Inflammatory Bowel Disease

Transcription

1 Inflammatory Bowel Disease Ali J. Olyaei, PharmD, BCPS Associate Professor of Medicine Director, Clinical Research Nephrology and Hypertension Associate Professor of Pharmacology School of Nursing Oregon Health & Sciences University

2 HISTORY OF IBD Crohn's: In 850 AD King Alfred, "England's Darling had a GI illness that began at age 20 At the time the illness was thought to be due to witchcraft, or a punishment for the King's infidelities. It is now thought to be Crohn's disease

3 HISTORY OF IBD Crohn's: In 1913 Dr. Dalziel described transmural intestinal inflammation in 13 autopsied patients. The medical community was not receptive to his findings at the time. In 1930 Burril Crohn's described terminal ileitis in a landmark publication in JAMA Ulcerative Colitis: A Greek physician with the unfortunate name of Soranus first described the diarrheal d/o in 130 AD First officially described by Wilks and Moxon in 1875 Before this discovery, all diarrheal diseases were believed to be caused by infectious agents and bacteria.

4 Pathogenesis of IBD

5 Introduction Ulcerative Colitis: Ulcerative colitis is a chronic inflammatory disease of unknown etiology Primarily affects the colon and rectum Lesions are characterized by superficial infiltration of the bowel wall by inflammatory white cells Results in mucosal ulcerations and crypt abscesses

6 Ulcerative Colitis A chronic inflammatory condition of the mucosa limited to the colon Characteristically involves the rectum and can extend, symmetrically, throughout the large bowel 1/5 will have extensive colitis Etiology - Unknown

7 Epidemiology - UC Incidence 2-6/100,000/yr in the US Prevalence 50-80/100,000 in the US Age 20-40, but can occur anytime Female preponderance (??) Cost

8 Epidemiology The incidence of UC occurs in distinct patterns Northern countries such as United Kingdom, Norway, Sweden, and the United States have the highest rates of the disease A northern California study revealed that of 10.9 per 100,000 people have UC

9 Epidemiology A study from Baltimore suggested that the incidence of UC is greater in caucasians than in African Americans 3:1 Friedman et al stated that the incidence of UC is 4-fold higher in Jewish decent than in other ethnic groups Smoking is the most extensively studied factor associated with IBD. Smokers have a decreased risk for developing UC. Increased risk of Crohn s

10 Epidemiology Ulcerative Colitis Whites Jewish Genetic Non-Smokers 6 to 12 per 100,000

11 Sign and Symptoms - UC Bloody diarrhea, tenesmus, passage of mucus Anorexia, nausea, abdominal pain, weight loss Mild to moderate disease - benign exam Severe disease - febrile, tender abdomen, illappearing

12 Clinically Patient presents with bloody diarrhea, anorexia, abdominal pain, fever, mucous, and weight loss About 5% of patients have only one acute UC episode and never reoccurs 20-25% of patients that develop severe UC do not respond to pharmacotherapy

13 Clinical Presentation In a study by Rao et al the prevalence of symptoms and stool patterns was assessed 96 patients with UC were subdivided according to the extent and activity of the disease All symptoms were significantly more common in patients with active colitis

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 Radiographic Normal Thumbprinting Dilated colon ABD Exam Normal Tender, no rebound Distended, BS, +/- rebound

15 Clinical Presentation Symptoms 100% 85% 83% 80% 60% 63% 47% 40% 20% 0% Urgency Increased Defecation Tenesmus Hard or Formed Stools Frequency

16 Diagnosis The diagnosis of UC is based on the clinical picture, stool examination, colonoscopic appearance, and histologic assessment of biopsied specimens The differential diagnosis includes infectious, chemical, IBS, ischemia, and miscellaneous

17 Extraintestinal Manifestations Skin - erythema nodosum 2-4%, pyoderma gangrenosum 1-2% Mouth - aphthous ulcers 10% Eyes - uveitis, episcleritis 5% Joint - acute arthropathy 15%, sacroilitis 12-15% Liver disease - PSC 3%

18 Diagnosis History & Exam Stool Studies Endoscopy Biopsy Inflammatory Bowel Disease Irritable Bowel Syndrome Microscopic Colitis Drug Induced Infectious Ulcerative Colitis

