1. Common Errors in the Treatment of IBD: Case Studies
Gary R. Lichtenstein, MD
David T. Rubin, MD

2. Gary Lichtenstein, MD Disclosures
Research, Advisory, and/or Honorarium
Abbott
Luitpold / American Regent
Santarus
Alaven
Schering- Plough
Bristol-Myers Squibb
Millenium
Shire
Elan
Ono
Takeda
Ferring
Pfizer
UCB
Hospira
Prometheus
Warner Chilcott
Meda
Salix

3. Some Common Errors in IBD Management
Delay in diagnosis! This is not usually a gastroenterologist’s error.
Steroids as initial therapy for mild to moderate UC- trust the evidence!
Using anti-TNF therapy as mono therapy- concomitant is favored for most patients at least for induction.
Avoiding surgery when it is needed.
Under dosing therapies:
5-ASA – focus on delivery
Thiopurines – understand metabolism and shunters
TNF – in some patients (maybe less than we would like to think)
Not vaccinating
Ignoring vitamin D
Relying on “crisis management” rather than proactive monitoring and control
Dismissing patient interests in diet or complementary therapies rather than working with them
Not referring to mental health professionals

4. Why Do Patients With IBD Not Respond To Their Medications?
Primary Nonresponse
Secondary Nonresponse
Drug/mechanism just doesn’t work
Wrong diagnosis
Infection
Ischemia
Crohn’s disease
Wrong dose
Not enough
Too much?
pK issues
Wrong delivery
Rationale
Allergy/intolerance
Change in dose (by you)
Change in delivery
Change in physiology
Does disease change over time?
Intentional nonadherence
Episodic dosing strategy
Denial
Fear of therapy
Unintentional nonadherence
Can’t afford medication
Inconvenient dosing regimen

5. Patient Case 1

6. Diagnostic Evaluation
Female, age 23 yr; well until 5 mo ago
Symptoms
Pain
Diarrhea (4–6 loose stools/day)
5-lb weight loss
Physical examination
Tender RLQ
No mass
Social History
Cigs: 1ppd x 5 yrs
Laboratory values
WBC: 4,500 cells/µL
Hgb: 10.5 g/dL
CRP: 5.5 mg/dL
Albumin: 3.5 g/dL
Colonoscopy
Terminal ileum and cecum with numerous aphthous ulcerations
Biopsies c/w Crohn’s
SBFT
Mild bowel-wall thickening with slight narrowing in terminal ileum only
CRP = C-reactive protein; RLQ = right lower quadrant.

7. Initial Treatment Diagnosis Mild-to-moderate ileocecal CD
Treatment goals
Induce rapid, complete remission
Minimize the potential for side effects
Treatment prescribed
Mesalamine 1.2 g TID
Response
No clinical improvement after 3 weeks
Mesalamine is not FDA approved for the treatment of Crohn’s disease in the United States.

8. Induction Nonresponder
What is the most appropriate treatment option in this patient ?
Continue mesalamine at a higher dose
Change to another 5-ASA derivative
Add a systemic corticosteroid –prednisone 40 mg orally daily
Switch to EC budesonide at 9 mg a day
Reference
1. Schoon EJ, Bollani S, Mills PR, et al. Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn's disease. Clin Gastroenterol Hepatol. 2005;3:

9. Treatment Options for Mild - Moderate Crohn’s Disease

10. Step-Up according to severity at presentation or failure at prior step
Sequential Therapies for Crohn’s Disease
Disease Severity
at Presentation
Natalizumab
Anti-TNF+/-
Thiopurine/MTX
Anti-TNF
Severe
Moderate
Mild
Corticosteroid
Thiopurine/MTX
Aminosalicylate
Budesonide
Aminosalicylate
Budesonide/Thiopurine
Induction
Maintenance
Step-Up according to severity at presentation or failure at prior step

