10/13- Management of IBD Flashcards
Goals of IBD Therapy?
- Induce clinical remission
- Maintain remission
- Enhance quality of life
- Avoid long-term toxicity
What types of drugs should be given as severity increases?
(Low severity -> high severity)
- Salicylates
- Steroids
- Immunosuppressives
- Transplant meds
- Infliximab
How should flare ups be treated? Remission?
Flare:
- Cyclosporine??
- New biologics?
- Anti-adhesion Tx?
- Anti-TNFs
- Steroids
- Salicylates
Remission:
- Anti-adhesion molecules
- Anti-TNFs
- Immunosuppressives
- Salicylates
New goals of therapy? Benefits
Mucosal Healing not Clinical Remission
- Predicts Clinical Remission
- Fewer hospitalizations, surgeries
- Prevents Complications of Crohn’s Disease
- Fewer penetrating complications (fistula, abscess)
- Less steroid, anti-TNF rx
- Lower colectomy rates in UC
- Reduces Risk of Colon Cancer
Possibly Reverse the Natural History
New strategies for therapy?
Top down vs. bottom up
- If you flip the pyramid and start with big guns…
Pros:
- May reverse natural history
Cons:
- Not everyone may need the big drugs
- Cost, complications
In flipped pyramid model, what drugs do you start with? End with?
1st level:
- CyA
- Infliximab
2nd level:
- MTX
- AZA/6-MP
- Systemic steroids
3rd level:
- Budesonide
- Antibiotics
- 5-ASA
What factors correspond to the risk of progression in CD?
- Smoking
- Severe initial presentation
- Perianal disease
- Extra intestinal manifestations
- Younger age of onset
- If steroids required
- Stricture/penetrating phenotype (compared to inflammatory)
Sustained remission of IBD with therapy STRONGLY depends on what?
Adherence
What factors play into adherence?
Treatment-Related Factors
- Dosage/dosing regimen
- Formulation
- Cost/reimbursement
- Adverse effects
Illness-Related Factors
- Severity, extent, duration of disease
- Frequency and intensity of flare-ups
- Complications
Patient-Related Factors
- Skills/knowledge to follow regimen
- Belief systems
- Psychiatric disorders
- Male gender, nonmarried status
What is Mesalamine?
2nd generation (1st gen = Sulfasalazine)
Topical
- Suppositories
- Enemas
Describe delivery/absorption of Mesalamine?
- Sulfapyridine component prevented from absorption/degradation in proximal GIT (released in proximal colon -> hepatic circulation)
- 5-ASA portion released in colon to provide therapeutic benefit
Toxicity of 5-ASA vs. Sulfasalazine
- Why is sulfa still used?
Only sulfa:
- Male infertility
- Hemolytic anemia
- Agranulocytosis
Sulfa >> 5-ASA
- Rash, fever, headache, nausea
- Dyspepsia
- Neutropenia
- Hepatitis
Both:
- Alveolitis
- Pancreatitis
5- ASA:
- Nephritis
Sulfa used because it’s ~ 1/100 the cost
Systemic corticosteroids can be used to treat IBD.
What forms are used? When? What forms?
Oral
- Indications: moderate/severe ulcerative colitis or Crohn’s disease
- Preparations: prednisone, prednisolone, budesonide
Parenteral:
- Indications: severe/toxic ulcerative colitis or Crohn’s disease
- Preprations: hydrocortisone, methylprednisone, corticotropin (ACTH)
Results/efficacy of corticosteroids in Ulcerative Colitis?
At 1 mo:
- Complete remission (51%)
- Partial remission (31%)
- No response (18%)
At 1 yr:
- Prolonged response without steroids (55%)
- Steroid dependent (17%)
- Surgery (21%)
Results/efficacy of corticosteroids in Crohn’s Disease?
At 1 mo:
- Complete remission (5%)
- Partial remission (26%)
- No response (16%)
At 1 yr:
- Prolonged response without steroids (32%)
- Steroid dependent (28%)
- Surgery (28%)
Differing opinions in regards to using steroids….
Internists- use steroids!
Gastroenterologists- avoid steroids!
- Complications, side effects
- Tipping point
- Exit strategy
What are downsides of steroids?
- Osteopenia
- Infections
- Hypeglycemia
- HTN
- ACNE
- Moon facies, Buffalo hump
- Insomnia
- Mood changes
What are some immunosuppressive treatments for IBD?
- 6- mercaptopurine
- Azathioprine
- Methotrexate
Characteristics of 6-mercaptopurine and azathioprine?
- Onset
- Uses
- ASEs
- Slow onset of action
- Effective for maintenance and steroid sparing
- Monitoring enzyme activity
- Monitoring drug levels
ASEs:
- Allergic reaction
- GI disturbances
- Hepatotoxicity
- Infection
- Pancreatitis
- Bone marrow suppression
- Malignancy/lymphoma (?)
Characteristics of Methotrexate?
- Onset
- Uses
- Form
- Faster acting than 6MP/Azathioprine
- Maintenance therapy for Crohn’s disease
- Only parenteral rx is proven effective
What is the AZA metabolite pathway? Significance?
AZA -> 6MP
- Some portion of the population is missing a critical enzyme (?)
