Inflammatory Bowel Disease (IBD)

Transcription

1 Inflammatory Bowel Disease (IBD) Pharmacotherapy 3 for PharmD Prof. Nailya Bulatova, MD, PhD Fall

2 References DiPiro. Inflammatory Bowel Disease Koda-Kimble. Lower Gastrointestinal Disorders Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology (ACG), Practice Parameters Committee. Am J Gastroenterol 2010; 105: ACG Guideline: Management of Crohn s Disease in Adults. Am J Gastroenterol advance online publication, 6 January

3 Definition: Crohn s Disease (CD) chronic transmural patchy granulomatous inflammatory disease can involve entire GI tract, from mouth to anus discontinuous ulceration (socalled skip lesions ) fistula formation perianal involvement. Applied Therapeutics;Koda-Kimble, 3

4 Definition: CD (cont d) - Colonic Involvement is variable; however terminal ileum is most commonly affected. - Intestinal involvement is characteristically segmented & can be interrupted by areas of normal tissues. Presentation usually with one of three patterns: Predominantly inflammatory. Stricturing Fistulizing. Disease course is variable. Years of frequent relapses may be followed by complete remission. Applied Therapeutics;Koda-Kimble 4

5 Definition: CD 5

6 Definition: Ulcerative colitis (UC) UC is a chronic disease characterized by diffuse mucosal inflammation limited to colon. It involves rectum in ~95% of cases & may extend proximally in symmetrical, circumferential, & uninterrupted pattern to involve parts or all of large intestine. Hallmark clinical symptom is bloody diarrhea often with prominent symptoms of rectal urgency & tenesmus. 6

7 Epidemiology of IBD The reported rates of IBD are highest in Scandinavia, Great Britain, & North America. CD prevalence: per 100,000 people. UC prevalence: per 100,000 persons. M=F Peaks in 20 s-30 s, & s, Western hemisphere has higher incidence Jews>; orientals & blacks - lowest incidence 7

8 Proposed etiologies of IBD 8

9 Pathophysiology- UC is confined to colon & rectum (in some instances, short segment of terminal ileum may be inflamed) affects primarily mucosa & submucosa primary lesion occurs in crypts of mucosa as crypt abscess fistulas, perforation, or obstruction are uncommon because inflammation is usually confined to mucosa & submucosa local complications (involving colon) occur in the majority of UC patients relatively minor complications include hemorrhoids, anal fissures, or perirectal abscesses 9

10 Pathophysiology- UC Major complication: toxic megacolon, severe condition that occurs in up to 8% of UC patients admitted to hospitals & 50% dies- Usually high fever, tachycardia, distended abdomen, elevated white blood cell count, & dilated colon. Risk of colonic carcinoma is much > in patients with UC as compared with general population. ~11% of patients with UC have hepatobiliary complications including fatty liver, pericholangitis, chronic active hepatitis, cirrhosis, sclerosing cholangitis, cholangiocarcinoma, & gallstones. 10

11 Pathophysiology- UC Arthritis commonly occurs in IBD patients & is typically asymptomatic & migratory Arthritis typically involves one or a few large joints such as knees, hips, ankles, wrists, & elbows Ocular complications (iritis, episcleritis, & conjunctivitis) occur in up to 10% of patients. 5-10% of patients experience dermatologic or mucosal complications (erythema nodosum, pyoderma gangrenosum, aphthous stomatitis). 11

12 Figures: Pyoderma gangrenosum Erythema nodosum 12

13 Figures: Aphthous Stomatitis 13

14 Pathophysiology- CD CD is transmural inflammatory process terminal ileum is the most common site, but disorder may occur in any part of GI tract ~2/3 of patients have some colonic involvement, & 15-25% of patients have only colonic disease Patients often have normal bowel separating segments of diseased bowel (disease is often discontinuous) Small-bowel stricture (> common than in UC) & subsequent obstruction is complication that may require surgery Fistula (enterocutaneous & enterovesicular) formation is common & occurs much > frequently than with UC 14

15 Pathophysiology- CD Systemic complications of CD are common & similar to those found with UC. Arthritis, iritis, skin lesions, & liver disease often accompany CD Nutritional deficiencies are common Increased renal stones formation 15

16 Comparison of CD & UC 16

17 Exacerbating Factors for IBD Intercurrent infections (upper respiratory tract, enteric) Smoking (Crohn s only) Non-steroidal anti-inflammatory drugs? Stress 17