11. Conventional CD Therapy is Sequential
Mild
Moderate
Severe
Aminosalicylates
TNF antagonists
(IFX, ADA, CZP)
Parental Corticosteroids
Antibiotics
Oral Corticosteroids
Bowel Rest
Natalizumab
Locally Active Oral Corticosteroids
Antimetabolites
(AZA,6-MP, MTX)
Surgery

12. Treatment of IBD Ulcerative Colitis versus Crohn’s Disease
I. Establish the Correct Diagnosis, Severity of Disease & Extent of Disease
Ulcerative Colitis versus Crohn’s Disease
Disease Distribution
Severity of Disease 12

13. ACG Guidelines Determining Severity of Crohn’s Disease
Mild to Moderate
Ambulatory without toxicity, no abdominal tenderness, painful mass, or obstruction
Moderate to Severe
Unresponsive to treatment for mild-to-moderate stage or with prominent fever, weight loss, anemia, abdominal pain and tenderness, or intermittent nausea or vomiting
Severe to Fulminant
Persistent symptoms on corticosteroids or with high fever, rebound tenderness, cachexia, or abscess
Remission
Asymptomatic, no inflammatory sequelae, responsive to medication or surgery, or not requiring systemic corticosteroids
Lichtenstein GR, Hanauer SB, Sandborn WJ. Am J Gastroenterol ; 104(2):

14. Mesalamine Delivery Systems
Olsalazine
(Dipentum)
Sulfasalazine
(Azulfidine)
COOH
5-ASA
NHSO2
5-ASA
5-ASA N N
N=N CH
N=N
Sulfapyridine
Mesalamine
Rectal suspension enema / suppository
(Rowasa, Canasa)
5-ASA
Mesalamine
Controlled-release Capsules
(Pentasa)
Mesalamine
Delayed-release Capsules (Asacol)
Mesalamine
Gastro-resistant/pH
(Lialda)
Balsalazide Disodium Capsules
(Colazal)
(ABA)
inert
carrier
NaOOC OH
5-ASA
5-ASA
5-ASA
Ethylcellulose
Microspheres
Eudragit S/L
MMX technology
Mesalamine
Granulated formulation (Apriso)

15. NCCDS: Response to Therapy for Active Crohn’s Disease60 50 40 30 20 10 70
Sulfasalazine 1 g/15 kg (5 g)
Patients (%)
13%
Placebo 5 10 15
Weeks after Randomization
NCCDS, National Cooperative Crohn’s Disease Study.
Summers RW et al. Gastroenterology 1979;77:

16. Meta-Analysis: Mesalamine in Active Crohn’s Disease
Pentasa® 4 g minus Placebo
Pentasa® 4 g
Placebo
-10
-10
P=0.7
P=0.5
-20
-20
-30
P=0.04
-30
Change from baseline in CDAI score
-40
-50
P=0.7
-40
-60
-50
-70
P=0.04
P=0.005
P=0.005
P=0.05
-60
-80
Crohn's I
Crohn's II
Crohn's III
Overall
Crohn's I
Crohn’s II
Crohn's III
Overall
n=155
n=150
n=310
n=615
n=155
n=150
n=310
n=615
Hanauer, Stromberg. Clinical Gastroenterology & Hepatology 2004

17. Role of Antibiotics in Crohn’s Disease
Widespread use despite insufficient evidence
Inadequate data for metronidazole and ciprofloxacin as first-line therapy
May be useful in the management of
Complications
Perianal disease
Small Intestinal Bacterial Overgrowth
Postoperative prophylaxis
Little, if any, effect on small bowel disease
Potential for resistance and selective overgrowth and Clostridium Difficile infection

18. Corticosteroid Therapy for Crohn’s Disease
Complete
Remission
58%
(n = 43)
Partial
Remission
26%
(n = 19) No
Response
16%
(n = 12)
Immediate
Outcome*
(n = 74)
Prolonged Response
32%
(n = 24)
Steroid Dependent
28%
(n = 21)
Surgery
38%
(n = 28)
1-Year
Outcome
(n = 74)
*30 days after initiating corticosteroid therapy.
Faubion W, et al. Gastroenterology. 2001;121:

