17 - IBD

Question 1

What are the types of inflammatory bowel disease?

Answer 1

• Crohn’s and ulcerative colitis -> based on pathophysiology

- Indeterminate colitis: features of both CD and UC; make up 15% of IBD

Question 2

Describe the pathophysiology of IBD

Answer 2

• Genetic predisposition w/ infectious and immunological responses involved
• Keys in CD include:
• • NOD 2 gene on chromosome 16 (carriers of 2 copy of risk alleles have CD risk 20-40x normal population)
• • NF KB

Question 3

Ulcerative colitis

Answer 3

• Disease confined to bowel wall
• Rectum almost always affected then progresses proximally
• • Initial sx can include urgency or pain when passing bowel movement
• GI tract involvement confined to terminal ileum, colon and rectum

Question 4

Crohn’s disease

Answer 4

• Extensive destruction of bowel wall; invasion of adjacent tissues
• Any part of GI tract may be involved (mouth to rectum); most common in colon + another site
• Can occur in patchy segments; have sections of healthy bowel in between affected areas

Question 5

Extra-intestinal manifestations of CD

Answer 5

• Many organs involved; may or may not be related to disease activity
• Eye -> iritis, uveitis
• Skin and joints -> arthritis
• Liver -> increased LFTs in 40%; rarely severe
• Psychological -> depression, anxiety

Question 6

Classic features of IBD

Answer 6

• Crohn’s -> RLQ tenderness, painful w/ masses, diarrhea w/ low grade fever
• Ulcerative colitis -> rectal bleeding and diarrhea, no masses or specific tenderness
• • Bloody diarrhea is almost always either an infectious cause (from recent travel) or UC

Question 7

Prognosis of IBD

Answer 7

• Crohn’s -> some px only have one attack; more common for px to have combination of years in relapse or remission in first 8 years after diagnosis
• UC -> relapses frequent (50-70% in 1 year w/o therapy); higher risk for rectal cancer (over decades)

Question 8

Goals of therapy for IBD

Answer 8

• Control acute flares
• Induce remission
• Maintain remission
• Avoid or manage complications
• Can be very individualized in Crohn’s
• Location, severity, previous response to therapy involved in the selection

Question 9

Non-drug therapy for IBD

Answer 9

• Avoid precipitants, such as:
• • NSAIDs – increase risk of CD ulcers, colitis (may still be used, but if causes a flare then stop taking)
• • Constipating drugs in severe UC
• • Smoking -> helps UC, worsens CD
• Nutrition
• • Malnutrition common in moderate to severe disease (especially Crohn’s)
• • Some foods may trigger abdominal pain
• • Lactase deficiency due to active inflammation (CD)

Question 10

Surgery for IBD

Answer 10

• Crohn’s -> MB data suggests 20% need resection at 5 years, 40% at 20 years
• • 1/3 of those need another surgery in the next 10 years
• • Generally reserved for strictures and obstructions as there is an increased risk of CD recurrence at surgical site
• UC = “cured” w/ a colectomy; some post-op issues (ex: pouchitis)

Question 11

Drug therapy options for IBD

Answer 11

• Aminosalicylates
• Corticosteroids
• Immunomodulators (ex: azathioprine)
• Cytokines (ex: infliximab)

Question 12

Aminosalicylates – types and MOA

Answer 12

• Sulfasalazine and 5-ASA (mesalamine)
• May act in a few ways:
• • Prostaglandins
• • Decrease cytokines
• • Free radical scavenging

Question 13

Sulfasalazine – MOA, SE, and AE

Answer 13

• Diazo bond cleaved by bacteria
• Sulfapyridine rapidly absorbed into circulation from colon
• SE = fever, fatigue, headache, N/V, diarrhea, dyspepsia; many are dose related; occur in about 30% of px
• Adverse effects:
• • Allergic reactions – rashes (SJS)
• • Hematologic – hemolysis, agranulocytosis, thrombocytopenia
• • Drug interactions

Question 14

Mesalamine (5 ASA)

Answer 14

• *Backbone of mild to moderate UC
• About 25% absorbed from colon; rest passes through colon unchanged
• Products to target different sites:
• • Asacol -> released in terminal ileum
• • Pentasa -> 40% released in small intestine; increases diarrhea
• Don’t really worry which one is used

