1. IBD: What drugs in what patients?
Stephen B. Hanauer, MD
Professor of Medicine
Feinberg School of Medicine
Medical Director, Digestive Health Center
Northwestern Medicine
Conflicts
AbbVie, Actavis, Janssen, Pfizer, Prometheus, Salix, Shire, Takeda, UCB

2. IBD in 2014: Therapeutic Goals
Rapid and safe induction of remission
Absence of inflammatory symptoms
Normalized laboratory results
Healing of the bowel
Patient feeling healthy and well
Corticosteroid-free durable maintenance of remission
Restoration of growth and development; correction of malnutrition
Avoidance of drug-related and disease-related complications
Kornbluth A, et al. Am J Gastroenterol. 2010;105: ; Lichtenstein GR, et al. Am J Gastroenterol. 2009;104:

3. IBD in 2014: Medical Therapy Options
Aminosalicylates
Mesalamine
Balsalazide (UC)
Olsalazine (UC)
Sulfasalazine
Immunomodulators
Azathioprine
6-mercaptopurine
Cyclosporine (UC)
Methotrexate (CD)
Corticosteroids
Budesonide
Systemic
Biologics
TNF-α inhibitors
Adalimumab
Certolizumab pegol (CD)
Golimumab (UC)
Infliximab
Anti-integrin
Natalizumab
vedolizumab

4. Classification of UC Severity
FULMINANT
>10 stools/day
Continuous bleeding
Toxicity
Abdominal tenderness/distension
Transfusion requirement
Colonic dilation on x-ray
SEVERE
>6 bloody stools/day
Fever
Tachycardia
Anemia or  ESR
MODERATE
≥4 stools/day
± blood
Minimal signs of toxicity
MILD
<4 stools/day ± blood
Normal ESR
No signs of toxicity
Truelove SC, Witts LJ. Br Med J. 1955;2:1041.
Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.

5. Sequential Therapies for Ulcerative Colitis
Disease Severity
at Presentation
Cyclosporine
Colectomy
Anti-TNF/
Thiopurine
Anti-Integrin
Anti-TNF +/IS
Anti-Integrin
Severe
Moderate
Mild
Aminosalicylate/
Thiopurine
Corticosteroid
Aminosalicylate
Oral/Topical/Combo
Budesonide
Aminosalicylate
Oral/Topical/Combo
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

6. Sequential Therapies for Crohn’s Disease
Disease Severity
at Presentation
Surgery
Anti-TNF/
Thiopurine
Anti-Integrin
Anti-TNF +/IS
Anti-Integrin
Severe
Moderate
Mild
Thiopurine/
Methotrexate
Corticosteroid
Budesonide
(Aminosalicylate)
Budesonide/
Thiopurine
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

7. 5-ASA Agents: Sites of Delivery
Colon
Terminal Ileum
Colon
(release at pH  7)
Terminal Ileum
Colon
(release at pH  6)
Duodenum Ileum
Colon
Sulfasalazine
Olsalazine
Balsalazide
Delayed release mesalamine
MMX mesalamine
Granulated mesalamine
Controlled release mesalamine
Baumgart DC, Sandborn WJ. Lancet. 2007;369:
Sandborn WJ. J Clin Gastroenterol. 2008;42:

8. Aminosalicylates (5-ASA) Monitoring
Sulfasalazine:
Nausea, vomiting, headache, reversible male infertility, anemia
Olsalazine:
Diarrhea
All:
Paradoxical worsening of colitis (rare)
Pancreatitis/Hepatitis/Pericarditis/Pneumonitis (rare)
Requires Monitoring
Renal Function (~yearly) Interstitial nephritis (rare)

9. Budesonide Metabolism and Characteristics
~90% metabolism in the liver
~10% Budesonide
Rectal budesonide1
Enema/Foam
Oral budesonide1
pH release: ileum/right colon
MMX: pan-colonic
Budesonide characteristics2
Non-halogenated corticosteroid, highly lipophilic
Good tissue penetration
9x greater receptor binding than dexamethasone
Rapidly absorbed in GI tract
Metabolites are almost inactive
Terminal half-life 2.7 +/- 0.6 hours
Needs specifically designed release system
1 Brattsand R. Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Canadian Journal of Gastroenterology 1990; 4:
Image adapted from figure 4 in publication.
Gross V. Oral pH-modified release budesonide for treatment of inflammatory bowel disease, collagenous and lymphocytic colitis. Expert Opinion on Pharmacotherapy. 2008; 9 (7):
“Approximately 90% of an oral dose of budesonide undergoes first-pass metabolism in the liver.”
“As budesonide is rapidly absorbed from the gastrointestinal tract it has to be administered as a retarded formulation, which allows release of the active compound in the ileum and colon, where inflammatory bowel diseases are located.”
Adapted from 1Brattsand R. Can J Gastroenterol. 1990;4(7): ; 2Gross V. Expert Opin Pharmacother. 2008;9(7):