18 Diagnosis of IBD Clinical signs/symptoms Upper/lower GI endoscopy/biopsy Radiology 18

19 Clinical Presentation Both UC & CD are characterized by waxing & waning course over many years. There is highly variable presentation between patients There is overlap between two conditions, with small fraction of patients showing features of both diseases. 19

20 Clinical Presentation of UC 20

21 Clinical Presentation- UC Mild disease (2/3 of patients) < 4 stools daily ± blood no systemic disturbance & normal ESR Moderate disease (1/4 of patients) >4 stools per day minimal systemic disturbance 21

22 Clinical Presentation- UC Severe disease > 6 stools per day with blood, systemic disturbance: fever, tachycardia, anemia, or ESR > 30 Fulminant disease > 10 bowel movement daily continuous bleeding toxicity abdominal tenderness & distension blood transfusion requirement colonic dilation 22

23 Clinical Presentation- CD as with UC, presentation is highly variable single episode may not be followed by further episodes other patients may experience continuous, unremitting disease patient may present with diarrhea & abdominal pain or perirectal or perianal lesion Course of CD is characterized by periods of remission & exacerbation 23

24 Clinical Presentation of CD 24

25 CD With colonic involvement diarrhea & pain most common complaint blood much less common fistula, fissures, perirectal abcesses, arthritis more common With small bowel involvement fatigue weight loss right lower quadrant pain diarrhea fever anorexia nausea, vomiting 25

26 Nutritional Deficiencies in CD weight loss, growth failure in children, iron deficiency anemia, vitamin B12 deficiency, folate deficiency, hypoalbuminemia, hypokalemia, osteomalacia, usually decreased fat stores & lean tissue.

27 ACG grading of CD Individual is in symptomatic remission (usually corresponding to CDAI < 150) when that patient is asymptomatic or without any symptomatic inflammatory sequelae. Individuals who require use of conventional corticosteroids to achieve clinical well-being are said to be steroid dependent & are not considered to be in remission.

28 ACG grading of CD (cont d) Individuals with mild moderate disease (usually corresponding to CDAI ) are ambulatory able to tolerate oral alimentation without manifestations of: - dehydration, - systemic toxicity (high fevers, rigors, prostration), - abdominal tenderness, - painful mass, - intestinal obstruction, - or >10 % weight loss.

29 ACG grading of CD (cont d) Individuals who are considered to have moderate severe disease (usually corresponding to CDAI ) are considered to have failed to respond to treatment for mild moderate disease, or those with more prominent symptoms of: - fever, - significant weight loss, - abdominal pain or tenderness, - intermittent nausea or vomiting (without obstructive findings), - or significant anemia.

30 ACG grading of CD (cont d) Individuals who are considered to have severe / fulminant disease (usually corresponding to CDAI >450) are patients with persistent symptoms despite introduction of conventional corticosteroids or biologic agents (infliximab, adalimumab, certolizumab pegol, or natalizumab) as outpatients, or individuals presenting with: - high fevers, - persistent vomiting, - evidence of intestinal obstruction, - significant peritoneal signs such as involuntary guarding or rebound tenderness, - cachexia, - or evidence of an abscess.

31 DESIRED OUTCOME induce remission maintain remission avoid or resolve complications of disease alleviate of systemic manifestations surgical palliation 31

32 Approach to treatment Principle & type of treatment is determined by: severity- mild, moderate & severe. location (terminal ileum, colon, rectum) type (inflammatory, fistulizing & fibrostenotic) 32

33 GENERAL APPROACH Treatment of IBD centers on agents used to relieve inflammatory process. Salicylates, glucocorticoids, antimicrobials, & immunosuppressive agents such as azathioprine & mercaptopurine are commonly used to treat active disease &, for some agents, to lengthen time of disease remission. In addition to drugs, surgical procedures are sometimes performed when active disease is not adequately controlled or when required drug dosages pose an unacceptable risk of adverse effects 33

34 Nutritional Support Patients with moderate to severe disease IBD are often malnourished. The nutritional needs of majority of patients can be adequately addressed with enteral supplementation. Patients who have severe disease may require course of parenteral nutrition. Probiotic formulas have been effective in maintaining remission in ulcerative colitis. 34

