency with prolonged use DO NOT maintain remission Dose- and duration-related related adverse events with acute and chronic therapy *Summers RW et al. Gastroenterology. 1979;77:847. Faubion WA Jr et al. Gastroenterology. 2001;121:255. Malchow H et al. Gastroenterology. 1984;86:249. Keenan GF et al. Clin Chest Med. 1997;18:507. Modigliani R et al. Gastroenterology. 1990;98:811. Munkholm P et al. Gut. 1994;35:360. Singleton JW et al. Gastroenterology. 1979;77:870. Steinhart AH et al. Cochrane Database Syst Rev. 2003;CD

80 Maintenance Therapy for Crohn s Disease: Issues Definition of remission Clinical, endoscopic, radiologic, laboratory Induction therapy 5-ASA, steroids, antibiotics, immunomodulators Surgery Disease location Disease behavior Inflammatory, fibrostenotic, fistulizing Smoking

81 Oral Budesonide as Maintenance 1 Therapy for CD Budesonide 6 mg Budesonide 3 mg Cumulative probability of remission 0.5 Placebo P = ns Days Adapted from Greenberg GR et al. Gastroenterology 1996;110:45-51

82 Outcomes for Mild-Moderate Moderate Disease Mild-Moderate Disease Aminosalicylate Response 40-50% Antibiotic (Colonic Disease) Response 40-50% Budesonide (Ileum-Right Colon) Response 50-65% Placebo Response 30-40%

83 Evidence-Based Approach of Sandborn and Feagan Mild-Moderate Moderate Crohn s Disease Left-sided disease restricted to colon Disease involving the ileum and/or ascending colon Sulfasalazine 16 weeks Budesonide capsules 8-16 weeks Sulfa-allergic/failed allergic/failed treatment Failed treatment >60% 45% acute 80% 1 year Sandborn, Feagan, 2003 Conventional steroids

84 Evidence/Experience Aminosalicylate Induction Mesalamine/Sulfasalazine Response No Response Maintain Ileum-R. Colon Colon Moderate Disease Budesonide AZA/MTX Antibiotic AZA/MTX Prednisone/ Elemental Diet Infliximab

85 MTX Results: Remission 50 P =0.025 % Response % 39.4% Placebo MTX Feagan. N Eng J Med. 1995;332(5):292-7

86 Methotrexate in IBD: Toxicity Major Hepatic Myelosuppressive Pulmonary Fertility-related related Teratogenic Enteritic/colitic Minor Gastrointestinal Alopecia-inductive inductive Allergic Neurologic Egan LJ, Sandborn WJ. Mayo Clin Proc 1996;71:69-80

87 Infliximab: Mechanism of Action

88 Healing of Colonic Ulceration with Infliximab Pretreatment 4 weeks post-treatment treatment Van Dullemen HM et al. Gastroenterology 1995;109:

89 ACCENT I Median Time to Loss of Response Week 2 Responders Through Week 54 Hanauer S, Feagan B. Lancet. 2002;359:1541-9

90 ACCENT I Clinical Remission at Week 54* Proportion of Patients (%) % P=0.007 P< % P=NS 38% 0 Single Dose (n=110) 5 mg/kg q 8 wk (n=113) 10 mg/kg q 8 wk (n=112) *Week-2 responders Hanauer SB, et al. Lancet 2002

91 REMICADE (infliximab) in Present, et al. Patients with Fistulizing Crohn s Disease Complete Response: All Fistulas Closed P=0.04 P=0.001 * *Placebo=Conventional Therapy Present D, et al. N Engl J Med. 1999;340:

92 Nutritional Therapy Elemental Diet Case reports of effectiveness in acute flares during pregnancy [Teahon[ Teahon,, Gut 1991] Important to maintain nutrition to the fetus Total Parenteral Nutrition Less desirable, but case reports of effectiveness [Gatenby[ Gatenby,, Human Nutrition 1987]

93 CD: Moderate to Severe Moderate CD Severe CD Observe Success Taper Adequate response PO Steroids Adequate response IV Steroids Maintain 6-MP/AZA or MTX Failure Adequate response Adequate response Inadequate response 6-MP/AZA Inadequate response/intolerant Consider change to MTX Inadequate response Consider infliximab + 6-MP/AZA or MTX Consider surgery Maintain infliximab + 6-MP/AZA or MTX Adequate response Inadequate response/intolerant Add infliximab Inadequate response/intolerant Surgery or investigational therapy

94 Infliximab indicated Infliximab Exclude enteric pathogen Exclude abscess, stricture Exclude latent/active TB (Start 6-MP/AZA or MTX) Infliximab 5 mg/kg wks 0, 2, 6 Response Observe up to 8 wks Consider steroid pre-treatment Consider acetaminophen, diphenhydramine pre-treatment Recurrent sx 4 wks Recurrent sx > 4 - < 8 wks Recurrent sx 8 wks Inadequate response Infliximab 10 mg/kg Maintain infliximab 5 mg/kg q 4-8 wks Inadequate response Surgery or investigational Rx Inadequate response Escalate dose or shorten interval Loss of response Maintain infliximab 5 mg/kg q 8 wks

95 Fistula Fistula Diagnostic evaluation Fistula type Not superficial Superficial Tacrolimus Failure Seton Antibiotics Failure Antibiotics Consider fistulotomy Failure Definitive surgery Failure 6-MP/AZA ± infliximab Maintain 6-MP/AZA and/or infliximab Observe

96 Summary: IBD and pregnancy Fertility IPAA Surgery clearly reduces fertility rates in women Pregnancy Outcomes Complicated pregnancies occur in majority of patients Increased rates Preterm birth, SGA LBW No increase in congenital anomalies Aggressive management of IBD flare during pregnancy with medications is warranted Medications Yes: 5ASA, Steroids, 6MP/AZA, Infliximab No: MTX, Thalidomide

97 Final Points There is no one size fits all to IBD therapy Therapy and decision making are tailored to the individual Algorithms are based upon available evidence Evidence is in constant flux Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome Skillful application of medical therapy makes all the difference in outcomes

98 Thank You