10. Mild-Moderate UC
Most UC patients present with mild to moderate disease
Aminosalicylates:
Do not have a clear dose response from 2.4 to 4.8 grams
4.8 g/day may be more effective than 2.4 g/day in patients with a history of more difficult to treat disease (e.g., previous use of oral 5-ASAs, rectal therapies, steroids, or multiple medications)
Topical steroids:
Effective to treat active UC
Fewer adverse effects than oral corticosteroids

11. Mild-Moderate UC
Patients with left-sided UC are most effectively treated with topical mesalamine therapy
Topical mesalamine demonstrated to be more effective than oral mesalamine in left-sided UC
Budesonide MMX is effective for left-sided colitis and pancolitis
Positioning will depend upon future clinical trials

12. Management of Moderate UC:
Maximize 5-ASA therapy first
Increase to maximal dose of 5-ASA
Add topical therapy
Confirm medication adherence, simplify regimen if indicated
? 5-ASA hypersensitivity
Rule out Clostridium difficile infection at least once for change in UC symptoms

13. Management of Moderate UC:
If corticosteroids are necessary, plan for an exit strategy on Day 1
Recurrent steroid tapers are not efficacious
Calcium + Vitamin D supplementation while on steroids
Bone densitometry if indicated
Routine vaccinations prior to starting immunosuppression

14. Corticosteroid Therapeutic Monitoringdverse Effects to Steroids
Annual ophthalmologic exams recommended
Vaccinations: flu, pneumonia
GI upset
Nausea
Osteoporosis
Avascular
Necrosis
Myopathy
Fatty liver
Infection
Swelling
Moon facies
Abdominal striae
Easy bruising
Diabetes
Palpitations
Hypertension
Glaucoma
Cataracts
Calcium + Vit D supplementation
Bone densitometry
Monitor for adrenal insufficiency?
Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.Kornbluth and Sachar. Am JGastroenterol. 2010;105:

15. Thiopurines: Azathioprine (AZA) & 6-Mercaptopurine (6-MP)
Minimal efficacy for induction versus placebo
More effective for maintenance versus placebo

16. Thiopurine Pharmacology
Inactive
6-TU
Active
Bone Marrow Suppression XO
HPRT
AZA
6-MP
6-TIMP
6-TXMP
6-TGN
6-TGN
TPMT
TPMT
6-MMP
6-MMPR
Inactive
Elevated LFTs

17. Thiopurines: Therapeutic Monitoring
Vaccinations: flu, pneumonia
GI disturbances
Allergic reaction:
Fever, rash, arthralgias,
Myalgias, fatigue
Hepatotoxicity, ? Nodular regenerative hyperplasia
Infection
Malignancy/
lymphoma
Pancreatitis
Kornbluth A, Sachar DB. Am J Gastroenterol. 2004;88:1371.
deBoer N et al. Nature Clin Pract Gastroenterol Hepatol. 2007;4:686.
Bone marrow
suppression
TPMT testing
Routine CBC, LFT monitoring
Routine dermatology exams
Sun protection

18. Timing of CBCs with Thiopurine Therapy
Close monitoring during first 8 weeks of therapy appears warranted
If mild leukopenia during the first 8 weeks and/or large reduction in WBC from baseline, hold drug and recheck CBC
After the first 8 weeks, less frequent monitoring is reasonable
Continue Monitoring every 3 months!

19. Risk of Developing Non-Hodgkin’s Lymphoma
Patient with Crohn’s disease
Estimated annual risk =
2 per 10,000 treated patients

20. Risk of Developing Non-Hodgkin’s Lymphoma
Patient with Crohn’s disease receiving 6MP or Azathioprine
Estimated annual risk =
4 per 10,000 treated patients

21. Methotrexate Side Effects
Rash
Nausea, mucositis, diarrhea
Bone marrow suppression
Hypersensitivity pneumonitis
Increased liver enzymes
Hepatic fibrosis/cirrhosis
Known abortifacient
No documented increased risk of lymphoma or skin cancer

22. Methotrexate Therapeutic Monitoring
Regular counseling regarding birth control
1 mg folic acid supplementation daily
Monitor CBC, liver enzymes every 6 weeks
Evaluate risk factors for liver disease
Diabetes
Obesity
Alcohol abuse
Routine dose based liver biopsy no longer recommended

23. Anti-TNF biologics: Fusion protein, antibodies and PEGylated Fab' fragment
Certolizumab pegol
PEG
PEGylated humanized Fab′ fragment
2 × 20 kDa PEG
Etanercept
IgG1 Fc
Receptor
Infliximab
Adalimumab
Golimumab
IgG1Fc
Fab
Fab′
Etanercept (Enbrel): Fusion of IgG1 Fc and TNF receptor
Infliximab (Remicade): IgG1 Fc and FAB / bivalent with 25% murine component
Adalimumab (Humira): IgG1 Fc and FAB / bivalent fully human
Certolizumab pegol (Cimzia): IgG1 FAB fragment (Fc free) that is pegylated / univalent and ~ 95% humanized
Chimeric
Human
Human recombinant receptor/Fc fusion protein
Monoclonal antibody 23 23