19 Disease Distribution at Presentation 1,116 patients with a confirmed diagnosis of UC were studied at the Cleveland Clinic Foundation The mean age at diagnosis was 32 years Early complications included colonic hemorrhage (16.7%) and toxic colitis (12.7%) Complications were highest among patients with pancolitis Surgery was required for 37.6%

20 Disease Distribution at Presentation n= % 46% 17%

21 Recommendations for Cancer Surveillance -UC Annual (1-2 yrs) colonoscopy 8-10 years after the first exacerbation Risk for colon CA increases by 0.5-1%/yr after 10 years with extensive UC

22 Course and Prognosis - UC 80%-intermittent exacerbations followed by variable periods of remission 15%-chronic colitis requiring colectomy 5%-severe first attack requiring colectomy Long term life expectancy - no different than the general population

23 Approach to Management Therapeutic goals 1) Induce remission 2) maintain remission Medical management Surgical Aminosalicylates Corticosteroids immunosuppressants

24 Aminosalicylates Sulfasalazine (Azulfidine) Dose dependent ADR - nausea, anorexia, folate def, headache, alopecia Dose independent ADR - male infertility, rash, hemolytic anemia, hepatitis, pancreatitis and agranulocytosis

25 Sulfasalazine Became available in the 1940 s when Svatz et al discovered that sulfasalazine, originally used to treat RA, was also noted to reduce colonic mucosal inflammation and bloody diarrhea

26 Sulfasalazine (Azulfidine) N (sulfasalazine) O COOH NHS O N=N OH Sulfapyridine 5-ASA Colonic bacterial cleave N=N bond and release 5-ASA Sulfapyridine causes rash and other side-effects 5-ASA is the active molecule that works topically to decrease inflammation

27 Aminosalicylates Mesalamine (Asacol, Pentasa, Rowasa) Asacol - enteric coated tablet Pentasa - time released caplet Rowasa - topical Olsalazine (Dipentum) - prodrug (second generation aminosalicylate)

28 5-ASA (Mesalamine( Mesalamine) ) Delivery Systems Pentasa Rowasa 5-ASA 5-ASA Microspheres Asacol 5-ASA Eudragit S Colazal COOH Inert COOH carrier N= N OH OH 5-ASA

29 Location of Oral Mesalamine Release Stomach Mesalamine controlled-release release capsules (Pentasa ) Duodenum Jejunum Ileum Mesalamine delayed-release tablets (Asacol ( ) Balsalazide (Colazal ) Olsalazine (Dipentum ) Colon

30 Sulfasalazine Is indicated for the treatment of mild to moderate UC, as adjunctive therapy in severe cases, and for prolongation of remission It is a prodrug comprised of mesalamine and sulfapyridine joined by a diazo bond About 1/3 of the dose is absorbed in the small intestine

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32 Sulfasalazine The efficacy of sulfasalazine is dose-dependent Doses greater than 4.0 g/d and serum sulfapyridine concentrations above 50 ug/ml are associated with a greater risk of toxicity up to 1/3 of patients given sulfasalazine experience some degree of intolerance to the drug

33 Sulfasalazine Adverse events of sulfasalazine are of two types: dose-related or hypersensitivity nausea, vomiting, abdominal discomfort, anorexia, and headache and Less common include hemolytic anemia, reticulocytosis, and methemoglobinemia The second group are non-dose dependent exfoliative dermatitis, aplastic anemia, hepatitis, pancreatitis, pneumonitis, autoimmune hemolysis, pericarditis, nephrotic syndrome, and severe exacerbation of symptoms of colitis

34 Sulfa-Free Oral Mesalamine Studies have shown that mesalamine is the principal therapeutically active component of sulfasalazine, while sulfapyridine is the carrier Recognition that sulfapyridine is associated with dose-related adverse events led to efforts to develop sulfa-free products These include Asacol (mesalamine), Dipentum (olsalazine), Pentasa (mesalamine), and Colazal (balsalazide)

35 Asacol (mesalamine) Asacol tablets were introduced to the US in 1992 Unlike sulfasalazine, olsalazine, and balsalazine, Asacol is not a prodrug It contains a core of 400 mg of mesalamine coated with a ph-sensitive acrylic polymer call Eudragit- S which delays release of mesalamine until the tablet reaches an environment of ph of 7 or above The coating typically dissolves in the terminal ileum(?) or colon

