8.Inflammatory Bowel Disease.pptx........

Therapy

1. Inflammatory Bowel Disease (IBD)

2. Overview IBD Definition: generic term for a group of chronic , idiopathic , relapsing inflammatory disorders of the gastrointestinal tract. Two forms of idiopathic IBD are: Ulcerative colitis (UC) Mucosa l inflammatory condition that is limited to the rectum and colon Crohn’s disease (CD) Transmura l inflammatory condition that can affect any part of the GI tract , from the mouth to the anus

3. Epidemiology Rates of IBD are highest in North America, Northern Europe, and Great Britain Ulcerative colitis (UC) Incidence: 6 – 15.5 cases per 100,000 per year in the U.S. Prevalence: 7.6-246 per 100,000 persons per year in the U.S. Crohn’s disease (CD) Incidence: 6-15cases per 100,000 per year in the U.S. Prevalence: 3.6-214 per 100,000 persons per year in the U.S.

4. Epidemiology The peak incidence occurs in the second or third decade of life with a second peak occurring between the ages of 60 and 70 IBD affects both sexes somewhat equally overall 20% to 30% more woman are affected with CD Slightly more men (60%) are affected with UC Caucasians are affected more than non-whites for both UC and CD

5. Etiology The exact etiology of IBD is unknown. Dysregulation of the inflammatory response within the GI tract in response to environmental or microbiologic factors is thought to be the prevailing mechanism It is postulated that the cause of IBD is a combination of: Infectious factors : viruses , protozoans, and mycobacteria may promote alteration of the intestinal barrier and/or propagate an inflammatory response Genetic factors: First-degree relatives with IBD…a 20-fold increase risk Immunologic mechanisms: an abnormal regulation of the normal immune response or an autoimmune reaction to self-antigens Environmental causes Psychological factors Lifestyle, Dietary, and drug-related causes

6. Ulcerative Colitis (UC) Pathophysiology The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-) UC is confined to the rectum and colon Lesions affect the mucosal and submucosal layers In UC, the mucosal appearance includes edema, mucopus , erosions, and the lesions are continuous in nature Lesions are sometimes referred to as having a “lead pipe” appearance Fistulas, strictures, perforations are rare

7. Crohn’s Disease (CD) Pathophysiology CD is characterized by a transmural inflammatory process Cytokines thought to play major roles in CD are derived from T-helper type 1 cells and include interferon-, transforming growth factor-, TNF-, and IL-1, IL-6, IL-8, IL-12, and IL-23. TNF-, IL-12, and IL-23 are major contributors to the inflammatory process and development of fibrosis in CD. Lesions can occur anywhere in the GI tract but the terminal ileum is the most common site In CD, the mucosal appearance often includes ulcers, strictures, fistulas and the lesions are discontinuous and segmented Lesions are sometimes said to give a “cobblestone ” appearance Fistulas and strictures are common Nutritional deficiencies are common

8. Extraintestinal Manifestations of IBD Both UC and CD are associated with the development of symptoms and organ involvement outside of the GI tract and these are referred to as extra intestinal manifestations Several of these have immunologic components associated with them Extra intestinal manifestations include hepatobiliary complications; joint complications; ocular complications; dermatologic complications; hematologic, coagulation, and metabolic abnormalities

9. Clinical Presentation of IBD Presenting symptoms common to both UC and CD include: Diarrhea Abdominal cramping Fever Rectal bleeding Weight loss Most people with IBD have periods of exacerbations and remissions

10. UC Clinical Presentation There is a wide range of presentation in UC There is no standard disease severity scoring system The arbitrary distinctions of mild, moderate, severe, and fulminant disease activity are generally accepted and used in treatment guidelines These classifications are determined by clinical signs and symptoms

11. UC Clinical Presentation Mild Less than 4 stools per day, with or without blood, with no systemic disturbance and a normal erythrocyte sedimentation rate (ESR) Moderate Four or more stools per day but with minimal systemic disturbance Severe More than 6 stools per day with blood and systemic disturbance Fulminant More than 10 stools per day with continuous bleeding that may require transfusion, abdominal tenderness, colonic dilation, and additional marked systemic disturbance/toxicity

12. UC Clinical Presentation Systemic disturbance includes: Fever (temperature > 99.5 degrees Fahrenheit) Tachycardia (HR > 90-100 bpm ) Anemia (hemoglobin < 75% of normal) ESR > 30 mm/h Abdominal tenderness Bowel wall edema