35 Surgery For UC, colectomy may be performed when patient has disease uncontrolled by maximum medical therapy or when there are complications such as colonic perforation, toxic dilatation (megacolon), uncontrolled colonic hemorrhage, or colonic strictures. Indications for surgery with CD are not as well established as they are for UC, & surgery is usually reserved for complications of disease. 35

36 Drug Therapies for IBD Supportive agents Antidiarrheal Bile sequestrants Bulk formers Antidepressants Pain management Anti -spasmodics Aminosalicylates Sulfasalazine Mesalamine Olsalazine Balsalazide Antibiotics Metronidazole Quinolones Rifaximin Other Corticosteroids Prednisone / Prednisolone Budesonide ACTH Immunomodulators 6MP / Azathioprine Methotrexate Cyclosporine Anti -TNF 36

37 Miscellaneous Drugs Antidiarrheals Loperamide, diphenoxylate, codeine Avoid in acute attacks (toxic megacolon) Iron Avoid in acute attacks Cholestyramine Bile salt-assoc. Acid-suppressing (in CD) H2RAs, sucralfate or PPIs 37

38 Sulfasalazine (SASP) Mechanism of Action: Is cleaved by colonic bacteria to sulfapyridine (which is mostly absorbed & excreted in urine) & mesalamine (5-ASA, which mostly remains in colon & is excreted in stool). Aminosalicylates may block production of prostaglandins & leukotrienes, inhibit bacterial peptide-induced neutrophil chemotaxis & adenosineinduced secretion, scavenge reactive oxygen metabolites, inhibit activation of nuclear regulatory factor NF- B. 38

39 SASP (cont d) Sulfasalazine is often used initially before oral mesalamine derivatives when expense is an issue; however, it is not tolerated as well as mesalamine alternatives. Clinical Use: UC: initial maintenance tx good if concurrent arthritis (DMARD) Crohn s: initial tx (colitis+ileocolitis only) good in concurrent arthritis (as above) (? maintenance) 39

40 SASP (cont d) Adverse Effects 10-45% incidence (*sulfapyridine*) Dose-related: N, V, anorexia, dyspepsia, HA, oligospermia, esp. during 1 st 8-12 wk of tx Not dose related: rash, fever, hepatotoxicity, hematologic, neuropathy, bloody diarrhea, 40

41 SASP (cont d) Dosing 1-6 gm/day in 2-4 divided doses (adults): (4-6 gm/day acute, 1-4 gm/day maintenance) mg/kg/day in 2-4 divided doses (peds) Give folate to prevent anemia Pregnancy & lactation not contraindication 41

42 Oral Salicylates 5-ASA delivery systems via: 1. Coated forms: Pentasa, Asacol, 2. Conjugation to itself: Olsalazine (Azodisalicylate) 3. Conjugation to inert carrier Balsalazide 42

43 Mesalamine Derivatives for IBD Treatment 43

44 Sites of action of various agents used for IBD treatment

45 5-ASA Therapies Clinical Use UC: as effective as SASP with fewer ADR Less effective than oral CS CD: may induce remission in ileal & colonic dz & be steroid-sparing, may prevent relapse (i.e. maintenance tx) & be steroid-sparing (primarily in ileal & colonic dz) 45

46 Oral Salicylates UC + CD Initial Dosing mesalazine 2-6 g/d, balsalazide 6.75 g/d, olsalazine g/d Maintenance dosing mesalazine 1-2 g/d, balsalazide 2.5 g/d, olsalazine 1.5 g/d 5-ASA colon cancer risk in UC (SASP does not) 46

47 Oral Salicylates (cont d) Adverse Effects: Beware cross-reactivity with SASP (20%)! Nephrotoxicity with Asacol Secretory diarrhea, esp. with olsalazine (slow dose titration, give with meals) No oligospermia +++ expensive 47

48 Oral Salicylates (cont d) 5-ASA drug are very safe Headaches 12% Abdominal pain 11% Nausea & vomiting 8% Back pain Dizziness 6% Arthritis / arthralgia 6% 48

49 Topical Salicylates 5-ASA, 4-ASA UC only: 1. Supps-rectum 2. Foam-proximal sigmoid colon 3. Enemas-splenic flexure 4. Superior to placebo, topical steroids, oral salicylates in remission induction 5. Similar to oral salicylates in maintenance of remission 6. Active dz: 1-4g /d, maintenance 1g/d thrice weekly Crohn s-few data, probably less effective Best to use PR alone or PR + PO salicylate in combo for active distal dz 49