36 Asacol (mesalamine) Asacol is indicated for the treatment of mildly to moderately active UC and the maintenance of remission The usual dose is two 400-mg tablets to be taken three times a day for a total daily dose of 2.4 g for a duration of 6 weeks For maintenance the recommended dose is 1.6 g daily, in divided doses

37 Pentasa (mesalamine) Pentasa has been marketed in the US since 1993 Pentasa is also not a prodrug Unlike Asacol, the delivery system is made up of mesalamine microspheres It is moisture activated, thus the capsules disintegrate in the stomach, dispersing controlledrelease microspheres into the small bowel and throughout the rest of the colon

38 Pentasa (mesalamine) Pentasa is indicated for the induction of remission and for the treatment of mildly to moderately active UC The recommended dose is four 250-mg capsules four times a day for a total daily dose of 4.0 g Treatment duration is up to 8 weeks $$$

39 Dipentum (olsalazine) Dipentum was introduced to the US in 1990 and contains 250-mg of olsalazine sodium It is a prodrug consisting of two molecules of mesalamine joined by a diazo bond which is cleaved by bacterial action in the colon

40 Dipentum (olsalazine) Dipentum is indicated for maintenance of remission of UC in patients intolerant to sulfasalazine The usual dose is two 250-mg capsules twice a day for a total daily dose of 1.0 g

41 Colazal (balsalazide) Colazal was introduced to the US in 2000 and contains 750-mg of balsalazide sodium It is a prodrug and is delivered intact to the colon where it is cleaved by bacterial azoreduction to release mesalamine 70% of patients intolerant of sulfasalazine are able to tolerate balsalazide

42 Colazal (balsalazide) The recommended dose of 6.75 g/day contains 2.4 g of mesalamine It is indicated for the treatment of mildly to moderately active ulcerative colitis

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44 Oral 5-ASA 5 Release Sites Pentasa Asacol COLAZAL Stomach Small Intestine Large Intestine Mesalamine in microgranules Mesalamine w/ eudragit-s Azo bond

45 Variance in Colonic ph ph-dependent Delivery Requirements ph Ulcerative Colitis Patients

46 Mild-moderate distal colitis - Active Disease (UC) 1st line therapy 5-ASA PO Sulfasalazine 4-6g/day divided qid Mesalamine 2-4g/day divided bid-qid Olsalazine 1.5-3g/day divided bid-qid *Effective in achieving a remission in 80% within first 2-4 weeks

47 Mild-moderate distal colitis - Active Disease (UC) Alternate 1st line therapy - topical (PR) Mesalamine supp 500mg bid Mesalamine enema 2-4g bid Hydrocortisone enema 100mg bid 10% cortisone foam bid 2nd line - corticosteroids 3rd line - immunosuppressants (rare)

48 Maintenance distal Disease - UC Mesalamine supp 500mg bid Mesalamine enema 2-4g bid Oral sulfasalazine 2-4g/day or mesalamine 1-2g/day is also effective Corticosteroids are not effective in maintenance of remission

49 Mild-moderate extensive colitis - Active Disease (UC) 1st line - PO sulfasalazine or mesalamine 2nd line - prednisone 40-60g/day 3rd line - azathioprine mg/kg/day or an equivalent dose of 6-MP Maintenance - PO aminosalicylates or immunosuppressants

50 6-MP/Azathioprine Metabolism

51 Severe colitis - UC Admission to hospital - IVF and lytes Indications for IV steroids - signs of toxicity or failure of max outpatient TX Hydrocortisone 300mg/day divided qid Methylprednisolone 48mg/day Failure of IV steroids after 7-10 days; colectomy or IV cyclosporine

52 Indications for colectomy- UC Severe exacerbation failing to respond to medical therapy Complication of severe attack Chronic disease with decreased quality of life Dysplasia on surveillance endoscopy

53 Sequential Therapy Induction of Acute Disease Rectosigmoid Disease 5-ASA Enema Prednisone 5-ASA Oral STOP 6MP/ Azathioprine Surgery Extensive Disease IV Cyclosporine 5-ASA Oral Prednisone 5-ASA Enema STOP 6MP/ Azathioprine IV Steroids Surgery

