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Flashcards in 10/13- Management of IBD Deck (41)
1

Goals of IBD Therapy?

- Induce clinical remission

- Maintain remission

- Enhance quality of life

- Avoid long-term toxicity

2

What types of drugs should be given as severity increases?

(Low severity -> high severity)

- Salicylates

- Steroids

- Immunosuppressives

- Transplant meds

- Infliximab

3

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

4

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

5

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

6

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

7

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)

8

Sustained remission of IBD with therapy STRONGLY depends on what?

Adherence

9

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

10

What is Mesalamine?

2nd generation (1st gen = Sulfasalazine)

Topical

- Suppositories

- Enemas

11

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 

12

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

13

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)

14

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%)

15

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%)

16

Differing opinions in regards to using steroids....

Internists- use steroids!

Gastroenterologists- avoid steroids!

- Complications, side effects

- Tipping point

- Exit strategy

17

What are downsides of steroids?

- Osteopenia

- Infections

- Hypeglycemia

- HTN

--------------

- ACNE

- Moon facies, Buffalo hump

- Insomnia

- Mood changes

18

What are some immunosuppressive treatments for IBD?

- 6- mercaptopurine

- Azathioprine

- Methotrexate

19

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 (?)

20

Characteristics of Methotrexate?

- Onset

- Uses

- Form

- Faster acting than 6MP/Azathioprine

- Maintenance therapy for Crohn's disease

- Only parenteral rx is proven effective

21

What is the AZA metabolite pathway? Significance?

AZA -> 6MP

- Some portion of the population is missing a critical enzyme (?)

- May wipe out bone marrow 

22

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

23

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) 

24

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

25

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

26

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

27

What are the significant adhesion molecules being targeted?

CNS: a4B1 integrin

- VCAM-1

Gut: a4B7 integrin

- MadCAM-1

28

The following agents work on what integrin targets?

GI specific? PML risk?

- Natalizumab

- Vedolizumab

- Etrolizumab

- PF-00547659

29

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

30

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

31

What are surgical options in Crohn's disease?

- NOT curative (unlike ulcerative colitis)

- Specific goals:

  • Obstruction
  • Abscess
  • Medical failure

- Recurrence usually at anastamosis

32

What are big risks of therapy with Mesalamine, steroids, immunomodulators, and biologics?

- Infection

- Lymphoma (HSTCL)

33

Increased risk of lymphoma with what patient characteristics?

- Age

- Males

- IBD history

34

Increased risk of Hepatosplenic T-cell lymphoma with what patient characteristics?

Prognosis?

- Almost always in young males

- Usually fatal

35

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

36

What is mortality risk of Crohn's disease?

1.5

37

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)

38

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

39

What is the risk of developing PML with Natalizumab?

- 10/10,000 pts with Crohn's disease and/or MS

40

Characteristics of different IBD drugs:

- Acute vs. Long term

- Safety

- Mucosal healing

FOR

- ASA

- Steroid

- 6MP/AZA/mtx - Mabs

41

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