Question 15

Use of aminosalicylates (formulation, indication, and SE)

Answer 15

• Oral, enemas, suppositories (all act topically)
• Enema or suppository preferred 1st line agents w/ distal UC
• Other than enemas, no clear signs that it has additive effects to steroids
• For mild to moderate UC -> combo of oral and rectal used as an alternative 1st line induction
• For CD or severe UC, common to use 2-4-fold higher doses
• SE -> less w/ 5 ASA (mesalamine) than w/ sulfasalazine; most common = flatulence, abdominal pain, nausea, diarrhea, headache

Question 16

Aminosalicylates – clinical pearls

Answer 16

• Can give any of the QID 5-ASA or capsules as a single daily dose despite what product monographs say
• Can give 5-ASA (non-acetylated salicylate) in a pt w/ ASA allergy and in px w/ sulfa allergy (as opposed to sulfasalazine)
• 4-8 weeks should be enough time to assess their clinical response (and need to modify tx)
• With oral, can try to decrease dose to 2 g/day if doing well; lower doses not recommended
• If fail 4.8 g of one agent, not recommended to try a different 5-ASA product -> pick a different agent
• Always look closely at adherence

Question 17

Aminosalicylates – efficacy in IBD

Answer 17

• UC -> induce remission in about 20%; decrease relapse rate in ½ px; most effective in more distal disease
• CD -> benefit in the colon; w/ ileal disease, data supporting use is soft (perhaps 10% better than placebo)

Question 18

Topical corticosteroids for IBD

Answer 18

• Suppositories for proctitis
• Enemas for left sided (sigmoid/rectum) disease
• • Mostly for UC mild to moderate left sided disease not controlled w/ 5-ASA (enema or suppository); faster onset but inferior
• In CD, decent data w/ budesonide MMX in mild to moderate right side colonic and ileal disease; often used 1st line for induction in ileal/ colonic CD
• • Problem = maintaining remission w/ it alone
• • In UC, MMX is an alternative 1st line induction tx

Question 19

Systemic corticosteroids for IBD

Answer 19

• Backbone of initial induction tx for moderate to severe UC and CD (of 5-ASA failures in UC)
• Better for flares, up to 60-90% response in UC
• Prednisone almost exclusively used
• Severe (hospitalized) cases = IV (hydrocortisone, methylprednisolone)
• Quick onset -> see effect w/in few days to 1 week; in outpatient setting, re-evaluate pt w/in 2 weeks
• Don’t taper too fast once you get a response
• In severe disease, if fail 1 week of steroids look to other agents
• Not good long-term to prevent relapse though many CD px can’t get off them

Question 20

Azathioprine & 6-mercaptopurine – MOA, onset, interaction

Answer 20

• Induce T-cell apoptosis, might be important mechanism of how it works
• Helps induce and maintain remission in up to 2/3 of px w/ CD or UC; also heals fistulas
• Allow 25-55% elimination of steroids
• Slow onset, need at least 3-month trial (1 month to start working and 3 months to see full effect, therefore need something to bridge them until it kicks in if pt has active disease; commonly use prednisone for this)
• Risk of relapse when discontinued
• Azathioprine broken down into 6-mercaptopurine
• *Big interaction w/ azathioprine is allopurinol

Question 21

Thiopurine methyltransferase (TPMT)

Answer 21

• Major regulator of 6-TG concentration
• Low TPMT activity leads to preferential metabolism to 6-TG (ie: increased efficacy and toxicity)
• Enzyme activity is genetically determined (polymorphism)
• *Some people can be poor metabolizers of azathioprine

Question 22

TPMT testing issues

Answer 22

• Testing becoming a standard of care in GI guidelines
• Genotyping done by most labs is only for 3 most common alleles; other 14 are considered “rare”
• Especially important in Inuit and other populations
• Problem = px w/ recent blood transfusion
• Can’t rely on TPMT testing alone to predict who will have severe myelosuppression (still have to follow CBCs)