- May wipe out bone marrow
What are biologics?
Examples of some used for IBD?
Monoclonal Antibodies Anti-TNFs:
- Infliximab (CD and UC)
- Adalimumab (CD and UC)
- Certolizumab (CD)
- Golilumumab (UC)
Anti-interleukin 12/23
- Ustekinumab (CD)
Anti-integrins
- Natalizumab
- Vedolizumab
Uses of Anti-TNFs?
- Downsides
- Examples
Effective in Treating Flares
- May Maintain Remission
- Treats Fulminant Colitis (= cyclosporine) and Crohn’s disease
Downsides
- Cost
- Side Effects
Examples:
- Infliximab (CD and UC)
- Adalimumab (CD and UC)
- Certolizumab (CD)
- Golilumumab (UC)
Adverse effects of biologics?
- Autoimmunity, immunogenicity
- Congestive heart failure
- Hepatotoxicity
- Malignancy/lymphoma (?)
- Demyelinating disease, PML
- Infection (TB, histo, granulomatous diseases…)
- BM suppression
- Infusion reactions, injection site reactions
How well do anti-TNFs work? Compared to AZA? Combo?
Combo was best for remission
- Infliximab + AZA => 57% remission
- Infliximab alone => 44% remission
- AZA alone => 31% remission
Combo was best for mucosal healing
- Infliximab + AZA => 44% healing
- Infliximab alone => 30% healing
- AZA alone => 17% healing
What is the theory behind using anti-adhesion therapies for IBD? List the meds used
Prevent firm adhesion/diapedesis of WBCs to control inflammation involved in IBD (anti-integrin)
Meds used:
- Natalizumab
- Vedolizumab
- Etrolizumab
What are the significant adhesion molecules being targeted?
CNS: a4B1 integrin
- VCAM-1
Gut: a4B7 integrin
- MadCAM-1
The following agents work on what integrin targets?
GI specific? PML risk?
- Natalizumab
- Vedolizumab
- Etrolizumab
- PF-00547659
What are surgical options in ulcerative colitis?
Colectomy cures UC!
- Brooke ileostomy
- Koch ileostomy: make pouch with continent ileostomy (drain pouch a few times a day; no bag)
- J pouch: functions as new rectum (most common now) (but people don’t always like this option)
Alternatives:
- Conventional ileostomy
- Continent ileostomy
- Ileo-anal anastamosis with J-pouch
Save lives… not colons
Weighing medical therapy vs. surgery risks
Medical therapy:
- Serious infection
- Lymphoma
- Bone marrow suppression
- Other toxicities: hepatic, neurologic, cardiac
Surgery:
- Postsurgical complications: anastamotic leak, cuffitis, bowel obstructions, fistulas, Crohn’s disease, pelvic sepsis
- Reoperation
- Pouchitis
- Reduced fecundity/fertility
Key point: both have risks
What are surgical options in Crohn’s disease?
- NOT curative (unlike ulcerative colitis)
- Specific goals:
- Obstruction
- Abscess
- Medical failure
- Recurrence usually at anastamosis
What are big risks of therapy with Mesalamine, steroids, immunomodulators, and biologics?
- Infection
- Lymphoma (HSTCL)
Increased risk of lymphoma with what patient characteristics?
- Age
- Males
- IBD history
Increased risk of Hepatosplenic T-cell lymphoma with what patient characteristics?
Prognosis?
- Almost always in young males
- Usually fatal
What IBD treatment has the highest risk for infection?
(Most -> Least)
- Infliximab, 4.4RR (Histo)
- IMM, 3.8RR (Herpes)
- Steroids, 3.3RR (Candida)
- ASA (1.0 risk ratio)
Corticosteroid use is higher than all of these, and narcotic analgesics are even higher
What is mortality risk of Crohn’s disease?
1.5
What is omission bias?
People tend to worry more about a low risk of harm from something they do than a higher risk of harm from doing nothing (think vaccinations)
What is the risk of developing Non-Hodgkin’s Lymphoma in a patient with Crohn’s disease?
- What about if the pt receives 6MP or Azathioprine?
- What about receiving combo anti-TNF and immunomodulator?
- 2/10,000 treated patients annually
- 4/10,000 treated patients annually receiving 6MP or Azathioprine
- 6/10,000 treated patients annually receiving combo anti-TNF and immunomodulator
What is the risk of developing PML with Natalizumab?
- 10/10,000 pts with Crohn’s disease and/or MS
Characteristics of different IBD drugs:
- Acute vs. Long term
- Safety
- Mucosal healing
FOR
- ASA
- Steroid
- 6MP/AZA/mtx - Mabs
What is the role of nutritional therapy in IBD?
- When to use
- Alternatives
Nutrition support as proven therapy
- TPN may suppress symptoms, but relaps occurs upon refeeding
- EN is less effective than glucocorticosteroids
Treat with EN or TPN if:
- “Malnourished” and cannot maintain oral intake
- Short bowel syndrome unable to maintain fluid/energy balance
- Growth failure
Limited goals and benefits for both TPN and EN (enteral nutrition)
Alternative/Complementary rx is common in IBD patients
- Most evidence for circumin, from the turmeric plant (think curries)
- Marijuana