19. Budesonide in Active Ileal/ Right Colonic Crohn’s Disease
Budesonide CIR 9 mg
Mesalamine* 4 g
Prednisolone 40 mg
Placebo 80 70
66%
62% 60
53%
51% 50
Patients in Remission (%) 40
36% 30
20% 20 10
10 Weeks1
8 Weeks2
16 Weeks3
CIR = controlled ileal release. *Mesalamine controlled-release capsules (Pentasa).
1. Rutgeerts P, et al. N Engl J Med. 1994;331: Greenberg GR, et al. N Engl J Med. 1994;331: Thomsen OO, et al. N Engl J Med. 1998;339:

20. Corticosteroids in Crohn’s disease
Budesonide is first-line therapy for mild-moderate ileal or right colon disease
Maintenance therapy?
Systemic steroids for moderate-severe disease
High risk of steroid-dependence
Greatest risk of long-term side effects
AGA Quality guidance
Attempt steroid weaning
Monitor for osteoporosis

21. Change of Therapy Treatment EC budesonide 9 mg QD for 8 weeks Outcome
Remission attained at 5 weeks
Hgb: 11.2 g/dL
Mild facial acne
EC Budesonide successfully tapered to complete cessation after 8 weeks
Plan
Watchful waiting

22. Followup
Followup
2 weeks after cessation of EC Budesonide symptomatic recurrence is noted
6 BM / day with RLQ abdominal pain
Perianal drainage from a small fistula was noted
Labs:
WBC x 109 / L
Hgb: 8.7 g/dL
ESR- 45 mm/hr
CRP mg/L

23. Recommendations Which of the following are appropriate at this time
1.) MRI enterography
2.) CT enterography
3.) Stool for C diff
4.) Ask patient to stop smoking
5.) 1 and 4
6.) 1, 3 and 4

24. Refractory IBD
Establish the Correct Diagnosis, Severity of Disease & Extent of Disease
Evaluate for Disease Complications
Evaluate for Enteric Infections
Use Optimal Medication Doses
Miscellaneous
NonAdherence
Paradoxical Responses
NSAIDs
Cigarettes 24

25. Disease Complications
Abdominal / Pelvic Abscess
CT abdomen and pelvis with oral and iv contrast
MRI pelvis with gadolinium
Mesenteric Venous Thrombosis

26. Enteric Infections Bacterial Infections CMV Clostridium Difficile
Parasitic Diseases

27. “Pseudointractibility” of IBD
CMV
Clostridium Difficile
NSAIDs
Cigarette
Cessation in UC
Use in CD

28. MRI Enterography: Active Crohn’s Disease
T2 and Post-gad images demonstrating marked thickening and enhancement of TI. Note elevated T2 signal within and adjacent to TI (arrows) indicating active disease.

29. Followup
Followup
Therapy was initiated with infliximab 5 mg /kg at 0,2, and 6 weeks the every 8 weeks and also AZA 2.5 mg/kg was given (TPMT enzyme activity was normal).
Oral Iron was given (Ferritin checked was 10 ng/mL).
Within a period of 3 months symptomatic remission was noted.
Hgb grams
WBC g/dL
ESR mm/hr
CRP mg/L

30. CASE 2: The Patient Failing Thiopurine Therapy

31. Two Brothers with Ulcerative Colitis
Patient #1: 18 yo with pancolitis, steroid responsive but steroid dependent.
TPMT normal
6-MP started at 1.5 mg/kg
Unable to wean steroids below 15 mg
Patient #2: 15 yo brother of patient #1, ulcerative proctitis, steroid resistant
Not responding

32. Metabolism of Azathioprine and 6-Mercaptopurine
6-Methyl- mercaptopurine
TPMT
HPRT
Azathioprine
6-Mercaptopurine
Thioinosinic acid
6-Thioguainine nucleotides XO
6-Thiouric acid
Chan GL et al. J Clin Pharmacol. 1990;30:358.

33. Curatio PowerPoint Template
Association Between Clinical Response and Both 6-TGN and Intermediate Activity TPMT Genotype in Pediatric Patients With IBD
6-TG Quartiles
Therapeutic Efficacy
Frequency of response
(pmol/8 × 108 RBC) (%)
Frequency of 6-TG level >235 (pmol/8 × 108 RBC) (%)
78%
100
100 80 80
41% 65
Frequency of Response 60
Frequency of 6-TG level 60 40 40 27 20
n=44
n=42
n=43
n=44 20
0–173
174–235
236–367
368–1,203
Response
Failure
Dubinsky MC et al. Gastroenterology 2000;118:705.

34. The Patient not Responding to Thiopurine
Confirm adherence, consider metabolites:
6-TG
6-MMP
Possible cause
Recommendation
undetectable
Non-adherent or
underdosed
Understand why pt not taking med or
increase dose
Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

35. The Patient not Responding to Thiopurine
Confirm adherence, consider metabolites:
6-TG
6-MMP
Possible cause
Recommendation
undetectable
Non-adherent or
underdosed
Understand why pt not taking med or
increase dose
Low (<230)
Low or undetectable
Non-adherent or underdosed
Discuss adherence, increase dose
Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

36. The Patient not Responding to Thiopurine
Confirm adherence, consider metabolites:
6-TG
6-MMP
Possible cause
Recommendation
undetectable
Non-adherent or
underdosed
Understand why pt not taking med or
increase dose
Low (<230)
Low or undetectable
Non-adherent or underdosed
Discuss adherence, increase dose
High (>5700)
6-MMP shunter
Increase thiopurine, or
Consider allopurinol, or
Switch agents
Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

37. The Patient not Responding to Thiopurine
Confirm adherence, consider metabolites:
6-TG
6-MMP
Possible cause
Recommendation
undetectable
Non-adherent or
underdosed
Understand why pt not taking med or
increase dose
Low (<230)
Low or undetectable
Non-adherent or underdosed
Discuss adherence, increase dose
High (>5700)
6-MMP shunter
Increase thiopurine, or
Consider allopurinol, or
Switch agents
“Therapeutic” (>230-<400) or
High (>400)
Normal range or high
Primary non-responder
Assess disease
Switch to different mechanism
Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

38. Brothers with Shunting
6-MP monotherapy Pt
TPMT
6-TGN
6-MMP
ALT 1
23.0
137
13,477
114 2
19.7
301
12,796
141

39. The Patient not Responding to Thiopurine
Confirm adherence, consider metabolites:
6-TG
6-MMP
Possible cause
Recommendation
undetectable
Non-adherent or
underdosed
Understand why pt not taking med or
increase dose
Low (<230)
Low or undetectable
Non-adherent or underdosed
Discuss adherence, increase dose
High (>5700)
6-MMP shunter
Increase thiopurine, or
Consider allopurinol, or
Switch agents
“Therapeutic” (>230-<400) or
High (>400)
Normal range or high
Primary non-responder
Assess disease
Switch to different mechanism
Dubinsky. Curr Gastroenterol Rep. 2003;5(6):

40. Practical Approach to Allopurinol and Thiopurine Combination Therapy
Not for everyone! Be aware of safety concerns.
Choose patient (and MD) wisely:
Active disease
Adherence with thiopurines
Subtherapeutic 6-TGn, supratherapeutic 6-MMP
Elevated LFTs or nausea may be present but not necessary to consider this approach
Drop thiopurine to 25 mg (6-MP) or 50 mg (AZA)
Allopurinol 100 mg
Notify pharmacist!
CBC weekly for one month, then monthly…
Metabolites at week 3
Dose adjustment if necessary but in small increments
Govani and Higgins. J Crohns Colitis 2010;4(4):444-9.
Sparrow, et al. J Crohns Colitis 2009;3(3):162-7.

41. Brothers with Shunting
6-MP monotherapy
6-MP/allopurinol Pt
TPMT
6-TGN
6-MMP
ALT 1
23.0
137
13,477
114
422 -- 21 2
19.7
301
12,796
141
351 25
Both patients responded quickly (within 2-3 weeks), have been in stable steroid-free remission for >2 years.

42. Case 3
21 year old male with a 4 year history of extensive small bowel CD treated with infliximab for the past 3 years presents with increasing cramping abdominal pain, 12 pound weight loss and diarrhea
No recent travel or antibiotics
No previous abdominal surgery
SH: Does not smoke
FH: No FH of IBD
On infliximab 10mg/kg q 6 wk 42

43. Case 3 PE shows a well appearing male in NAD with fullness in the RLQ
Stool samples for enteric pathogens and C. diff negative
MRE- 5cm segment of small bowel disease with small bowel dilation proximal to the area of involvement but w/o inflammation
IFX level (trough: 9.0 mcg/ml)
ATI negative
LABS: WBC – 8.6 K
Hgb – 12
Ptlt- 334 K
CRP- 3.3 (Normal < 4 mg/dl)

44. Case 3 Please choose the best management strategy Increase infliximab
Add an antimetabolite (AZA/6MP/MTX) and continue infliximab
Switch to adalimumab or certolizumab
Switch to natalizumab
Continue infliximab but evaluate for small bowel intestinal overgrowth, irritable bowel syndrome and consider surgical options
Send for ileocecectomy

45. Factors that Influence the PK of TNF Antagonists
Impact on TNF antagonist PK
Presence of ADAs
Decreases drug concentration Increases clearance Worse clinical outcomes
Concomitant use of immunosuppressives
Reduces ADA formation Increases drug concentration
Decreases drug clearance Better clinical outcomes
Low serum albumin concentration
Increases drug clearance Worse clinical outcome
High baseline CRP concentration
Increase drug clearance
High baseline TNF concentration
May decrease drug concentration by increasing clearance
High body size
May increase drug clearance
Sex
Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:

46. Complete/partial response (%)
Clinical Outcomes of Patients With Detectable Human Anti-Chimeric Antibodies or Subtherapeutic IFX Concentrations
Aim
Examine the utility of measuring HACA and IFX concentrations and compare subsequent clinical management and response
Response to test
Complete/partial response (%)
P value
Detectable HACA
Increase IFX
1/6 (17)
<0.004
Change anti-TNF
11/12 (92)
Subtherapeutic concentrations
25/29 (86)
<0.016
2/6 (33)
HACA and IFX concentration testing impacted treatment decisions in 73% of patients and were a useful adjunct to clinical and endoscopic/radiologic assessment
Afif W, et al. Am J Gastroenterol. 2010; 105:

47. Followup: Case 3
Therapeutic infliximab trough level (7 μg/mL) and short segment of fixed non-inflammatory disease
Send to surgery and laparoscopic ileocecectomy performed
Treated postop with metronidazole 500mg po bid for 3 months as well as 6MP
Doing well 10 months postop with colonoscopy demonstrating 2 isolated aphthous erosions in the neoterminal ileum 47

48. Week 4 serum level and subsequent ATI titre
Drug Levels Predict Immunogenicity: Serum IFX at Week 4 After an Infusion Predicts Eventual Appearance of ATI’s in Episodic Dosing
Week 4 serum level and subsequent ATI titre
P = ns
“an IFX level of <4 μg/ml measured 4 weeks after the first infusion had a PPV of 81% to detect the development of high ATIs during the later course of treatment”
“an IFX level of >15 μg/ml measured 4 weeks after the first infusion was 80% predictive for the absence of ATIs during later follow-up.”
P<0.001
P<0.001
“Therefore, IFX levels measured early after the first infusion of IFX (at 4 weeks) are a good prognostic parameter for development of immunogenicity.”
Vermeire et al. Gut 2007;56;

49. Patients With Sustained ATI Associated With LOR
Patients who discontinued IFX treatment due to LOR/hypersensitivity (%)
Vande Casteele N, et al. Am J Gastroenterol DOI: /ajg

50. Time to IFX Discontinuation Due to LOR
Patients who discontinued IFX treatment due to LOR/hypersensitivity (%)
Transient ATI (n=12)
Sustained ATI (n=35)
Log-rank P=0.006
Years of IFX follow-up
Vande Casteele N, et al. Am J Gastroenterol DOI: /ajg

51. AAA Formation Lowers Adalimumab Trough Serum Levels
92% of the patients with a trough serum concentration measured below the threshold for detection were positive for AAA
Median ADA TR (μg/mL) 2 6 8 12 4
2.1
(n=9)
Week 4 10
6.1
(n=58)
0.6
(n=8)
8.9
(n=53)
Week 12
0.1
Week 24
8.8
(n=37)
0.02
(n=3)
11.1
(n=46)
Week 54
0.05
(n=10)
5.8
(n=30)
Therapy Discontinuation
AAA (+)
AAA (-)
Reprinted from Gastroenterology 137(5), Karminis K, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn's disease, Copyright 2009, with permission the AGA Institute.

52. Proposed Treatment Algorithm in the Setting of Loss of Response
High titers
Low titers
Switch within class
High Clearance
Drug
ADAs
Drug escalation or switch
Impact Clearance
LOR
High titers
Low titers
Switch
High Clearance
Negative & ADAs (+)
Positive
Drug escalation or switch
Impact Clearance
Subtherapeutic
Therapeutic
Subtherapeutic & normal CRP
Drug escalation
Change drug class (no benefit from dose escalation)
De-escalation
Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:

53. Can Antibodies to Biologic Therapies Be Overcome?
5 patients with loss of response to infliximab, undetectable infliximab trough levels, and positive antibodies to infliximab on 2 occasions
Antimetabolite therapy added without changing dose of infliximab
Methotrexate (2); Thiopurine (3)
ATI titer decreased and trough IFX levels rose over 1-5 months
Clinical response reestablished
Ben-Horin S. CGH 2013;11:444-7

54. Conclusion
Reactive Therapeutic Drug Monitoring effective for optimization of AntiTNF therapy in NonResponders
Most data studied with Infliximab- but likely applies to other antiTNF agents
Adalimumab
Certolizumab Pegol
Future prospective trial needed to define Proactive Drug monitoring

55. CASE 4
24 year old woman with newly diagnosed Crohn’s disease of the colon, ileum and perianal skin tags with a small simple fistula
Anemic
Elevated CRP
Treated with infliximab and azathioprine
Excellent response and clinical remission
Laboratory values return to normal

56. CASE 4 - continued
After 6 months of continuous therapy, requests to stop azathioprine
6 weeks later, has blood per rectum, loose stools
Steroids started
Infliximab given early at higher dose
No improvement

57. CASE 4 - continued What happened here? Colonoscopy performed:
complete mucosal healing
Small irritated skin tag with friability
Fistula not draining

58. CASE 4 – continued - oops 4 months later Diarrhea, frank hematochezia
Anemic
CRP elevated again
C. diff negative
Therapeutic assessment
Infliximab level elevated (16 ug/ml)
No antibodies to infliximab

59. Antibodies to Infliximab Treatment recommendation
Interpretation of Infliximab Levels and Antibodies to Infliximab in a Patient Losing Response
Infliximab Level
Antibodies to Infliximab
Treatment recommendation
Elevated
Absent
Switch treatment mechanism
Present
Unclear, consider switching to another TNF-inhibitor
Not elevated
Adjust dose, interval of infliximab
Switch to another
TNF-inhibitor
Afif, et al. Am J Gastroenterol ;105(5):

60. Who is at risk for anti-drug antibodies?
The patient receiving episodic therapy
Intentional
Unintentional: break in therapy due to coverage issues or complication
“Pseudo-episodic therapy”
Sub-therapeutic serum drug levels1
The patient with drug clearance between doses
The patient who developed anti-drug antibodies previously
1Vermeire S et al. Gut. 2007;56(9);1226.

61. Switching to Another Biologic Therapy What to choose and when to choose it?
Evidence only exists in one direction (infliximab first), assumption is the opposite is true
Primary non-responder: anti-TNFα loading dose with no response:
Where is the drug going?
try a different mechanism (not a different anti-TNFα therapy!)
Primary responder now relapsing
Assess for inflammation
If suspect immunogenicity, switching to second anti-TNF is reasonable1-3
If not immunogenicity, consider a different mechanism of treatment
1. Sandborn, et al. Ann Int Med, 2007
2. Panaccione R, et al. DDW 2008: #920
3. Rutgeerts PJ, et al. DDW 2008: #494

62. Switching Between TNF Inhibitors: Rheumatoid Arthritis Experience
Response to a second inhibitor is lower relative to first 1
Response to a second inhibitor will be comparable if initial discontinuation was due to adverse events 1, 2
Patients who do not respond to 2 TNF inhibitors are not likely to respond to a third 2
Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29
Solau-Gervais et al. Rheumatology. 2006;epub ahead of print.

63. Don’t Forget about Clinical Trials!
Non-Anti-TNF Mechanisms of Management for the Patient Failing anti-TNF Therapy Confirm Inflammation First
Crohn’s Disease
Ulcerative Colitis
Natalizumab
Methotrexate
Surgery
Including staged approaches or diversion for induction of remission
Bowel rest
Less evidence:
Mycophenolate
Tacrolimus
Cyclosporine
Tacrolimus
Surgery
Don’t Forget about Clinical Trials!

64. Leukocyte Trafficking Inhibition

65. Updated Utilization and Safety Results of Natalizumab in CD and MS (TOUCH, CD INFORM, TYGRIS & Pregnancy Registry Studies)
118,100 patients have received globally (post-marketing) as of 6/30/2013
Predominantly MS patients
PML (Progressive Multifocal Leukoencephalopathy)
Rare but serious – 410 cases reported globally as of 01-Oct-2013; 23% have died
Longer duration and prior immunosuppressant use increases risk
Risk for patients treated months similar to rates seen in clinical trials
Limited safety data beyond 4 yrs of treatment
No known treatment or prevention interventions for PML
(accessed 12-Dec-2011); PML Incidence according to Elan Pharmaceuticals at 04-Nov-2013.

66. Recommendations for JCV Antibody Testing
Testing prior to treatment with natalizumab
If positive, consider retesting.
If confirmed, option is treatment with natalizumab for 9-12 months
If negative, may treat with natalizumab, retest every 6 months
If converts to positive, stop therapy
The benefit and safety of a drug holiday and restarting after “resetting” the exposure has not been tested in Crohn’s disease
Vedolizumab (expected approval Q2 2014) does not have PML associated with it.

67. CASE 4 - conclusion JCV antibody negative TOUCH program
Natalizumab initiated (300 mg IV q month)
Stable remission returns
Ongoing monitoring
Repeat JCV antibody assessment q6 months

68. What happens to the patients who receive natalizumab in the current post-TNF paradigm? Chicago Experience
Sakuraba et al. Inflamm Bowel Dis 2013; ;19(3):621-6.

69. SUMMARY: Avoiding Errors in IBD
Clarify diagnosis and the presence of inflammation when making treatment adjustments
“Optimize” therapy – delivery, metabolism and pK
Rule out confounders
Don’t stay within class if the mechanism has clearly failed
Remember surgery