15 - Inflammatory Bowel Disease (IBD) Flashcards
Define IBD
chronic inflammatory disorder of the GI tract
List two types of IBD
CD: Crohn’s disease
UC: Ulcerative colitis
What is indeterminate colitis ?
features of both CD and UC
Describe the pathophysiology of IBD
-genetic predisposition with infectious and immunological responses involved
Ulcerative Colitis:
Where is it confined to ?
- bowel wall
- GI tract involvement confined to terminal ileum, colon and rectum
- will only go as far as the ileum
Ulcerative Colitis:
What is almost always affected?
rectum almost always affected (>95%) then progresses proximally
Crohn’s Disease:
Describe it.
- extensive destruction of bowel wall
- invasion of adjacent tissues
- any part of the GI tract may be involved
- colon + another site in 2/3 of patients
List some other organs involved in IBD
Many organs involved. May or may not be related to disease activity.
- Eye
- Skin & joints
- Liver
- Psychological (depression and anxiety)
Crohn’s:
Classic signs?
- RLQ tenderness
- painful with masses
- diarrhea with low grade fever
UC:
Classic signs?
- RECTAL BLEEDING
- diarrhea
- no masses or specific tenderness
Crohn’s:
Lifetime risk of a ___ is 30%
fistula
UC:
high risk of _____ _____
rectal cancer
Goals of therapy for IBD?
- 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
Non-pharms for IBD
1) Avoid precipitants:
- NSAIDs: increase risk of CD ulcers and colitis (but may still be used)
- Constipating drugs in severe UC
- Smoking: helps UC, worsens CD
2) Nutrition:
- malnutrition is common
- some foods trigger abdominal pain
- lactase deficiency due to active inflammation (CD)
3) Surgery
How does smoking affect UC
helps it
How does smoking affect CD
worsens it
*stopping smoking is as good as any drug therapy for CD
How does constipating drugs affect IBD?
*constipating drugs can cause colon to expand 4-5 times it’s size and you lose ability to regulate balance and if it perforates, it has a very high mortality rate
How does inflammation cause lactase deficiency ?
Inflammation can shed lactase enzyme and produce temporary lactose intolerance
*easy way to tell is just to see if you tolerate dairy
Describe surgery for Crohns
-generally reserved for strictures and obstructions as there is an increased risk of CD recurrence at surgical site
Describe surgery for UC
- “cured” with a colectomy
- some post op issues (ex. pouchitis)
List the options for drug therapy
- Aminosalicylates
- Corticosteroids
- Immunomodulators (ex. Azathoprine)
- Cytokines (ex. Infliximab)
Aminosalicylates:
List 2 examples
- sulfasalazine
- 5-ASA (mesalamine)
Aminosalicylates:
MOA
May be a few ways they act:
- PGs
- decrease cytokines
- free radical scavenging
Aminosalicylates:
How much sulfasalazine is equivalent to 5-ASA ?
1g sulfasalazine = 400 mg 5-ASA
Aminosalicylates:
Describe the metabolism of sulfasalazine
- diazo bond cleaved by bacteria
- turned into sulfapyridine which is rapidly absorbed into circulation from colon
- sulfapyridine is responsible for adverse effects
Aminosalicylates:
SE of sulfasalazine
Many dose and phenotypic related:
- fever, fatigue, headache, n/v/d, dyspepsia
- allergic reactions (SJS rash)
- hematologic: hemolysis, agranulocytosis, thrombocytopenia
- drug interactions
Aminosalicylates:
Describe the absorption of Melamine (5 ASA)
- 25% absorbed from colon
- rest passes through colon unchanged
Aminosalicylates:
List 2 examples of 5-ASA products and where they target
1) Asacol: released in terminal ileum
2) Pentasa: 40% released in small bowel. Increased diarrhea
Aminosalicylates:
What is good about Pentasa (5 ASA) ?
can open capsules which is good if you’re putting it into a feeding tube
Aminosalicylates:
Is Asacol or Pentasa better than the other?
Doesn’t seem to matter which 5-ASA product you use, they all seem to work
Aminosalicylates:
Are NOT _____ inhibitors
cox 2
Aminosalicylates:
What forms do they come in?
oral, enemas, suppositories
*all act topically
Aminosalicylates:
Other than enemas, no clear signs has additive effects to _____
steroids
Aminosalicylates:
Common to use higher doses for ?
CD or bad UC
Aminosalicylates:
Most common SE
Less than with sulfasalazine
Most common SE: flatulence, ab pain, nausea, diarrhea, headache
Aminosalicylates:
List 2 clinical pearls
1) Can give any of the QID 5-ASA tabs or caps as a single daily dose (ex. asacol as 800mg QID or 3200mg once daily) despite what the product monographs say
2) Can give 5-ASA (non-acetylated salicylate) in a patient with an ASA (aspirin) allergy
Aminosalicylates:
____ weeks should be enough time to assess their clinical response (and need to modify tx)
4-8
Aminosalicylates:
With oral formulation, can try to decrease dose to ___ g/day if doing well. Lower doses not recommended.
2
Aminosalicylates:
If they fail _____ g of one agent, it is not recommended to try a different 5-ASA product.
After ensuring adherence, pick a different agent
4.8
Aminosalicylates:
Why do we ensure adherence?
Bc once you move past the 5-ASA products, they are associated with big time toxicities and you don’t want to use these agents unless absolutely necessary
Aminosalicylates:
How effective are they for UC?
- induce remission in 20%
- decrease relapse rate in 1/2 patients from 60% to 20%
- most effective in a more DISTAL disease
Aminosalicylates:
How effective are they for CD?
- benefit is in the colon (>3 years)
- with ideal disease data supporting use is soft-perhaps 10% better than placebo
Topical Corticosteroids:
Suppositories for _____
proctitis (inflammation of rectum and anus)
Topical Corticosteroids:
Enemas for ?
-left sided (sigmoid/rectum) disease
- lie on left side then on right side for 20 min HS
- mostly for UC not controlled with 5-ASA
- faster onset
Topical Corticosteroids:
When are they used in UC ?
mostly mild-mod left sided disease not controlled with 5-ASA - recommend an enema or suppository
Topical Corticosteroids:
When are they used in CD ?
- decent data with budesonide MMX in mild-mod right side colonic and ideal disease
- many are using it first line for induction in ideal-colonic CD
- problem is maintaining remission with it alone
- in UC, the MMX is an alternate 1st line induction Tx
Systemic Corticosteroids:
Role in IBD ?
- backbone of initial induction Tx for mod-severe UC & CD (or 5-ASA failures in UC)
- better for flares, up to 60-90% response in UC
Systemic Corticosteroids:
most common one?
prednisone
Systemic Corticosteroids:
What IV corticosteroids are used for severe/hospitalized cases?
- hydrocortisone
- methylprednisolone
Systemic Corticosteroids:
onset of action
Quick: see within a few days to 1 week
In outpatient setting, re-evaluate patient within 2 weeks
Systemic Corticosteroids:
Once you get a response, _____ the dose
taper (ex. 5mg/week)
Systemic Corticosteroids:
In severe disease, if fail 1 ____ of steroids, look to use the big guns
week
Systemic Corticosteroids:
Are they good long term?
Not good long term to prevent relapse though many CD patients can’t get off of them
Systemic Corticosteroids:
What is affected with long term use?
bones, eyes, muscles
Azathioprine & 6-MP:
MOA
Inducing T cell apoptosis may be important mechanism of how it works
Azathioprine & 6-MP:
Role in IBD ?
- helps induce & maintain remission in up to 2/3 of patients with CD or UC
- also heals fistulas
Azathioprine & 6-MP:
onset ?
slow onset, need > 3 month trial
Azathioprine & 6-MP:
Risk of _____ when discontinued
relapse
Thiopurine Methyltransferase (TPMT):
What is it?
- major regulator of 6 TG concentration
- low TPMT activity leads to preferential metabolism to 6 TG (i.e. increase efficacy and toxicity)
- enzyme activity is genetically determined (polymorphism)
- homozygous low TPMT < 1%
- heterozygous low TPMT 10%
- high TPMT 90%
TMPT Testing Issues
- TPMT testing becoming a standard of care in GI guidelines
- There are 17 mutant alleles
- Genotyping done by most labs is only for the 3 most common ones. Other ones are considered “rare”
- Esp. important in Inuit and other populations
- Functional Assay available in WPG ($70/test). Problem with it is in pt with recent blood transfusion
- If they had a blood transfusion, they will have other ppl’s RBC’s and may have normal TPMT when in fact their own RBCs have low TPMT
- Have to wait 3 months til RBC dies
Side effect of AZA/6-MP (azathioprine) ?
-Severe myleosuppression
How do we test for severe myleosuppression that can be caused by AZA/6-MP ?
- genetic testing for TPMT activity in 41 CD patients with severe myleosuppression on AZA/6-MP
- can’t rely on on TPMT testing alone to predict who will have severe myleosuppression
- Still need to check RBC and WBC regularly
What is a severe interaction ?
-Azathioprine & Allopurinol
Azathioprine & 6-MP:
Major SE ?
- neutropenia, atypical infections, pancreatitis, skin rash
- small increase in malignancies (lymphomas) in CD
Azathioprine & 6-MP:
Monitoring?
- CBCs weekly for 1st month then q2w for months 2-3, then monthly
- monitor for infections
- generally no PJP prophylaxis unless also on high dose steroids
- monitor for pancreatitis (mostly in first 6 weeks, watch for new abdominal or back pain and vomiting)
Methotrexate is an ______
immunomodulator
MTX is primarily for ___
CD
MTX has similar results to ____
AZA (except for combo with TNF where trial not positive for extra efficacy combo)
Is MTX recommended for UC ?
not recommended yet
*consider if intolerant or refractory to AZA
MTX has a ____ onset compared to AZA
faster
*still need at least 1 month trial
Do you give MTX to pregnant patients?
nope
MTX Dosing regimen
no set standard dosing regimen
we start with 25mg IM x 16 weeks then switched to oral
SE of MTX ?
- neutropenia
- atypical infections
- liver dysfunction
- pneumonitis
Cyclosporine:
Role in IBD ?
- for severe active UC refusing surgery or are bad surgical risks
- also used to bridge patients to AZA/6-MP
Cyclosporine:
___% of patients on cyclosporine need a colectomy
50
Cyclosporine:
Dose
Given 2mg/kg/day IV for 7-14 days then orally for 3-6 months
Cyclosporine:
Serious long term SE ?
renal, lipids, BP
Cyclosporine:
Limit use in UC to __ months
6
Bc prednisone doesn’t work we recommend surgery, if they refuse, try an ?
anti-TNF
What are some anti-TNFs ?
- Adalimumab
- Certolizumab
- Golimumab
- Infliximab
- Ustekinumab
- Vedolizumab
Infliximab:
MOA
- Antibody that binds to tumor necrosis factor
- Also induces T cell apoptosis
Infliximab:
Used in ?
IBD and rheumatoid arthritis
Infliximab:
Role in IBD ?
used in severe active or fistulizing CD disease or active UC
Infliximab:
Best data for ?
inducing remission in fistulizing Crohn’s perianal closure rate
Infliximab:
Dosing regimen ?
3 doses of 5mg/kg at 0, 2 and 6 weeks
*usually see response at end of 1st week
Maintenance:
-dosed 5mg/kg q8 weeks (range of 4-12 weeks)
Infliximab:
If not responding to induction doses, what do you do?
no benefit in continuing into maintenance therapy with the same agent
Infliximab:
If not responding to first agent, can you try another agent?
there is evidence of benefit in trying another one though response is lower than in the anti-TNF naive
Infliximab:
SE?
-nausea, URT infections, GI pain
- infections (impairment of immune system - TB reactivation)
- too rapid closure of fistulas
*sometimes will put a string through the fistula to keep it a little bit open and allow drainage ?
Infliximab:
Long term issues ?
- infections - Tb
- malignancies
- lupus like syndromes
- demyelinating: optic neuritis, MS
- hematologic - WBC, PLT, pancytopenia
- hepatic
- lymphomas in kids & young adults
- leukemias in adults, adolescents and children
- new onset psoriasis
Describe allergic rxns of Infliximab ?
Allergic reactions - acute and delayed hypersensitivity
Infusion-related reactions - most commonly include:
- headache
- dizziness
- flushing
- pruritus
- dyspnea
Infliximab antibodies develop to _____ component
murine
*yet you will still see antibody formation in non-murine anti-TNF agents (ex. adalimumab)
____ infliximab increases risk of antibodies
intermittent
How does antibody formation affect infliximab?
- impact on effectiveness of infliximab is important
- loss of response or need to increase dose/frequency
For the reason of antibody formation, usually won’t start Infliximab unless patient also aggress to go on ______. Also pretreat with _____ if just starting tx.
AZA/6MP
steroids
Some questions for the pharmacist about anti-TNFs?
- Has pt previously been exposed to anti TNF ?
- Is pretreatment steroids required ?
- Has a Mantoux Test (or CXR), baseline, LFTs and hepatitis viral studies been performed recently ?
CXR = chest x ray
List some supportive therapies
Antidiarrheals:
- Loperamide, Codeine: prior to playing sports to decrease ileostomy drainage
- Should always stop temporarily when CD deteriorates quickly
- In UC, ok in mild - moderate disease but never in severe disease as increased risk of toxic megacolon
-Cholestyramine: For bile salt related diarrhea - terminal ileum disease/resection in CD
What drugs induce remission in UC ?
- Aminosalicylates (with mild-mod disease)
- Corticosteroids (backbone therapy for inducing remission)
- Cyclosporine
- Anti TNF
- vedolizumab
What drugs maintain remission in UC ?
- Aminosalicylates (with mild-mod disease)
- Azathioprine, 6-MP, maybe MTX
- Anti TNF
- vedolizumab
look at algorithms on page 11
ok
Monitoring for UC ?
- scoring systems of disease activity available and usually recommended (ex. Mayo score)
- rectal bleeding and diarrhea, frequency of stools/day, can they make it to the bathroom in time ?
- anemia, low albumin, increased ESR, fever, ab pain
- adherence important
What drugs induce remission in Crohn’s ?
- corticosteroids
- anti TNFs
What drugs maintain remission in Crohn’s?
- aminosalicylates?
- budesonide ?
- azathioprine, 6 MP, methotrexate
- anti TNF
- metronidazole, ciprofloxacin
Monitoring for Crohn’s ?
- Heterogenous features
- Heal fistula, decrease diarrhea and abdominal pain - frequency & severity
- weight, hemoglobin, endoscopic features
- frequency of needing supportive therapy (ex. number of loperamide tabs per week)
- frequency of missing work or school
IBD (UC and Crohn’s) are common ______ diseases.
autoimmune
____ is the backbone of mild-mod UC
5-ASA
Many patients with advanced IBD need ______ and/or _______
immunosuppressives and/or cytokines