24. Therapeutic Levels for Anti-TNF Agents
Theoretical threshold
Subtherapeutic

25. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD
Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes
Patient-related factors* may influence the pharmacokinetics of these agents
Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes
Incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time
* Sex and/or body size, and disease severity, including TNF burden and serum albumin concentration
Ordás I, Feagan BG, Sandborn WJ. Clin Gastroenterol Hepatol. 2012;10(10):

26. Therapeutic Monitoring for Anti-TNF
Vaccinations: flu, pneumonia
TB testing
Hepatitis screening
Congestive
heart failure
Autoimmunity,
immunogenicity
Demyelinating disease, PML*
Infection
Malignancy/
lymphoma
Infusion reactions,
injection-site reactions
Hepatotoxicity
Bone marrow
suppression
*Reported with natalizumab.
Use combination therapy with thiopurines?
Check anti-TNF levels?
Check for antibodies?
Switch to another anti-TNF agent?
Switch to agent with different mechanism of action?

27. Risk of Developing Non-Hodgkin’s Lymphoma
Patient with Crohn’s disease receiving combination anti-TNF + 6MP or azathioprine
Estimated annual risk =
6 per 10,000 treated patients

28. α4β7 Integrin–MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CD
Gut lumen
Dendritic cells
Infiltrating lymphocytes
Chemokines/ILs
Macrophage
Inappropriate and sustained recruitment of inflammatory cells

29. Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1
Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1
Endothelial cell
MAdCAM-1
vedolizumab
Vedolizumab:
A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin
Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1
Entyvio is a humanized monoclonal antibody that binds to the α4β7 integrin receptor expressed on the surface of a discrete subset of memory T lymphocytes and blocks the interaction of these cells with MAdCAM-1.
The α4β7 integrin is expressed on the surface of a discrete subset of memory T lymphocytes that preferentially migrate into the gastrointestinal tract.
MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue.
On the left, the adhesion molecule MAdCAM-1 is shown interacting with the α4β7 integrin receptor.
The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC and CD.
On the right, the humanized monoclonal antibody Entyvio is shown bound to the α4β7 integrin receptor. This binding blocks the interaction of α4β7 integrin with MAdCAM-1 and inhibits the migration of memory T lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue.
Reference
Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014. α4
subunit β7
subunit α4
subunit β7
subunit
Memory T lymphocyte
Artist’s rendition

30. Anti-Integrins inhibit inflammatory cells from getting into the (gut) tissues
Entyvio
Memory T lymphocyte migration inhibited
Vedolizumab inhibits the migration of memory T lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Entyvio does not bind to or inhibit function of the α4β1 or αεβ7 integrins.
Memory T lymphocyte homing to gut tissue inhibited
Artist’s rendition

31. Therapeutic Monitoring and Adverse Events with Vedolizumab
Rare Infusion-related reactions & hypersensitivity
30 minute infusion and no post-infusion monitoring
Not recommended in patients with active, severe infections until the infections are controlled
No cases of PML have been observed
Rare reports of elevations of transaminase and/or bilirubin
All patients should be brought up to date with all immunizations Patients may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.
Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

32. High Risk Patients Older Multiple co-morbidities
Concomitant steroids and/or narcotics
Long-standing disease
Young “healthy” patients are not in the clear, but probably much less at risk
? Prior malignancy

33. Vaccinations in the IBD Patient
Titers to check at first office visit:
MMR
If vaccination history unknown
Varicella
If vaccination history or history of chicken pox/zoster unknown
Hepatitis A
Except those with evidence of protective titer within 5 years of vaccine administration
Hepatitis B
Vaccinations to administer in specific patient groups regardless of immunosuppressive drug use:
Tdap
Hepatitis A
HPV
Hepatitis B
Influenza
Meningococcal
Pneumococcal
Vaccinations to consider if NO plans to start immunosuppressive therapy in 4-12 weeks:
MMR
Varicella
Zoster
* OK for thiopurines
Wasan SK, et al. Am J Gastroenterol. 2010;105(6):
DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7:163-9.

34. Summary of Selective Therapeutic Monitoring
5-ASAs
Cortico-steroids
Immuno-modulators
Biologics
CBC1,2 x
Liver enzymes3,4
Creatinine/Urinalysis/BUN3
Eye examination1
Opportunistic infections (e.g., TB, Hep B, and varicella)
Immunizations1,4
TPMT
Bone mineral density for >3 mo use
Kornbluth A, et al. Am J Gastroenterol. 2010;105: Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2):
Agency for Healthcare Research and Quality (AHRQ).
Sands BE, et al. Inflamm Bowel Dis. 2004;10: