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Gastroenterology > Crohn's Disease > Flashcards

Crohn's Disease Flashcards

1
Q

What is the difference between infliximab and adalimumab/golimumab as monoclonal antibodies?

A

Infliximab is chimeric

Adalimumab/golimumab are humanized

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2
Q

What are the 4 anti-TNF biologics available for treating IBD?

A
  1. Infliximab (remicade)
  2. Adalimumab (humara)
  3. Golimumab (simponi)
  4. Certolizumab pegol (cimzia)
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3
Q

What is the difference in structure of certolizumab pegol and infliximab/adalimumab/golimumab?

A

Cetolizumab pegol has PEGylated humanized Fab’ fragment, the others are intact IgG antibodies

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4
Q

What are 2 consequences of pegylating certolizumab in terms of pharmacodynamics?

A
  1. Persistence in bloodstream

2. Does not cross the placenta

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5
Q

What are the 2 anti-integrins used to treat IBD?

A
  1. Natalizumab (Tysabri)

2. Vedolizumab (Entyvio)

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6
Q

What is the binding target of Natalizumab (Tysabri)?

A

Alpha-4 integrins

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7
Q

What is the binding target of vedilizumab (Entyvio)?

A

Alpha-4-beta-7 integrin to prevent binding to MAdCAM (mucosal addressin cell adhesion molecule)

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8
Q

Using infliximab, adalimumab or certolimab pegol in Crohn’s disease, what percentage of patients will achieve clinical remission in the first 6-12 weeks of therapy?

A

60%

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9
Q

What are the 3 anti-TNF monoclonal antibodies approved for the treatment of IBD?

A
  1. Infliximab (remicade)
  2. Adalimunab (humara)
  3. Golimumab (Simponi)
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10
Q

Using infliximab, adalimumab or certolimab pegol in Crohn’s disease, what percentage of patients will achieve steroid-free remission at the end of 1 year?

A

25-30%

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11
Q

Using infliximab, adalimumab or golimumab in Ulcerative Colitis, what percentage of patients will achieve clinical remission in the first 8 weeks of therapy?

A

40%

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12
Q

Using infliximab, adalimumab or golimumab in Ulcerative Colitis, what percentage of patients will have steroid-free remission at the end of 1 year?

A

30%

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13
Q

What are the safety concerns/serious sequelae that can occur with anti-TNF therapy? (8)

A
  1. Serious infections
  2. Malignancy (e.g. skin cancer, HSTCL)
  3. Reactivation of TB or Hepatitis B
  4. Psoriatic skin rash (usually on hands and feet)
  5. Autoimmunity (lupus-like syndrome)
  6. Demyelinating disorders (eg multiple sclerosis, Guillan-Barre)
  7. Congestive heart failure
  8. Liver toxicity
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14
Q

What 4 factors drive loss of response to monoclonal anti-TNF antibodies?

A
  1. Low drug levels
  2. Anti-drug antibodies
  3. Other immune pathways driving inflammation
  4. No residual inflammation
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15
Q

Describe the algorithm for evaluating loss of response to anti-TNF therapy?

A
  1. Assess if there is active disease
    2a. If yes, measure drug level and anti-drug antibodies
    2b. If no, assess for other cause of symptoms, e.g. IBS, SBBO, bile acid diarrhea, strictures
    3a. If drug level therapeutic and no ADA, need to use other MOA to treat IBD
    3b. If drug level subtherapeutic and no ADA, need to increase dose or frequency
    3c. If presence of ADA, need to switch to different monoclonal antibody
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16
Q

What is the possible anatomic locations of Crohn’s Disease?

A

Anywhere in the GI tract

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17
Q

What is the estimated prevalence of Crohn’s Disease in the US?

A

500,000

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18
Q

What percentage of patient’s will require surgery within 10 years of initial diagnosis in Crohn’s Disease?

A

63%

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19
Q

What are the 12 quality measures for care of patients with Crohn’s disease, that include the 2011 AGA physician performance measures and the 2013 CCF quality indicators for IBD?