Question 23

AZA and 6-MP – SE and monitoring

Answer 23

• Major SE = neutropenia, atypical infections, pancreatitis, skin rash
• • Small increase in malignancies (lymphomas) in CD
• CBCs – weekly for 1st month then q2weeks for month 2-3 then monthly
• Atypical infections occur later; generally, no PJP prophylaxis unless also on high dose steroids
• Pancreatitis -> mostly in first 6 weeks; watch for new abdominal or back pain, vomiting

Question 24

Immunomodulators – methotrexate for IBD

Answer 24

• Primarily for CD
• Similar results to AZA (except for combo w/ TNF)
• Not recommended yet for UC; consider if intolerant or refractory to AZA
• Somewhat faster onset than AZA, but still need at least a 1-month trial
• No set standard dosing regimen
• Major SE = neutropenia, atypical infections, liver dysfunction, pneumonitis

Question 25

Anti-TNFs for IBD

Answer 25

- Adalimumab, golimumab, infliximab - Ab binds to tumour necrosis factor; also act by inducing T cell apoptosis - For moderate to severe UC and CD and fistulizing CD - Recommended regimen = induction regimen followed by assessment of response before going on to maintenance tx - Usually see response at end of 1st week

Question 26

Pivotal anti-TNF trials

Answer 26

- SONIC -> established safety and efficacy endpoints of anti-TNF or AZA alone or in combination therapy - STORI -> provided guidance on long-term outcome of px who were d/c’ed anti-TNF after in “deep remission” for at least 1 year

Question 27

Anti-TNFs – clinical pearl

Answer 27

- If not responding to induction doses, no benefit in continuing into maintenance therapy w/ the same agent - If not responding to first agent, there is evidence of benefit in trying another one though response is lower than in the anti-TNF naive

Question 28

Infliximab SE

Answer 28

- Nausea, URT infections, GI pain - Infections - - Impairment of immune system (TB reactivation) - - Too rapid closure of fistulas

Question 29

Hepatosplenic T-cell lymphomas

Answer 29

- Reports showed occurred in very young people (12-31 y/o) & 6 of the 8 cases were fatal - All cases w/ infliximab; all px also taking AZA, 6-MP

Question 30

Infliximab – Ab formation

Answer 30

- Develop to murine component, yet still see Ab formation in non-murine anti-TNF agents (ex: adalimumab) - Impact on effectiveness of infliximab important -> loss of response or need to increase dose/ frequency - Intermittent infliximab use also increases risk of Ab - B/c of this, usually won’t start infliximab unless pt also agrees to go on AZA/6-MP; also pre-treat w/ steroids if just starting tx

Question 31

Supportive therapies – antidiarrheals for IBD

Answer 31

- Loperamide, codeine (ex: prior to playing sports to decrease ileostomy drainage) -> should always stop temporarily when CD deteriorates quickly - - In UC -> ok in mild to moderate disease but never in severe disease as increases risk of toxic megacolon - Cholestyramine for bile salt related diarrhea -> ok for terminal ileum disease/ resection in CD

Question 32

Which agents induce remission in UC?

Answer 32

- Aminosalicylates (w/ mild to moderate disease) - Corticosteroids - Cyclosporine - Anti-TNF (all 3) - Vedolizumab

Question 33

Which agents maintain remission in UC?

Answer 33

- Aminosalicylates (w/ mild to moderate disease) - AZA, 6-MP, maybe MTX - Anti-TNF (all 3) - Vedolizumab

Question 34

Monitoring UC

Answer 34

- Scoring systems of disease activity available and usually recommended - Rectal bleeding and diarrhea, frequency of stools/day - Anemia, low albumin, increased ESR, fever, abdominal pain -> more serious findings - Fever, new abdominal pain -> refer to MD - Adherence very important (especially w/ 5-ASA)

Question 35

Which agents induce remission in CD?

Answer 35

- Corticosteroids | - Anti-TNFs

Question 36

Which agents maintain remission in CD?

Answer 36

- Aminosalicylates? - Budesonide? - AZA, 6-MP, MTX - Anti-TNFs - Metronidazole, cipro (sometimes in ileal or colonic CD)

Question 37

Monitoring CD

Answer 37

- Heterogeneous features - Heal fistula, decrease diarrhea and abdominal pain frequency and severity - Weight, Hgb, endoscopic features - Frequency of needing supportive therapy (ex: # loperamide tabs/week) - Frequency of missing work or school