50 (RowasaR) 5-ASA, oral, suppository, or retention enema. Not more efficacious than sulfasalazine, but may be better tolerated. Dose 500 mg suppository BID for 3-6 weeks. Retain suppository for 1-3 hours for maximum benefit. 4 gm via rectal suspension enema QD for 3-6 weeks. Bedtime is preferred time of administration to provide 8 hour retention time 50

51 Use of steroids Revolutionized management of severe dz in UC & CD Excellent medication for induction of remission. Topical, IV, oral preps available Give high dose & taper off slowly. E.g. Prednisone 40 mg/day for 2 weeks then reduce by 5 mg every week Used if mesalamine derivatives fail Oral agents are not initial choices for mild-moderate disease No role in maintenance of remission Avoid using corticosteroids for more than 3 months especially in children 51

52 Use of steroids (cont d) Budesonide is administered orally in controlled-release formulation designed to release in terminal ileum. Undergoes extensive first-pass metabolism; so systemic exposure is thought to be minimized Steroids are effective in the treatment of active, distal UC. However, rectal mesalamine is more effective than rectal steroids for inducing remission

53 Corticosteroids (cont d) Clinical use UC acute Tx 1. Proctitis, use local steroids (enema/foam)+oral SASP/5-ASA 2. Mild dz, PO prednisone (20 mg/d)+local steroid x 4wks, then taper (1/8-1/6 per week) 3. Mod. dz, PO prednisone (20-40mg/d)+local steroid X 6 wks, then taper as above 4. Severe dz, IV (1-2mg/kg/d methylprednisolone) with failures to surgery UC maintenance Tx: ineffective in maintaining remission Crohn s: as UC 53

54 54

55 Antimicrobials (CD or severe-fulminant UC only) Metronidazole (Flagyl) 1. Crohn s colitis or ileocolitis (800 mg bid), perianal dz (10-20 mg/kg/d), pouchitis (ileal reservoir) 2. Delays recurrence + decr. severity of Crohn s after ileal resection (20mg/kg/d) 3. No role in UC 4. AE-nausea, metallic taste, alcohol intolerance, neuropathy in 50% with long-term use. D-D interactions 5. Can use in pregnancy 55

56 Immunosuppressives 6-mercaptopurine, azathioprine (6-MP, AZA) Clinical use UC: induce & maintains remission & steroid-sparing CD: induce & maintain remission, fistulas close, steroidsparing, requires 4-6 months to show effect Equieffective in UC + CD 56

57 6-MP & AZA These agents are generally reserved for patients who are refractory to or dependent upon corticosteroids. Must be used for extended periods of time, ranging from a few weeks up to 12 months, before benefits may be observed. Early use of azathioprine in combination with infliximab for patients with CD who are naive to treatment with immunosuppressive agents or corticosteroids improves outcomes versus use of these agents individually

58 Immunosuppressives: AZA & 6-MP (cont d) Recommendations for UC If pt. prefers medical tx prior to surgery & failed other med. modalities CS toxicity, continuous CS-(>15 mg/d > 6 months) needed, needs 2 courses of CS/yr. or relapse within 6 wk of D/C CS Universal dz, continually active & hasn t had dz long enough to be at carcinoma risk 58

59 Immunosuppressives; AZA & 6-MP (cont d) Recommendations for Crohn s Chronic, active dz unresponsive to SASP/ASA, steroids, metronidazole (abscesses, SBO) Steroid toxicity & continuous steroids needed Fistulae present Prior to extensive surgery Maintenance of remission 59

60 Immunosuppressives; AZA & 6-MP (cont d) Active CD: Use for induction of remission -AZA mg/kg/day -6MP mg/kg/day Slow to act. effect in about 3-4 months? Useful in fistulous disease. Maintenance of remission after medically or surgically induced remission. -Do not reduce dose used to achieve remission -Keep patient on AZA for a long time while tapering steroids. 60

61 Immunosuppressives; AZA & 6-MP (cont d) Continue AZA/6MP for up to 4-5 years before considering stopping. They are steroid sparing After steroid use no need to continue 5-ASA with AZA 5-ASA are useful as chemoprevention against colorectal cancer in UC patients 61

62 Toxicity of AZA/6MP Overall 14% Severe GI SE Pancreatitis 3-15% Bone marrow suppression (neutropenia) Hepatitis Drug allergy Malignant neoplasm-ebv+ lymphoma Pregnancy: use at time of conception not indication for abortion (transplant data), prefer contraception during & for 3 mo. following tx Allopurinol interaction! 62

63 6-MP & AZA Serious ADRs: lymphomas, pancreatitis, or nephrotoxicity. Predisposition to development of these ADRs may be related to polymorphisms in enzyme thiopurine methyl transferase (TPMT), which is partially responsible for activation & metabolism of these drugs. FDA recommends that patients be tested for TPMT genotype & phenotype (activity) prior to initiating therapy to identify patients that may have reduced TPMT activity & thus be at risk for toxicity. Adjusting AZA & 6-MP doses by measuring concentrations of metabolites, particularly 6-thioguanine (6-TGN), may be useful, with higher levels associated with greater remission rates.

64 Methotrexate(MTX) Used in similar way to AZA/6MP No use in UC Given IV or IM 25 mg/week, cheap induces & maintains remission? Works faster than 6-MP/AZA & in 6-MP/AZA nonresponders Best as maintenance tx folic acid supplementation - 1mg po QD ADR: bone marrow, pulmonary Major drawbacks: 1.Teratogenic-avoid in anybody considering pregnancy 2.Hepatic fibrosis. 64

65 Cyclosporine Severe, chronic, active UC failing CSc (IV) No role in maintenance tx (use PO bridge to AZA, 6- MP, MTX, etc. Does not cause bone marrow suppression. Dose 2-4 mg/kg/day IV (continuous infusion) for 15 days. Low dose oral regimens have not been shown to be beneficial. 65

66 Infliximab (Anti-TNF alpha Antibody) Rescue of fulminant UC in single dose but no role in maintenance (yet) 30% do not respond at all + not all responders respond fully Predictors of response: - active inflammation ( CRP), - nonstricturing dz, - pure colonic dz, - early in dz course, - concurrent immunosupp. tx Adults (peds need RCTs) 66

67 Infliximab Tx of moderate-severe active CD in pts with inadequate response to conventional tx (5 mg/kg IV X 1 dose only) use single dose today only for rescue Tx of enterocutaneous fistulizing CD (5 mg/kg X 3 doses: 0, 2, 6 weeks only) Maintenance of CD (10 mg/kg every 8 weeks for 32 weeks) - only in AZA/6-MP/MTX failures CS-sparing 67

68 Infliximab (cont d) AE: infusion rx, hypersensitivity rx, autoimmunity, immunosuppression Devel. antibodies (murine protein) ( response), immed. infusion rxs, serum sickness-like or delayed infusion rx (if latter, change to fully human anti-tnftx)) HA Infections Same MoA as thalidomide, so avoid in pregnancy TB risk-screen before use, INH (start 2 mo. before) Drug-induced lupus, lymphoma Avoid live attenuated vaccines within 3 months of Tx exacerbations of congestive heart failure 68

69 Other biologic therapies Adalimumab is also IgG1 antibody to TNF- α; however, it is fully humanized & contains no murine sequences: may cause less antibody development seen with use of infliximab. Can be administered SC. Is a treatment option for patients with moderate to severe active CD previously treated with infliximab who have lost response. Certolizumab pegol is humanized pegylated Fab fragment directed against TNF-α, used SC Demonstrates similar efficacy to adalimumab & infliximab. Natalizumab: novel agent that inhibits leukocyte adhesion & migration by targeting 4 integrin. Can be used in CD for patients who are unresponsive to other therapies, including corticosteroids & TNF-α inhibitors.

70 Other biologic therapies (cont d) Vedolizumab Vedolizumab is a humanized anti-alpha-4- beta-7 integrin monoclonal antibody. Vedolizumab was approved by the US FDA in May 2014 for use in patients with moderate to severe Crohn disease or ulcerative colitis. Used as 300 mg IV doses at week 0 and 2 for induction therapy For maintenance of remission, in case of clinical response at six weeks, vedolizumab was used eother every eight weeks, or four weeks, for up to 52 weeks. 70

71 Other biologic therapies (cont d) Investigational! Ustekinumab Ustekinumab is a human IgG 1k monoclonal antibody that blocks the biologic activity of IL-12 and IL-23 by inhibiting receptors for these cytokines on T cells, natural killer cells and antigen presenting cells. In a phase II trial, it was tried in patients with moderate to severe Crohn disease Larger studies are needed to establish the efficacy of ustekinumab in patients with moderate to severe Crohn disease that is resistant to TNF antagonists. 71