13. UC Clinical Presentation In addition to determining disease severity, determining disease extent or which parts of the colon are involved is important Distal disease (AKA left-sided disease) – inflammation limited to areas distal to the splenic flexure Extensive colitis – inflammation extending proximal to the splenic flexture Proctitis – inflammation confined to the rectum Proctosigmoiditis – inflammation involving the rectum and sigmoid colon Pancolitis – inflammation occurring in the majority of the colon

14. CD Clinical Presentation Presentation of CD is highly variable Treatment guidelines use the presence of signs and symptoms as their marker for disease activity and severity The primary classifications used are: Mild to Moderate disease Moderate to Severe disease Severe to Fulminant disease

15. CD Clinical Presentation Mild to Moderate Disease Ambulatory patients who are able to tolerate food and beverage intake Absence of fever, dehydration, systemic toxicity, abdominal tenderness, mass, obstruction No weight loss or a non-significant weight loss Less than 10% of body weight

16. CD Clinical Presentation Moderate to Severe Disease Those who fail to respond to treatment for mild/moderate disease OR Those with more prominent symptoms such as fever, abdominal pain/tenderness, intermittent nausea/vomiting, dehydration, significant weight loss, significant anemia

17. CD Clinical Presentation Severe to Fulminant Disease Those with persistent symptoms despite the use of corticosteroid or biologic treatment OR Those with high fever, persistent vomiting, rebound tenderness, evidence of intestinal obstruction or abscess

18. Selected Complications Toxic Megacolon IBD patients are at increased risk of developing toxic megacolon , which is a segmental or total colonic distension of greater than 6cm with acute colitis and signs of systemic toxicity Colon Cancer IBD patients are at higher risk of colorectal carcinoma (CRC) Risk factors for CRC include: young age at IBD onset (<50 years old), severe inflammation, positive family history of CRC Screening colonoscopy should be performed at 8 years after onset of IBD symptoms with subsequent screenings every 1 to 2 year if negative

19. IBD Diagnosis The diagnosis of IBD is made on clinical suspicion confirmed by a thorough medical evaluation using: Sigmoidoscopy or colonoscopy Biopsy Stool examinations Barium radiographic contrast studies Laboratory testing: ESR , CRP, faecal calprotectin, CBC ( Leukocytosis, Hgb ) The presence of extraintestinal manifestations may also aid in establishing a diagnosis

20. Treatment of IBD Goals of Therapy IBD is a chronic lifelong illness characterized by exacerbations and periods of remission . Goals of therapy include: Provide relief of symptoms (induce remission) Improve quality of life Maintain adequate nutritional status Relieve intestinal inflammation Decrease frequency of recurrence Resolve complications

21. Nonpharmacologic Therapy: Nutritional Support Proper nutritional support is an important aspect Individual patients can try avoiding specific foods that may exacerbate their symptoms Nutritional needs of patients with IBD may be adequately addressed with enteral supplementation in acute or chronic situations Parenteral nutrition has a more limited role in IBD and is reserved for patients with severe malnutrition or those who fail enteral therapy

22. Nonpharmacologic Therapy: Nutritional Support Probiotic therapy involves the reestablishment of normal bacterial flora within the gut by oral administration of live bacteria such as nonpathogenic Escherichia coli , bifodbaceria , lactobacilli, Streptococcus thermophilus , Saccharomyces boulardii Probiotics have demonstrated some effectiveness in inducing and maintaining remission in some trials for patients with UC Evidence of probiotic use in the induction and maintenance of CD is less compelling and has led to recommendations not supporting widespread use

23. Nonpharmacologic Therapy: Surgery Even with many medications available to treat IBD, many patients will require surgery Surgical procedures may involve resection of segments of intestine that are affected, correction of complications (e.g., fistulas, strictures, obstructions, perforations, etc.), or drainage of abscesses

24. Pharmacologic Treatment of IBD Aminosalicylates Corticosteroids Immunomodulators Tumor necrosis factor (TNF)-inhibitors and other biologics Miscellaneous agents (antimicrobials)

25. Pharmacotherapy for IBD Treatment selection is dependent on the Type (UC or CD) Severity (mild, moderate, severe, fulminant) Site of disease ( proctitis , distal disease, extensive disease, small intestine involvement, etc.) Need for acute treatment or maintenance therapy

26. UC Pharmacotherapy Proctitis – inflammation confined to the rectum Topical therapy used most often Distal disease (AKA left-sided disease) – inflammation limited to areas distal to the splenic flexure May use either systemic or topical therapy or a combination Extensive colitis – inflammation extending proximal to the splenic flexure Must use systemic therapy. May add topical therapy to systemic therapy if needed/appropriate Pancolitis – inflammation occurring in the majority of the colon Must use systemic therapy. May add topical therapy to systemic therapy if needed/appropriate