A
  1. Type, anatomic location and activity of IBD documented
  2. Corticosteroid-sparing therapy
  3. Corticosteroid-related bone loss assessment (i.e. DEXA)
  4. Influenza immunization for patients on immunomodulators and/or biologics
  5. Pneumococcal immunization for patients on immunomodulators and/or biologics
  6. Testing for latent TB before starting anti-TNF therapy
  7. Assessing HBV status before starting anti-TNF therapy
  8. Tobacco use screening and cessation counseling
  9. Testing for Clostridium Difficile in IBD patients who develop diarrhea
  10. BMI screening and follow up
  11. Monitoring for medication-related adverse events
  12. Colon cancer surveillance
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20
Q

What are the 2 treatment paradigms for IBD?

A
  1. Step-up

2. Top-down or accelerated step-up

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21
Q

Is smoking a risk factor or a protective factor in Crohn’s disease?

A

Risk factor

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22
Q

What are 6 prognostic factors for aggressive Crohn’s disease?

A
  1. Smoking/tobacco use
  2. Age of onset
  3. Family history
  4. NSAID use
  5. Oral contraceptives use
  6. Genetic markers
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23
Q

Is tumor necrosis factor alpha over-expressed or under-expressed in the GI mucosa of patient’s with Crohn’s disease?

A

Over-expressed

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24
Q

What are 3 general mechanisms that TNF-alpha contributes to intestinal inflammation?

A
  1. Disrupts the epithelial barrier
  2. Induces apoptosis of villous epithelial cells
  3. Induces secretion of chemokines
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25
Q

What is the predominant role of alpha-4 integrin in the gut?

A

Initiate lymphocyte attachment to mucosal surfaces

26
Q

What is the typical sequence of medical therapy in traditional “step-up” therapy in Crohn’s disease?

A
  1. Corticosteroids to initially control active disease and control symptoms
  2. Immunomodulators (azathioprine, methotrexate) if flares persist or Crohn’s disease complications occur
  3. Anti-TNF or anti-adhesion inhibitors as final step if disease uncontrolled with steroids and/or immunomodulators
27
Q

What is the AGA 2013 recommendation for using infliximab in the induction and maintenance of remission in moderate-to-severe active Crohn’s disease?

A

Use in patients who have had an inadequate response to conventional therapy

28
Q

What is the recommended dosing for induction with infliximab?

A

5 mg/kg IV infusion with doses at weeks 0, 2 and 6

29
Q

What is the recommended dosing for maintenance with infliximab?

A

5 mg/kg IV infusion every 8 weeks

30
Q

What is the AGA 2013 recommendation for using adalimumab in the induction and maintenance of remission in moderate-to-severe active Crohn’s disease?

A
  1. Use in patients who have had an inadequate response to conventional therapy
  2. Use in patients who have lost response to or are intolerant to infliximab
31
Q

What is the recommended dosing for induction with adalimumab?

A 
160 mg (4 pens) subcutaneous injection initially
80 mg (2 pens) subcutaneous injection 2 weeks later
32
Q

What is the recommended dosing for maintenance with adalimumab?

A

40 mg (1 pen) subcutaneous injection every 2 weeks

33
Q

What is the AGA 2013 recommendation for using certolizumab pegol in the induction and maintenance of remission in moderate-to-severe active Crohn’s disease?

A

In patients who have had an inadequate response to conventional therapy

34
Q

What is the recommended dosing for induction with certolizumab pegol?

A

400 mg (2 injections) subcutaneously at week 0, 2 and 4

35
Q

What is the recommended dosing for maintenance with certolizumab pegol?

A

400 mg (2 injections) subcutaneously every 4 weeks

36
Q

What is the AGA 2013 recommendation for using natalizumab in the induction and maintenance of remission in moderate-to-severe active Crohn’s disease?

A

In patients with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF

37
Q

What is the recommended dosing for both induction and maintenance with natalizumab?