72 Immunosuppressive, immunomodulator & biologic therapies for IBD

73 73

74 Mild-to moderate UC treatment

75 Moderate-to-severe UC treatment 75

76 Steroid-resistant UC treatment 76

77 Maintenance of Remission Major agents used for maintenance of remission are sulfasalazine & mesalamine derivatives; Steroids should be gradually withdrawn after remission is induced (over 3-4 weeks). Sulfasalazine also appears to be more effective in maintaining remission compared with newer agents, such as olsalazine. For patients with distal disease or proctitis, mesalamine enemas or suppositories are considered first-line agents (every third night) Combination of topical & oral mesalamine is superior to either regimen alone for maintenance therapy. Azathioprine is effective in preventing relapse of UC for periods of up to 2 years. However, 3-6 months may be required for beneficial effect. 77

78 Nicotine Cochrane systematic review of transdermal nicotine in active UC identified five relevant studies. While less effective than aminosalicylates, transdermal nicotine in daily doses of mg may improve symptoms for patients with mild to moderate active UC, particularly for patients who are ex-smokers, & can be considered as adjunctive therapy in both distal & extensive disease HW: Fecal microbial transplant in UC?

79 CD Treatment

80 (cont d) 80

81 Interventions for CD Oral 5-ASA are effective for mild to moderate ileal, ilealocolonic, or colonic active disease (D) Metronidazole may be effective in patients not responding to sulfasalazine (D) Ileal release budesonide is effective for mild to moderate ileal or right-sided colonic disease (A) Topical hydrocortisone is effective for distal colonic inflammation (A) Systemic corticosteroids are effective in moderate to severe active disease (A) Systemic corticosteroids are not effective for patients with perianal fistulas (c)

82 Interventions for CD (cont d) Hospitalization for parenteral steroids is indicated for patients with severe disease or those failing to respond to oral steroids (A) Parenteral MTX is effective for induction of remission in patients with active disease & for reducing corticosteroid dependency (B) Infliximab, adalimumab, & certolizumab are effective for moderate to severe disease in those patients not responding to corticosteroids or immunosuppressive agent (A) Infliximab & adalimumab are effective for those patients with fistulas who have not responded to antibiotics, immunosuppressive agents, or surgical drainage (A) High-dose oral cyclosporine (7.6 mg/kg) has short-term efficacy in patients with active disease (B) IV cyclosporine is effective for treatment of fistulizing disease (B)

83 Interventions for CD (cont d) Corticosteroids are not effective as maintenance treatment (A) Budesonide is effective as short-term maintenance therapy (3 months) but not long term (A) AZA, 6-MP, or infliximab are effective in lowering or eliminating corticosteroid use in corticosteroid-dependent patients (A) AZA, 6-MP, or infliximab may be effective in patients with severe disease flares or those requiring retreatment with corticosteroids within 1 year (A)

84 Interventions for CD (cont d) AZA, 6-MP is effective for maintenance of remission regardless of disease distribution (A) AZA or 6-MP may be effective for treating perianal or enteric fistulae (A) MTX maintenance therapy (15 25 mg IM weekly) is effective for patients whose active disease has responded to IM methotrexate (A) MTX 25 mg IM for up to 16 weeks followed by 15 mg IM weekly is effective for patients with chronic active disease (A) Infliximab, adalimumab, & certolizumab therapy is effective for maintenance if there is initial response (A)

85 Treatment of severe-to-fulminant CD Hospitalization is required Therapy for patients with severe or fulminant disease should consist of bowel rest, parenteral nutrition, and intravenous glucocorticoids. If an abdominal mass is present, broad spectrum antibiotics are also indicated. Patients who do not respond to steroids may require treatment with biologic therapy. 85

86 VENOUS THROMBOEMBOLISM in IBD Studies have demonstrated an increased risk of venous thromboembolism in patients with IBD Current guidelines recommend prophylaxis for venous thromboembolism or consideration of prophylaxis for hospitalized patients with IBD HW: Probiotics in IBD? (from 86

87 EVALUATION OF THERAPEUTIC OUTCOMES patient-reported complaints, signs & symptoms, direct physician examination (including endoscopy), history & physical examination, selected laboratory tests, quality of life measures. 87