54 THE IBD COMPARISON FEATURE CLINICAL SITE ULCERATIVE COLITIS F, D, brbpr, wt loss, malnutrition, Smoking improves, extraintestinal manifestations more common (JSEM) Colon exclusively CROHN`S F, D, Abd pain, brbpr, wt loss, malnutrition, perianal dz, abd mass, growth failure kids, associated with PSC, smoking makes worse Colon, ileum, infrequently other sites COMPLICATIONS Cancer, Fistulas absent Stricture, Fistula, & cancer, Toxic megacolon absent, Perforation uncommon

55 IBD COMPARISON CONTINUED FEATURE PATHOLOGY ULCERATIVE COLITIS Mucosal, Crypt abscesses CROHN`S Submucosal, mucosal, transmural inflammation Granulomas, serosal erythema and creeping fat ENDOSCOPY Friability, pseudopolyps, rectal dz Friability, apththous and linear ulcers, cobble stone, pesuopolyps and rectal dz RADIOLOGY LABS Continuous distribution, superficial ulceration, dilated ileal disease ( backwash ileitis ) 70% p-anca+ Discontinuous, segmented, deep submucosal ulceration, fissures, strictures or fistulae, narrow and nodular ileal dz, String sign on SBFT >50% ASCA +

56 Pathogenesis Crohn's Strongly debated recently Previously thought to be T-cell mediated Recent work shifting away from T-cell adaptive immunity and towards an aberrant innate immune response, which subsequently leads to T-cell activation

57 Diagnosis of IBD Crohn's disease with the characteristic patchy erythema (left panel) and ulceration (right panel) that occur next to areas of normal mucosa. Courtesy of James B McGee, MD. From Uptodate 2007

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60 Perianal Disease Seen only with Crohn s disease Rest of GI tract may have inactive disease Treat with antibiotics (metronidazole & Ciprofloxacin) Biologics very effective

61 TNF- α Antibodies

62 Infliximab (TNF-α antibody) In patients with Crohn's disease refractory to steroids or conventional immunosuppressive drugs a single infusion of infliximab at 4 weeks produced improvement in 64% of patients and remission in 33% compared with 17% and 4% respectively after placebo. Relapse tended to occur in the ensuing months: repeated infusions at 4-8 weeks may produce more lasting remissions.

63 IBD Therapy per AGA 2006 Guidlines Infliximab (TNF-α antibody) CD with inadequate response to conventional tx If used for induction, continue w/ maintenance Fistulizing CD UC patients without adequate response to conventional tx Withdraw or taper concomitant steroids Avoid: active infection, demyelinating d/o, CHF, malignancy, screen for TB

64 IBD Therapy per AGA 2006 Guidlines

65 IBD Therapy per AGA 2006 Guidlines Steroids: Budesonide : ileal and R sided colonic CD Prednisone: moderate to severe dz, failure of 1st line tx such as mesalamine (UC) or budesonide (CD) Topical hydrocortisone or budesonide for d. colon inflammation Perianal fistulas: steroids not useful IV steroids/ hospitalize if severe dz and failure of PO Not recommended as maintenance tx for CD/ UC If unable to taper steroid, this is indication for antimetabolite and/or infliximab Monitor: bone mineral density, ophtho exam, adrenal insuff, glucose intolerance

66 IBD Therapy per AGA 2006 Guidlines Azathioprine and 6-MP: For steroid- dependent IBD in order to attempt to d/c steroids Measure CBC w/diff q2wk during dose adjustment Thiopurine methyltransferase genotype post-op recurrence in CD Perianal and enteric fistulae Remission maintenance in CD

67 IBD Therapy per AGA 2006 Guidlines Methotrexate: IV MTX for induction in active CD or maintenance of remission in inactive CD Induction w/ steroid withdrawal in active CD Weekly IM MTX is effective for chronic active CD Do not use in pregnancy and CKD Insufficient evidence for induction or maintenance in UC Monitor: CBC, LFT

68 IBD Therapy per AGA 2006 Guidelines Cyclosporine Induction in UC Efficacy for CD w/ high doses ( toxicity) Fistulizing CD w/ IV cyclosporine Severe steroid-refractory UC Concomitant steroids used in severe UC Goal to bridge to AZA or 6-MP as maintenance tx Fistulizing CD with bridge to AZA or 6-MP