A

300 mg IV infusion every 4 weeks

38
Q

What are the 3 anti-TNF drugs and 2 anti-adhesion drugs approved for use in Crohn’s Disease?

A

Anti-TNF:

  1. Infliximab (Remicade)
  2. Adalimumab (Humira)
  3. Certolizumab pegol (Cimzia)

Anti-Adhesion:

  1. Natalizumab (Tysabri)
  2. Vedolizumab (Entyvio)
39
Q

What are the 2 main benefits of pegylating the monoclonal antibody fragment in certolizumab pegol?

A
  1. Lessens immunogenicity of the drug, i.e. less anti-drug antibody formation
  2. Longer half-life of the drug
40
Q

What are the more common side effects of anti-TNF drugs?

A
  1. Infusion or injection site reactions

2. Opportunistic infections (TB, HBV)

41
Q

What are the more rare side effects of anti-TNF drugs?

A
  1. Serious infections
  2. Malignancies
  3. Hematologic abnormalities
  4. Demyelination
  5. Worsening of CHF
  6. Drug-induced lupus
  7. Hepatotoxicity
42
Q

Should live vaccines be given during therapy with anti-TNF drugs?

A

No

43
Q

What are the available live vaccines?

A
  1. MMR or MMRV
  2. Herpes Zoster (Shingles)
  3. Influenza intranasal spray
  4. Varicella
  5. Oral adenovirus
  6. Oral polio
  7. Oral Rotavirus
  8. Oral typhoid
  9. Yellow fever
  10. Tuberculosis (BCG)
  11. Vaccinia (small pox)
44
Q

What are the most common side effects of natalizumab?

A
  1. Headache
  2. Fatigue
  3. URIs
  4. Nausea
45
Q

What rare, but serious and potentially disabling or fatal, side effect is possible with natalizumab?

A

Progressive multifocal leukoencephalopathy (PML)

46
Q

What causes progressive multifocal leukoencephalopathy (PML)?

A

Infection of oligodendrocytes by reactivation of JC virus

47
Q

What is the associated risk of PML with nataluzimab?

A

1 in 1000

48
Q

How many cases of PML in a patient with Crohn’s disease in association with natalizumab have been reported?

A

1

49
Q

Should antibody testing for JC virus be done before starting natalizumab?

A

Yes

50
Q

What percentage of patients with Crohn’s disease will fail to respond to anti-TNF therapy initially (primary nonresponders)?

A

Approximately 1/3

51
Q

What percentage of patients with Crohn’s disease will fleetingly response to anti-TNF therapy initially and require a dose increase or a different anti-TNF drug?

A

Approximately 1/3

52
Q

What is the most likely explanation for loss of response in anti-TNF therapy?

A

Development of anti-drug antibodies

53
Q

What are 2 negative consequences associated with anti-drug antibodies?

A
  1. Increased drug clearance rate

2. Increased rate of infusion reactions

54
Q

What can be done to reduce the formation of anti-drug antibodies?

A

Concomitant use of immunomodulators

55
Q

The results of the SONIC and COMMIT trials suggest which immunomodulator is preferred in combination with anti-TNF therapy - azathioprine or methotrexate?

A

Azathioprine

56
Q

What is the recommended induction dosing for vedolizumab?

A

300 mg IV infusion at weeks 0, 2 and 6

57
Q

What is the recommended maintenance dosing for vedolizumab?

A

300 mg IV infusion every 8 weeks

58
Q

What percentage of patient’s with Crohn’s disease will reach remission?

A

Approximately 1/3

59
Q

What is the target of vedolizumab?

A

Alpha-4-beta-7 integrin

60
Q

Why is vedolizumab less likely to cause PML than natalizumab?

A

Vedolizumab targets alpha-4-beta-7 intern, which is responsible for leukocyte trafficking to the gut only, thereby leaving immune surveillance in the CNS intact

Gastroenterology (5 decks)

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