27. Mild/Moderate DISTAL UC Treatment of ACTIVE Disease First-line therapy: topical (enema/suppository) amino salicylates If inadequate or no response to #1, use an oral amino salicylate or topical corticosteroid May combine oral and topical amino salicylates

28. Mild/Moderate DISTAL UC Remission/Maintenance Therapy: Mesalamine suppository or enema used 3 times per week OR Oral aminosalicylate tapered to a maintenance dose Topical or oral corticosteroids have no role in maintenance therapy

29. Mild/Moderate EXTENSIVE UC Treatment of ACTIVE Disease First-line therapy: Oral aminosalicylate If #1 doesn’t work, use budesonide 9mg/day for up to 8 weeks Remission/Maintenance Therapy Preferred: Oral aminosalicylate If used budesonide for induction, then budesonide 6mg/day for up to 3 months plus oral aminosalicylate at maintenance dose

30. Moderate/Severe UC Treatment of ACTIVE disease First-line therapy: Oral aminosalicylate PLUS prednisone 40-60mg/day If inadequate or no response to #1, ADD azathioprine, mercaptorpurine , infliximab, adalimumab, or golimumab Remission/Maintenance Therapy Taper prednisone, then after 1 to 2 months reduce oral aminosalicylate dose to maintenance dose Continue azathioprine, mercaptopurine , infliximab, adalimumab , or golimumab if previously added

31. Severe/Fulminant UC Treatment of ACTIVE disease 7 to 10 day course of intravenous corticosteroids (hydrocortisone) Patients refractory to IV corticosteroids (no response in 5 to 7 days) are candidates for IV cyclosporine

32. Severe/Fulminant UC Remission/Maintenance Therapy If remission achieved with IV hydrocortisone: Change IV hydrocortisone to oral prednisone and ADD azathioprine, mercaptopurine , adalimumab , or golimumab . Attempt to withdraw prednisone after 1 – 2 months. Can also consider adding oral aminosalicylate into the mix. If corticosteroid refractory disease and needed cyclosporine to achieve remission: Change IV cyclosporine to oral cyclosporine and ADD either azathioprine or mercaptopurine . May consider TNF-inhibitor at maintenance dose in the future, but if using oral cyclosporine, must use azathioprine or mercaptopurine with it

33. Refractory UC Oral tacrolimus (has been used in combination with oral aminosalicylates , AZA, or 6-MP) Vedolizumab Surgery

34. CD Pharmacotherapy

35. CD Pharmacotherapy Mild/Moderate CD Treatment of ACTIVE disease First-line therapy: Oral aminosalicylate Alternative therapies: Budesonide 9mg daily up to 8 weeks Metronidazole 10 – 20mg/kg/day for up to 10 weeks Ciprofloxacin 500mg bid for 6 to 10 weeks Rifaximin 800mg bid for 12 weeks Ciprofloxacin 500mg bid + metronidazole 250mg tid for 10 weeks

36. Mild/Moderate CD Specific choice of agent(s) for active disease can be informed by location of disease Ileocolonic or colonic Sulfasalazine OR oral mesalamine OR metronidazole +/- ciprofloxacin Perianal Sulfasalazine or oral mesalamine and/or metronidazole Small bowel Oral mesalamine or metronidazole Budesonide 9mg/day for terminal ileal or ascending colonic disease

37. Moderate/Severe CD Treatment of ACTIVE disease First-line: Aminosalicylate OR metronidazole +/- ciprofloxacin PLUS prednisone at a dose of 40-60mg/day until resolution of symptoms or resumption of weight gain (7-28 days) If steroid refractory and/or fistulizing disease Add infliximab, adalimumab , or certolizumab +/- azathioprine, mercaptopurine , or methotrexate If no response to TNF-inhibitor and/or immunomodulator , change to natalizumab or vedolizumab

38. Severe/Fulminant CD Treatment of ACTIVE disease May need surgical intervention (mass, obstruction, abscess, etc.) Administer IV hydrocortisone 100mg every 6 to 8 hours If no response to hydrocortisone in 5 to 7 days, then IV cyclosporine 4mg/kg/day OR infliximab is not attempted before

39. Remission/Maintenance Therapy for Crohn’s Disease No role for long-term corticosteroid use First Line: Azathioprine or 6-mercaptopurine plus or minus oral aminosalicylate If intolerant to AZA or 6-MP, then try methotrexate Second Line: TNF-inhibitor plus or minus azathioprine or 6-mercaptopurine or methotrexate (if intolerant of AZA or 6-MP) Alternative: Vedolizumab

40. Refractory CD Oral tacrolimus (has been used in combination with oral aminosalicylates , AZA, or 6-MP) Natalizumab Surgery

41. Aminosalicylates MOA Not completely understood but postulated to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing prostaglandins, leukotrienes resulting in decreased inflammation Agents Sulfasalazine Mesalamine Suppository Enema Oral formulations Olsalazine Balsalazide

42. Aminosalicylates Sulfasalazine Prototype aminosalicylate The drug is cleaved by colonic bacteria to an active portion Mesalamin (5-aminosalicylate or 5-ASA) and an inactive carrier molecule ( sulfapyridine ) AVOID in patients with a SULFA allergy Mesalamine Available in various formulations including a rectal suppository, enema, and various oral formulations that release the drug at different points in the GI tract

43. Aminosalicylates Olsalazine A dimer of two 5-ASA molecules linked by an azo bond Mesalamine is released in the colon after colonic bacteria cleave the azo bond High incidence of diarrhea as an adverse effect (up to 25% of patients) Balsalazide A mesalamine prodrug that couples mesalamine with an inert carrier molecule and is enzymatically cleaved in the colon to release mesalamine

44. Aminosalicylates Different amino salicylate products have different sites of action and hence location of the disease in the GI tract is factored into the selection of an agent Suppositories have local activity in the rectum and are useful in proctitis Enemas have local activity in the rectum and distal colon and are useful to treat left-sided disease Different oral formulations release drug at different points in the small intestine and colon

45. Corticosteroids MOA Corticosteroids are used to suppress acute inflammation in the treatment of IBD, and may be given parenterally, orally, or rectally. They modulate the immune system and inhibit production of cytokines and mediators. Agents Prednisone Prednisolone Methylprednisolone Hydrocortisone Budesonide

46. Corticosteroids Corticosteroids work very quickly to suppress inflammation and reduce flare-ups Corticosteroids should NOT be used for maintenance therapy Budesonide has a high ratio of local anti-inflammatory to systemic effect due to an extensive first pass metabolism Administered orally in a controlled-release formulation designed to release in the terminal ileum or the colon depending on the product This results in a decrease in systemic effects and systemic adverse effects

47. Patient Counseling F or Mesalamine and Hydrocortisone Enema Administration An enema is a procedure introducing liquid into the rectum and colon through the anus Enemas are most commonly used as laxatives to relieve constipation or to deliver medication to the rectum and colon for inflammatory bowel disease

48. How to Use an Enema Shake to mix (particularly mesalamine and hydrocortisone enemas because they are suspensions) Remove the cap/cover from the applicator tip Hold the bottle at the neck so you don’t accidently squeeze out any medication

49. How to Use an Enema (Administration) Get into appropriate position (either of the following positions) Lie on the floor on left side with right knee bent This is the most comfortable position and hence the one most patients prefer Lie on floor on stomach and then bring both knees to chest For enemas used for IBD, specifically mesalamine and hydrocortisone enemas, it is recommended to Remain in the position the enema was administered in for at least 30 minutes to allow the thorough distribution of the medication Retain the enema all night (preferably 8 hours), if possible Hence, these enemas are typically administered at bedtime

50. Immunomodulators MOA Immunosuppressive actions through a variety of mechanisms Agents Azathioprine Mercaptopurine Methotrexate Cyclosporin

51. Azathioprine (AZA) and Mercaptopurine (6-MP ) Are effectively used in long-term treatment of both UC and CD Generally reserved for patients who fail 5-ASA therapy or are refractory to or dependent on corticosteroids May be used in conjunction with 5-ASAs, corticosteroids, and TNF-inhibitors Are indicated for IBD maintenance therapy due to a long onset of action Onset of action can range from a few weeks to up to 12 months before benefits are seen

52. Methotrexate (MTX) Useful for the treatment and maintenance of CD; data supporting use in UC is lacking Cyclosporine Used in severe flares of IBD not responding to IV corticosteroids Poses a risk of nephrotoxicity and neurotoxicity

53. Tumor Necrosis Factor (TNF) Inhibitors MOA Inhibits endogenous TNFα. Elevated levels of TNFα have been found in involved tissues of various disease states including CD and UC. Biological activities of TNFα include the induction of proinflammatory cytokines, enhancement of leukocyte migration, activation of neutrophils and eosinophils , and the induction of acute phase reactants and disease degrading enzymes. Indicated for both CD and UC Moderate to severe active disease Maintenance therapy in moderate to severe disease Fistulizing disease Agents Infliximab Adalimumab Certolizumab Golimumab

54. Other Biologics: Natalizumab MOA A humanized monoclonal antibody that targets integrin molecules expressed on the cell surface of leukocytes. Integrins bind to vascular receptors in the gut, allowing leukocytes to migrate across the vacular endothelium. Natalizumab blocks this process and inhibits the inflammatory cascade. Indication: Induction and maintenance treatment of CD refractory to conventional therapies and TNF inhibitors .

