17 - IBD Flashcards
1
Q
What are the types of inflammatory bowel disease?
A
- Crohn’s and ulcerative colitis -> based on pathophysiology
- Indeterminate colitis: features of both CD and UC; make up 15% of IBD
2
Q
Describe the pathophysiology of IBD
A
- 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
3
Q
Ulcerative colitis
A
- 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
4
Q
Crohn’s disease
A
- 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
5
Q
Extra-intestinal manifestations of CD
A
- 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
6
Q
Classic features of IBD
A
- 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
7
Q
Prognosis of IBD
A
- 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)
8
Q
Goals of therapy for IBD
A
- 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
9
Q
Non-drug therapy for IBD
A
- 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)
10
Q
Surgery for IBD
A
- 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)
11
Q
Drug therapy options for IBD
A
- Aminosalicylates
- Corticosteroids
- Immunomodulators (ex: azathioprine)
- Cytokines (ex: infliximab)
12
Q
Aminosalicylates – types and MOA
A
- Sulfasalazine and 5-ASA (mesalamine)
- May act in a few ways:
- Prostaglandins
- Decrease cytokines
- Free radical scavenging
13
Q
Sulfasalazine – MOA, SE, and AE
A
- 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
14
Q
Mesalamine (5 ASA)
A
- *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
15
Q
Use of aminosalicylates (formulation, indication, and SE)
A
- 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
16
Q
Aminosalicylates – clinical pearls
A
- 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
17
Q
Aminosalicylates – efficacy in IBD
A
- 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)
18
Q
Topical corticosteroids for IBD
A
- 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
19
Q
Systemic corticosteroids for IBD
A
- 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
20
Q
Azathioprine & 6-mercaptopurine – MOA, onset, interaction
A
- 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
21
Q
Thiopurine methyltransferase (TPMT)
A
- 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
22
Q
TPMT testing issues
A
- 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)
23
Q
AZA and 6-MP – SE and monitoring
A
- 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
24
Q
Immunomodulators – methotrexate for IBD
A
- 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
25
Q
Anti-TNFs for IBD
A
- 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
26
Q
Pivotal anti-TNF trials
A
- 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
27
Q
Anti-TNFs – clinical pearl
A
- 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
28
Q
Infliximab SE
A
- Nausea, URT infections, GI pain
- Infections
- Impairment of immune system (TB reactivation)
- Too rapid closure of fistulas
29
Q
Hepatosplenic T-cell lymphomas
A
- 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
30
Q
Infliximab – Ab formation
A
- 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
31
Q
Supportive therapies – antidiarrheals for IBD
A
- 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
32
Q
Which agents induce remission in UC?
A
- Aminosalicylates (w/ mild to moderate disease)
- Corticosteroids
- Cyclosporine
- Anti-TNF (all 3)
- Vedolizumab
33
Q
Which agents maintain remission in UC?
A
- Aminosalicylates (w/ mild to moderate disease)
- AZA, 6-MP, maybe MTX
- Anti-TNF (all 3)
- Vedolizumab
34
Q
Monitoring UC
A
- 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)
35
Q
Which agents induce remission in CD?
A
- Corticosteroids
- Anti-TNFs
36
Q
Which agents maintain remission in CD?
A
- Aminosalicylates?
- Budesonide?
- AZA, 6-MP, MTX
- Anti-TNFs
- Metronidazole, cipro (sometimes in ileal or colonic CD)
37
Q
Monitoring CD
A
- 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
