IBD Medical Therapies

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IBD Medical Therapies

• Mark Flasar, M.D., M.S.
• Assistant Professor of Medicine
• Div. of Gastroenterology Hepatology
• University of Maryland Medical Center
• 1 April 2009

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IBD Therapy

• Medical Treatment Goals
• To make you well (remission)
• To keep you well (maintenance)
• To improve your quality of life
• Avoid side effects
• Short term
• Long term
• Dont break the bank!

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Balancing
Cost Side Effects Quality of life Adherence
Effectiveness
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Same, but Same Same, but Different
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Important Questions to Consider Before Beginning
Treatment

• Are the symptoms consistent with IBD?
• Infections (C. difficile)
• Irritable bowel syndrome
• Other forms of colitis
• Where is the disease located?
• How severe are the symptoms?
• Are other factors present?
• NSAIDs
• Lactose Intolerance

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IBD Therapy

• Induction

• Maintenance

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Surgery Clinical Trials anti-TNF
anti-TNF CyA Surgery GI Rest
Systemic Steroids
Systemic Steroids 6-MP/AZA/MTX
anti-TNF (early intervention??)
Topical/rapidly metabolized steroids
5-ASA Antibiotics
Alternative Rx
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PILLS
SUPPOSITORIES
ENEMAS
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Topical/rapidly metabolized steroids
5-ASA Antibiotics
Alternative Rx
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Aminosalicylates (5-ASA)

• Pill, enema, suppository forms
• - Mild-moderate colon UC
• Sulfasalazine (Azulfidine)

• First on the block
• Inexpensive
• Works for some with mild colon disease
• Side effects (10-45)
• Contains SULFA

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5-ASA.the next generation

• Targeted delivery
• Mesalamine
• Asacol, Pentasa
• Lialda
• Apriso
• Olsalazine (Dipentum)
• Balsalazide (Colazal)
• Less side effects (15)
• Dose frequency

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5-ASA Pills
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Antibiotics

• Post-op prevention after surgery
• Crohns limited to the colon
• Perianal Crohns
• Cipro
• Flagyl
• Rifaximin
• Amoxacillin/CA
• Side effects

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Systemic Steroids 6-MP/AZA/MTX
anti-TNF (early intervention??)
Topical/rapidly metabolized steroids
5-ASA Antibiotics
Alternative Rx
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Steroids

• Used since 1950s
• IV, pill, enema forms
• Solu-Medrol
• Hydrocortisone
• PREDNISONE
• VERY effective (2/3)
• Moderate-severe disease
• Remission ONLY
• VERY cheap

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Short and Long Term Response to Prednisone
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Steroids

• Does not prevent flares
• Almost 1/3 patients will not respond
• More than 1/3 will be unable to come off without
  a flare
• SIDE EFFECTS
• You could write a book!

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Fancy Prednisone

• Controlled-release Budesonide (Entocort)
• Locally-acting, slowly-released steroid
• Absorbed by gut, 80-90 cleared by liver
• 10-20 of drug enters circulation
• For Crohns in the ileum/upper colon
• All the potential for prednisone side effects
• Much less frequent
• Much less severe

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Immunomodulators

• Remission (slow)
• MTX in CD
• 6-MP/AZA in CD and UC
• Steroid sparing in both by both
• Prevents flares by both
• 6-MP/Azathioprine (CD and UC)
• MTX (CD alone)
• ? Biologic helper

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Surgery Clinical Trials anti-TNF
anti-TNF CyA Surgery GI Rest
Systemic Steroids
Systemic Steroids 6-MP/AZA/MTX
anti-TNF (early intervention??)
Topical/rapidly metabolized steroids
5-ASA Antibiotics
Alternative Rx
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Anti-TNF Biologic Agents
Mouse
VL
VH
CH1
Ck
Certolizumab pegol Pegylated Humanized FAb
fragment 95 human
Adalimumab Fully Human 100 human IgG1 isotype
Infliximab Chimeric 75 human IgG1 isotype
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Biologic Therapy

• All block key players of IBD inflammation
• Infliximab (Remicade)
• 3-hour IV treatments lifelong
• Mod-severe CD/UC (2/3 respond, 1/3 remission)
• Prevents flares (1/3 at 1 year)
• Adalimumab (Humira) CD only
• Weekly injections (patient-given)
• Certulizumab pegol (Cimzia) CD only
• Monthly injections

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Biologic Therapy

• 75 human, 25 mouse protein
• Allergies possible
• Infection (awaken old TB, blood, overall)
• Lymphoma?
• 1/3 of patients will need higher doses
• 1/3 of patients lose response

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Biologics
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20-30, serious in 3-4
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Anti-Integrins
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Crohns Disease Treatment Algorithm
Crohns Disease
Steroids
Prior AZA
Yes
IFX monotherapy
IFX AZA
OR
6 months
IFX monotherapy
Sandborn, WJ et al. ACG 2008.
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Corticosteroid-Free Clinical Remission at Week 26
100
80
56.8
60
44.4
Proportion of Patients ()
40
30.6
20
52/170
75/169
96/169
0
AZA placebo
IFX placebo
IFX AZA
Sandborn, WJ et al. ACG 2008.
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Crohns Disease Treatment Algorithm
Crohns Disease
Steroids
Prior AZA
Yes
IFX monotherapy
IFX AZA
OR
6 months
IFX monotherapy
Sandborn, WJ et al. ACG 2008.
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Step-up vs Top-down Approach
Hommes D, Baert F, van Assche G, et al.
Gastroenterology. 2006130(suppl 2)A108-A109.
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Odds of

• Dating a millionaire 215 to 1
• Becoming a pro athlete 22,000 to 1
• Winning an academy award 11,500 to 1
• Dying from an injury in the next year 1,820 to 1
• Getting the flu this year 10 to 1
• Getting breast cancer 9 to 1
• Getting prostate cancer 6 to 1

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Thank You
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Top down versus step up Results
Proportion of pts on immunosuppressants
CDAI lt150 AND no steroids AND no surgery
Patients ()
Patients ()



plt0.01plt0.05
Weeks
Weeks
D'Haens G, Baert F, van Assche G, et al. Lancet
2008
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Results IMID
Median IFX levels, Week 8 to Week 104 combined
No need for early rescue IFX primary endpoint
100
plt0.005
10
IFX trough levels (µg)
CONTINUED DISCONTINUED
1
0
Continued
Discontinued
Van Assche G, et al. Gastroenterology 2008
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Serious Adverse Events in Crohns Disease
Clinical Trials
Data on file, Abbott Laboratories
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Safety of infliximab and other Crohns disease
therapies TREAT Registry Data
Serious infections (Multivariate)
Mortality (Multivariate)
plt0.0001
p0.001 plt0.001
Lichtenstein GR, et al. Clin Gastroenterol
Hepatol. 20064621630.
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Risk factors for opportunistic infections in IBD
a case-control study (100 cases, 1983-2003)
Combined use of immunosuppressive drugs increased
risk of opportunistic infections
Toruner M, et al. DDW 2006, Los Angeles. Abstract
489
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What is Hepatosplenic T-cell Lymphoma?

• ?d T lymphocytes represent a normal subset of T
  cells with cytotoxic functions
• ?d T-cell lymphoma (HS?dTCL) described in 1990,
  and HSaßTCL reported in 2000
• Tend to be young, reported in ages 12-58
• Many (but not all) on chronic immunosuppression
• Clinical presentation hepatosplenomegaly
  cytopenias B symptoms no lymphadenopathy
• Diagnosis made on biopsy of liver, spleen or bone
  marrow
• Treatment with multi-agent chemotherapy
  (CHOP-like)
• Median survival 16 months, almost universally
  fatal

Belhadj et al. Blood 20031024261-4269.