55. Other Biologics: Vedolizumab MOA reduces chronically inflamed gastrointestinal parenchymal tissue associated with ulcerative colitis and Crohn disease by binding specifically to the alpha-4-beta-7-integrin receptor and blocking its interaction with mucosal addressing cell adhesion molecule-1. This inhibits the movement of memory T-lymphocytes across the endothelium into inflamed gastrointestinal tissue Indications: Induction and maintenance in adults with moderate to severe active UC and CD who have had an inadequate response with, lost response to, or were intolerant to a TNF inhibitor or immunomodulator ; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids .

56. Drug Brand Name Initial Dose (g) Usual Range Sulfasalazine Azulfidine Azulfidine EN 500 mg-1 g 500 mg-1 g 4-6 g/day 4-6 g/day Mesalamine suppository Rowasa 1 g 1 g daily to three times weekly Mesalamine enema Canasa 4 g 4 g daily to three times weekly Mesalamine (oral) Asacol HD Apriso Lialda Pentasa Delzicol 1.6 g/day 1.5 g/day 1.2-2.4 g/day 2 g/day 1.2 g/day 2.8-4.8 g/day 1.5 g/day once daily 1.2-4.8 g/day once daily 2-4 g/day 2.4-4.8 g/day Olsalazine Dipentum 1.5 g/day 1.5-3 g/day Balsalazide Colazal 2.25 g/day 2.25-6.75 g/day Azathioprine Imuran, Azasan 50-100 mg 1-2.5 mg/kg/day Cyclosporine Gengraf Neoral , Sandimmune 2-4 mg/kg/day IV 2-8 mg/kg/day oral 2-4 mg/kg/day IV Agents for the Treatment of Inflammatory Bowel Disease

57. Agents for the Treatment of Inflammatory Bowel Disease Mercaptopurine Purinethol 50-100 mg 1-2.5 mg/kg/day Methotrexate No branded IM injection 15-25 mg IM weekly 15-25 mg IM weekly Adalimumab Humira 160 mg SC day 1 80 mg SC 2 (day 15), and then 40 mg every 2 weeks Certolizumab Cimzia 400 mg SC 400 mg SC weeks 2 and 4, and then 400 mg SC monthly Infliximab Remicade 5 mg/kg IV 5 mg/kg weeks 2 and 6, 5-10 mg/kg every 8 weeks Natalizumab Tysabri 300 mg IV 300 mg IV every 4 weeks Budesonide Enterocort EC, Uceris 9 mg 6-9 mg daily Vedolizumab Entyvio 300 mg IV 300 mg IV weeks 2 and 6 and then every 8 weeks Golimumab Simponi 200 mg SC 100 mg SC weeks 2 and 4

58. Drug(s) Adverse Drug Reaction Monitoring Parameters Comments Sulfasalazine Nausea, vomiting, headache Rash , anemia, pneumonitis Hepatotoxicity, nephritis Thrombocytopenia, lymphoma Folate, complete blood count, Liver function tests, Scr , BUN Increase the dose slowly, over 1-2 weeks Mesalamine Nausea, vomiting, headache GI disturbances Corticosteroids Hyperglycemia, dyslipidemia Osteoporosis, hypertension, acne Edema, infection, myopathy, psychosis Blood pressure, fasting lipid panel, Glucose , vitamin D, bone density Avoid long-term use if possible or consider budesonide Azathioprine / mercaptopurine Bone marrow suppression, pancreatitis Complete blood count Liver dysfunction, rash, arthralgia Scr , BUN, liver function tests, genotype/phenotype Drug Monitoring Guidelines

59. Drug Monitoring Guidelines Methotrexate Bone marrow suppression, pancreatitis Complete blood count, Scr, BUN Check baseline pregnancy test Pneumonitis, pulmonary fibrosis, hepatitis Liver function tests Chest x-ray Infliximab Infusion-related reactions (infliximab), infection Blood pressure/heart rate (infliximab) Need negative PPD and viral serologies Adalimumab Heart failure, optic neuritis, demyelination, injection site reaction, signs of infection Neurologic exam, mental status Certolizumab Lymphoma Trough concentrations (infliximab) Natalizumab Vedolizumab Infusion-related reactions Brain MRI, mental status, progressive multifocal leukoencephalopathy Vedolizumab not associated with PML

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